tbuckley/cabot-search huggingface dataset:
An Infant-Type Hemispheric Glioma With SOX5::ALK: A Novel Fusion
Authors: Chia Chin Tsai, Man-Hsu Huang, Chia-Lang Fang, Kevin Li-Chun Hsieh, Tsung-Han Hsieh, Wan-Ling Ho, Hsi Chang, Min-Lan Tsai, Yu-Chien Kao, James S. Miser, Tai-Tong Wong, Min-Yu Su, Yen-Lin Liu
Journal: Journal of the National Comprehensive Cancer Network (2024)

Infant-type hemispheric glioma (IHG) is a rare pediatric brain tumor with variable response to chemotherapy and radiotherapy. Molecular insights into IHG can be useful in identifying potentially active targeted therapy. A male fetus was found to have congenital hydrocephalus at the gestational age of 37 weeks. Fetal MRI showed a 2.6 × 2.0-cm tumor located at the frontal horn of the left lateral ventricle, involving the left basal nuclei and thalamus. Tumor biopsy at the age of 2 days revealed an IHG consisting of spindle tumor cells with strong expression of GFAP and ALK. Targeted RNA sequencing detected a novel fusion gene of SOX5::ALK . After initial chemotherapy with cyclophosphamide, carboplatin, and etoposide for 2 cycles, the tumor size progressed markedly and the patient underwent a subtotal resection of brain tumor followed by treatment with lorlatinib, an ALK tyrosine kinase inhibitor with central nervous system (CNS) activity. After 3 months of treatment, reduction of tumor size was observed. After 14 months of treatment, partial response was achieved, and the infant had normal growth and development. In conclusion, we identified a case of congenital IHG with a novel SOX5::ALK fusion that had progressed after chemotherapy and showed partial response and clinical benefit after treatment with the CNS-active ALK inhibitor lorlatinib.
A 3D Bioprinted Human Neurovascular Unit Model of Glioblastoma Tumor Growth
Authors: Yen‐Ting Tung, Yu‐Chi Chen, Kristy Derr, Kelli Wilson, Min Jae Song, Marc Ferrer
Journal: Advanced Healthcare Materials (2024)

Abstract A 3D bioprinted neurovascular unit (NVU) model is developed to study glioblastoma (GBM) tumor growth in a brain‐like microenvironment. The NVU model includes human primary astrocytes, pericytes and brain microvascular endothelial cells, and patient‐derived glioblastoma cells (JHH‐520) are used for this study. Fluorescence reporters are used with confocal high content imaging to quantitate real‐time microvascular network formation and tumor growth. Extensive validation of the NVU‐GBM model includes immunostaining for brain relevant cellular markers and extracellular matrix components; single cell RNA sequencing (scRNAseq) to establish physiologically relevant transcriptomics changes; and secretion of NVU and GBM‐relevant cytokines. The scRNAseq reveals changes in gene expression and cytokines secretion associated with wound healing/angiogenesis, including the appearance of an endothelial mesenchymal transition cell population. The NVU‐GBM model is used to test 18 chemotherapeutics and anti‐cancer drugs to assess the pharmacological relevance of the model and robustness for high throughput screening.
Use of External Control Cohorts in Pediatric Brain Tumor Clinical Trials
Authors: Ashley S. Margol, Annette M. Molinaro, Arzu Onar-Thomas, Adam Resnick, Derek Hanson, Mark Kieran, Pallavi Mishra-Kalyani, Donna Rivera, Amy Barone, David Arons, Clair Meehan, Michael Prados
Journal: Journal of Clinical Oncology (2024)

Why, when, and how to consider external control cohorts in pediatric brain tumor clinical trials.
In This Issue of <i>Diabetes Care</i>
Authors: Max Bingham
Journal: Diabetes Care (2024)

