tbuckley/cabot-search huggingface dataset:
Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis
Authors: A Schmidt, M H Davidson, M Ditmarsch, J J Kastelein, C Finan
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): New Amterdam Pharma Background Elevated levels of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia. Methods Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (µg/mL) on plasma lipids, cardiovascular disease, Lewy body dementia (LBD), as well as Parkinson’s dementia. Replication was sought by performed Apo-A1 and Apo-B weighted MR analyses of CETP variants. Genetic associations with protein expression in cerebrospinal fluid (CSF) and brain were consulted to identify potential associations of plasma CETP with dementia implicated proteins. Results MR analysis of lower CETP concentration (per µg/mL) recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on CHD (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96); Figure. Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson’s dementia risk (OR 0.26, 95%CI 0.14; 0.48). APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE-ε4+ participants (OR 0.61 95%CI 0.51; 0.73), compared to APOE-ε4- (OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81×10-4. The aforementioned associations were replicated using Apo-B and Apo-A1 weighted analyses; Figure. Additionally, MR was employed to link plasma CETP concentration to the levels of CSF and brain proteins such as EPHA2 and CSF-1, which are in development as dementia drug targets. Conclusion These results suggest that inhibition of CETP may be a viable strategy to treat dementia.
AAV-mediated gene delivery to the cardiac conduction system
Authors: T Jonker, A R Boender, M Klerk, P Barnett, A A F De Vries, V M Christoffels, G J J Boink
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NWO open technology program Biopace #18485 Background Gene therapy for cardiac arrhythmias has so far mostly focused on modifying the arrhythmogenic substrate in working myocardium or on creating biological pacemakers with viral vectors that did not selectively target the cardiac conduction system (CCS). As a result, CCS targeting by viral vectors is a relatively unexplored area. Aim In the current project, we explored the basic requirements for CCS targeting using adeno-associated virus (AAV) vectors. Methods Regular AAV9 and AAV-Myo4A capsid-pseudotyped AAV2 vectors (hereafter called AAV2/9 and AAV2/Myo4A vectors, respectively) expressing enhanced green fluorescent protein (eGFP) from a CMV or TNNT2 promoter, respectively, and an AAV2/9 vector expressing eGFP from a human GJA5 regulatory element were systemically injected in mice. After 4 weeks, hearts were harvested, fixed with paraformaldehyde and stained for TNNT2, eGFP, HCN4 and DNA to determine CCS transduction. Results Transduction of the sinoatrial and atrioventricular (AV) node using AAV2/9 vectors was very poor, while transduction was visible in the atrioventricular (i.e. His) bundle and working myocardium. In contrast, the transduction rate of the AV node and bundle using AAV2/Myo4A vectors were similar to that of the working myocardium. The human GJA5 regulatory element was able to restrict eGFP expression by AAV2/9 vectors to the AV bundle in 2/3 animals but the transduction efficiency was low. A third animal showed no transduction of any tissue, either indicative of the low transduction efficiency or of a failed injection. Conclusion This study not only provides proof-of-principle for CCS-targeted gene therapy but also shows that CCS transduction can be improved through AAV capsid engineering and be restricted to (parts of) the CCS by using specific transcriptional control elements.
Early biomarkers of disease in hypertrophic cardiomyopathy: does telomere length matter?
