bluuebunny/crossref_metadata_2025_split huggingface dataset:
A PD-1/PD-L1 Proximity Assay as a Theranostic Marker for PD-1 Blockade in Patients with Metastatic Melanoma
Authors: Girault Isabelle , Adam Julien , Shen Shensi , Roy Séverine , Brard Caroline , Faouzi Sara , Routier Emilie , Lupu Jéremy , Warren Sarah , Sorg Kristina , Ong SuFey , Morel Pascale , Scoazec Jean-Yves , Vagner Stéphan , Robert Caroline 
Published: November 2021

AbstractPurpose:Less than 50% of patients with melanoma respond to anti–programmed cell death protein 1 (anti–PD-1), and this treatment can induce severe toxicity. Predictive markers are thus needed to improve the benefit/risk ratio of immune checkpoint inhibitors (ICI). Baseline tumor parameters such as programmed death ligand 1 (PD-L1) expression, CD8+ T-cell infiltration, mutational burden, and various transcriptomic signatures are associated with response to ICI, but their predictive values are not sufficient. Interaction between PD-1 and its main ligand, PD-L1, appears as a valuable target of anti–PD-1 therapy. Thus, instead of looking at PD-L1 expression only, we evaluated the predictive value of the proximity between PD-1 and its neighboring PD-L1 molecules in terms of response to anti–PD-1 therapy.Experimental Design:PD-1/PD-L1 proximity was assessed by proximity ligation assay (PLA) on 137 samples from two cohorts (exploratory n = 66 and validation n = 71) of samples from patients with melanoma treated with anti–PD-1±anti–CTLA-4. Additional predictive biomarkers, such as PD-L1 expression (MELscore), CD8+ cells density, and NanoString RNA signature, were also evaluated.Results:A PD-1/PD-L1 PLA model was developed to predict tumor response in an exploratory cohort and further evaluated in an independent validation cohort. This score showed higher predictive ability (AUC = 0.85 and 0.79 in the two cohorts, respectively) for PD-1/PD-L1 PLA as compared with other parameters (AUC = 0.71–0.77). Progression-free and overall survival were significantly longer in patients with high PLA values (P = 0.00019 and P &lt; 0.0001, respectively).Conclusions:The proximity between PD-1 and PD-L1, easily assessed by this PLA on one formalin-fixed paraffin-embedded section, appears as a new biomarker of anti–PD-1 efficacy.
Multi-scale Pan-cancer Integrative Analyses Identify the STAT3-VSIR Axis as a Key Immunosuppressive Mechanism in Head and Neck Cancer
Authors: Katabathula Ramachandra , Joseph Peronne , Singh Salendra , Zhao Songzhu , Kumar Bhavna , Gaule Patricia , Pan Quintin , Old Matthew , Tuck David P. , Varadan Vinay 
Published: November 2021

Abstract

Purpose:
VSIR is a novel immune checkpoint protein whose expression on tumor cells across cancers remains largely uncharacterized. Here we purposed to decode the pan-cancer biologic and clinical significance of VSIR overexpression in the tumor compartment.

Experimental Design:
We performed multi-omics integrative analyses of 9,735 tumor samples to identify cancers with non-leukocytic expression of VSIR (VSIR High), followed by association with overall survival and immune cell infiltration levels. Orthogonal assessments of VSIR protein expression and lymphocytic infiltration were performed using quantitative immunofluorescence (QIF).

Results:
Integrative modeling identified a subset of cancer types as being enriched for VSIR High tumors. VSIR High tumors were associated with significantly poorer overall survival in immunogenic ovarian serous adenocarcinoma (SA) and oral cavity squamous cell carcinoma (SCC). QIF assessments in an independent validation cohort confirmed overexpression of VSIR as being associated with poorer overall survival within immunogenic oral cavity SCC. VSIR overexpression was associated with lower CD4 helper T-cell infiltration in both ovarian SA and oral cavity SCC, but did not impact CD8 T-cell infiltration. VSIR overexpressing tumors in both cancer types exhibited significantly higher STAT3 signaling activity. Pharmacologic inhibition of STAT3 signaling resulted in dose-dependent reduction of VSIR expression in ovarian SA and oral cavity SCC cells.