Two-Thirds of Individuals Surveyed Were Unaware of Cardiovascular Risk Associated With DiabetesA globally administered survey, reported by Chaudhary et al. (p.379), suggests that about two-thirds of individuals in 50 high-and middle-income countries are unaware of diabetes being a major risk factor for cardiovascular disease.Given the predicted increases in the global burden of diabetes over the next 25 years (a 50% increase), the authors urge that concerted actions are needed now to raise awareness of the risks involved.They do note, however, that addressing the knowledge gap will require a complex multifaceted strategy tailored to different audiences, and that it will likely need the active engagement of multiple stakeholders and significant levels of investment.The findings come from an online YouGov survey that was conducted by the American Heart Association in 2021 and asked questions broadly related to heart disease.In this secondary analysis, the authors focused on one question that aimed to identify the level of awareness of risk factors for cardiovascular disease, one of which was diabetes.They also examined variation according to demographics, geography, and economic development.There were just under 49,000 respondents, with ~16,000, or one-third, identifying diabetes as a major risk factor for cardiovascular disease.Awareness levels were similar among men and women but did increase with age.Awareness levels were also higher in high-income countries compared with those classed as middle income.Meanwhile, the spread of awareness is notable, ranging from 7.4% in Slovenia to 47.3% in Lithuania.No low-income countries were included in the survey because of the limited capacity of the survey vendor to provide nationally representative samples via its online design at the time of the survey."The knowledge gap identified in our study has important public health consequences," said author Dhruv S. Kazi."People with this knowledge may also be more likely to get screened and treated for diabetes and may be more likely to make the lifestyle changes necessary for preventing cardiovascular disease."
Decreasing microtubule detyrosination modulates Nav1.5 subcellular distribution and restores sodium current in <i>mdx</i> cardiomyocytes
Authors: Giovanna Nasilli, Tanja M de Waal, Gerard A Marchal, Giorgia Bertoli, Marieke W Veldkamp, Eli Rothenberg, Simona Casini, Carol Ann Remme
Journal: Cardiovascular Research (2024)

Abstract Aims The microtubule (MT) network plays a major role in the transport of the cardiac sodium channel Nav1.5 to the membrane, where the latter associates with interacting proteins such as dystrophin. Alterations in MT dynamics are known to impact on ion channel trafficking. Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, is associated with an increase in MT detyrosination, decreased sodium current (INa), and arrhythmias. Parthenolide (PTL), a compound that decreases MT detyrosination, has shown beneficial effects on cardiac function in DMD. We here investigated its impact on INa and Nav1.5 subcellular distribution. Methods and results Ventricular cardiomyocytes (CMs) from wild-type (WT) and mdx (DMD) mice were incubated with either 10 µM PTL, 20 µM EpoY, or dimethylsulfoxide (DMSO) for 3–5 h, followed by patch-clamp analysis to assess INa and action potential (AP) characteristics in addition to immunofluorescence and stochastic optical reconstruction microscopy (STORM) to investigate MT detyrosination and Nav1.5 cluster size and density, respectively. In accordance with previous studies, we observed increased MT detyrosination, decreased INa and reduced AP upstroke velocity (Vmax) in mdx CMs compared to WT. PTL decreased MT detyrosination and significantly increased INa magnitude (without affecting INa gating properties) and AP Vmax in mdx CMs, but had no effect in WT CMs. Moreover, STORM analysis showed that in mdx CMs, Nav1.5 clusters were decreased not only in the grooves of the lateral membrane (LM; where dystrophin is localized) but also at the LM crests. PTL restored Nav1.5 clusters at the LM crests (but not at the grooves), indicating a dystrophin-independent trafficking route to this subcellular domain. Interestingly, Nav1.5 cluster density was also reduced at the intercalated disc (ID) region of mdx CMs, which was restored to WT levels by PTL. Treatment of mdx CMs with EpoY, a specific MT detyrosination inhibitor, also increased INa density, while decreasing the amount of detyrosinated MTs, confirming a direct mechanistic link. Conclusion Attenuating MT detyrosination in mdx CMs restored INa and enhanced Nav1.5 localization at the LM crest and ID. Hence, the reduced whole-cell INa density characteristic of mdx CMs is not only the consequence of the lack of dystrophin within the LM grooves but is also due to reduced Nav1.5 at the LM crest and ID secondary to increased baseline MT detyrosination. Overall, our findings identify MT detyrosination as a potential therapeutic target for modulating INa and subcellular Nav1.5 distribution in pathophysiological conditions.
The gene regulatory basis of bystander activation in CD8 <sup>+</sup> T cells
Authors: Neva B. Watson, Ravi K. Patel, Connor Kean, Janelle Veazey, Oyebola O. Oyesola, Nathan Laniewski, Jennifer K. Grenier, Jocelyn Wang, Cybelle Tabilas, Kristel J. Yee Mon, Adrian J. McNairn, Seth A. Peng, Samantha P. Wesnak, Kito Nzingha, Miles P. Davenport, Elia D. Tait Wojno, Kristin M. Scheible, Norah L. Smith, Andrew Grimson, Brian D. Rudd
Journal: Science Immunology (2024)

