id
stringlengths 11
17
| article_id
stringlengths 8
11
| path
stringlengths 11
60
| section_title
stringlengths 1
1.33k
| educational_score
float64 0
5.16
| domain
stringclasses 4
values | document_type
stringclasses 5
values | domain_scores
listlengths 0
3
| document_type_scores
listlengths 0
4
| text
stringlengths 1
110k
| authors
listlengths 0
8.02k
| article_url
stringlengths 3
63
| license_type
stringclasses 1
value | license_url
stringclasses 15
values | language
stringclasses 45
values | language_score
float64 0
1
|
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
38960143_p2
|
38960143
|
sec[1]/p[2]
|
Introduction
| 3.96875 |
biomedical
|
Review
|
[
0.9970703125,
0.001708984375,
0.0009794235229492188
] |
[
0.053497314453125,
0.0767822265625,
0.86865234375,
0.000965118408203125
] |
While cytology is still the best strategy of triage in high income settings, it is not feasible in LMIC, which makes the stratification of hrHPV+ women who require treatment even more difficult. The World Health Organization (WHO) recommends visual assessment for immediate treatment after positive HPV DNA testing for populations living in remote areas where there are few opportunities to screen women at proper intervals and for follow-up after screening . However, most HPV infections are transient, so immediate ablative treatments can lead to over treatment for women with low risk of disease . Hence, the identification of novel molecular biomarkers that detect underlying disease could revolutionise screening by providing new triage tests to identify women at highest risk of cancer.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
38960143_p3
|
38960143
|
sec[1]/p[3]
|
Introduction
| 4.003906 |
biomedical
|
Review
|
[
0.99853515625,
0.0007433891296386719,
0.0007300376892089844
] |
[
0.43994140625,
0.0013284683227539062,
0.55810546875,
0.0004405975341796875
] |
Host DNA methylation markers are a promising option for detection of HSIL lesions in hrHPV+ women in high income countries. Methylation assays have advantages over other triage strategies as they can be automated, are high throughput, have accurate quantitation, are robust to operator variations and can be performed in the same specimen as the screening hrHPV test . A literature review performed by our group found that approximately 10 human genes have been evaluated in more than one study; in different clinical settings these showed consistently increased levels of methylation with increasing disease grade. Of these host methylation markers as FAM19A4, hTERT and EPB41L3 , alone or in combination with other genes, have shown good performance for detection of CIN2+ among hrHPV+ women from high-income countries [ , , , , ]. However, more basic, clinical and epidemiological information is required on the performance of these genes at individual CpG-sites in hrHPV+ women. There are substantial gaps in knowledge around marker performance in self-collected samples, and in women from LMIC where the burden of hrHPV infection and disease are high and better triage strategies are essential.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
38960143_p4
|
38960143
|
sec[1]/p[4]
|
Introduction
| 4.097656 |
biomedical
|
Study
|
[
0.99951171875,
0.00021278858184814453,
0.0001398324966430664
] |
[
0.998046875,
0.0011148452758789062,
0.0008449554443359375,
0.00008368492126464844
] |
The majority of DNA methylation occurs on cytosines that precede a guanine nucleotide or CpG-sites . Pyrosequencing is a technique that allows for relative quantitation of the base composition at each site sequenced. The ratio of C:T after bisulphite treatment indicates the proportion of unmethylated and methylated cytosines at each CpG site in the original sequence giving a more specific information of the methylation status and their possible biological and clinical role in the development of disease . It is important to determine differences in methylation levels at individual CpG-sites to better define thresholds and algorithms for the detection of HSIL+ lesions. This analysis will allow us to evaluate their clinical performance individually, collectively in panels, and in combination with specific HPV typing.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
38960143_p5
|
38960143
|
sec[1]/p[5]
|
Introduction
| 4.058594 |
biomedical
|
Study
|
[
0.99951171875,
0.0004253387451171875,
0.00024056434631347656
] |
[
0.99951171875,
0.0002658367156982422,
0.0001537799835205078,
0.00006747245788574219
] |
The aims of the current study were: (i) To analyse DNA methylation at individual CpG-sites of EPB41L3, hTERT and FAM19A4 genes for predicting underlying HSIL in an exploratory study of hrHPV+ women that participated in a field trial of HPV- screening-same-day-treatment in Papua New Guinea (PNG) (ii) To compare levels of methylation at individual CpG-sites in paired self/clinician-collected samples.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
38960143_p6
|
38960143
|
sec[2]/sec[0]/p[0]
|
Study population and design of the trial
| 4.136719 |
biomedical
|
Study
|
[
0.990234375,
0.009185791015625,
0.0004391670227050781
] |
[
0.99365234375,
0.0051727294921875,
0.0003974437713623047,
0.0006194114685058594
] |
We performed an exploratory study from women who participated in a field trial in PNG known as HPV-STAT, a prospective, single-arm intervention trial . The trial is registered with ISRCTN, ISRCTN13476702 . Study design, recruitment and protocols have been described . Briefly, between June 5, 2018, and Jan 6, 2020, 4285 women aged 30–59 years gave informed consent and were enrolled sequentially. Inclusion and exclusion criteria were described previously . A mid-cavity vaginal specimen was collected using a cytobrush (“Just for Me”, Preventative Oncology International, Cleveland Heights, Ohio) and placed into 20 ml ThinPrep PreservCyt (Hologic, Marlborough, MA). From the PreservCyt fluid 1 ml was then tested for hrHPV types using the Xpert HPV Test (GeneXpert; Cepheid, Sunnyvale, CA, USA) as per the manufacturer's instructions. HPV results were provided to women before midday to allow same-day, pelvic examination and treatment/referral. All women with a negative HPV test received their results and were advised to return to the clinic for HPV-based screening in five years.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p7
|
38960143
|
sec[2]/sec[0]/p[1]
|
Study population and design of the trial
| 3.972656 |
biomedical
|
Study
|
[
0.9970703125,
0.002635955810546875,
0.00036454200744628906
] |
[
0.9951171875,
0.00415802001953125,
0.00036025047302246094,
0.00026297569274902344
] |
A cervical specimen was collected by a clinician for all HPV+ women using a Cervex-Brush Combi (Rovers Medical Devices, Oss, The Netherlands), placed in 20 ml PreservCyt, and stored at 4 °C prior to shipment to Victorian Cytology Service Foundation (VCS) in Melbourne, Australia for liquid-based cytology (LBC) and p16/Ki67 dual stain cytology. A 15% random sample of HPV negative women were also asked to provide a clinician-collected cervical specimen for LBC, as above.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
38960143_p8
|
38960143
|
sec[2]/sec[0]/p[2]
|
Study population and design of the trial
| 4.039063 |
biomedical
|
Study
|
[
0.9931640625,
0.006542205810546875,
0.0004050731658935547
] |
[
0.994140625,
0.004650115966796875,
0.0005574226379394531,
0.0004911422729492188
] |
LBC was performed in accordance with standard operating procedures at VCS. All slides were independently assessed by two experimented cytologists and pathologists blinded to HPV-DNA test results. Where both readers agreed on a diagnosis of HSIL or worse (HSIL+), a final diagnosis was recorded. If the assessment differed, dual p16/Ki-67 immuno-staining was performed by using CINTec PLUS Cytology (Roche Diagnostics, Rotkreuz, Switzerland) to make a final diagnosis . LBC was the reference standard rather than histology (gold reference in high-resource settings). It is not currently feasible to provide colposcopy examination or to collect cervical biopsies for histological analysis in PNG due limited specialist staff and infrastructure.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p9
|
38960143
|
sec[2]/sec[1]/p[0]
|
Participants in the exploratory study and design
| 4.109375 |
biomedical
|
Study
|
[
0.99951171875,
0.0004935264587402344,
0.00021350383758544922
] |
[
0.99951171875,
0.00042700767517089844,
0.00016927719116210938,
0.00007748603820800781
] |
The exploratory study included 44 hrHPV+ paired cervical and vaginal samples from women that participated in the HPV screening-same day treatment trial at Mt Hagen General Hospital (Mount Hagen, Western Highlands Province). This included all 23 hrHPV+ HSIL or SCC (19 HSIL and 4 SCC) cases identified on LBC conducted at VCS by the end of 2018 and 21 randomly selected hrHPV+ normal/LSIL samples (17 normal LBC and 4 LSIL). The choice of this sample size was based on methylation data published that showed through simulation studies and real data from the NCBI Gene Expression Omnibus, that at least 12 specimens in each group is needed to detect truly differential DNA methylation with a power ≥80%, reproducible results and consistent when using different statistical methods .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p10
|
38960143
|
sec[2]/sec[1]/p[1]
|
Participants in the exploratory study and design
| 2.382813 |
biomedical
|
Study
|
[
0.99609375,
0.0020236968994140625,
0.00196075439453125
] |
[
0.80615234375,
0.1871337890625,
0.004726409912109375,
0.00211334228515625
] |
Molecular biologists and technicians were blinded to point of care HPV results and clinical diagnosis during the performance of the different molecular assays.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
38960143_p11
|
38960143
|
sec[2]/sec[2]/p[0]
|
DNA extraction and HPV specific typing
| 4.097656 |
biomedical
|
Study
|
[
0.99951171875,
0.0003173351287841797,
0.00019562244415283203
] |
[
0.99853515625,
0.0011243820190429688,
0.0002465248107910156,
0.00009769201278686523
] |
These molecular analyses were carried out at the Royal Women's Hospital, in Melbourne, Australia. DNA was extracted by using the MagNA Pure 96 System (DNA and Viral Nucleic Acid Small Volume Kit; Roche Molecular Diagnostics; Mannheim, Germany) as per the manufacturer's Pathogen Universal 200 protocol, and eluted in 100 μL. DNA concentration was quantitated by Qubit® Fluorometer (Life technologies, California, USA). Extracted DNA was assessed for integrity by quantitative polymerase chain reaction (PCR) amplification of a 260 base-pair product of the human beta-globin gene .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p12
|
38960143
|
sec[2]/sec[2]/p[1]
|
DNA extraction and HPV specific typing
| 4.046875 |
biomedical
|
Study
|
[
0.99951171875,
0.000255584716796875,
0.00018513202667236328
] |
[
0.99169921875,
0.007320404052734375,
0.0006146430969238281,
0.00017130374908447266
] |
HPV genotyping was performed using Anyplex II HPV HR14 HPV detection multiplex assay (Seegene, Seoul, South Korea), which detects 14 oncogenic HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) and an internal control according to manufacturer's recommendations.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p13
|
38960143
|
sec[2]/sec[3]/p[0]
|
Bisulphite modification
| 4.070313 |
biomedical
|
Study
|
[
0.99951171875,
0.00021064281463623047,
0.0001844167709350586
] |
[
0.99755859375,
0.0020751953125,
0.0002925395965576172,
0.0001055002212524414
] |
DNA extracted from clinician and self-collected samples (1–100 ng) and a SiHa cervical cell line control (1–2 copies of HPV16 per cell, ATCC Cat# HTB-35, RRID:CVCL_0032; American Type Culture Collection (ATCC), Manassas, Virginia, USA; 100 ng) were bisulphite treated using Methylamp DNA modification Kit (Epigentek, Brooklyn, NY, USA) as per the manufacturer's instructions. Modified DNA was eluted in 40 μL of the Methylamp elution buffer.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
38960143_p14
|
38960143
|
sec[2]/sec[4]/p[0]
|
DNA methylation analysis: PCR amplification and pyrosequencing for EPB41L3 , FAM19A4 and hTERT genes
| 4.253906 |
biomedical
|
Study
|
[
0.99951171875,
0.0003333091735839844,
0.0002186298370361328
] |
[
0.9990234375,
0.00048470497131347656,
0.00035881996154785156,
0.00008726119995117188
] |
Individual PCR targeting specific CpG-sites of EPB41L3, FAM19A4 and hTERT genes were performed using the converted DNA. EPB41L3 and hTERT amplifications were performed as previously described with minor modifications. Briefly, 12.5 μl of Hot Start Taq Master mix (Qiagen, Valencia, CA), 0.25 pmol of each primer, 8.25 μl of water and 3 μl sample were mixed for each reaction. For FAM19A4 amplification, 0.5 pmol of each primer and 7 μl of water were used. PCR conditions were: 95 °C for 15 min and then 45 cycles: 30 s at 94 °C; 30 s at the optimized primer-specific annealing temperature ( EPB41L3 , 56 °C, hTERT , 58 °C , FAM19A4 , 50 °C), 30 s at 72 °C and a final extension for 10 min at 72 °C. Sequences of the primers and characteristics of the amplified products are shown in Table 1 . Amplification was confirmed by agarose gel electrophoresis. A 20 μl aliquot of each amplified product was used for pyrosequencing, which was carried out on the PyroMark Q24 instrument (Qiagen) at the Australian Genome Research Facility (AGRF, Perth, AU) using the appropriate sequence primers for each gene. Assay setup, sequence run, and analysis were performed with PyroMark Q24 Software . No-template negative controls, and SiHa cell line was used as a positive methylation control. Briefly, each PCR/pyrosequencing run had an established bisulphite modified SiHa cell line that had been previously validated for methylation analysis and a new SiHa cell line (bisulphite modified at the same time as the samples). This approach controlled for variation in the bisulphite modification procedure between assays and variation in methylation analysis between runs (reproducibility of % of methylation of the positive control for each gene) . Table 1 Primers used for pyrosequencing. Table 1 Primer Name Sequence 5’---- 3’ Size (bp) Position in gene CpG sites Annealing Temp (°) Reference Amplification EPB41L3 F GGGGGATTTGTGTAAATTGG 83 376 to 458 6 54 Amplification EPB41L3 R (Bio) (Bio)- ACCTAAAAACCTCCCTAAAATC Sequencing EPB41L3 s GGGATTTGTGTAAATTGG Amplification TERT F (Bio) (Bio)-GAGGGGTTGGGAGGGTT 106 −144 to −249 10 56 Amplification TERT R TCCTACCCCTTCACCTTCCAA Sequencing TERT s CCTTCACCTTCCAACT Amplification FAM19A4 F ATTAAATTAAGTAAGGGATTTGTG 152 548 to 700 5 50 New primers designed Amplification FAM19A4 R (Bio) (Bio)-AACTTCAACACAAAAAAATTAAAC Sequencing FAM19A4 F s AGTAAGGGATTTGTGAGGTGG EPB41L3 and hTERT primers directed to the promoter region, according Vasiljević et al. . FAM19A4 New primers designed to the proximal exonic region.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
38960143_p15
|
38960143
|
sec[2]/sec[4]/p[1]
|
DNA methylation analysis: PCR amplification and pyrosequencing for EPB41L3 , FAM19A4 and hTERT genes
| 3.642578 |
biomedical
|
Study
|
[
0.99951171875,
0.00021767616271972656,
0.00045561790466308594
] |
[
0.998046875,
0.0016021728515625,
0.0003387928009033203,
0.0001061558723449707
] |
Reproducibility of the assays were performed utilising dilution series of SiHa cell line by triplicate in intra and inter assays and by using a training panel of samples as reported previously .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
38960143_p16
|
38960143
|
sec[2]/sec[5]/p[0]
|
Data and statistical analysis
| 4.105469 |
biomedical
|
Study
|
[
0.99951171875,
0.00032067298889160156,
0.00016963481903076172
] |
[
0.9990234375,
0.00023865699768066406,
0.0004589557647705078,
0.00007551908493041992
] |
For pyrosequencing we calculated the percentage of methylation at individual CpG-sites . Percentage of median DNA methylation for each individual CpG-site [ EPB41L3 (CpG-sites 1–6), hTERT (CpG-sites 1–10) and FAM19A4 (CpG-sites 1–5)], for each disease grade [SCC, HSIL, LSIL and normal] was compared using two non-parametric comparative analyses, Wilcoxon test for between groups and Kruskal-Wallis for overall analysis, which was visualised using box and whisker plots . Area under the curve (AUC) was used to assess the ability of the methylated genes at individual CpG-sites and by using the average of all CpG-sites of each gene to distinguish HSIL and SCC from normal/LSIL samples. The optimal cut-off point for each individual CpG-site was calculated by using the maximum sum of sensitivity and specificity as described previously . We assessed the potential of different models in detecting HSIL or worse with respect to their sensitivity [number of correct positives (i.e. positive for at least one marker)/number of reference assay positives] and specificity (number of correct negatives on all markers/number of reference assay negatives).
