tbuckley/cabot-search huggingface dataset:
Late Toxicity After Adjuvant Conventional Radiation Versus Image-Guided Intensity-Modulated Radiotherapy for Cervical Cancer (PARCER): A Randomized Controlled Trial
Authors: Supriya Chopra, Sudeep Gupta, Sadhana Kannan, Tapas Dora, Reena Engineer, Akshay Mangaj, Amita Maheshwari, T. Surappa Shylasree, Jaya Ghosh, Siji N. Paul, Reena Phurailatpam, Mayuri Charnalia, Mitali Alone, Jamema Swamidas, Umesh Mahantshetty, Kedar Deodhar, Rajendra Kerkar, Shyam K. Shrivastava
Journal: Journal of Clinical Oncology (2021)

Postoperative Adjuvant Radiation in Cervical Cancer (PARCER), a phase III randomized trial, compared late toxicity after image-guided intensity-modulated radiotherapy (IG-IMRT) with three-dimensional conformal radiation therapy (3D-CRT) in women with cervical cancer undergoing postoperative radiation.Patients were randomly assigned to receive either IG-IMRT or 3D-CRT after stratification for the type of hysterectomy and use of concurrent chemotherapy. The primary end point was 3-year grade ≥ 2 late GI toxicity assessed using Common Toxicity Criteria for Adverse Events v 3.0 and estimated using time-to-event, intention-to-treat analysis, with a study level type I error of 0.05 and a nominal α of .047 after accounting for one interim analysis. Secondary end points included acute toxicity, health-related quality of life, and pelvic relapse-free, disease-free, and overall survival.Between 2011 and 2019, 300 patients were randomly assigned (IG-IMRT 151 and 3D-CRT 149). At a median follow-up of 46 (interquartile range, 20-72) months, the 3-year cumulative incidence of grade ≥ 2 late GI toxicity in the IG-IMRT and 3D-CRT arms were 21.1% versus 42.4% (hazard ratio [HR] 0.46; 95% CI, 0.29 to 0.73; P < .001). The cumulative incidence of grade ≥ 2 any late toxicity was 28.1% versus 48.9% (HR 0.50; 95% CI, 0.33 to 0.76; P < .001), respectively. Patients reported reduced diarrhea (P = .04), improved appetite (P = .008), and lesser bowel symptoms (P = .002) with IG-IMRT. However, no difference was observed in the time by treatment interaction. The 3-year pelvic relapse-free survival and disease-free survival in the IG-IMRT versus the 3D-CRT arm were 81.8% versus 84% (HR 1.17; 95% CI, 0.68 to 1.99; P = .55) and 76.9% versus 81.2% (HR 1.03; 95% CI, 0.62 to 1.71; P = .89), respectively.IG-IMRT results in reduced toxicity with no difference in disease outcomes.
Next-generation sequencing: insights to advance clinical investigations of the microbiome
Authors: Caroline R. Wensel, Jennifer L. Pluznick, Steven L. Salzberg, Cynthia L. Sears
Journal: Journal of Clinical Investigation (2022)

Next-generation sequencing (NGS) technology has advanced our understanding of the human microbiome by allowing for the discovery and characterization of unculturable microbes with prediction of their function. Key NGS methods include 16S rRNA gene sequencing, shotgun metagenomic sequencing, and RNA sequencing. The choice of which NGS methodology to pursue for a given purpose is often unclear for clinicians and researchers. In this Review, we describe the fundamentals of NGS, with a focus on 16S rRNA and shotgun metagenomic sequencing. We also discuss pros and cons of each methodology as well as important concepts in data variability, study design, and clinical metadata collection. We further present examples of how NGS studies of the human microbiome have advanced our understanding of human disease pathophysiology across diverse clinical contexts, including the development of diagnostics and therapeutics. Finally, we share insights as to how NGS might further be integrated into and advance microbiome research and clinical care in the coming years.
Update on and Future Directions for Use of Anti–SARS-CoV-2 Antibodies: National Institutes of Health Summit on Treatment and Prevention of COVID-19
Authors: César Boggiano, Robert W. Eisinger, Andrea M. Lerner, James M. Anderson, Janet Woodcock, Anthony S. Fauci, Francis S. Collins
Journal: Annals of Internal Medicine (2021)