Conclusions:
The STAT3-VSIR axis is a potentially significant immunomodulatory mechanism in oral cavity and ovarian cancers, whose activation is associated with poorer survival and an immune microenvironment marked by decreased CD4 helper T-cell activity. The role of VSIR as a tumor-intrinsic modulator of resistance to immunotherapy warrants further exploration.
Agrin Loss in Barrett's Esophagus-Related Neoplasia and Its Utility as a Diagnostic and Predictive Biomarker
Authors: Rickelt Steffen , Neyaz Azfar , Condon Charlene , Whittaker Charles A. , Zaidi Ali H. , Taylor Martin S. , Abbruzzese Genevieve , Mattia Anthony R. , Zukerberg Lawrence , Shroff Stuti G. , Yilmaz Omer H. , Yilmaz Osman , Wu Elizabeth Y. , Choi Won-Tak , Jobe Blair A. , Odze Robert D. , Patil Deepa T. , Deshpande Vikram , Hynes Richard O. 
Published: November 2021

Abstract

Purpose:
There is an unmet need for identifying novel biomarkers in Barrett's esophagus that could stratify patients with regards to neoplastic progression. We investigate the expression patterns of extracellular matrix (ECM) molecules in Barrett's esophagus and Barrett's esophagus–related neoplasia, and assess their value as biomarkers for the diagnosis of Barrett's esophagus–related neoplasia and to predict neoplastic progression.

Experimental Design:
Gene-expression analyses of ECM matrisome gene sets were performed using publicly available data on human Barrett's esophagus, Barrett's esophagus–related dysplasia, esophageal adenocarcinoma (ADCA) and normal esophagus. Immunohistochemical expression of basement membrane (BM) marker agrin (AGRN) and p53 was analyzed in biopsies of Barrett's esophagus–related neoplasia from 321 patients in three independent cohorts.

Results:
Differential gene-expression analysis revealed significant enrichment of ECM matrisome gene sets in dysplastic Barrett's esophagus and ADCA compared with controls. Loss of BM AGRN expression was observed in both Barrett's esophagus–related dysplasia and ADCA. The mean AGRN loss in Barrett's esophagus glands was significantly higher in Barrett's esophagus–related dysplasia and ADCA compared with non-dysplastic Barrett's esophagus (NDBE; P &lt; 0.001; specificity = 82.2% and sensitivity = 96.4%). Loss of AGRN was significantly higher in NDBE samples from progressors compared with non-progressors (P &lt; 0.001) and identified patients who progressed to advanced neoplasia with a specificity of 80.2% and sensitivity of 54.8%. Moreover, the combination of AGRN loss and abnormal p53 staining identified progression to Barrett's esophagus–related advanced neoplasia with a specificity and sensitivity of 86.5% and 58.7%.

Conclusions:
We highlight ECM changes during Barrett's esophagus progression to neoplasia. BM AGRN loss is a novel diagnostic biomarker that can identify patients with NDBE at increased risk of developing advanced neoplasia.
Identification of Immunogenic MHC Class II Human HER3 Peptides that Mediate Anti-HER3 CD4+ Th1 Responses and Potential Use as a Cancer Vaccine
Authors: Basu Amrita , Albert Gabriella K. , Awshah Sabrina , Datta Jashodeep , Kodumudi Krithika N. , Gallen Corey , Beyer Amber , Smalley Keiran S.M. , Rodriguez Paulo C. , Duckett Derek R. , Forsyth Peter A. , Soyano Aixa , Koski Gary K. , Lima Barros Costa Ricardo , Han Heather , Soliman Hatem , Lee Marie Catherine , Kalinski Pawel , Czerniecki Brian J. 
Published: November 2021

Abstract
The HER3/ERBB3 receptor is an oncogenic receptor tyrosine kinase that forms heterodimers with EGFR family members and is overexpressed in numerous cancers. HER3 overexpression associates with reduced survival and acquired resistance to targeted therapies, making it a potential therapeutic target in multiple cancer types. Here, we report on immunogenic, promiscuous MHC class II–binding HER3 peptides, which can generate HER3-specific CD4+ Th1 antitumor immune responses. Using an overlapping peptide screening methodology, we identified nine MHC class II–binding HER3 epitopes that elicited specific Th1 immune response in both healthy donors and breast cancer patients. Most of these peptides were not identified by current binding algorithms. Homology assessment of amino acid sequence BLAST showed &gt;90% sequence similarity between human and murine HER3/ERBB3 peptide sequences. HER3 peptide–pulsed dendritic cell vaccination resulted in anti-HER3 CD4+ Th1 responses that prevented tumor development, significantly delayed tumor growth in prevention models, and caused regression in multiple therapeutic models of HER3-expressing murine tumors, including mammary carcinoma and melanoma. Tumors were robustly infiltrated with CD4+ T cells, suggesting their key role in tumor rejection. Our data demonstrate that class II HER3 promiscuous peptides are effective at inducing HER3-specific CD4+ Th1 responses and suggest their applicability in immunotherapies for human HER3-overexpressing tumors.
Echocardiographic and Electrocardiographic Abnormalities Among Elderly Adults With Cardiovascular Disease in Rural South Africa
Authors: Ferro Enrico G. , Abrahams-Gessel Shafika , Jardim Thiago Veiga , Wagner Ryan , Gomez-Olive F. Xavier , Wade Alisha N. , Peters Ferande , Tollman Stephen , Gaziano Thomas A. 
Published: November 2021