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
38960143_p17
|
38960143
|
sec[2]/sec[5]/p[1]
|
Data and statistical analysis
| 4.050781 |
biomedical
|
Study
|
[
0.99951171875,
0.00020623207092285156,
0.0001556873321533203
] |
[
0.9990234375,
0.0003829002380371094,
0.0003745555877685547,
0.00006222724914550781
] |
Triage strategies used were (I) individual analysis of methylation at specific CpG-sites for each gene, (II) combination of two or more individual CpG-sites (III) Individual or combined methylation analysis at individual CpG-sites and adding HPV16/18 typing (IV) Individual or combined methylation analysis at individual CpG-sites and adding extended genotyping (HPV 16/18/31/33/45/52/58. Percentage of median DNA methylation for each individual CpG-site between cervical and vaginal specimens was also compared using Wilcoxon signed rank test and visualised by using box and whisker plots. The results were analysed by using XLSTAT, the statistical platform R studio (v4.0.1) and programs ggplots2 (v3.3.2), ggpubr (v0.4), pROC (v1.16.2) and cutpointr (v1.1.1) .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
38960143_p18
|
38960143
|
sec[2]/sec[6]/p[0]
|
Ethical considerations
| 1.054688 |
biomedical
|
Other
|
[
0.51025390625,
0.03857421875,
0.451171875
] |
[
0.007221221923828125,
0.99169921875,
0.00039196014404296875,
0.0008745193481445312
] |
Approval of the trial and biomarker analysis was provided by the Medical Research Advisory Committee (MRAC) of the Papua New Guinea National Department of Health (approval number 17.36), the Institutional Review Board of the Papua New Guinea Institute of Medical Research , and the Human Research Ethics Committee (HREC) of UNSW Australia . Written informed consent was obtained from all participants prior to enrolment.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p19
|
38960143
|
sec[3]/sec[0]/p[0]
|
DNA methylation at individual CpG-sites of EPB41L3 , FAM19A4 and hTERT genes and lesion grade
| 4.085938 |
biomedical
|
Study
|
[
0.99951171875,
0.00037097930908203125,
0.00023543834686279297
] |
[
0.99951171875,
0.00020778179168701172,
0.0001811981201171875,
0.00006878376007080078
] |
We performed the analysis of DNA methylation at individual CpG-sites of EPB41L3, hTERT and FAM19A4 genes in 44 hrHPV+ clinician and self-collected vaginal samples [23 cases (19 HSIL and 4 SCC 8) and 21 normal/LSIL (17 normal LBC and 4 LSIL)]. Of these samples, 42/44 (95.4%) clinician-collected cervical samples were successfully amplified for EPB41L3 and hTERT (1 normal and 1 HSIL did not amplify) and 40/44 (90.9%) for FAM19A4 (2 normal and 2 HSIL did not amplify). All the 44 self-collected vaginal samples produced an amplicon for the three genes, and thus were considered optimal for pyrosequencing.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p20
|
38960143
|
sec[3]/sec[0]/sec[0]/p[0]
|
EPB41L3
| 4.078125 |
biomedical
|
Study
|
[
0.99951171875,
0.000308990478515625,
0.00021028518676757812
] |
[
0.99951171875,
0.00017392635345458984,
0.0002415180206298828,
0.000060558319091796875
] |
In clinician-collected samples, we observed an increasing of DNA methylation with increasing of lesion grade at all six individual CpG-sites analysed of EPB41L3 gene . DNA methylation at each CpG site (CpG-sites 1–6) was significantly higher in HSIL than in normal/LSIL samples, and in cervical cancer compared to normal cytology . Fig. 1 Percentage of DNA methylation at individual CpG-sites of EPB41L3 gene according to cytology diagnosis in hrHPV+ women. Clinician-collected cervical samples (Cervical) are presented in the top panel, and self-collected vaginal samples (Vaginal) in the bottom panel. Comparisons were assessed by the nonparametric Wilcoxon test, with whiskers corresponding to the first and third quartiles (the 25th and 75th percentiles). Significance values p ≤ 0.05. Fig. 1
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p21
|
38960143
|
sec[3]/sec[0]/sec[0]/p[1]
|
EPB41L3
| 3.126953 |
biomedical
|
Study
|
[
0.9990234375,
0.0004799365997314453,
0.00064849853515625
] |
[
0.998046875,
0.0012569427490234375,
0.00034356117248535156,
0.00011259317398071289
] |
In self-collected samples, there was an increased level of methylation in women with cervical cancer compared to women with normal cytology at some individual CpG-sites (CpG-site 1, 3 and 5), but the association was not statistically significant .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p22
|
38960143
|
sec[3]/sec[0]/sec[1]/p[0]
|
hTERT
| 4.085938 |
biomedical
|
Study
|
[
0.99951171875,
0.00029349327087402344,
0.00022339820861816406
] |
[
0.99951171875,
0.00016760826110839844,
0.000232696533203125,
0.000054001808166503906
] |
In clinician-collected samples we observed an increase of hTERT DNA methylation at some specific CpG-sites in women with SCC compared to women with normal cytology (CpG-site 4, p = 0.013) and in women with SCC compared to women with HSIL (CpG-site 4, p = 0.033 and CpG-site 7, p = 0.014) Fig. 2 , top row. Fig. 2 Percentage of DNA methylation at individual CpG-sites of hTERT gene according to cytology diagnosis in hrHPV+ women. Clinician-collected cervical samples (Cervical) are presented in the top panel and self-collected vaginal samples (Vaginal) in the lower panel. Comparisons were assessed by the nonparametric Wilcoxon test, with whiskers corresponding to the first and third quartiles (the 25th and 75th percentiles). Significance values p ≤ 0.05. Fig. 2
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
38960143_p23
|
38960143
|
sec[3]/sec[0]/sec[1]/p[1]
|
hTERT
| 2.398438 |
biomedical
|
Study
|
[
0.99658203125,
0.0008807182312011719,
0.0025196075439453125
] |
[
0.98681640625,
0.011688232421875,
0.0012254714965820312,
0.0003707408905029297
] |
In self-collected samples, there was not a clear association of DNA methylation of hTERT with lesion grade .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p24
|
38960143
|
sec[3]/sec[0]/sec[2]/p[0]
|
FAM19A4
| 4.050781 |
biomedical
|
Study
|
[
0.99951171875,
0.0003006458282470703,
0.0002658367156982422
] |
[
0.99951171875,
0.00016570091247558594,
0.00020253658294677734,
0.00005418062210083008
] |
In clinician-collected samples, methylation at CpG-sites 1, 2 and 3 of FAM19A4 showed a decrease in the levels of methylation in cancer samples compared to normal samples, although not statistically significant (p = 0.097, p = 0.096 and p = 0.077 respectively) . Fig. 3 Percentage of DNA methylation at individual CpG-sites of FAM19A4 gene according to cytological diagnosis in hrHPV+ women. Clinician-collected cervical samples (Cervical) are presented in the top panel, and self-collected vaginal (Vaginal) samples in the bottom panel. Comparisons were assessed by the nonparametric Wilcoxon test, with whiskers corresponding to the first and third quartiles (the 25th and 75th percentiles). Significance values p ≤ 0.05. Fig. 3
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p25
|
38960143
|
sec[3]/sec[0]/sec[2]/p[1]
|
FAM19A4
| 4.023438 |
biomedical
|
Study
|
[
0.99951171875,
0.00022864341735839844,
0.0003333091735839844
] |
[
0.99951171875,
0.00024437904357910156,
0.00018513202667236328,
0.00005060434341430664
] |
In self–collected samples, methylation at CpG-site 1 of FAM19A4 showed an increase in the levels of methylation in cancer samples compared to normal samples (p = 0.068) and methylation at CpG-site 5 showed an increase in the levels of methylation in women with HSIL compared to women with normal samples (p = 0.05).
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p26
|
38960143
|
sec[3]/sec[1]/p[0]
|
AUC of DNA methylation markers for HSIL, HSIL+ and SCC
| 4.175781 |
biomedical
|
Study
|
[
0.99951171875,
0.00035691261291503906,
0.00025200843811035156
] |
[
0.9990234375,
0.0002110004425048828,
0.0005078315734863281,
0.00006461143493652344
] |
AUC analysis showed that in clinician-collected samples , EPB41L3 was the best methylation marker to distinguish HSIL and SCC (from normal/LSIL). EPB41L3 methylation distinguished HSIL from normal/LSIL at CpG-sites 2 (AUC value 0.808), 4 (0.831) and 5 (0.833), HSIL+ from normal/LSIL at CpG-sites 1 (0.764), 2 (0.827), 4 (0.852) and 5 (0.830), and SCC from normal/LSIL at CpG-sites 2 (0.912), 4 (0.920) and 6 (0.900). EPB41L3 methylation distinguished HSIL and HSIL+ from normal/LSIL with significant p-values (p < 0.05) at the respective CpG-sites, while the p-values for SCC from normal/LSIL were not significant . hTERT methylation distinguished HSIL from normal/LSIL at CpG-sites 7 (AUC value 0.700) and 3 (0.693), HSIL+ from normal/LSIL at CpG-sites 1 (0.673) and 3 (0.658) and SCC from normal/LSIL at CpG-sites 4 (0.880), 6 (0.800) and 8 (0.800). However, the p-values were not significant. FAM19A4 methylation showed a lower performance for detecting HSIL. DNA methylation at CpG site 1 distinguished HSIL from normal/LSIL (AUC value 0.655), HSIL+ from normal/LSIL at CpG-sites 1 (0.678) and 3 (0.642) and SCC from normal/LSIL at CpG-sites 1, and 3 (AUC values of 0.776, and 0.789, respectively). FAM19A4 methylation distinguished HSIL+ and SCC from normal/LSIL with significant p-values (p < 0.05) at CpG sites 1 and 3. Fig. 4 Area under the curve values of FAM19A4 (CpG-sites 1–5) , EPB41L3 (CpG-sites 1–6) and hTERT (CpG-sites 1–10) methylation for distinguishing HSIL, HSIL+ and SCC from normal/LSIL, stratified by sample type Orange bars and green bars represent clinician-collected cervical and self-collected vaginal samples respectively. HSIL, in the top panel, HSIL+ in the middle panel and SCC in the bottom panel. The p values in the figure represent p < 0.05 = * , p < 0.01 = **, p < 0.005 = ***, p < 0.001 = ****. Fig. 4
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
38960143_p27
|
38960143
|
sec[3]/sec[1]/p[1]
|
AUC of DNA methylation markers for HSIL, HSIL+ and SCC
| 4.121094 |
biomedical
|
Study
|
[
0.99951171875,
0.00025916099548339844,
0.0002574920654296875
] |
[
0.99951171875,
0.00025153160095214844,
0.0003094673156738281,
0.000054717063903808594
] |
In self-collected samples, FAM19A4 was the best methylation marker to stratify disease grade. FAM19A4 methylation distinguished HSIL from normal/LSIL at CpG-site 5 (AUC value 0.670), and HSIL+ from normal/LSIL at CpG-site 1 (0.627) and CpG site 5 (0.638) and SCC from normal/LSIL at CpG-sites 1 (0.776), 2 (0.737) and 3 (0.776). For EPB41L3, CpG-site 2 distinguished HSIL from normal/LSIL with an AUC of 0.619, and methylation at CpG-sites 3 and 6 distinguished SCC from normal/LSIL with an AUC of 0.688 each.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
38960143_p28
|
38960143
|
sec[3]/sec[1]/p[2]
|
AUC of DNA methylation markers for HSIL, HSIL+ and SCC
| 3.957031 |
biomedical
|
Study
|
[
0.99951171875,
0.00019252300262451172,
0.0003867149353027344
] |
[
0.99951171875,
0.00036787986755371094,
0.0002340078353881836,
0.000050902366638183594
] |
For hTERT, methylation at CpG-site 4 and site 10 were the best markers to distinguish HSIL and HSIL+ from normal/LSIL and CpG-sites 1, 3 and 4 distinguished SCC from normal/LSIL . However, the p-values for FAM19A4, EPB41L3 and hTERT at the respective CpG sites were not significant.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
