tbuckley/cabot-search huggingface dataset:
Di-PEGylated insulin: A long-acting insulin conjugate with superior safety in reducing hypoglycemic events
Authors: Zhipeng Zeng, Runcheng Tan, Shi Chen, Haolin Chen, Zhijia Liu, Lixin Liu, Mingqiang Li, Yongming Chen
Journal: Acta Pharmaceutica Sinica B (2024)

Although the discovery of insulin 100 years ago revolutionized the treatment of diabetes, its therapeutic potential is compromised by its short half-life and narrow therapeutic index. Current long-acting insulin analogs, such as insulin-polymer conjugates, are mainly used to improve pharmacokinetics by reducing renal clearance. However, these conjugates are synthesized without sacrificing the bioactivity of insulin, thus retaining the narrow therapeutic index of native insulin, and exceeding the efficacious dose still leads to hypoglycemia. Here, we report a kind of di-PEGylated insulin that can simultaneously reduce renal clearance and receptor-mediated clearance. By impairing the binding affinity to the receptor and the activation of the receptor, di-PEGylated insulin not only further prolongs the half-life of insulin compared to classical mono-PEGylated insulin but most importantly, increases its maximum tolerated dose 10-fold. The target of long-term glycemic management in vivo has been achieved through improved pharmacokinetics and a high dose. This work represents an essential step towards long-acting insulin medication with superior safety in reducing hypoglycemic events.
Organ-specific biological clocks: Ageotyping for personalized anti-aging medicine
Authors: Francesco Prattichizzo, Chiara Frigé, Valeria Pellegrini, Lucia Scisciola, Aurelia Santoro, Daniela Monti, Maria Rita Rippo, Mikhail Ivanchenko, Fabiola Olivieri, Claudio Franceschi
Journal: Ageing Research Reviews (2024)

Aging is a complex multidimensional, progressive remodeling process affecting multiple organ systems. While many studies have focused on studying aging across multiple organs, assessment of the contribution of individual organs to overall aging processes is a cutting-edge issue. An organ's biological age might influence the aging of other organs, revealing a multiorgan aging network. Recent data demonstrated a similar yet asynchronous inter-organs and inter-individuals progression of aging, thereby providing a foundation to track sources of declining health in old age. The integration of multiple omics with common clinical parameters through artificial intelligence has allowed the building of organ-specific aging clocks, which can predict the development of specific age-related diseases at high resolution. The peculiar individual aging-trajectory, referred to as ageotype, might provide a novel tool for a personalized anti-aging, preventive medicine. Here, we review data relative to biological aging clocks and omics-based data, suggesting different organ-specific aging rates. Additional research on longitudinal data, including young subjects and analyzing sex-related differences, should be encouraged to apply ageotyping analysis for preventive purposes in clinical practice.
Abstract B033: Histone H3.3 K27M and G34R/V glioma driver mutations inhibit mitotic phosphorylation of H3.3 S31, driving tumor formation by inducing chromosomal instability
Authors: Charles A. Day, Florina Grigore, Alyssa Langfald, Faruck Hakkim, David Daniels, Kevin Vaughan, James Robinson, Edward Hinchcliffe
Journal: Cancer Research (2024)