CD8 + T cells are classically recognized as adaptive lymphocytes based on their ability to recognize specific foreign antigens and mount memory responses. However, recent studies indicate that some antigen-inexperienced CD8 + T cells can respond to innate cytokines alone in the absence of cognate T cell receptor stimulation, a phenomenon referred to as bystander activation. Here, we demonstrate that neonatal CD8 + T cells undergo a robust and diverse program of bystander activation, which corresponds to enhanced innate-like protection against unrelated pathogens. Using a multi-omics approach, we found that the ability of neonatal CD8 + T cells to respond to innate cytokines derives from their capacity to undergo rapid chromatin remodeling, resulting in the usage of a distinct set of enhancers and transcription factors typically found in innate-like T cells. We observed that the switch between innate and adaptive functions in the CD8 + T cell compartment is mediated by changes in the abundance of distinct subsets of cells. The innate CD8 + T cell subset that predominates in early life was also present in adult mice and humans. Our findings provide support for the layered immune hypothesis and indicate that the CD8 + T cell compartment is more functionally diverse than previously thought.
Beyond BCR::ABL1—The Role of Genomic Analyses in the Management of CML
Authors: Susan Branford, Adelina Fernandes, NurHezrin Shahrin, Muneeza Maqsood, Naranie Shanmuganathan, Carol Wadham
Journal: Journal of the National Comprehensive Cancer Network (2024)

Chronic myeloid leukemia (CML) is a model of genomically based diagnosis and management where BCR :: ABL1 is successfully targeted by tyrosine kinase inhibitor (TKI) therapy in most patients. The dynamics of BCR :: ABL1 transcript decline during therapy is a dependable biomarker of response, relapse, and drug resistance. Missense mutations acquired within the BCR :: ABL1 kinase domain that disrupt TKI binding can evolve during therapy and are frequently detected in patients for whom TKI treatment fails. Importantly, specific BCR :: ABL1 missense mutations are targetable alterations and direct therapeutic decisions based on the individual mutant TKI sensitivity profile. Nevertheless, BCR :: ABL1 mutations are only implicated in approximately half of the cases of acquired resistance. Furthermore, not all patients with a single BCR :: ABL1 mutation that is predicted to be sensitive to a specific TKI will experience a response when switched to that TKI. Progression to blast phase heralds independence from BCR :: ABL1 , and this phase of the disease is notoriously difficult to treat. The independent drivers of resistance and disease progression have long been investigated to both predict progression and to find targets for therapeutic intervention. Recent data reaffirm that drug resistance and disease progression is a mutation-driven process in CML, and somatic variants in genes that are known to drive acute myeloid and lymphoid leukemia have been detected in patients in the advanced phases of CML. Genomic testing over the last few decades for patients with blood cancer has revealed of variety of genomic aberrations that drive disease. Consequently, incorporation of genomic factors into patient management for a range of blood cancers has led to the implementation of high-throughput gene testing to detect clinically actionable variants. Is it time to integrate broader genomic screening into clinical management strategies for patients with CML?
One model to unite them all: Personalized federated learning of multi-contrast MRI synthesis
Authors: Onat Dalmaz, Muhammad U. Mirza, Gokberk Elmas, Muzaffer Ozbey, Salman U.H. Dar, Emir Ceyani, Kader K. Oguz, Salman Avestimehr, Tolga Çukur
Journal: Medical Image Analysis (2024)
Implementation strategies to build mental health-care capacity in Malawi: a health-economic evaluation
Authors: Juan Yanguela, Brian W Pence, Michael Udedi, Jonathan Chiwanda Banda, Kazione Kulisewa, Chifundo C Zimba, Jullita K Malava, Christopher Akiba, Josée M Dussault, Abigail M Morrison, Steve Mphonda, Mina C Hosseinipour, Bradley N Gaynes, Stephanie B Wheeler
Journal: The Lancet Global Health (2024)

Depression is a major contributor to morbidity and mortality in sub-Saharan Africa. Due to low system capacity, three in four patients with depression in sub-Saharan Africa go untreated. Despite this, little attention has been paid to the cost-effectiveness of implementation strategies to scale up evidence-based depression treatment in the region. In this study, we investigate the cost-effectiveness of two different implementation strategies to integrate the Friendship Bench approach and measurement-based care in non-communicable disease clinics in Malawi.
An observer-blind, randomised, placebo-controlled, phase 1, single ascending dose study of dengue monoclonal antibody in healthy adults in Australia
Authors: Bhagwat Gunale, Nicholas Farinola, Chandrashekhar D Kamat, Cyrus S Poonawalla, Sambhaji S Pisal, Rajeev M Dhere, Claire Miller, Prasad S Kulkarni
Journal: The Lancet Infectious Diseases (2024)
Remote digital health technologies for improving the care of people with respiratory disorders
Authors: Jessilyn Dunn, Andrea Coravos, Manuel Fanarjian, Geoffrey S Ginsburg, Steven R Steinhubl
Journal: The Lancet Digital Health (2024)

