tbuckley/cabot-search huggingface dataset:
Common Postzygotic Mutational Signatures in Healthy Adult Tissues Related to Embryonic Hypoxia
Authors: Yaqiang Hong, Dake Zhang, Xiangtian Zhou, Aili Chen, Amir Abliz, Jian Bai, Liang Wang, Qingtao Hu, Kenan Gong, Xiaonan Guan, Mengfei Liu, Xinchang Zheng, Shujuan Lai, Hongzhu Qu, Fuxin Zhao, Shuang Hao, Zhen Wu, Hong Cai, Shaoyan Hu, Yue Ma, Junting Zhang, Yang Ke, Qian-Fei Wang, Wei Chen, Changqing Zeng
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Postzygotic mutations are acquired in normal tissues throughout an individual’s lifetime and hold clues for identifying mutagenic factors. Here, we investigated postzygotic mutation spectra of healthy individuals using optimized ultra-deep exome sequencing of the time-series samples from the same volunteer as well as the samples from different individuals. In blood, sperm, and muscle cells, we resolved three common types of mutational signatures. Signatures A and B represent clock-like mutational processes, and the polymorphisms of epigenetic regulation genes influence the proportion of signature B in mutation profiles. Notably, signature C, characterized by C&amp;gt;T transitions at GpCpN sites, tends to be a feature of diverse normal tissues. Mutations of this type are likely to occur early during embryonic development, supported by their relatively high allelic frequencies, presence in multiple tissues, and decrease in occurrence with age. Almost none of the public datasets for tumors feature this signature, except for 19.6% of samples of clear cell renal cell carcinoma with increased activation of the hypoxia-inducible factor 1 (HIF-1) signaling pathway. Moreover, the accumulation of signature C in the mutation profile was accelerated in a human embryonic stem cell line with drug-induced activation of HIF-1α. Thus, embryonic hypoxia may explain this novel signature across multiple normal tissues. Our study suggests that hypoxic condition in an early stage of embryonic development is a crucial factor inducing C&amp;gt;T transitions at GpCpN sites; and individuals’ genetic background may also influence their postzygotic mutation profiles.
542P Ezabenlimab (BI 754091) monotherapy in patients (pts) with advanced solid tumours
Authors: M.R. Patel, M.L. Johnson, I. Winer, H-T. Arkenau, N. Cook, V. Samouëlian, R. Aljumaily, S. Kitano, C. Duffy, M. Ge, M. Elgadi, L.L. Siu
Journal: Annals of Oncology (2021)
1338P A phase III study comparing BCD-021, a bevacizumab biosimilar, and reference bevacizumab in patients with stage IIIB or IV non-squamous NSCLC
Authors: N. Fadeeva, B. Roy, R. Nagarkar, H. Adamchuk, M. Matrosova, S. Tjulandin, D. Stroyakovskiy, D. Zhuravleva, G. Voevodin, M. Shustova, K.A. Kryukov, V. Chistiakov
Journal: Annals of Oncology (2021)
1090TiP A phase II, open label, multicenter study to investigate the efficacy and safety of domatinostat in combination with avelumab in patients with treatment-naïve metastatic Merkel cell carcinoma: The MERKLIN 1 study
Authors: P.A. Ascierto, A.C.J. van Akkooi, P. Nghiem, F. Hermann, J-P. Henneberg, J.C. Becker
Journal: Annals of Oncology (2021)
1068P Efficacy of combined hypo-fractionated radiotherapy (RT) in anti-PD-1 monotherapy-treated melanoma pts
Authors: P. Saiag, R. Molinier, A. Roger, B. Boru, Y. Otmezguine, J. Otz, C. Valery, A. Blom Fily, C. Longvert, A. Beauchet, E. Funck-Brentano
Journal: Annals of Oncology (2021)
562TiP A phase Ib dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy in patients with platinum-resistant or -refractory ovarian, peritoneal, or fallopian tube cancer
Authors: S. Fu, A. Pasic, G. Richardson, Z.J. Vranjes, T. Meniawy, P.R. de Jong, F. Donate, A.A. Samatar, J. Rodriguez, P. Pultar, D. Voliotis
Journal: Annals of Oncology (2021)
Serrated lesions and adenomas in colonoscopic surveillance: additive or exponential?