As the fourth wave of the SARS-CoV-2 pandemic encircles the globe, there remains an urgent challenge to identify safe and effective treatment and prevention strategies that can be implemented in a range of health care and clinical settings. Substantial advances have been made in the use of anti-SARS-CoV-2 antibodies to mitigate the morbidity and mortality associated with COVID-19. On 15 June 2021, the National Institutes of Health, in collaboration with the U.S. Food and Drug Administration, convened a virtual summit to summarize existing knowledge on anti-SARS-CoV-2 antibodies and to identify key unanswered scientific questions to further catalyze the clinical development and implementation of antibodies.
Antibody durability at 1 year after Sputnik V vaccination
Authors: Lautaro Sanchez, Santiago Oviedo Rouco, Marina Pifano, Diego S Ojeda, Carla A Pascuale, Bianca Mazzitelli, Facundo Di Diego Garcia, María M Gonzalez Lopez Ledesma, Pamela E Rodriguez, Esteban A Miglietta, Ana Ceballos, Andrés H Rossi, Nicolas Kreplak, Jorge Geffner, Andrea V Gamarnik
Journal: The Lancet Infectious Diseases (2022)
American Heart Association’s Life’s Simple 7: Lifestyle Recommendations, Polygenic Risk, and Lifetime Risk of Coronary Heart Disease
Authors: Natalie R. Hasbani, Symen Ligthart, Michael R. Brown, Adam S. Heath, Allison Bebo, Kellan E. Ashley, Eric Boerwinkle, Alanna C. Morrison, Aaron R. Folsom, David Aguilar, Paul S. de Vries
Journal: Circulation (2022)

Understanding the effect of lifestyle and genetic risk on the lifetime risk of coronary heart disease (CHD) is important to improving public health initiatives. Our objective was to quantify remaining lifetime risk and years free of CHD according to polygenic risk and the American Heart Association's Life's Simple 7 (LS7) guidelines in a population-based cohort study.Our analysis included data from participants of the ARIC (Atherosclerosis Risk in Communities) study: 8372 White and 2314 Black participants; 45 years of age and older; and free of CHD at baseline examination. A polygenic risk score (PRS) comprised more than 6 million genetic variants was categorized into low (<20th percentile), intermediate, and high (>80th percentile). An overall LS7 score was calculated at baseline and categorized into "poor," "intermediate," and "ideal" cardiovascular health. Lifetime risk and CHD-free years were computed according to polygenic risk and LS7 categories.The overall remaining lifetime risk was 27%, ranging from 16.6% in individuals with an ideal LS7 score to 43.1% for individuals with a poor LS7 score. The association of PRS with lifetime risk differed according to ancestry. In White participants, remaining lifetime risk ranged from 19.8% to 39.3% according to increasing PRS categories. Individuals with a high PRS and poor LS7 had a remaining lifetime risk of 67.1% and 15.9 fewer CHD-free years than did those with intermediate polygenic risk and LS7 scores. In the high-PRS group, ideal LS7 was associated with 20.2 more CHD-free years compared with poor LS7. In Black participants, remaining lifetime risk ranged from 19.1% to 28.6% according to increasing PRS category. Similar lifetime risk estimates were observed for individuals of poor LS7 regardless of PRS category. In the high-PRS group, an ideal LS7 score was associated with only 4.5 more CHD-free years compared with a poor LS7 score.Ideal adherence to LS7 recommendations was associated with lower lifetime risk of CHD for all individuals, especially in those with high genetic susceptibility. In Black participants, adherence to LS7 guidelines contributed to lifetime risk of CHD more so than current PRSs. Improved PRSs are needed to properly evaluate genetic susceptibility for CHD in diverse populations.
Abstract 11868: A Reduced Anticoagulation Strategy Among Patients Supported With Ventricular Assist Device is Not Associated With Increased Mortality
Authors: Soomin Shin, Brett Sheridan, Qiwen Huang, Sylvia Sudat, Michael X Pham
Journal: Circulation (2021)

