tbuckley/cabot-search huggingface dataset:
Fiftieth Anniversary of Uncovering the Tuskegee Syphilis Study: The Story and Timeless Lessons
Authors: Martin J. Tobin
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

This year marks the 50th anniversary of the uncovering of the Tuskegee syphilis study, when the public learned that the Public Health Service (precursor of the CDC) for 40 years intentionally withheld effective therapy against a life-threatening illness in 400 African American men. In 2010, we learned that the same research group had deliberately infected hundreds of Guatemalans with syphilis and gonorrhea in the 1940s, with the goal of developing better methods for preventing these infections. Despite 15 journal articles detailing the results, no physician published a letter criticizing the Tuskegee study. Informed consent was never sought; instead, Public Health Service researchers deceived the men into believing they were receiving expert medical care. The study is an especially powerful parable because readers can identify the key players in the narrative and recognize them as exemplars of people they encounter in daily life-these flesh-and-blood characters convey the principles of research ethics more vividly than a dry account in a textbook of bioethics. The study spurred reforms leading to fundamental changes in the infrastructure of research ethics. The reason people fail to take steps to halt behavior that in retrospect everyone judges reprehensible is complex. Lack of imagination, rationalization, and institutional constraints are formidable obstacles. The central lessons from the study are the need to pause and think, reflect, and examine one's conscience; the courage to speak; and above all the willpower to act. History, although about the past, is our best defense against future errors and transgressions.
NLRP3 and pyroptosis blockers for treating inflammatory diseases
Authors: Rebecca C. Coll, Kate Schroder, Pablo Pelegrín
Journal: Trends in Pharmacological Sciences (2022)

The nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as a key mediator of pathological inflammation in many diseases and is an exciting drug target. Here, we review the molecular basis of NLRP3 inhibition by drug-like small molecules under development as novel therapeutics. We also summarize recent strategies to block pyroptosis as a novel approach to suppress chronic inflammation. Major recent developments in this area include the elucidation of mechanisms of action (MoAs) by which small molecules block NLRP3 inflammasome assembly and gasdermin D (GSDMD)-induced pyroptosis. We also discuss the status of clinical trials using agents that block specific components of the NLRP3 pathway, including their potential clinical applications for the treatment of many diseases.
Dose Escalation Data from the Phase 1 Study of the Liposomal Formulation of Eribulin (E7389-LF) in Japanese Patients with Advanced Solid Tumors
Authors: Jun Sato, Toshio Shimizu, Takafumi Koyama, Satoru Iwasa, Akihiko Shimomura, Shunsuke Kondo, Shigehisa Kitano, Kan Yonemori, Yutaka Fujiwara, Kenji Tamura, Takuya Suzuki, Takao Takase, Reiko Nagai, Kohei Yamaguchi, Taro Semba, Zi-Ming Zhao, Min Ren, Noboru Yamamoto
Journal: Clinical Cancer Research (2022)

We report the dose-escalation part of a phase I study of liposomal eribulin (E7389-LF) in Japanese patients with advanced solid tumors and no alternative standard therapy.
Editor's Note: Deficiency of NRH: Quinone Oxidoreductase 2 Increases Susceptibility to 7,12-Dimethylbenz(a)anthracene and Benzo(a)pyrene-Induced Skin Carcinogenesis
Authors: Karim Iskander, Marilene Paquet, Cory Brayton, Anil K. Jaiswal
Journal: Cancer Research (2022)

The editors are publishing this note to alert readers to a concern about this article (1). The authors made the editors aware that an investigation by the NIH Office of Research Integrity identified that the background of the Western blot analysis in Fig. 2B was digitally altered, which affected the relative expression of p53 among the samples. Because of the length of time since publication of this article, original data are not available to correct the figures in this article.
AMPK–mTOR–Mediated Activation of Autophagy Promotes Formation of Dormant Polyploid Giant Cancer Cells
Authors: Bo You, Tian Xia, Miao Gu, Zhenxin Zhang, Qicheng Zhang, Jianhong Shen, Yue Fan, Hui Yao, Si Pan, Yingna Lu, Tianyi Cheng, Zhiyuan Yang, Xin He, Hao Zhang, Muqi Shi, Dong Liu, Yiwen You
Journal: Cancer Research (2021)

