tbuckley/cabot-search huggingface dataset:
Cerebellar Functions Beyond Movement and Learning
Authors: Linda H. Kim, Detlef H. Heck, Roy V. Sillitoe
Journal: Annual Review of Neuroscience (2024)

The cerebellum has a well-established role in controlling motor functions, including coordination, posture, and the learning of skilled movements. The mechanisms for how it carries out motor behavior remain under intense investigation. Interestingly though, in recent years the mechanisms of cerebellar function have faced additional scrutiny since nonmotor behaviors may also be controlled by the cerebellum. With such complexity arising, there is now a pressing need to better understand how cerebellar structure, function, and behavior intersect to influence behaviors that are dynamically called upon as an animal experiences its environment. Here, we discuss recent experimental work that frames possible neural mechanisms for how the cerebellum shapes disparate behaviors and why its dysfunction is catastrophic in hereditary and acquired conditions—both motor and nonmotor. For these reasons, the cerebellum might be the ideal therapeutic target.
The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders
Authors: Bess Frost, Josh Dubnau
Journal: Annual Review of Neuroscience (2024)

Over 40% of the human genome is composed of retrotransposons, DNA species that hold the potential to replicate via an RNA intermediate and are evolutionarily related to retroviruses. Retrotransposons are most studied for their ability to jump within a genome, which can cause DNA damage and novel insertional mutations. Retrotransposon-encoded products, including viral-like proteins, double-stranded RNAs, and extrachromosomal circular DNAs, can also be potent activators of the innate immune system. A growing body of evidence suggests that retrotransposons are activated in age-related neurodegenerative disorders and that such activation causally contributes to neurotoxicity. Here we provide an overview of retrotransposon biology and outline evidence of retrotransposon activation in age-related neurodegenerative disorders, with an emphasis on those involving TAR-DNA binding protein-43 (TDP-43) and tau. Studies to date provide the basis for ongoing clinical trials and hold promise for innovative strategies to ameliorate the adverse effects of retrotransposon dysregulation in neurodegenerative disorders.
Exposure to Concurrent Heatwaves and Ozone Pollution and Associations with Mortality Risk: A Nationwide Study in China
Authors: Hang Du, Meilin Yan, Xin Liu, Yu Zhong, Jie Ban, Kailai Lu, Tiantian Li
Journal: Environmental Health Perspectives (2024)

Concurrent extreme events are projected to occur more frequently under a changing climate. Understanding the mortality risk and burden of the concurrent heatwaves and ozone (
Author Correction: The complex aetiology of cerebral palsy
Authors: Steven J. Korzeniewski, Jaime Slaughter, Madeleine Lenski, Peterson Haak, Nigel Paneth
Journal: Nature Reviews Neurology (2024)

In the version of the article initially published, in Fig. 1 the year "1868" is incorrect and should instead read "1897" in the timeline.In the top right box in Fig. 1, "(Freud, 1868)" should read " (Freud, 1968)."In the "Socio-ecomonic status and correlates" section, citation of reference 25 in the sentence "in South Carolina (USA), Norway and Denmark, and Sweden produced similar results" is incorrect, and the correct citation
Clinical and Biomarker Analysis of a Phase I/II Study of PDR001 Plus Imatinib for Advanced Treatment-Refractory Gastrointestinal Stromal Tumors
Authors: Hyung-Don Kim, Min-Hee Ryu, Young Soo Park, Changhoon Yoo, Sung-Joo Kim, Yoon-Koo Kang
Journal: Clinical Cancer Research (2024)

