tbuckley/cabot-search huggingface dataset:
Stratified Medicine Paediatrics: Cell free DNA and serial tumour sequencing identifies subtype specific cancer evolution and epigenetic states
Authors: Sally L. George, Claire Lynn, Reda Stankunaite, Debbie Hughes, Carolin M. Sauer, Jane Chalker, Saira Waqar Ahmed, Minou Oostveen, Paula Z. Proszek, Lina Yuan, Ridwan Shaikh, Sabri Jamal, Ama Brew, Jennifer Tall, Tony Rogers, Steven C. Clifford, Josef Vormoor, Janet M. Shipley, Deborah A. Tweddle, Chris Jones, Courtney Willis, G.A. Amos Burke, Aditi Vedi, Lisa Howell, Robert Johnston, Helen Rees, Madeleine Adams, Angela Jesudason, Milind Ronghe, Martin Elliott, Emma Ross, Guy Makin, Quentin Campbell-Hewson, Richard G. Grundy, Jennifer Turnbull, Shaun Wilson, Victoria Lee, Juliet C. Gray, Sara Stoneham, Susanne A. Gatz, Lynley V. Marshall, Paola Angelini, John Anderson, George D. Cresswell, Trevor A. Graham, Bissan Al-Lazikani, Isidro Cortes-Ciriano, Pamela Kearns, J. Ciaran Hutchinson, Darren Hargrave, Thomas S. Jacques, Michael Hubank, Andrea Sottoriva, Louis Chesler
Journal: Cancer Discovery (2024)

Abstract We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and paired plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intra-tumour heterogeneity captured by the latter, if sufficient circulating tumour-derived DNA (ctDNA) was present. Serial tumour sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomics analysis of cfDNA identified tumour-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intra-tumoural heterogeneity and the epigenetic state of cancer cells.
Clinical differences between patients with and without a positive family history of hidradenitis suppurativa - a retrospective analysis of 1452 patients
Authors: Nessr Abu Rached, Kristina Spies, Thilo Gambichler, Yannik Haven, Lennart Ocker, Daniel Myszkowski, Eggert Stockfleth, Falk Bechara
Journal: British Journal of Dermatology (2024)

Approximately 30% of Hidradenitis suppurativa (HS) patients report a positive family history of the disease. Currently, there is a limited data available on familial HS. To address this gap, we conducted a retrospective analysis at our centre to identify differences between patients with and without a positive family history of HS.
myCAF-derived exosomal PWAR6 accelerates CRC liver metastasis via altering glutamine availability and NK cell function in the tumor microenvironment
Authors: Hongsheng Fang, Weixing Dai, Ruiqi Gu, Yanbo Zhang, Jin Li, Wenqin Luo, Shanyou Tong, Lingyu Han, Yichao Wang, Chengyao Jiang, Xue Wang, Renjie Wang, Guoxiang Cai
Journal: Journal of Hematology & Oncology (2024)