38960143_p29
|
38960143
|
sec[3]/sec[1]/p[3]
|
AUC of DNA methylation markers for HSIL, HSIL+ and SCC
| 3.539063 |
biomedical
|
Study
|
[
0.9990234375,
0.00022590160369873047,
0.0007791519165039062
] |
[
0.99609375,
0.0032558441162109375,
0.0004730224609375,
0.0001226663589477539
] |
Global methylation analysis for each gene (the average of all the CpG-sites) performed best for EPB41L3 using clinical-collected samples and FAM19A4 in self-collected samples .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p30
|
38960143
|
sec[3]/sec[2]/p[0]
|
Diagnostic performance of DNA methylation markers in the detection of HSIL+
| 4.207031 |
biomedical
|
Study
|
[
0.99951171875,
0.0004246234893798828,
0.00024199485778808594
] |
[
0.9990234375,
0.0002856254577636719,
0.0005950927734375,
0.00007742643356323242
] |
In clinician-collected samples methylation at CpG-site 4 of EPB41L3 showed the highest individual performance for HSIL+ detection, with a sensitivity of 86.4% and specificity of 70%. Combined detection of methylation at CpG-site 2 and 4 of EPB41L3 improved the diagnostic performance with a sensitivity of 95.5% and specificity of 60%; when these two CpG-sites were further combined with methylation at CpG-site 1 of FAM19A4 , the best diagnostic performance was reached with a sensitivity of 100% and specificity of 63.2% ( Table 2 ). Table 2 Diagnostic performance of methylation markers at individual CpG-sites in the detection of HSIL + on clinician-collected samples and self-collected samples. Table 2 Sample type Gene and CpG-sites a Best cut off (% methylation) Sensitivity % (95 % CI) Specificity % (95 % CI) Cervical, clinician-collected EPB41L3 CpG site 1 5 81.8 (59.7–94.8) 40.0 (19.1–63.9) EPB41L3 CpG-site 2 10.5 86.3 (65.1–97.1) 65.0 (40.8–84.6) EPB41L3 CpG-site 3 5 81.8 (59.7–94.8) 55.0 (31.5–77.1) EPB41L3 CpG-site 4 6 86.4 (65.1–97.1) 70.0 (45.7–88.1) EPB41L3 CpG-site 5 6 81.8 (59.1–94.8) 60.0 (36.1–88.9) EPB41L3 CpG-site 6 10.5 86.4 (65.1–97.1) 50.0 (27.2–72.8) EPB41L3 CpG-site 2/site 4 10.5/6 95.5 (77.2–99.9) 60.0 (36.1–88.9) EPB41L3 CpG-site 2/site 5 10.5/6 90.9 (70.8–98.9) 50.0 (27.2–72.8) EPB41L3 CpG-site 4/site 5 6/6 90.9 (70.8–98.9) 50.0 (27.2–72.8) hTERT CpG-site 4 9.2 50.0 (28.2–71.8) 70.0 (45.7–88.1) FAM19A4 CpG-site 1 <86 52.4 (29.8–74.3) 89.5 (66.9–98.7) EPB41L3 CpG-site 4/FAM19A4 site 1 6/<86 90.5 (69.6–98.8) 68.4 (43.5–87.4) EPB41L3 CpG-site 2/4/FAM19A4 site 1 10.5/6/<86 100 (83.9–100) 63.2 (38.4–83.7) EPB41L3 CpG-site 4/hTERT site 4 6/9.2 90.9(70.8–98.9) 60.0 (36.1–80.9) EPB41L3 CpG-site 2/ 4/hTERT site 4 10.5/6/9.2 95.5 (77.2–99.9) 50.0 (27.2–72.8) b Global EPB41L1 CpG-site 1/2/3 Mean site 1/2/3 (7.5) 77.3 (54.6–92.2) 60.0 (36.1–80.9) c Global EPB41L3 CpG-site 1-6 Mean site 1/2/3/4/5/6 (7.5) 81.8 (59.7–94.8) 65.0 (40.8–84.6) d Global FAM19A4 CpG-site 1-5 Mean site 1/2/3/4/5 (<93) 52.4 (29.8–74.3) 84.2 (60.4–96.6) e Global hTERT CpG-site 1-10 Mean sites 1–10 (7) 54.6 (32.2–75.6) 60.0 (36.1–80.9) Vaginal, self-collected EPB41L3 CpG-site 2 9 82.6 (61.2–95.1) 28.6 (11.3–52.2) EPB41L3 CpG-site 3 3 65.2(42.7–83.6) 38.1 (18.1–61.6) EPB41L3 CpG-site 2/site 3 9/3 91.3(72.0–98.9) 23.8 (8.2–47.2) FAM19A4 CpG-site 1 90 60.9 (38.6–80.3) 66.7 (40.0–85.4) FAM19A4 CpG-site 5 92.5 87.0 (66.4–97.2) 42.9 (21.8–66.0) FAM19A4 CpG-site 1/site 5 90/92.5 95.7 (78.1–99.8) 28.6 (11.3–52.2) EPB41L3 CpG-site 3/FAM19A4 site 1 3/90 91.3 (72.0.-98.9) 23.8 (8.2–47.2) EPB41L3 CpG-site 3/FAM19A4 site 5 3/92.5 100 (85.2–100) 9.5 (1.2–30.4) hTERT CpG-site 4 8 73.9 (51.6–89.8) 33.3 (14.6–57.0) hTERT CpG-site 10 5.5 91.3 (72.0–98.9) 33.3 (14.6–57.0) EPB41L3 CpG-site 3/hTERT site 4 3/8 95.7 (78.1–99.9) 19.1 (5.5–41.9) EPB41L3 CpG-site3/hTERT site 10 3/5.5 100 (85.2–100) 14.3 (3.0–36.3) FAM19A4 CpG-site1/hTERT site 4 90/8 82.6 (61.2–95.1) 23.8 (8.2–47.2) FAM19A4 CpG-site 1/hTERT site 10 90/5.5 95.7 (78.1–99.9) 23.8 (8.2–47.2) b Global EPB41L3 CpG-site1/2/3 Mean site 1/2/3 (5.5) 69.6 (47.1–86.8) 33.3 (14.6–57.0) c Global EPB41L3 CpG-site 1-6 Mean site 1/2/3/4/5/6 (6) 65.2 (42.7–83.6) 38.1 (18.1–61.6) d Global FAM19A4 CpG-site 1-5 Mean site 1/2/3/4/5 (93.5) 69.6 (41.1–86.8) 42.9 (21.8–66.0) e Global hTERT CpG-site 1-10 Mean site 1–10 (6.5) 73.9 (51.6–89.8) 28.6 (11.3–52.2) Image 1 High-light in grey individual CpG-sites or combination of different CpG-sites with the best diagnostic performance for detection of HSIL+. a Positive for at least one of the indicated CpG-sites. b Global EPB41L 3 CpG site 1/CpG site 2/CpG site 3 is equivalent to the three CpG-sites of EPB41L3 (438, 427 and 425) studied by Lorincz group and others. There is the S5 classifier methylation assay that include, the mean % of EPB41L3 methylation of these three CpG-sites, the mean % of methylation of HPV16-L1: 6367, 6389; HPV18-L2: 4256, 4261, 4265, 4269, 4275, 4281; HPV31-L1: 6352 and 6364 and HPV33-L2: 5557, 5560, 5566) and the proportion of CpGs methylated in HPV16-L2 sites: 4238, 4259, 4275 for diagnostic detection of CIN2+. c Global EPB41L 3 gene: mean % of methylation of CpG-sites 1/2/3/4/5/6. d Global FAM19A4 gene: mean % of methylation of CpG-sites 1/2/3/4/5. e Global hTER T gene: mean % of methylation of CpG-sites 1/2/3/4/5/6/7/8/9/10.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p31
|
38960143
|
sec[3]/sec[2]/p[1]
|
Diagnostic performance of DNA methylation markers in the detection of HSIL+
| 4.089844 |
biomedical
|
Study
|
[
0.99951171875,
0.00030517578125,
0.0002703666687011719
] |
[
0.99951171875,
0.00018155574798583984,
0.00035381317138671875,
0.000057816505432128906
] |
In self-collected samples, methylation at CpG-site 5 of FAM19A4 showed the best individual diagnostic performance with a sensitivity of 87% and specificity of 42.9% ( Table 2 ). Combined detection of at least two methylation markers improved the sensitivity (values between 82.6% and 100%), but with a low specificity (values between 4.5% and 28.3%) ( Table 2 ).
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
38960143_p32
|
38960143
|
sec[3]/sec[3]/p[0]
|
Diagnostic performance of DNA methylation at specific CpG-sites combined with HPV infection for the detection of HSIL+
| 4.214844 |
biomedical
|
Study
|
[
0.99951171875,
0.0003681182861328125,
0.0002505779266357422
] |
[
0.9990234375,
0.0003292560577392578,
0.000637054443359375,
0.00006663799285888672
] |
For clinician-collected samples, adding HPV16/18 detection to methylation at CpG-site 4 of EPB41L3 increased sensitivity from 86.4% to 100%, and reduced specificity from 70.0% to 55% for detection of HSIL+. Combination of methylation at CpG-site 2 and 4 of EPB41L3 and adding HPV16/18 detection increased sensitivity from 95.5% to 100% but reduced specificity from 60% to 50% ( Table 3 ). Table 3 Performance of HPV genotyping combined with methylation at specific CpG-sites for the detection of HSIL+. Table 3 Sample type Combined HPV/methylation detection for decision making Sensitivity % (95 % CI) Specificity % (95 % CI) HPV genotype a Host Gene b Best cut off (% methylation) Cervical, clinician-collected 16 NA NA 52.2 (30.6–73.2) 81.0 (58.1–94.6) 16,18 NA NA 60.9 (38.5–80.3) 81.0 (58.1–94.6) 16,18,31,33,45,52,58 NA NA 95.7 (78.1–99.9) 33.3 (14.6–56.9) 16,18 EPB41L3 CpG-site 2 10.5 90.9 (70.8–98.9) 50.0 (27.2–72.8) 16,18,31,33,45,52,58 EPB41L3 CpG-site 2 10.5 100 (84.6–100) 25.0 (8.7–49.1) 16,18 EPB41L3 CpG-site 4 6.0 100 (84.6–100) 55.0 (31.5–76.9) 16,18,31,33,45,52,58 EPB41L3 CpG-site 4 6.0 100 (84.6–100) 30.0 (11.9–54.3) 16,18 EPB41L3 CpG-site 5 6.0 90.9 (70.8–98.9) 50.0 (27.2–72.8) 16,18,31,33,45,52,58 EPB41L3 CpG-site 5 6.0 100 (84.6–100) 25.0 (8.7–49.1) 16,18 EPB41L3 CpG-site 2/4 10.5/6.0 100 (84.6–100) 50.0 (27.2–72.8) 16,18,31,33,45,52,58 EPB41L3 CpG-site 2/4 10.5/6.0 100 (84.6–100) 25.0 (8.7–49.0) 16,18 EPB41L3 CpG-site2/5 10.5/6.0 95.5 (77.2–99.9) 40.0 (19.1–64.0) 16,18,31,33,45,52,58 EPB41L3 CpG-site 2/5 10.5/6.0 100 (84.6–100) 20.0 (5.7–43.7) 16,18 EPB41L3 CpG-site 4/5 6.0/6.0 100 (84.6–100) 45.0 (23.1–68.5) 16,18,31,33,45,52,58 EPB41L3 CpG-site 4/5 6.0/6.0 100 (84.6–100) 30.0 (11.9–54.3) 16,18 EPB41L3 CpG-site 1/2/3 5.0/10.5/5 95.5 (77.2–99.9) 30.0 (11.9–54.3) 16,18,31,33,45,52,58 EPB41L3 CpG-site 1/2/3 5.0/10.5/5 100 (84.6–100) 15.0 (3.2–37.9) 16,18 Global EPB41L3 CpG-site 1/2/3 Mean1/2/3(7) 86.4 (65.1–97.1) 45.0 (23.1–68.5) 16,18,31,33,45,52,58 Global EPB41L3 CpG- site 1/2/3 Mean1/2/3(7) 95.5 (77.2–99.9) 25.0 (8.7–49.1) 16,18 FAM19A4 CpG-site 1 <86 76.2 (52.8–91.8) 68.4 (43.5–87.4) 16,18,31,33,45,52,58 FAM19A4 CpG-site 1 <86 95.2 (76.2–99.9) 26.3 (9.2–51.2) 16,18 hTERT CpG-site 4 9.2 72.7 (49.8–89.3) 55.0 (31.5–76.9) 16,18,31,33,45,52,58 hTERT CpG-site 4 9.2 100 (84.6–100) 35.0 (15.4–59.2) Vaginal, self-collected 16,18 NA NA 60.9 (38.5–80.3) 81.0 (58.1–94.6) 16,18,31,33,45,52,58 NA NA 95.7 (78.1–99.9) 33.3 (14.6–56.9) 16,18 EPB41L3 CpG-site 2 9 87.0 (66.4–97.2) 23.8 (8.2–47.2) 16,18,31,33,45,52,58 EPB41L3 CpG-site 2 9 100 (85.2–100) 4.8 (0.1–23.8) 16,18 FAM19A4 CpG-site 1 90 82.6 (61.2–95.1) 61.9 (38.4–81.9) 16,18,31,33,45,52,58 FAM19A4 CpG-site 1 90 100 (85.2–100) 23.8 (8.2–47.2) 16,18 FAM19A4 CpG-site 5 92.5 95.7 (78.1–99.9) 28.6 (11.3–52.2) 16,18,31,33,45,52,58 FAM19A4 CpG-site 5 92.5 100 (85.2–100) 9.5 (1.2–30.4) 16,18 hTERT CpG-site 4 8.0 91.3 (72.0–98.9) 23.8 (8.2–47.2) 16,18,31,33,45,52,58 hTERT CpG-site 4 8.0 100 (85.2–100) 14.3 (3.1–36.3) 16,18 hTERT CpG-site 10 5.5 95.7 (78.1–99.9) 23.8 (8.2–47.2 16,18,31,33,45,52,58 hTERT CpG-site 10 5.5 100 (85.2–100) 14.3 (3.1–36.3) Image 1 High-light CpG-sites and HPV typing with the best diagnostic performance for detection of HSIL or worse. a Detection of at least one of the indicated HPV genotypes. b Positive for at least one of the indicated CpG-sites.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
38960143_p33
|
38960143
|
sec[3]/sec[3]/p[1]
|
Diagnostic performance of DNA methylation at specific CpG-sites combined with HPV infection for the detection of HSIL+
| 3.876953 |
biomedical
|
Study
|
[
0.99951171875,
0.00023317337036132812,
0.00043392181396484375
] |
[
0.998046875,
0.0015859603881835938,
0.00045752525329589844,
0.0000922083854675293
] |
Combination of any methylation marker with extended genotyping (HPV16/18/31/33/45/52/58), showed a sensitivity of 100% at the expense of a low specificity (values between 15.0% and 35.0%).
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p34
|
38960143
|
sec[3]/sec[3]/p[2]
|
Diagnostic performance of DNA methylation at specific CpG-sites combined with HPV infection for the detection of HSIL+
| 4.113281 |
biomedical
|
Study
|
[
0.99951171875,
0.00030875205993652344,
0.00025010108947753906
] |
[
0.9990234375,
0.00028896331787109375,
0.0006151199340820312,
0.00006705522537231445
] |
In self-collected samples, adding HPV16/18 detection to methylation at CpG-site 1 of FAM19A4 showed the best diagnostic performance with a sensitivity of 82.6% and specificity of 61.9%. Methylation at CpG-site 5 of EPB41L3 plus HPV16/18 detection also showed a high sensitivity of 95.7% but at expenses of a low specificity of 28.6%. Combination of any methylation marker with extended genotyping (HPV16/18/31/33/45/52/58), showed a sensitivity of 100% at the expense of a low specificity (values between 4.8% and 23.0%).
