tbuckley/cabot-search huggingface dataset:
Histone demethylase KDM5 regulates cardiomyocyte maturation by promoting fatty acid oxidation, oxidative phosphorylation, and myofibrillar organization
Authors: Manisha Deogharia, Leslye Venegas-Zamora, Akanksha Agrawal, Miusi Shi, Abhinav K Jain, Kevin J McHugh, Francisco Altamirano, Ali J Marian, Priyatansh Gurha
Journal: Cardiovascular Research (2024)

Human pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) provide a platform to identify and characterize factors that regulate the maturation of CMs. The transition from an immature foetal to an adult CM state entails coordinated regulation of the expression of genes involved in myofibril formation and oxidative phosphorylation (OXPHOS) among others. Lysine demethylase 5 (KDM5) specifically demethylates H3K4me1/2/3 and has emerged as potential regulators of expression of genes involved in cardiac development and mitochondrial function. The purpose of this study is to determine the role of KDM5 in iPSC-CM maturation.
Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma
Authors: Frederick L. Locke, Simone Filosto, Justin Chou, Saran Vardhanabhuti, Regis Perbost, Peter Dreger, Brian T. Hill, Catherine Lee, Pier L. Zinzani, Nicolaus Kröger, Armando López-Guillermo, Hildegard Greinix, Wangshu Zhang, Gayatri Tiwari, Justin Budka, Francesco M. Marincola, Christina To, Mike Mattie, Marco Schupp, Paul Cheng, Adrian Bot, Rhine Shen, Davide Bedognetti, Harry Miao, Jérôme Galon
Journal: Nature Medicine (2024)

Abstract The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel ( P = 0.0002 for B cell GES; P = 0.0165 for CD19 expression) but not SOC ( P = 0.9374 for B cell GES; P = 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression ( P = 8.56 × 10 –9 for B cell GES high; P = 0.0019 for B cell GES low; P = 3.85 × 10 –9 for CD19 gene high; P = 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.
Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma
Authors: Yuna Kim, Kwan-Young Jung, Yun Hak Kim, Pan Xu, Baeki E. Kang, Yunju Jo, Navin Pandit, Jeongho Kwon, Karim Gariani, Joanna Gariani, Junguee Lee, Jef Verbeek, Seungyoon Nam, Sung-Jin Bae, Ki-Tae Ha, Hyon-Seung Yi, Minho Shong, Kyun-Hwan Kim, Doyoun Kim, Hee Jung Jung, Chang-Woo Lee, Kwang Rok Kim, Kristina Schoonjans, Johan Auwerx, Dongryeol Ryu
Journal: Drug Resistance Updates (2024)

Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance.
Reply to the letter regarding the article ‘<scp>Head‐to‐head</scp> comparison between recommendations by the <scp>ESC</scp> and <scp>ACC</scp>/<scp>AHA</scp>/<scp>HFSA</scp> heart failure guidelines’
Authors: Antoni Bayes‐Genis, Alberto Aimo
Journal: European Journal of Heart Failure (2024)
Selected Articles from This Issue
Journal: Clinical Cancer Research (2024)

Highlights| January 17 2024 Selected Articles from This Issue Author & Article Information Online ISSN: 1557-3265 Print ISSN: 1078-0432 ©2024 American Association for Cancer Research2024American Association for Cancer Research Clin Cancer Res (2024) 30 (2): 253. https://doi.org/10.1158/1078-0432.CCR-30-2-HI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record January 17 2024 Citation Selected Articles from This Issue. Clin Cancer Res 15 January 2024; 30 (2): 253. https://doi.org/10.1158/1078-0432.CCR-30-2-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search The limited availability of HLA-matched donors prevents the use of allogeneic hematopoietic cell transplantation (HCT) for some patients with blood cancers. Alternative treatments with HLA-haploidentical donors can circumvent these limitations, but safe and effective approaches are still needed to prevent graft versus host disease (GVHD) and improve relapse rates. Within recent years, preparative regimens of radioimmunotherapy with 131I-coupled hematological-targeting monoclonal antibodies to deliver high doses of radiation have shown promise in improving patient response. In this phase I/II study, Orozco and colleagues assess the use of an 131I-conjugated BC8 antibody targeting CD45 (131I-BC8), combined with fludarabine, cyclophosphamide, and low-dose TBI conditioning prior to HLA-haploidentical HCT in adults with high-risk relapsed/refractory acute myeloid or lymphoid leukemia (AML or ALL), or myelodysplastic syndrome (MDS). The authors show that all patients achieved a morphologic remission 28 days after HCT, with only 8% of patients showing minimal residual disease. Probabilities... You do not currently have access to this content.
Choosing to End African American Health Disparities in Patients With Systemic Lupus Erythematosus
Authors: Matthew H. Liang, Edward R. Lew, Patricia A. Fraser, Cindy Flower, Edward H. Hennis, Sang‐Cheol Bae, Anselm Hennis, Mohammed Tikly, W. Neal Roberts
Journal: Arthritis & Rheumatology (2024)

