tbuckley/cabot-search huggingface dataset:
Precision Targeting of Mutant PI3Kα
Authors: Grace Q. Gong, Bart Vanhaesebroeck
Journal: Cancer Discovery (2024)

Summary: PIK3CA, which encodes the p110α catalytic subunit of PI 3-kinase alpha (PI3Kα), is one of the most frequently genetically activated kinases in solid tumors. In two back-to-back papers, Varkaris and colleagues report on the development of a novel allosteric PI3Kα-mutant–selective inhibitor and early clinical experience with this compound. See related article by Varkaris et al., p. 227 (6) . See related article by Varkaris et al., p. 240 (5) .
A Metabolic–Epigenetic Mechanism Directs Cell Fate and Therapeutic Sensitivity in Breast Cancer
Authors: Matthew J. Bernard, Andrew S. Goldstein
Journal: Cancer Research (2024)

Abstract Over the past decade, studies have increasingly shed light on a reciprocal relationship between cellular metabolism and cell fate, meaning that a cell's lineage both drives and is governed by its specific metabolic features. A recent study by Zhang and colleagues, published in Cell Metabolism, describes a novel metabolic–epigenetic regulatory axis that governs lineage identity in triple-negative breast cancer (TNBC). Among the key findings, the authors demonstrate that the metabolic enzyme pyruvate kinase M2 (PKM2) directly binds to the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in the nucleus to silence expression of a set of genes that includes the mitochondrial carnitine transporter SLC16A9. Perturbation of this metabolic–epigenetic regulatory mechanism induces a metabolic shift away from glycolysis and toward fatty acid oxidation. The ensuing influx of carnitine facilitates the deposition of the activating epigenetic mark H3K27Ac onto the promoter of GATA3, driving a committed luminal lineage state. Importantly, this metabolic–epigenetic axis represents a potentially targetable vulnerability for the treatment of TNBC, a subtype that currently lacks effective therapeutic strategies. These findings lend further support for the paradigm shift underlying our understanding of cancer metabolism: that a cellular fuel source functions not only to provide energy but also to direct the epigenetic regulation of cell fate.
FastEval Parkinsonism: an instant deep learning–assisted video-based online system for Parkinsonian motor symptom evaluation
Authors: Yu-Yuan Yang, Ming-Yang Ho, Chung-Hwei Tai, Ruey-Meei Wu, Ming-Che Kuo, Yufeng Jane Tseng
Journal: npj Digital Medicine (2024)

Abstract The Motor Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) is designed to assess bradykinesia, the cardinal symptoms of Parkinson’s disease (PD). However, it cannot capture the all-day variability of bradykinesia outside the clinical environment. Here, we introduce FastEval Parkinsonism ( https://fastevalp.cmdm.tw/ ), a deep learning-driven video-based system, providing users to capture keypoints, estimate the severity, and summarize in a report. Leveraging 840 finger-tapping videos from 186 individuals (103 patients with Parkinson’s disease (PD), 24 participants with atypical parkinsonism (APD), 12 elderly with mild parkinsonism signs (MPS), and 47 healthy controls (HCs)), we employ a dilated convolution neural network with two data augmentation techniques. Our model achieves acceptable accuracies (AAC) of 88.0% and 81.5%. The frequency-intensity (FI) value of thumb-index finger distance was indicated as a pivotal hand parameter to quantify the performance. Our model also shows the usability for multi-angle videos, tested in an external database enrolling over 300 PD patients.
Zeb2 drives the formation of CD11c <sup>+</sup> atypical B cells to sustain germinal centers that control persistent infection
Authors: Xin Gao, Qian Shen, Jonathan A. Roco, Becan Dalton, Katie Frith, C. Mee Ling Munier, Fiona D. Ballard, Ke Wang, Hannah G. Kelly, Maxim Nekrasov, Jin-Shu He, Rebecca Jaeger, Patricia Carreira, Julia I. Ellyard, Lynette Beattie, Anselm Enders, Matthew C. Cook, John J. Zaunders, Ian A. Cockburn
Journal: Science Immunology (2024)

