tbuckley/cabot-search huggingface dataset:
Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine
Authors: Christoph Röcken, Anu Amallraja, Christine Halske, Luka Opasic, Arne Traulsen, Hans-Michael Behrens, Sandra Krüger, Anne Liu, Jochen Haag, Jan-Hendrik Egberts, Philip Rosenstiel, Tobias Meißner
Journal: Genome Medicine (2021)

Abstract Background Cancer is a somatic evolutionary disease and adenocarcinomas of the stomach and gastroesophageal junction (GC) may serve as a two-dimensional model of cancer expansion, in which tumor subclones are not evenly mixed during tumor progression but rather spatially separated and diversified. We hypothesize that precision medicine efforts are compromised when clinical decisions are based on a single-sample analysis, which ignores the mechanisms of cancer evolution and resulting intratumoral heterogeneity. Using multiregional whole-exome sequencing, we investigated the effect of somatic evolution on intratumoral heterogeneity aiming to shed light on the evolutionary biology of GC. Methods The study comprised a prospective discovery cohort of 9 and a validation cohort of 463 GCs. Multiregional whole-exome sequencing was performed using samples form 45 primary tumors and 3 lymph node metastases (range 3–10 tumor samples/patient) of the discovery cohort. Results In total, the discovery cohort harbored 16,537 non-synonymous mutations. Intratumoral heterogeneity of somatic mutations and copy number variants were present in all tumors of the discovery cohort. Of the non-synonymous mutations, 53–91% were not present in each patient’s sample; 399 genes harbored 2–4 different non-synonymous mutations in the same patient; 175 genes showed copy number variations, the majority being heterogeneous, including CD274 (PD-L1). Multi-sample tree-based analyses provided evidence for branched evolution being most complex in a microsatellite instable GC. The analysis of the mode of evolution showed a high degree of heterogeneity in deviation from neutrality within each tumor. We found evidence of parallel evolution and evolutionary trajectories: different mutations of SMAD4 aligned with different subclones and were found only in TP53 mutant GCs. Conclusions Neutral and non-neutral somatic evolution shape the mutational landscape in GC along its lateral expansions. It leads to complex spatial intratumoral heterogeneity, where lymph node metastases may stem from different areas of the primary tumor, synchronously. Our findings may have profound effects on future patient management. They illustrate the risk of mis-interpreting tumor genetics based on single-sample analysis and open new avenues for an evolutionary classification of GC, i.e., the discovery of distinct evolutionary trajectories which can be utilized for precision medicine.
<i>Aim2</i> Couples With <i>Ube2i</i> for Sumoylation‐Mediated Repression of Interferon Signatures in Systemic Lupus Erythematosus
Authors: Ailing Lu, Shuxian Wu, Junling Niu, Mengmeng Cui, Mengdan Chen, William L. Clapp, Betsy J. Barnes, Guangxun Meng
Journal: Arthritis & Rheumatology (2021)

Objective Systemic lupus erythematosus (SLE) involves kidney damage, and the inflammasome‐caspase‐1 axis has been demonstrated to promote renal pathogenesis. The present study was designed to explore the function of the Absent in Melanoma 2 (Aim2) protein in SLE. Methods Female wild‐type Aim2 −/− , Aim2 −/− Ifnar1 −/− , Aim2 −/− Rag1 −/− , and Asc −/− mice ages 8–10 weeks received 1 intraperitoneal injection of 500 μl pristane or saline, and survival of mice was monitored twice a week for 6 months. Results The absence of Aim2 , but not Asc , led to enhanced SLE in mice that received pristane treatment. Increased immune cell infiltration and type I interferon (IFN) signatures in the kidneys of Aim2 −/− mice coincided with severity of lupus, which was alleviated by blockade of Ifnar1 ‐mediated signal. Adaptive immune cells were also involved in the glomerular lesions of Aim2 −/− mice after pristane challenge. Importantly, even in the absence of pristane, plasmacytoid dendritic cells in the kidneys of Aim2 −/− mice were significantly increased compared to control animals. Accordingly, transcriptome analysis revealed that Aim2 deficiency led to enhanced expression of type I IFN–induced genes in the kidneys even at an early developmental stage. Mechanistically, Aim2 bound ubiquitin‐conjugating enzyme 2i (Ube2i), which mediates sumoylation‐based suppression of type I IFN expression deficiency of Aim2 decreased cellular sumoylation, resulting in an augmented type I IFN signature and kidney pathogenesis. Conclusion The present study demonstrates a critical role for Aim2 in an optimal Ube2i ‐mediated sumoylation‐based suppression of type I IFN generation and development of SLE. As such, the Aim2 – Ube2i axis can thus be a novel target for intervention in SLE.
In women aged 40 to 48 y, annual mammography vs. usual care reduced breast cancer mortality at 10 but not 23 y
Authors: Pelin Batur
Journal: Annals of Internal Medicine (2021)