Abstract Diffuse gliomas are pediatric high-grade gliomas that frequently harbor heterozygous histone H3.3 K27M, G34R, or G34V mutations. These mutations alter histone methylations, although the precise mechanism(s) of gliomagenesis remains uncertain. H3.3 contains a unique Serine at position 31 that is phosphorylated in prophase and dephosphorylated in anaphase during normal cell division. Previously we have reported that chromosome missegregation triggers H3.3 S31 phosphorylation along chromosome arms in ana/telophase leading to p53-induced cell cycle arrest. Here we show, in vitro and in vivo, that H3.3 K27M, G34R, and G34V suppress S31 phosphorylation by its mitotic kinase, Chk1. In diploid cells, overexpression of H3.3 K27M, G34R, G34V, or non-phosphorylatable S31A significantly increases the frequency of chromosome missegregation, while H3.3 K36M did not. This missegregation phenotype could be rescued by overexpression of K27M/S31E or G34R/S31E double mutants. Next, we used CRISPR/Cas9 gene editing to revert K27M or G34V patient-derived DMG cells to WT or replace the mutant allele with S31A. Reversion to WT increased metaphase S31 phosphorylation and reduced chromosome missegregations, but inserting an S31A mutation caused more mitotic defects. Following a mitotic error, newly formed aneuploid cells overexpressing K27M, G34R, or G34V suppress p53 levels and continue to divide, while WT overexpressing cells always arrest. To test the effects of diminished S31 phosphorylation on gliomagenesis, we utilized a novel mouse model of glioma. Expression of PDGFß linked to H3.3K27M, H3.3G34R, and H3.3S31A in neural stem cells in vivo promoted the development of high-grade gliomas in under 100 days, whereas PDFß-H3.3WT did not. Notably, the S31A tumors had histologically normal levels of K27me3 and K36me3. This work shows that a single glioma-associated point mutation in H3.3 can generate chromosomal instability, and which is a major contributing factor to H3.3 K27M and G34-altered glioma formation. Citation Format: Charles A. Day, Florina Grigore, Alyssa Langfald, Faruck Hakkim, David Daniels, Kevin Vaughan, James Robinson, Edward Hinchcliffe. Histone H3.3 K27M and G34R/V glioma driver mutations inhibit mitotic phosphorylation of H3.3 S31, driving tumor formation by inducing chromosomal instability [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B033.
Sequential dual-locking strategy using photoactivated Pt(IV)-based metallo-nano prodrug for enhanced chemotherapy and photodynamic efficacy by triggering ferroptosis and macrophage polarization
Authors: Jun Li, Qiang Zhang, Hao Yang, Wenli Lu, Yulong Fu, Yingcai Xiong, Xuan Wang, Tianming Lu, Yanlin Xin, Zejuan Xie, Weichao Chen, Guoqiang Wang, Yuanyuan Guo, Ruogu Qi
Journal: Acta Pharmaceutica Sinica B (2024)

Selective activation of Pt(IV) prodrugs within tumors has emerged as a promising strategy in tumor treatment. Although progress has been made with photo- and ultrasound-activated Pt(IV) prodrugs, concerns remain over the non-specific activation of photosensitizers (PS) and the potential for phototoxicity and chemical toxicity. In this study, a sequential dual-locked Pt(IV) nano-prodrug that can be activated by both the acidic tumor microenvironment and light was developed. The Pt(IV) prodrug was prepared by conjugating PS-locked Pt(IV) to a polymeric core, which was then chelated with metallo iron to lock its photoactivity and form a metallo-nano prodrug. Under acidic tumor microenvironment conditions, the metallo-nano prodrug undergoes dissociation of iron, triggering a reduction process in oxaliplatin under light irradiation, resulting in the activation of both chemotherapy and photodynamic therapy (PDT). Additionally, the prodrug could induce metallo-triggered ferroptosis and polarization of tumor-associated macrophages (TAM), thereby enhancing tumor inhibition. The dual-lock strategy employed in a nanoparticle delivery system represents an expansion in the application of platinum-based anticancer drugs, making it a promising new direction in cancer treatment.
ctDNA improves prognostic prediction for patients with relapsed/refractory MM receiving ixazomib, lenalidomide, and dexamethasone
Authors: Yasunori Kogure, Hiroshi Handa, Yuta Ito, Masaki Ri, Yuichi Horigome, Masaki Iino, Yoriko Harazaki, Takahiro Kobayashi, Masahiro Abe, Tadao Ishida, Shigeki Ito, Hiromi Iwasaki, Junya Kuroda, Hirohiko Shibayama, Kazutaka Sunami, Hiroyuki Takamatsu, Hideto Tamura, Toshiaki Hayashi, Kiwamu Akagi, Tomohiro Shinozaki, Takahiro Yoshida, Ikuo Mori, Shinsuke Iida, Takahiro Maeda, Keisuke Kataoka
Journal: Blood (2024)

Abstract It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here, we performed targeted-capture sequencing using bone marrow plasma cells (BMPCs) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis–associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, whereas KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the 6 relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index, classifying patients into 3 categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM. This study is a part of the C16042 study, which is registered at www.clinicaltrials.gov as #NCT03433001.
Recurrent infections drive persistent bladder dysfunction and pain via sensory nerve sprouting and mast cell activity
Authors: Byron W. Hayes, Hae Woong Choi, Abhay P.S. Rathore, Chunjing Bao, Jianling Shi, Yul Huh, Michael W. Kim, Andrea Mencarelli, Pradeep Bist, Lai Guan Ng, Changming Shi, Joo Hwan Nho, Aram Kim, Hana Yoon, Donghoon Lim, Johanna L. Hannan, J. Todd Purves, Francis M. Hughes, Ru-Rong Ji, Soman N. Abraham
Journal: Science Immunology (2024)

