tbuckley/cabot-search huggingface dataset:
The “diagnose and leave in” strategy for diminutive rectosigmoid polyps in Lynch syndrome: a post hoc analysis from a randomized controlled trial
Authors: Liseth Rivero-Sánchez, Aleksandar Gavric, Jesús Herrero, David Remedios, Victoria Alvarez, Eduardo Albéniz, Jordi Gordillo, Ignasi Puig, Jorge López-Vicente, Alain Huerta, María López-Cerón, Inmaculada Salces, Beatriz Peñas, Sofía Parejo, Enrique Rodriguez, Maite Herraiz, Cristina Carretero, Antonio Z. Gimeno-Garcia, Esteban Saperas, Cristina Alvarez, Coral Arnau-Collell, Oswaldo Ortiz, Ariadna Sánchez, Gerhard Jung, Francesc Balaguer, María Pellisé
Journal: Endoscopy (2020)

Abstract Background The “diagnose-and-leave-in” policy has been established to reduce the risks and costs related to unnecessary polypectomies in the average-risk population. In individuals with Lynch syndrome, owing to accelerated carcinogenesis, the general recommendation is to remove all polyps, irrespective of size, location, and appearance. We evaluated the feasibility and safety of the diagnose-and-leave-in strategy in individuals with Lynch syndrome. Methods We performed a post hoc analysis based on per-polyp data from a randomized, clinical trial conducted by 24 dedicated colonoscopists at 14 academic centers, in which 256 patients with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with confidence level for all detected lesions was obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Primary outcome was the negative predictive value (NPV) for neoplasia of high-confidence optical diagnosis among diminutive (≤ 5 mm) rectosigmoid lesions. Histology was the reference standard. Results Of 147 rectosigmoid lesions, 128 were diminutive. In 103 of the 128 lesions (81 %), the optical diagnostic confidence was high and showed an NPV of 96.0 % (95 % confidence interval [CI] 88.9 %–98.6 %) and accuracy of 89.3 % (95 %CI 81.9 %–93.9 %). By following the diagnose-and-leave-in policy, we would have avoided 59 % (75/128) of polypectomies at the expense of two diminutive low grade dysplastic adenomas and one diminutive sessile serrated lesion that would have been left in situ. Conclusion In patients with Lynch syndrome, the diagnose-and-leave-in strategy for diminutive rectosigmoid polyps would be feasible and safe.
14232 Basal cell carcinoma: An emerging epidemic in women in Iceland
Authors: Jonas A. Adalsteinsson, Desiree Ratner, Elinborg J. Olafsdottir CSc, Jane M. Grant-Kels, Jonathan P. Ungar, Jonathan I. Silverberg, Arni K. Kristjansson, Jon G. Jonasson, Laufey Tryggvadottir
Journal: Journal of the American Academy of Dermatology (2020)
A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor–Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention
Authors: Spencer C. Wei, Wouter C. Meijers, Margaret L. Axelrod, Nana-Ama A.S. Anang, Elles M. Screever, Elizabeth C. Wescott, Douglas B. Johnson, Elizabeth Whitley, Lorenz Lehmann, Pierre-Yves Courand, James J. Mancuso, Lauren E. Himmel, Benedicte Lebrun-Vignes, Matthew J. Wleklinski, Bjorn C. Knollmann, Jayashree Srinivasan, Yu Li, Oluwatomisin T. Atolagbe, Xiayu Rao, Yang Zhao, Jing Wang, Lauren I.R. Ehrlich, Padmanee Sharma, Joe-Elie Salem, Justin M. Balko, Javid J. Moslehi, James P. Allison
Journal: Cancer Discovery (2020)

Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events, including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which monoallelic loss of Ctla4 in the context of complete genetic absence of Pdcd1 leads to premature death in approximately half of mice. Premature death results from myocardial infiltration by T cells and macrophages and severe ECG abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients. Using this model, we show that Ctla4 and Pdcd1 functionally interact in a gene dosage-dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4-Ig (abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis. SIGNIFICANCE: We provide a preclinical model of ICI-associated myocarditis which recapitulates this clinical syndrome. Using this model, we demonstrate that CTLA4 and PD-1 (ICI targets) functionally interact for myocarditis development and that intervention with CTLA4-Ig (abatacept) attenuates myocarditis, providing mechanistic rationale and preclinical support for therapeutic clinical studies.See related commentary by Young and Bluestone, p. 537.This article is highlighted in the In This Issue feature, p. 521.
Estimated impact of RTS,S/AS01 malaria vaccine allocation strategies in sub-Saharan Africa: A modelling study
Authors: Alexandra B. Hogan, Peter Winskill, Azra C. Ghani
Journal: PLoS Medicine (2020)

The RTS,S/AS01 vaccine against Plasmodium falciparum malaria infection completed phase III trials in 2014 and demonstrated efficacy against clinical malaria of approximately 36% over 4 years for a 4-dose schedule in children aged 5-17 months. Pilot vaccine implementation has recently begun in 3 African countries. If the pilots demonstrate both a positive health impact and resolve remaining safety concerns, wider roll-out could be recommended from 2021 onwards. Vaccine demand may, however, outstrip initial supply. We sought to identify where vaccine introduction should be prioritised to maximise public health impact under a range of supply constraints using mathematical modelling.
Atrial Fibrillation and Obesity: An Association of Increasing Importance⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Nikolaos Dagres, Maria Anastasiou-Nana
Journal: Journal of the American College of Cardiology (2010)
398P Real-world mechanism of crizotinib-resistance in MET exon 14 skipping mutations non-small-cell lung cancer using next generation sequencing: A multicenter study
Authors: D. Wang, W-X. Wang, C. Xu, L. Lei, Y-C. Zhu, Y-B. Zhang, X-X. Pu, L-P. Wang, H-J. Feng, W. Zhuang, H. Wang, Y. Fang, M-Y. Fang, T-F. Lv, Y. Song
Journal: Annals of Oncology (2020)
High-affinity neoantigens correlate with better prognosis and trigger potent antihepatocellular carcinoma (HCC) activity by activating CD39<sup>+</sup>CD8<sup>+</sup> T cells
Authors: Ting Liu, Jizhou Tan, Minhao Wu, Wenzhe Fan, Jialiang Wei, Bowen Zhu, Jian Guo, Shutong Wang, Penghui Zhou, Hui Zhang, Liangrong Shi, Jiaping Li
Journal: Gut (2020)

It remains controversial whether tumour mutational burden (TMB) or neoantigens are prognostic markers in hepatocellular carcinoma (HCC). This study aimed to define the function of TMB or neoantigens in antitumour immunotherapy.Neoantigens of patients (n=56) were analysed by pVAC tools with major histocompatibility complex-1 (MHC-I) algorithms based on whole exome sequencing and neoantigens with mutant type IC50 <50 nM were defined as high-affinity neoantigens (HANs). Patients were segregated into HAN-high/low groups by median of HAN value, and overall survival (OS) was analysed. Autologous organoid killing model was developed to clarify the antitumour activity of HANs.The value of HAN showed a better correlation with OS (p=0.0199) than TMB (p=0.7505) or neoantigens (p=0.2297) in patients with HCC and positively correlated with the frequency of CD39+CD8+ tumour infiltrating lymphocytes (TILs). Furthermore, HAN-specific CD8+ T cells were identified in CD39+CD8+ TILs, which showed better antitumour activity in HAN-high versus HAN-low group. In addition, more effective HAN peptides were identified in HAN-high versus HAN-low group. Besides, flow cytometry data showed that in fresh tumour, CD39+PD-1intCD8+ TILs displayed an effector phenotype and stronger antitumour activity in HAN-high versus HAN-low group. More importantly, patients in HAN-high versus HAN-low group showed a better prognosis after anti-PD-1 therapy.Our study first demonstrates that HAN value positively correlates with better OS in patients with HCC. HANs trigger antitumour activity by activating tumour-reactive CD39+CD8+ T cells, and patients in HAN-high group benefited more from anti-PD-1 therapy than HAN-low group. These findings may provide a novel strategy for personalised antitumour therapies for HCC.
Phyloarray: a phylogenetic approach to cancer gene-expression microarray analysis
Authors: Mones Abu-Asab, Mohamed Chaouchi, Hakima Amri
Journal: Cancer Research (2007)