Duffy SW, Vulkan D, Cuckle H, et al. Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial. Lancet Oncol. 2020;21:1165-72. 32800099.
Federated semi-supervised learning for COVID region segmentation in chest CT using multi-national data from China, Italy, Japan
Authors: Dong Yang, Ziyue Xu, Wenqi Li, Andriy Myronenko, Holger R. Roth, Stephanie Harmon, Sheng Xu, Baris Turkbey, Evrim Turkbey, Xiaosong Wang, Wentao Zhu, Gianpaolo Carrafiello, Francesca Patella, Maurizio Cariati, Hirofumi Obinata, Hitoshi Mori, Kaku Tamura, Peng An, Bradford J. Wood, Daguang Xu
Journal: Medical Image Analysis (2021)
Rectal and Anal Surgery; with Description of the Secret Methods of the Itinerant Specialists.
Journal: JAMA (1889)

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Simplified Geriatric Assessment in Older Patients With Diffuse Large B-Cell Lymphoma: The Prospective Elderly Project of the Fondazione Italiana Linfomi
Authors: Francesco Merli, Stefano Luminari, Alessandra Tucci, Annalisa Arcari, Luigi Rigacci, Eliza Hawkes, Carlos S. Chiattone, Federica Cavallo, Giuseppina Cabras, Isabel Alvarez, Alberto Fabbri, Alessandro Re, Benedetta Puccini, Allison Barraclough, Marcia Torresan Delamain, Simone Ferrero, Sara Veronica Usai, Angela Ferrari, Emanuele Cencini, Elsa Pennese, Vittorio Ruggero Zilioli, Dario Marino, Monica Balzarotti, Maria Christina Cox, Manuela Zanni, Alice Di Rocco, Arben Lleshi, Barbara Botto, Stefan Hohaus, Michele Merli, Roberto Sartori, Guido Gini, Luca Nassi, Gerardo Musuraca, Monica Tani, Chiara Bottelli, Sofia Kovalchuk, Francesca Re, Leonardo Flenghi, Annalia Molinari, Giuseppe Tarantini, Emanuela Chimienti, Luigi Marcheselli, Caterina Mammi, Michele Spina
Journal: Journal of Clinical Oncology (2021)

PURPOSE To prospectively validate the use of a simplified geriatric assessment (sGA) at diagnosis and to integrate it into a prognostic score for older patients with diffuse large B-cell lymphoma (DLBCL). METHODS We conducted the prospective Elderly Project study on patients with DLBCL older than 64 years who underwent our Fondazione Italiana Linfomi original geriatric assessment (oGA) (age, Cumulative Illness Rating Scale for Geriatrics, activities of daily living, and instrumental activities of daily living) before treatment. Treatment choice was left to the physician's discretion. The primary end point was overall survival (OS) (ClinicalTrials.gov identifier: NCT02364050 ). RESULTS We analyzed 1,163 patients (median age 76 years), with a 3-year OS of 65% (95% CI, 62 to 68). Because at multivariate analysis on oGA, age &gt; 80 years retained an independent correlation with OS, we also developed a new, simplified version of the GA (sGA) that classifies patients as fit (55%), unfit (28%), and frail (18%) with significantly different 3-year OS of 75%, 58%, and 43%, respectively. The sGA groups, International Prognostic Index, and hemoglobin levels were independent predictors of OS and were used to build the Elderly Prognostic Index (EPI). Three risk groups were identified: low (23%), intermediate (48%), and high (29%), with an estimated 3-year OS of 87% (95% CI, 81 to 91), 69% (95% CI, 63 to 73), and 42% (95% CI, 36 to 49), respectively. The EPI was validated using an independent external series of 328 cases. CONCLUSION The Elderly Project validates sGA as an objective tool to assess fitness status and defines the new EPI to predict OS of older patients with DLBCL.
Advances of adipose-derived mesenchymal stem cells-based biomaterial scaffolds for oral and maxillofacial tissue engineering
Authors: Tong Liu, Jia Xu, Xun Pan, Zhangfan Ding, Hao Xie, Xiaoyi Wang, Huixu Xie
Journal: Bioactive Materials (2021)