Dormant cancer cells that survive anticancer therapy can lead to cancer recurrence and disseminated metastases that prove fatal in most cases. Recently, specific dormant polyploid giant cancer cells (PGCC) have drawn our attention because of their association with the clinical risk of nasopharyngeal carcinoma (NPC) recurrence, as demonstrated by previous clinical data. In this study, we report the biological properties of PGCC, including mitochondrial alterations, and reveal that autophagy is a critical mechanism of PGCC induction. Moreover, pharmacologic or genetic inhibition of autophagy greatly impaired PGCC formation, significantly suppressing metastasis and improving survival in a mouse model. Mechanistically, chemotherapeutic drugs partly damaged mitochondria, which then produced low ATP levels and activated autophagy via the AMPK-mTOR pathway to promote PGCC formation. Analysis of the transcriptional and epigenetic landscape of PGCC revealed overexpression of RIPK1, and the scaffolding function of RIPK1 was required for AMPK-mTOR pathway-induced PGCC survival. High numbers of PGCCs correlated with shorter recurrence time and worse survival outcomes in patients with NPC. Collectively, these findings suggest a therapeutic approach of targeting dormant PGCCs in cancer.Pretreatment with an autophagy inhibitor before chemotherapy could prevent formation of therapy-induced dormant polyploid giant cancer cells, thereby reducing recurrence and metastasis of nasopharyngeal carcinoma.
Venovenous extracorporeal membrane oxygenation in patients with acute covid-19 associated respiratory failure: comparative effectiveness study
Authors: Martin Urner, Adrian G Barnett, Gianluigi Li Bassi, Daniel Brodie, Heidi J Dalton, Niall D Ferguson, Silver Heinsar, Carol L Hodgson, Giles Peek, Kiran Shekar, Jacky Y Suen, John F Fraser, Eddy Fan
Journal: BMJ (2022)

Abstract Objective To estimate the effect of extracorporeal membrane oxygenation (ECMO) compared with conventional mechanical ventilation on outcomes of patients with covid-19 associated respiratory failure. Design Observational study. Setting 30 countries across five continents, 3 January 2020 to 29 August 2021. Participants 7345 adults admitted to the intensive care unit with clinically suspected or laboratory confirmed SARS-CoV-2 infection. Interventions ECMO in patients with a partial pressure of arterial oxygen to fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio &lt;80 mm Hg compared with conventional mechanical ventilation without ECMO. Main outcome measure The primary outcome was hospital mortality within 60 days of admission to the intensive care unit. Adherence adjusted estimates were calculated using marginal structural models with inverse probability weighting, accounting for competing events and for baseline and time varying confounding. Results 844 of 7345 eligible patients (11.5%) received ECMO at any time point during follow-up. Adherence adjusted mortality was 26.0% (95% confidence interval 24.5% to 27.5%) for a treatment strategy that included ECMO if the PaO 2 /FiO 2 ratio decreased &lt;80 mm Hg compared with 33.2% (31.8% to 34.6%) had patients received conventional treatment without ECMO (risk difference –7.1%, 95% confidence interval –8.2% to –6.1%; risk ratio 0.78, 95% confidence interval 0.75 to 0.82). In secondary analyses, ECMO was most effective in patients aged &lt;65 years and with a PaO 2 /FiO 2 &lt;80 mm Hg or with driving pressures &gt;15 cmH 2 O during the first 10 days of mechanical ventilation. Conclusions ECMO was associated with a reduction in mortality in selected adults with covid-19 associated respiratory failure. Age, severity of hypoxaemia, and duration and intensity of mechanical ventilation were found to be modifiers of treatment effectiveness and should be considered when deciding to initiate ECMO in patients with covid-19.
BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer
Authors: Mathieu Rouanne, Julien Adam, Camélia Radulescu, Diane Letourneur, Delphine Bredel, Séverine Mouraud, Anne-Gaëlle Goubet, Marion Leduc, Noah Chen, Tuan Zea Tan, Nicolas Signolle, Amélie Bigorgne, Michael Dussiot, Lambros Tselikas, Sandrine Susini, François-Xavier Danlos, Anna K. Schneider, Roman Chabanon, Sophie Vacher, Ivan Bièche, Thierry Lebret, Yves Allory, Jean-Charles Soria, Nicholas Arpaia, Guido Kroemer, Oliver Kepp, Jean Paul Thiery, Laurence Zitvogel, Aurélien Marabelle
Journal: Journal of Clinical Investigation (2022)