3697  Advances in targeted individualized treatment of cancer will only progress when a highly predictive classification model becomes available where class discovery and prediction are based on an evolutionary paradigm. Current gene-listing, gene-linkage, and clustering do not resolve interplatform comparability and reliability, and are incongruent with the nature of cancer progression. An accurate and predictive analytical model should account for the multiphasic nature of cancer and be able to place any of its profiles in a proper taxonomy. Phyloarray produces its classification by polarizing data values into derived and ancestral states using our polarity assessment algorithm, UNIPAL, followed by a phylogenetic analysis of the polarized matrix with the parsimony algorithm, MIX. Phyloarray is a phylogenetic approach that offers an alternative to gene-listing, statistical gene-linkage, and clustering, and produces a biologically meaningful classification of specimens through hierarchical class discovery. It incorporates genes with asynchronous expressions (above & below normal) into the analysis, produces higher interplatform congruity, and resolves interplatform comparability. Class discovery here is defined by shared derived expressions (synapomorphies) that delimit natural groups (clades), while gene linkage is inferred from the parsimonious distribution of polarized expressions among the specimens. Interplatform comparability can be carried out with phyloarray by pooling together multiple polarized datasets produced separately and analyzed as long as they have identical probes; we pooled the polarized matrices of leiomyosarcoma and gastric carcinoma, and the two cancers were separated from each other on the cladogram, and each type proved to be a natural assemblage (a clade) defined by a set of unique synapomorphies. Interplatform congruity was tested by comparing the lists of synapomorphies produced by the polarity assessment of two independent datasets each representing myometrium and leiomyoma, and found a subset of synapomorphies (46/146, 31%) shared by the two groups of leiomyoma, a higher percentage than was produced by statistical methods (13%), despite a quantitative probes difference between the two datasets (7,000 v. 22,000). Phyloarray is a double-algorithmic approach to the analysis of gene-expression microarray data that offers an alternative to t-test and fold-change methods for generating a differentially-expressed gene-list, resolves interplatform comparability problem, produces a higher interplatform congruity, defines biomarkers as synapomorphies, and circumscribes cancer types as clades defined by synapomorphies. It transforms microarray into diagnostic, prognostic, and predictive tool, and provides support for a relationship between uterine fibroids and leiomyosarcoma.
Endocannabinoid Inhibition: A New Cardioprotective Strategy Against Doxorubicin Cardiotoxicity⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Giovanni Fajardo, Daniel Bernstein
Journal: Journal of the American College of Cardiology (2007)
Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC—an Update From the PACIFIC Trial
Authors: Corinne Faivre-Finn, David Vicente, Takayasu Kurata, David Planchard, Luis Paz-Ares, Johan F. Vansteenkiste, David R. Spigel, Marina C. Garassino, Martin Reck, Suresh Senan, Jarushka Naidoo, Andreas Rimner, Yi-Long Wu, Jhanelle E. Gray, Mustafa Özgüroğlu, Ki H. Lee, Byoung C. Cho, Terufumi Kato, Maike de Wit, Michael Newton, Lu Wang, Piruntha Thiyagarajah, Scott J. Antonia
Journal: Journal of Thoracic Oncology (2021)