Authors: A Judez Serrano, S Louchachha Medhi, S E M Munteanu, M E Nicolas Rocamora, M Sabater Molina, J R Gimeno Blanes
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Biomedical Research Institute of Murcia (IMIB-Arrixaca) Introduction Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden death in people under 35 years of age. (1) The variability of the phenotype together with its incomplete penetrance has been an obstacle to a complete understanding of the clinical spectrum and consequences of the disease. In recent years, there has been increasing interest in telomeric shortening and several authors have linked it to age-related diseases and HCM. (2, 3) Our aim was to study whether telomere length could affect the age at presentation and the severity of the HCM phenotype in genetic carriers. Methods Measurement of telomere length in circulating leukocytes (LTLc) was performed in 96 patients carrying a mutation in MYBPC3 causing HCM [58 affected (24 severely affected), 38 unaffected]. The variants included were c.2308+1G&amp;gt;A, p.Pro108Alafs*9, p.Arg891Alafs*160 and p.Glu258Lys, all considered founder mutations in our region. Peripheral venous blood samples were obtained from patients at the Inherited Heart Diseases Unit and stored at -80 ºC after informed consent had been signed by all participants. For telomere length analysis, a telomeric restriction fragment (TRF) assay was performed using the TeloTAGGGTelomereLenghtAssay kit (Roche, 12209136001) according to the manufacturer's protocol with slight modifications. Results Our results show a lower LTLc in those affected patients with a more severe HCM phenotype compared to the affected and unaffected group (p=0.023) independently of age and sex, which are two variables that affect LTLc. Similarly, a shorter telomere length was associated with greater severity of the phenotype, with patients presenting a larger left atrial size (p=0.032), septal size (p=0.023) and greater obstruction (p=0.044). The presence of atrial fibrillation (p=0.039) and sudden death (p=0.024) was also higher in patients with shorter telomeres. Conclusions Telomere length is a variable that influences the expression of the phenotype in HCM patients carrying a MYBPC3 variant. This is an observation that supports the thesis of numerous publications linking HCM and other age-related diseases, sometimes called telomeropathies,(2) to telomere shortening. It has also been linked to non-hereditary conditions(3). This fact sheds some light on the complex phenotypic variability present in HCM, raising LTL as a promising prognostic biomarker of the disease, as has already been suggested by other authors.(4, 5, 6).Workflow in the telomere legth analysisClinical associations of LTLc
Whole-genome Mutational Analysis for Tumor-informed Detection of Circulating Tumor DNA in Patients with Urothelial Carcinoma
Authors: Iver Nordentoft, Sia Viborg Lindskrog, Karin Birkenkamp-Demtröder, Santiago Gonzalez, Maja Kuzman, Jurica Levatic, Dunja Glavas, Ryan Ptashkin, James Smadbeck, Danielle Afterman, Tomer Lauterman, Yarin Cohen, Zohar Donenhirsh, Iman Tavassoly, Ury Alon, Amanda Frydendahl, Mads Heilskov Rasmussen, Claus Lindbjerg Andersen, Philippe Lamy, Michael Knudsen, Paz Polak, Asaf Zviran, Boris Oklander, Mads Agerbæk, Jørgen Bjerggaard Jensen, Lars Dyrskjøt
Journal: European Urology (2024)

Circulating tumor DNA (ctDNA) can be used for sensitive detection of minimal residual disease (MRD). However, the probability of detecting ctDNA in settings of low tumor burden is limited by the number of mutations analyzed and the plasma volume available. We used a whole-genome sequencing (WGS) approach for ctDNA detection in patients with urothelial carcinoma.
Prognostic scores for ursodeoxycholic acid-treated patients predict graft loss and mortality in recurrent primary biliary cholangitis after liver transplantation
Authors: Aldo J Montano-Loza, Ellina Lytvyak, Gideon Hirschfield, Bettina E Hansen, Maryam Ebadi, Thierry Berney, Christian Toso, Giulia Magini, Alejandra Villamil, Frederik Nevens, Natalie Van den Ende, Albert Pares, Pablo Ruiz, Débora Terrabuio, Palak J Trivedi, Nadir Abbas, Maria Francesca Donato, Lei Yu, Charles Landis, Jérôme Dumortier, Jessica Katharine Dyson, Adriaan J van der Meer, Rozanne de Veer, Mark Pedersen, Marlyn Mayo, Michael P Manns, Richard Taubert, Theresa Kirchner, Luca S Belli, Chiara Mazzarelli, Guido Stirnimann, Annarosa Floreani, Nora Cazzagon, Francesco Paolo Russo, Patrizia Burra, Udi Zigmound, Inbal Houri, Marco Carbone, Giacomo Mulinacci, Stefano Fagiuoli, Daniel Stephan Pratt, Alan Bonder, Thomas D Schiano, Brandy Haydel, Ansgar Lohse, Christoph Schramm, Darius Rüther, Stefania Casu, Xavier Verhelst, Benedetta Terziroli Beretta-Piccoli, Mercedes Robles, Andrew L Mason, Christophe Corpechot
Journal: Journal of Hepatology (2024)

Background/aim: Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT).There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC.We evaluated a large, international, multi-center cohort to assess the performance of scores for PBC to predict the risk of graft and overall survival after LT in patients with rPBC.Methods: A total of 332 patients with rPBC after LT were evaluated from 28 centres across Europe, North and South America.The median age at the time of rPBC was 58.0 years [IQR 53.2 -62.6], and 298 patients (90%) were females.The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation.Results: During a median follow-up of 8.7 years .9]after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died.After 1 year of UDCA initiation the histological stage at rPBC (HR, 3.97, P=0.01), use of prednisone (HR 3.18, 95%CI 1.04-9.73,P=0.04), ALP xULN (HR 1.59, 95%CI 1.26-2.01,P<0.001), Paris-2 criteria (HR 4.14, 95%CI 1.57-10.92,P=0.004), GLOBE score (HR 2.82, 95%CI 1.71-4.66,P<0.001), and the UK-PBC score (HR 1.06, 95%CI 1.03-1.09,P<0.001) were associated with graft survival in the multivariate analysis.Similar results were found in the overall survival analysis. Conclusion:Patients with rPBC and disease activity as indicated by standard PBC risk scores have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pretransplant PBC.