Introduction: Patients with left ventricular assist device (VAD) are typically treated with aspirin and warfarin. However, some patients are unable to tolerate full anticoagulation (AC). There is limited information available regarding intermediate-term outcomes in patients on reduced or no anticoagulation. Methods: Patients who underwent VAD implantation at California Pacific Medical Center from January 2015 to January 2020 were studied retrospectively. Patients received aspirin 81 mg daily and warfarin with a target INR of 2-3, and anticoagulation was gradually de-intensified or withdrawn in response to recurrent mucosal bleeding. Pre-implantation characteristics, thrombolytic events (hemolysis, pump thrombosis requiring exchange, TIA, or ischemic CVA), and survival post-implant were compared among patients treated with full AC vs. reduced or no AC. We performed nonparametric survival analysis to obtain Kaplan-Meier survival estimates as of 9/15/2020. Cox proportional hazards regression was used to adjust for confounders measured at baseline. Results: 91 patients underwent VAD implant (80 HeartMate 3 and 11 HeartMate II). The median age was 65, and the majority of patients (79%) were treated as destination therapy. Reduced AC was used in 43 patients (47%), including no anticoagulation (12 patients), aspirin monotherapy (2 patients), warfarin monotherapy (16), warfarin monotherapy with a reduced INR target (10), and aspirin plus warfarin with a reduced INR target (3). During a median follow-up of 22 months, 15 thrombotic events were observed (12 in the reduced AC group and 3 in the full AC group, P=0.19). Two patients underwent pump exchange. 67% of thrombotic events and both pump exchanges occurred in HMII recipients. Survival was similar in both groups (Figure). Conclusions: The use of a reduced or no anticoagulation strategy after VAD implant is not uncommon and is associated with acceptable outcomes, particularly among HeartMate 3 recipients.
Comparative Analysis and Isoform-Specific Therapeutic Vulnerabilities of<i>KRAS</i>Mutations in Non–Small Cell Lung Cancer
Authors: Biagio Ricciuti, Jieun Son, Jeffrey J. Okoro, Alessia Mira, Enrico Patrucco, Yoonji Eum, Xinan Wang, Raymond Paranal, Haiyun Wang, Mika Lin, Heidi M. Haikala, Jiaqi Li, Yue Xu, Joao Victor Alessi, Chhayheng Chhoeu, Amanda J. Redig, Jens Köhler, Kshiti H. Dholakia, Yunhan Chen, Elodie Richard, Marie-Julie Nokin, David Santamaria, Prafulla C. Gokhale, Mark M. Awad, Pasi A. Jänne, Chiara Ambrogio
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Activating missense mutations of KRAS are the most frequent oncogenic driver events in lung adenocarcinoma (LUAD). However, KRAS isoforms are highly heterogeneous, and data on the potential isoform-dependent therapeutic vulnerabilities are still lacking. Experimental Design: We developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability of KRAS-mutant isoforms. In parallel, we analyzed clinicopathologic and genomic data from 3,560 patients with non–small cell lung cancer (NSCLC) to survey allele-specific features associated with oncogenic KRAS mutations. Results: In isogenic cell lines expressing different mutant KRAS isoforms, we identified isoform-specific biochemical, biological, and oncogenic properties both in vitro and in vivo. These exclusive features correlated with different therapeutic responses to MEK inhibitors, with KRAS G12C and Q61H mutants being more sensitive compared with other isoforms. In vivo, combined KRAS G12C and MEK inhibition was more effective than either drug alone. Among patients with NSCLCs that underwent comprehensive tumor genomic profiling, STK11 and ATM mutations were significantly enriched among tumors harboring KRAS G12C, G12A, and G12V mutations. KEAP1 mutation was significantly enriched among KRAS G12C and KRAS G13X LUADs. KRAS G13X-mutated tumors had the highest frequency of concurrent STK11 and KEAP1 mutations. Transcriptomic profiling revealed unique patterns of gene expression in each KRAS isoform, compared with KRAS wild-type tumors. Conclusions: This study demonstrates that KRAS isoforms are highly heterogeneous in terms of concurrent genomic alterations and gene-expression profiles, and that stratification based on KRAS alleles should be considered in the design of future clinical trials.
Bicyclic Peptide Makes Targeting EphA2 Possible
Journal: Cancer Discovery (2021)