Systemic lupus erythematosus (SLE) is three times more common and its manifestations are more severe in African American women compared to women of other races. It is not clear whether this is due to genetic differences or factors related to the physical or social environments, differences in health care, or a combination of these factors. Health disparities in patients with SLE between African American patients and persons of other races have been reported since the 1960s and are correlated with measures of lower socioeconomic status. Risk factors for these disparities have been demonstrated, but whether their mitigation improves outcomes for African American patients has not been tested except in self-efficacy. In 2002, the first true US population-based study of patients with SLE with death certificate records was conducted, which demonstrated a wide disparity between the number of African American women and White women dying from SLE. Five years ago, another study showed that SLE mortality rates in the United States had improved but that the African American patient mortality disparity persisted. Between 2014 and 2021, one study demonstrated racism's deleterious effects in patients with SLE. Racism may have been the unmeasured confounder, the proverbial "elephant in the room"-unnamed and unstudied. The etymology of "risk factor" has evolved from environmental risk factors to social determinants to now include structural injustice/structural racism. Racism in the United States has a centuries-long existence and is deeply ingrained in US society, making its detection and resolution difficult. However, racism being man made means Man can choose to change the it. Health disparities in patients with SLE should be addressed by viewing health care as a basic human right. We offer a conceptual framework and goals for both individual and national actions.
Preclinical evidence using synthetic compounds and natural products indicates that AMPK represents a potential pharmacological target for the therapy of pulmonary diseases
Authors: Chao Yang, Limor Rubin, Xiyong Yu, Philip Lazarovici, Wenhua Zheng
Journal: Medicinal Research Reviews (2024)

Abstract Adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK) is a highly conserved eukaryotic enzyme discovered as a key regulator of cellular energy homeostasis, with anti‐inflammation, antioxidative stress, anticancer, and antifibrosis beneficial effects. AMPK is dysregulated in human pulmonary diseases such as acute lung injury, nonsmall cell lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma. This review provides an overview of the beneficial role of natural, synthetic, and Chinese traditional medicines AMPK modulators in pulmonary diseases, and highlights the role of the AMPK signaling pathway in the lung, emphasizing the importance of finding lead compounds and drugs that can target and modulate AMPK to treat the lung diseases.
Tissue-resident macrophages exacerbate lung injury after remote sterile damage
Authors: Hanhui Zhong, Jingjing Ji, Jinling Zhuang, Ziying Xiong, Pengyun Xie, Xiaolei Liu, Jundi Zheng, Wangli Tian, Xiaoyang Hong, Jing Tang
Journal: Cellular and Molecular Immunology (2024)
INPP5A phosphatase is a synthetic lethal target in GNAQ and GNA11-mutant melanomas
Authors: Ahmed M. O. Elbatsh, Ali Amin-Mansour, Anne Haberkorn, Claudia Textor, Nicolas Ebel, Emilie Renard, Lisa M. Koch, Femke C. Groenveld, Michelle Piquet, Ulrike Naumann, David A. Ruddy, Vincent Romanet, Julia M. Martínez Gómez, Matthew D. Shirley, Peter Wipfli, Christian Schnell, Markus Wartmann, Martin Rausch, Martine J. Jager, Mitchell P. Levesque, Sauveur-Michel Maira, Eusebio Manchado
Journal: Nature Cancer (2024)