The management of oral and maxillofacial tissue defects caused by tumors, trauma, and congenital or acquired deformities has been a major challenge for surgeons over the last few decades. Autologous tissue transplantation, the gold standard of tissue reconstruction, is a valid method for repairing the oral and maxillofacial functions and aesthetics. However, several limitations hinder its clinical applications including complications of donor sites, limited tissue volume, and uncertain long-term outcomes. Adipose-derived mesenchymal stem cells (ADMSCs) widely exist in adipose tissue and can be easily obtained through liposuction. Like the bone marrow-derived mesenchymal stem cells (BMSCs), ADMSCs also have the multi-pluripotent potencies to differentiate into osteoblasts, chondrocytes, neurons, and myocytes. Therefore, the multilineage capacity of ADMSCs makes them valuable for cell-based medical therapies. In recent years, researchers have developed many candidates of ADMSCs-based biomaterial scaffolds to cater for the needs of oral and maxillofacial tissue engineering due to their superior performance. This review presents the advances and applications of ADMSCs-based biomaterial scaffolds, and explores their tissue engineering prospects in oral and maxillofacial reconstructions.
Implementing genomic screening in diverse populations
Authors: Noura S. Abul-Husn, Emily R. Soper, Giovanna T. Braganza, Jessica E. Rodriguez, Natasha Zeid, Sinead Cullina, Dean Bobo, Arden Moscati, Amanda Merkelson, Ruth J. F. Loos, Judy H. Cho, Gillian M. Belbin, Sabrina A. Suckiel, Eimear E. Kenny
Journal: Genome Medicine (2021)

Population-based genomic screening has the predicted ability to reduce morbidity and mortality associated with medically actionable conditions. However, much research is needed to develop standards for genomic screening and to understand the perspectives of people offered this new testing modality. This is particularly true for non-European ancestry populations who are vastly underrepresented in genomic medicine research. Therefore, we implemented a pilot genomic screening program in the BioMe Biobank in New York City, where the majority of participants are of non-European ancestry.
Synergism of Akt, ERK, or STAT3 inhibitors on gefitinib in lung adenocarcinoma cell lines.
Authors: Hiroshi Kitagawa, Keiki Sugimoto, Hidenori Kage, Atsushi Sano, Naomi Aki, Takahide Nagase, Nobuya Ohishi, Daiya Takai
Journal: Cancer Research (2007)