A tumor-penetrating bicyclic peptide that delivers a toxic payload may have finally unlocked the therapeutic potential of targeting EphA2. According to phase I trial data, BT5528 yielded clinical responses in three patients with ovarian and urothelial cancers-without any of the toxicity issues that have plagued other EphA2-directed therapeutic candidates.
Randomized Phase III Trial Evaluating Radiation Following Surgical Excision for Good-Risk Ductal Carcinoma In Situ: Long-Term Report From NRG Oncology/RTOG 9804
Authors: Beryl McCormick, Kathryn A. Winter, Wendy Woodward, Henry M. Kuerer, Nour Sneige, Eileen Rakovitch, Barbara L. Smith, Isabelle Germain, Alan C. Hartford, Mark A. O'Rourke, Eleanor M. Walker, Eric A. Strom, Judith O. Hopkins, Lori J. Pierce, Anthony T. Pu, Kenneth N. M. Sumida, Danny Vesprini, Jennifer Moughan, Julia R. White
Journal: Journal of Clinical Oncology (2021)

To our knowledge, NRG/RTOG 9804 is the only randomized trial to assess the impact of whole breast irradiation (radiation therapy [RT]) versus observation (OBS) in women with good-risk ductal carcinoma in situ (DCIS), following lumpectomy. Long-term results focusing on ipsilateral breast recurrence (IBR), the primary outcome, are presented here.Eligible patients underwent lumpectomy for DCIS that was mammogram detected, size ≤ 2.5 cm, final margins ≥ 3 mm, and low or intermediate nuclear grade. Consented patients were randomly assigned to RT or OBS. Tamoxifen use was optional. Cumulative incidence was used to estimate IBR, log-rank test and Gray's test to compare treatments, and Fine-Gray regression for hazard ratios (HRs).A total of six hundred thirty-six women were randomly assigned from 1999 to 2006. Median age was 58 years and mean pathologic DCIS size was 0.60 cm. Intention to use tamoxifen was balanced between arms (69%); however, actual receipt of tamoxifen varied, 58% RT versus 66% OBS (P = .05). At 13.9 years' median follow-up, the 15-year cumulative incidence of IBR was 7.1% (95% CI, 4.0 to 11.5) with RT versus 15.1% (95% CI, 10.8 to 20.2) OBS (P = .0007; HR = 0.36; 95% CI, 0.20 to 0.66); and for invasive LR was 5.4% (95% CI, 2.7 to 9.5) RT versus 9.5% (95% CI, 6.0 to 13.9) OBS (P = .027; HR = 0.44; 95% CI, 0.21 to 0.91). On multivariable analysis, only RT (HR = 0.34; 95% CI, 0.19 to 0.64; P = .0007) and tamoxifen use (HR = 0.45; 95% CI, 0.25 to 0.78; P = .0047) were associated with reduced IBR.RT significantly reduced all and invasive IBR for good-risk DCIS with durable results at 15 years. These results are not an absolute indication for RT but rather should inform shared patient-physician treatment decisions about ipsilateral breast risk reduction in the long term following lumpectomy.
There is no generalizability crisis
Authors: Daniël Lakens, Duygu Uygun Tunç, Mehmet Necip Tunç
Journal: Behavioral and Brain Sciences (2022)