Liver metastasis from colorectal cancer (CRC) is a major clinical challenge that severely affects patient survival. myofibroblastic cancer-associated fibroblasts (myCAFs) are a major component of the CRC tumor microenvironment, where they contribute to tumor progression and metastasis through exosomes. Single-cell analysis highlighted a notable increase in myCAFs in colorectal cancer liver metastases (CRLM). Exosomal sequencing identified PWAR6 as the most significantly elevated lncRNA in these metastatic tissues. In vivo and in vitro assays confirmed PWAR6's roles in CRC cell stemness, migration, and glutamine uptake. RNA pulldown, RIP, and Co-IP assays investigated the molecular mechanisms of the PWAR6/NRF2/SLC38A2 signaling axis in CRC progression, flow cytometry was used to assess NK cell activity and cytotoxicity. Clinically, higher PWAR6 expression levels are strongly associated with increased 68Ga FAPI-PET/CT SUVmax values, particularly in CRLM patients, where expression significantly exceeds that of non-LM cases and normal colon tissues. Regression analysis and survival data further support PWAR6 as a negative prognostic marker, with elevated levels correlating with worse patient outcomes. Mechanistically, PWAR6 promotes immune evasion by inhibiting NRF2 degradation through competitive binding with Keap1, thereby upregulating SLC38A2 expression, which enhances glutamine uptake in CRC cells and depletes glutamine availability for NK cells. myCAFs derived exosomes PWAR6 represents a pivotal marker for CRC liver metastasis, and its targeted inhibition with ASO-PWAR6, in combination with FAPI treatment, effectively curtails metastasis in preclinical models, offering promising therapeutic potential for clinical management.
Microglial CD2AP deficiency exerts protection in an Alzheimer’s disease model of amyloidosis
Authors: Lingliang Zhang, Lingling Huang, Yuhang Zhou, Jian Meng, Liang Zhang, Yunqiang Zhou, Naizhen Zheng, Tiantian Guo, Shanshan Zhao, Zijie Wang, Yuanhui Huo, Yingjun Zhao, Xiao-fen Chen, Honghua Zheng, David M. Holtzman, Yun-wu Zhang
Journal: Molecular Neurodegeneration (2024)

Abstract Background The CD2-associated protein (CD2AP) was initially identified in peripheral immune cells and regulates cytoskeleton and protein trafficking. Single nucleotide polymorphisms (SNPs) in the CD2AP gene have been associated with Alzheimer’s disease (AD). However, the functional role of CD2AP, especially its role in microglia during AD onset, remains elusive. Methods CD2AP protein levels in cultured primary cells and in 5xFAD mice was studied. Microglial CD2AP-deficient mice were crossed with 5xFAD mice and the offspring were subjected to neuropathological assessment, behavioral tests, electrophysiology, RNA-seq, Golgi staining, and biochemistry analysis. Primary microglia were also isolated for assessing their uptake and morphology changes. Results We find that CD2AP is abundantly expressed in microglia and its levels are elevated in the brain of AD patients and the 5xFAD model mice at pathological stages. We demonstrate that CD2AP haploinsufficiency in microglia significantly attenuates cognitive and synaptic deficits, weakens the response of microglia to Aβ and the formation of disease-associated microglia (DAM), and alleviates synapse loss in 5xFAD mice. We show that CD2AP-deficient microglia exhibit compromised uptake ability. In addition, we find that CD2AP expression is positively correlated with the expression of the complement C1q that is important for synapse phagocytosis and the formation of DAM in response to Aβ deposition. Moreover, we reveal that CD2AP interacts with colony stimulating factor 1 receptor (CSF1R) and regulates CSF1R cell surface levels, which may further affect C1q expression. Conclusions Our results demonstrate that CD2AP regulates microgliosis and identify a protective function of microglial CD2AP deficiency against Aβ deposition, suggesting the importance of detailed investigation of AD-associated genes in different brain cells for thoroughly understanding their exact contribution to AD.
Recent advances in sarcoma therapy: new agents, strategies and predictive biomarkers
Authors: Minggui Pan, Maggie Zhou, Lu Xie, Nam Bui, Kristen Ganjoo
Journal: Journal of Hematology & Oncology (2024)

Abstract Soft tissue and bone sarcomas are a heterogenous group of uncommon mesenchymal tumors with high unmet needs for novel therapeutic and diagnostic strategies. Despite many challenges that persist, innovative therapeutics are emerging. Here we provide a review of the studies presented at the 2024 American Society of Clinical Oncology annual meeting that were focused on sarcoma. There were many outstanding studies that were reported at the meeting. We begin by discussing the clinical studies on soft tissue sarcoma (STS) that included multiple histology subtypes, followed by highlighting developments in cellular therapy, before delving into specific STS histologic subtypes followed by a section covering the studies that were focused on predictive biomarkers. We conclude by discussing the studies in bone sarcomas. Some of the studies discussed here are likely to be practice changing. Some of the early-phase clinical trials have shown encouraging results.
Safety and efficacy of amulirafusp alfa (IMM0306), a fusion protein of CD20 monoclonal antibody with the CD47 binding domain of SIRPα, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: a phase 1/2 study
Authors: Jianliang Yang, Yongping Song, Keshu Zhou, Zhiming Li, Mingzhi Zhang, Hongmei Jing, Zhen Wang, Li Yu, Wei Meng, Qiying Lu, Wenzhi Tian, Yuankai Shi
Journal: Journal of Hematology & Oncology (2024)

