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International audience; Background: Acinic cell carcinomas (AciCCs) are malignant tumours of the salivary glands. The aim of this work was to analyse data from the national REFCOR multicenter cohort (i) to investigate the prognostic factors influencing survival outcomes in AciCC, (ii) to assess the impact on survival of postoperative radiotherapy (RT) in patients treated for AciCC without high-grade transformation and (iii) to explore the prognostic impact of prophylactic neck dissection (ND) in patients treated for AciCC of the major salivary glands.Patients and methods: Data from all the patients treated for salivary AciCC between 2009 and 2020 were extracted from the REFCOR database. Survival outcomes and prognostic factors influencing Disease-Free Survival (DFS) and Overall Survival (OS) were investigated using univariate and multivariate analyses. Propensity score matching was used to assess the impact of postoperative RT and prophylactic ND on DFS.Results: A total of 187 patients were included. After a median follow-up of 53 months, their 5-year OS and DFS rates were 92.8% and 76.2%, respectively. In multivariate analysis, male sex, older age, higher T and N status, and high grade were independently associated with a worse DFS. In the subpopulation analysed after propensity score matching, patients with cN0 AciCC without high-grade transformation who were treated by surgery and RT did not have an improved DFS compared to patients who were treated by surgery alone (hazard ratio (HR) = 0.87, p = 0.8). Factors associated with nodal invasion were T3-T4 status and intermediate/high histological grade. After propensity score matching, prophylactic ND was associated with a trend toward a better DFS (HR = 0.46, p = 0.16).Conclusions: These results suggest that (i) long-term follow-up (>5 years) should be considered in patients with AciCC, (ii) treatment by surgery alone could be an option in selected cN0 patients with AciCC without high-grade transformation and (iii) prophylactic ND may be considered preferentially in patients with T3-T4 status and/or intermediate/high histological grade.

As the number of online labor platforms and the diversity of jobs on these platforms increase, ensuring group fairness for workers needs to be the focus of job-matching services. Risk of discrimination against workers occurs in two different job-matching services: when someone is looking for a job (i.e., a job seeker) and when someone wants to deploy jobs (i.e., a job provider). To maximize their chances of getting hired, job seekers submit their profiles on different platforms. Similarly, job providers publish their job offers on multiple platforms with the goal of reaching a wide and diverse workforce. In this paper, we propose a theoretical framework to maximize group fairness for workers 1) when job seekers are looking for jobs on multiple platforms, and 2) when jobs are being deployed by job providers on multiple platforms. We formulate each goal as different optimization problems with different constraints, prove most of them are computationally hard to solve and propose various efficient algorithms to solve all of them in reasonable time. We then design a series of experiments that rely on synthetic and semi-synthetic data generated from a real-world online labor platform to evaluate our framework.

ASC-G4 is an algorithm for the calculation of the advanced structural characteristics of G-quadruplexes (G4). It allows the unambiguous determination of the intramolecular G4 topology, based on the oriented strand numbering. It also resolves the ambiguity in the determination of the guanine glycosidic configuration. With this algorithm, we showed that the use of the C3’ or C5’ atoms to calculate the groove width in G4 is more appropriate than the P atoms and that the groove width does not always reflect the space available within the groove. For the latter, the minimum groove width is more appropriate. The application of ASC-G4 to 207 G4 structures guided the choices made for the calculations. A website based on ASC-G4 (http://tiny.cc/ASC-G4) was created, where the user uploads his G4 structure and gets its topology, the types of its loops and their lengths, the presence of snapbacks and bulges, the distribution of guanines in the tetrads and strands, the glycosidic configuration of these guanines, their rise, the groove widths, the minimum groove widths, the tilt and twist angles, the backbone dihedral angles, etc. It also provides a large number of atom-atom and atom-plane distances that are relevant to evaluating the quality of the structure.

Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of patients with clear-cell renal cell carcinomas (ccRCC). Although analyses of transcriptome, genetic alterations, and the tumor microenvironment (TME) have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown. Experimental Design: We investigated the methylome of six ccRCC cohorts as well as one cell line dataset. Of note, we took advantage of the BIONIKK trial aiming to tailor treatments according to Paris Descartes 4-gene expression subgroups, and performed Illumina EPIC profiling for 46 samples related to patients treated with ipilimumab plus nivolumab, and 17 samples related to patients treated with sunitinib. Results: A group of tumors associated with enhancer demethylation was discovered, namely TED. TED was associated with tumors with sarcomatoid differentiation and poor clinical outcome. TED harbored TET1 promoter demethylation, activated the gene expression signature of epithelial–mesenchymal transition and IL6/JAK/STAT3 pathways, and displayed a TME characterized by both immune activation and suppressive populations, fibroblast infiltration, and endothelial depletion. In addition, TED was a predictive factor of resistance to the combination of first-line ipilimumab-nivolumab in the BIONIKK clinical trial. Finally, TED was associated with activation of specific regulons, which we also found to be predictive of resistance to immunotherapy in an independent cohort. Conclusions: We report on the discovery of a novel epigenetic phenotype associated with resistance to ICIs that may pave the way to better personalizing patients’ treatments. See related commentary by Zhou and Kim, p. 1170

Background: The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically ill COVID-19 patients remain uncertain. Methods: COVID-PACT (Prevention of Arteriovenous Thrombotic Events in Critically-ill COVID-19 Patients Trial) was a multicenter, 2×2 factorial, open-label, randomized-controlled trial with blinded end point adjudication in intensive care unit–level patients with COVID-19. Patients were randomly assigned to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomly assigned to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death attributable to venous or arterial thrombosis, pulmonary embolism, clinically evident deep venous thrombosis, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent deep venous thrombosis, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win ratio and time-to-first event analysis while patients were on treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was moderate to severe bleeding. Recruitment was stopped early in March 2022 (≈50% planned recruitment) because of waning intensive care unit–level COVID-19 rates. Results: At 34 centers in the United States, 390 patients were randomly assigned between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio, 1.95 [95% CI, 1.08–3.55]; P =0.028). Results were consistent in time-to-event analysis for the primary efficacy end point (full-dose versus standard-dose incidence 19/191 [9.9%] versus 29/191 [15.2%]; hazard ratio, 0.56 [95% CI, 0.32–0.99]; P =0.046). The primary safety end point occurred in 4 (2.1%) on full dose and in 1 (0.5%) on standard dose ( P =0.19); the secondary safety end point occurred in 15 (7.9%) versus 1 (0.5%; P =0.002). There was no difference in all-cause mortality (hazard ratio, 0.91 [95% CI, 0.56–1.48]; P =0.70). There were no differences in the primary efficacy or safety end points with clopidogrel versus no antiplatelet therapy. Conclusions: In critically ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04409834.

Monocular 3D object detection continues to attract attention due to the cost benefits and wider availability of RGB cameras. Despite the recent advances and the ability to acquire data at scale, annotation cost and complexity still limit the size of 3D object detection datasets in the supervised settings. Self-supervised methods, on the other hand, aim at training deep networks relying on pretext tasks or various consistency constraints. Moreover, other 3D perception tasks (such as depth estimation) have shown the benefits of temporal priors as a self-supervision signal. In this work, we argue that the temporal consistency on the level of object poses, provides an important supervision signal given the strong prior on physical motion. Specifically, we propose a self-supervised loss which uses this consistency, in addition to render-and-compare losses, to refine noisy pose predictions and derive high-quality pseudo labels. To assess the effectiveness of the proposed method, we finetune a synthetically trained monocular 3D object detection model using the pseudo-labels that we generated on real data. Evaluation on the standard KITTI3D benchmark demonstrates that our method reaches competitive performance compared to other monocular self-supervised and supervised methods.

Oral mucosal melanoma (OMM) is the subject of few studies, resulting in a lack of understanding. The aim of this study is to review the current literature on OMM. The term searched was "oral mucosal melanoma" between 01/01/2000 and 03/15/2021 in the PubMed Database (MEDLINE). Patients presenting with OMM and treated in our center between January 2009 and January 2020 were included in a case series. Demographics, location, risk factors, genetic mutations, treatment performed, and overall survival (OS) rates were evaluated. The PubMed database search yielded a total of 513 results, thirty-eight articles were finally included, which amounted to 2230 cases of OMM. 13 patients were included in the case series. A male-to-female ratio of 1.28:1.00 was found with a mean age at first diagnosis of 58.2 years old. Hard palate (1060 cases) and then gingiva (794 cases) were the two main locations. No risk factors could be identified. OMM were staged III or IV at diagnosis. Mutations were described as such: KIT in 14.6% of cases, BRAF in 7%, and NRAS in 5.6%. Treatment protocols varied but radical surgery was the cornerstone treatment associated with adjuvant therapies. Immunotherapy has not been evaluated for OMM. OS rates were 43.4% at 3 years, 33.1% at 5 year and 15.4% at 10 years. OMM show distinct features from cutaneous melanoma (CM): typical locations, no identified risk factors, different mutations profile, worse prognosis with advanced stage at diagnosis. Targeted therapies are still underused compared to CM.

