tbuckley/cabot-search huggingface dataset:
Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy
Authors: Yuexiao Tang, Tao Yao, Xin Tian, Xintong Xia, Xingxiao Huang, Zhewen Qin, Zhong Shen, Lin Zhao, Yaping Zhao, Bowen Diao, Yan Ping, Xiaoxiao Zheng, Yonghao Xu, Hui Chen, Tao Qian, Tao Ma, Ben Zhou, Suowen Xu, Qimin Zhou, Yong Liu, Mengle Shao, Wei Chen, Bo Shan, Ying Wu
Journal: The Journal of Experimental Medicine (2024)

Platinum-based chemotherapy drugs can lead to the development of anorexia, a detrimental effect on the overall health of cancer patients. However, managing chemotherapy-induced anorexia and subsequent weight loss remains challenging due to limited effective therapeutic strategies. Growth differentiation factor 15 (GDF15) has recently gained significant attention in the context of chemotherapy-induced anorexia. Here, we report that hepatic GDF15 plays a crucial role in regulating body weight in response to chemo drugs cisplatin and doxorubicin. Cisplatin and doxorubicin treatments induce hepatic Gdf15 expression and elevate circulating GDF15 levels, leading to hunger suppression and subsequent weight loss. Mechanistically, selective activation by chemotherapy of hepatic IRE1α-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1α is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1α as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1α RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.
Retraction Notice to: Precise editing of FGFR3-TACC3 fusion genes with CRISPR-Cas13a in glioblastoma
Authors: Ye Wu, Weili Jin, Qixue Wang, Junhu Zhou, Yunfei Wang, Yanli Tan, Xiaoteng Cui, Fei Tong, Eryan Yang, Jian Wang, Chunsheng Kang
Journal: Molecular Therapy (2024)
Human gut microbiota and their production of endocannabinoid-like mediators are directly affected by a dietary oil
Authors: Charlène Roussel, Mathilde Sola, Jacob Lessard-Lord, Nayudu Nallabelli, Pamela Généreux, Camille Cavestri, Oumaima Azeggouar Wallen, Rosaria Villano, Frédéric Raymond, Nicolas Flamand, Cristoforo Silvestri, Vincenzo Di Marzo
Journal: Gut Microbes (2024)

Dietary omega-3 polyunsaturated fatty acids (
Inhibition of fatty acid uptake by TGR5 prevents diabetic cardiomyopathy
Authors: Hu Wang, Jiaxing Wang, Hao Cui, Chenyu Fan, Yuzhou Xue, Huiying Liu, Hui Li, Jianping Li, Houhua Li, Ying Sun, Wengong Wang, Jiangping Song, Changtao Jiang, Ming Xu
Journal: Nature Metabolism (2024)
Sex differences in the prognostic role of achieving target doses of heart failure medications: Data from the Swedish Heart Failure Registry
Authors: Amerigo Ferrari, Davide Stolfo, Alicia Uijl, Nicola Orsini, Lina Benson, Gianfranco Sinagra, Peter Mol, Sieta T. de Vries, Ulf Dahlström, Giuseppe Rosano, Lars H. Lund, Gianluigi Savarese
Journal: European Journal of Heart Failure (2024)

Abstract Aims Guidelines recommend target doses (TD) of heart failure (HF) with reduced ejection fraction (HFrEF) medications regardless of sex. Differences in pharmacokinetics and pharmacodynamics may explain heterogeneity in treatment response, adverse reactions, and tolerability issues across sexes. The aim of this study was to explore sex‐based differences in the association between TD achievement and mortality/morbidity in HFrEF. Methods and results Patients with HFrEF and HF duration ≥6 months registered in the Swedish HF Registry between May 2000 and December 2020 (follow‐up until December 2021) were analysed. Treatments of interest were renin–angiotensin system inhibitors (RASI) or angiotensin receptor–neprilysin inhibitors (ARNI), and beta‐blockers. Multivariable Cox regression models were performed to explore the risk of cardiovascular mortality or hospitalization for HF across dose categories in females versus males. A total of 17 912 patients were analysed (median age 77.0 years, interquartile range [IQR] 70.0–83.0), 29% were female. Over a median follow‐up of 1.33 years (IQR 0.29–3.22), for RASI/ARNI there was no significant difference in outcome for females achieving 50–99% versus 100% of TD (hazard ratio 0.92, 95% confidence interval 0.83–1.03), whereas males showed a gradual lowering in risk together with the achievement of higher % of TD ( p ‐interaction = 0.030). For beta‐blockers the achievement of TD was associated with the lowest risk of outcome regardless of sex. Conclusions Our findings suggest that females and males might differently benefit from the same dose of RASI/ARNI, and do represent a general call for randomized controlled trials to consider sex‐specific up‐titration schemes when testing HFrEF treatments in need of up‐titration.
Transient pacing in pigs with complete heart block via myocardial injection of mRNA coding for the T-box transcription factor 18
Authors: David W. Wolfson, Nam Kyun Kim, Ki Hong Lee, Jared P. Beyersdorf, Jonathan J. Langberg, Natasha Fernandez, Dahim Choi, Nadine Zureick, Tae Yun Kim, Seongho Bae, Jin-Mo Gu, Jonathan L. Kirschman, Jinqi Fan, Christina Y. Sheng, Danielle Gottlieb Sen, Bret Mettler, Jung Hoon Sung, Young-sup Yoon, Sung-Jin Park, Philip J. Santangelo, Hee Cheol Cho
Journal: Nature Biomedical Engineering (2024)