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
38960143_p35
|
38960143
|
sec[3]/sec[4]/p[0]
|
Comparison of methylation between paired self-collected and clinician-collected samples
| 4.027344 |
biomedical
|
Study
|
[
0.99951171875,
0.0003762245178222656,
0.0002951622009277344
] |
[
0.99951171875,
0.00021028518676757812,
0.0001844167709350586,
0.00006240606307983398
] |
Analysis of methylation at specific CpG-sites for EPB41L3 and hTERT genes was performed in 42 patients, and for FAM19A4 in 40 patients with paired assessable samples. For women with HSIL and SCC, the levels of methylation at all CpG-sites (1–6) of EPB41L3 in self-collected samples were lower than the levels of methylation of their paired clinician-collected samples .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p36
|
38960143
|
sec[3]/sec[4]/p[1]
|
Comparison of methylation between paired self-collected and clinician-collected samples
| 3.671875 |
biomedical
|
Study
|
[
0.9990234375,
0.0004277229309082031,
0.0005397796630859375
] |
[
0.9990234375,
0.000545501708984375,
0.0003044605255126953,
0.0000661015510559082
] |
In contrast, for women with HSIL and normal/LSIL the levels of methylation of hTERT were higher at almost all the CpG-sites in self-collected samples compared to paired clinician-collected samples . In women with SCC, there was no clear trend.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p37
|
38960143
|
sec[3]/sec[4]/p[2]
|
Comparison of methylation between paired self-collected and clinician-collected samples
| 3.976563 |
biomedical
|
Study
|
[
0.99951171875,
0.00028014183044433594,
0.0003287792205810547
] |
[
0.99951171875,
0.0003192424774169922,
0.00023448467254638672,
0.00005245208740234375
] |
For FAM19A4, significant differences in methylation at individual sites were found for women with normal/LSIL samples (higher for clinician-collected samples at CpG-sites 1 and 3 compared to paired self-collected samples). However, in women with HSIL and cancer, methylation at CpG site 1 seems to be higher for self-collected samples than clinician-collected samples .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
38960143_p38
|
38960143
|
sec[4]/p[0]
|
Discussion
| 4.183594 |
biomedical
|
Study
|
[
0.99951171875,
0.0005183219909667969,
0.0002009868621826172
] |
[
0.9990234375,
0.00024330615997314453,
0.0004825592041015625,
0.00010508298873901367
] |
This study analysed the clinical performance of DNA methylation at individual CpG-sites of EPB41L3, hTERT and FAM19A4 for predicting HSIL+ in clinician and self-collected samples from HPV+ women from PNG, where the burden of hrHPV infection and disease are high, and the development of new triage strategies for detection of HSIL+ are urgently needed. Methylation at individual CpG-sites in clinician and self-collected allowed us to differentiate HSIL vs normal samples, and cancer vs normal samples and to define the best combination of markers, algorithms and thresholds for the detection of HSIL+. The best clinical performance for detection of HSIL+ was obtained by using EPB41L3 site 2/4 /FAM19A4 site 1 with a sensitivity of 100% and specificity of 63.2% for clinician collected samples, and FAM19A4 site 1 combined with HPV16/18 with a sensitivity of 82.6% and specificity of 61.9% for self-collected samples. Comparison of DNA methylation at individual CpG-sites of these genes in paired self/clinician-collected samples differed according to the sample type, lesion grade and gene analysed, generating novel information at basic, clinical and epidemiological level. Our study demonstrated the importance of performing analysis at individual CpG-sites on the promoter and proximal exonic regions of host genes, as some CpG-sites appear to be more susceptible to tumour-associated changes than others.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
38960143_p39
|
38960143
|
sec[4]/sec[0]/p[0]
|
DNA methylation of EPB41L3
| 4.195313 |
biomedical
|
Study
|
[
0.99951171875,
0.0003294944763183594,
0.0001804828643798828
] |
[
0.9990234375,
0.00020813941955566406,
0.0006527900695800781,
0.00009322166442871094
] |
EPB41L3 is a tumour suppressor gene that suppresses metastasis by regulating the proper arrangements of actin stress fibres and increasing cell motility associated with metastatic behaviour . Hyper-methylation of the EPB41L3 promoter down-regulates expression during tumour development in ovarian, lung, cervix, breast, prostate and oral squamous cell carcinomas . In cervical disease, methylation of EPB41L3 has been evaluated in clinical studies generally with global analysis of the percentage of methylation in the gene . Increased levels of DNA methylation according to lesion grade have been observed in clinician-collected samples from high-income populations by using different techniques and analysing the gene alone or in combination with other genes [ 13 , 18 , , , , ]. In LMIC, only one study has been performed using clinician collected samples, also showing increased levels of methylation according lesion grade . Although we cannot perform a direct comparison of our results with other studies, when we performed global methylation analysis of the EPB41L3 gene, our results are similar to those obtained in high-income populations . In our exploratory setting, this gene showed a promising performance for the detection of HSIL, HSIL+ and SCC, making it a striking triage marker to validate in large scale studies in LMIC. Notably, we found individual CpG-sites yield higher performance than an averaged “global” methylation across the region. These values were also higher than those obtained by other researchers using a global approach , highlighting the importance of considering analysis at individual CpG-sites.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
38960143_p40
|
38960143
|
sec[4]/sec[0]/p[1]
|
DNA methylation of EPB41L3
| 4.066406 |
biomedical
|
Study
|
[
0.99951171875,
0.0004792213439941406,
0.00020933151245117188
] |
[
0.99951171875,
0.0002627372741699219,
0.0003082752227783203,
0.00007480382919311523
] |
In our study analysis of methylation at individual CpG site 2/4 of EPB41L3 increased the diagnostic performance for the detection of HSIL+ with an excellent sensitivity of 95.5% and a specificity of 60% in clinician-collected samples. However, the best diagnostic performance was observed by combining methylation of EPB41L3 site 2/4 and FAM19A4 site 1, showing that combination of individual CpG sites of different genes could improve the detection of HSIL+. By using any of these models, the percentage of referrals to treatment in our PNG exploratory study would theoretically have been 60–70%, lower than that of transferring all hrHPV + women under the current algorithm, thus reducing unnecessary referrals and overtreatments without affecting sensitivity.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p41
|
38960143
|
sec[4]/sec[0]/p[2]
|
DNA methylation of EPB41L3
| 4.152344 |
biomedical
|
Study
|
[
0.99951171875,
0.00017392635345458984,
0.0001798868179321289
] |
[
0.99853515625,
0.00018787384033203125,
0.001399993896484375,
0.00007128715515136719
] |
A study analysed specific CpG sites methylation and their role in the EPB41L3 expression in gastric cancer, finding a strong correlation between CpG hypermethylation and decreased EPB41L3 mRNA and protein levels . Recently an integrated bioinformatics approach identified that EPB41L3 was hypermethylated and correlated with a decreased expression of EPB41L3 mRNA in cervical cancer tissues compared with normal tissues. In addition, a lower expression of the gene was correlated with a shorter survival time .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p42
|
38960143
|
sec[4]/sec[0]/p[3]
|
DNA methylation of EPB41L3
| 4.113281 |
biomedical
|
Study
|
[
0.99951171875,
0.0003352165222167969,
0.0002143383026123047
] |
[
0.99951171875,
0.0001742839813232422,
0.0003018379211425781,
0.000059664249420166016
] |
In self-collected samples, the performance of EPB41L3 methylation for detection of HSIL or cancer was lower than in clinician-collected cervical samples. A few studies, using qMSP, have analysed methylation of this gene in self-collected samples, all performed in high-income countries . Two of them compared methylation levels of self-collected samples with clinician collected samples and both showed decreased methylation levels in self-collected samples when compared with clinician-collected samples, as observed in our study. Furthermore, to the best of our knowledge, our study is the first one to perform methylation analysis of the EPB41L3 gene (global and at individual CpG-sites) in self-collected samples from a LMIC. Global methylation analysis of EPB41L3 in these samples showed a limited sensitivity/specificity for the detection of HSIL+ but analysis of methylation at individual CpG-sites 2 and 3 increased the sensitivity for the detection of HSIL+ to 91.3% at the expense of a low specificity. Similar results were observed when we combined methylation at individual CpG-sites with HPV16/18 or extended genotyping. In summary these results show that analysis of EPB41L3 methylation will be better to analyse in clinician collected samples in case that this gene is used for diagnosis of HSIL+ for screening purpose in this setting.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p43
|
38960143
|
sec[4]/sec[1]/p[0]
|
DNA methylation of hTERT
| 3.664063 |
biomedical
|
Study
|
[
0.99951171875,
0.00014281272888183594,
0.00029087066650390625
] |
[
0.99560546875,
0.001956939697265625,
0.0020961761474609375,
0.0001392364501953125
] |
DNA methylation plays a role in deregulated hTERT expression and is implicated in HPV-mediated pathogenesis of cervical cancer [ , , , , ]. Studies using clinician-collected samples from high-income populations have found increasing hTERT methylation with escalating lesion grade . Only one study has been done in a LMIC, in cervical cancer biopsies .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p44
|
38960143
|
sec[4]/sec[1]/p[1]
|
DNA methylation of hTERT
| 4.03125 |
biomedical
|
Study
|
[
0.99951171875,
0.0003790855407714844,
0.00026988983154296875
] |
[
0.99951171875,
0.0002415180206298828,
0.00025653839111328125,
0.00005906820297241211
] |
In our study, global methylation analysis showed a similar performance for detection of HSIL+ as observed in high income countries for CIN2+ in clinician-collected samples (sensitivities 40–69% and specificities 54–88%) and in self-collected samples (sensitivity of 62.9%) .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p45
|
38960143
|
sec[4]/sec[1]/p[2]
|
DNA methylation of hTERT
| 4.183594 |
biomedical
|
Study
|
[
0.99951171875,
0.00020897388458251953,
0.00021314620971679688
] |
[
0.99951171875,
0.00022113323211669922,
0.0003485679626464844,
0.00006335973739624023
] |
Analysis at individual CpG-sites found site 4 was the best marker to distinguish normal/cancer samples and CpG site 4 and 10 the best markers to distinguish normal/HSIL in clinician and self-collected samples respectively. The hTERT promoter region harbors binding sites for transcription factors that positively or negatively regulate hTERT expression. SMAD3 is a repressor protein that binds to the hTERT gene promoter (from position −218 to −206 to the transcriptional initiation codon) and inhibits hTERT gene transcription activity . Methylation of site 4 (position −212) could reduce the binding of SMAD3 favouring hTERT transcription, but additional research at transcriptional level is required to confirm this idea. A study in colorectal samples showed that three specific CpG sites in the hTERT promoter region were related with increasing of hTERT e xpression during malignant progression of colorectal carcinoma . Hence, some CpG-sites appear to be more susceptible to tumour-associated changes than others.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p46
|
38960143
|
sec[4]/sec[2]/p[0]
|
DNA methylation of FAM19A4
| 4 |
biomedical
|
Study
|
[
0.99951171875,
0.00008678436279296875,
0.00021398067474365234
] |
[
0.9931640625,
0.004268646240234375,
0.002185821533203125,
0.00016427040100097656
] |
FAM19A4 is a member of the TAFA family of five highly homologous genes that encode small, secreted proteins predominantly expressed in the brain . FAM19A4 also has been identified as a promising biomarker for cervical oncogenesis by using genome wide DNA screening . Furthermore, FAM19A4 promoter methylation analysis has been shown to predict underlying CIN3/CIN3+ .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
38960143_p47
|
38960143
|
sec[4]/sec[2]/p[1]
|
DNA methylation of FAM19A4
| 4.097656 |
biomedical
|
Study
|
[
0.99951171875,
0.0003058910369873047,
0.00019788742065429688
] |
[
0.99951171875,
0.0001627206802368164,
0.000354766845703125,
0.00006747245788574219
] |
In our study, we used a new set of primers for analysis of DNA methylation directed to the proximal exonic region in the gene FAM19A4, showing promising results for detection of HSIL+. We performed the methylation analysis globally and at individual CpG-sites by using pyrosequencing to get comprehensive information on the methylation status in this region and its possible biological, and diagnostic role in cervical disease. Although this exon region has not been analysed before, and a direct comparison is not possible, global methylation results in clinician-collected samples are similar to reports analysing the promoter region of FAM19A4 in high income countries . The performance of FAM19A4 in combination with miR124-2 methylation have shown to improve the sensitivity (range of reported studies from 68.2 to 86.7%) and specificity (ranging from 60.6 to 91%) for the detection of CIN3+ in these cervical specimens [ 9 , , , ].