Abstract Activating mutations in GNAQ/GNA11 occur in over 90% of uveal melanomas (UMs), the most lethal melanoma subtype; however, targeting these oncogenes has proven challenging and inhibiting their downstream effectors show limited clinical efficacy. Here, we performed genome-scale CRISPR screens along with computational analyses of cancer dependency and gene expression datasets to identify the inositol-metabolizing phosphatase INPP5A as a selective dependency in GNAQ/11-mutant UM cells in vitro and in vivo. Mutant cells intrinsically produce high levels of the second messenger inositol 1,4,5 trisphosphate (IP3) that accumulate upon suppression of INPP5A, resulting in hyperactivation of IP3-receptor signaling, increased cytosolic calcium and p53-dependent apoptosis. Finally, we show that GNAQ/11-mutant UM cells and patients’ tumors exhibit elevated levels of IP4, a biomarker of enhanced IP3 production; these high levels are abolished by GNAQ/11 inhibition and correlate with sensitivity to INPP5A depletion. Our findings uncover INPP5A as a synthetic lethal vulnerability and a potential therapeutic target for GNAQ/11-mutant-driven cancers.
Age-related noncanonical TRMT6–TRMT61A signaling impairs hematopoietic stem cells
Authors: Hanqing He, Yuqian Wang, Xiaoting Zhang, Xiaoyu Li, Chao Liu, Dingfei Yan, Haiteng Deng, Wanling Sun, Chengqi Yi, Jianwei Wang
Journal: Nature Aging (2024)
cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment
Authors: Hongying Zhang, Yongliang Liu, Jieya Liu, Jinzhu Chen, Jiao Wang, Hui Hua, Yangfu Jiang
Journal: Journal of Hematology & Oncology (2024)

Cancer is a complex disease resulting from abnormal cell growth that is induced by a number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells and angiogenesis, plays a critical role in tumor progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME. The downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), exchange protein activated by cAMP (EPAC) and ion channels. While cAMP can activate PKA or EPAC and promote cancer cell growth, it can also inhibit cell proliferation and survival in context- and cancer type-dependent manner. Tumor-associated stromal cells, such as CAF and immune cells, can release cytokines and growth factors that either stimulate or inhibit cAMP production within the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits in cancer. Small-molecule agents that inhibit adenylate cyclase and PKA have been shown to inhibit tumor growth. In addition, cAMP-elevating agents, such as forskolin, can not only induce cancer cell death, but also directly inhibit cell proliferation in some cancer types. In this review, we summarize current understanding of cAMP signaling in cancer biology and immunology and discuss the basis for its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer will be critical for the development of effective therapies. Future studies aimed at investigating the cAMP-cancer axis and its regulation in the TME may provide new insights into the underlying mechanisms of tumorigenesis and lead to the development of novel therapeutic strategies.
Causes of sudden cardiac arrest and death and the diagnostic yield of sport preparticipation screening in children
Authors: Francesca Graziano, Maurizio Schiavon, Alberto Cipriani, Francesco Savalla, Monica De Gaspari, Barbara Bauce, Stefania Rizzo, Chiara Calore, Gaetano Thiene, Stefano Paiaro, Cristina Basso, Alessandro Zorzi
Journal: British Journal of Sports Medicine (2024)

Objective Evidence on the increased risk of sports-related sudden cardiac arrest and death (SCA/D) and the potential benefit of cardiovascular preparticipation screening (PPS) in children is limited. We assessed the burden and circumstances of SCA/D and the diagnostic yield of cardiovascular PPS in children aged 8–15 years. Methods Data on the incidence and causes of SCA/D from 2011 to 2020 were obtained from the Veneto region (Italy) sudden death registry, hospital records and local press. During the same period, we assessed the results of annual PPS in 25 251 young competitive athletes aged 8–15 years who underwent 58 185 evaluations (mean 2.3/athlete) in Padua, Italy. Results Over 10 years, 26 SCA/D occurred in children aged 8–15 years in the Veneto region: 6 in athletes (incidence 0.7/100 000/year, all ≥12 years) versus 20 in non-athletes (0.7/100 000/year, 17/20 ≥12 years). In total, 4/6 athletes versus 1/20 non-athletes survived. The cause of SCA/D remained unexplained in four athletes and in nine non-athletes. No athlete suffered SCA/D from structural diseases potentially identifiable by PPS. The incidence of SCA/D in athletes and non-athletes was 0.2/100 000/year in the 8–11 years group versus 1.3/100 000/year in the 12–15 years group. PPS identified 26 new diagnoses of cardiovascular diseases (CVDs) at risk of SCA/D, more often in children ≥12 years old (0.06%/evaluation) than &lt;12 years old (0.02%/evaluation, p=0.02). Among athletes with a negative PPS, two suffered unexplained SCA/D during follow-up, one during exercise. Conclusions In children aged 8–15 years, the incidence of SCA/D and the yield of PPS for identifying at-risk CVD were both substantially higher in those ≥12 years, suggesting that systematic PPS may be more useful beyond this age.
Pragmatic targets for moderate/severe SLE and their implications for clinical care and trial design: sustained DORIS or LLDAS for at least 6 months is sufficient while their attainment for at least 24 months ensures high specificity for damage-free progression
Authors: Sofia Pitsigavdaki, Myrto Nikoloudaki, Panagiotis Garantziotis, Ettore Silvagni, Argyro Repa, Antonio Marangoni, Irini Flouri, Nestor Avgoustidis, Konstantinos Parperis, Antonis Fanouriakis, Marcello Govoni, Prodromos Sidiropoulos, Dimitrios T Boumpas, Alessandra Bortoluzzi, George Bertsias
Journal: Annals of the Rheumatic Diseases (2024)