Amulirafusp alfa (IMM0306) is a fusion protein of CD47 binding domain of signal-regulatory protein alpha (SIRPα) with CD20 monoclonal antibody on both heavy chains. This study aimed to evaluate the safety and preliminary efficacy of amulirafusp alfa in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). We enrolled patients with CD20 + r/r B-NHL who had previously received at least two lines of therapy to receive a single-dose of amulirafusp alfa in the first 2 weeks, followed by a multiple-dose period, in which the patients received the same intravenous dose every week in 4-week cycles. The primary endpoints were to evaluate the safety, determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of amulirafusp alfa. Between May 22, 2020 and February 10, 2022, 48 patients with r/r B-NHL were enrolled and received amulirafusp alfa at the doses of 40–2000 μg/kg. As of the data cut-off date of April 18, 2024, no dose-limiting toxicity was observed, and the MTD was not reached. The dose of 2000 μg/kg was identified as the RP2D. All grades and ≥ grade 3 treatment-related adverse events (TRAEs) occurred in 48 (100%) and 33 (68.8%) patients, respectively. The most common ≥ grade 3 TRAEs were lymphocyte count decreased (28/48, 58.3%), white blood cell count decreased (10/48, 20.8%), absolute neutrophil count decreased (9/48, 18.8%) and anemia (5/48, 10.4%). At the doses of 800–2000 μg/kg, objective response rate in follicular lymphoma and marginal zone lymphoma was 41.2% (7/17, 95% confidence interval [CI] 18.4–67.1) and 33.3% (2/6, 95% CI 3.7–71.0), respectively. Amulirafusp alfa showed favorable safety profile and preliminary efficacy in patients with r/r B-NHL, meriting further investigation. Trial registration NCT05805943.
Advancing digital sensing in mental health research
Authors: Samir Akre, Darsol Seok, Christopher Douglas, Adrian Aguilera, Simona Carini, Jessilyn Dunn, Matthew Hotopf, David C. Mohr, Alex A. T. Bui, Nelson B. Freimer
Journal: npj Digital Medicine (2024)

Abstract Digital sensing tools, like smartphones and wearables, offer transformative potential for mental health research by enabling scalable, longitudinal data collection. Realizing this promise requires overcoming significant challenges including limited data standards, underpowered studies, and a disconnect between research aims and community needs. This report, based on the 2023 Workshop on Advancing Digital Sensing Tools for Mental Health, articulates strategies to address these challenges to ensure rigorous, equitable, and impactful research.
The significance of free light-chain ratio in light-chain monoclonal gammopathy of undetermined significance: a flow cytometry sub-study of the iStopMM screening study
Authors: Jón Þórir Óskarsson, Sæmundur Rögnvaldsson, Sigrun Thorsteinsdottir, Thorir Einarsson Long, Andri Ólafsson, Elias Eythorsson, Ásbjörn Jónsson, Brynjar Viðarsson, Páll T. Önundarson, Bjarni A. Agnarsson, Róbert Pálmason, Margrét Sigurðardóttir, Ingunn Þorsteinsdóttir, Ísleifur Ólafsson, Stephen J. Harding, Brian G. M. Durie, Thorvardur Jon Love, Sigurdur Y. Kristinsson
Journal: Blood Cancer Journal (2024)

