tbuckley/cabot-search huggingface dataset:
Anlotinib in Locally Advanced or Metastatic Medullary Thyroid Carcinoma: A Randomized, Double-Blind Phase IIB Trial
Authors: Dapeng Li, Yihebali Chi, Xiaohong Chen, Minghua Ge, Yuan Zhang, Zhuming Guo, Jun Wang, Jie Chen, Jiewu Zhang, Ying Cheng, Zhendong Li, Hui Liu, Jianwu Qin, Jingqiang Zhu, Ruochuan Cheng, Zhengang Xu, Xiangqian Zheng, Pingzhang Tang, Ming Gao
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Medullary thyroid cancer (MTC) accounts for about 2% of all thyroid cancer, but has a relatively poor prognosis compared with differentiated thyroid cancer. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This multicenter, randomized, double-blind, placebo-controlled phase IIB study (ALTER 01031 and NCT02586350) was conducted to investigate the efficacy and safety of anlotinib in MTC. Patients and Methods: Patients with histopathologically confirmed, unresectable locally advanced or metastatic MTC were enrolled and randomly assigned in a 2:1 ratio to receive anlotinib (12 mg once daily from day 1 to 14 every 3 weeks) or placebo. Patients in placebo group were allowed to receive open-label anlotinib after disease progression. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Results: Ninety-one patients were enrolled. At data cutoff date, the median PFS was significantly prolonged in the anlotinib group than in the placebo group (20.7 months vs. 11.1 months, P = 0.029; HR, 0.53; 95% confidence interval, 0.30–0.95). The ORR of anlotinib treatment was 48.4%. The incidence of treatment-related adverse events (TRAE) was 100% and 89.7% in the anlotinib and placebo groups, respectively. The most common TRAEs of all grades in the anlotinib group were palmar–plantar erythrodysesthesia syndrome (62.9%), proteinuria (61.3%), and hypertriglyceridemia (48.4%). Conclusions: Anlotinib demonstrates its efficacy and safety in this phase IIB trial for the treatment of MTC and may become a new choice for this rare disease, especially for Chinese patients.
Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian cancer
Authors: Shini Liu, Qiong Zou, Jie-Ping Chen, Xiaosai Yao, Peiyong Guan, Weiting Liang, Peng Deng, Xiaowei Lai, Jiaxin Yin, Jinghong Chen, Rui Chen, Zhaoliang Yu, Rong Xiao, Yichen Sun, Jing Han Hong, Hui Liu, Huaiwu Lu, Jianfeng Chen, Jin-Xin Bei, Joanna Koh, Jason Yongsheng Chan, Baohua Wang, Tiebang Kang, Qiang Yu, Bin-Tean Teh, Jihong Liu, Ying Xiong, Jing Tan
Journal: Journal of Clinical Investigation (2021)

Ovarian cancer is characterized by aberrant activation of the mitogen-activated protein kinase (MAPK), highlighting the importance of targeting the MAPK pathway as an attractive therapeutic strategy. However, the clinical efficacy of MEK inhibitors is limited by intrinsic or acquired drug resistance. Here, we established patient-derived ovarian cancer models resistant to MEK inhibitors and demonstrated that resistance to the clinically approved MEK inhibitor trametinib was associated with enhancer reprogramming. We also showed that enhancer decommissioning induced the downregulation of negative regulators of the MAPK pathway, leading to constitutive ERK activation and acquired resistance to trametinib. Epigenetic compound screening uncovered that HDAC inhibitors could alter the enhancer reprogramming and upregulate the expression of MAPK negative regulators, resulting in sustained MAPK inhibition and reversal of trametinib resistance. Consequently, a combination of HDAC inhibitor and trametinib demonstrated a synergistic antitumor effect in vitro and in vivo, including patient-derived xenograft mouse models. These findings demonstrated that enhancer reprogramming of the MAPK regulatory pathway might serve as a potential mechanism underlying MAPK inhibitor resistance and concurrent targeting of epigenetic pathways and MAPK signaling might provide an effective treatment strategy for advanced ovarian cancer.
Emergence of bedaquiline resistance in a high tuberculosis burden country
Authors: Elena Chesov, Dumitru Chesov, Florian P. Maurer, Sönke Andres, Christian Utpatel, Ivan Barilar, Ana Donica, Maja Reimann, Stefan Niemann, Christoph Lange, Valeriu Crudu, Jan Heyckendorf, Matthias Merker
Journal: European Respiratory Journal (2021)

Bedaquiline has been classified as a group A drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the World Health Organization; however, globally emerging resistance threatens the effectivity of novel MDR-TB treatment regimens.
Presenting the new incoming editorial team for hepatology: Team members and perspectives
Authors: Gregory J. Gores, Harmeet Malhi
Journal: Hepatology (2021)

Since its inception, the flagship and initial journal of the American Association for the Study of Liver Diseases (AASLD) HEPATOLOGY has changed editorial teams at five-year intervals (Table 1). Each team has leveraged the success of the prior team to enhance the status of the journal, increasing its value to the AASLD membership, and expanding the readership. Over the last 40 years, HEPATOLOGY has evolved from a mission of aggregating knowledge on liver diseases and liver biology to a more selective journal.
Evaluation of Necrosis as a Diagnostic and Prognostic Indicator in Adrenocortical Carcinoma
Authors: Sarah S. Pearlstein, Patricia C. Conroy, Kathryn Chomsky Menut, Jina Kim, Claire E. Graves, Robert Ruiz-Cordero, Quan-Yang Duh
Journal: JAMA Surgery (2021)

This case series examines the presence of necrosis in adrenocortical carcinoma as a diagnostic and prognostic indicator.
Metabolizable pH/H2O2 dual-responsive conductive polymer nanoparticles for safe and precise chemo-photothermal therapy
Authors: Xin Liu, Yang Liu, Yijun Guo, Wei Shi, Yanan Sun, Zi He, Yuqing Shen, Xiuming Zhang, Haihua Xiao, Dongtao Ge
Journal: Biomaterials (2021)
Immunosuppressive biologics did not increase the risk of COVID-19 or subsequent mortality: A retrospective matched cohort study from Massachusetts
Authors: Vartan Pahalyants, William S. Murphy, Nikolai Klebanov, Chenyue Lu, Nicholas Theodosakis, R. Monina Klevens, Hossein Estir, Evelyn Lilly, Maryam Asgari, Yevgeniy R. Semenov
Journal: Journal of the American Academy of Dermatology (2021)
Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis
Authors: Philip Joseph, Gholamreza Roshandel, Peggy Gao, Prem Pais, Eva Lonn, Denis Xavier, Alvaro Avezum, Jun Zhu, Lisheng Liu, Karen Sliwa, Habib Gamra, Shrikant I Bangdiwala, Koon Teo, Rafael Diaz, Antonio Dans, Patricio Lopez-Jaramillo, Dorairaj Prabhakaran, Jose Maria Castellano, Valentin Fuster, Anthony Rodgers, Mark D Huffman, Jackie Bosch, Gilles R Dagenais, Reza Malekzadeh, Salim Yusuf
Journal: The Lancet (2021)
Severe Hemophilia A in a Patient with Sexual Differentiation Disorder: A Case Report
Authors: Analía Sánchez Lucero, Samuel Ernesto Veber, Alejandra Casanovas, Gabriela Martinez, Karina D'Aloi, Graciela Onelda Elena, Claudia Pamela Radic, Miguel Martín Abelleyro, Salvador Bruno
Journal: Blood (2017)
Response by Shah et al to Letter Regarding Article, “Cell-Free DNA to Detect Heart Allograft Acute Rejection”
Authors: Palak Shah, Sean Agbor-Enoh, Ilker Tunc, Steven Hsu, Stuart Russell, Erika Feller, Keyur Shah, Maria E. Rodrigo, Samer S. Najjar, Hyesik Kong, Mehdi Pirooznia, Ulgen Fideli, Alfiya Bikineyeva, Argit Marishta, Kenneth Bhatti, Yanqin Yang, Cedric Mutebi, Kai Yu, Moon Kyoo Jang, Charles Marboe, Gerald J. Berry, Hannah A. Valantine
Journal: Circulation (2021)
Engineered nasal cartilage for the repair of osteoarthritic knee cartilage defects
Authors: Lina Acevedo Rua, Marcus Mumme, Cristina Manferdini, Salim Darwiche, Ahmad Khalil, Morgane Hilpert, David A. Buchner, Gina Lisignoli, Paola Occhetta, Brigitte von Rechenberg, Martin Haug, Dirk J. Schaefer, Marcel Jakob, Arnold Caplan, Ivan Martin, Andrea Barbero, Karoliina Pelttari
Journal: Science Translational Medicine (2021)