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p48
|
38960143
|
sec[4]/sec[2]/p[2]
|
DNA methylation of FAM19A4
| 4.070313 |
biomedical
|
Study
|
[
0.99951171875,
0.0002033710479736328,
0.00018084049224853516
] |
[
0.99951171875,
0.00028896331787109375,
0.0002391338348388672,
0.0000622868537902832
] |
We found that some specific CpG sites were promising to distinguish HSIL and cancer from normal/LSIL and combination of EPB41L3 sites 2/4 plus FAM19A4 site 1 dramatically improved sensitivity to 100%, with a specificity of 63.2% for detection of HSIL+. These results warrant more studies of DNA methylation at specific CpG sites in the proximal exonic region of FAM19A4 and its function in cervical carcinogenesis.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
38960143_p49
|
38960143
|
sec[4]/sec[2]/p[3]
|
DNA methylation of FAM19A4
| 4.0625 |
biomedical
|
Study
|
[
0.99951171875,
0.00039267539978027344,
0.0002148151397705078
] |
[
0.99951171875,
0.00021898746490478516,
0.000278472900390625,
0.00006747245788574219
] |
In self-collected samples, methylation at some specific CpG sites of FAM19A4 also were promising to distinguish HSIL and cancer from normal/LSIL samples and combining FAM19A4 CpG site1 and HPV16/18 detection showed the best diagnostic performance with a sensitivity and specificity values [82.6% (61.2–95.1) and 61.9% (38.4–81.9) respectively]. Combining this site 1 with extended genotyping increased sensitivity of 100% at expenses of specificity (23.8%). Despite the reduced specificity, employing either of these models would have reduced the referrals to treatment in our exploratory study compared to hrHPV typing alone, reducing overtreatment and the burden on the limited health resources.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p50
|
38960143
|
sec[4]/sec[2]/p[4]
|
DNA methylation of FAM19A4
| 3.021484 |
biomedical
|
Study
|
[
0.99853515625,
0.0002231597900390625,
0.001033782958984375
] |
[
0.9873046875,
0.009307861328125,
0.003063201904296875,
0.00023126602172851562
] |
Analysis of the promoter region of FAM19A4 combined with other genes and/or HPV16/18 have shown a good performance for CIN3+ in self collected samples, in high income countries . The results from these studies highlight the promising performance of FAM19A4 methylation in this type of samples.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
38960143_p51
|
38960143
|
sec[4]/sec[3]/p[0]
|
Levels of methylation at specific CpG-sites in paired samples differed according to lesion grade, type of sample and gene analysed
| 4.121094 |
biomedical
|
Study
|
[
0.99951171875,
0.00023686885833740234,
0.00019943714141845703
] |
[
0.9990234375,
0.00022673606872558594,
0.0005970001220703125,
0.00006198883056640625
] |
Analysis of methylation in paired samples showed that the levels of methylation at specific CpG sites not always follow the same pattern, reflected in the significant p value for some CpG sites and not others. Self-collected vaginal and clinician collected cervical samples are different. While in the self-collected vaginal sample, the women obtain cells from the vagina (a mid-cavity vaginal specimen) by using a swab or brush, the clinician collected cervical sample is collected by a clinician by using a Cervex-Brush Combi device which enable simultaneous collection of specific cells of the ectocervix, endocervix, and transformation zone in a single sample. Therefore, paired samples will have differences in cellular composition, cellular environment, and cells with differences in methylation levels, influenced by these factors but also related to the disease stage, gene, region and the specific CpG site studied, etc. These results have important implications for the translation of methylation findings from one sampling strategy to another and confirm the importance of defining specific thresholds and algorithms for the detection of HSIL+ lesions according to the sample type and other characteristics.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
38960143_p52
|
38960143
|
sec[4]/sec[3]/p[1]
|
Levels of methylation at specific CpG-sites in paired samples differed according to lesion grade, type of sample and gene analysed
| 4.09375 |
biomedical
|
Study
|
[
0.9990234375,
0.0005421638488769531,
0.0002281665802001953
] |
[
0.99951171875,
0.0002684593200683594,
0.00024008750915527344,
0.00007671117782592773
] |
Limitations of this study include the small sample size specially on the number of SCC as these results were part of an exploratory study, leading to broad confidence intervals which restricted the statistical power of the current analysis. However, these results showed the reliability of the markers evaluated and allowed us to define thresholds and choose the best methylation markers and CpG-sites to be evaluated in all hrHPV+ women that participated in the PNG trial. Diagnosis was based on LBC HSIL rather than a histological end-point. Although histology is the best end point in high-income countries, in many LMIC and remote settings it is not feasible to perform colposcopy and histological diagnosis which can lead to disease misclassification. We used some strategies to decrease disease misclassification: HPV detection was used as primary screening tool, all slides were assessed by two independent experienced cytologists working at VCS in Melbourne, dual p16/Ki-67 immuno-staining was performed to resolve disagreements and diagnosis based in LBC HSIL have shown to be highly predictive of underlying histological disease in some settings .
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p53
|
38960143
|
sec[4]/sec[3]/p[2]
|
Levels of methylation at specific CpG-sites in paired samples differed according to lesion grade, type of sample and gene analysed
| 4.113281 |
biomedical
|
Study
|
[
0.99951171875,
0.0003018379211425781,
0.00019025802612304688
] |
[
0.99951171875,
0.00018084049224853516,
0.000255584716796875,
0.00006562471389770508
] |
This study is innovative as for the first time, individual CpG sites of different genes (alone or in combination) were proposed as candidates for detection of HSIL+ showing increased sensitivity and specificity in the detection of HSIL+ in both, clinician and self-collected samples, supporting this strategy to be validated in large scale studies. Also, analyses of the proximal exon region of FAM19A4 gene, not explored previously, allowed us to identify methylation at one specific CpG site that showed very promising results for detection of HSIL+ when combined with other markers, these results show that this region is also important for the control of expression of FAM19A4 and in cervical carcinogenesis.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
38960143_p54
|
38960143
|
sec[4]/sec[3]/p[3]
|
Levels of methylation at specific CpG-sites in paired samples differed according to lesion grade, type of sample and gene analysed
| 4.074219 |
biomedical
|
Study
|
[
0.99951171875,
0.0005140304565429688,
0.00020933151245117188
] |
[
0.9990234375,
0.0004634857177734375,
0.0004875659942626953,
0.000087738037109375
] |
In conclusion, individual CpG methylation of EPB41L3 (promoter region) and FAM19A4 (proximal exonic region) highlighted in this study had high performance for detection of HSIL+ in clinician and self-collected samples and warrant further evaluation. The introduction of triage assays targeting methylation at individual CpG-sites could help to reduce overtreatment rates, loss of follow-up associated with repeated clinic visits, and improvement of care in LMIC. In PNG where POC hrHPV detection is used, overtreatment could be reduced by performing methylation analysis from self-collected or clinician-collected samples prior to referring the hrHPV+ woman to ablative treatment. Large-scale implementation studies are underway across multiple LMIC settings that will allow us to confirm findings presented in current paper.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p55
|
38960143
|
sec[5]/p[0]
|
Disclosure of potential conflicts of interest
| 1.022461 |
other
|
Other
|
[
0.0208740234375,
0.0019016265869140625,
0.97705078125
] |
[
0.0024280548095703125,
0.99658203125,
0.0005459785461425781,
0.0004227161407470703
] |
AJV, JG, JB, GMM, PJT, SGB, JMK have received subsidized test kits for research from Cepheid. MS, JMLB, GT, DH have received donated test kits for research from Roche, Abbott, Seegene, Cepheid, Aus Diagnostics and Becton Dickinson. AJV and MS jointly lead the Elimination of Cervical Cancer in the 10.13039/100007159 Western Pacific (ECCWP) program with philanthropic funding support from the 10.13039/501100016056 Minderoo Foundation and the Frazer Family Foundation; and equipment, tests and consumables donated by 10.13039/100017037 Cepheid for HPV-based cervical screening in Papua New Guinea and Vanuatu. SMG is a member of the 10.13039/100008086 Global Advisory Board HPV 10.13039/100004334 Merck , and has led investigator-initiated grants from 10.13039/100004334 Merck on HPV in young women. MM, DAM, SP, PB, RH, ZK, GLM, declare no conflicting interests.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p56
|
38960143
|
sec[6]/p[0]
|
Data statement
| 1.061523 |
other
|
Other
|
[
0.311767578125,
0.0024871826171875,
0.685546875
] |
[
0.00882720947265625,
0.990234375,
0.000553131103515625,
0.0004298686981201172
] |
The data are not publicly available due to confidentiality and ethical considerations. Deidentified data are available from the authors upon reasonable request and subject to approval by the ethics committees overseeing the study.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p57
|
38960143
|
sec[7]/p[0]
|
Grant support
| 1.082031 |
other
|
Other
|
[
0.01015472412109375,
0.0016193389892578125,
0.98828125
] |
[
0.0009298324584960938,
0.998046875,
0.0005402565002441406,
0.0004584789276123047
] |
This work was funded through the 10.13039/501100000925 National Health and Medical Research Council , Australia , grants 1,013,209 and 1104938) (AJV), Government of Papua New Guinea (ICRAS 297/1), the 10.13039/501100000925 NHMRC Centre for Research Excellence in Cervical Cancer Control APP1135172 (JMLB, MS, AJV) and 10.13039/501100000925 NHMRC Investigator Grant APP1197951 (SMG).
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p58
|
38960143
|
sec[8]/p[0]
|
CRediT authorship contribution statement
| 1.012695 |
other
|
Other
|
[
0.12261962890625,
0.00322723388671875,
0.8740234375
] |
[
0.003692626953125,
0.9951171875,
0.0005679130554199219,
0.00042629241943359375
] |
Monica Molano: Writing – original draft, Visualization, Software, Methodology, Investigation, Data curation, Conceptualization. Dorothy A. Machalek: Writing – review & editing, Visualization, Supervision, Investigation, Funding acquisition. Samuel Phillips: Writing – review & editing, Software, Methodology, Data curation. Grace Tan: Writing – review & editing, Project administration, Methodology, Investigation. Suzanne M. Garland: Writing – review & editing, Supervision, Project administration, Investigation, Funding acquisition. David Hawkes: Writing – review & editing, Methodology, Investigation. Prisha Balgovind: Writing – review & editing, Methodology, Investigation. Reza Haqshenas: Writing – review & editing, Methodology, Investigation. Steve G. Badman: Writing – review & editing, Project administration, Methodology, Conceptualization. John Bolnga: Writing – review & editing, Methodology. Josephine Gabuzzi: Writing – review & editing, Project administration. Zure Kombati: Writing – review & editing, Project administration, Investigation. Gloria M. Munnull: Writing – review & editing, Project administration, Investigation. Julia ML. Brotherton: Writing – review & editing, Funding acquisition, Conceptualization. Marion Saville: Writing – review & editing, Funding acquisition, Conceptualization. John M. Kaldor: Writing – review & editing, Funding acquisition, Conceptualization. Pamela J. Toliman: Writing – review & editing. Andrew J. Vallely: Writing – review & editing, Supervision, Project administration, Methodology, Funding acquisition, Formal analysis, Conceptualization. Gerald L. Murray: Writing – review & editing, Visualization, Supervision, Project administration, Investigation, Funding acquisition.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
38960143_p59
|
38960143
|
sec[9]/p[0]
|
Declaration of competing interest
| 0.998047 |
other
|
Other
|
[
0.005924224853515625,
0.0008344650268554688,
0.9931640625
] |
[
0.001953125,
0.9970703125,
0.0005655288696289062,
0.0006089210510253906
] |
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
38960143_p60
|
38960143
|
sec[9]/p[1]
|
Declaration of competing interest
| 1.053711 |
other
|
Other
|
[
0.01468658447265625,
0.0017461776733398438,
0.9833984375
] |
[
0.002155303955078125,
0.99658203125,
0.000583648681640625,
0.0004439353942871094
] |
AJV, JG, JB, GMM, PJT, SGB, JMK have received subsidized test kits for research from Cepheid. MS, JMLB, GT, DH have received donated test kits for research from Roche, Abbott, Seegene, Cepheid, Aus Diagnostics and Becton Dickinson. AJV and MS jointly lead the Elimination of Cervical Cancer in the 10.13039/100007159 Western Pacific (ECCWP) program with philanthropic funding support from the 10.13039/501100016056 Minderoo Foundation and the Frazer Family Foundation; and equipment, tests and consumables donated by 10.13039/100017037 Cepheid for HPV-based cervical screening in Papua New Guinea and Vanuatu. SMG is a member of the 10.13039/100008086 Global Advisory Board HPV 10.13039/100004334 Merck , and has led investigator-initiated grants from 10.13039/100004334 Merck on HPV in young women. All other authors report no potential conflicts.
|
[
"Monica Molano",
"Dorothy A. Machalek",
"Samuel Phillips",
"Grace Tan",
"Suzanne M. Garland",
"David Hawkes",
"Prisha Balgovind",
"Reza Haqshenas",
"Steve G. Badman",
"John Bolnga",
"Josephine Gabuzzi",
"Zure Kombati",
"Gloria M. Munnull",
"Julia ML. Brotherton",
"Marion Saville",
"John M. Kaldor",
"Pamela J. Toliman",
"Andrew J. Vallely",
"Gerald L. Murray"
] |
https://doi.org/10.1016/j.tvr.2024.200288
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p0
|
PMC11278987
|
sec[0]/p[0]
|
1. Introduction
| 3.576172 |
other
|
Study
|
[
0.363525390625,
0.0008993148803710938,
0.6357421875
] |
[
0.587890625,
0.40869140625,
0.0029773712158203125,
0.00036334991455078125
] |
The Al-43.4wt%Zn-2wt%Mg-1.6wt%Si (Al–Zn–Mg–Si) alloy is used as a corrosion-resistant coating for steel sheets and offers superior cut and barrier protection against corrosion . The coated steel is produced on a continuous hot-dip galvanising line, where a steel sheet is run into the hot liquid alloy bath and is then pulled out after it turns around a sink roll immersed inside the bath. However, on the production line, Fe is constantly deposited into the liquid bath, leading to the formation of unwanted intermetallic compounds (IMCs), which must be manually removed from the bath . These unwanted IMCs are treated as three types, which are top dross, suspended dross and bottom dross. Top dross located on the surface of the coating bath can be scraped off during operation. A small proportion of the dross remains suspended floating in the melt, and dross that settles at the bottom of the bath requires the coating bath to be removed and the dross manually removed. Neither the frequent cleaning of the hot dipping baths nor the potential inclusion of dross in the coated strip are practical, so an understanding of the dross formation mechanism is valuable . Reduced bath cleaning frequency has economic benefits for the manufacturer, and a higher-quality coating will yield superior performance for the end user.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p1
|
PMC11278987
|
sec[0]/p[1]
|
1. Introduction
| 4.1875 |
biomedical
|
Study
|
[
0.9794921875,
0.0006546974182128906,
0.019775390625
] |
[
0.99951171875,
0.0002982616424560547,
0.00016021728515625,
0.0000388026237487793
] |
The degree of IMC formation has been determined to be a function of the Fe content in the coating bath, which has been found to reach equilibrium solubility at 0.4 wt% Fe in the Al–Zn–Mg–Si alloy bath at 600 °C . During the manufacturing process, the nominal 600 ° C bath is continuously topped up with fresh liquid Al–Zn–Mg–Si alloy. The virgin alloy added to the bath is known to contain a nominal 0.1 wt% Fe because of the alloy preparation process . The two primary Fe-bearing phases of interest are the τ 5c Al 20 Fe 5 Si 2 and the τ 6 Al 9 Fe 2 Si 2 phases, of which the crystal lattices are determined to be body-centred cubic (bcc) and monoclinic , respectively. The bcc structure of the τ 5 phase results from the presence of Zn in the alloy, which transforms the α phase. The τ 5c Al 20 Fe 5 Si 2 (+Zn) equilibrium IMC phase usually forms on the substrate steel, below the coating alloy . However, it also forms within the solution, where it can also act as a reservoir for Fe when bath temperatures rise . The bcc structure of the τ 5c phase is the result of trace transition metals in the alloy, and in the case of the Al–Zn–Mg–Si alloy analysed, incidental Cr is believed to be the main stabilising agent . The goal of this paper is to determine the distribution of Fe in the alloy system as it solidifies as well as to form a hypothesis on the formation mechanisms of IMCs. A challenge for understanding the formation mechanisms for these IMCs is that although the IMCs themselves contain enough Fe for conventional analysis techniques, the nominal concentration of Fe in the liquid phase and liquid–solid boundary is very low. Therefore, they often cannot be reliably detected. This paper aims to address this challenge. It should be noted that the main focus of this paper is the fundamentals of Fe-bearing IMC formation in this alloy system, and the performance of the coating alloy or the coated product will not be discussed.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278987_p2
|
PMC11278987
|
sec[0]/p[2]
|
1. Introduction
| 4.246094 |
biomedical
|
Study
|
[
0.9921875,
0.0003883838653564453,
0.007312774658203125
] |
[
0.9990234375,
0.00027632713317871094,
0.0006213188171386719,
0.00004500150680541992
] |
Previous work by Tong et al. found that the primary Fe-containing IMCs of interest consist of τ 6 and τ 5c , and the formation temperature as well as the phase fraction of τ 6 have been found to increase with increasing Fe content. It was found in bulk air-cooled samples that with less than 0.4 wt% Fe, the τ 5c phase would fail to appear. Above the liquidus temperature of the alloy, the Fe is believed to stay suspended in solution; however, upon cooling below the liquidus temperature, these IMCs are known to nucleate and grow from the liquid and are distributed in the interdendritic region within the α-Al network afterwards. Thermal analysis by Tong et al. identified the formation temperatures of several primary phases including α-Al and various Zn-/Mg-containing phases. However, due to the low concentration of Fe in the alloy mixture, the energy released in the solidification events is not enough to be observed. Observation using SEM EDS has identified that these phases nucleate at a similar temperature to the much more prominent α-Al phase, suggesting that their solidification peaks have overlapped with that of the α phase . The solubility of Fe in the Al–Zn–Mg–Si alloy has been quantified by Setargew et al. as (1) ln F e = − 7220 T + 7.39 ,
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p3
|
PMC11278987
|
sec[0]/p[3]
|
1. Introduction
| 4.207031 |
biomedical
|
Study
|
[
0.9912109375,
0.0005860328674316406,
0.0080108642578125
] |
[
0.99951171875,
0.00021946430206298828,
0.0001780986785888672,
0.00004166364669799805
] |
Here, T is the absolute temperature of the coating bath. In this experimental series, the bath temperature is analogous to the temperature of the sample at the time of quench. As the sample undergoes rapid cooling during the quench, Fe is also rapidly segregated out of the melt. At 600 °C, the solubility of Fe in the melt is 0.41 wt%, but by the time it has cooled to 500 °C, the equilibrium concentration has decreased to 0.14 wt%. This is predicted to cause a high degree of constitutional undercooling ahead of the solidification front, creating favourable conditions for the nucleation of IMCs, which depends on the segregation of Fe out of the solution to form. It can be seen from the Al-rich end of the binary Al–Fe phase diagram that up to the first eutectic point of approximately 2 wt%, adding Fe has a stabilising effect on the liquidus temperature of the system. Figure 1 shows a decrease in the formation temperature of the highest temperature formation peak, corresponding to the α phase when Fe content is increased from 0.1 wt% to 0.4 wt%. When Fe content is increased from 0.1 wt% to 0.4 wt%, the formation temperature of the α phase decreases from 560 ° C to 549 ° C , showing the stabilising effect of the Fe. It is predicted that this lower formation temperature for the α phase will result in a lower formation barrier for Fe-based IMCs. Lastly, another driving factor for the formation of Fe-based IMCs is believed to be the presence of a thermal gradient, which was found to have a dominant effect on the formation of Fe-bearing IMCs compared to the cooling rate, as found by Feng et al. . The presence of a thermal gradient during solidification as well as the alloy temperature can be seen as critical in the formation mechanism of IMCs in the Al–Zn–Mg–Si alloy. This paper will attempt to verify the mechanisms behind these observations.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278987_p4
|
PMC11278987
|
sec[1]/sec[0]/p[0]
|
2.1. Casting and Initial Preparation of Samples
| 3.298828 |
biomedical
|
Study
|
[
0.5263671875,
0.0007691383361816406,
0.47314453125
] |
[
0.85595703125,
0.1429443359375,
0.0006780624389648438,
0.0002968311309814453
] |
Samples were prepared using an industrial Al–Zn–Mg–Si master alloy. The master alloy was re-melted in an induction furnace and cast into a graphite pencil mould. Then, the samples for the directional solidification (DS) tests were machined out of the cast pencil sample into a 4.5 mm diameter rod of approximately 100 mm length using a lathe. These rods were then inserted into a 1.6 mm wall-thickness 316L stainless-steel tube, which was attached to the frame of the Bridgman furnace, as seen in Figure 2 .
