tbuckley/cabot-search huggingface dataset:
PIEZO Ion Channels in Cardiovascular Functions and Diseases
Authors: Bertrand Coste, Patrick Delmas
Journal: Circulation Research (2024)

The cardiovascular system provides blood supply throughout the body and as such is perpetually applying mechanical forces to cells and tissues. Thus, this system is primed with mechanosensory structures that respond and adapt to changes in mechanical stimuli. Since their discovery in 2010, PIEZO ion channels have dominated the field of mechanobiology. These have been proposed as the long-sought-after mechanosensitive excitatory channels involved in touch and proprioception in mammals. However, more and more pieces of evidence point to the importance of PIEZO channels in cardiovascular activities and disease development. PIEZO channel-related cardiac functions include transducing hemodynamic forces in endothelial and vascular cells, red blood cell homeostasis, platelet aggregation, and arterial blood pressure regulation, among others. PIEZO channels contribute to pathological conditions including cardiac hypertrophy and pulmonary hypertension and congenital syndromes such as generalized lymphatic dysplasia and xerocytosis. In this review, we highlight recent advances in understanding the role of PIEZO channels in cardiovascular functions and diseases. Achievements in this quickly expanding field should open a new road for efficient control of PIEZO-related diseases in cardiovascular functions.
Long-term outcomes after upfront second-generation tyrosine kinase inhibitors for chronic myeloid leukemia: managing intolerance and resistance
Authors: Simone Claudiani, Farhan Chughtai, Afzal Khan, Chloe Hayden, Fiona Fernando, Jamshid Khorashad, Victoria Orovboni, Glenda Scandura, Andrew Innes, Jane F. Apperley, Dragana Milojkovic
Journal: Leukemia (2024)

Abstract Second-generation tyrosine kinase inhibitors (2GTKI) are more effective in inducing rapid molecular responses than imatinib when used first-line in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, failure of first line-2GTKI (1L-2GTKI) still occurs and there is no consensus regarding subsequent management. We retrospectively analyzed the outcome of 106 CML-CP patients treated with 1L-2GTKI and with a median follow-up of 91 months. 45 patients (42.4%) switched to an alternative TKI, 28 for intolerance (26.4%) and 17 (16%) for resistance. Most patients who remained on 1L-2GTKI achieved deep molecular responses (DMR) and 15 (14.1%) are in treatment-free remission (TFR). Intolerant patients also obtained DMR, although most required multiple TKI changes and were slower to respond, particularly if treated with 2L-imatinib. Inferior outcomes were observed in resistant patients, who failed alternative 2L-2GTKI and required 3/4GTKI and/or allogeneic hematopoietic stem cell transplant (alloSCT). 7yr-OS was significantly lower for these individuals (66.1%) than for intolerant patients and those who remained on 1L-2GTKI (100% and 97.9%, respectively; p = 0.001). It is apparent that failure of 1L-2GTKI is a challenging problem in modern CML therapy. Intolerance can be effectively managed by switching to an alternative 2GTKI, but resistance requires early consideration of 3/4GTKI.
PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K+ secretion
Authors: Rolando Carrisoza-Gaytan, Stephanie M Mutchler, Francisco Carattino, Joanne Soong, Marianela G Dalghi, Peng Wu, WenHui Wang, Gerard Apodaca, Lisa M Satlin, Thomas R Kleyman
Journal: Journal of Clinical Investigation (2024)

Ca2+-activated BK channels in renal intercalated cells (ICs) mediate luminal flow-induced K+ secretion (FIKS), but how ICs sense increased flow remains uncertain. We examined whether PIEZO1, a mechanosensitive Ca2+-permeable channel expressed in the basolateral membranes of ICs, is required for FIKS. In isolated cortical collecting ducts (CCDs), the mechanosensitive cation-selective channel inhibitor GsMTx4 dampened flow-induced increases in intracellular Ca2+ concentration ([Ca2+]i), whereas the PIEZO1 activator Yoda1 increased [Ca2+]i and BK channel activity. CCDs from mice fed a high-K+ (HK) diet exhibited a greater Yoda1-dependent increase in [Ca2+]i than CCDs from mice fed a control K+ diet. ICs in CCDs isolated from mice with a targeted gene deletion of Piezo1 in ICs (IC-Piezo1-KO) exhibited a blunted [Ca2+]i response to Yoda1 or increased flow, with an associated loss of FIKS in CCDs. Male IC-Piezo1-KO mice selectively exhibited an increased blood [K+] in response to an oral K+ bolus and blunted urinary K+ excretion following a volume challenge. Whole-cell expression of BKα subunit was reduced in ICs of IC-Piezo1-KO mice fed an HK diet. We conclude that PIEZO1 mediates flow-induced basolateral Ca2+ entry into ICs, is upregulated in the CCD in response to an HK diet, and is necessary for FIKS.
Tipping the balance toward transplantation tolerance: in vivo therapy using a mutated IL-2
Authors: Geoffrey Camirand, Fadi G. Lakkis
Journal: Journal of Clinical Investigation (2024)