IntroductionIn the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53–0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42–65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized.MethodsPatients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (≤12 months), stratified by age, sex, and smoking history. OS and PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS and PFS rates were estimated by the Kaplan–Meier method.ResultsOverall, 709 of 713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of March 20, 2020 (median follow-up = 34.2 months; range: 0.2–64.9), updated OS (HR = 0.71; 95% CI: 0.57–0.88) and PFS (HR = 0.55; 95% CI: 0.44–0.67) remained consistent with the primary analyses. The median OS for durvalumab was reached (47.5 mo; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively.ConclusionThese updated exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab after chemoradiotherapy. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression-free (placebo, 19.5%).
16127 Efficacy of ingenol mebutate in patients with actinic keratosis on face and scalp: Subgroup analysis of a 12-month observational follow-up study according to age (&lt;65 and ≥65 years)
Authors: Hee Jin Kim, Nikeshia Dunkelly-Allen, Jes B. Hansen, Karen A. Veverka, Mark Lebwohl
Journal: Journal of the American Academy of Dermatology (2020)
CXCR4 in Waldenström’s Macroglobulinema: chances and challenges
Authors: Lisa Marie Kaiser, Zachary R. Hunter, Steven P. Treon, Christian Buske
Journal: Leukemia (2020)

Abstract It is one of the major aims in cancer research to improve our understanding of the underlying mechanisms which initiate and maintain tumor growth and to translate these findings into novel clinical diagnostic and therapeutic concepts with the ultimate goal to improve patient care. One of the greater success stories in this respect has been Waldenström’s Macroglobulinemia (WM), which is an incurable B-cell neoplasm characterized by serum monoclonal immunoglobulin M (IgM) and clonal lymphoplasmacytic cells infiltrating the bone marrow. Recent years have succeeded to describe the molecular landscape of WM in detail, highlighting two recurrently mutated genes, the MYD88 and the CXCR4 genes: MYD88 with an almost constant and recurrent point mutation present in over 90% of patients and CXCR4 with over 40 different mutations in the coding region affecting up to 40% of patients. Intriguingly, both mutations are activating mutations leading in the case of CXCR4 to an indelible activation and perpetual signaling of the chemokine receptor. These data have shed light on the essential role of CXCR4 in this disease and have paved the way to use these findings for predicting treatment response to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and novel therapeutic approaches in WM, which might be transferable to other related CXCR4 positive diseases. Well known for its central role in cancer progression and distribution, CXCR4 is highlighted in this review with regard to its biology, prognostic and predictive relevance and therapeutic implications in WM.
MDMX Recruits UbcH5c to Facilitate MDM2 E3 Ligase Activity and Subsequent p53 Degradation <i>In Vivo</i>
Authors: Jing Yang, Aiwen Jin, Jing Han, Xin Chen, Junnian Zheng, Yanping Zhang
Journal: Cancer Research (2020)

MDM2 regulates p53 degradation by functioning as an E3 ubiquitin ligase. The role of MDMX, an MDM2 homolog that lacks E3 ligase activity, in the regulation of p53 degradation remains incompletely understood and sometime controversial. This confusion is due at least in part to studies of p53 degradation mainly carried out in
Metaproteome and metabolome of oral microbial communities
Authors: Nagihan Bostanci, Melissa Grant, Kai Bao, Angelika Silbereisen, Franziska Hetrodt, Daniel Manoil, Georgios N. Belibasakis
Journal: Periodontology 2000 (2020)

Abstract The emergence of high‐throughput technologies for the comprehensive measurement of biomolecules, also referred to as “omics” technologies, has helped us gather “big data” and characterize microbial communities. In this article, we focus on metaproteomic and metabolomic approaches that support hypothesis‐driven investigations on various oral biologic samples. Proteomics reveals the working units of the oral milieu and metabolomics unveils the reactions taking place; and so these complementary techniques can unravel the functionality and underlying regulatory processes within various oral microbial communities. Current knowledge of the proteomic interplay and metabolic interactions of microorganisms within oral biofilm and salivary microbiome communities is presented and discussed, from both clinical and basic research perspectives. Communities indicative of, or from, health, caries, periodontal diseases, and endodontic lesions are represented. Challenges, future prospects, and examples of best practice are given.
Abstract PO-022: The NKX3.1 homeoprotein functions in the mitochondria to protect against oxidative stress-dependent prostate tumorigenesis
Authors: Alexandros Papachristodoulou, Sukanya Panja, Antonina Mitrofanova, Aditya Dutta, Cory Abate-Shen
Journal: Cancer Research (2020)