Background:
Sub-Saharan Africa is undergoing an epidemiological transition fueled by the interaction between infectious and cardiovascular diseases. Our cross-sectional study aimed to characterize the spectrum of abnormalities suggesting end-organ damage on ECG and transthoracic echocardiograms (TTE) among older adults with cardiovascular diseases in rural South Africa.

Methods:

The prevalence of ECG and TTE abnormalities was estimated; χ
2
analyses and multivariable logistic regressions were performed to test their association with sex, hypertension, and other selected comorbidities.

Results:

Overall, 729 ECGs and 155 TTEs were completed, with 74 participants completing both. ECG evaluation showed high rates of left ventricular hypertrophy (LVH, 36.5%) and T wave abnormalities (13.6%). TTE evaluation showed high rates of concentric LVH (31.6%), with moderate-severe (56.8%) diastolic dysfunction. Participants with hypertension showed more cardiac remodeling on ECG by LVH (45.4% versus 22.1%,
P
<0.01), and TTE by concentric LVH (42.5% versus 8.2%,
P
<0.01) and increased left ventricular mass (58.5% versus 20.4%,
P
<0.0001). In multivariable logistic regression, systolic blood pressure remained significantly associated with LVH on ECG (adjusted odds ratio, 1.03 per mm Hg [95% CI, 1.03–1.04],
P
<0.0001) and increased left ventricular mass on TTE (adjusted odds ratio, 1.04 per mm Hg [95% CI, 1.01–1.06],
P
=0.001). Male participants (n=326, 40.2%) were more likely than females (n=484, 59.8%) to show ECG abnormalities like LVH (45% versus 30.8%,
P
<0.01), whereas females were more likely to show TTE abnormalities like concentric LVH (40.8% versus 13.5%,
P
<0.01) and increased left ventricular mass (58.4% versus 23.1%,
P
<0.0001). Similar results were confirmed in multivariable models.

Conclusions:
Our findings suggest that cardiovascular diseases are widespread in rural South Africa, with a larger burden of hypertensive heart disease than previously appreciated, and define the severity of end-organ damage that is already underway. Local health systems must adapt to face the growing burden of hypertension, as suboptimal rates of hypertension diagnosis and treatment may dramatically increase the heart failure burden.
Survival in Patients With Suspected Myocardial Infarction With Nonobstructive Coronary Arteries: A Comprehensive Systematic Review and Meta-Analysis From the MINOCA Global Collaboration
Authors: Pasupathy Sivabaskari , Lindahl Bertil , Litwin Peter , Tavella Rosanna , Williams Michael J.A. , Air Tracy , Zeitz Christopher , Smilowitz Nathaniel R. , Reynolds Harmony R. , Eggers Kai M. , Nordenskjöld Anna M. , Barr Peter , Jernberg Tomas , Marfella Raffaele , Bainey Kevin , Sodoon Alzuhairi Karam , Johnston Nina , Kerr Andrew , Beltrame John F. 
Published: November 2021

Background:
Suspected myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) occurs in ≈5% to 10% of patients with MI referred for coronary angiography. The prognosis of these patients may differ to those with MI and obstructive coronary artery disease (MI-CAD) and those without a MI (patients without known history of MI [No-MI]). The primary objective of this study is to evaluate the 12-month all-cause mortality of patients with MINOCA.