Abstract Purpose: In this phase Ib/II study, we aimed to evaluate the safety and efficacy of PDR001, an anti-PD1 antibody, in combination with imatinib in patients with treatment-refractory gastrointestinal stromal tumor (GIST). Patients and Methods: Patients with advanced GIST whose disease had progressed on imatinib, sunitinib, and regorafenib were enrolled. In phase Ib, the standard 3 + 3 dose escalation scheme was applied. Intravenous administration of PDR001 at 400 mg for every 4 weeks plus imatinib (300 and 400 mg daily for dose levels I and II, respectively) was given. The primary outcome for phase II was the disease control rate at 12 weeks. Exploratory biomarker analysis was performed based on PDL1 IHC, next-generation sequencing, and multiplexed IHC. Results: No dose-limiting toxicity was observed in the phase Ib part (n = 10), and dose level II was selected as the recommended phase II dose. In the phase II part (n = 29), there was no objective response, and the disease control rate at 12 weeks was 37.9%, not meeting the primary efficacy endpoint. For patients in phase Ib–dose level II and phase II (n = 36), the median progression-free survival (PFS) and overall survival were 2.3 and 9.5 months, respectively. The most common grade 3 to 4 adverse event was anemia. Exploratory biomarker analysis indicated that a higher CD8+ T-cell density was associated with a favorable PFS but to a limited degree. Tumor mutational burden and PDL1 were not associated with better PFS. Conclusions: In patients with treatment-refractory GIST, PDR001 in combination with imatinib was generally tolerable, but it was not effective.
Bridging the Gap from Bench to Bedside: A Call for <i>In Vivo</i> Preclinical Models to Advance Endometrial Cancer and Cervical Cancer Immuno-oncology Research
Authors: Laura Chambers, Paulina Haight, Julia Chalif, Yogita Mehra, Daniel Spakowicz, Floor J. Backes, Casey M. Cosgrove, David M. O'Malley, Roberto Vargas, Bradley R. Corr, Victoria L. Bae-Jump, Rebecca C. Arend
Journal: Clinical Cancer Research (2024)

Abstract Advanced-stage endometrial and cervical cancers are associated with poor outcomes despite contemporary advances in surgical techniques and therapeutics. Recent clinical trial results have led to a shift in the treatment paradigm for both malignancies, in which immunotherapy is now incorporated as the standard of care up front for most patients with advanced endometrial and cervical cancers as the standard of care. Impressive response rates have been observed, but unfortunately, a subset of patients do not benefit from immunotherapy, and survival remains poor. Continued preclinical research and clinical trial development are crucial for our understanding of resistance mechanisms to immunotherapy and maximization of therapeutic efficacy. In this setting, syngeneic models are preferred over xenograft models as they allow for the evaluation of the tumor–immune interaction in an immunocompetent host, most closely mimicking the tumor–immune interaction in patients with cancer. Unfortunately, significant disparities exist about syngeneic models in gynecologic malignancy, in which queries from multiple large bioscience companies confirm no commercial availability of endometrial or cervical cancer syngeneic cell lines. Published data exist about the recent development of several endometrial and cervical cancer syngeneic cell lines, warranting further investigation. Closing the disparity gap for preclinical models in endometrial and cervical cancers will support physician scientists, basic and translational researchers, and clinical trialists who are dedicated to improving outcomes for our patients with advanced disease and poor prognosis.
Real-world effectiveness and safety of risankizumab in adult patients with plaque psoriasis: A 1-year international multicenter retrospective cohort study
Authors: Ahmed Bagit, Khalad Maliyar, Mark Mansour, Jorge R Georgakopoulos, Brian Rankin, Yuliya Lytvyn, Hiba Zaaroura, Ye-Jean Park, Emilie Wang, Asfandyar Mufti, Tiago Torres, Ana M Le, Ronald Vender, Vimal H Prajapati, Jensen Yeung
Journal: Journal of the American Academy of Dermatology (2024)
Disparities in Mortality by Sexual Orientation in a Large, Prospective Cohort of Female Nurses
Authors: Sarah McKetta, Tabor Hoatson, Landon D. Hughes, Bethany G. Everett, Sebastien Haneuse, S. Bryn Austin, Tonda L. Hughes, Brittany M. Charlton
Journal: JAMA (2024)