Respiratory diseases are a leading cause of morbidity and mortality globally. However, existing systems of care, built around scheduled appointments, are not well designed to support the needs of people with chronic and acute respiratory conditions that can change rapidly and unexpectedly. Home-based and personal digital health technologies (DHTs) allow implementation of new models of care catering to the unique needs of individuals. The high number of respiratory triggers and unique responses to them require a personalised solution for each patient. The real-world, repetitive monitoring capabilities of DHTs enable identification of the normal operating characteristics for each individual and, therefore, recognition of the earliest deviations from that state. However, despite this potential, the number of clinical efficacy studies of DHTs is quite small. Evaluation of clinical effectiveness of DHTs in improving health quality in real-world settings is urgently needed.
Novel endotypes of antisynthetase syndrome identified independent of anti-aminoacyl transfer RNA synthetase antibody specificity that improve prognostic stratification
Authors: Shiyu Wu, Xinyue Xiao, Yingfang Zhang, Xinxin Zhang, Guochun Wang, Qinglin Peng
Journal: Annals of the Rheumatic Diseases (2024)

To systemically analyse the heterogeneity in the clinical manifestations and prognoses of patients with antisynthetase syndrome (ASS) and evaluate the transcriptional signatures related to different clinical phenotypes.
Executive functioning in antisocial behavior: A multi-level systematic meta-analysis
Authors: Jochem Milan Jansen, Melanie Elisabeth Franse
Journal: Clinical Psychology Review (2024)

Neurobiological information – including executive function – is increasingly relevant for forensic clinical practice, as well as for the criminal justice system. Previous meta-analyses report that antisocial populations show impaired performance on executive functioning tasks, but these meta-analyses are outdated, have limitations in their methodological approach, and are therefore in need of an update. The current multi-level meta-analysis including 133 studies (2008-2023) confirms impaired performance in executive functioning (d=.42), but studies are heterogeneous. Several moderator analyses showed that neuropsychological test used, type of executive function component, and control group characteristics moderated the overall effect. Specifically, matching psychiatric problems in the non-antisocial control group eliminated any differences in executive functioning between groups. No moderation effects were found for assessment quality, hot or cold executive functions, and various population characteristics. These results could indicate that the assessment of executive functioning in antisocial populations may be less relevant for recidivism risk assessment than thought, although this should first be assessed in prospective longitudinal studies. Executive functioning could potentially be used to identify or screen for individuals with certain treatment needs or be used as a responsivity factor, especially in disorders which are often underdiagnosed in criminal justice settings.
From “Inclusion in What” to “Equity in What”: (Re)Thinking the Question of In/Equity in Precision Medicine and Health
Authors: Alessia Costa, Jerome Atutornu, Tuba Bircan, Daniela Boraschi, Sasha Henriques, Richard Milne, Lydia Okoibhole, Christine Patch, Anna Middleton
Journal: The American Journal of Bioethics (2024)
A Bionic Thermosensitive Sustainable Delivery System for Reversing the Progression of Osteoarthritis by Remodeling the Joint Homeostasis
Authors: Min‐Ji Tong, Meng‐Xiong Song, Zhe Liu, Wei Yu, Chen‐Zhong Wang, Chuan‐Dong Cai, Ying‐Kai Zhang, Yue‐Qi Zhang, Li‐Peng Wang, Zhen‐Zhong Zhu, Xiao‐Fan Yin, Zuo‐Qin Yan
Journal: Advanced Healthcare Materials (2024)

Although the pathogenesis of osteoarthritis (OA) is unclear, inflammatory cytokines are related to its occurrence. However, few studies focused on the therapeutic strategies of regulating joint homeostasis by simultaneously remodeling the anti-inflammatory and immunomodulatory microenvironments. Fibroblast growth factor 18 (FGF18) is the only disease-modifying OA drug (DMOAD) with a potent ability and high efficiency in maintaining the phenotype of chondrocytes within cell culture models. However, its potential role in the immune microenvironment remains unknown. Besides, information on an optimal carrier, whose interface and chondral-biomimetic microenvironment mimic the native articular tissue, is still lacking, which substantially limits the clinical efficacy of FGF18. Herein, to simulate the cartilage matrix, chondroitin sulfate (ChS)-based nanoparticles (NPs) are integrated into poly(D, L-lactide)-poly(ethylene glycol)-poly(D, L-lactide) (PLEL) hydrogels to develop a bionic thermosensitive sustainable delivery system. Electrostatically self-assembled ChS and ε-poly-l-lysine (EPL) NPs are prepared for the bioencapsulation of FGF18. This bionic delivery system suppressed the inflammatory response in interleukin-1β (IL-1β)-mediated chondrocytes, promoted macrophage M2 polarization, and inhibited M1 polarization, thereby ameliorating cartilage degeneration and synovitis in OA. Thus, the ChS-based hydrogel system offers a potential strategy to regulate the chondrocyte-macrophage crosstalk, thus re-establishing the anti-inflammatory and immunomodulatory microenvironment for OA therapy.
A signature of enhanced proliferation associated with response and survival to anti-PD-L1 therapy in early-stage non-small cell lung cancer
Authors: Nasser K. Altorki, Bhavneet Bhinder, Alain C. Borczuk, Olivier Elemento, Vivek Mittal, Timothy E. McGraw
Journal: Cell Reports Medicine (2024)