Os cálculos biliares se encontram em mais de 10% da população mundial, sendo que esta incidência se torna maior com o avanço da idade. Sendo assim a colecistite pode ser considerada como uma emergência comum no mundo, sendo que na maior parte dos casos é decorrente da inflamação da parede interna da vesícula devido á impactação do cálculo e decorrente obstrução no ducto cístico, produzindo assim dor repentina e aguda, entretanto a colecistite aguda alitiásica ocorre sem que haja cálculos em seu interior. Esse trabalho possui como sua pergunta de pesquisa qual conduta deve ser adotada para reduzir a taxa de internação em UTI’s em pacientes que apresentem colicistite aguda alitiásica. E assim como seu objetivo geral demonstrar a conduta adequada para manejo de pacientes que apresentem colicistite aguda alitiásica. E como seus objetivos específicos: Identificar do que se trata um quadro de colicistite aguda alitiásica; Auxiliar na tomada de conduta pelos profissionais acerca do tratamento adequado; Disponibilizar informações acerca do assunto. Esse trabalho trata-se de uma revisão sistemática de artigos extraídos das plataformas do PubMed, BVS, Lilacs, Medline, Scielo, esses que possuem datas dos últimos 5 anos e escritos nos seguintes idiomas: português, inglês e espanhol. Com isso conclui-se que ainda são escassos os estudos acerca do tema, portanto é necessário que os médicos consigam de forma significativa o diagnóstico com agilidade, e para isso o conhecimento sobre assunto por uma equipe multidisciplinar deve ser amplamente desenvolvido.

Kaposi sarcoma (KS) is a rare skin tumour caused by herpesvirus 8 infection and characterized by either indolence or an aggressive course necessitating systemic therapies. The genetic basis of this difference remains unknown.To explore the tumour mutational burden in indolent and aggressive KS.We performed whole-exome sequencing on a cohort of 21 KS patients. We compared genetic landscape including tumor mutational burden between the two forms of indolent and agressive KS.Aggressive KS tumours had a significantly higher TMB and a larger cumulative number of deleterious mutations than indolent KS tumours. In addition, all aggressive tumours had at least three deleterious mutations, whereas most indolent tumours harboured only one or no predicted deleterious mutations. Deleterious mutations listed in the Cancer Gene Census were detected exclusively in patients with aggressive disease. An analysis of somatic copy-number alterations (SCNA) revealed a tendency towards higher number of alterations in aggressive KS.These data suggest that SCNA alterations and an increase in mutational burden promote aggressive KS and that it might be more appropriate to consider indolent KS as an opportunistic skin disease rather than a cancer.

Thoracic aortic aneurysm and dissection are complex diagnoses that require management by multidisciplinary providers using a variety of medical therapies, surgical interventions, and lifestyle modifications. Pharmacological agents, such as β-blockers (atenolol) and angiotensin II type 1 receptor blockers (losartan), have been mainstay treatments for several years, and research from the past decade has continued to evaluate these and other medication classes to further improve patient morbidity and mortality. Combination β- and renin-aldosterone-angiotensin blockade, statins, metformin, antioxidants, and vitamins have been evaluated as therapeutics in both thoracic and abdominal aortic aneurysms, as well as the effects of various antibiotics (ie, fluoroquinolones and tetracyclines) and benefits of lifestyle modifications (eg, diet and exercise) and enhanced patient-centered care and treatment adherence. In addition, as our understanding of the genetic, biochemical, and pathophysiological mechanisms behind these diseases expands, so do potential targets for future therapeutic research (eg, interleukins, matrix metalloproteases, and mast cells). This review incorporates the major meta-analyses, systematic and generalized reviews, and clinical trials published from 2010 through 2021 that focus on these topics in thoracic aortic aneurysms (and abdominal aneurysms when thoracic literature is scarce). Several key ongoing clinical trials, case studies, and in vivo/in vitro studies are also mentioned. Furthermore, we discuss current gaps in the literature and the abundance of clinical evidence for some interventions in abdominal aneurysms with few thoracic correlates, thus indicating a need for investigation of these subjects in the latter.