Objectives Treatment targets in systemic lupus erythematosus (SLE) have been validated in unselected—in terms of severity—cohorts, which limits their generalisability. We assessed remission (Definition of Remission in SLE (DORIS)) and Lupus Low Disease Activity State (LLDAS) in a historical cohort of 348 patients with active moderate-to-severe disease and median follow-up of 5 years. Methods Active SLE was defined as Physician Global Assessment ≥1.5 and/or SLE Disease Activity Index 2000 ≥6, requiring therapy intensification. DORIS/LLDAS, organ damage, flares and adverse events were monitored. Shared frailty survival, generalised linear models and K-means clustering were applied. Results Sustained DORIS and LLDAS for ≥6 months occurred in 41.1% and 80.4%, respectively, and resulted in reduced damage accrual (HR: 0.58; 95% CI 0.36 to 0.93 and 0.61; 0.43 to 0.86) and severe flares (HR: 0.14; 0.08 to 0.27 and 0.19; 0.13 to 0.27). LLDAS without DORIS was also protective (HR: 0.65; 0.43 to 0.98 for damage, 0.49; 0.36 to 0.67 for flares). Models fitting increasing duration of targets showed that DORIS ≥50% and LLDAS ≥60% of time, or alternatively, ≥24 and ≥36 months, achieved optimal balance between feasibility (20.2–41.7%) and specificity (73.3–86.1%) for damage-free outcome. These targets were linked to reduced serious adverse events (risk ratio (RR): 0.56–0.71), hospitalisation (RR: 0.70) and mortality (RR: 0.06–0.13). Patients with predominant arthritis and mucocutaneous disease experienced reduced DORIS/LLDAS, compared with counterparts with major organ involvement. Conventional drugs were more frequently used in the former group, whereas potent immunosuppressive/biological agents in the latter. Conclusions In moderate-to-severe SLE, sustained DORIS/LLDAS for at least 6 months is sufficient, while attainment for at least 24 months ensures higher specificity for damage-free progression, thus facilitating treat-to-target strategies and clinical trials. Arthritis and skin disease represent unmet therapeutic needs that could benefit from novel biologics.
Fibrosis in IBD: from pathogenesis to therapeutic targets
Authors: Florian Rieder, Pranab K Mukherjee, William J Massey, Yan Wang, Claudio Fiocchi
Journal: Gut (2024)

Background Intestinal fibrosis resulting in stricture formation and obstruction in Crohn’s disease (CD) and increased wall stiffness leading to symptoms in ulcerative colitis (UC) is among the largest unmet needs in inflammatory bowel disease (IBD). Fibrosis is caused by a multifactorial and complex process involving immune and non-immune cells, their soluble mediators and exposure to luminal contents, such as microbiota and environmental factors. To date, no antifibrotic therapy is available. Some progress has been made in creating consensus definitions and measurements to quantify stricture morphology for clinical practice and trials, but approaches to determine the degree of fibrosis within a stricture are still lacking. Objective We herein describe the current state of stricture pathogenesis, measuring tools and clinical trial endpoints development. Design Data presented and discussed in this review derive from the past and recent literature and the authors’ own research and experience. Results and conclusions Significant progress has been made in better understanding the pathogenesis of fibrosis, but additional studies and preclinical developments are needed to define specific therapeutic targets.
Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis
Authors: Can Cheng, Hanhui Yao, Heng Li, Jingwen Liu, Zhengyi Liu, Yang Wu, Liang Zhu, Hejie Hu, Zhengdong Fang, Liang Wu
Journal: Acta Pharmaceutica Sinica B (2024)