LB-333  The epidermal growth factor receptor (EGFR) is an important target molecule in lung cancer. Now selective EGFR tyrosine kinase inhibitors are in clinical use. Meanwhile, downstream molecules of the EGFR-signal pathway, such as Akt, extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription-3 (STAT3) are under clinical trial.  In this study, combination treatment of gefitinib and inhibitors of Akt (LY294002), ERK (U0126), or STAT3 (STAT3 inhibitor) are examined on lung adenocarcinoma cell lines, NCI-H1650 (gefitinib-sensitive, delE746-750), NCI-H1975 (gefitinib-resistant, L858R/T790M), and NCI-H2347 (gefitinib-resistant, wild-type EGFR). Each inhibitor was combined with gefitinib in a constant ratio, cultured for 72 hours, and analyzed by a modified MTT assay. The median effect method was applied to determine a combination index (CI), where drug synergism was indicated by CI 1. The phosphorylation status of these molecules before and after treatments was determined by ELISA.  >In NCI-H1650, combination of gefitinib and LY294002 showed stronger synergistic effect with higher concentrations. In NCI-H1975, all combination therapy showed strong synergism. In NCI-H2347, each combination therapy resulted from nearly additive effect to moderate antagonism (Table). Analyses of phosphorylation revealed correlations between the activation patterns of Akt, ERK, and STAT3 and the effects of combination treatment.  >Together, these data suggest that combination therapy of gefitinib and inhibitors of Akt, ERK, and STAT3 is potentially a practical option for therapy of lung adenocarcinoma. Especially, the addition of these inhibitors to gefitinib would be a novel strategy for gefitinib resistance from the T790M mutation.  >
The relationship between cultural tightness–looseness and COVID-19 cases and deaths: a global analysis
Authors: Michele J Gelfand, Joshua Conrad Jackson, Xinyue Pan, Dana Nau, Dylan Pieper, Emmy Denison, Munqith Dagher, Paul A M Van Lange, Chi-Yue Chiu, Mo Wang
Journal: The Lancet Planetary Health (2021)

The COVID-19 pandemic is a global health crisis, yet certain countries have had far more success in limiting COVID-19 cases and deaths. We suggest that collective threats require a tremendous amount of coordination, and that strict adherence to social norms is a key mechanism that enables groups to do so. Here we examine how the strength of social norms-or cultural tightness-looseness-was associated with countries' success in limiting cases and deaths by October, 2020. We expected that tight cultures, which have strict norms and punishments for deviance, would have fewer cases and deaths per million as compared with loose cultures, which have weaker norms and are more permissive.
Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial
Authors: Binghe Xu, Min Yan, Fei Ma, Xichun Hu, Jifeng Feng, Quchang Ouyang, Zhongsheng Tong, Huiping Li, Qingyuan Zhang, Tao Sun, Xian Wang, Yongmei Yin, Ying Cheng, Wei Li, Yuanting Gu, Qianjun Chen, Jinping Liu, Jing Cheng, Cuizhi Geng, Shukui Qin, Shusen Wang, Jinsong Lu, Kunwei Shen, Qiang Liu, Xiaojia Wang, Hong Wang, Ting Luo, Jin Yang, Yudong Wu, Zhiyong Yu, Xiaoyu Zhu, Chunxia Chen, Jianjun Zou
Journal: The Lancet Oncology (2021)
Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†
Authors: M.A. Dimopoulos, P. Moreau, E. Terpos, M.V. Mateos, S. Zweegman, G. Cook, M. Delforge, R. Hájek, F. Schjesvold, M. Cavo, H. Goldschmidt, T. Facon, H. Einsele, M. Boccadoro, J. San-Miguel, P. Sonneveld, U. Mey
Journal: Annals of Oncology (2021)
NCCN Guidelines Insights: Prostate Cancer, Version 1.2021
Authors: Edward Schaeffer, Sandy Srinivas, Emmanuel S. Antonarakis, Andrew J. Armstrong, Justin E. Bekelman, Heather Cheng, Anthony Victor D’Amico, Brian J. Davis, Neil Desai, Tanya Dorff, James A. Eastham, Thomas A. Farrington, Xin Gao, Eric Mark Horwitz, Joseph E. Ippolito, Michael R. Kuettel, Joshua M. Lang, Rana McKay, Jesse McKenney, George Netto, David F. Penson, Julio M. Pow-Sang, Robert Reiter, Sylvia Richey, Mack Roach, III, Stan Rosenfeld, Ahmad Shabsigh, Daniel E. Spratt, Benjamin A. Teply, Jonathan Tward, Dorothy A. Shead, Deborah A. Freedman-Cass
Journal: Journal of the National Comprehensive Cancer Network (2021)

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel’s discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.
BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib
Authors: H. Yesid Estupiñán, Qing Wang, Anna Berglöf, Gerard C. P. Schaafsma, Yuye Shi, Litao Zhou, Dara K. Mohammad, Liang Yu, Mauno Vihinen, Rula Zain, C. I. Edvard Smith
Journal: Leukemia (2021)