Pregnancy-associated aortic dissection (AD) is a rare event, with an incidence of 0.0004% per pregnancy. The work of the Aortic Dissection Collaborative identified pregnancy-associated AD as a high-priority topic, despite its rarity. The Pregnancy Working Group, which included physicians and patient stakeholders, performed a systematic literature review of pregnancy-associated AD from 1960 to 2021 and identified 6,333 articles through PubMed, OVID MEDLINE, Cochrane, Embase, CINAHL and Web of Science. The inclusion criterion was AD in pregnant populations and exclusion criteria were case reports, conference abstracts, and languages other than English. Assessment of full-text articles for eligibility after removal of duplicates from all databases yielded 68 articles to be included in the final review. Topics included were timing of AD in pregnancy, type of AD, and management considerations of pregnancy-associated AD. The Pregnancy Working Group identified gaps in knowledge and future areas of research for pregnancy-associated AD, including clinical management, mental health outcomes post AD, reproductive and genetic counseling, and contraception after AD. Future collaborative projects could be a multicenter, international registry for all pregnancy-associated AD to refine the risk factors, best practice and management of AD in pregnancy. In addition, future mixed methodology studies may be useful to explore social, mental, and emotional factors related to pregnancy-associated AD and to determine support groups' effect on anxiety and depression related to these events in the pregnancy and postpartum period.

Telemedicine uses telephone-based or any form of digital communication for remote clinical services. It has been a field of interest for the last century, with broader implementation of telemedicine technologies during the last 25 years. The COVID-19 pandemic was an impetus for the adoption of these technologies globally across all health care services, including patient care, surgical practice, and workflow. As part of the patient engagement work in the Aortic Dissection Collaborative, this topic was identified as an important patient-centered research topic. Telemedicine has been adopted increasingly in vascular surgery; however, there is little evidence on appropriate use of these technologies pertaining to treating patients with aortic dissection or aortopathy in general. This landscape review summarizes the uses of telemedicine applications pre and post pandemic in medicine and vascular surgery, with a particular focus on uses in aortopathy. Using common resource databases, we identified articles related to the history of telemedicine, its current utilization, and application to vascular surgery and/or aortopathy. We briefly review the history of telemedicine and illustrate a range of applications in medicine before the pandemic, along with its rapid uptake globally during the COVID-19 pandemic. The enablers and barriers to using telemedicine are explored, although as a whole there is satisfaction with its integration among patients and providers. To address these, we offer recommendations to address future research as it pertains to telemedicine technologies in aortic dissection.

Although the topics of surgical techniques and medical therapies have been widely studied in aortic dissection (AD), studies examining the short- and long-term impact of this event on mental health are largely lacking. Many of the studies have used the 36-Item Short Form Survey at variable time points after the event. However, AD as medical trauma has a complex impact on a person's identity. Its implications for emotional, mental, social, existential, and self-concept could be explored more robustly. This topic was identified as a topic of interest by the AD Collaborative. The AD Collaborative Mental Health Working Group was formed and performed a landscape review to summarize current literature surrounding quality of life research in those who have experienced AD, identify gaps in knowledge, and to outline future research questions.

Aortic dissection confers high mortality and morbidity rates despite advances in treatment, impacts quality of life, and contributes immense burden to the healthcare system globally. Efforts to prevent aortic dissection through screening and management of modifiable risk factors and early detection of aneurysms should incorporate genomic information, as it is integral to stratifying risk. However, effective integration of genomic-guided risk assessment into clinical practice will require addressing implementation barriers that currently permeate our healthcare systems. The Aortic Dissection Collaborative was established to define aortic dissection research priorities through patient engagement. Using a collaborative patient-centered feedback model, our Genomic Medicine Working Group identified related research priorities that could be investigated by pragmatic interventional studies aimed at aortic dissection prevention, utilization of genomic information to improve patient outcomes, and access to genomic medicine services. Further research is also needed to identify the genomic, lifestyle, and environmental risk factors that contribute to aortic dissection so these data can be incorporated into future comparative effectiveness studies to prevent aortic dissection.