In early-stage non-small cell lung cancer, the combination of neoadjuvant anti-PD-L1 and subablative stereotactic body radiation therapy (SBRT) is associated with higher rates of major pathologic response compared to anti-PD-L1 alone. Here, we identify a 140-gene set, enriched in genes characteristic of highly proliferating cells, associated with response to the dual therapy. Analysis of on-treatment transcriptome data indicate roles for T and B cells in response. The 140-gene set is associated with disease-free survival when applied to the combined trial arms. This 140-gene set identifies a subclass of tumors in all 7 of The Cancer Genome Atlas tumor types examined. Worse survival is associated with the 140-gene signature in 5 of these tumor types. Collectively, our data support that this 140-gene set, discovered in association with response to combined anti-PD-L1 and SBRT, identifies a clinically aggressive subclass of solid tumors that may be more likely to respond to immunotherapies.
Vonoprazan: A Review in Helicobacter pylori Infection
Authors: Matt Shirley
Journal: Drugs (2024)

Treatment for the eradication of Helicobacter pylori infection, a leading cause of peptic ulcer disease and an important risk factor for gastric cancer and mucosa-associated lymphoid tissue lymphoma, is indicated whenever infection is identified. However, treatment success rates with current guideline-recommended proton-pump inhibitor (PPI)-based regimens remain suboptimal, with one potential factor associated with treatment failure being inadequate acid suppression. Vonoprazan (Voquezna®) is a first-in-class potassium-competitive acid blocker with the potential to provide potent and sustained acid suppression. Following clinical trials conducted mainly in Asia (supported by post-marketing experience from Asia) and the phase III PHALCON-HP trial conducted in the USA and Europe, vonoprazan is now approved in the USA for use in combination with amoxicillin (dual therapy) or amoxicillin and clarithromycin (triple therapy) for the treatment of H. pylori infection in adults. The vonoprazan-based dual and triple therapy regimens were generally well tolerated in PHALCON-HP. In addition, vonoprazan has advantages including a rapid onset of action and no food effect, making vonoprazan-based dual and triple therapy regimens valuable alternatives to standard PPI-based triple therapy in the treatment of H. pylori infection. Infection with the bacterium Helicobacter pylori is a leading cause of peptic ulcer disease and has been identified as an important risk factor for gastric cancer. Current recommended treatments for H. pylori infection generally involve a combination of antibiotics together with an acid suppressant, such as a proton-pump inhibitor (PPI). However, treatment success rates with current guideline-recommended PPI-based regimens remain suboptimal. Vonoprazan (Voquezna®), from a new class of drugs known as potassium-competitive acid blockers, has the potential to provide potent and sustained acid suppression. Based on the findings of a pivotal trial (PHALCON-HP) conducted in the USA and Europe, vonoprazan is now approved in the USA for the treatment of H. pylori infection in adults when used in combination with amoxicillin, or amoxicillin and clarithromycin. Alongside the demonstrated efficacy and tolerability of the vonoprazan-based regimens, vonoprazan has a rapid onset of action and can be taken with or without food. Thus, vonoprazan-based dual and triple therapy regimens present valuable alternatives to standard PPI-based triple therapy in the treatment of H. pylori infection.
Author Correction: Systematic profiling of conditional pathway activation identifies context-dependent synthetic lethalities
Authors: Liang Chang, Nancy Y. Jung, Adel Atari, Diego J. Rodriguez, Devishi Kesar, Tian-Yu Song, Matthew G. Rees, Melissa Ronan, Ruitong Li, Paloma Ruiz, Saireudee Chaturantabut, Takahiro Ito, Laurens M. van Tienen, Yuen-Yi Tseng, Jennifer A. Roth, William R. Sellers
Journal: Nature Genetics (2024)