Authors: James Edward East
Journal: Gut (2021)

Our view of serrated polyps has come a long way in the last two decades, moving from seeing them as benign lesions that do not develop into cancer to recognising them as lesions that may account for up to one-third of all colorectal cancers (CRCs).1 The ‘serrated pathway’ to CRC is now widely accepted, and serrated lesions are now a target for identification and removal at screening colonoscopy. They represent a special challenge for colonoscopists as they are difficult to detect and are up to 3.7 times more likely than adenomas to be incompletely resected.2 It is assumed that removal of precursor serrated lesions prevents development of CRC in the future; however, direct evidence for this is much more limited than for adenomas. Work on intensive surveillance of patients with serrated polyposis syndrome suggests that effective detection and resection can reduce cancer risk in a polyposis scenario.3

The role of adenomas in colonoscopic screening is not just limited to being a removable precursor lesion that halts the ‘adenoma–carcinoma sequence’ to reduce future risk. Adenoma size and multiplicity also predicts future risk of developing further advanced adenomas or CRC. On this basis, international guidelines have recommended surveillance examinations after large or multiple adenomas have been resected.4 5 Data to support such an approach for serrated polyps have been much more limited, in part because we do not have large longitudinal datasets at times where serrated polyps were being effectively detected by colonoscopists, and correctly classified by pathologists. The study by Li et al in Gut is therefore a very welcome addition …
Digital Gonioscopy Based on Three-dimensional Anterior-Segment OCT
Authors: Fei Li, Yifan Yang, Xu Sun, Zhen Qiu, Shihao Zhang, Tin Aung Tun, Baskaran Mani, Monisha Esther Nongpiur, Sunee Chansangpetch, Kitiya Ratanawongphaibul, Anita Manassakorn, Visanee Tantisevi, Prin Rojanapongpun, Fengbin Lin, Weijing Cheng, Rouxi Zhou, Yuhong Liu, Yu Chen, Jian Xiong, Mingkui Tan, Tin Aung, Yanwu Xu, Daniel S.W. Ting, Xiulan Zhang
Journal: Ophthalmology (2021)
From the Cochrane Library: Interventions for infantile seborrheic dermatitis (including cradle cap)
Authors: Shahzeb Hassan, Mindy D. Szeto, Torunn E. Sivesind, Rohail Memon, Abraar Muneem, Anousha Victoire, Parker J. Magin, Mieke L. van Driel, Motassem Nashawaty, Robert P. Dellavalle
Journal: Journal of the American Academy of Dermatology (2021)
1776P Immune microenvironment, homologous recombination deficiency and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: JBCRG22 TR
Authors: T. Ueno, S. Kitano, N. Masuda, D. Ikarashi, M. Yamashita, T. Kadoya, H. Bando, T. Yamanaka, S. Ohtani, S. Nagai, T. Nakayama, M. Takahashi, S. Saji, K. Aogi, R.M. Velaga, K. Kawaguchi, S. Morita, H. Haga, S. Ohno, M. Toi
Journal: Annals of Oncology (2021)
Novel pharmacological strategies to treat cognitive dysfunction in chronic obstructive pulmonary disease
Authors: Aleksandar Dobric, Simone N. De Luca, Sarah J. Spencer, Steven Bozinovski, Michael M. Saling, Christine F. McDonald, Ross Vlahos
Journal: Pharmacology & Therapeutics (2021)

Chronic obstructive pulmonary disease (COPD) is a major incurable global health burden and currently the 3rd largest cause of death in the world, with approximately 3.23 million deaths per year. Globally, the financial burden of COPD is approximately €82 billion per year and causes substantial morbidity and mortality. Importantly, much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and viral and bacterial-induced acute exacerbations (AECOPD). Recent clinical studies have shown that cognitive dysfunction is present in up to 60% of people with COPD, with impairments in executive function, memory, and attention, impacting on important outcomes such as quality of life, hospitalisation and survival. The high prevalence of cognitive dysfunction in COPD may also help explain the insufficient adherence to therapeutic plans and strategies, thus worsening disease progression in people with COPD. However, the mechanisms underlying the impaired neuropathology and cognition in COPD remain largely unknown. In this review, we propose that the observed pulmonary oxidative burden and inflammatory response of people with COPD 'spills over' into the systemic circulation, resulting in damage to the brain and leading to cognitive dysfunction. As such, drugs targeting the lungs and comorbidities concurrently represent an exciting and unique therapeutic opportunity to treat COPD and cognitive impairments, which may lead to the production of novel targets to prevent and reverse the debilitating and life-threatening effects of cognitive dysfunction in COPD.
Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue
Authors: Gretchen Thomsen, Arthur H. M. Burghes, Caroline Hsieh, Janet Do, Binh T. T. Chu, Stephanie Perry, Basam Barkho, Petra Kaufmann, Douglas M. Sproule, Douglas E. Feltner, Wendy K. Chung, Vicki L. McGovern, Robert F. Hevner, Miriam Conces, Christopher R. Pierson, Mariacristina Scoto, Francesco Muntoni, Jerry R. Mendell, Kevin D. Foust
Journal: Nature Medicine (2021)
Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors
Authors: Ana Marcu, Andreas Schlosser, Anne Keupp, Nico Trautwein, Pascal Johann, Matthias Wölfl, Johanna Lager, Camelia Maria Monoranu, Juliane S Walz, Lisa M Henkel, Jürgen Krauß, Martin Ebinger, Martin Schuhmann, Ulrich Wilhelm Thomale, Torsten Pietsch, Erdwine Klinker, Paul G Schlegel, Florian Oyen, Yair Reisner, Hans-Georg Rammensee, Matthias Eyrich
Journal: Journal for ImmunoTherapy of Cancer (2021)

Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells.Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM.Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8+ T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors.These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.
Moving fast and seeing slow? The visual consequences of vigorous movement
Authors: Martin Rolfs, Sven Ohl
Journal: Behavioral and Brain Sciences (2021)

Abstract In active agents, sensory and motor processes form an inevitable bond. This wedding is particularly striking for saccadic eye movements – the prime target of Shadmehr and Ahmed's thesis – which impose frequent changes on the retinal image. Changes in movement vigor (latency and speed), therefore, will need to be accompanied by changes in visual and attentional processes. We argue that the mechanisms that control movement vigor may also enable vision to attune to changes in movement kinematics.
533P Efficacy and safety of entrectinib in patients with locally advanced/metastatic NTRK fusion-positive (NTRK-fp) solid tumours
Authors: L. Bazhenova, S.V. Liu, J.J. Lin, S. Lu, A. Drilon, S.P. Chawla, M. Fakih, M. Krzakowski, L. Paz-Ares, C. Blakely, G.L. Buchschacher, P. Cassier, Y. Fan, G. Folprecht, S. McCallum, B. Pitcher, D. Chen, R. Freund, C. Springfeld
Journal: Annals of Oncology (2021)
890P Concordance analysis of PD-L1 CPS in different sample types of head and neck squamous cell cancer
Authors: S.J. De Keukeleire, T. Vermassen, P. Deron, W. Huvenne, F. Duprez, J. Van Dorpe, D. Creytens, L. Ferdinande, S. Rottey
Journal: Annals of Oncology (2021)
Integration of glucose and cardiolipin anabolism confers radiation resistance of HCC
Authors: Yuan Fang, Yizhi Zhan, Yuwen Xie, Shisuo Du, Yuhan Chen, Zhaochong Zeng, Yaowei Zhang, Keli Chen, Yongjia Wang, Li Liang, Yi Ding, Dehua Wu
Journal: Hepatology (2021)

Abstract Background and Aims Poor response to ionizing radiation (IR) due to resistance remains a clinical challenge. Altered metabolism represents a defining characteristic of nearly all types of cancers. However, how radioresistance is linked to metabolic reprogramming remains elusive in hepatocellular carcinoma (HCC). Approach and Results Baseline radiation responsiveness of different HCC cells were identified and cells with acquired radio‐resistance were generated. By performing proteomics, metabolomics, metabolic flux, and other functional studies, we depicted a metabolic phenotype that mediates radiation resistance in HCC, whereby increased glucose flux leads to glucose addiction in radioresistant HCC cells and a corresponding increase in glycerophospholipids biosynthesis to enhance the levels of cardiolipin. Accumulation of cardiolipin dampens the effectiveness of IR by inhibiting cytochrome c release to initiate apoptosis. Mechanistically, mammalian target of rapamycin complex 1 (mTORC1) signaling‐mediated translational control of hypoxia inducible factor‐1α (HIF‐1α) and sterol regulatory element‐binding protein‐1 (SREBP1) remodels such metabolic cascade. Targeting mTORC1 or glucose to cardiolipin synthesis, in combination with IR, strongly diminishes tumor burden. Finally, activation of glucose metabolism predicts poor response to radiotherapy in cancer patients. Conclusions We demonstrate a link between radiation resistance and metabolic integration and suggest that metabolically dismantling the radioresistant features of tumors may provide potential combination approaches for radiotherapy in HCC.