Abstract The NKX3.1 homeobox gene is a key regulator of prostate differentiation, whose loss-of-function predisposes to prostate cancer. Here, we uncover an unexpected role for NKX3.1 in mitochondrial function and bioenergetics that regulates cancer initiation under conditions of oxidative stress. To investigate whether NKX3.1 plays a direct functional role in protection against oxidative stress, we studied the consequences of its loss- or gain-of-function in tumorigenic and non-tumorigenic human prostate cells, mutant mice, and primary human prostate cultures. Utilizing redox compounds to exogenously induce and study oxidative stress responses in our models, we show that NKX3.1 localizes to the mitochondria to protect against oxidative stress, while its loss-of-function leads to deregulation of mitochondrial-encoded oxidative phosphorylation genes, elevated reactive oxygen species, and accelerated prostate cancer initiation. Importantly, our studies reveal that cells lacking NKX3.1 have impaired intracellular energetics under oxidative stress, warranting further investigation into the role of NKX3.1 loss in cancer metabolism. These observations uncover a novel function for a tissue-specific differentiation regulator in mitochondria and demonstrate its functional relevance for suppressing prostate cancer initiation. Citation Format: Alexandros Papachristodoulou, Sukanya Panja, Antonina Mitrofanova, Aditya Dutta, Cory Abate-Shen. The NKX3.1 homeoprotein functions in the mitochondria to protect against oxidative stress-dependent prostate tumorigenesis [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-022.
Estimation of Primary Prevention of Gout in Men Through Modification of Obesity and Other Key Lifestyle Factors
Authors: Natalie McCormick, Sharan K. Rai, Na Lu, Chio Yokose, Gary C. Curhan, Hyon K. Choi
Journal: JAMA Network Open (2020)

The population impact of modifying obesity and other key risk factors for hyperuricemia has been estimated in cross-sectional studies; however, the proportion of incident gout cases (a clinical end point) that could be prevented by modifying such factors has not been evaluated.To estimate the proportion of incident gout cases that could be avoided through simultaneous modification of obesity and other key risk factors.The Health Professionals Follow-up Study is a US prospective cohort study of 51 529 male health professionals enrolled in 1986 and followed up through questionnaires every 2 years through 2012. Self-reported gout cases were confirmed through June 2015. Clean and complete data used for this analysis were available in June 2016, with statistical analyses performed from July 2016 to July 2019.From data collected in the validated questionnaires, men were categorized to low-risk groups according to combinations of the following 4 factors: normal body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]; <25), no alcohol intake, adherence to Dietary Approaches to Stop Hypertension (DASH)-style diet (highest quintile of DASH diet score), and no diuretic use.Population attributable risks (PARs) for incident gout meeting the preliminary American College of Rheumatology survey criteria, overall and stratified by BMI.We analyzed 44 654 men (mean [SD] age, 54.0 [9.8] years) with no history of gout at baseline. During 26 years of follow-up, 1741 (3.9%) developed incident gout. Among all participants, PAR for the 4 risk factors combined (BMI, diet, alcohol use, and diuretic use) was 77% (95% CI, 56%-88%). Among men with normal weight (BMI <25.0) and overweight (BMI 25.0-29.9), we estimated that more than half of incident gout cases (69% [95% CI, 42%-83%] and 59% [95% CI, 30%-75%], respectively) may have been prevented by the combination of DASH-style diet, no alcohol intake, and no diuretic use. However, among men with obesity (BMI ≥30), PAR was substantially lower and not significant (5% [95% CI, 0%-47%]).The findings of this cohort study suggest that addressing excess adiposity and other key modifiable factors has the potential to prevent the majority of incident gout cases among men. Men with obesity may not benefit from other modifications unless weight loss is addressed.