Importance Extensive evidence documents health disparities for lesbian, gay, and bisexual (LGB) women, including worse physical, mental, and behavioral health than heterosexual women. These factors have been linked to premature mortality, yet few studies have investigated premature mortality disparities among LGB women and whether they differ by lesbian or bisexual identity. Objective To examine differences in mortality by sexual orientation. Design, Setting, and Participants This prospective cohort study examined differences in time to mortality across sexual orientation, adjusting for birth cohort. Participants were female nurses born between 1945 and 1964, initially recruited in the US in 1989 for the Nurses’ Health Study II, and followed up through April 2022. Exposures Sexual orientation (lesbian, bisexual, or heterosexual) assessed in 1995. Main Outcome and Measure Time to all-cause mortality from assessment of exposure analyzed using accelerated failure time models. Results Among 116 149 eligible participants, 90 833 (78%) had valid sexual orientation data. Of these 90 833 participants, 89 821 (98.9%) identified as heterosexual, 694 (0.8%) identified as lesbian, and 318 (0.4%) identified as bisexual. Of the 4227 deaths reported, the majority were among heterosexual participants (n = 4146; cumulative mortality of 4.6%), followed by lesbian participants (n = 49; cumulative mortality of 7.0%) and bisexual participants (n = 32; cumulative mortality of 10.1%). Compared with heterosexual participants, LGB participants had earlier mortality (adjusted acceleration factor, 0.74 [95% CI, 0.64-0.84]). These differences were greatest among bisexual participants (adjusted acceleration factor, 0.63 [95% CI, 0.51-0.78]) followed by lesbian participants (adjusted acceleration factor, 0.80 [95% CI, 0.68-0.95]). Conclusions and Relevance In an otherwise largely homogeneous sample of female nurses, participants identifying as lesbian or bisexual had markedly earlier mortality during the study period compared with heterosexual women. These differences in mortality timing highlight the urgency of addressing modifiable risks and upstream social forces that propagate and perpetuate disparities.
Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice
Authors: Baolin Guo, Tiaotiao Liu, Soonwook Choi, Honghui Mao, Wenting Wang, Kaiwen Xi, Carter Jones, Nolan D. Hartley, Dayun Feng, Qian Chen, Yingying Liu, Ralf D. Wimmer, Yuqiao Xie, Ningxia Zhao, Jianjun Ou, Mario A. Arias-Garcia, Diya Malhotra, Yang Liu, Sihak Lee, Samuel Pasqualoni, Ryan J. Kast, Morgan Fleishman, Michael M. Halassa, Shengxi Wu, Zhanyan Fu
Journal: Cell Reports Medicine (2024)

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.
SARS-CoV-2 Viral Shedding and Rapid Antigen Test Performance — Respiratory Virus Transmission Network, November 2022–May 2023
Authors: Sarah E. Smith-Jeffcoat, Alexandra M. Mellis, Carlos G. Grijalva, H. Keipp Talbot, Jonathan Schmitz, Karen Lutrick, Katherine D. Ellingson, Melissa S. Stockwell, Son H. McLaren, Huong Q. Nguyen, Suchitra Rao, Edwin J. Asturias, Meredith E. Davis-Gardner, Mehul S. Suthar, Hannah L. Kirking, Melissa A. Rolfes, Jessica E. Biddle, Yuwei Zhu, Karla Ledezma, Kathleen Pryor, Ellen Sano, Joshua G. Petrie
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

As population immunity to SARS-CoV-2 evolves and new variants emerge, the role and accuracy of antigen tests remain active questions. To describe recent test performance, the detection of SARS-CoV-2 by antigen testing was compared with that by reverse transcription-polymerase chain reaction (RT-PCR) and viral culture testing during November 2022-May 2023. Participants who were enrolled in a household transmission study completed daily symptom diaries and collected two nasal swabs (tested for SARS-CoV-2 via RT-PCR, culture, and antigen tests) each day for 10 days after enrollment. Among participants with SARS-CoV-2 infection, the percentages of positive antigen, RT-PCR, and culture results were calculated each day from the onset of symptoms or, in asymptomatic persons, from the date of the first positive test result. Antigen test sensitivity was calculated using RT-PCR and viral culture as references. The peak percentage of positive antigen (59.0%) and RT-PCR (83.0%) results occurred 3 days after onset, and the peak percentage of positive culture results (52%) occurred 2 days after onset. The sensitivity of antigen tests was 47% (95% CI = 44%-50%) and 80% (95% CI = 76%-85%) using RT-PCR and culture, respectively, as references. Clinicians should be aware of the lower sensitivity of antigen testing compared with RT-PCR, which might lead to false-negative results. This finding has implications for timely initiation of SARS-CoV-2 antiviral treatment, when early diagnosis is essential; clinicians should consider RT-PCR for persons for whom antiviral treatment is recommended. Persons in the community who are at high risk for severe COVID-19 illness and eligible for antiviral treatment should seek testing from health care providers with the goal of obtaining a more sensitive diagnostic test than antigen tests (i.e., an RT-PCR test).
Multi-omic profiling reveals the endogenous and neoplastic responses to immunotherapies in cutaneous T cell lymphoma
Authors: David R Glass, Koshlan Mayer-Blackwell, Nirasha Ramchurren, K Rachael Parks, George E Duran, Anna K Wright, Armando N Bastidas Torres, Laura Islas, Youn H Kim, Steven P Fling, Michael S Khodadoust, Evan W Newell
Journal: Cell Reports Medicine (2024)