Endoscopic management of colocolic intussusception in an adult with colonic stent placement
Authors: Raosaheb Rathod, Sridhar Sundaram, Aadish Kumar Jain, Kiran Mane, Prachi Patil, Shaesta Mehta
Journal: Endoscopy (2021)

A 47-year-old man with a history of gastric cancer, initially treated by subtotal gastrectomy, with subsequent recurrence in the periampullary region and peritoneal metastases, presented with abdominal distension and obstipation for 3 days. He was started on intravenous hydration and kept nil per os. A computed tomography (CT) scan of the abdomen showed involution of the right-sided colon and neighboring peritoneal thickening, with a target sign, and dilated cecum and small-bowel loops, suggestive of right-sided colocolic intussusception ([Fig. 1]).
Camrelizumab plus apatinib in patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia (CAP 01): a single-arm, open-label, phase 2 trial
Authors: Hongyan Cheng, Liju Zong, Yujia Kong, Xiaoyu Wang, Yu Gu, Wei Cang, Jun Zhao, Xirun Wan, Junjun Yang, Yang Xiang
Journal: The Lancet Oncology (2021)
1743MO MERAIODE: A redifferentiation phase II trial with trametinib followed by radioactive iodine for metastatic radioactive iodine refractory differentiated thyroid cancer patients with a RAS mutation
Authors: S. Leboulleux, D. Benisvy, D. Taieb, M. Attard, C. Bournaud, M. Terroir, A. Al Ghuzlan, L. Lamartina, M.J. Schlumberger, Y. Godbert, I. Borget
Journal: Annals of Oncology (2021)
1393P Phase I/II clinical trial of combination of anti-PD-1 mAb, nivolumab with radiotherapy for unresectable and recurrent gastric cancer who failed to standard chemotherapy
Authors: K. Kono, K. Mimura, T. Ogata, Y. Yoshimoto, D. Yoshida, S. Nakajima, H. Sato, N. Machida, T. Yamada, Y. Watanabe, T. Tamaki, H. Fujikawa, Y. Inokuchi, H. Onozawa, S. Hayase, H. Hanayama, Z. Saze, H. Katoh, T. Oshima, Y. Suzuki
Journal: Annals of Oncology (2021)
955P Prognostic factor analysis of atezolizumab-bevacizumab in unresectable hepatocellular carcinoma: Korean cancer study group (KCSG) study
Authors: J. Cheon, C. Yoo, J.Y. Hong, H.S. Kim, D-W. Lee, M.A. Lee, J.W. Kim, I. Kim, S-B. Oh, J-E. Hwang, H.J. Chon, H.Y. Lim
Journal: Annals of Oncology (2021)
Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial
Authors: Randolph P. Matthews, Munjal Patel, Stephanie E. Barrett, Liesbeth Haspeslagh, Tom Reynders, Saijuan Zhang, Sylvie Rottey, Adrian Goodey, Ryan C. Vargo, Jay A. Grobler, S. Aubrey Stoch, Marian Iwamoto
Journal: Nature Medicine (2021)
Increased coexpression of PD-L1 and TIM3/TIGIT is associated with poor overall survival of patients with esophageal squamous cell carcinoma
Authors: Peipei Wang, Yueyun Chen, Qingqin Long, Qing Li, Jiangfang Tian, Ting Liu, Yong Wu, Zhenyu Ding
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Immune checkpoint (IC) blockades (ICBs) significantly improve patients’ clinical outcomes with solid tumors. Because the objective response rate of single-agent ICB is limited, it is meaningful to explore the combination of ICs for immunotherapy. Methods RNA sequencing data of 95 newly diagnosed patients with esophageal squamous cell carcinoma (ESCC) from The Cancer Genome Atlas (TCGA) database were used to explore the prognostic significance of ICs. The results were validated by immunohistochemistry of 58 ESCC tissue samples from our clinical center. Results The results of both TCGA and validation data suggested that high expression of programmed cell death 1 ligand 1 (PD-L1), T-cell immunoglobulin and mucin-domain-containing-3 (TIM3), and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) was associated with poor overall survival (OS) of patients with ESCC. Importantly, PD-L1/TIM3 or PD-L1/TIGIT was the optimal combination for predicting poor OS and short restricted mean survival time of patients with ESCC and was an independent prognostic factor. Moreover, a nomogram model constructed by PD-L1, TIM3, and TIGIT together with the primary tumor, regional lymph node, distant metastasis stage could provide a concise and precise prediction of 1-year and 2-year OS rates and median survival time. PD-L1/TIM3 or PD-L1/TIGIT had a positive correlation with CD8+ T cells. Notably, PD-1 and TIM3/TIGIT were primarily coexpressed on CD8+ tumor-infiltrating lymphocyte in patients with ESCC by multiplexed immunofluorescence. Conclusion High expression of ICs was associated with poor OS of patients with ESCC. PD-L1/TIM3 and PD-L1/TIGIT were the optimal combinations for predicting OS, which might be potential targets for future ICBs therapy of ESCC.