Understanding what matters most to patients can help guide research in a direction that is best situated to provide evidence that is responsive to their core concerns. This can better inform the treatment decision-making process for patients and their physicians. The Aortic Dissection (AD) Collaborative built a collaborative AD research infrastructure involving patients and other stakeholders to facilitate patient-centered outcomes research training, support, and networking among those affected by AD. Two surveys and semi-structured interviews were conducted between January and October 2020 to gather information from people with and at risk for AD and their family members to better understand their experiences and needs. Discussion of survey and interview results were then articulated as seven key topics for future research to meet the needs of the AD community. Working groups were assembled to address each of the key topics. The groups conducted landscape reviews that were focused on providing guidance for future research that directly addresses the needs identified by the AD community. Recommendations for future research generated by the working groups were compiled by the Aortic Dissection Collaborative. From these recommendations, the Aortic Dissection Collaborative advisors and stakeholders identified high-priority research questions. The research questions form the basis for a third survey, disseminated to the Virtual Research Network between November 2021 and February 2022. Final analysis of the survey will identify top ranked research questions and assess willingness to participate. These results will inform the development of future patient-centered outcomes research and comparative effectiveness research proposals.

Purpose:Immune checkpoint inhibitors (ICI) have revolutionized the treatment of patients with clear-cell renal cell carcinomas (ccRCC). Although analyses of transcriptome, genetic alterations, and the tumor microenvironment (TME) have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown.Experimental Design:We investigated the methylome of six ccRCC cohorts as well as one cell line dataset. Of note, we took advantage of the BIONIKK trial aiming to tailor treatments according to Paris Descartes 4-gene expression subgroups, and performed Illumina EPIC profiling for 46 samples related to patients treated with ipilimumab plus nivolumab, and 17 samples related to patients treated with sunitinib.Results:A group of tumors associated with enhancer demethylation was discovered, namely TED. TED was associated with tumors with sarcomatoid differentiation and poor clinical outcome. TED harbored TET1 promoter demethylation, activated the gene expression signature of epithelial–mesenchymal transition and IL6/JAK/STAT3 pathways, and displayed a TME characterized by both immune activation and suppressive populations, fibroblast infiltration, and endothelial depletion. In addition, TED was a predictive factor of resistance to the combination of first-line ipilimumab-nivolumab in the BIONIKK clinical trial. Finally, TED was associated with activation of specific regulons, which we also found to be predictive of resistance to immunotherapy in an independent cohort.Conclusions:We report on the discovery of a novel epigenetic phenotype associated with resistance to ICIs that may pave the way to better personalizing patients’ treatments.See related commentary by Zhou and Kim, p. 1170

Figure S2. Focal copy number deletion identified by the GISTIC algorithm for a) 𝑇𝐸𝐷+ and b) 𝑇𝐸𝐷−, respectively, in the TCGA-KIRC cohort.

Figure S4. Focal copy number deletion identified by the GISTIC algorithm for a) 𝑇𝐸𝐷+ and b) 𝑇𝐸𝐷−, respectively, in the immunotherapy arm of the BIONIKK cohort.

Supplementary Tables S1-S23

Figure S7. a) Heatmap showing the methylation profiles of two 𝑇𝐸𝐷 phenotypes by unsupervised clustering of enhancer probes in the Beuselinck cohort in which 102 patients developed metastatic ccRCC and were treated with the first-line TKI of sunitinib. Kaplan-Meier survival curves showing the survival rate of two 𝑇𝐸𝐷 phenotypes in view of b) OS and c) PFS.

Figure S6. a) Heatmap showing the methylation profiles of two 𝑇𝐸𝐷 phenotypes by unsupervised clustering of enhancer probes in the BIONIKK cohort; samples were combined from both immunotherapy and target therapy arms. Kaplan-Meier survival curves showing the survival rate of two 𝑇𝐸𝐷 phenotypes in view of b) OS, c) PFS, and d) TST.

Figure S5. Box violin plots showing the distribution of the methylation level of the TET1 associated promoter probe (i.e., cg23602092) in four cohorts and one cell line dataset with DNA methylation profiles where three of them had available normal samples.

Figure S1. Flow chart of the study. A total of six ccRCC cohorts and one cell line dataset were used in this study.