Urinary tract infections (UTIs) account for almost 25% of infections in women. Many are recurrent (rUTI), with patients frequently experiencing chronic pelvic pain and urinary frequency despite clearance of bacteriuria after antibiotics. To elucidate the basis for these bacteria-independent bladder symptoms, we examined the bladders of patients with rUTI. We noticed a notable increase in neuropeptide content in the lamina propria and indications of enhanced nociceptive activity. In mice subjected to rUTI, we observed sensory nerve sprouting that was associated with nerve growth factor (NGF) produced by recruited monocytes and tissue-resident mast cells. Treatment of rUTI mice with an NGF-neutralizing antibody prevented sprouting and alleviated pelvic sensitivity, whereas instillation of native NGF into naïve mice bladders mimicked nerve sprouting and pain behavior. Nerve activation, pain, and urinary frequency were each linked to the presence of proximal mast cells, because mast cell deficiency or treatment with antagonists against receptors of several direct or indirect mast cell products was each effective therapeutically. Thus, our findings suggest that NGF-driven sensory sprouting in the bladder coupled with chronic mast cell activation represents an underlying mechanism driving bacteria-independent pain and voiding defects experienced by patients with rUTI.
Why do probabilistic clinical models fail to transport between sites
Authors: Thomas A. Lasko, Eric V. Strobl, William W. Stead
Journal: npj Digital Medicine (2024)

Abstract The rising popularity of artificial intelligence in healthcare is highlighting the problem that a computational model achieving super-human clinical performance at its training sites may perform substantially worse at new sites. In this perspective, we argue that we should typically expect this failure to transport , and we present common sources for it, divided into those under the control of the experimenter and those inherent to the clinical data-generating process. Of the inherent sources we look a little deeper into site-specific clinical practices that can affect the data distribution, and propose a potential solution intended to isolate the imprint of those practices on the data from the patterns of disease cause and effect that are the usual target of probabilistic clinical models.
TGF-β specifies T <sub>FH</sub> versus T <sub>H</sub> 17 cell fates in murine CD4 <sup>+</sup> T cells through c-Maf
Authors: Yinshui Chang, Luisa Bach, Marko Hasiuk, Lifen Wen, Tarek Elmzzahi, Carlson Tsui, Nicolás Gutiérrez-Melo, Teresa Steffen, Daniel T. Utzschneider, Timsse Raj, Paul Jonas Jost, Sylvia Heink, Jingyuan Cheng, Oliver T. Burton, Julia Zeiträg, Dominik Alterauge, Frank Dahlström, Jennifer-Christin Becker, Melanie Kastl, Konstantinos Symeonidis, Martina van Uelft, Matthias Becker, Sarah Reschke, Stefan Krebs, Helmut Blum, Zeinab Abdullah, Katrin Paeschke, Caspar Ohnmacht, Christian Neumann, Adrian Liston, Felix Meissner, Thomas Korn, Jan Hasenauer, Vigo Heissmeyer, Marc Beyer, Axel Kallies, Lukas T. Jeker, Dirk Baumjohann
Journal: Science Immunology (2024)

T follicular helper (T
Mast cells help organize the Peyer’s patch niche for induction of IgA responses
Authors: Marco De Giovanni, Vivasvan S. Vykunta, Adi Biram, Kevin Y. Chen, Hanna Taglinao, Jinping An, Dean Sheppard, Helena Paidassi, Jason G. Cyster
Journal: Science Immunology (2024)