HMGA2, a pivotal transcription factor, functions as a versatile regulator implicated in the progression of diverse aggressive malignancies. In this study, mass spectrometry was employed to identify ubiquitin-specific proteases that potentially interact with HMGA2, and USP48 was identified as a deubiquitinating enzyme of HMGA2. The enforced expression of USP48 significantly increased HMGA2 protein levels by inhibiting its degradation, while the deprivation of USP48 promoted HMGA2 degradation, thereby suppressing tumor invasion and metastasis. We discovered that USP48 undergoes SUMOylation at lysine 258, which enhances its binding affinity to HMGA2. Through subsequent phenotypic screening of small molecules, we identified DUB-IN-2 as a remarkably potent pharmacological inhibitor of USP48. Interestingly, the small-molecule inhibitor targeting USP48 induces destabilization of HMGA2. Clinically, upregulation of USP48 or HMGA2 in cancerous tissues is indicative of poor prognosis for patients with colorectal cancer (CRC). Collectively, our study not only elucidates the regulatory mechanism of DUBs involved in HMGA2 stability and validates USP48 as a potential therapeutic target for CRC, but also identifies DUB-IN-2 as a potent inhibitor of USP48 and a promising candidate for CRC treatment.
The classical and non-classical axes of renin-angiotensin system in Parkinson disease: The bright and dark side of the moon
Authors: Hayder M. Al-kuraishy, Sadiq M. Al-Hamash, Majid S. Jabir, Ali I. Al-Gareeb, Ali K. Albuhadily, Salim Albukhaty, Ghassan M. Sulaiman
Journal: Ageing Research Reviews (2024)
Biomarkers associated with cognitive impairment in post-traumatic stress disorder: A systematic review of current evidence
Authors: Junling Guo, Vasiliki Orgeta, Isadora Olivé, Erik Hoff, Jonathan Huntley, Miranda Olff, Sjacko Sobczak
Journal: Ageing Research Reviews (2024)

This systematic review aimed at synthesizing current evidence on biomarkers associated with cognitive impairment (CI) in Post-Traumatic Stress Disorder (PTSD).
Misclassified Alcohol-related Liver Disease is Common in Presumed Metabolic Dysfunction-associated Steatotic Liver Disease and Highly Increases Risk for Future Cirrhosis
Authors: Patrik Nasr, Axel Wester, Mattias Ekstedt, Rickard Strandberg, Stergios Kechagias, Ying Shang, Linnea Widman, Hannes Hagström
Journal: Clinical Gastroenterology and Hepatology (2024)

Background and aims: Alcohol overconsumption is a risk factor for disease progression in patients with presumed metabolic dysfunction-associated steatotic liver disease (MASLD).How commonly this occurs and how it affects progression to major adverse liver outcomes (MALO) is not well known.Methods: We did a register-based cohort study, including all patients with a diagnosis of MASLD in Sweden between 1987 and 2020.Patients were stratified on cooccurrence of diagnoses of alcohol-related liver disease (ALD) or alcohol use disorder (AUD) prior to MASLD diagnosis.Incident MALO:s were derived from national registers.Cox regression was used to calculate hazard ratios for incident MALO.Results: A total of 15,107 patients with MASLD were identified.Median age was 55 years and 52% were female.1,843 (12%) had a prior diagnosis of ALD or AUD.During follow-up, a further 787 (5.2%) received a diagnosis of ALD or AUD.Patients with previous ALD or AUD diagnoses at or before baseline had considerably higher rates of MALO compared to patients without (19.5% vs 7.8%, aHR=3.12,95%CI=2.74-3.55).Acquiring an ALD or AUD diagnosis after MASLD diagnosis was associated with higher rates of MALO (aHR=5.81,.Conclusions: ALD or AUD is commonly diagnosed prior to or after MASLD diagnosis.Such patients have considerably higher rates of progression to MALO.Correctly separating between MASLD and ALD is vital to assess prognosis.