Supplementary Figure 1. Independent validation of C-CIMP A) Supervised clustering of TCGA samples in ccRCC validation dataset assessed by 27k Infinium arrays. The (beta value) level of DNA methylation is represented with a color scale. Each column represents a sample; each row a probe set. The transcriptomic subtype in TCGA, the copy number variation at 9p23.1 locus (CDKN2A), somatic mutation status of four genes (PBRM1, BAP1, SETD2 and VHL) are indicated by red, green and gray squares, with annotations in the legend. B) Kaplan-Meier curves showing distinct outcome of patients according to the three subgroups of DNA methylation classification, with patients belonging to C-CIMP subgroup having the worst outcome. Supplementary Figure 2. Expression vs DNA methylation between C-CIMP and no-CIMP subgroups using volcano and starburst plots. A) All CpG loci analyzed for C-CIMP association; x-axis: β-value difference in DNA methylation between C-CIMP and no-CIMP clusters; y-axis: p-value of the corrected FDR between the two groups; red: probes significantly different between the two subgroups. B) TCGA promoter DNA methylation vs. gene expression analyzed by RNAseq. Log-10 (FDR adjusted p-value) is plotted for DNA methylation (x-axis) and gene expression for each gene (y-axis). Green indicates genes that are downregulated for gene expression and which gain DNA methylation in C-CIMP cluster versus no-CIMP cluster. Red indicates genes that are upregulated for gene expression and gain DNA methylation. Supplementary Figure 3. Association between somatic mutations and DNA methylation subgroups. A) Mutational load is increased in C-CIMP as compared to no-CIMP and low-CIMP subgroups. B) Association between somatic mutations of BAP1 and SETD2 in C-CIMP subgroup as compared to low-CIMP and no-CIMP subgroups. Supplementary Figure 4. Predictive value of VEGF receptor methylation to predict response to sunitinib. Kaplan-Meier curves for progression-free survival of patients treated with sunitinib according to tumor methylation status of (A) FLT4, (B) FLT1, and (C) FLT3 genes in Beuselinck study. Supplementary Figure 5. C-CIMP subgroup in metastatic ccRCC A) Supervised clustering of DNA methylation in Beuselinck study was consistent with the three DNA methylation subgroups C-CIMP, low-CIMP and no-CIMP. B) Kaplan-Meier curves for progression-free survival of patients treated with sunitinib according to their CIMP status. Supplementary Figure 6. Correlation between methylome signature of NSD1 mutations of patients with Sotos syndrome and ccRCC. A) Supervised clustering of DNA methylation in TCGA ccRCC using genome-wide methylome signature of NSD1 mutations in Sotos syndrome. B) Kaplan-Meier curves for overall survival of patients with ccRCCs according to NSD1 mutations in genome-wide methylome signature. Note that the analyzed cohort encompasses 271 ccRCCs assessed by Infinium 450K arrays.

Supplementary Table 3: Ingenuity Pathway Analysis (IPA) for genes which gain promoter DNA methylation in C1 relative to C2 epi-cluster. Supplementary Table 4: Gene Ontology analysis for differentially methylated regions (DMR) between C1 and C2 epi-clusters, as assessed by GREAT online tool. Supplementary Table 5: List of motifs enriched in differentially methylated regions between C1 and C2 epi-clusters, as assessed by GREAT online tool. Supplementary Table 6: DAVID functional annotations analysis for enriched pathways related to genes which gain DNA methylation in renal cell carcinoma samples. Supplementary Table 7: List of gene promoters located in CG islands and which are assessed for DNA methylation using DREAM. The genes which showed the highest frequency of DNA methylation in our dataset are in the top. Furthermore, the frequency of gene promoters which gain DNA methylation in either RCC samples derived from the proximal or distal cells of the nephron are also reported. Supplementary Table 8: Validation dataset showing the prevalence of promoter DNA methylation for 25 genes in clear-cell renal cell carcinoma dataset of The Cancer Genome Atlas (TCGA) project. Those genes were both methylated and repressed in the TCGA dataset.

Unsupervised clustering of DNA methylation using 56 genes epi-signature in an independent data set encompassing 37 renal cell carcinomas cases. C2 contains the majority of oncocytoma and chromophobe RCC cases (n=11/13) as compared to C1 which encompasses the remaining RCC subtypes including clear-cell RCC (ccRCC) , papillary RCC (pRCC) and translocation RCC (tRCC).