Immune tolerance to allogenic transplanted tissues remains elusive, and therapeutics promoting CD4+FOXP3+ Tregs are required to achieve this ultimate goal. In this issue of the JCI, Efe and colleagues engineered an Fc domain fused to a human mutein IL-2 (mIL-2-Fc) bearing mutations that confer preferential binding to the high-affinity IL-2 receptor expressed on Tregs. In vivo mIL-2-Fc therapy effectively heightened mouse, monkey, and human Treg numbers, promoted tolerance to minor antigen mismatched skin grafts in mice, and synergized with immunosuppressive drugs used in the clinic. These findings warrant clinical trials that assess the efficacy of mIL-2-Fc in transplantation.
Stromal Pbrm1 mediates chromatin remodeling necessary for embryo implantation in the mouse uterus
Authors: Qiliang Xin, Iris Feng, Guoyun Yu, Jurrien Dean
Journal: Journal of Clinical Investigation (2024)

Early gestational loss occurs in approximately 20% of all clinically recognized human pregnancies and is an important cause of morbidity. Either embryonic or maternal defects can cause loss, but a functioning and receptive uterine endometrium is crucial for embryo implantation. We report that the switch/sucrose nonfermentable (SWI/SNF) remodeling complex containing polybromo-1 (PBRM1) and Brahma-related gene 1 (BRG1) is essential for implantation of the embryonic blastocyst on the wall of the uterus in mice. Although preimplantation development is unaffected, conditional ablation of Pbrm1 in uterine stromal cells disrupts progesterone pathways and uterine receptivity. Heart and neural crest derivatives expressed 2 (Hand2) encodes a basic helix-loop-helix (bHLH) transcription factor required for embryo implantation. We identify an enhancer of the Hand2 gene in stromal cells that requires PBRM1 for epigenetic histone modifications/coactivator recruitment and looping with the promoter. In Pbrm1cKO mice, perturbation of chromatin assembly at the promoter and enhancer sites compromises Hand2 transcription, adversely affects fibroblast growth factor signaling pathways, prevents normal stromal-epithelial crosstalk, and disrupts embryo implantation. The mutant female mice are infertile and provide insight into potential causes of early pregnancy loss in humans.
Absence of Stat1 in donor CD4+ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice
Authors: Huihui Ma, Caisheng Lu, Judith Ziegler, Ailing Liu, Antonia Sepulveda, Hideho Okada, Suzanne Lentzsch, Markus Y. Mapara
Journal: Journal of Clinical Investigation (2024)
A role for TMEM63 in the lung
Authors: Jaime L Hook
Journal: Journal of Clinical Investigation (2024)

Surfactants are essential for breathing. Although major progress has been made in the past half century toward an understanding of surfactant secretion mechanisms, the identity of the mechanosensor that couples breathing to surfactant secretion has remained elusive. In this issue of the JCI, Chen, Li, and colleagues provide evidence that the mechanosensor is the transmembrane 63 (TMEM63) ion channel. These findings open new avenues for future research into lung mechanobiology.
The twin model: decolonising research and knowledge sharing through equitable collaborations
Authors: Caroline Juhl Arnbjerg, Tara Ballav Adhikari, Emmanuel Musoni-Rwililiza, Per Kallestrup
Journal: BMJ (2024)