DNA-binding protein-A promotes kidney ischemia/reperfusion injury and participates in mitochondrial function
Authors: Charlotte Reichardt, Sabine Brandt, Anja Bernhardt, Anna Krause, Jonathan A. Lindquist, Sönke Weinert, Robert Geffers, Tobias Franz, Sascha Kahlfuss, Anne Dudeck, Akash Mathew, Rajiv Rana, Berend Isermann, Peter R. Mertens
Journal: Kidney International (2024)

DNA-binding protein-A (DbpA; gene: Ybx3) belongs to the cold shock protein family with known functions in cell cycling, transcription, translation, and tight junction communication. In chronic nephritis, DbpA is upregulated. However, its activities in acute injury models, such as kidney ischemia/reperfusion injury (IRI), are unclear. To study this, mice harboring Ybx3+/+, Ybx3+/- or the Ybx3-/- genotype were characterized over 24 months and following experimental kidney IRI. Mitochondrial function, number and integrity were analyzed by mitochondrial stress tests, MitoTracker staining and electron microscopy. Western Blot, immunohistochemistry and flow cytometry were performed to quantify tubular cell damage and immune cell infiltration. DbpA was found to be dispensable for kidney development and tissue homeostasis under healthy conditions. Furthermore, endogenous DbpA protein localizes within mitochondria in primary tubular epithelial cells. Genetic deletion of Ybx3 elevates the mitochondrial membrane potential, lipid uptake and metabolism, oxygen consumption rates and glycolytic activities of tubular epithelial cells. Ybx3-/- mice demonstrated protection from IRI with less immune cell infiltration, endoplasmic reticulum stress and tubular cell damage. A presumed protective mechanism was identified via upregulated antioxidant activities and reduced ferroptosis, when Ybx3 was deleted. Thus, our studies reveal DbpA acts as a mitochondrial protein with profound adverse effects on cell metabolism and highlights a protective effect against IRI when Ybx3 is genetically deleted. Hence, preemptive DbpA targeting in situations with expected IRI, such as kidney transplantation or cardiac surgery, may preserve post-procedure kidney function.
Enduring Clinical Remission in Refractory Celiac Disease Type II with Tofacitinib: An Open-Label Clinical Study
Authors: Tessa Dieckman, Michael Schumann, Hanneke Beaumont, Hetty J Bontkes, Frits Koning, Gerd Bouma
Journal: Clinical Gastroenterology and Hepatology (2024)

Refractory celiac disease type 2 (RCDII) is a rare condition with high mortality because of a lack of effective treatment strategies. RCDII is caused by clonal expansion of intraepithelial lymphocytes (IELs). Gain-of-function JAK1 mutations are frequently found in these cells.
Safety, dosimetry, and efficacy of an optimized long-acting somatostatin analog for peptide receptor radionuclide therapy in metastatic neuroendocrine tumors: From preclinical testing to first-in-human study
Authors: Wei Guo, Xuejun Wen, Yuhang Chen, Tianzhi Zhao, Jia Liu, Yucen Tao, Hao Fu, Hongjian Wang, Weizhi Xu, Yizhen Pang, Liang Zhao, Jingxiong Huang, Pengfei Xu, Zhide Guo, Weibing Miao, Jingjing Zhang, Xiaoyuan Chen, Haojun Chen
Journal: Acta Pharmaceutica Sinica B (2024)

Peptide receptor radionuclide therapy (PRRT) with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors (NETs). Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue (denoted as 177Lu-EB-TATE) is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs. This study aimed to enhance the in vivo stability, pharmacokinetics, and pharmacodynamics of 177Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain, resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical, 177Lu-LNC1010, for PRRT. In preclinical studies, 177Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts. Thereafter, we presented the first-in-human dose escalation study of 177Lu-LNC1010 in patients with advanced/metastatic NETs. 177Lu-LNC1010 was well-tolerated by all patients, with minor adverse effects, and exhibited significant uptake and prolonged retention in tumor lesions, with higher tumor radiation doses than those of 177Lu-EB-TATE. Preliminary PRRT efficacy results showed an 83% disease control rate and a 42% overall response rate after two 177Lu-LNC1010 treatment cycles. These encouraging findings warrant further investigations through multicenter, prospective, and randomized controlled trials.