Extensive dysregulation of chromatin-modifying genes in clear cell renal cell carcinoma (ccRCC) has been uncovered through next-generation sequencing. However, a scientific understanding of the cross-talk between epigenetic and genomic aberrations remains limited. Here we identify three ccRCC epigenetic clusters, including a clear cell CpG island methylator phenotype (C-CIMP) subgroup associated with promoter methylation of VEGF genes (FLT4, FLT1, and KDR). C-CIMP was furthermore characterized by silencing of genes related to vasculature development. Through an integrative analysis, we discovered frequent silencing of the histone H3 K36 methyltransferase NSD1 as the sole chromatin-modifying gene silenced by DNA methylation in ccRCC. Notably, tumors harboring NSD1 methylation were of higher grade and stage in different ccRCC datasets. NSD1 promoter methylation correlated with SETD2 somatic mutations across and within spatially distinct regions of primary ccRCC tumors. ccRCC harboring epigenetic silencing of NSD1 displayed a specific genome-wide methylome signature consistent with the NSD1 mutation methylome signature observed in Sotos syndrome. Thus, we concluded that epigenetic silencing of genes involved in angiogenesis is a hallmark of the methylator phenotype in ccRCC, implying a convergence toward loss of function of epigenetic writers of the H3K36 histone mark as a root feature of aggressive ccRCC. Cancer Res; 77(18); 4835–45. ©2017 AACR.

List of 369 probe sets defining the C-CIMP (CpG island methylator phenotype) in ccRCCs, including mean beta-values of those in C-CIMP (cluster 3) versus no-CIMP (cluster 2). Expression values as well as fold-changes of gene expression of those genes are also reported.

Purpose: DNA methylation is a heritable covalent modification that is developmentally regulated and is critical in tissue-type definition. Although genotype–phenotype correlations have been described for different subtypes of renal cell carcinoma (RCC), it is unknown if DNA methylation profiles correlate with morphological or ontology based phenotypes. Here, we test the hypothesis that DNA methylation signatures can discriminate between putative precursor cells in the nephron.Experimental Designs: We performed deep profiling of DNA methylation and transcriptome in diverse histopathological RCC subtypes and validated DNA methylation in an independent dataset as well as in The Cancer Genome Atlas Clear Cell and Chromophobe Renal Cell Carcinoma Datasets.Results: Our data provide the first mapping of methylome epi-signature and indicate that RCC subtypes can be grouped into two major epi-clusters: C1, which encompasses clear-cell RCC, papillary RCC, mucinous and spindle cell carcinomas and translocation RCC; C2, which comprises oncocytoma and chromophobe RCC. Interestingly, C1 epi-cluster displayed 3-fold more hypermethylation as compared with C2 epi-cluster. Of note, differentially methylated regions between C1 and C2 epi-clusters occur in gene bodies and intergenic regions, instead of gene promoters. Transcriptome analysis of C1 epi-cluster suggests a functional convergence on Polycomb targets, whereas C2 epi-cluster displays DNA methylation defects. Furthermore, we find that our epigenetic ontogeny signature is associated with worse outcomes of patients with clear-cell RCC.Conclusions: Our data define the epi-clusters that can discriminate between distinct RCC subtypes and for the first time define the epigenetic basis for proximal versus distal tubule derived kidney tumors. Clin Cancer Res; 22(24); 6236–46. ©2016 AACR.

A) Kaplan-Meier curves according to the 56 genes epi-signature in a training dataset of patients with clear-cell renal cell carcinomas from The Cancer Genome Atlas (TCGA) dataset. B) Kaplan-Meier curves according to the 56 genes epi-signature in a validation dataset of patients with clear-cell renal cell carcinomas from The Cancer Genome Atlas (TCGA) dataset.

Raw data for β-values of probe sets related to our 56 genes signature in an independent dataset encompassing 4 normal kidneys and 37 renal cell carcinomas belonging to diverse histopathological subtypes.

Supplementary Table 10: List of samples misclassified among the clear-cell renal cell carcinomas dataset with the corresponding new classification. Among those, many of them have been demonstrated to belong to the C4 cluster of long non-coding RNA classification. The first table reports the 5 misclassified TCGA clear-cell RCC (KIRC) using gene expression and which turned out to be chromophobe RCC (chRCC). The second table reports on misclassified TCGA KIRC cases with DNA methylation available. Supplementary Table 11: List of importance scores for genes used in the statistical model for predicting outcome of patients with clear-cell RCC. Supplementary Table 12: Associations (both training and validation datasets) between mutational load, TCGA clear-cell renal cell carcinomas transcriptomic subtypes classification and recurrent somatic mutations (VHL, PBRM1, BAP1 and KDM6A) identified in clear-cell renal cell carcinoma TCGA dataset with our 56 genes epi-signature. P-values less than 0.05 is considered as statistically significant.