Patients with high-risk, nonmuscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical bacillus Calmette-Guérin (BCG) therapy and may have a dismal outcome. The mechanisms of resistance to such immunotherapy remain poorly understood. Here, using cancer cell lines, freshly resected human bladder tumors, and samples from cohorts of patients with bladder cancer before and after BCG therapy, we demonstrate 2 distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a posttranscriptional downregulation of HLA-I membrane expression via inhibition of autophagy flux. Patients with HLA-I-deficient cancer cells following BCG therapy had a myeloid immunosuppressive tumor microenvironment (TME) with epithelial-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I-proficient cancer cells after BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines, and immune checkpoint-inhibitory molecules. The latter patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse following BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts a dismal prognosis. HLA-I scoring of cancer cells by IHC staining can be easily implemented by pathologists in routine practice to stratify future treatment strategies for patients with urothelial cancer.
Concurrent Activation of Kras and Canonical Wnt Signaling Induces Premalignant Lesions That Progress to Extrahepatic Biliary Cancer in Mice
Authors: Munemasa Nagao, Akihisa Fukuda, Mayuki Omatsu, Mio Namikawa, Makoto Sono, Yuichi Fukunaga, Tomonori Masuda, Osamu Araki, Takaaki Yoshikawa, Satoshi Ogawa, Kenji Masuo, Norihiro Goto, Yukiko Hiramatsu, Yu Muta, Motoyuki Tsuda, Takahisa Maruno, Yuki Nakanishi, Makoto Mark Taketo, Jorge Ferrer, Tatsuaki Tsuruyama, Yasuni Nakanuma, Kojiro Taura, Shinji Uemoto, Hiroshi Seno
Journal: Cancer Research (2022)

Abstract Biliary cancer has long been known to carry a poor prognosis, yet the molecular pathogenesis of carcinoma of the extrahepatic biliary system and its precursor lesions remains elusive. Here we investigated the role of Kras and canonical Wnt pathways in the tumorigenesis of the extrahepatic bile duct (EHBD) and gall bladder (GB). In mice, concurrent activation of Kras and Wnt pathways induced biliary neoplasms that resembled human intracholecystic papillary-tubular neoplasm (ICPN) and biliary intraepithelial neoplasia (BilIN), putative precursors to invasive biliary cancer. At a low frequency, these lesions progressed to adenocarcinoma in a xenograft model, establishing them as precancerous lesions. Global gene expression analysis revealed increased expression of genes associated with c-Myc and TGFβ pathways in mutant biliary spheroids. Silencing or pharmacologic inhibition of c-Myc suppressed proliferation of mutant biliary spheroids, whereas silencing of Smad4/Tgfbr2 or pharmacologic inhibition of TGFβ signaling increased proliferation of mutant biliary spheroids and cancer formation in vivo. Human ICPNs displayed activated Kras and Wnt signals and c-Myc and TGFβ pathways. Thus, these data provide direct evidence that concurrent activation of the Kras and canonical Wnt pathways results in formation of ICPN and BilIN, which could develop into biliary cancer. Significance: This work shows how dysregulation of canonical cell growth pathways drives precursors to biliary cancers and identifies several molecular vulnerabilities as potential therapeutic targets in these precursors to prevent oncogenic progression.
Molecular Characterization and Prospective Evaluation of Pathologic Response and Outcomes with Neoadjuvant Therapy in Metaplastic Triple-Negative Breast Cancer
Authors: Clinton Yam, Nour Abuhadra, Ryan Sun, Beatriz E. Adrada, Qing-Qing Ding, Jason B. White, Elizabeth E. Ravenberg, Alyson R. Clayborn, Vicente Valero, Debu Tripathy, Senthilkumar Damodaran, Banu K. Arun, Jennifer K. Litton, Naoto T. Ueno, Rashmi K. Murthy, Bora Lim, Luis Baez, Xiaoxian Li, Aman U. Buzdar, Gabriel N. Hortobagyi, Alistair M. Thompson, Elizabeth A. Mittendorf, Gaiane M. Rauch, Rosalind P. Candelaria, Lei Huo, Stacy L. Moulder, Jeffrey T. Chang
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer that is commonly triple-negative and poorly responsive to neoadjuvant therapy in retrospective studies. Experimental Design: To better define clinical outcomes and correlates of response, we analyzed the rate of pathologic complete response (pCR) to neoadjuvant therapy, survival outcomes, and genomic and transcriptomic profiles of the pretreatment tumors in a prospective clinical trial (NCT02276443). A total of 211 patients with triple-negative breast cancer (TNBC), including 39 with MpBC, received doxorubicin-cyclophosphamide–based neoadjuvant therapy. Results: Although not meeting the threshold for statistical significance, patients with MpBCs were less likely to experience a pCR (23% vs. 40%; P = 0.07), had shorter event-free survival (29.4 vs. 32.2 months, P = 0.15), metastasis-free survival (30.3 vs. 32.4 months, P = 0.22); and overall survival (32.6 vs. 34.3 months, P = 0.21). This heterogeneity is mirrored in the molecular profiling. Mutations in PI3KCA (23% vs. 9%, P = 0.07) and its pathway (41% vs. 18%, P = 0.02) were frequently observed and enriched in MpBCs. The gene expression profiles of each histologically defined subtype were distinguishable and characterized by distinctive gene signatures. Among nonmetaplastic (non-Mp) TNBCs, 10% possessed a metaplastic-like gene expression signature and had pCR rates and survival outcomes similar to MpBC. Conclusions: Further investigations will determine if metaplastic-like tumors should be treated more similarly to MpBC in the clinic. The 23% pCR rate in this study suggests that patients with MpBC should be considered for NAT. To improve this rate, a pathway analysis predicted enrichment of histone deacetylase (HDAC) and RTK/MAPK pathways in MpBC, which may serve as new targetable vulnerabilities.
Child health and wellbeing dashboards: accountability for children's rights
Authors: Jennifer Requejo, Theresa Diaz, Lois Park, Kathleen Strong, Gerard Lopez, John Borrazzo, Anthony Costello, Sarah L Dalglish, Theresa Diaz, Tanya Doherty, Caterina Felici, Lu Gram, Gerard Lopez, Karen Ofosu-Orchard, Lois Park, Timothy Powell-Jackson, Srivatsan Rajagopalan, Jennifer Requejo, Marina Romanello, Harshpal S Sachdev, Kwame S Sakyi, Kathleen Strong
Journal: The Lancet (2022)
Genetic, Pharmacogenomic, and Immune Landscapes of Enhancer RNAs Across Human Cancers
Authors: Zhao Zhang, Mei Luo, Qiang Li, Yuan Liu, Charles Lussier, Jian Zhang, Youqiong Ye, An-Yuan Guo, Leng Han
Journal: Cancer Research (2022)