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278987_p5
|
PMC11278987
|
sec[1]/sec[1]/p[0]
|
2.2. Directional Solidification and Sample Mounting
| 4.167969 |
biomedical
|
Study
|
[
0.9990234375,
0.00030231475830078125,
0.0004963874816894531
] |
[
0.9892578125,
0.0099639892578125,
0.00046896934509277344,
0.0001748800277709961
] |
A temperature gradient of 6.2 K/mm was applied to the DS sample and the sample was pulled for a total of 60 mm at a rate of 0.02 mm/min, then rapidly quenched in a refrigerated ethylene glycol-based coolant bath held at 2 ° C . The samples were sectioned parallel to the direction of pull and mounted in 25 mm long segments in Struers Polyfast conductive resin, then ground and polished using silicon carbide sandpaper and Struers Diapro Nap B and Mol B solution until fit for SEM observation (JEOL 7800F (JEOL, Tokyo, Japan) at 15 keV accelerating voltage, probe current set to 11 , aperture size of 4, backscattered and with 10 mm working distance).
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278987_p6
|
PMC11278987
|
sec[1]/sec[2]/p[0]
|
2.3. Description of Mounted Samples and Temperature Zones
| 3.763672 |
biomedical
|
Study
|
[
0.892578125,
0.0005769729614257812,
0.10699462890625
] |
[
0.99169921875,
0.00807952880859375,
0.0002918243408203125,
0.00006604194641113281
] |
The temperature range of the directionally solidified section was calculated to be between 240 °C and 600 °C by calibrating the furnace first using a Type N thermocouple. The three 25 mm sample segments, henceforth indicated as ‘low’, ‘medium’ and ‘high,’ were calculated to correspond to the following temperature ranges: 240–310 °C, 310–480 °C and 480–600 °C. These temperatures were calculated by referencing the temperature gradient recorded inside the furnace with the Type N thermocouple against the position of the sample inside.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278987_p7
|
PMC11278987
|
sec[1]/sec[3]/p[0]
|
2.4. XFM Sample Preparation
| 4.144531 |
biomedical
|
Study
|
[
0.99755859375,
0.00020062923431396484,
0.0024127960205078125
] |
[
0.9990234375,
0.0006017684936523438,
0.00016367435455322266,
0.00003218650817871094
] |
Samples for the synchrotron X-ray fluorescence (XFM) were prepared by using a diamond saw to slice a thin wafer off the resin-mounted samples; then, using a handheld wafer carrier, the films were ground down to nominal 30 μm thin films, verified using a micrometre. The synchrotron XFM analysis was performed at the XFM beamline at the Australian Synchrotron. The samples were scanned using an incident X-ray beam of 18.5 keV with the scanning pixel size 1 μm × 1 μm. The reflected X-ray signal was recorded using the Maia 385 array detector. In metallurgical studies, alternative techniques such as X-ray dispersive spectroscopy (EDS) and electron backscatter diffraction (EBSD) are used for phase identification and the analysis of crystallography, but this paper will attempt a novel application of XFM on a metallurgical sample instead. This is due to the higher sensitivity limits for detecting low concentration elements (<1 wt%), and for determining their distribution.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p8
|
PMC11278987
|
sec[1]/sec[4]/p[0]
|
2.5. Phase Verification
| 2.052734 |
other
|
Study
|
[
0.306884765625,
0.0009889602661132812,
0.6923828125
] |
[
0.96240234375,
0.036163330078125,
0.0009641647338867188,
0.0003299713134765625
] |
The detailed verification and identification of the IMC phases found in this paper were out of scope, as the primary objective of the paper was to study the formation mechanism of these phases. Hence, only SEM-EDS was used to verify the composition of IMC crystals found in this study, which are already well known in the context of this alloy system. In-depth phase identification can be found in the works by Setargew et al., Qu et al. and Khaliq et al. .
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278987_p9
|
PMC11278987
|
sec[1]/sec[5]/p[0]
|
2.6. Verification of Stainless-Steel Reaction
| 3.832031 |
biomedical
|
Study
|
[
0.91259765625,
0.0004055500030517578,
0.08697509765625
] |
[
0.99462890625,
0.00518798828125,
0.0002639293670654297,
0.00005984306335449219
] |
It should be noted that the sample studied using DS and subsequent XFM samples were generated by directly inserting the Al–Zn samples into an uncoated stainless-steel tube. A side effect of this direct insertion into the tube is the formation of an IMC phase between the wall of the tube and the alloy, resulting from the dissolution of mainly Fe, but also trace amounts of Cr and Ni, into the liquid Al–Zn alloy inside the tube to form the modified τ 5c phase, which occurs as a result of Cr and Zn substituting Fe atoms in the τ 5 c phase . This reaction may be seen in XFM images in the latter part of the paper.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p10
|
PMC11278987
|
sec[1]/sec[5]/p[1]
|
2.6. Verification of Stainless-Steel Reaction
| 4.183594 |
biomedical
|
Study
|
[
0.89697265625,
0.0008392333984375,
0.10205078125
] |
[
0.9990234375,
0.0007066726684570312,
0.0003173351287841797,
0.000041425228118896484
] |
An adverse effect of the dissolution of Fe into the liquid is that the nominal Fe content of the alloy can no longer be 0.4 wt%, with much higher local Fe concentrations suspected in the vicinity of the stainless-steel tube wall. To verify that this additional Fe dissolution has no or a negligible effect on the solidification sequence of the alloy, a literature review was performed, and EDS analysis of the Fe content in the boundary region was performed. Setargew found that when a rectangular coupon made of 316L stainless steel was dipped into an alloy coating bath, two distinct IMC layers would form, with the first layer (directly bordering the stainless-steel substrate) being denoted as AL1 and the second AL2, with AL2 resulting in small clusters of IMCs that break off and drift into the liquid coating alloy. The composition of the AL2 layer found by Setargew is seen in Table 1 . This was compared to the composition of an IMC crystal observed in a directionally solidified sample, which was believed to result from direct contact between the stainless-steel tube and the alloy. The compositions are similar, except there is a considerably lower amount of Cr content in the directionally solidified samples, which can be attributed to limited diffusion time within the Bridgman furnace. Both the coupon used by Setargew and the tube in the directionally solidified sample were manufactured out of 316L stainless steel.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278987_p11
|
PMC11278987
|
sec[1]/sec[5]/p[2]
|
2.6. Verification of Stainless-Steel Reaction
| 4.164063 |
biomedical
|
Study
|
[
0.9560546875,
0.0008687973022460938,
0.042877197265625
] |
[
0.99951171875,
0.0003192424774169922,
0.00021398067474365234,
0.000043451786041259766
] |
EDS measurement of two types of area in the ‘high’ part of the directionally solidified sample containing 0.4 wt% Fe was undertaken, with the two measurement areas consisting of a location where the modified τ 5c IMC has formed and the second consisting of a point where there has been direct contact between the stainless-steel tube and the liquid alloy but with no visible reaction, as illustrated in Figure 3 . The composition of the alloy with distance from the stainless-steel tube was mapped and is presented in Figure 4 , Figure 5 and Figure 6 . The deposition of Cr and Ni from the stainless steel was exclusively limited to the modified τ 5c phase (verified with SEM-EDS), with no further dissolution into the quenched liquid, as seen in Figure 4 . Figure 4 shows that outside the crystal of the modified τ 5c phase, the Cr and Ni content drops to undetectable levels. It is believed that this is due to Cr and Ni’s low solubility in the Al liquid. The composition of the liquid was found to stabilise quickly with increasing distance from the stainless-steel tube wall, with Fe content decreasing sharply following the transition from the modified τ 5c crystal to α-Al and the quenched liquid, as seen in Figure 5 . In areas where there is no visible reaction between the stainless-steel tube and the alloy, the Fe content is seen to be elevated near the edge of the stainless-steel tube but quickly drops to equilibrium within 60 μm. Likewise, even in samples where the modified τ 5c phase has formed, the composition stabilises within approximately 20 μm, as seen in Figure 6 .