CD11c
Fibroblasts in the Aged Pancreas Drive Pancreatic Cancer Progression
Authors: Daniel J. Zabransky, Yash Chhabra, Mitchell E. Fane, Emma Kartalia, James M. Leatherman, Laura Hüser, Jacquelyn W. Zimmerman, Daniel Delitto, Song Han, Todd D. Armstrong, Soren Charmsaz, Samantha Guinn, Sneha Pramod, Elizabeth D. Thompson, Steven J. Hughes, Jennifer O'Connell, Josephine M. Egan, Elizabeth M. Jaffee, Ashani T. Weeraratna
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is more prevalent in older individuals and often carries a poorer prognosis for them. The relationship between the microenvironment and pancreatic cancer is multifactorial, and age-related changes in nonmalignant cells in the tumor microenvironment may play a key role in promoting cancer aggressiveness. Because fibroblasts have profound impacts on pancreatic cancer progression, we investigated whether age-related changes in pancreatic fibroblasts influence cancer growth and metastasis. Proteomics analysis revealed that aged fibroblasts secrete different factors than young fibroblasts, including increased growth/differentiation factor 15 (GDF-15). Treating young mice with GDF-15 enhanced tumor growth, whereas aged GDF-15 knockout mice showed reduced tumor growth. GDF-15 activated AKT, rendering tumors sensitive to AKT inhibition in an aged but not young microenvironment. These data provide evidence for how aging alters pancreatic fibroblasts and promotes tumor progression, providing potential therapeutic targets and avenues for studying pancreatic cancer while accounting for the effects of aging. Significance: Aged pancreatic fibroblasts secrete GDF-15 and activate AKT signaling to promote pancreatic cancer growth, highlighting the critical role of aging-mediated changes in the pancreatic cancer microenvironment in driving tumor progression. See related commentary by Isaacson et al., p. 1185
Ethical considerations for artificial intelligence in dermatology: a scoping review
Authors: Emily R Gordon, Megan H Trager, Despina Kontos, Chunhua Weng, Larisa J Geskin, Lydia S Dugdale, Faramarz H Samie
Journal: British Journal of Dermatology (2024)

The field of dermatology is experiencing the rapid deployment of artificial intelligence (AI), from mobile applications (apps) for skin cancer detection to large language models like ChatGPT that can answer generalist or specialist questions about skin diagnoses. With these new applications, ethical concerns have emerged. In this scoping review, we aimed to identify the applications of AI to the field of dermatology and to understand their ethical implications. We used a multifaceted search approach, searching PubMed, MEDLINE, Cochrane Library and Google Scholar for primary literature, following the PRISMA Extension for Scoping Reviews guidance. Our advanced query included terms related to dermatology, AI and ethical considerations. Our search yielded 202 papers. After initial screening, 68 studies were included. Thirty-two were related to clinical image analysis and raised ethical concerns for misdiagnosis, data security, privacy violations and replacement of dermatologist jobs. Seventeen discussed limited skin of colour representation in datasets leading to potential misdiagnosis in the general population. Nine articles about teledermatology raised ethical concerns, including the exacerbation of health disparities, lack of standardized regulations, informed consent for AI use and privacy challenges. Seven addressed inaccuracies in the responses of large language models. Seven examined attitudes toward and trust in AI, with most patients requesting supplemental assessment by a physician to ensure reliability and accountability. Benefits of AI integration into clinical practice include increased patient access, improved clinical decision-making, efficiency and many others. However, safeguards must be put in place to ensure the ethical application of AI.
Prenatal exposure to antiseizure medications and fetal growth: a population-based cohort study from the Nordic countries
Authors: Jakob Christensen, Helga Zoega, Maarit K. Leinonen, Nils Erik Gilhus, Mika Gissler, Jannicke Igland, Yuelian Sun, Torbjörn Tomson, Silje Alvestad, Marte-Helene Bjørk, Julie Werenberg Dreier
Journal: The Lancet Regional Health - Europe (2024)