Enhancer RNAs (eRNA) regulate gene expression and play critical roles in cancer. Using large-scale omics data from The Cancer Genome Atlas (TCGA), we systematically investigated the impact of genetic variants on eRNA expression and identified approximately 1 million eRNA quantitative trait loci (eRNA-QTL) as cis- and trans-acting. Over 16,000 eRNA-QTLs were associated with patient overall survival. Assessing the impact of eRNAs on more than 1,000 imputed anticancer drug responses across approximately 10,000 patients with cancer revealed more than 7 million significant associations. Furthermore, approximately 240,000 significant associations were identified between eRNA expression and immune cell abundance deconvoluted by TIMER, CIBERSORT, ImmuCellAI, and ImmuneCellGSVA. Finally, a user-friendly data portal was generated: Genetic, Pharmacogenomic, and Immune Landscapes of eRNAs (GPIeR; https://hanlab.tamhsc.edu/GPIeR/). GPIeR is a large-scale multidimensional data portal that can be used to explore eRNA-associated genetic variants, drug responses, and immune infiltration, with the purpose of facilitating functional and clinical investigations of eRNAs in cancer.This study provides insights into the impact of the enhancer RNA (eRNA) landscape on patient outcome, the immune microenvironment, and drug response across cancers and develops a multidimensional data portal to facilitate eRNA research.
Oncogene Convergence in Extrachromosomal DNA Hubs
Authors: Natasha E. Weiser, King L. Hung, Howard Y. Chang
Journal: Cancer Discovery (2022)