Abstract Falsificationist and confirmationist approaches provide two well-established ways of evaluating generalizability. Yarkoni rejects both and invents a third approach we call neo-operationalism . His proposal cannot work for the hypothetical concepts psychologists use, because the universe of operationalizations is impossible to define, and hypothetical concepts cannot be reduced to their operationalizations. We conclude that he is wrong in his generalizability-crisis diagnosis.
146P Impact of heart, lung and oesophageal doses on overall survival (OS) of small cell lung cancer (SCLC) patients following radical chemo-radiotherapy (RT)
Authors: B.A. Tahir, J.M. Reilly, J. Tay, H. Clinch, N. Boindala, J. Hughes, S. Riley, P. Roxby, S. Tozer-Loft, T. Aung, M. Qureshi, T. Das, M. Hatton
Journal: Annals of Oncology (2022)
To Degrade or Not to Degrade DNMT3A
Authors: Yuhong Ma, Britta Will
Journal: Cancer Discovery (2022)

Abstract Summary: Aberrant DNA cytosine methylation is a critical contributor to compromised tissue regeneration and malignant transformation, particularly during aging. In this issue of Cancer Discovery, Huang and colleagues define a new class of disease-associated DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A) variants with decreased de novo DNA methylation activity due increased proteasomal degradation that are able to drive clonal expansion of hematopoietic stem cells. See related article by Huang et al., p. 220.
Neuronal mitochondria transport Pink1 mRNA via synaptojanin 2 to support local mitophagy
Authors: Angelika B. Harbauer, J. Tabitha Hees, Simone Wanderoy, Inmaculada Segura, Whitney Gibbs, Yiming Cheng, Martha Ordonez, Zerong Cai, Romain Cartoni, Ghazaleh Ashrafi, Chen Wang, Fabiana Perocchi, Zhigang He, Thomas L. Schwarz
Journal: Neuron (2022)
Phenotypes of Patients with COVID-19 Who Have a Positive Clinical Response to Helmet Noninvasive Ventilation
Authors: Domenico Luca Grieco, Luca S. Menga, Melania Cesarano, Savino Spadaro, Maria Maddalena Bitondo, Cecilia Berardi, Tommaso Rosà, Filippo Bongiovanni, Salvatore Maurizio Maggiore, Massimo Antonelli, Jonathan Montomoli, Giulia Falò, Tommaso Tonetti, Salvatore L. Cutuli, Gabriele Pintaudi, Eloisa S. Tanzarella, Edoardo Piervincenzi, Antonio M. Dell’Anna, Luca Delle Cese, Simone Carelli, Maria Grazia Bocci, Luca Montini, Giuseppe Bello, Daniele Natalini, Gennaro De Pascale, Matteo Velardo, Carlo Alberto Volta, V. Marco Ranieri, Giorgio Conti, Riccardo Maviglia, Giovanna Mercurio, Paolo De Santis, Mariano Alberto Pennisi, Gian Marco Anzellotti, Flavia Torrini, Carlotta Rubino, Tony C. Morena, Veronica Gennenzi, Stefania Postorino, Joel Vargas, Nicoletta Filetici, Donatella Settanni, Miriana Durante, Laura Cascarano, Mariangela Di Muro, Roberta Scarascia, Martina Murdolo, Alessandro Mele, Serena Silva, Carmelina Zaccone, Francesca Pozzana, Alessio Maccaglia, Martina Savino, Antonella Potalivo, Francesca Ceccaroni, Angela Scavone, Gianmarco Lombardi, Teresa Michi
Journal: American Journal of Respiratory and Critical Care Medicine (2021)
Hazardous alcohol use and alcohol-related harm in rural and remote communities: a scoping review
Authors: Erik Loewen Friesen, Jacob Bailey, Sarah Hyett, Sina Sedighi, Mitchell Lennox de Snoo, Kenneth Williams, Rebecca Barry, Anders Erickson, Farid Foroutan, Peter Selby, Laura Rosella, Paul Kurdyak
Journal: The Lancet Public Health (2021)
A novel peptide encoded by N6-methyladenosine modified circMAP3K4 prevents apoptosis in hepatocellular carcinoma
Authors: Jin-Ling Duan, Wei Chen, Juan-Juan Xie, Mao-Lei Zhang, Run-Cong Nie, Hu Liang, Jie Mei, Kai Han, Zhi-Cheng Xiang, Feng-Wei Wang, Kai Teng, Ri-Xin Chen, Min-Hua Deng, Yi-Xin Yin, Nu Zhang, Dan Xie, Mu-Yan Cai
Journal: Molecular Cancer (2022)