Signaling through cAMP-Epac1 induces metabolic reprogramming to protect podocytes in glomerulonephritis
Authors: Lilia Abbad, Maximin Détrait, Panagiotis Kavvadas, Dorian Bergonnier, Lisa Melis, Marion Laudette, Tiffany Migeon, Marie-Christine Verpont, Alexandre Lucas, Christos Chatziantoniou, Frank Lezoualc’h
Journal: Kidney International (2024)
Saliva antibody profiles are associated with reaction threshold and severity of peanut allergic reactions
Authors: Hsi-en Ho, Zoe Arditi, Lin Radigan, Galina Grishina, Lingdi Zhang, Yoojin Chun, Tracy Lo, Julie Wang, Scott Sicherer, Supinda Bunyavanich
Journal: Journal of Allergy and Clinical Immunology (2024)
Senescence-targeted MicroRNA/Organoid composite hydrogel repair cartilage defect and prevention joint degeneration via improved chondrocyte homeostasis
Authors: Ye Sun, Yongqing You, Qiang Wu, Rui Hu, Kerong Dai
Journal: Bioactive Materials (2024)

Cartilage defect (CD) is a common complication in osteoarthritis (OA). Impairment of chondrogenesis and cellular senescence are considered as hallmarks of OA development and caused failure of cartilage repair in most clinical CD cases. Exploring markers for cellular senescence in CD patients might provide new perspectives for osteoarthritic CD patients. In the present study, we aim to explore senescent markers in CD patients with OA to fabricate a senescence-targeted SMSC organoid hydrogel for cartilage repair.
Induced CD8α identifies human NK cells with enhanced proliferative fitness and modulates NK cell activation
Authors: Celia C Cubitt, Pamela Wong, Hannah K Dorando, Jennifer A Foltz, Jennifer Tran, Lynne Marsala, Nancy D Marin, Mark Foster, Timothy Schappe, Hijab Fatima, Michelle Becker-Hapak, Alice Y Zhou, Kimberly Hwang, Miriam T Jacobs, David A Russler-Germain, Emily M Mace, Melissa M Berrien-Elliott, Jacqueline E Payton, Todd A Fehniger
Journal: Journal of Clinical Investigation (2024)

The surface receptor CD8α is present on 20%-80% of human (but not mouse) NK cells, yet its function on NK cells remains poorly understood. CD8α expression on donor NK cells was associated with a lack of therapeutic responses in patients with leukemia in prior studies, thus, we hypothesized that CD8α may affect critical NK cell functions. Here, we discovered that CD8α- NK cells had improved control of leukemia in xenograft models compared with CD8α+ NK cells, likely due to an enhanced capacity for proliferation. Unexpectedly, we found that CD8α expression was induced on approximately 30% of previously CD8α- NK cells following IL-15 stimulation. These induced CD8α+ (iCD8α+) NK cells had the greatest proliferation, responses to IL-15 signaling, and metabolic activity compared with those that sustained existing CD8α expression (sustained CD8α+) or those that remained CD8α- (persistent CD8α-). These iCD8α+ cells originated from an IL-15Rβhi NK cell population, with CD8α expression dependent on the transcription factor RUNX3. Moreover, CD8A CRISPR/Cas9 deletion resulted in enhanced responses through the activating receptor NKp30, possibly by modulating KIR inhibitory function. Thus, CD8α status identified human NK cell capacity for IL-15-induced proliferation and metabolism in a time-dependent fashion, and its presence had a suppressive effect on NK cell-activating receptors.
Neoadjuvant dalpiciclib, exemestane, and goserelin in premenopausal women with HR-positive, HER2-negative breast cancer: A prospective, multicenter, randomized two-group, non-controlled phase 2 clinical trial.