Peyer’s patches (PPs) are lymphoid structures situated adjacent to the intestinal epithelium that support B cell responses that give rise to many intestinal IgA-secreting cells. Induction of isotype switching to IgA in PPs requires interactions between B cells and TGFβ-activating conventional dendritic cells type 2 (cDC2s) in the subepithelial dome (SED). However, the mechanisms promoting cDC2 positioning in the SED are unclear. Here, we found that PP cDC2s express GPR35, a receptor that promotes cell migration in response to various metabolites, including 5-hydroxyindoleacetic acid (5-HIAA). In mice lacking GPR35, fewer cDC2s were found in the SED, and frequencies of IgA + germinal center (GC) B cells were reduced. IgA plasma cells were reduced in both the PPs and lamina propria. These phenotypes were also observed in chimeric mice that lacked GPR35 selectively in cDCs. GPR35 deficiency led to reduced coating of commensal bacteria with IgA and reduced IgA responses to cholera toxin. Mast cells were present in the SED, and mast cell–deficient mice had reduced PP cDC2s and IgA + cells. Ablation of tryptophan hydroxylase 1 (Tph1) in mast cells to prevent their production of 5-HIAA similarly led to reduced PP cDC2s and IgA responses. Thus, mast cell–guided positioning of GPR35 + cDC2s in the PP SED supports induction of intestinal IgA responses.
Impact of Helicobacter pylori Infection and Treatment on Colorectal Cancer in a Large, Nationwide Cohort
Authors: Shailja C. Shah, M. Constanza Camargo, Mark Lamm, Ranier Bustamante, Christianne L. Roumie, Otis Wilson, Alese E. Halvorson, Robert Greevy, Lin Liu, Samir Gupta, Joshua Demb
Journal: Journal of Clinical Oncology (2024)

is the most common cause of infection-associated cancer worldwide. We aimed to evaluate the impact of H. pylori infection and treatment on colorectal cancer (CRC) incidence and mortality.
HDL and SARS CoV-2: emerging theragnostic implications
Authors: Alankrita Rani, Julia T. Stadler, Gunther Marsche
Journal: Trends in Molecular Medicine (2024)

High-density lipoproteins (HDLs) are complex particles with multiple functions. They are thought to have evolved as part of the body's innate defense system against infection. Recent research suggests that HDL levels influence susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the severity of associated complications, making it a promising target for therapeutic intervention.
Sickle cell disease iPSC-derived sensory neurons exhibit increased excitability and sensitization to patient plasma
Authors: Reilly L. Allison, Emily Welby, Vanessa Ehlers, Anthony Burand, Olena Isaeva, Damaris Nieves Torres, Janelle Highland, Amanda M. Brandow, Cheryl L. Stucky, Allison D. Ebert
Journal: Blood (2024)
Endothelial lipid droplets drive atherosclerosis and arterial hypertension
Authors: Suowen Xu, Stefan Offermanns
Journal: Trends in Endocrinology and Metabolism (2024)

Lipid droplets (LDs) are essential for cellular pathophysiology. In two recent reports, Kim et al. and Boutagy et al. show that accumulation of LDs in endothelial cells (ECs) elevates blood pressure and accelerates progression of atherosclerosis. These findings identify a novel mechanism of EC lipid metabolism which drives cardiometabolic diseases.
Phase II Trial of <i>nab-</i>Sirolimus in Patients With Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT): Long-Term Efficacy and Safety Update
Authors: Andrew J. Wagner, Vinod Ravi, Richard F. Riedel, Kristen Ganjoo, Brian A. Van Tine, Rashmi Chugh, Lee Cranmer, Erlinda M. Gordon, Jason L. Hornick, Heng Du, Li Ding, Anita N. Schmid, Willis H. Navarro, David J. Kwiatkowski, Mark A. Dickson
Journal: Journal of Clinical Oncology (2024)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. nab-Sirolimus is approved in the United States for the treatment of metastatic or locally advanced malignant perivascular epithelioid cell tumor (PEComa) on the basis of the primary analysis results of the phase II Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT) trial (ClinicalTrials.gov identifier: NCT02494570 ). Results from the primary analysis were previously published; however, the median duration of response (mDOR) had not been reached at that time. Here, 3 years after the primary analysis, we report final efficacy and safety data (data cutoff: April 29, 2022). At study completion, the confirmed overall response rate (by independent radiologist review using RECIST v1.1) was 38.7% (95% CI, 21.8 to 57.8), with an additional converted confirmed complete response (n = 2). Median progression-free survival remained the same at 10.6 months (95% CI, 5.5 to 41.2). The mDOR was reached at 39.7 months (95% CI, 6.5 to not reached [NR]), and the median overall survival at completion was 53.1 months (95% CI, 22.2 to NR). The most common treatment-related adverse events (TRAEs) were stomatitis (82.4%) and fatigue and rash (each 61.8%). No new or unexpected adverse events occurred, and no grade ≥4 TRAEs were reported. These results highlight the long-term clinical benefit of nab-sirolimus in patients with advanced malignant PEComa, with a DOR of &gt;3 years.
Oxygen‐Vacancy‐Rich Monolayer BiO<sub>2−</sub><i><sub>X</sub></i> Nanosheets for Bacterial Sepsis Management via Dual Physically Antibacterial and Chemically Anti‐inflammatory Functions
Authors: Fang Liu, Kun Zhang, Bin Lu, Xiaochun Wang, Qingrong Dong, Tingyu Xue, Yan Tan, Xing Wang, Jiangfeng Du
Journal: Advanced Healthcare Materials (2024)