Abstract Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the “gatekeeper” residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or methionine (T474M) combined with catalytically active cysteine 481 to serine (C481S), are insensitive to ≥16-fold the pharmacological serum concentration, and therefore defined as super-resistant to irreversible inhibitors. Conversely, reversible inhibitors showed a variable pattern, from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors, which may affect their clinical application.
Virus-positive Merkel Cell Carcinoma Is an Independent Prognostic Group with Distinct Predictive Biomarkers
Authors: Kelly L. Harms, Lili Zhao, Bryan Johnson, Xiaoming Wang, Shannon Carskadon, Nallasivam Palanisamy, Daniel R. Rhodes, Rahul Mannan, Josh N. Vo, Jae Eun Choi, May P. Chan, Douglas R. Fullen, Rajiv M. Patel, Javed Siddiqui, Vincent T. Ma, Steven Hrycaj, Scott A. McLean, Tasha M. Hughes, Christopher K. Bichakjian, Scott A. Tomlins, Paul W. Harms
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage. Experimental Design: We classified 346 MCC tumors from 300 patients for MCPyV using a combination of IHC, ISH, and qPCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by IHC. Results: A total of 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer disease-specific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized oncogene or tumor suppressor mutations were frequent in VN-MCC but rare in VP-MCC. TP53 mutation developed with recurrence in one VP-MCC case. Importantly, for the first time we find that VP-MCC and VN-MCC display distinct sets of prognostic molecular biomarkers. For VP-MCC, shorter survival was associated with decreased expression of immune markers including granzyme and IDO1. For VN-MCC, shorter survival correlated with high expression of several genes including UBE2C. Conclusions: MCPyV status is an independent prognostic factor for MCC. Features of the tumor genome, transcriptome, and microenvironment may modify prognosis in a manner specific to viral status. MCPyV status has clinicopathologic significance and allows for identification of additional prognostic subgroups.
Socioeconomic position and use of hospital-based care towards the end of life: a mediation analysis using the English Longitudinal Study of Ageing
Authors: Joanna M Davies, Matthew Maddocks, Kia-Chong Chua, Panayotes Demakakos, Katherine E Sleeman, Fliss E M Murtagh
Journal: The Lancet Public Health (2021)

BackgroundMany patients prefer to avoid hospital-based care towards the end of life, yet hospitalisation is common and more likely for people with low socioeconomic position. The reasons underlying this socioeconomic inequality are not well understood. This study investigated health, service access, and social support as potential mediating pathways between socioeconomic position and receipt of hospital-based care towards the end of life.MethodsFor this observational cohort study, we included deceased participants from the nationally representative English Longitudinal Study of Ageing of people aged 50 years or older in England. We used a multiple mediation model with age-adjusted and gender-adjusted probit regression to estimate the direct effect of socioeconomic position (measured by wealth and education) on death in hospital and three or more hospital admissions in the last 2 years of life, and the indirect effects of socioeconomic position via three mediators: health and function, access to health-care services, and social support.Findings737 participants were included (314 [42·6%] female, 423 [57·4%] male), with a median age at death of 78 years (IQR 71–85). For death in hospital, higher wealth had a direct negative effect (probit coefficient −0·16, 95% CI −0·25 to −0·06), which was not mediated by any of the pathways tested. For frequent hospital admissions, health and function mediated the effect of wealth (−0·04, −0·08 to −0·01), accounting for 34·6% of the total negative effect of higher wealth (−0·13, −0·23 to −0·02). Higher wealth was associated with better health and function (0·25, 0·18 to 0·33). Education was associated with the outcomes only indirectly via wealth.InterpretationOur findings suggest that worse health and function could partly explain why people with lower wealth have more hospital admissions, highlighting the importance of socioeconomically driven health differences in explaining patterns of hospital use towards the end of life. The findings should raise awareness about the related risk factors of low wealth and worse health for patients approaching the end of life, and strengthen calls for resource allocation to be made on the basis of health need and socioeconomic profile.FundingDunhill Medical Trust Fellowship Grant (RTF74/0116).