Light-chain (LC) monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. LC-MGUS is characterized by free light-chain (FLC) levels outside defined reference intervals, indirectly indicating underlying plasma cell (PC) monoclonality. Next-generation flow cytometry (NGF) was used to evaluate clonal PC presence in bone marrow (BM) samples from individuals with LC-MGUS in the iStopMM study, aiming to assess the predictive value of the FLC ratio for clonal PC presence and its prognostic implications. BM samples from 61 individuals with LC monoclonal gammopathy were analyzed. Clonal plasma cells were detected in 53.6% of LC-MGUS samples (n = 28) and in all samples from individuals with more advanced conditions (n = 33). The FLC ratio was predictive of clonal PC presence for kappa-involved FLC ratios (p < 0.05; n = 42), with an optimal cutoff of 3.15 (96.7% sensitivity, 91.7% specificity). Of 195 individuals with kappa-involved LC-MGUS in follow-up within the iStopMM study, none with FLC ratios >1.65 to 3.15 progressed to MM (n = 124), whereas 4/71 (5.6%) with FLC ratios >3.15 progressed over median follow-up of 55 months. These findings support using a kappa-involved FLC ratio cutoff of >3.15 to more accurately identify individuals at increased risk of developing symptomatic PC disorders.
Glycemic Management and Individualized Diabetes Care in Dialysis-Dependent Kidney Failure
Authors: Klara R. Klein, Ildiko Lingvay, Katherine R. Tuttle, Jennifer E. Flythe
Journal: Diabetes Care (2024)

Of the nearly 600,000 people in the U.S. who receive dialysis for chronic kidney failure, &amp;gt;60% have diabetes. People receiving dialysis who have diabetes have worse overall and cardiovascular survival rates than those without diabetes. Diabetes care in the dialysis setting is complicated by kidney failure–related factors that render extrapolation of glycated hemoglobin (HbA1c) targets to the dialysis population unreliable and may change the risk-benefit profiles of glucose-lowering and disease-modifying therapies. No prospective studies have established the optimal glycemic targets in the dialysis population, and few randomized clinical trials of glucose-lowering medications included individuals receiving dialysis. Observational data suggest that both lower and higher HbA1c are associated with mortality in the dialysis population. Existing data suggest the potential for safety and effectiveness of some glucose-lowering medications in the dialysis population, but firm conclusions are hindered by limitations in study design and sample size. While population-specific knowledge gaps about optimal glycemic targets and diabetes medication safety and effectiveness preclude the extension of all general population diabetes guidelines to the dialysis-dependent diabetes population, these uncertainties should not detract from the importance of providing person-centered diabetes care to people receiving dialysis. Diabetes care for individuals with and without dialysis-dependent kidney failure should be holistic, based on individual preferences and prognoses, and tailored to integrate established treatment approaches with proven benefits for glycemic control and cardiovascular risk reduction. Additional research is needed to inform how recent pharmacologic and technological advances can be applied to support such individualized care for people receiving maintenance dialysis.
ARIE: A Health Equity Framework for Public Health Interventions Informed by Critical Race Theory and Critical Gerontology
Authors: Lester Darryl Geneviève, Tenzin Wangmo, Helene Seaward, Mohamed Amine Bouchlaghem, Sarah Blacker, Félix Pageau
Journal: The American Journal of Bioethics (2024)

Older racialized minorities were particularly vulnerable during the last pandemic due to the interlocking influences of structural racism and ageism, which are often disregarded in public health planning. This oversight not only compromises the social justice and health equity goals of public health efforts but it also calls for a more inclusive approach that systematically addresses these deficiencies at every stage of a public health response. To achieve this, we propose Age- and Race-conscious Interventions done Equitably (ARIE), a novel analytical framework grounded in critical race theory and critical gerontology. ARIE is based on a four-step approach, which aligns with different stages of public health interventions. It will help ensure that structural discrimination influencing access to healthcare resources during a biological event is not ignored, and that public health authorities work actively toward identifying and addressing ageist and racist biases in their response plans and interventions.
NCCN CNS Tumor Guidelines Update for 2024
Authors: Louis Burt Nabors, Jona Hattangadi-Gluth, Craig Horbinski, Jana Portnow
Journal: Neuro-Oncology (2024)