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p12
|
PMC11278987
|
sec[1]/sec[5]/p[3]
|
2.6. Verification of Stainless-Steel Reaction
| 2.255859 |
biomedical
|
Study
|
[
0.61376953125,
0.0014410018920898438,
0.384521484375
] |
[
0.81005859375,
0.1884765625,
0.0011081695556640625,
0.0006232261657714844
] |
Although the nominal Fe content could no longer be considered to be 0.4 wt% due to the extensive dissolution of Fe into the liquid, this reaction is largely contained within a thin reaction layer. The centre of the alloy sample is unaffected and can still be used to study the solidification mechanics of Fe-based IMCs.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278987_p13
|
PMC11278987
|
sec[2]/sec[0]/p[0]
|
3.1. Directional Solidification
| 4.160156 |
biomedical
|
Study
|
[
0.94189453125,
0.0008115768432617188,
0.057525634765625
] |
[
0.9990234375,
0.0006136894226074219,
0.00019061565399169922,
0.000047326087951660156
] |
Prior to investigation using XFM, SEM-EDS analysis was employed to investigate the Fe distribution in the alloy. The primary areas of interest lay within the boundary between the quenched liquid and the site of early primary α-Al dendrite formation, as this is where Fe-based IMCs were predicted to nucleate. An image taken with a JEOL 7800F SEM of a nominal 0.4 wt% Fe-containing Al–Zn–Mg–Si DS sample shows that at the liquid–solid boundary (LSB), needle-like crystals of the τ 6 IMC phase are observed, with some of them embedded within α-Al dendrites. SEM-EDS spot analysis is used to verify their composition. SEM-EDS mapping shows the concentration of Fe to be largely concentrated within these IMCs . This solidification event of τ 6 was calculated to occur at 495 ° C by referencing the location of the event to the measured temperature gradient inside the furnace.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p14
|
PMC11278987
|
sec[2]/sec[0]/p[1]
|
3.1. Directional Solidification
| 4.144531 |
biomedical
|
Study
|
[
0.9736328125,
0.0005879402160644531,
0.0259552001953125
] |
[
0.99951171875,
0.0002987384796142578,
0.00020778179168701172,
0.000040531158447265625
] |
While there is a possibility that these Fe-bearing IMC crystals grew because of the rapid coolant quench, their size and distribution indicate that they were already present at the time of quench. The IMCs nucleated in close succession to the α-Al phase, as predicted by the one-axis equivalent phase diagram in Figure 8 . This is shown by the presence of IMC crystals embedded inside dendrites of the α-Al phase. SEM-EDS analysis of the α-Al phase composition along the temperature gradient found no clear trend in the concentration of Fe with decreasing temperature. This suggests that although Fe has a stabilising effect on the liquidus temperature of the α-Al phase, Fe only has limited solubility in the α-Al dendrites and remains mostly within the interdendritic liquid. This is verified using synchrotron XFM in the following section of this paper. It was noted that the highest concentrations of dissolved Fe occurred in the higher-temperature regions of the directionally solidified sample, consistent with Setargew et al.’s prediction of decreasing equilibrium concentration with decreasing temperature, leading to the segregation of Fe out of solution.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278987_p15
|
PMC11278987
|
sec[2]/sec[0]/p[2]
|
3.1. Directional Solidification
| 3.583984 |
biomedical
|
Study
|
[
0.79736328125,
0.0006456375122070312,
0.2020263671875
] |
[
0.99462890625,
0.005069732666015625,
0.0003650188446044922,
0.00007832050323486328
] |
The τ 6 phase was predicted by the Thermo-Calc one-axis equivalent phase diagram, shown in Figure 8 , to occur below 550 °C at a 0.4 wt% Fe concentration. Likewise, the τ 5 phase is predicted to occur prior to the initial nucleation of the α-Al phase, and according to Gorny et al. , either undergoes a peritectic transformation into the τ 6 phase or remains suspended in solution.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278987_p16
|
PMC11278987
|
sec[2]/sec[0]/p[3]
|
3.1. Directional Solidification
| 3.351563 |
biomedical
|
Study
|
[
0.68212890625,
0.00086212158203125,
0.31689453125
] |
[
0.99560546875,
0.004276275634765625,
0.00024008750915527344,
0.00008916854858398438
] |
Crystals of the τ 5c phase were observed in the high-temperature (480–600 °C) region of the sample amidst the recently solidified α-Al phase, as seen in Figure 9 . The τ 5 c phase was observed in the absence of the similar τ 6 phase, confirming that its formation preceded that of both the α-Al phase and the τ 6 phase. The cubic τ 5c phase was largely observed to diffuse through the solidified microstructure via the interdendritic liquid, like the τ 6 phase.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p17
|
PMC11278987
|
sec[2]/sec[0]/p[4]
|
3.1. Directional Solidification
| 2.892578 |
biomedical
|
Study
|
[
0.63037109375,
0.0009274482727050781,
0.36865234375
] |
[
0.97412109375,
0.025146484375,
0.00037479400634765625,
0.0001951456069946289
] |
Although the τ 6 phase typically has the appearance of a needle-like morphology, there have been instances where it has been observed with a broader-faceted morphology, not unlike the morphology of the divorced τ 5c crystals. This is taken as evidence that in three-dimensional space, the τ 6 phase has a flake-like morphology. In Figure 9 b, a perpendicular interaction of two τ 6 flakes, verified by SEM-EDS, is observed, supporting this observation.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p18
|
PMC11278987
|
sec[2]/sec[0]/p[5]
|
3.1. Directional Solidification
| 3.974609 |
biomedical
|
Study
|
[
0.8427734375,
0.0005688667297363281,
0.1568603515625
] |
[
0.99755859375,
0.001804351806640625,
0.00042057037353515625,
0.00005507469177246094
] |
Although the τ 5c phase was observed in a Chinese script morphology in Tong et al.’s work, it was only observed in a faceted divorced microstructure. It was shown by Awano and Shimizu that the morphology of the resultant Fe-based IMCs can be dependent on the degree of superheat applied to Al–Si alloys before cooling, with increasing superheat associated with a higher abundance of Chinese script-like morphologies. A 750 °C superheating temperature was used by Tong et al. , resulting in a corresponding abundance of faceted/needle-like and Chinese-script morphologies. All Fe-based IMCs found in the directionally solidified sample analysed contained a mixture of needle-like or faceted microstructures with no Chinese script, indicating that the level of superheating was low.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278987_p19
|
PMC11278987
|
sec[2]/sec[0]/p[6]
|
3.1. Directional Solidification
| 3.128906 |
other
|
Study
|
[
0.306884765625,
0.0008797645568847656,
0.6923828125
] |
[
0.8095703125,
0.1883544921875,
0.0017986297607421875,
0.0004792213439941406
] |
For directionally solidified samples, the resultant microstructure of the final structure is heavily dependent on the ratio of the temperature gradient applied ( G ) to the growth rate ( V ), which is approximated as the rate of furnace movement. This ratio ( G / V ) can also be used to determine the transition point for constitutional undercooling at the LSB, using the expression provided by Stefanescu . (2) G V ≥ m L C 0 1 − k D L ,
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278987_p20
|
PMC11278987
|
sec[2]/sec[0]/p[7]
|
3.1. Directional Solidification
| 4.078125 |
biomedical
|
Study
|
[
0.9638671875,
0.0004069805145263672,
0.03594970703125
] |
[
0.9990234375,
0.0009603500366210938,
0.0001475811004638672,
0.00003987550735473633
] |
The temperature gradient of −6150 K/m and pull rate of 8.33 × 10 − 6 m/s results in a G / V ratio of −7.38 × 10 8 Ks/m 2 . The precise calculation of the right-hand-side of the equation in a quaternary alloy such as Al–Zn–Mg–Si is out of the scope for this paper—hence, approximations may be used instead by looking at the range of possible values for the concentration C 0 , diffusivity D L , liquidus slope m L and partition coefficient k for the primary constituent binary system, namely Al–Zn. The value for the right-hand-side of the equation was calculated using the values for the Al–Zn binary system in Table 2 and was found to be equal to −5.372 × 10 4 Ks/m 2 .
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278987_p21
|
PMC11278987
|
sec[2]/sec[0]/p[8]
|
3.1. Directional Solidification
| 4.078125 |
biomedical
|
Study
|
[
0.98779296875,
0.00032639503479003906,
0.01165771484375
] |
[
0.9990234375,
0.0007953643798828125,
0.00014531612396240234,
0.00003743171691894531
] |
The difference in magnitudes of the left-hand-side and right-hand-side of the equation suggests that there is a high energy barrier for crystal growth. This corresponds to the high degree of segregation seen in solvents, including Fe, from the liquid phase during cooling, suggesting that the Al–Zn–Mg–Si alloy has high sensitivity to the cooling rate and Fe content. Gravity is another aspect that should be taken into consideration for this variety of DS experiment, as the sample is held vertically without stirring for an extended period. However, the nucleation of the τ 5c phase from the wall of the tube into the centre of the sample has been observed to be slow enough that diffusion of IMCs due to gravity was not an issue in the scope of this paper. From a practical perspective, if Fe content in the alloy cannot be controlled due to continued deposition from the steel sheet, some formation of these IMCs will be inevitable.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278987_p22
|
PMC11278987
|
sec[2]/sec[1]/p[0]
|
3.2. Synchrotron XFM
| 1.982422 |
biomedical
|
Study
|
[
0.87841796875,
0.0013284683227539062,
0.12005615234375
] |
[
0.74609375,
0.25048828125,
0.0025577545166015625,
0.000980377197265625
] |
Although the presence and solidification order of the τ 5c and τ 6 Fe-containing IMCs have been confirmed via prior studies, further work on the distribution of Fe in the liquid phase can still be undertaken.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278987_p23
|
PMC11278987
|
sec[2]/sec[1]/p[1]
|
3.2. Synchrotron XFM
| 4.265625 |
biomedical
|
Study
|
[
0.9912109375,
0.0005788803100585938,
0.00829315185546875
] |
[
0.99951171875,
0.0002818107604980469,
0.0003039836883544922,
0.00004982948303222656
] |
Using synchrotron XFM, the distribution of Fe can be measured in directionally solidified samples to observe their distribution. In Figure 10 , the concentration of Fe in the liquid at the LSB is observed to be consistent; however, much higher concentrations of Fe can be observed between primary α-Al phase dendrite arms, as seen in Figure 11 . It is believed that as the α-Al dendrites solidify from the liquid, Fe is segregated into the liquid and becomes concentrated in areas of small dendrite arm spaces. This is supported by the positive concentration gradient for Fe radially from the centre of each α-Al dendrite, observed in Figure 11 . It is through this that Fe concentrations reach high enough levels for the τ 6 IMC to form. A high cooling rate applied to the liquid phase during the quench may result in the microsegregation of Fe out of solution to form the fine τ 6 needles of less than 50 μm in length. The proposed IMC formation mechanism due to the microsegregation of Fe during cooling is supported by Gorny et al. and Christian , who suggested that Al–Fe–Si-based IMCs in the Al–Fe–Si systems often nucleate on the primary α-Al phase due to their favourable lattice matching. The presence of these fine τ 6 particles shows that the τ 5 phase formed from the precipitated Fe can bypass the reaction with trace transition metals to form τ 6 instead of τ 5c by rapidly being cooled. It is thought that the presence of an α-Al dendrite network helps to raise the local concentration of Fe to encourage the formation of the τ 5 phase. Although the level of Zn in these interdendritic pockets is also higher, it is believed that the formation of an τ 5c (Zn) IMC is bypassed during solidification, as suggested by Gorny et al. .
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278987_p24
|
PMC11278987
|
sec[2]/sec[1]/p[2]
|
3.2. Synchrotron XFM
| 4.292969 |
biomedical
|
Study
|
[
0.98876953125,
0.0006017684936523438,
0.01045989990234375
] |
[
0.99951171875,
0.00038504600524902344,
0.0002818107604980469,
0.000055789947509765625
] |
The peritectic reaction between the τ 5 phase and liquid could only be valid for the formation of the τ 6 phase as the τ 5c phase is known to form before a network of α-Al phases is grown from the liquid. This suggests that the τ 5c phase can also nucleate heterogeneously from an Fe-rich environment—in the case of the experimental samples, this surface is the wall of the stainless-steel sample tube, or Fe-rich liquid. Reduced τ 5c formation was observed between the wall and the alloy in samples where the inside of the tube had been coated using boron nitride, supporting this theory. It should be noted, however, that Tong found τ 5c in bulk samples despite a lack of an Fe-rich interface to nucleate on. It should be established that the τ 5 c particles that form between the wall and the alloy have a different morphology and composition to that which forms between α-Al dendrites. The phase that forms against the wall of the tube is τ 5c Al 8 Fe 2 Si (Cr), whereas the phase that forms in the interdendritic area is τ 5c Al 8 Fe 2 Si (Zn). Gorny et al. noted that the cooling rate as well as Fe content had a strong influence on the IMCs formed in Al–Si alloys, with higher cooling rates increasing the likelihood of the transformation from τ 5 to τ 6 . This partially agrees with the high cooling rate induced by the quench in refrigerated coolant resulting in a microstructure containing a mixture of both τ 6 and τ 5c . It is likely that the evolution from τ 5 to τ 5c is responsible for its continued existence below the minimum temperature predicted by Figure 8 , as the extra stability granted by its cubic structure has prevented it from participating in the peritectic reaction with the liquid to form more τ 6 . EDS analysis has been unable to detect the presence of the τ 5 phase without modification, suggesting that the transformation from τ 5 to τ 5 c occurs in most incidences.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p25
|
PMC11278987
|
sec[2]/sec[1]/p[3]
|
3.2. Synchrotron XFM
| 4.238281 |
biomedical
|
Study
|
[
0.97216796875,
0.0007658004760742188,
0.0270843505859375
] |
[
0.99951171875,
0.0003426074981689453,
0.00023448467254638672,
0.00004756450653076172
] |
In the lower-temperature region seen in Figure 12 , the τ 6 phase has been found to intersect with fully formed α-Al dendrites, confirming that it forms in close succession with the α-Al phase as predicted by the cooling curve analysis. Finer τ 6 needles of approximately 50 μm in length can still be observed in the interdendritic liquid, resulting from the rapid quenching of the remaining liquid. The distribution of Fe becomes almost fully concentrated within the IMCs and only low concentrations are found in the interdendritic liquid, consistent with the exponential solubility relationship derived by . This supports that Fe may have a stabilising effect on the Al-rich region of the Al–Fe binary system , with increasing Fe content causing the α-Al phase to nucleate at a lower temperature. There is a broader distribution of Fe in the liquid, where it is believed to help suppress the formation of α-Al. However, the concentration of Fe detected in the liquid region of the sample is shown to be up to 3 wt%, far exceeding the equilibrium concentration. This can be attributed to the rapid formation of IMCs during the quenching process, quantitative EDS of the liquid region has found that the average Fe concentration remains close to the equilibrium value. Average SEM-EDS mapping of the liquid (excluding any IMCs) has found the Fe concentration to remain close to or below the nominal 0.4 wt%, supporting the gradual segregation of Fe out of the liquid phase where it goes on to react and form IMCs.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p26
|
PMC11278987
|
sec[2]/sec[1]/p[4]
|
3.2. Synchrotron XFM
| 2.289063 |
biomedical
|
Study
|
[
0.62646484375,
0.0015077590942382812,
0.3720703125
] |
[
0.7861328125,
0.2115478515625,
0.0014829635620117188,
0.0007367134094238281
] |
In the lower-temperature region, it can be observed that the τ 6 phase maintains good stability and persists with decreasing temperature. Fe solubility has decreased to the point that very little is still present in the interdendritic liquid, and most of the Fe is now contained in IMCs.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p27
|
PMC11278987
|
sec[2]/sec[1]/p[5]
|
3.2. Synchrotron XFM
| 4.054688 |
biomedical
|
Study
|
[
0.92919921875,
0.0006151199340820312,
0.07025146484375
] |
[
0.99853515625,
0.001308441162109375,
0.0001652240753173828,
0.000052809715270996094
] |