Cutaneous T cell lymphomas (CTCLs) are skin cancers with poor survival rates and limited treatments. While immunotherapies have shown some efficacy, the immunological consequences of administering immune-activating agents to CTCL patients have not been systematically characterized. We apply a suite of high-dimensional technologies to investigate the local, cellular, and systemic responses in CTCL patients receiving either mono- or combination anti-PD-1 plus interferon-gamma (IFN-γ) therapy. Neoplastic T cells display no evidence of activation after immunotherapy. IFN-γ induces muted endogenous immunological responses, while anti-PD-1 elicits broader changes, including increased abundance of CLA
Use of Ebola Vaccines — Worldwide, 2021–2023
Authors: Ruth Kallay, Reena H. Doshi, Pierre Muhoza, Mary J. Choi, Anaïs Legand, Emma Aberle-Grasse, Aminata Bagayoko, Terri B. Hyde, Pierre Formenty, Alejandro Costa
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Ebola virus disease (Ebola) is a rare but severe illness in humans, with an average case fatality rate of approximately 50%.Two licensed vaccines are currently available against Orthoebolavirus zairense, the virus that causes Ebola: the 1-dose rVSVΔG-ZEBOV-GP (ERVEBO [Merck]) and the 2-dose regimen of Ad26.ZEBOV and MVA-BN-Filo (Zabdeno/ Mvabea [Johnson & Johnson]).The Strategic Advisory Group of Experts on Immunization recommends the use of 1-dose ERVEBO during Ebola outbreaks, and in 2021, a global stockpile of ERVEBO was established to ensure equitable, timely, and targeted access to vaccine doses for future Ebola outbreaks.This report describes the use of Ebola vaccines and the role of the stockpile developed and managed by the International Coordinating Group (ICG) on Vaccine Provision during 2021-2023.A total of 145,690 doses have been shipped from the ICG stockpile since 2021.However, because outbreaks since 2021 have been limited and rapidly contained, most doses (139,120; 95%) shipped from the ICG stockpile have been repurposed for preventive vaccination of high-risk groups, compared with 6,570 (5%) used for outbreak response.Repurposing doses for preventive vaccination could be prioritized in the absence of Ebola outbreaks to prevent transmission and maximize the cost-efficiency and benefits of the stockpile.
Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses
Authors: Rashmi Ray, Faez Amokrane Nait Mohamed, Daniel P Maurer, Jiachen Huang, Berk A Alpay, Larance Ronsard, Zhenfei Xie, Julianna Han, Monica Fernandez-Quintero, Quynh Anh Phan, Rebecca L Ursin, Mya Vu, Kathrin H Kirsch, Thavaleak Prum, Victoria C Rosado, Thalia Bracamonte-Moreno, Vintus Okonkwo, Julia Bals, Caitlin McCarthy, Usha Nair, Masaru Kanekiyo, Andrew B Ward, Aaron G Schmidt, Facundo D Batista, Daniel Lingwood
Journal: Immunity (2024)

Broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem of influenza A viruses (IAVs) tend to be effective against either group 1 or group 2 viral diversity. In rarer cases, intergroup protective bnAbs can be generated by human antibody paratopes that accommodate the conserved glycan differences between the group 1 and group 2 stems. We applied germline-engaging nanoparticle immunogens to elicit a class of cross-group bnAbs from physiological precursor frequency within a humanized mouse model. Cross-group protection depended on the presence of the human bnAb precursors within the B cell repertoire, and the vaccine-expanded antibodies enriched for an N55T substitution in the CDRH2 loop, a hallmark of the bnAb class. Structurally, this single mutation introduced a flexible fulcrum to accommodate glycosylation differences and could alone enable cross-group protection. Thus, broad IAV immunity can be expanded from the germline repertoire via minimal antigenic input and an exceptionally simple antibody development pathway.
Sequencing of Anti-CD19 Therapies in the Management of Diffuse Large B-Cell Lymphoma
Authors: Joseph Lownik, Jonathan Boiarsky, Ruemu Birhiray, Akil Merchant, Monica Mead
Journal: Clinical Cancer Research (2024)

Several second- and third-line immunotherapeutic options for patients with relapsed or refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplant are directed against the B-cell antigen cluster of differentiation 19 (CD19). The anti-CD19 monoclonal antibody tafasitamab, paired with the immunomodulator lenalidomide, mediates antibody-dependent cellular toxicity and phagocytosis; the antibody-drug conjugate loncastuximab tesirine delivers the DNA cross-linking agent tesirine via CD19 binding and internalization; and CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) products are engineered from autologous T cells. Although CD19 expression is assessed at diagnosis, clinically relevant thresholds of CD19 expression-which may not be detectable using current routine methodologies-have not been defined and may vary between CD19-directed treatment modalities. Determining optimal treatment sequencing strategies for CD19-directed therapy is hampered by the exclusion of patients who have received prior CD19-directed therapies from major clinical trials. Antigen escape, which is attributed to mechanisms including epitope loss and defective cell surface trafficking of CD19, is an important cause of CAR-T failure. Limited data suggest that CD19 expression may be maintained after non-CAR-T CD19-directed therapy, and retrospective analyses indicate that some patients with disease relapse after CAR-T may benefit from subsequent CD19-directed therapy. To date, clinical evidence on the effect of anti-CD19 therapy prior to CAR-T has been limited to small case series. Prospective studies and detailed analyses are needed to understand how pretreatment and posttreatment CD19 expression correlates with clinical responses to subsequent CD19-directed therapy to fully maximize treatment strategies.
TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis
Authors: Roi Isaac, Gautam Bandyopadhyay, Theresa V. Rohm, Sion Kang, Jinyue Wang, Narayan Pokhrel, Sadatsugu Sakane, Rizaldy Zapata, Avraham M. Libster, Yaron Vinik, Asres Berhan, Tatiana Kisseleva, Zea Borok, Yehiel Zick, Francesca Telese, Nicholas J.G. Webster, Jerrold M. Olefsky
Journal: Cell Metabolism (2024)
Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers
Authors: Sarah T. Diepstraten, Yin Yuan, John E. La Marca, Savannah Young, Catherine Chang, Lauren Whelan, Aisling M. Ross, Karla C. Fischer, Giovanna Pomilio, Rhiannon Morris, Angela Georgiou, Veronique Litalien, Fiona C. Brown, Andrew W. Roberts, Andreas Strasser, Andrew H. Wei, Gemma L. Kelly
Journal: Cancer Cell (2024)

TP53-mutant blood cancers remain a clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins, inducing cancer cell apoptosis. Despite acting downstream of p53, functional p53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report p53 is activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feedforward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 can be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through p53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetic drugs efficiently kills TRP53/TP53-mutant mouse B lymphoma, human NK/T lymphoma, and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.
Commentary on “Circumferential resection margin rates in esophageal cancer resection- oncological equivalency and comparable clinical outcomes between open versus minimally invasive techniques: a retrospective cohort study “
Authors: Kexun Li, Simiao Lu, Xuefeng Leng, Lin Peng
Journal: International Journal of Surgery (2024)

Li, Kexun MD, PhD; Lu, Simiao MD; Leng, Xuefeng MD, PhD; Peng, Lin MD Author Information