Journal Article Accepted manuscript NCCN CNS Tumor Guidelines Update for 2024 Get access Louis Burt Nabors, MD, Louis Burt Nabors, MD Professor and Director, Department of Neurology, Division of Neuro-oncology, Vice Chair for Research, Department of Neurology and Neurosurgery, O'Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, 510 20th Street South, FOT 1020, Birmingham, AL Corresponding: [email protected] https://orcid.org/0000-0001-5926-2230 Search for other works by this author on: Oxford Academic PubMed Google Scholar Jona Hattangadi-Gluth, MD, Jona Hattangadi-Gluth, MD Department of Radiation Medicine and Applied Sciences, Moores Cancer Center, University of California San Diego https://orcid.org/0000-0001-8222-606X Search for other works by this author on: Oxford Academic PubMed Google Scholar Craig Horbinski, MD, PhD, Craig Horbinski, MD, PhD Robert H. Lurie Comprehensive Cancer Center, Northwestern University https://orcid.org/0000-0001-8340-9992 Search for other works by this author on: Oxford Academic PubMed Google Scholar Jana Portnow, MD Jana Portnow, MD Department of Medical Oncology and Research Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, noae267, https://doi.org/10.1093/neuonc/noae267 Published: 18 December 2024 Article history Received: 19 November 2024 Published: 18 December 2024
Association of Chronic Exercise on Cardiometabolic Health: A Systematic Review and Meta-Analysis
Authors: Nicola Veronese, Marianna Ilarj Burgio, Caterina Mandalà, Dario Saguto, Ligia J Dominguez, Mario Barbagallo, Lee Smith, Luigi Fontana, Gregory Y H Lip, Konstantinos Prokopidis
Journal: Ageing Research Reviews (2024)
A Model for Decoding Resistance in Precision Oncology: Acquired Resistance to FGFR inhibitors in Cholangiocarcinoma
Authors: L Goyal, D DiToro, F Facchinetti, E E Martin, P Peng, I Baiev, R Iyer, J Maurer, S Reyes, K Zhang, U Majeed, J E Berchuck, C T Chen, C Walmsley, C Pinto, D Vasseur, J D Gordan, K Mody, M Borad, T Karasic, N Damjanov, B P Danysh, E Wehrenberg-Klee, A R Kambadakone, S K Saha, I D Hoffman, K J Nelson, S Iyer, X Qiang, C Sun, H Wang, L Li, M Javle, B Lin, W Harris, A X Zhu, J M Cleary, K T Flaherty, T Harris, R T Shroff, I Leshchiner, L Parida, R K Kelley, J Fan, J R Stone, N V Uboha, H Hirai, H Sootome, F Wu, D C Bensen, A Hollebecque, L Friboulet, J K Lennerz, G Getz, D Juric
Journal: Annals of Oncology (2024)
Tedros Adhanom Ghebreyesus: peace is the best medicine
Authors: Tedros Adhanom Ghebreyesus
Journal: BMJ (2024)

War and disease are old friends.In the Napoleonic wars and the American Civil War, more soldiers died from disease than in battle.It was no coincidence that the 1918 influenza pandemic erupted during the first world war or that the final frontier for eradicating polio is in the most insecure regions of Afghanistan and Pakistan.In the Democratic Republic of the Congo, the Ebola outbreak in the relatively stable Équateur province in 2018 took just two months to control, whereas the outbreak in the insecure provinces of North Kivu and Ituri in 2020 took two years.
Observational study for multiparametric assessment of cardiac congestion in outpatient worsening heart failure (<scp>EVOLUTION</scp>)
Authors: Gad Cotter, Beth Davison, Philip Janiak, Christopher Edwards, Maria Novosadova, Koji Takagi, Marie‐Laure Ozoux, Francesca Lawson, Hamlet Hayrapetyan, Hamayak Sisakian, Victor R. Ter‐Grigoryan, Katell Peoc'h, Alexandre Raynor, Paul Bruzeau, Alexis Nguyen, Alexandre Mebazaa
Journal: European Journal of Heart Failure (2024)