Methods:

Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the terms “MI,” “nonobstructive,” “angiography,” and “prognosis” were searched in PubMed and Embase databases from inception to December 2018, including original, English language MINOCA studies with >100 consecutive patients. Publications with a heterogeneous cohort, unreported coronary stenosis, or exclusively focusing on MINOCA-mimicking conditions, were excluded. Unpublished data were obtained from the MINOCA Global Collaboration. Data were pooled and analyzed using Paule-Mandel, Hartung, Knapp, Sidik & Jonkman, or restricted maximum-likelihood random-effects meta-analysis methodology. Heterogeneity was assessed using Cochran’s Q and I
2
statistics. The primary outcome was 12-month all-cause mortality in patients with MINOCA, with secondary comparisons to MI-CAD and No-MI.

Results:

The 23 eligible studies yielded 55 369 suspected MINOCA, 485 382 MI-CAD, and 33 074 No-MI. Pooled meta-analysis of 14 MINOCA studies accounting for 30 733 patients revealed an unadjusted 12-month all-cause mortality rate of 3.4% (95% CI, 2.6%–4.2%) and reinfarction (n=27 605; 10 studies) in 2.6% (95% CI, 1.7%–3.5%). MINOCA had a lower 12-month all-cause mortality than those with MI-CAD (3.3% [95% CI, 2.5%–4.1%] versus 5.6% [95% CI, 4.1%–7.0%]; odds ratio, 0.60 [95% CI, 0.52–0.70],
P
<0.001). In contrast, there was a statistically nonsignificant trend towards increased 12-month all-cause mortality in patients with MINOCA (2.6% [95% CI, 0%–5.9%]) compared with No-MI (0.7% [95% CI, 0.1%–1.3%]; odds ratio, 3.71 [95% CI, 0.58–23.61],
P
=0.09).

Conclusions:
In the largest contemporary MINOCA meta-analysis to date, patients with suspected MINOCA had a favorable prognosis compared with MI-CAD, but statistically nonsignificant trend toward worse outcomes compared to those with No-MI.

Registration:

URL:
https://www.crd.york.ac.uk/PROSPERO/
; Unique identifier: CRD42020145356.
Clinical Efficacy of Intersphincteric Resection for Low Rectal Cancer Compared With Abdominoperineal Resection: A Single-Center Retrospective Study
Authors: He Zijian , Peng Baifu , Chen Wenbin , Zhu JiaDun , Chen BaoQi , Li Guanwei , Cao Jie , Li Wanglin 
Published: November 2021

Background In recent years, intersphincteric resection (ISR) has been increasingly used to replace abdominoperineal resection (APR) in the surgical treatment of ultra-low rectal cancer. Aim This study was to compare the clinical efficacy of ISR and APR. Methods Between 2012 and 2018, 74 consecutive patients with ultra-low rectal cancer underwent ISR or APR in our medical center. A retrospective comparison of these 2 procedures was performed. Results A total of 43 patients underwent ISR and 31 underwent APR were included in the study. No significant differences were found between 2 groups in gender, age, BMI, and ASA score. Intersphincteric resection group showed shorter operative time ( P = .02) and less blood loss ( P = .001). Hospital stays, time to soft diet, and postoperative 30-day complications were not significantly different between the 2 groups. R0 resection achieved 100% in both the groups. As for the long-term outcomes, the survival and recurrence rate were similar between 2 groups. Moreover, the LARS and Wexner score showed that the postoperative anal function after ISR were satisfactory. Conclusion This study suggested that ISR was feasible and safe for selected patients with ultra-low rectal cancer, with clinically superior outcomes in select patients (small tumors/further from the anal verge) and similar oncological outcomes to APR, and the anal functional outcomes after ISR were acceptable.
Arts engagement facilitated by artists with individuals with life-limiting illness: A systematic integrative review of the literature
Authors: Lee Jenny Baxley , McIlfatrick Sonja , Fitzpatrick Lisa 
Published: November 2021

Background: Living with life-limiting illness significantly impacts quality of life. A growing body of evidence suggests that arts engagement facilitated by artists promotes well-being. However, no synthesis of the literature exists to describe arts engagement delivered by artists with individuals receiving palliative care. Aim: To systematically review and synthesize evidence to identify outcomes and key knowledge gaps to inform future research and practice. Design: A systematic integrative literature review was conducted using a pre-defined search strategy and reported using PRISMA guidelines. Analysis was conducted iteratively and synthesis achieved using constant comparison to generate themes. Data sources: PubMed/MEDLINE, CINAHL, PsycINFO, Scopus, Web of Science, and Embase were searched for studies published between database inception and August 2020. Search terms included variations on arts/artists; patients/service users; and palliative or end-of-life care. Eligibility criteria was applied and study quality assessed. Results: Seven reviewed studies explored literary, performing, and visual arts engagement in hospitals, hospice and community settings in England, the United States, France, and Canada. Study designs, interventions and findings were discussed. Themes identified across studies associated arts engagement with (1) a sense of well-being, (2) a newly discovered, or re-framed, sense of self, (3) connection with others, and (4) challenges associated with practice. Conclusion: Recommendations for future research were offered in order to maximize benefits, minimize risks and address complexity of artists’ engagement in palliative care including: (1) consistency in methods and reporting; (2) inclusion of wider perspectives; and (3) key considerations for adapting the arts by health condition and art form.
Comparison of a Vegetable-Based Dental Chew to 2 Other Chews for Oral Health Prevention
Authors: Gawor Jerzy , Jodkowska Katarzyna , Klim Emilia , Jank Michał , Nicolas Celine S. 
Published: November 2021