Circular RNAs (circRNAs) regulate various biological activities and have been shown to play crucial roles in hepatocellular carcinoma (HCC) progression. However, only a few coding circRNAs have been identified in cancers, and their roles in HCC remain elusive. This study aimed to identify coding circRNAs and explore their function in HCC.
Eosinophilic Granulomatosis with Polyangiitis
Authors: Geng-Yi Yong, Amelia L-S Lim
Journal: New England Journal of Medicine (2022)

A 42-year-old man presented with red, painful eyes, facial-nerve palsy on the left side, a large oral ulcer, and petechiae. Tests for antibodies against perinuclear antineutrophil cytoplasmic antibody and proteinase 3 were positive. Skin biopsy revealed leukocytoclastic vasculitis with perivascular eosinophils. A diagnosis of eosinophilic granulomatosis with polyangiitis was made.
Neonatal Resuscitation in 22-Week Pregnancies
Authors: Clement D. Lee, Leif Nelin, Elizabeth E. Foglia
Journal: New England Journal of Medicine (2022)

This interactive feature about infants born very prematurely offers a case vignette accompanied by two essays supporting resuscitation in all neonates born at 22 weeks’ gestation or selective resuscitation. Vote and comment at NEJM.org.
PINCH-1 promotes IGF-1 receptor expression and skin cancer progression through inhibition of the GRB10-NEDD4 complex
Authors: Xiaoxiao Wang, Rong Wang, Kun Jiang, Maohua Zhu, Ling Guo, Chuanyue Wu
Journal: Theranostics (2022)

Background: Insulin-like growth factor 1 receptor (IGF-1R) expression and signaling play important roles in promotion of skin cancer progression.Identification of signaling pathways that regulate IGF-1R is crucial for understanding the pathogenesis and therapeutic treatment of skin cancer.Methods: Molecular, cellular and genetic approaches were used to investigate the function of PINCH-1 in regulation of IGF-1R expression and skin cell behavior.Furthermore, conditional PINCH-1 knockout mouse and carcinogen (7, 12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA))-induced skin cancer model were employed to determine the function of PINCH-1 in regulation of IGF-1R expression and skin carcinogenesis in vivo.Results: Knockdown of PINCH-1 from HaCaT keratinocytes or A431 squamous carcinoma cells diminished IGF-1R levels, suppressed cell proliferation and increased apoptosis.Re-expression of PINCH-1 in PINCH-1 knockdown cells restored IGF-1R expression, cell proliferation and survival.Furthermore, depletion of NEDD4 effectively reversed PINCH-1 deficiency-induced down-regulation of IGF-1R expression, cell proliferation and survival.Conditional knockout of PINCH-1 from keratin 5 (K5) positive keratinocytes in mice, like depletion of PINCH-1 from keratinocytes in culture, reduced the IGF-1R level.Using a mouse model of DMBA/TPA-induced skin cancer, we show that the levels of both PINCH-1 and IGF-1R were significantly increased in response to treatment with the carcinogens.Genetic ablation of PINCH-1 from the epidermis markedly reduced the IGF-1R expression and cell proliferation despite stimulation with DMBA/TPA, resulting in resistance to chemical carcinogen-induced skin cancer initiation and progression.Conclusions: Our results reveal a PINCH-1-NEDD4-IGF-1R signaling axis that is critical for promotion of skin tumorigenesis and suggest a new strategy for therapeutic control of skin cancer progression.
Case 36-2021: A 22-Year-Old Man with Pain and Erythema of the Left Hand
Authors: Lisa G. Winston, Marisa L. Winkler, Arvin Kheterpal, Julian A. Villalba
Journal: New England Journal of Medicine (2021)

A 22-year-old man was admitted with pain and erythema of the left hand. On the day of admission, he awoke with pain and swelling of the hand that involved the second and fourth fingers. Over several hours, the pain progressed and bullae began to form. The patient had recently begun practicing taxidermy. A diagnostic test was performed.