Aspirin Use to Prevent Preeclampsia and Related Morbidity and Mortality
Authors: Karina W. Davidson, Michael J. Barry, Carol M. Mangione, Michael Cabana, Aaron B. Caughey, Esa M. Davis, Katrina E. Donahue, Chyke A. Doubeni, Martha Kubik, Li Li, Gbenga Ogedegbe, Lori Pbert, Michael Silverstein, Melissa A. Simon, James Stevermer, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2021)

<h3>Importance</h3> Preeclampsia is one of the most serious health problems that affect pregnant persons. It is a complication in approximately 4% of pregnancies in the US and contributes to both maternal and infant morbidity and mortality. Preeclampsia also accounts for 6% of preterm births and 19% of medically indicated preterm births in the US. There are racial and ethnic disparities in the prevalence of and mortality from preeclampsia. Non-Hispanic Black women are at greater risk for developing preeclampsia than other women and experience higher rates of maternal and infant morbidity and perinatal mortality. <h3>Objective</h3> To update its 2014 recommendation, the USPSTF commissioned a systematic review to evaluate the effectiveness of low-dose aspirin use to prevent preeclampsia. <h3>Population</h3> Pregnant persons at high risk for preeclampsia who have no prior adverse effects with or contraindications to low-dose aspirin. <h3>Evidence Assessment</h3> The USPSTF concludes with moderate certainty that there is a substantial net benefit of daily low-dose aspirin use to reduce the risk for preeclampsia, preterm birth, small for gestational age/intrauterine growth restriction, and perinatal mortality in pregnant persons at high risk for preeclampsia. <h3>Recommendation</h3> The USPSTF recommends the use of low-dose aspirin (81 mg/d) as preventive medication for preeclampsia after 12 weeks of gestation in persons who are at high risk for preeclampsia. (B recommendation)
1666TiP Phase II study of berzosertib (M6620) + topotecan in patients with relapsed platinum-resistant SCLC: DDRiver SCLC 250
Authors: A. Thomas, F. Cappuzzo, C. Ying, N. Yamamoto, Y. Chen, A.B. Cortot, T. Berghmans, N. Reguart Aransay, Y. Shibata, Z. Jianying, T. Yoshida, C. Moulin, B. Sarholz, J. Ferrer-Playan, A. Kalapur, J. Bolleddula, L. Paz-Ares
Journal: Annals of Oncology (2021)
Complex karyotype in unfit patients with CLL treated with ibrutinib and rituximab: the GIMEMA LLC1114 phase 2 study
Authors: Gian Matteo Rigolin, Ilaria Del Giudice, Antonella Bardi, Aurora Melandri, Rocio Edith García-Jacobo, Francesca Cura, Sara Raponi, Caterina Ilari, Luciana Cafforio, Alfonso Piciocchi, Valentina Arena, Gianluigi Reda, Francesco Albano, Stefano Molica, Paolo Sportoletti, Livio Trentin, Monia Marchetti, Mauro Nanni, Nadia Peragine, Paola Mariglia, Marco Vignetti, Anna Guarini, Francesca Romana Mauro, Robin Foà, Antonio Cuneo
Journal: Blood (2021)