List of ccRCCs from TCGA dataset assessed for DNA methylation using Infinium 450K arrays. One column lists the DNA methylation subgroup to which each ccRCC sample belongs (CIMP= C-CIMP; CIMPL= low-CIMP; CIMPN= no-CIMP).

A) Box-plot for average gene expression of promoters located in CpG islands according to their methylation levels. B) Box-plot for average gene expression of promoters located outside CpG islands according to their methylation levels. Note that unmethylated promoters show the highest expression levels.

List of 95 CpG located in promoter CG islands which are differentially methylated and expressed between C1 and C2 epi-clusters.

List of DNA methylation levels for each CpG sites detected by DREAM in the 2 normal kidneys and the 22 renal cell carcinomas samples. Each column represents one sample and each raw one CpG site with the relative annotations (coordinates, CpG islands or not, distance from transcription start site (TSS). The coordinates of each CpG sites are provided according to Hg18 version of the Human Genome.

Background: The revised Opioid Risk Tool (ORT-OUD) is a brief, self-report scale designed to provide clinicians with a simple, validated method to screen for the risk of developing an Opioid Use Disorder (OUD) in patients without a prior history of substance abuse. This study aimed to translate and validate the Arabic version of ORT-OUD in the Lebanese population and assess its clinical validity in a sample of patients with OUD. Methods: This cross-sectional study in the Lebanese population used several validated scales to assess the risk of OUD, including the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). Other tools evaluated chronotype and sleep and mood disturbances. Principal component analysis with Varimax rotation was applied to assess ORT-OUD construct validity. Convergent validity with the Arabic version of ASSIST was evaluated. The ORT-OUD criterion validity was then assessed in a clinical sample of patients with OUD. Results: This study included 581 participants. The prevalence of the OUD risk in the Lebanese population using the ORT-OUD scale and the ASSIST-opioids scale was estimated at 14.5% and 6.54%, respectively. No items of the ORT-OUD were removed; all items converged over a solution of four factors with an eigenvalue>1, explaining a total of 68.2% of the variance (Cronbach’s alpha=0.648). The correlation coefficients between the ORT-OUD total score and ASSIST subscales were as follows: ASSIST-opioids (r=0.174; p=Conclusion: This study is the first to validate the Arabic version of ORT-OUD in the Lebanese population, an essential step towards improving the detection and management of OUD in this population.

Kawasaki Disease (KD) is still the most common acquired heart disease in children below the age of five years; it has been well described in the developed world; however, data from the Arab world are limited to case reports or single-center case series. In an effort of optimizing KD research in the Arab world, a group of physicians and researchers established the KD Arab Initiative (Kawarabi) in 2021, and published the first survey, which showed disparities in the availability of intravenous immunoglobulin (IVIG); this had prompted Kawarabi to assess the access to care and therapy of KD patients in Arab countries. A 32 structured questions survey was conducted in thirteen Arab countries and addressed KD patients’ access to healthcare in urban and rural settings. The survey results showed that access to care was uniform across large, mid-size cities and rural areas in 7/13 (54%) countries, while in 6/13 (46%) countries, it was in favor of large and mid-size cities over rural areas. The quality of medical services received by children with KD in large cities was rated as excellent in 6/13 or good in 7/13 countries compared to fair in 4/13 or poor in 4/13 countries in rural areas. Availability of IVIG was limited (23%) in mid-size cities and almost impossible (23%) in rural areas. The KD patients in mid-size cities and rural areas have limited access to standard healthcare in the Arab world. This survey laid the foundation for future Kawarabi endeavors to improve the care of children with KD.

For autonomous vehicles, driving safely is highly dependent on the capability to correctly perceive the environment in 3D space, hence the task of 3D object detection represents a fundamental aspect of perception. While 3D sensors deliver accurate metric perception, monocular approaches enjoy cost and availability advantages that are valuable in a wide range of applications. Unfortunately, training monocular methods requires a vast amount of annotated data. Interestingly, self-supervised approaches have recently been successfully applied to ease the training process and unlock access to widely available unlabelled data. While related research leverages different priors including LIDAR scans and stereo images, such priors again limit usability. Therefore, in this work, we propose a novel approach to self-supervise 3D object detection purely from RGB sequences alone, leveraging multi-view constraints and weak labels. Our experiments on KITTI 3D dataset demonstrate performance on par with state-of-the-art self-supervised methods using LIDAR scans or stereo images.