Giving dental chews to dogs is part of the passive homecare that helps prevent the formation of plaque and tartar. The objectives of these studies were to assess the effectiveness of a vegetable-based dental chew (VF) to maintain oral health, and to compare it to 2 different reference chews (RC) with a proven effectiveness. The first study was conducted on 45 small dogs (<10 kg) and the second on 60 larger dogs (15-30 kg) who were randomly assigned to 3 different groups. During 30 days, one group received no chew (control) while the second and third group received either one RC (RC1 or RC2) or one VF per day. All dogs had their teeth scaled on Day 0. On Day 30, scores were given for plaque and calculus. Gingival parameters were also assessed. Statistical analysis (analysis of variance and Tukey tests ± Bonferroni's adjustment) were performed to compare groups with α set at .05 for significance. The 3 types of chews were found to be efficacious to reduce plaque and calculus formation and the gingival bleeding compared to control ( P < .05). There was no significant difference between RCs and VF in both trials except for the gingival bleeding parameters which showed a greater improvement with VF. Therefore, daily administration of the VF is effective to reduce plaque and calculus formation and gingival bleeding and has a better efficacy on gingival bleeding than the other reference products tested. It can therefore be used with confidence at home for preventative dental care.
Reproduction and Genetic Responsibility: An Interpretive Description of Reproductive Decision-Making for Young People With Li-Fraumeni Syndrome
Authors: Forbes Shepherd Rowan , Werner-Lin Allison , Keogh Louise A. , Delatycki Martin B. , Forrest Laura E. 
Published: November 2021

The reproductive decision-making of young people (aged 15–39 years) with Li-Fraumeni syndrome (LFS), an early onset inherited cancer syndrome, has not been studied in depth. Using interpretive description methodology, we conducted semi-structured interviews with 30 young Australians (mean age 25.5 years) diagnosed with LFS or at 50% genetic risk. With reflexive thematic analysis, we show how young people’s reproductive decision-making and ideals for family formation were shaped by a sense of genetic responsibility to ensure the health of future biological kin. Reproductive technology provided choices for family formation in the context of LFS and also complicated reproductive decisions, as these choices were difficult to understand, make, or carry out. We uphold that reproductive decision-making when living with LFS is a profoundly moral practice that may pose significant challenges for young people navigating their formative years. We offer genetic counseling practice recommendations to support individuals with LFS when making reproductive decisions.
Response with pembrolizumab in a patient with EGFR mutated non-small cell lung cancer harbouring insertion mutations in V834L and L858R
Authors: Hadfield Matthew J. , Turshudzhyan Alla , Shalaby Khalid , Reddy Aswanth 
Published: November 2021

Introduction Lung cancer is the leading cause of cancer-related deaths with non-small cell lung cancer (NSCLC) being the most common of them. About a third of NSCLC cases have an epidermal growth factor (EGFR) mutation, which is usually susceptible to tyrosine kinase inhibitors (TKIs). In rare cases where patients progress through TKI therapy, the use of immune checkpoint inhibitors (ICIs) remains controversial. Case report We describe a case of a patient with significant history of smoking and EGFR mutated programmed death ligand-1 (PD-L1) positive NSCLC who was initially treated with TKI therapy. Management/Outcome While patient progressed on TKI therapy, he was able to achieve a durable response with a single PD-L1 agent, pembrolizumab. Contrary to the available evidence, the presented EGFR mutant NSCLC responded to PD-L1 pathway inhibition. Discussion From our observation Pembrolizumab could be promising in patients with rare EGFR mutations who do not respond to EGFR directed therapy. Our report provides supporting data for the use of immunotherapies in patients with EGFR mutated NSCLC.