Helicopter or parachute research in global collaborations in medicine is a long standing and concerning practice. 1 When this occurs, it involves researchers from the Global North conducting studies in the Global South with little or no involvement of and credit to local researchers.This is still too commonplace despite calls for more inclusive and equitable approaches, which started in the early part of the 21st century among the global health community and are now extending to the realms of research and advocacy for planetary health.Calls to "decolonise" and engender more equitable collaborations are a demand to distance collective global health work from its predecessors, such as colonial medicine, tropical medicine, and certain approaches to international health. 2 -4 The lack of equitable partnerships between researchers in the Global North and Global South contributes to the perpetuation of coloniality-the "invisible power matrix" that continues to uphold power structures and attitudes originating from historical colonialism-in science and medicine.
Sacroiliac radiographic progression over 10 years in axSpA: data from the DESIR inception cohort
Authors: Anna Molto, Clementina López-Medina, Alexandre Sepriano, Sofia Ramiro, Manouk de Hooge, Miranda van Lunteren, Victoria Navarro-Compán, Daniel Wendling, Maxime Dougados
Journal: Annals of the Rheumatic Diseases (2024)

To evaluate sacroiliac radiographic progression over a 10-year follow-up and determine the baseline factors associated with such progression in patients with recent-onset axial spondyloarthritis (axSpA, <3 years).
Internet- and mobile-based psychological interventions for post-traumatic stress symptoms in youth: a systematic review and meta-analysis
Authors: Christina Schulte, Mathias Harrer, Cedric Sachser, Jasmina Weiss, Anna-Carlotta Zarski
Journal: npj Digital Medicine (2024)

Abstract Psychological interventions can help reduce posttraumatic stress symptoms (PTSS) in youth, but many do not seek help. Internet- and mobile-based interventions (IMIs) show promise in expanding treatment options. However, the overall evidence on IMIs in reducing PTSS among youth remains unclear. This systematic review and meta-analysis investigated the efficacy of IMIs in PTSS reduction for youth exposed to traumatic events. A comprehensive literature search was conducted in January 2023 including non-randomized and randomized-controlled trials (RCT) investigating the effects of IMIs on PTSS in youth aged ≤25 years. Six studies were identified with five providing data for the meta-analysis. The majority of studies included youth with different types of trauma irrespective of PTSS severity at baseline ( k = 5). We found a small within-group effect in reducing PTSS from baseline to post-treatment ( g = −0.39, 95% CrI: −0.67 to −0.11, k = 5; n = 558; 9 comparisons). No effect emerged when comparing the effect of IMIs to control conditions ( g = 0.04; 95%-CrI: -0.52 to 0.6, k = 3; n = 768; k = 3; 4 comparisons). Heterogeneity was low between and within studies. All studies showed at least some concerns in terms of risk of bias. Current evidence does not conclusively support the overall efficacy of IMIs in addressing youth PTSS. This review revealed a scarcity of studies investigating IMIs for youth exposed to traumatic events, with most being feasibility studies rather than adequately powered RCTs and lacking a trauma focus. This underscores the demand for more high-quality research.
Single-cell transcriptomics reveals cell atlas and identifies cycling tumor cells responsible for recurrence in ameloblastoma
Authors: Gan Xiong, Nan Xie, Min Nie, Rongsong Ling, Bokai Yun, Jiaxiang Xie, Linlin Ren, Yaqi Huang, Wenjin Wang, Chen Yi, Ming Zhang, Xiuyun Xu, Caihua Zhang, Bin Zou, Leitao Zhang, Xiqiang Liu, Hongzhang Huang, Demeng Chen, Wei Cao, Cheng Wang
Journal: International Journal of Oral Science (2024)

Abstract Ameloblastoma is a benign tumor characterized by locally invasive phenotypes, leading to facial bone destruction and a high recurrence rate. However, the mechanisms governing tumor initiation and recurrence are poorly understood. Here, we uncovered cellular landscapes and mechanisms that underlie tumor recurrence in ameloblastoma at single-cell resolution. Our results revealed that ameloblastoma exhibits five tumor subpopulations varying with respect to immune response (IR), bone remodeling (BR), tooth development (TD), epithelial development (ED), and cell cycle (CC) signatures. Of note, we found that CC ameloblastoma cells were endowed with stemness and contributed to tumor recurrence, which was dominated by the EZH2-mediated program. Targeting EZH2 effectively eliminated CC ameloblastoma cells and inhibited tumor growth in ameloblastoma patient-derived organoids. These data described the tumor subpopulation and clarified the identity, function, and regulatory mechanism of CC ameloblastoma cells, providing a potential therapeutic target for ameloblastoma.
ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice
Authors: Kristen H. Schuster, Annie J. Zalon, Danielle M. DiFranco, Alexandra F. Putka, Nicholas R. Stec, Sabrina I. Jarrah, Arsal Naeem, Zaid Haque, Hanrui Zhang, Yuanfang Guan, Hayley S. McLoughlin
Journal: Molecular Therapy (2024)
Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa
Authors: Chun Hang Lau, Maral J. Rouhani, Elizabeth F. Maughan, Jessica C. Orr, Krishna K. Kolluri, David R. Pearce, Elizabeth K. Haughey, Liam Sutton, Sam Flatau, Pablo Lopez Balboa, Maria Laura Bageta, Christopher O’Callaghan, Claire M. Smith, Sam M. Janes, Richard Hewitt, Gabriela Petrof, Anna E. Martinez, John A. McGrath, Colin R. Butler, Robert E. Hynds
Journal: Molecular Therapy (2024)

The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom's national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3 encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wild-type LAMA3 expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. In vitro lentiviral overexpression of LAMA3A in EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof of concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB. The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom's national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3 encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wild-type LAMA3 expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. In vitro lentiviral overexpression of LAMA3A in EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof of concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB.
Dynamic Prediction of Advanced Colorectal Neoplasia in Inflammatory Bowel Disease
Authors: Anouk M. Wijnands, Bas B.L. Penning de Vries, Maurice W.M.D. Lutgens, Zeinab Bakhshi, Ibrahim Al Bakir, Laurent Beaugerie, Charles N. Bernstein, Ryan Chang-ho Choi, Nayantara Coelho-Prabhu, Trevor A. Graham, Ailsa L. Hart, Joren R. ten Hove, Steven H. Itzkowitz, Julien Kirchgesner, Erik Mooiweer, Seth R. Shaffer, Shailja C. Shah, Sjoerd G. Elias, Bas Oldenburg, Adriaan A. van Bodegraven, Herma H. Fidder, Meike M.C. Hirdes, Frank Hoentjen, Jeroen M. Jansen, Nofel Mahmmod, Andrea E. van der Meulen-de Jong, Cyriel Y. Ponsioen, Fiona D.M. van Schaik, C. Janneke van der Woude
Journal: Clinical Gastroenterology and Hepatology (2024)

Background & AimsColonoscopic surveillance is recommended in patients with colonic inflammatory bowel disease (IBD) given their increased risk of colorectal cancer (CRC). We aimed to develop and validate a dynamic prediction model for the occurrence of advanced colorectal neoplasia (aCRN, including high-grade dysplasia and CRC) in IBD.MethodsWe pooled data from 6 existing cohort studies from Canada, The Netherlands, the United Kingdom, and the United States. Patients with IBD and an indication for CRC surveillance were included if they underwent at least 1 follow-up procedure. Exclusion criteria included prior aCRN, prior colectomy, or an unclear indication for surveillance. Predictor variables were selected based on the literature. A dynamic prediction model was developed using a landmarking approach based on Cox proportional hazard modeling. Model performance was assessed with Harrell's concordance-statistic (discrimination) and by calibration curves. Generalizability across surveillance cohorts was evaluated by internal–external cross-validation.ResultsThe surveillance cohorts comprised 3731 patients, enrolled and followed-up in the time period from 1973 to 2021, with a median follow-up period of 5.7 years (26,336 patient-years of follow-up evaluation); 146 individuals were diagnosed with aCRN. The model contained 8 predictors, with a cross-validation median concordance statistic of 0.74 and 0.75 for a 5- and 10-year prediction window, respectively. Calibration plots showed good calibration. Internal–external cross-validation results showed medium discrimination and reasonable to good calibration.ConclusionsThe new prediction model showed good discrimination and calibration, however, generalizability results varied. Future research should focus on formal external validation and relate predicted aCRN risks to surveillance intervals before clinical application.Graphical abstract
Dupilumab in patients with chronic spontaneous urticaria (LIBERTY-CSU CUPID): Two randomized, double-blind, placebo-controlled, phase 3 trials
Authors: Marcus Maurer, Thomas B. Casale, Sarbjit S. Saini, Moshe Ben-Shoshan, Ana M. Giménez-Arnau, Jonathan A. Bernstein, Akiko Yagami, Aleksandra Stjepanovic, Allen Radin, Heribert W. Staudinger, Naimish Patel, Nikhil Amin, Bolanle Akinlade, Chunpeng Fan, Deborah Bauer, George D. Yancopoulos, Kiran Patel, Leda P. Mannent, Elizabeth Laws
Journal: Journal of Allergy and Clinical Immunology (2024)

Graphical abstractAbstractBackgroundChronic spontaneous urticaria (CSU) is a chronic inflammatory disease characterized by recurrent pruritic wheals (hives) and/or angioedema. Patients with CSU could remain symptomatic despite standard-of-care H1 antihistamines (H1-AH) or anti-IgE (omalizumab) treatment. Dupilumab blocks IL-4/IL-13 signaling and is approved for multiple type 2/atopic indications.ObjectiveWe conducted two phase 3, randomized, placebo-controlled, double-blind trials comparing dupilumab with placebo in patients with symptomatic CSU despite H1-AH.MethodsIn LIBERTY-CSU CUPID Study A, patients were omalizumab-naive (n = 138, aged ≥6 years). In Study B, patients were omalizumab-intolerant/incomplete responders (n = 108, aged ≥12 years). The primary end point was either change from baseline over 7 days in the Urticaria Activity Score (UAS7) or Itch Severity Score (ISS7) at week 24, with the other as a key secondary end point, depending on regional regulatory requirements. Studies were pooled for safety assessment.ResultsIn Study A, UAS7 and ISS7 improved with dupilumab versus placebo (difference −8.5 [95% CI, −13.2 to −3.9; P = .0003] and −4.2 [95% CI, −6.6 to −1.8; P = .0005]). In Study B, tested at α = 0.043 after interim analysis, UAS7 improved (difference −5.8 [95% CI, −11.4 to −0.3; P = .0390]), with a numerical trend in ISS7 (difference −2.9 [95% CI, −5.7 to −0.07; nominal P = .0449, not significant]). Pooled safety data were consistent between dupilumab and placebo and with the known dupilumab safety profile.ConclusionsDupilumab reduced urticaria activity by reducing itch and hives severity in omalizumab-naive patients with CSU uncontrolled with H1-AH. Although the primary end point for Study B was not met, dupilumab effects were small in patients who were omalizumab-intolerant/incomplete responders.
Improved Risk-Stratification Scheme for Mismatch-Repair Proficient Stage II Colorectal Cancers Using the Digital Pathology Biomarker QuantCRC
Authors: Christina Wu, Reetesh K. Pai, Heidi Kosiorek, Imon Banerjee, Ashlyn Pfeiffer, Catherine E. Hagen, Christopher P. Hartley, Rondell P. Graham, Mohamad B. Sonbol, Tanios Bekaii-Saab, Hao Xie, Frank A. Sinicrope, Bhavik Patel, Thomas Westerling-Bui, Sameer Shivji, James Conner, Carol Swallow, Paul Savage, David P. Cyr, Richard Kirsch, Rish K. Pai
Journal: Clinical Cancer Research (2024)

Abstract Purpose: There is a need to improve current risk stratification of stage II colorectal cancer to better inform risk of recurrence and guide adjuvant chemotherapy. We sought to examine whether integration of QuantCRC, a digital pathology biomarker utilizing hematoxylin and eosin–stained slides, provides improved risk stratification over current American Society of Clinical Oncology (ASCO) guidelines. Experimental Design: ASCO and QuantCRC-integrated schemes were applied to a cohort of 398 mismatch-repair proficient (MMRP) stage II colorectal cancers from three large academic medical centers. The ASCO stage II scheme was taken from recent guidelines. The QuantCRC-integrated scheme utilized pT3 versus pT4 and a QuantCRC-derived risk classification. Evaluation of recurrence-free survival (RFS) according to these risk schemes was compared using the log-rank test and HR. Results: Integration of QuantCRC provides improved risk stratification compared with the ASCO scheme for stage II MMRP colorectal cancers. The QuantCRC-integrated scheme placed more stage II tumors in the low-risk group compared with the ASCO scheme (62.5% vs. 42.2%) without compromising excellent 3-year RFS. The QuantCRC-integrated scheme provided larger HR for both intermediate-risk (2.27; 95% CI, 1.32–3.91; P = 0.003) and high-risk (3.27; 95% CI, 1.42–7.55; P = 0.006) groups compared with ASCO intermediate-risk (1.58; 95% CI, 0.87–2.87; P = 0.1) and high-risk (2.24; 95% CI, 1.09–4.62; P = 0.03) groups. The QuantCRC-integrated risk groups remained prognostic in the subgroup of patients that did not receive any adjuvant chemotherapy. Conclusions: Incorporation of QuantCRC into risk stratification provides a powerful predictor of RFS that has potential to guide subsequent treatment and surveillance for stage II MMRP colorectal cancers.