Extrachromosomal DNA circles (ecDNA) are a common mechanism for oncogene amplification and are associated with worse clinical outcomes compared with other types of oncogene amplification. Several recent discoveries of ecDNA hubs-local congregations of ecDNAs in the nucleus-highlight unique features of ecDNA biology that may contribute to higher oncogene expression and rapid tumor evolution.
Youth perspective on chronic disease prevention
Authors: Radhika Valanju, Meera Barani, Dominik Mautner, Imeelya Al Hadaya, Alexi Cross, Melani Gunawardana, Ava Lambie, Emily McMahon, Arnav Narula, Bowen Ren, Dominique Rose, Aviral Sharda, Alexander Sinnett, Azman Tanvir, Henrik Tran, Fulin Yan, Mariam Mandoh, Hoi Lun Cheng, Seema Mihrshahi, Philayrath Phongsavan, Julie Redfern, Rebecca Raeside, Stephanie R Partridge
Journal: The Lancet Child & Adolescent Health (2022)
Air Pollutants and Asthma Hospitalization in the Medicaid Population
Authors: Yaguang Wei, Xinye Qiu, Matthew Benjamin Sabath, Mahdieh Danesh Yazdi, Kanhua Yin, Longxiang Li, Adjani A. Peralta, Cuicui Wang, Petros Koutrakis, Antonella Zanobetti, Francesca Dominici, Joel D. Schwartz
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Risk of asthma hospitalization and its disparities associated with air pollutant exposures are less clear within socioeconomically disadvantaged populations, particularly at low degrees of exposure. Objectives: To assess effects of short-term exposures to fine particulate matter (particulate matter with an aerodynamic diameter of ⩽2.5 μm [PM2.5]), warm-season ozone (O3), and nitrogen dioxide (NO2) on risk of asthma hospitalization among national Medicaid beneficiaries, the most disadvantaged population in the United States, and to test whether any subpopulations were at higher risk. Methods: We constructed a time-stratified case-crossover dataset among 1,627,002 hospitalizations during 2000–2012 and estimated risk of asthma hospitalization associated with short-term PM2.5, O3, and NO2 exposures. We then restricted the analysis to hospitalizations with degrees of exposure below increasingly stringent thresholds. Furthermore, we tested effect modifications by individual- and community-level characteristics. Measurements and Main Results: Each 1-μg/m3 increase in PM2.5, 1-ppb increase in O3, and 1-ppb increase in NO2 was associated with 0.31% (95% confidence interval [CI], 0.24–0.37%), 0.10% (95% CI, 0.05 − 0.15%), and 0.28% (95% CI, 0.24 − 0.32%) increase in risk of asthma hospitalization, respectively. Low-level PM2.5 and NO2 exposures were associated with higher risk. Furthermore, beneficiaries with only one asthma hospitalization during the study period or in communities with lower population density, higher average body mass index, longer distance to the nearest hospital, or greater neighborhood deprivation experienced higher risk. Conclusions: Short-term air pollutant exposures increased risk of asthma hospitalization among Medicaid beneficiaries, even at concentrations well below national standards. The subgroup differences suggested individual and contextual factors contributed to asthma disparities under effects of air pollutant exposures.
Why US Cervical Cancer Survival Rates Haven’t Improved for Decades
Authors: Melissa Suran
Journal: JAMA (2022)

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Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation
Authors: Vivek D. Gandhi, Jacqueline-Yvonne Cephus, Allison E. Norlander, Nowrin U. Chowdhury, Jian Zhang, Zachary J. Ceneviva, Elie Tannous, Vasiliy V. Polosukhin, Nathan D. Putz, Nancy Wickersham, Amrit Singh, Lorraine B. Ware, Julie A. Bastarache, Ciara M. Shaver, Hong Wei Chu, R. Stokes Peebles, Dawn C. Newcomb
Journal: Journal of Clinical Investigation (2022)

Women have higher prevalence of asthma compared with men. In asthma, allergic airway inflammation is initiated by IL-33 signaling through ST2, leading to increased IL-4, IL-5, and IL-13 production and eosinophil infiltration. Foxp3+ Tregs suppress and ST2+ Tregs promote allergic airway inflammation. Clinical studies showed that the androgen dehydroepiandrosterone (DHEA) reduced asthma symptoms in patients, and mouse studies showed that androgen receptor (AR) signaling decreased allergic airway inflammation. Yet the impact of AR signaling on lung Tregs remains unclear. Using AR-deficient and Foxp3 fate-mapping mice, we determined that AR signaling increased Treg suppression during Alternaria extract (Alt Ext; allergen) challenge by stabilizing Foxp3+ Tregs and limiting the number of ST2+ ex-Tregs and IL-13+ Th2 cells and ex-Tregs. AR signaling also decreased Alt Ext-induced ST2+ Tregs in mice by limiting expression of Gata2, a transcription factor for ST2, and by decreasing Alt Ext-induced IL-33 production from murine airway epithelial cells. We confirmed our findings in human cells where 5α-dihydrotestosterone (DHT), an androgen, decreased IL-33-induced ST2 expression in lung Tregs and decreased Alt Ext-induced IL-33 secretion in human bronchial epithelial cells. Our findings showed that AR signaling stabilized Treg suppressive function, providing a mechanism for the sex difference in asthma.
CTLA-4 Blockade Resistance after Relatlimab and Nivolumab
Authors: Alexander M. Menzies, Ines Pires da Silva, Claudia Trojaniello, Elisabeth Vieu, Rodabe N. Amaria, Lisa Zimmer, Serigne N. Lo, Elizabeth M. Burton, Hussein A. Tawbi, Dirk Schadendorf, Jean J. Grob, Paolo A. Ascierto, Georgina V. Long
Journal: New England Journal of Medicine (2022)