The XFM spectra for the nominal 0.4 wt% Fe-containing Al–Zn–Mg–Si sample in Figure 13 shows strong peaks for Fe and Zn, as well as a peak for Cr that originates from the stainless-steel tube wall. The prevalence of this τ 5c (Cr) throughout the temperature range shows that by evolving to this cubic structure, it has been prevented from being transformed into the τ 6 phase. The implications of this are that the formation of the τ 5c phase is sensitive to trace transition-metal additions in the coating bath, which are unavoidable. Without the formation of the τ 5c phase, τ 5 would be free to undergo the peritectic reaction to form τ 6 . However, it could be argued that the concentration of the τ 5c phase along the edges of the stainless-steel tube is related to the faster cooling rate experienced by the outside of the sample.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278987_p28
|
PMC11278987
|
sec[2]/sec[1]/p[6]
|
3.2. Synchrotron XFM
| 4.179688 |
biomedical
|
Study
|
[
0.97705078125,
0.0007386207580566406,
0.0223846435546875
] |
[
0.99951171875,
0.0002510547637939453,
0.00019752979278564453,
0.000041484832763671875
] |
A scan was taken of the composition of the DS sample used in the XFM experiments to study the quantitative distribution of Fe in the LSB in Figure 14 . The first finding of note was that the quantity of Fe increased significantly over areas of liquid compared to the solid α-Al phase, and the Fe content was generally found to increase in the direction of dendrite growth. Measurements were also taken in only the liquid region along the direction of growth, and it was found that the average Fe content in the liquid was approximately 0.90 at. %. Although this was still higher than that interior of α-Al dendrites, the Fe content of the liquid phase immediately adjoining an α-Al dendrite was found to be 1.00 at. % and decreased with the distance from the dendrite to the equilibrium concentration found in the liquid. This suggests that even in these early stages of solidification, there is a high degree of partitioning of Fe out from the solid phase. The line scan taken along the direction of growth traversing several α-Al dendrites and the interdendritic liquid pockets between them found that the Fe content between the dendrites increased to as much as 1.60 at. %. This suggests that the conditions the Fe-bearing-phase IMC required to nucleate coincide with a high degree of partitioning, and although the homogenous nucleation of Fe-bearing IMCs in the liquid, such as the smaller τ 6 phase growths observed in the quenched interdendritic liquid, has been observed, nucleation is far more likely when Fe concentrations are highest between dendrite arms.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p29
|
PMC11278987
|
sec[2]/sec[1]/p[7]
|
3.2. Synchrotron XFM
| 4.21875 |
biomedical
|
Study
|
[
0.96435546875,
0.0009326934814453125,
0.034576416015625
] |
[
0.9990234375,
0.00040435791015625,
0.00031685829162597656,
0.00004756450653076172
] |
In Figure 14 , the trend of both Fe and Zn content falling across α phase dendrites can be observed, with a sharp rise across areas of quenched liquid. The concentration is lowest at the middle of the dendrite due to interface layer effects and the active rejection of solutes during solidification. Although the concentrations of Zn and Fe differ greatly in magnitude, the peaks and valleys of the line scan in Figure 14 still show that they share the same trends across α -phase dendrites and the quenched liquid. There is an exception circled in Figure 14 ; however, analysis of the backscattered SEM image indicates that the discrepancy is most likely caused by a small Fe-bearing IMC particle in the liquid. An interesting observation is that from the LHS (cooler end) to the RHS (hotter end) of the graph, the average concentration of both Fe and Zn can be observed to increase across the positive temperature gradient. This is contrary to the Al–Fe and Al–Zn phase diagrams, which predict the solubility of Fe and Zn in Al to decrease with temperature . It is possible then that the concentration gradient observed is a result of constitutional undercooling, which is known to create favourable conditions for the nucleation of new phases, especially Fe-bearing IMCs. The exception to this trend, observed in Figure 14 , is at the transition from the final α -phase dendrite to the liquid: although the Zn concentration continues to increase according to the measured trend, the Fe concentration decreases sharply in the quenched liquid beyond the solidified dendrite network. This may be explained either by an error in measurement due to the relatively low concentration of Fe in the alloy, or by reviewing the Al-rich corner of the Al–Fe binary phase diagram , which shows the solubility of Fe decreasing with increasing temperature below 1.7 wt% Fe, due to the existence of a eutectic point. Hence, it can be speculated that during the cooling of the alloy, initially, the Fe concentration in the liquid decreases, but following this eutectic point, it will increase again to concentrations that may permit the homogenous nucleation of fine Fe-bearing IMC phases.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278987_p30
|
PMC11278987
|
sec[2]/sec[1]/p[8]
|
3.2. Synchrotron XFM
| 4.164063 |
biomedical
|
Study
|
[
0.9619140625,
0.0005207061767578125,
0.03759765625
] |
[
0.9990234375,
0.0008864402770996094,
0.0001996755599975586,
0.000045359134674072266
] |
It is known that the τ 5 c phase contains 31.91 at. % Fe and the τ 6 phase contains 27.20 at. % Fe , which is considerably greater than the nominal Fe concentration of 0.4 wt%. Analysis of the XFM spectra indicates that in both high- and medium-temperature regions, corresponding to the theoretical respective nucleation temperature ranges of these two phases, there are no pockets of interdendritic liquid showing concentrations of Fe equal to or higher than the atomic mass of Fe in the Fe-bearing intermetallics. It can therefore be speculated that the heterogenous nucleation of these IMCs is largely necessary, and that even with the maximum equilibrium concentration of bath Fe, homogenous nucleation is difficult. The exception to this is the formation of fine τ 6 in the quenched liquid, but this may be explained by the rapid microsegregation of Fe within the fine α − Al dendrite network of the quenched liquid.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p31
|
PMC11278987
|
sec[2]/sec[1]/p[9]
|
3.2. Synchrotron XFM
| 3.603516 |
biomedical
|
Study
|
[
0.994140625,
0.0002689361572265625,
0.00580596923828125
] |
[
0.99755859375,
0.0022144317626953125,
0.0001647472381591797,
0.00006115436553955078
] |
The right half of Figure 14 also shows that as the measurement area moves away from the dendritic network, the Fe content drops significantly with the distance from the α Al dendrites, supporting the notion that the dendritic network helps to concentrate Fe and that the average concentration of Fe in the liquid is low compared to the space between dendrites.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278987_p32
|
PMC11278987
|
sec[2]/sec[1]/p[10]
|
3.2. Synchrotron XFM
| 2.478516 |
biomedical
|
Study
|
[
0.978515625,
0.0009317398071289062,
0.0204925537109375
] |
[
0.634765625,
0.362548828125,
0.0016269683837890625,
0.0008745193481445312
] |
Areas in measurement where the concentration does not seem to correspond to the microstructure are believed to be a result of IMC inclusions, as the microstructure is not entirely homogeneous.
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278987_p33
|
PMC11278987
|
sec[3]/p[0]
|
4. Conclusions
| 2.101563 |
biomedical
|
Study
|
[
0.56591796875,
0.0013866424560546875,
0.4326171875
] |
[
0.76513671875,
0.2332763671875,
0.0009293556213378906,
0.0008139610290527344
] |
By using directional solidification to generate samples of the Al–Zn–Mg–Si alloy and analysing them using SEM EDS and synchrotron XFM, it was discovered that
|
[
"He Tian",
"Dongdong Qu",
"Nega Setargew",
"Daniel J. Parker",
"David J. Paterson",
"David StJohn",
"Kazuhiro Nogita"
] |
https://doi.org/10.3390/ma17143583
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278999_p0
|
PMC11278999
|
sec[0]/p[0]
|
1. Introduction
| 3.767578 |
biomedical
|
Review
|
[
0.912109375,
0.0025768280029296875,
0.08544921875
] |
[
0.0176849365234375,
0.0048828125,
0.97705078125,
0.00022709369659423828
] |
The increasing interest in biomass-to-char conversion stems from a confluence of factors: economic incentives, sustainability imperatives, and a rising demand . The transformation of lignocellulosic biomass waste into char is particularly appealing in addressing solid waste management, reducing raw material costs, and offering tailor-made properties for diverse applications. Bio-based char, with its carbon-rich composition, exhibits distinctive chemical, physical, and biological characteristics, depending on the carbonization technologies used in its production . It is therefore an excellent candidate for various applications, including soil quality improvement, environmental remediation, enzyme immobilization, and sensing . New materials derived from bio-based chars are also gaining attention for catalytic applications, as recently reviewed by Lyu et al. , Lee et al. , Xiong et al. , and Cao et al. amongst others.
|
[
"Assunta Marrocchi",
"Elisa Cerza",
"Suhas Chandrasekaran",
"Emanuela Sgreccia",
"Saulius Kaciulis",
"Luigi Vaccaro",
"Suanto Syahputra",
"Florence Vacandio",
"Philippe Knauth",
"Maria Luisa Di Vona"
] |
https://doi.org/10.3390/molecules29143286
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278999_p1
|
PMC11278999
|
sec[0]/p[1]
|
1. Introduction
| 4.050781 |
biomedical
|
Study
|
[
0.552734375,
0.0015192031860351562,
0.44580078125
] |
[
0.75732421875,
0.0190582275390625,
0.2232666015625,
0.0004189014434814453
] |
For most of the current renewable energies, even if well established, there is a need to mitigate the production costs and minimize the use of raw materials. In this context, bio-based char has demonstrated potential applications in renewable energy conversion and storage, as recently reported, particularly in microbial fuel cells, supercapacitors, and batteries (metal–ion and metal–air) . In recent years, there has been notable interest in the utilization of hydrothermal carbonization (HTC) for converting biomass waste into valuable carbonaceous materials . This method has garnered attention due to its capability to produce hydrochars (HCs) with desirable characteristics that enhance their efficient utilization across various applications, particularly in the materials domain . Hydrothermal carbonization is an eco-friendly thermochemical conversion method utilizing subcritical water to convert wet or dry biomass into carbonaceous products by fractionating the feedstock. The carbonization temperature is moderate, typically in the range of 180–300 °C and depends on the starting materials and their decomposition temperatures. This process effectively hydrolyzes and dehydrates biomass, resulting in hydrochars with a substantial content of oxygenated functional groups, contributing to a richer surface chemistry compared to pyrochars . Moreover, HTC has the capability to leach inorganic elements into the liquid phase, reducing the ash content . While significant advancements have been made, a hydrochar is a relatively new type of bio-based char compared to established options like pyrochars. This means that there is a smaller pool of existing research and a less complete understanding of its properties and applications, necessitating further research to unlock its full potential.
|
[
"Assunta Marrocchi",
"Elisa Cerza",
"Suhas Chandrasekaran",
"Emanuela Sgreccia",
"Saulius Kaciulis",
"Luigi Vaccaro",
"Suanto Syahputra",
"Florence Vacandio",
"Philippe Knauth",
"Maria Luisa Di Vona"
] |
https://doi.org/10.3390/molecules29143286
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278999_p2
|
PMC11278999
|
sec[0]/p[2]
|
1. Introduction
| 4.070313 |
biomedical
|
Study
|
[
0.9931640625,
0.00037169456481933594,
0.00655364990234375
] |
[
0.9560546875,
0.003200531005859375,
0.040618896484375,
0.00012981891632080078
] |
N-doping of nitrogen-poor feedstocks introduces N-containing functional groups into the carbon framework from an external source. These nitrogen species may influence the electrochemical properties, the surface chemistry, the surface charge, and the surface wettability of the hydrochar, which can further influence the catalytic performance . Different methods have been employed to introduce nitrogen into a carbon framework via thermochemical processes . Notably, it has been demonstrated that nitrogen-containing compounds can deeply penetrate the biomass structure under HTC conditions . This phenomenon facilitates the increased nitrogen integration within the bulk of the resulting hydrochar, thereby tuning the potential impacts on the electrochemical properties. Currently, the exploration of heteroatom-doped carbon is in its early stages, underscoring the need for further dedicated efforts for guiding the future endeavours in material design.
|
[
"Assunta Marrocchi",
"Elisa Cerza",
"Suhas Chandrasekaran",
"Emanuela Sgreccia",
"Saulius Kaciulis",
"Luigi Vaccaro",
"Suanto Syahputra",
"Florence Vacandio",
"Philippe Knauth",
"Maria Luisa Di Vona"
] |
https://doi.org/10.3390/molecules29143286
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278999_p3
|
PMC11278999
|
sec[0]/p[3]
|
1. Introduction
| 3.707031 |
biomedical
|
Study
|
[
0.962890625,
0.0005517005920410156,
0.036468505859375
] |
[
0.99853515625,
0.0010805130004882812,
0.00037741661071777344,
0.0000616908073425293
] |
In this context, we investigated the catalytic properties of nitrogen (N)-doped hydrochars derived from the HTC of pine needle waste, for two electrochemical reactions with environmental relevance: oxygen reduction (ORR) and carbon dioxide reduction (CO 2 RR). To the best of our knowledge, the utilization of hydrochars for the fabrication of electrodes for these reactions is poor in the existing literature . On the other hand, strategies enhancing the greenness of electrode materials are crucial for developing materials planned with a ‘benign by design’ approach.
|
[
"Assunta Marrocchi",
"Elisa Cerza",
"Suhas Chandrasekaran",
"Emanuela Sgreccia",
"Saulius Kaciulis",
"Luigi Vaccaro",
"Suanto Syahputra",
"Florence Vacandio",
"Philippe Knauth",
"Maria Luisa Di Vona"
] |
https://doi.org/10.3390/molecules29143286
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278999_p4
|
PMC11278999
|
sec[0]/p[4]
|
1. Introduction
| 2.580078 |
biomedical
|
Study
|
[
0.92578125,
0.0007081031799316406,
0.07342529296875
] |
[
0.6953125,
0.29052734375,
0.01328277587890625,
0.00074005126953125
] |
In basic conditions, the ORR has a faster kinetic and was demonstrated to be feasible on various carbon-based electrocatalysts without the addition of critical raw materials . Some papers report the use of biomass-derived carbons as electrocatalysts pointing out the importance of the selection of biomass resources and synthesis procedures .
|
[
"Assunta Marrocchi",
"Elisa Cerza",
"Suhas Chandrasekaran",
"Emanuela Sgreccia",
"Saulius Kaciulis",
"Luigi Vaccaro",
"Suanto Syahputra",
"Florence Vacandio",
"Philippe Knauth",
"Maria Luisa Di Vona"
] |
https://doi.org/10.3390/molecules29143286
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278999_p5
|
PMC11278999
|
sec[0]/p[5]
|
1. Introduction
| 3.308594 |
biomedical
|
Study
|
[
0.7333984375,
0.0007047653198242188,
0.26611328125
] |
[
0.681640625,
0.31396484375,
0.00392913818359375,
0.0004487037658691406
] |
The CO 2 RR is a process of considerable interest due to its capacity to address the environmental concerns related to CO 2 emissions and to contribute to the development of greenhouse gas (GHG) neutral sustainable energy systems. An added value is the conversion of CO 2 into valuable products including hydrocarbons, formic acid, and multi-carbon products . In all cases, the presence of anion exchange ionomers (AEIs) in the catalyst layers, required for the hydroxide ion transport, is paramount for high electrocatalytic performance .
|
[
"Assunta Marrocchi",
"Elisa Cerza",
"Suhas Chandrasekaran",
"Emanuela Sgreccia",
"Saulius Kaciulis",
"Luigi Vaccaro",
"Suanto Syahputra",
"Florence Vacandio",
"Philippe Knauth",
"Maria Luisa Di Vona"
] |
https://doi.org/10.3390/molecules29143286
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278999_p6
|
PMC11278999
|
sec[0]/p[6]
|
1. Introduction
| 2.220703 |
biomedical
|
Other
|
[
0.720703125,
0.0014295578002929688,
0.278076171875
] |
[
0.368408203125,
0.6279296875,
0.0030536651611328125,
0.0008025169372558594
] |
The adoption of the HTC process could enable the fabrication of ORR and CO 2 RR electrocatalysts with much lower environmental impact showing comparable performance as the state-of-the-art materials.
|
[
"Assunta Marrocchi",
"Elisa Cerza",
"Suhas Chandrasekaran",
"Emanuela Sgreccia",
"Saulius Kaciulis",
"Luigi Vaccaro",
"Suanto Syahputra",
"Florence Vacandio",
"Philippe Knauth",
"Maria Luisa Di Vona"
] |
https://doi.org/10.3390/molecules29143286
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |