tbuckley/cabot-search huggingface dataset:
Covid-19: Preliminary figures show 1.2% of people in England had infection at end of November
Authors: Jacqui Wise
Journal: BMJ (2023)

Preliminary figures show 1.2% of people in England had infection at end of November Jacqui WiseThe UK Health Security Agency (UKHSA) has delayed the planned release of modelled, weighted prevalence data from the Winter Coronavirus Infection Study until 21 December, although the raw data show a relatively low positivity rate of 1.2% in England in the week to 29 November.
RIPK1 plays a crucial role in maintaining regulatory T-Cell homeostasis by inhibiting both RIPK3- and FADD-mediated cell death
Authors: Xiaoxue Deng, Lingxia Wang, Yunze Zhai, Qiuyue Liu, Fengxue Du, Yu Zhang, Wenxing Zhao, Tingtao Wu, Yiwen Tao, Jie Deng, Yongbing Cao, Pei Hao, Jiazi Ren, Yunli Shen, Zuoren Yu, Yuejuan Zheng, Haibing Zhang, Haikun Wang
Journal: Cellular and Molecular Immunology (2023)
“Ever since I knew I was trans I knew I wanted hormone therapy”: a qualitative exploration into the journey of Australian trans individuals accessing feminizing gender-affirming hormone therapy
Authors: James A. Fowler, Sarah Warzywoda, Nia Franks, Fiona Bisshop, Penny Wood, Judith A. Dean
Journal: International Journal of Transgender Health (2023)

For many trans folks, gender-affirming hormone therapy (GAHT) is a desired affirming procedure that has been linked with positive health outcomes, however literature has had little focus on the journeys of trans people as they access GAHT.
Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites
Authors: Talya L. Dayton, Nicolas Alcala, Laura Moonen, Lisanne den Hartigh, Veerle Geurts, Lise Mangiante, Lisa Lap, Antonella F.M. Dost, Joep Beumer, Sonja Levy, Rachel S. van Leeuwaarde, Wenzel M. Hackeng, Kris Samsom, Catherine Voegele, Alexandra Sexton-Oates, Harry Begthel, Jeroen Korving, Lisa Hillen, Lodewijk A.A. Brosens, Sylvie Lantuejoul, Sridevi Jaksani, Niels F.M. Kok, Koen J. Hartemink, Houke M. Klomp, Inne H.M. Borel Rinkes, Anne-Marie Dingemans, Gerlof D. Valk, Menno R. Vriens, Wieneke Buikhuisen, José van den Berg, Margot Tesselaar, Jules Derks, Ernst Jan Speel, Matthieu Foll, Lynnette Fernández-Cuesta, Hans Clevers
Journal: Cancer Cell (2023)

Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with BCL-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models.
Cancer Drug Price and Novelty in Mechanism of Action
Authors: Miloš D. Miljković, Jordan Tuia, Timothée Olivier, Alyson Haslam, Vinay Prasad
Journal: JAMA Network Open (2023)

Importance Many economic theories point to regulatory issues and subsidization of research and development costs as the primary factor in the high cancer drug prices in the US. Even so, the association between the median annual cost and novelty of cancer drugs approved in the US remains unclear. Objective To evaluate the association between the median annual cost and novelty of cancer drugs approved in the US over a 6-year period. Design, Setting, and Participants This cross-sectional study included all cancer drugs approved by the US Food and Drug Administration (FDA) from January 1, 2015, to December 31, 2020. Drug names, indications, manufacturer, dosage, and measures of activity/efficacy were extracted from the FDA announcement. The search was performed in December 2021. Data were analyzed from January 2022 until April 2022. Main Outcomes and Measures Annual cost of treatment was calculated based on average wholesale price collected from the 2021 Micromedex Red Book database. Mechanism of action was inferred from trial publication or its references. Results There were 224 cancer drug approvals across 119 individual drugs, with a median annual cost of $196 000 (IQR, $170 000-$277 000). Gene and viral therapies were the most expensive (median, $448 000 [IQR, $448 000-$479 000]), followed by small molecule therapy (median, $244 000 [IQR, $203 000-$321 000), and biologics (median, $185 000 [IQR, $148 000-$195 000]). There was no significant difference in cost between first-in-class, next-in-class, and subsequent approvals of an already approved drug. Conclusions and Relevance Findings of this study indicate that the median annual price of anticancer drugs in the US is not associated with the novelty of their mechanism of action.
Targeting NR1D1 in organ injury: challenges and prospects
Authors: Zi-Yin Zhang-sun, Xue-Zeng Xu, Germaine Escames, Wang-Rui Lei, Lin Zhao, Ya-Zhe Zhou, Ye Tian, Ya-Nan Ren, Darío Acuña-Castroviejo, Yang Yang
Journal: Military Medical Research (2023)

Abstract Nuclear receptor subfamily 1, group D, member 1 (NR1D1, also known as REV-ERBα) belongs to the nuclear receptor (NR) family, and is a heme-binding component of the circadian clock that consolidates circadian oscillators. In addition to repressing the transcription of multiple clock genes associated with circadian rhythms, NR1D1 has a wide range of downstream target genes that are intimately involved in many physiopathological processes, including autophagy, immunity, inflammation, metabolism and aging in multiple organs. This review focuses on the pivotal role of NR1D1 as a key transcription factor in the gene regulatory network, with particular emphasis on the milestones of the latest discoveries of NR1D1 ligands. NR1D1 is considered as a promising drug target for treating diverse diseases and may contribute to research on innovative biomarkers and therapeutic targets for organ injury-related diseases. Further research on NR1D1 ligands in prospective human trials may pave the way for their clinical application in many organ injury-related disorders.
Safety of GLP-1 Receptor Agonists and Other Second-Line Antidiabetics in Early Pregnancy
Authors: Carolyn E. Cesta, Ran Rotem, Brian T. Bateman, Gabriel Chodick, Jacqueline M. Cohen, Kari Furu, Mika Gissler, Krista F. Huybrechts, Lars J. Kjerpeseth, Maarit K. Leinonen, Laura Pazzagli, Helga Zoega, Ellen W. Seely, Elisabetta Patorno, Sonia Hernández-Díaz
Journal: JAMA Internal Medicine (2023)

Importance Increasing use of second-line noninsulin antidiabetic medication (ADM) in pregnant individuals with type 2 diabetes (T2D) may result in fetal exposure, but their teratogenic risk is unknown. Objective To evaluate periconceptional use of second-line noninsulin ADMs and whether it is associated with increased risk of major congenital malformations (MCMs) in the infant. Design, Setting, and Participants This observational population-based cohort study used data from 4 Nordic countries (2009-2020), the US MarketScan Database (2012-2021), and the Israeli Maccabi Health Services database (2009-2020). Pregnant women with T2D were identified and their live-born infants were followed until up to 1 year after birth. Exposure Periconceptional exposure was defined as 1 or more prescription fill of sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, or insulin (active comparator) from 90 days before pregnancy to end of first trimester. Main Outcomes and Measures Relative risks (RRs) and 95% CIs for MCMs were estimated using log-binomial regression models, adjusting for key confounders in each cohort and meta-analyzed. Results Periconceptional exposure to second-line noninsulin ADMs differed between countries (32, 295, and 73 per 100 000 pregnancies in the Nordics, US, and Israel, respectively), and increased over the study period, especially in the US. The standardized prevalence of MCMs was 3.7% in all infants (n = 3 514 865), 5.3% in the infants born to women with T2D (n = 51 826), and among infants exposed to sulfonylureas was 9.7% (n = 1362); DPP-4 inhibitors, 6.1% (n = 687); GLP-1 receptor agonists, 8.3% (n = 938); SGLT2 inhibitors, 7.0% (n = 335); and insulin, 7.8% (n = 5078). Compared with insulin, adjusted RRs for MCMs were 1.18 (95% CI, 0.94-1.48), 0.83 (95% CI, 0.64-1.06), 0.95 (95% CI, 0.72-1.26), and 0.98 (95% CI, 0.65-1.46) for infants exposed to sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors, respectively. Conclusions and Relevance Use of second-line noninsulin ADMs is rapidly increasing for treatment of T2D and other indications, resulting in an increasing number of exposed pregnancies. Although some estimates were imprecise, results did not indicate a large increased risk of MCMs above the risk conferred by maternal T2D requiring second-line treatment. Although reassuring, confirmation from other studies is needed, and continuous monitoring will provide more precise estimates as data accumulate.
Missing Funding Information
Journal: JAMA Network Open (2023)

Hakyoung Kim, MD; Tae In Yoon, MD; Seonok Kim, MSc; Sae Byul Lee, MD, PhD; Jisun Kim, MD, PhD; Il Yong Chung, MD, PhD; Beom Seok Ko, MD, PhD; Jong Won Lee, MD, PhD; Byung Ho Son, MD, PhD; Sungchan Gwark, MD, PhD; Jeong Kyeung Kim, MD; Hee Jeong Kim, MD, PhD
Opportunities to Advance Equity Through Informed Consent Discussions
Authors: Puja J. Umaretiya, Emily E. Johnston
Journal: JAMA Network Open (2023)

Paula Aristizabal, MD, MAS; Shilpa Nataraj, MD; Arissa K. Ma, MD; Nikhil V. Kumar, MD; Bianca P. Perdomo, MA; Maria Elena Martinez, PhD; Jesse Nodora, DrPH; Lin Liu, PhD; Euyhyun Lee, MS; Courtney D. Thornburg, MD, MS
Ownership and Interoperability Challenges of Alzheimer Monoclonal Antibody Registries
Authors: Mariana P. Socal, Ilina C. Odouard, Hadi Kharrazi
Journal: JAMA Neurology (2023)

This Viewpoint addresses the challenges that the Centers for Medicare and Medicaid Services faces to collect real-world data on the effectiveness and safety of lecanemab from external registries to achieve its coverage with evidence development objectives.
Pivotal Trial Demographic Representation and Clinical Development Times for Oncology Therapeutics
Authors: Alissa K. Wong, Jennifer E. Miller, Maryam Mooghali, Reshma Ramachandran, Joseph S. Ross, Joshua D. Wallach
Journal: JAMA (2023)

This study evaluates whether FDA-approved novel cancer therapeutics supported by pivotal trials with adequate representation of minoritized groups were associated with slower clinical development times than those with inadequate representation.
BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma
Authors: Debasmita Dutta, Jiye Liu, Kenneth Wen, Keiji Kurata, Mariateresa Fulciniti, Annamaria Gulla, Teru Hideshima, Kenneth C. Anderson
Journal: Blood Cancer Journal (2023)

Abstract Bortezomib (BTZ) is a standard-of-care treatment in multiple myeloma (MM); however, adverse side effects and development of resistance limit its long term benefit. To improve target specificity, therapeutic efficacy, and overcome resistance, we designed nanoparticles that encapsulate BTZ and are surface-functionalized with BCMA antibodies (BCMA-BTZ-NPs). We confirmed efficient cellular internalization of the BCMA-BTZ-NPs only in BCMA-expressing MM cells, but not in BCMA-knockout (KO) cells. In addition, BCMA-BTZ-NPs showed target-specific cytotoxicity against MM cell lines and primary tumor cells from MM patients. The BCMA-BTZ-NPs entered the cell through receptor-mediated uptake, which escapes a mechanism of BTZ resistance based on upregulating P-glycoprotein. Furthermore, BCMA-BTZ-NPs induced cell death more efficiently than non-targeted nanoparticles or free BTZ, triggering potent mitochondrial depolarization followed by apoptosis. In BTZ-resistant cells, BCMA-BTZ-NPs inhibited proteasome activity more effectively than free BTZ or non-targeted nanoparticles. Additionally, BCMA-BTZ-NPs enhanced immunogenic cell death and activated the autophagic pathway more than free BTZ. Finally, we found that BCMA-BTZ-NPs selectively accumulated at the tumor site in a murine xenograft model, enhanced tumor reduction, and prolonged host survival. These results suggest BCMA-BTZ-NPs provide a promising therapeutic strategy for enhancing the efficacy of BTZ and establish a framework for their evaluation in a clinical setting.
Change in Epidemiology of Creutzfeldt-Jakob Disease in the US, 2007-2020
Authors: Matthew A. Crane, Sameer Nair-Desai, Alison Gemmill, John A. Romley, John C. Probasco
Journal: JAMA Neurology (2023)

This cross-sectional study uses Centers for Disease Control and Prevention multiple cause of death data to examine recent US trends in Creutzfeldt-Jakob disease.
Lack of Effect for Oropharyngeal Surfactant for Preterm Neonates—Method or Timing?
Authors: David M. Rub, Nicolas A. Bamat
Journal: JAMA Pediatrics (2023)

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 2024 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
Trends in Age and Disease Severity in Children Hospitalized With RSV Infection Before and During the COVID-19 Pandemic
Authors: Cristina Garcia-Maurino, Helena Brenes-Chacón, Katia C. Halabi, Pablo J. Sánchez, Octavio Ramilo, Asuncion Mejias
Journal: JAMA Pediatrics (2023)

This cohort study evaluates respiratory syncytial virus (RSV)–related hospitalizations and disease severity from 2012 to 2023 in children younger than 5 years.
Prophylactic Oropharyngeal Surfactant for Preterm Newborns at Birth
Authors: Madeleine C. Murphy, Jan Miletin, Claus Klingenberg, Hans Jørgen Guthe, Vincent Rigo, Richard Plavka, Kajsa Bohlin, Almerinda Barroso Pereira, Tomáš Juren, Ekele Alih, Marie Galligan, Colm P. F. O’Donnell
Journal: JAMA Pediatrics (2023)

Preterm newborns at risk of respiratory distress syndrome are supported with continuous positive airway pressure (CPAP). Many newborns worsen despite CPAP and are intubated for surfactant administration, an effective therapy for treatment of respiratory distress syndrome. Endotracheal intubation is associated with adverse effects. Pharyngeal administration of surfactant to preterm animals and humans has been reported as an alternative.
Comparison of Circulating Tumor DNA Assays for Molecular Residual Disease Detection in Early-Stage Triple-Negative Breast Cancer
Authors: Maria Coakley, Guillermo Villacampa, Prithika Sritharan, Claire Swift, Kathryn Dunne, Lucy Kilburn, Katie Goddard, Christodoulos Pipinikas, Patricia Rojas, Warren Emmett, Peter Hall, Catherine Harper-Wynne, Tamas Hickish, Iain Macpherson, Alicia Okines, Andrew Wardley, Duncan Wheatley, Simon Waters, Carlo Palmieri, Matthew Winter, Rosalind J. Cutts, Isaac Garcia-Murillas, Judith Bliss, Nicholas C. Turner
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Detection of circulating tumor DNA (ctDNA) in patients who have completed treatment for early-stage breast cancer is associated with a high risk of relapse, yet the optimal assay for ctDNA detection is unknown. Experimental Design: The cTRAK-TN clinical trial prospectively used tumor-informed digital PCR (dPCR) assays for ctDNA molecular residual disease (MRD) detection in early-stage triple-negative breast cancer. We compared tumor-informed dPCR assays with tumor-informed personalized multimutation sequencing assays in 141 patients from cTRAK-TN. Results: MRD was first detected by personalized sequencing in 47.9% of patients, 0% first detected by dPCR, and 52.1% with both assays simultaneously (P &amp;lt; 0.001; Fisher exact test). The median lead time from ctDNA detection to relapse was 6.1 months with personalized sequencing and 3.9 months with dPCR (P = 0.004, mixed-effects Cox model). Detection of MRD at the first time point was associated with a shorter time to relapse compared with detection at subsequent time points (median lead time 4.2 vs. 7.1 months; P = 0.02). Conclusions: Personalized multimutation sequencing assays have potential clinically important improvements in clinical outcome in the early detection of MRD.
Econazole selectively induces cell death in NF1-homozygous mutant tumor cells
Authors: Yenal B. Lakes, Stefanie L. Moye, Juan Mo, Matthew Tegtmeyer, Ralda Nehme, Maura Charlton, Gabrielle Salinas, Renee M. McKay, Kevin Eggan, Lu Q. Le
Journal: Cell Reports Medicine (2023)

Cutaneous neurofibromas (cNFs) are tumors that develop in more than 99% of individuals with neurofibromatosis type 1 (NF1). They develop in the dermis and can number in the thousands. cNFs can be itchy and painful and negatively impact self-esteem. There is no US Food and Drug Administration (FDA)-approved drug for their treatment. Here, we screen a library of FDA-approved drugs using a cNF cell model derived from human induced pluripotent stem cells (hiPSCs) generated from an NF1 patient. We engineer an NF1 mutation in the second allele to mimic loss of heterozygosity, differentiate the NF1+/− and NF1−/− hiPSCs into Schwann cell precursors (SCPs), and use them to screen a drug library to assess for inhibition of NF1−/− but not NF1+/− cell proliferation. We identify econazole nitrate as being effective against NF1−/− hiPSC-SCPs. Econazole cream selectively induces apoptosis in Nf1−/− murine nerve root neurosphere cells and human cNF xenografts. This study supports further testing of econazole for cNF treatment.
Genome-wide study reveals novel roles for formin-2 in axon regeneration as a microtubule dynamics regulator and therapeutic target for nerve repair
Authors: Ngan Pan Bennett Au, Tan Wu, Xinyu Chen, Feng Gao, Yuen Tung Yolanda Li, Wing Yip Tam, Kwan Ngok Yu, Daniel H. Geschwind, Giovanni Coppola, Xin Wang, Chi Him Eddie Ma
Journal: Neuron (2023)
Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability
Authors: Altair Brito dos Santos, Silas Dalum Larsen, Liangchen Guo, Paola Barbagallo, Alexia Montalant, Matthijs Verhage, Jakob Balslev Sørensen, Jean-François Perrier
Journal: Cell Reports Medicine (2023)

De novo mutations in STXBP1 are among the most prevalent causes of neurodevelopmental disorders and lead to haploinsufficiency, cortical hyperexcitability, epilepsy, and other symptoms in people with mutations. Given that Munc18-1, the protein encoded by STXBP1, is essential for excitatory and inhibitory synaptic transmission, it is currently not understood why mutations cause hyperexcitability. We find that overall inhibition in canonical feedforward microcircuits is defective in a P15-22 mouse model for Stxbp1 haploinsufficiency. Unexpectedly, we find that inhibitory synapses formed by parvalbumin-positive interneurons were largely unaffected. Instead, excitatory synapses fail to recruit inhibitory interneurons. Modeling confirms that defects in the recruitment of inhibitory neurons cause hyperexcitation. CX516, an ampakine that enhances excitatory synapses, restores interneuron recruitment and prevents hyperexcitability. These findings establish deficits in excitatory synapses in microcircuits as a key underlying mechanism for cortical hyperexcitability in a mouse model of Stxbp1 disorder and identify compounds enhancing excitation as a direction for therapy.
Proteomic characterization of the colorectal cancer response to chemoradiation and targeted therapies reveals potential therapeutic strategies
Authors: Yan Li, Bing Wang, Fahan Ma, Dongxian Jiang, Ying Wang, Kai Li, Subei Tan, Jinwen Feng, Yunzhi Wang, Zhaoyu Qin, Ganfei Xu, Sha Tian, Xiaolei Zhang, Chen Xu, Jiaxue Wu, Jianmin Xu, Yingyong Hou, Chen Ding
Journal: Cell Reports Medicine (2023)

Chemoradiation and targeted therapies are the major treatments for colorectal cancer (CRC); however, molecular properties associated with therapy resistance are incompletely characterized. Here, we profile the proteome of 254 tumor tissues from patients with CRC undergoing chemotherapy, chemoradiation, or chemotherapy combined with targeted therapy. Proteome-based classification reveals four subtypes featured with distinct biological and therapeutic characteristics. The integrative analysis of CRC cell lines and clinical samples indicates that immune regulation is significantly associated with drug sensitivity. HSF1 can increase DNA damage repair and cell cycle, thus inducing resistance to radiation, while high expression of HDAC6 is negatively associated with response of cetuximab. Furthermore, we develop prognostic models with high accuracy to predict the therapeutic response, further validated by parallel reaction monitoring (PRM) assay in an independent validation cohort. This study provides a rich resource for investigating the mechanisms and indicators of chemoradiation and targeted therapy in CRC.
Distinct prefrontal projection activity and transcriptional state conversely orchestrate social competition and hierarchy
Authors: Tae-Yong Choi, Hyoungseok Jeon, Sejin Jeong, Eum Ji Kim, Jeongseop Kim, Yun Ha Jeong, Byungsoo Kang, Murim Choi, Ja Wook Koo
Journal: Neuron (2023)
Delayed maturation and migration of excitatory neurons in the juvenile mouse paralaminar amygdala
Authors: Pia J. Alderman, David Saxon, Lucía I. Torrijos-Saiz, Malaz Sharief, Chloe E. Page, Jude K. Baroudi, Sean W. Biagiotti, Vladimir A. Butyrkin, Anna Melamed, Chay T. Kuo, Stefano Vicini, Jose M. García-Verdugo, Vicente Herranz-Pérez, Joshua G. Corbin, Shawn F. Sorrells
Journal: Neuron (2023)