Abstract Aims We sought to characterize the clinical course of patients following worsening heart failure (WHF) treated in an outpatient setting and to identify factors associated with a poor response to standard of care with loop diuretics. Methods and results Between September 2022 and March 2023, 44 eligible patients (mean age 66.3 years, 84% male) with ejection fraction &lt;50% and with WHF symptoms in the preceding week treated in an outpatient setting were enrolled. Patients were assessed weekly over 4 weeks following the WHF episode. At week 4, responses to fluid expansion and furosemide administration were assessed in 39 patients to unmask persistent subclinical congestion. Patients were on stable doses of guideline‐directed medical therapy (GDMT) with a mean daily furosemide dose of 47.4 mg. Patient‐reported and physician‐assessed symptoms and quality of life improved over the 4 weeks. At 1 h following 1 L Ringer solution infused over 2 h, the median (interquartile range) urine volume and urine sodium excreted over 3 h were 300 (200.0–500.0) ml and 39.6 (12.4–63.0) mEq, respectively. Receiver‐operating characteristic curves suggest that cystatin C &gt;1.2 ng/ml, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) &gt;1500 pg/ml, and high‐sensitivity troponin T &gt;20 pg/ml represent good predictors of non‐response to a fluid challenge (diuresis, natriuresis, and rales) following an outpatient WHF, with having all three markers associated with the worst response. Conclusion Patients with high levels of troponin, or NT‐proBNP, or cystatin C who develop WHF despite being treated with a loop diuretic, need novel therapies for WHF.
ZDHHC20 mediated S-palmitoylation of fatty acid synthase (FASN) promotes hepatocarcinogenesis
Authors: Yaqi Mo, Yamei Han, Yang Chen, Chunling Fu, Qing Li, Zhuang Liu, Mingming Xiao, Bo Xu
Journal: Molecular Cancer (2024)

Protein palmitoylation is a reversible fatty acyl modification that undertakes important functions in multiple physiological processes. Dysregulated palmitoylations are frequently associated with the formation of cancer. How palmitoyltransferases for S-palmitoylation are involved in the occurrence and development of hepatocellular carcinoma (HCC) is largely unknown. Chemical carcinogen diethylnitrosamine (DEN)-induced and DEN combined CCl4 HCC models were used in the zinc finger DHHC-type palmitoyltransferase 20 (ZDHHC20) knockout mice to investigate the role of ZDHHC20 in HCC tumourigenesis. Palmitoylation liquid chromatography-mass spectrometry analysis, acyl-biotin exchange assay, co-immunoprecipitation, ubiquitination assays, protein half-life assays and immunofluorescence microscopy were conducted to explore the downstream regulators and corresponding mechanisms of ZDHHC20 in HCC. Knocking out of ZDHHC20 significantly reduced hepatocarcinogenesis induced by chemical agents in the two HCC mouse models in vivo. 97 proteins with 123 cysteine sites were found to be palmitoylated in a ZDHHC20-dependent manner. Among these, fatty acid synthase (FASN) was palmitoylated at cysteines 1471 and 1881 by ZDHHC20. The genetic knockout or pharmacological inhibition of ZDHHC20, as well as the mutation of the critical cysteine sites of FASN (C1471S/C1881S) accelerated the degradation of FASN. Furthermore, ZDHHC20-mediated FASN palmitoylation competed against the ubiquitin-proteasome pathway via the E3 ubiquitin ligase complex SNX8-TRIM28. Our findings demonstrate the critical role of ZDHHC20 in promoting hepatocarcinogenesis, and a mechanism underlying a mutual restricting mode for protein palmitoylation and ubiquitination modifications.