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Effective treatment of bacterial sepsis remains challenging due to the rapid progression of infection and the systemic inflammatory response. In this study, monolayer BiO
Targeting Molecular Measurable Residual Disease and Low-Blast Relapse in AML With Venetoclax and Low-Dose Cytarabine: A Prospective Phase II Study (VALDAC)
Authors: Ing Soo Tiong, Devendra K. Hiwase, Emad Abro, Ashish Bajel, Emma Palfreyman, Ashanka Beligaswatte, John Reynolds, Natasha Anstee, Tamia Nguyen, Sun Loo, Chong Chyn Chua, Michael Ashby, Kaitlyn M. Wiltshire, Shaun Fleming, Chun Y. Fong, Tse-Chieh Teh, Piers Blombery, Richard Dillon, Adam Ivey, Andrew H. Wei
Journal: Journal of Clinical Oncology (2024)

PURPOSE A prospective phase II study examined the safety and efficacy of venetoclax combined with low-dose cytarabine (LDAC) in AML at first measurable residual disease (MRD) or oligoblastic relapse. METHODS Patients with either MRD (≥1 log 10 rise) or oligoblastic relapse (blasts 5%-15%) received venetoclax 600 mg once daily D1-28 plus LDAC once daily D1-10 in 28-day cycles. The primary objective was MRD response in the MRD relapse cohort or complete remission (CR/CRh/CRi) in the oligoblastic relapse cohort. RESULTS Forty-eight adults with either MRD (n = 26) or oligoblastic (n = 22) relapse were enrolled. Median age was 67 years (range, 18-80) and 94% had received previous intensive chemotherapy. Patients received a median of four cycles of therapy; 17% completed ≥12 cycles. Patients with oligoblastic relapse had more grade ≥3 anemia (32% v 4%; P = .02) and infections (36% v 8%; P = .03), whereas grade 4 neutropenia (32 v 23%) or thrombocytopenia (27 v 15%) were comparable with the MRD relapse cohort. Markers of molecular MRD relapse included mutant NPM1 (77%), CBFB::MYH11 (4%), RUNX1::RUNX1T1 (4%), or KMT2A::MLLT3 (4%). Three patients with a log 10 rise in IDH1/ 2 (12%) were included. By cycle 2 in the MRD relapse cohort, a log 10 reduction in MRD was observed in 69%; 46% achieved MRD negative remission. In the oligoblastic relapse cohort, 73% achieved CR/CRh/CRi. Overall, 21 (44%) underwent hematopoietic cell transplantation. Median overall survival (OS) was not reached in either cohort. Estimated 2-year OS rate was 67% (95% CI, 50 to 89) in the MRD and 53% (95% CI, 34 to 84) in the oligoblastic relapse cohorts. CONCLUSION For AML in first remission and either MRD or oligoblastic relapse, venetoclax plus LDAC is well tolerated and highly effective.
When I use a word . . . Medical blue plaques—the Peckham Experiment
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

The Pioneer Health Centre in Peckham, also known as the Peckham Centre, running what became known at the Peckham Experiment, was founded in 1926 by two doctors, Innes Pearse (1889-1978) and her colleague George Scott Williamson (1884-1953). It closed down in 1929 and reopened in 1935 in new purpose-built premises. Families paid a shilling a week for membership, which gave them free medical consultations of various sorts and access to a wide variety of recreations, but no medical treatment. The purpose was to observe how their health progressed and to discover what factors were involved in good health and wellbeing. After closing down again during World War II the centre reopened, but was forced to close again in 1950, this time for good, because of lack of funds, due to a complex range of factors. In a 1938 publication, the founders stressed that health and wellbeing were not synonymous; health, they wrote, operates with a cumulative deposit account and wellbeing on a diminishing current account. Two blue plaques commemorate the Pioneer Health Centre: an English Heritage blue plaque at 142 Queen's Road, Peckham, London SE15, the site of the centre's original building, and a plaque put up by the London Borough of Southwark at the site of the second building, now converted to a block of flats, and situated round the corner from the Queen's Road premises, in Frobisher Place, St Mary's Road, Peckham.