Authors: Zhengjun Yang, Xin Wang, Aoxiang Chen, Ran Meng, Ying Zhao, Hong Liu, Jie Ge, Ruixue Huang, Jianping Bai, Xucheng Cao
Journal: Journal of Clinical Oncology (2024)

TPS625 Background: The combination of CDK4/6 inhibitors (CDK4/6i) with endocrine therapy has significantly improved progression-free survival and overall survival in patients with HR-positive, HER2-negative advanced breast cancer (BC), revolutionizing the treatment landscape. However, previous CDK4/6i neoadjuvant studies have predominantly focused on postmenopausal populations, leaving a gap in preoperative treatment for early HR-positive, HER2-negative premenopausal BC patients. Therefore, the present trial is conducted to investigate the efficacy of dalpiciclib, exemestane and goserelin as neoadjuvant therapy in premenopausal women with HR-positive, HER2-negative BC. Methods: This is a multicenter, randomized two-group, non-controlled phase 2 clinical trial. Key eligibility criteria include: Patients aged 18 years or older with no prior treatment, an ECOG performance status of 0-1, at least 1 measurable lesion, and clinical stage II-III HR-positive, HER2-negative premenopausal invasive BC. Initially, all enrolled patients will receive two cycles of treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC). Subsequently, patients with complete response (CR) or partial response (PR) will receive an additional four cycles of TAC, whereas patients with progressive disease (PD) will undergo surgery or treatment options decided upon by the investigators. Those with stable disease (SD) will be randomly assigned 1:1 to either an experimental group receiving 16 weeks of dalpiciclib, exemestane, and goserelin (dalpiciclib: 125 mg daily for 21 days followed by 7 days off, exemestane: 25 mg daily for 28 days, goserelin: 3.6 mg every 28 days) or a standard chemotherapy group receiving four more cycles of TAC. Treatment response is assessed according to RECIST 1.1 criteria. Surgery will be performed after completion of the planned neoadjuvant treatment, followed by radiation therapy and systemic treatment according to local guidelines or the investigators' choices. The study's primary endpoint is the objective response rate (ORR) of the experimental group. Secondary endpoints include the ORR, residual cancer burden, preoperative endocrine prognostic index, event-free survival, and safety of both. Using Simon's two-stage optimal design and assuming a 40% response rate as desirable in the experimental group, at least 13 responses among a total of 43 patients were required to meet the primary endpoint. The trial will be terminated if fewer than 3 patients respond in the first stage. Considering an 80% SD rate post two neoadjuvant TAC cycles and a 10% attrition, the sample size was ultimately set at 119. The trial is actively recruiting. Clinical trial information: NCT06009627 .
VPAC2 Receptor Signaling Promotes Growth and Immunosuppression in Pancreatic Cancer
Authors: Tenzin Passang, Shuhua Wang, Hanwen Zhang, Fanyuan Zeng, Po-Chih Hsu, Wenxi Wang, Jian-Ming Li, Yuan Liu, Sruthi Ravindranathan, Gregory B. Lesinski, Edmund K. Waller
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) harbors a complex tumor microenvironment, and cross-talk among cells in the tumor microenvironment can contribute to drug resistance and relapse. Vasoactive intestinal peptide (VIP) is overexpressed in PDAC, and VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to immunotherapy. In this study, we showed that pancreatic cancer cells engage in autocrine VIP signaling through VIP receptor 2 (VPAC2). High coexpression of VIP with VPAC2 correlated with reduced relapse-free survival in patients with PDAC. VPAC2 activation in PDAC cells upregulated Piwi-like RNA-mediated gene silencing 2, which stimulated cancer cell clonogenic growth. In addition, VPAC2 signaling increased expression of TGFβ1 to inhibit T-cell function. Loss of VPAC2 on PDAC cells led to reduced tumor growth and increased sensitivity to anti-PD-1 immunotherapy in mouse models of PDAC. Overall, these findings expand our understanding of the role of VIP/VPAC2 signaling in PDAC and provide the rationale for developing potent VPAC2-specific antagonists for treating patients with PDAC. Significance: Autocrine VIP signaling via VPAC2 promotes cancer cell growth and inhibits T-cell function in pancreatic ductal adenocarcinoma, highlighting its potential as a therapeutic target to improve pancreatic cancer treatment.