The short- and long-term consequences of restricted fetal growth cause considerable concern, and how prenatal exposure to different antiseizure medications (ASMs) affects fetal growth remains uncertain. This was a population-based cohort study of liveborn singleton children born in Denmark, Finland, Iceland, Norway, and Sweden from 1996 to 2017. Prenatal exposure was defined as maternal filling of prescriptions for ASM during pregnancy registered in national prescription registries and primary outcomes were adjusted odds ratios (aORs) of microcephaly or being born small for gestational age. We identified 4,494,918 children (males: 51.3%, 2,306,991/4,494,918), including 38,714 (0.9%) children of mothers with epilepsy. In the overall population, prenatal monotherapy exposure with carbamazepine (aOR: 1.25 (95% CI: 1.12–1.40)), pregabalin (aOR: 1.16 (95% CI: 1.02–1.31)), oxcarbazepine (aOR: 1.48 (95% CI: 1.28–1.71)), clonazepam (aOR: 1.27 (95% CI: 1.10–1.48)), and topiramate (aOR: 1.48 (95% CI: 1.18–1.85)) was associated with risk of being born small for gestational age, and carbamazepine was associated with microcephaly (aOR: 1.43 (95% CI: 1.17–1.75)). In children of mothers with epilepsy, prenatal exposure to carbamazepine (aOR: 1.27 (95% CI: 1.11–1.47)), oxcarbazepine (aOR: 1.42 (95% CI: 1.18–1.70)), clonazepam (aOR: 1.40 (95% CI: 1.03–1.89)), and topiramate (aOR: 1.86 (95% CI: 1.36–2.54)) was associated with being born small for gestational age; carbamazepine, with microcephaly (aOR: 1.51 (95% CI: 1.17–1.95)). No associations with small for gestational age and microcephaly were identified after prenatal exposure to lamotrigine, valproate, gabapentin, levetiracetam, phenobarbital, acetazolamide, phenytoin, clobazam, primidone, zonisamide, vigabatrin, ethosuximide and lacosamide, but except for lamotrigine, valproate, gabapentin, and levetiracetam, numbers of exposed children were small. Prenatal exposure to carbamazepine, oxcarbazepine, clonazepam, and topiramate was associated with increased risk of being born small for gestational age in both the overall population and in children of women with epilepsy suggesting that prenatal exposure to these drugs is associated with fetal growth restriction. The NordForsk Nordic Program on Health and Welfare (83539), the Independent Research Fund Denmark (1133-00026B), the Danish Epilepsy Association, the Central Denmark Region, the Novo Nordisk Foundation (NNF16OC0019126 and NNF22OC0075033), and the Lundbeck Foundation (R400-2022-1205).
Tenecteplase for Stroke — Opening the Window?
Authors: Dana Leifer
Journal: New England Journal of Medicine (2024)

Despite advances in intravenous thrombolysis and mechanical thrombectomy for acute ischemic strokes, many patients do not qualify for these treatments that restore cerebral blood flow and reduce ischemic damage. Intravenous alteplase and tenecteplase are now established as treatments for stroke when administered up to 4.5 hours after the time that the patient was last known to be well.1,2 Tenecteplase is a genetically modified variant of alteplase that has a higher specificity for fibrin and a longer half-life. Because studies suggest that tenecteplase is as safe and effective as alteplase and can be administered rapidly rather than requiring infusion over a . . .
Malaria vaccines: a test for global health
Authors: None The Lancet
Journal: The Lancet (2024)

Throughout recorded history, malaria has blighted populations across the globe. Today, by far, WHO's African region has the highest burden. In 2022, the region was home to 233 million (94%) malaria cases and 580 000 (95%) malaria deaths, about 80% of which were in children younger than 5 years. Despite ambitions to reduce this burden, efforts to control malaria have stagnated: global cases dropped by 29% between 2000 and 2019 but only by 2% between 2015 and 2019. Might this all be about to change? On Jan 22, 2024, Cameroon began the roll-out of RTS,S/AS01, the first malaria vaccine to be used in a national immunisation programme.
Hepatocellular carcinoma: signaling pathways, targeted therapy, and immunotherapy
Authors: Xiaoting Luo, Xin He, Xingmei Zhang, Xiaohui Zhao, Yuzhe Zhang, Yusheng Shi, Shengni Hua
Journal: MedComm (2024)

Abstract Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a high mortality rate. It is regarded as a significant public health issue because of its complicated pathophysiology, high metastasis, and recurrence rates. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Traditional treatment methods such as surgical resection, radiotherapy, chemotherapy, and interventional therapies have limited therapeutic effects for HCC patients with recurrence or metastasis. With the development of molecular biology and immunology, molecular signaling pathways and immune checkpoint were identified as the main mechanism of HCC progression. Targeting these molecules has become a new direction for the treatment of HCC. At present, the combination of targeted drugs and immune checkpoint inhibitors is the first choice for advanced HCC patients. In this review, we mainly focus on the cutting‐edge research of signaling pathways and corresponding targeted therapy and immunotherapy in HCC. It is of great significance to comprehensively understand the pathogenesis of HCC, search for potential therapeutic targets, and optimize the treatment strategies of HCC.
Correction to: Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK‐IDH2 pathway
Authors: Hao Huang, Shuai Guo, Ya‐Qin Chen, Yu‐Xing Liu, Jie‐Yuan Jin, Yun Liang, Liang‐Liang Fan, Rong Xiang
Journal: MedComm (2024)