Osteoarthritis (OA) is the most prevalent joint disorder, causing pain and disability predominantly in the aging population but also affecting young individuals. Current treatments are limited to use of anti-inflammatory drugs to alleviate symptoms or degenerated joint replacement by a prosthetic implant at the end stage of the disease. We hypothesized that degenerative cartilage defects can be treated using nasal chondrocyte–based tissue-engineered cartilage (N-TEC). We demonstrate that N-TEC maintained cartilaginous properties when exposed in vitro to inflammatory stimuli found in osteoarthritic joints and favorably altered the inflammatory profile of cells from osteoarthritic joints. These effects were at least partially mediated by down-regulation of the WNT (wingless/integrated) signaling pathway through sFRP1 (secreted frizzled-related protein-1). We further report that N-TEC survive and engraft in vivo in ectopic mouse models reproducing a human osteochondral OA tissue environment, as well as in sheep articular cartilage defects that mimic degenerative settings. Last, we tested the safety of autologous N-TEC for the treatment of osteoarthritic cartilage defects in the knees of two patients with advanced OA (Kellgren and Lawrence grades 3 and 4) who were otherwise considered for unicondylar knee arthroplasty. No adverse reactions were recorded, and patients reported reduced pain as well as improved joint function and life quality 14 months after surgery. Together, our findings indicate that N-TEC can directly contribute to cartilage repair in osteoarthritic joints. A suitably powered clinical trial is now required to assess its efficacy in the treatment of patients with OA.
Evolution of Methyltransferase-Like (METTL) Proteins in Metazoa: A Complex Gene Family Involved in Epitranscriptomic Regulation and Other Epigenetic Processes
Authors: Juliet M Wong, Jose M Eirin-Lopez
Journal: Molecular Biology and Evolution (2021)

Abstract The methyltransferase-like (METTL) proteins constitute a family of seven-beta-strand methyltransferases with S-adenosyl methionine-binding domains that modify DNA, RNA, and proteins. Methylation by METTL proteins contributes to the epigenetic, and in the case of RNA modifications, epitranscriptomic regulation of a variety of biological processes. Despite their functional importance, most investigations of the substrates and functions of METTLs within metazoans have been restricted to model vertebrate taxa. In the present work, we explore the evolutionary mechanisms driving the diversification and functional differentiation of 33 individual METTL proteins across Metazoa. Our results show that METTLs are nearly ubiquitous across the animal kingdom, with most having arisen early in metazoan evolution (i.e., occur in basal metazoan phyla). Individual METTL lineages each originated from single independent ancestors, constituting monophyletic clades, which suggests that each METTL was subject to strong selective constraints driving its structural and/or functional specialization. Interestingly, a similar process did not extend to the differentiation of nucleoside-modifying and protein-modifying METTLs (i.e., each METTL type did not form a unique monophyletic clade). The members of these two types of METTLs also exhibited differences in their rates of evolution. Overall, we provide evidence that the long-term evolution of METTL family members was driven by strong purifying selection, which in combination with adaptive selection episodes, led to the functional specialization of individual METTL lineages. This work contributes useful information regarding the evolution of a gene family that fulfills a variety of epigenetic functions, and can have profound influences on molecular processes and phenotypic traits.
Smoothened is a therapeutic target for reducing glutamate toxicity in ischemic stroke
Authors: Yuqing Wang, Shanshan Lu, Yifei Chen, Liang Li, Xia Li, Zhongwei Qu, Junbo Huang, Liu Fan, Chao Yuan, Nan Song, Jun Zhang, Wendong Xu, Shenglian Yang, Yizheng Wang
Journal: Science Translational Medicine (2021)

Activation of SHH pathway contributes to glutamate toxicity, and inhibition of SMO reduces ischemic brain damage in mice and monkeys.
Mobile health technology for diverse populations: challenges and opportunities
Authors: James A. Diao, Joseph Kvedar
Journal: npj Digital Medicine (2021)