In the process of checking the raw data,1 the authors noticed an inadvertent mistake occurring in Figure 1F that needed to be corrected after the online publication of the article. During the preparation of Figure 1F, the representative image showing the expression of RTN3 was pasted and placed by mistake. The correct result should be as shown below. The authors apologize for these oversights and declare that this correction does not affect the description, interpretation, or conclusions detailed in the original manuscript.
SiATG5-loaded cancer cell membrane-fused liposomes induced increased uptake of albumin-bound chemotherapeutics by pancreatic cancer cells
Authors: Jing Yan, Miaomiao Wang, Shunli Lv, Dagui Chen, Ziqing Wu, Dongyang Zhou, Shudong Zhang, Jiajing Lv, Ke Xu, Can Xu, Yan Wei
Journal: Journal of Controlled Release (2024)
An Injectable silk-based hydrogel as a novel biomineralization seedbed for critical-sized bone defect regeneration
Authors: Yuhui Zhu, Hao Gu, Jiawei Yang, Anshuo Li, Lingli Hou, Mingliang Zhou, Xinquan Jiang
Journal: Bioactive Materials (2024)

The healing process of critical-sized bone defects urges for a suitable biomineralization environment. However, the unsatisfying repair outcome usually results from a disturbed intricate milieu and the lack of in situ mineralization resources. In this work, we have developed a composite hydrogel that mimics the natural bone healing processes and serves as a seedbed for bone regeneration. The oxidized silk fibroin and fibrin are incorporated as rigid geogrids, and amorphous calcium phosphate (ACP) and platelet-rich plasma serve as the fertilizers and loam, respectively. Encouragingly, the seedbed hydrogel demonstrates excellent mechanical and biomineralization properties as a stable scaffold and promotes vascularized bone regeneration in vivo. Additionally, the seedbed serves a succinate-like function via the PI3K-Akt signaling pathway and subsequently orchestrates the mitochondrial calcium uptake, further converting the exogenous ACP into endogenous ACP. Additionally, the seedbed hydrogel realizes the succession of calcium resources and promotes the evolution of the biotemplate from fibrin to collagen. Therefore, our work has established a novel silk-based hydrogel that functions as an in-situ biomineralization seedbed, providing a new insight for critical-sized bone defect regeneration.
Adenosine-modulating synthetic high-density lipoprotein for chemoimmunotherapy of triple-negative breast cancer
Authors: Xiang Gong, Chao Zheng, Ying Cai, Wen Zhang, Binyu Zhu, Rong Rong, Ying Kong, Yuan Zhang, Jian Wang, Yaping Li, Pengcheng Zhang
Journal: Journal of Controlled Release (2024)
Single‐cell analysis of MYD88<sup>L265P</sup> and MYD88<sup>WT</sup> Waldenström macroglobulinemia patients
Authors: Tina Bagratuni, Foteini Aktypi, Ourania Theologi, Maria Sakkou, Kleio Maria Verrou, Nefeli Mavrianou‐Koutsoukou, Dimitrios Patseas, Christine Liacos, Stamatia Skourti, Alexandra Papadimou, Kostantina Taouxi, Foteini Theodorakakou, Georgios Kollias, Petros Sfikakis, Evangelos Terpos, Meletios A. Dimopoulos, Efstathios Kastritis
Journal: HemaSphere (2024)