Abstract Nearly half of US adults have hypertension, and three in four cases are not well-controlled. Due to structural barriers, underserved communities face greater burdens of disease, less consistent management, and worse outcomes. Mobile technology presents an opportunity to reduce financial, geographic, and workforce barriers, but little data currently support its use in populations with digital disparities. A recent article by Khoong et al. systematically reviews the literature to quantify outcomes for these populations and provide a roadmap toward more inclusive mobile health strategies.
Symptom‐based stratification for hay fever: A crowdsourced study using the smartphone application AllerSearch
Authors: Takenori Inomata, Masahiro Nakamura, Masao Iwagami, Jaemyoung Sung, Masahiro Nakamura, Nobuyuki Ebihara, Kumiko Fujisawa, Kaori Muto, Shuko Nojiri, Takuma Ide, Mitsuhiro Okano, Yuichi Okumura, Kenta Fujio, Keiichi Fujimoto, Masashi Nagao, Kunihiko Hirosawa, Yasutsugu Akasaki, Akira Murakami
Journal: Allergy (2021)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Racism, Diminished Returns of Socioeconomic Resources, and Black Middle-Income Children’s Health Paradox—Reply
Authors: Jason M. Nagata, Omar M. Sajjad, Kyle T. Ganson
Journal: JAMA Pediatrics (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Patients with systemic sclerosis show phenotypic and functional defects in neutrophils
Authors: Daniela Impellizzieri, Cecilie Egholm, Alan Valaperti, Oliver Distler, Onur Boyman
Journal: Allergy (2021)

Abstract Background Systemic sclerosis (SSc) is a multiorgan autoimmune disease characterized by inflammation, vascular modification, and progressive fibrosis of the skin and several visceral organs. Innate and adaptive immune cells, including myeloid, B and T cells, are believed to be central to the pathogenesis of SSc. However, the role and functional state of neutrophil granulocytes (neutrophils) are ill‐defined in SSc. Methods We performed a prospective study of neutrophils freshly isolated from SSc patients and healthy donors (HD) by measuring in these neutrophils (i) functional cell surface markers, including CD16, CD62L, CD66b, CD66c, CXCR1, CXCR2, and CXCR4; (ii) cytokine‐activated intracellular signal transducer and activator of transcription (STAT) pathways, such as phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6; (iii) production of neutrophil extracellular traps (NET) and intracellular myeloperoxidase (MPO); and (iv) phagocytosis of bacteria by the neutrophils. Results Neutrophils of SSc patients expressed lower CD16 and CD62L and higher pSTAT3 and pSTAT6 compared to HD. Moreover, neutrophils of SSc patients lacked CXCR1 and CXCR2, the receptors responding to the potent neutrophil chemoattractant CXCL8. Neutrophils of SSc patients were also deficient in MPO levels, NET formation, and phagocytosis of bacteria. Conclusions Neutrophils of patients with SSc display several functional defects affecting cell migration, NET formation, and phagocytosis of bacteria.
Genomic and evolutionary classification of lung cancer in never smokers
Authors: Tongwu Zhang, Philippe Joubert, Naser Ansari-Pour, Wei Zhao, Phuc H. Hoang, Rachel Lokanga, Aaron L. Moye, Jennifer Rosenbaum, Abel Gonzalez-Perez, Francisco Martínez-Jiménez, Andrea Castro, Lucia Anna Muscarella, Paul Hofman, Dario Consonni, Angela C. Pesatori, Michael Kebede, Mengying Li, Bonnie E. Gould Rothberg, Iliana Peneva, Matthew B. Schabath, Maria Luana Poeta, Manuela Costantini, Daniela Hirsch, Kerstin Heselmeyer-Haddad, Amy Hutchinson, Mary Olanich, Scott M. Lawrence, Petra Lenz, Maire Duggan, Praphulla M. S. Bhawsar, Jian Sang, Jung Kim, Laura Mendoza, Natalie Saini, Leszek J. Klimczak, S. M. Ashiqul Islam, Burcak Otlu, Azhar Khandekar, Nathan Cole, Douglas R. Stewart, Jiyeon Choi, Kevin M. Brown, Neil E. Caporaso, Samuel H. Wilson, Yves Pommier, Qing Lan, Nathaniel Rothman, Jonas S. Almeida, Hannah Carter, Thomas Ried, Carla F. Kim, Nuria Lopez-Bigas, Montserrat Garcia-Closas, Jianxin Shi, Yohan Bossé, Bin Zhu, Dmitry A. Gordenin, Ludmil B. Alexandrov, Stephen J. Chanock, David C. Wedge, Maria Teresa Landi
Journal: Nature Genetics (2021)
Phase 1 open-label trial of intravenous administration of MVA-BN-brachyury-TRICOM vaccine in patients with advanced cancer
Authors: Peter J DeMaria, Katherine Lee-Wisdom, Renee N Donahue, Ravi A Madan, Fatima Karzai, Angie Schwab, Claudia Palena, Caroline Jochems, Charalampos Floudas, Julius Strauss, Jennifer L Marté, Jason Mark Redman, Eva Dombi, Brigitte Widemann, Borys Korchin, Tatiana Adams, Cesar Pico-Navarro, Christopher Heery, Jeffrey Schlom, James L Gulley, Marijo Bilusic
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background MVA-BN-brachyury-TRICOM is a recombinant vector-based therapeutic cancer vaccine designed to induce an immune response against brachyury. Brachyury, a transcription factor overexpressed in advanced cancers, has been associated with treatment resistance, epithelial-to-mesenchymal transition, and metastatic potential. MVA-BN-brachyury-TRICOM has demonstrated immunogenicity and safety in previous clinical trials of subcutaneously administered vaccine. Preclinical studies have suggested that intravenous administration of therapeutic vaccines can induce superior CD8 + T cell responses, higher levels of systemic cytokine release, and stronger natural killer cell activation and proliferation. This is the first-in-human study of the intravenous administration of MVA-BN-brachyury-TRICOM. Methods Between January 2020 and March 2021, 13 patients were treated on a phase 1, open-label, 3+3 design, dose-escalation study at the National Institutes of Health Clinical Center. The study population was adults with advanced solid tumors and was enriched for chordoma, a rare sarcoma of the notochord that overexpresses brachyury. Vaccine was administered intravenously at three DLs on days 1, 22, and 43. Blood samples were taken to assess drug pharmacokinetics and immune activation. Imaging was conducted at baseline, 1 month, and 3 months post-treatment. The primary endpoint was safety and tolerability as determined by the frequency of dose-limiting toxicities; a secondary endpoint was determination of the recommended phase 2 dose. Results No dose-limiting toxicities were observed and no serious adverse events were attributed to the vaccine. Vaccine-related toxicities were consistent with class profile (ie, influenza-like symptoms). Cytokine release syndrome up to grade 2 was observed with no adverse outcomes. Dose-effect trend was observed for fever, chills/rigor, and hypotension. Efficacy analysis of objective response rate per RECIST 1.1 at the end of study showed one patient with a partial response, four with stable disease, and eight with progressive disease. Three patients with stable disease experienced clinical benefit in the form of improvement in pain. Immune correlatives showed T cell activation against brachyury and other tumor-associated cascade antigens. Conclusions Intravenous administration of MVA-BN-brachyury-TRICOM vaccine was safe and tolerable. Maximum tolerated dose was not reached. The maximum administered dose was 10 9 infectious units every 3 weeks for three doses. This dose was selected as the recommended phase 2 dose. Trial registration number NCT04134312 .
Why we need to make space for grief
Authors: Fiona Godlee
Journal: BMJ (2021)

The past 18 months have seen more than their share of human tragedy.Some four million people have died as a result of the covid-19 pandemic, and over 35 million have been bereaved.Grief is the natural and inevitable response, writes Lucy Selman, but for many it has been aggravated by the wider effects of the pandemic: poor experiences at the end of life, limited contact in the days before death, being unable to say goodbye in person, social isolation and loneliness, and the disruption to funerals and collective mourning (doi:10.1136/bmj.n1803). 1 Children are particularly vulnerable to the long term effects of loss, with most mental health disorders starting in the first two decades of life.The pandemic has affected more than 2.5 billion children and young people worldwide. 2 Research into the effects on their mental health and wellbeing is limited, but learning from previous large scale disasters can help shape our understanding and response.Young people may find their grieving complicated by disruption to normal routines, school closures, financial hardship, and lack of access to professional help.Elizabeth Rider and colleagues offer a stepwise approach for clinicians: universal care for all children and families; targeted care for those showing increased distress or with pre-existing trauma; and clinical treatment for those with severe, escalating, or persistent distress.In times of loss and uncertainty, open communication helps build resilience.But has the pandemic improved our ability to talk about death?Selman thinks it has. 1 Evidence suggests a shift in public attitudes: whereas bereaved people often experience lack of understanding and compassion among family and friends fueled by embarrassment and awkwardness, surveys indicate that people are now more comfortable talking about grief and more able to think about their own mortality.And this must be true for doctors too, who have their own grief to acknowledge and must make space for grief for the death of patients, colleagues, family, or friends.Doctors are often encouraged or even required to set aside their own grief in the name of professionalism and efficient patient care.But this makes us all less authentic and more alone.Being open about our own experiences of grief, showing "the strength of vulnerability," can help others as well as ourselves and may further shift society's attitudes to death and loss.