Abstract Waldenström macroglobulinemia (WM) is characterized by the expansion of clonal lymphoplasmacytic cells; the MYD88L265P somatic mutation is found in &gt;90% of patients, but malignant B cells may still display intra‐clonal heterogeneity. To assess clonal heterogeneity in WM, we generated and performed single‐cell RNA sequencing of CD19 + sorted cells from five patients with MYD88 L265P and two patients with MYD88 WT genotype as well as two healthy donors. We identified distinct transcriptional patterns in the clonal subpopulations not only between the two genetically distinct WM subgroups but also among MYD88 L265P patients, which affected the B cell composition in the different subgroups. Comparison of clonal and normal/polyclonal B cells within each patient sample enabled the identification of patient‐specific transcriptional changes. We identified gene signatures active in a subset of MYD88 L265P patients, while other signatures were active in MYD88 WT patients. Finally, gene expression analysis showed common transcriptional features between patients compared to the healthy control but also differentially expressed genes between MYD88 L265P and MYD88 WT patients involved in distinct pathways, including NFκΒ, BCL2, and BTK. Overall, our data highlight the intra‐tumor clonal heterogeneity in WM with potential prognostic and therapeutic implications.
Effects of Daylong Exposure to Indoor Overheating on Thermal and Cardiovascular Strain in Older Adults: A Randomized Crossover Trial
Authors: Robert D. Meade, Ashley P. Akerman, Sean R. Notley, Nathalie V. Kirby, Ronald J. Sigal, Glen P. Kenny
Journal: Environmental Health Perspectives (2024)

Health agencies recommend that homes of heat-vulnerable occupants (e.g., older adults) be maintained below 24-28°C to prevent heat-related mortality and morbidity. However, there is limited experimental evidence to support these recommendations.
The International Association for the Study of Lung Cancer Pleural Mesothelioma Staging Project: Expanded Database to Inform Revisions in the Ninth Edition of the TNM Classification of Pleural Mesothelioma
Authors: Andrea S. Wolf, Megan Eisele, Dorothy J. Giroux, Ritu Gill, Anna K. Nowak, Andrea Bille, David Rice, Robert T. Ripley, Isabelle Opitz, Francoise Galateau-Salle, Seiki Hasegawa, Hedy L. Kindler, Harvey I. Pass, Valerie W. Rusch
Journal: Journal of Thoracic Oncology (2024)

The International Association for the Study of Lung Cancer collaborated with the International Mesothelioma Interest Group to propose the first TNM stage classification system for diffuse pleural mesothelioma in 1995, accepted by the Union for International Cancer Control and the American Joint Committee on Cancer for the sixth and seventh edition stage classification manuals. The International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee Mesothelioma Domain developed and analyzed an international registry of patients with pleural mesothelioma and updated TNM descriptors for the eighth edition of the stage classification system. To inform revisions for the forthcoming ninth edition of the TNM stage classification system, data submission was solicited for patients diagnosed between 2013 and 2022 with expanded data elements on the basis of the first project's exploratory analyses, including pleural thickness measurements, updated surgical nomenclature, and molecular markers. The resulting database consisted of a total of 3598 analyzable cases from Europe, Australia, Asia, North America, and South America, with a median age of 71 years (range: 18–99 y), 2775 (77.1%) of whom were men. With only 1310 patients (36.4%) undergoing curative-intent operations, this iteration of the database includes far more patients treated nonsurgically compared with prior. Four separate manuscripts on T, N, M, and stage groupings submitted to this journal will summarize analyses of these data and will serve collectively as the primary source of the proposed changes to the upcoming ninth edition of the pleural mesothelioma stage classification system.
Navigating the landscape of liver cancer management: Study designs in clinical trials and clinical practice
Authors: Giuseppe Cabibbo, Ciro Celsa, Lorenza Rimassa, Ferran Torres, Jordi Rimola, Roman Kloeckner, Jordi Bruix, Calogero Cammà, Maria Reig
Journal: Journal of Hepatology (2024)

Randomized controlled trials (RCTs) represent the gold standard for evidence generation across all areas of medicine and especially in the oncology field, as they allow unbiased estimates of treatment effect without confounders. Observational studies have many problems that could reduce their internal and external validity. However, large prospective (well-conducted) observational real-world studies (RWS) can detect the occurrence of rare adverse events or monitoring for long-term adverse events. Impact of Real Word Data (RWD), which refers to data generated from routine, standard care of patients, and real-world 'evidence' (RWE), which is the evidence generated from RWD represent an open challenge.Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide and its prognosis is highly heterogeneous, being related not only to tumor burden but also to the severity of underlying chronic liver disease. Moreover, advances in systemic therapies for HCC have increased the complexity of HCC patient management.Aim of this review article is to provide an overview of the benefits and limitations of different study designs, particularly focusing on RCTs and observational studies, to address important and not fully resolved questions in HCC research.