The adenovirus-mediated somatic transfer of the embryonic T-box transcription factor 18 (TBX18) gene can convert chamber cardiomyocytes into induced pacemaker cells. However, the translation of therapeutic TBX18-induced cardiac pacing faces safety challenges. Here we show that the myocardial expression of synthetic TBX18 mRNA in animals generates de novo pacing and limits innate and inflammatory immune responses. In rats, intramyocardially injected mRNA remained localized, whereas direct myocardial injection of an adenovirus carrying a reporter gene resulted in diffuse expression and in substantial spillover to the liver, spleen and lungs. Transient expression of TBX18 mRNA in rats led to de novo automaticity and pacemaker properties and, compared with the injection of adenovirus, to substantial reductions in the expression of inflammatory genes and in activated macrophage populations. In rodent and clinically relevant porcine models of complete heart block, intramyocardially injected TBX18 mRNA provided rate-adaptive cardiac pacing for one month that strongly correlated with the animal's sinus rhythm and physical activity. TBX18 mRNA may aid the development of biological pacemakers.
Temporal dynamics and genomic programming of plasma cell fates
Authors: Godhev Kumar Manakkat Vijay, Ming Zhou, Kairavee Thakkar, Abigail Rothrauff, Amanpreet Singh Chawla, Dianyu Chen, Louis Chi-Wai Lau, Peter Habib Gerges, Kashish Chetal, Prabal Chhibbar, Jingyu Fan, Jishnu Das, Alok Joglekar, Lisa Borghesi, Nathan Salomonis, Heping Xu, Harinder Singh
Journal: Nature Immunology (2024)
Engineering Cell Instructive Microenvironments for In Vitro Replication of Functional Barrier Organs
Authors: Francesco Urciuolo, Giorgia Imparato, Paolo Antonio Netti
Journal: Advanced Healthcare Materials (2024)

Multicellular organisms exhibit synergistic effects among their components, giving rise to emergent properties crucial for their genesis and overall functionality and survival. Morphogenesis involves and relies upon intricate and biunivocal interactions among cells and their environment, that is, the extracellular matrix (ECM). Cells secrete their own ECM, which in turn, regulates their morphogenetic program by controlling time and space presentation of matricellular signals. The ECM, once considered passive, is now recognized as an informative space where both biochemical and biophysical signals are tightly orchestrated. Replicating this sophisticated and highly interconnected informative media in a synthetic scaffold for tissue engineering is unattainable with current technology and this limits the capability to engineer functional human organs in vitro and in vivo. This review explores current limitations to in vitro organ morphogenesis, emphasizing the interplay of gene regulatory networks, mechanical factors, and tissue microenvironment cues. In vitro efforts to replicate biological processes for barrier organs such as the lung and intestine, are examined. The importance of maintaining cells within their native microenvironmental context is highlighted to accurately replicate organ-specific properties. The review underscores the necessity for microphysiological systems that faithfully reproduce cell-native interactions, for advancing the understanding of developmental disorders and disease progression.
Ethnicity corrections in pulmonary function test reports: what to do?
Authors: Mike Hughes
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>Current opinions diverge about the need for corrections to lung volume prediction equations for people of non-European ancestry. This letter favours neither position at the present time, but recommends that "ethnic" corrections, if applied, must be stated.</b>https://bit.ly/4aAZwrV
Multitasking within the airway epithelium
Authors: James E. Gern, Carole Ober
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>The findings by Liu and co-workers demonstrate that GSDMB modifies virus-induced inflammatory responses, which may relate to how 17q12-q21 variants that increase GSDMB expression promote wheezing and childhood asthma</b> https://bit.ly/3tJskyv
Rifampicin has no role in treatment of<i>Mycobacterium avium</i>complex pulmonary disease and bactericidal sterilising drugs are needed: a viewpoint
Authors: Jakko van Ingen, Wouter Hoefsloot, Véronique Dartois, Thomas Dick
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>Rifampicin is used for the treatment of <i>Mycobacterium avium</i> complex pulmonary disease, but pharmacokinetic and pharmacodynamic studies suggest that rifampicin cannot have therapeutic utility. We need to find better alternatives, using PK-PD science.</b> https://bit.ly/3PUGvbV
Patient-derived follicular lymphoma spheroids recapitulate lymph node signaling and immune profile uncovering galectin-9 as a novel immunotherapeutic target
Authors: Cèlia Dobaño-López, Juan García Valero, Ferran Araujo-Ayala, Ferran Nadeu, Fabien Gava, Carla Faria, Marine Norlund, Renaud Morin, Pascale Bernes-Lasserre, Fabian Arenas, Marta Grau, Cristina López, Irene López-Oreja, Neus Serrat, Ares Martínez-Farran, Lluís Hernández, Heribert Playa-Albinyana, Rubén Giménez, Silvia Beà, Elías Campo, Jean-Michel Lagarde, Armando López-Guillermo, Laura Magnano, Dolors Colomer, Christine Bezombes, Patricia Pérez-Galán
Journal: Blood Cancer Journal (2024)

Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma, constitutes a paradigm of immune tumor microenvironment (TME) contribution to disease onset, progression, and heterogenous clinical outcome. Here we present the first FL-Patient Derived Lymphoma Spheroid (FL-PDLS), including fundamental immune actors and features of TME in FL lymph nodes (LNs). FL-PDLS is organized in disc-shaped 3D structures composed of proliferating B and T cells, together with macrophages with an intermediate M1/M2 phenotype. FL-PDLS recapitulates the most relevant B-cell transcriptional pathways present in FL-LN (proliferation, epigenetic regulation, mTOR, adaptive immune system, among others). The T cell compartment in the FL-PDLS preserves CD4 subsets (follicular helper, regulatory, and follicular regulatory), also encompassing the spectrum of activation/exhaustion phenotypes in CD4 and CD8 populations. Moreover, this system is suitable for chemo and immunotherapy testing, recapitulating results obtained in the clinic. FL-PDLS allowed uncovering that soluble galectin-9 limits rituximab, rituximab, plus nivolumab/TIM-3 antitumoral activities. Blocking galectin-9 improves rituximab efficacy, highlighting galectin-9 as a novel immunotherapeutic target in FL. In conclusion, FL-PDLS maintains the crosstalk between malignant B cells and the immune LN-TME and constitutes a robust and multiplexed pre-clinical tool to perform drug screening in a patient-derived system, advancing toward personalized therapeutic approaches.
Similar efficacy of ibrutinib arms across ALPINE and ELEVATE-RR trials in relapsed/refractory chronic lymphocytic leukemia: a matching-adjusted indirect comparison
Authors: Mazyar Shadman, Alessandra Tedeschi, Leyla Mohseninejad, Keri Yang, Nicole Lamanna, Sheng Xu, Aileen Cohen, Swetha Challagulla, Mei Xue, Rhys Williams, Susan M O'Brien, Jennifer R Brown, Constantine Tam
Journal: Blood Cancer Journal (2024)
Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension
Authors: Haiyang Tang, Akash Gupta, Seth A. Morrisroe, Changlei Bao, Tae-Hwi Schwantes-An, Geetanjali Gupta, Shuxin Liang, Yanan Sun, Aiai Chu, Ang Luo, Venkateswaran Ramamoorthi Elangovan, Shreya Sangam, Yinan Shi, Samisubbu R. Naidu, Jia-Rong Jheng, Sultan Ciftci-Yilmaz, Noel A. Warfel, Louise Hecker, Sumegha Mitra, Anna W. Coleman, Katie A. Lutz, Michael W. Pauciulo, Yen-Chun Lai, Ali Javaheri, Rohan Dharmakumar, Wen-Hui Wu, Daniel P. Flaherty, Jason H. Karnes, Sandra Breuils-Bonnet, Olivier Boucherat, Sebastien Bonnet, Jason X.-J. Yuan, Jeffrey R. Jacobson, Julio D. Duarte, William C. Nichols, Joe G.N. Garcia, Ankit A. Desai
Journal: Circulation (2024)

BACKGROUND: The ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1. METHODS: Tissues from animal pulmonary hypertension models as well as human pulmonary artery endothelial cells from patients with PAH exhibited increased vascular UCHL1 staining and protein expression. Exposure to LDN57444, a UCHL1-specific inhibitor, reduced human pulmonary artery endothelial cell and smooth muscle cell proliferation. Across 3 preclinical PAH models, LDN57444-exposed animals, Uchl1 knockout rats ( Uchl1 −/− ), and conditional Uchl1 knockout mice ( Tie2Cre-Uchl1 fl/fl ) demonstrated reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling. Lungs and pulmonary artery endothelial cells isolated from Uchl1 −/− animals exhibited reduced total and activated Akt with increased ubiquitinated Akt levels. UCHL1-silenced human pulmonary artery endothelial cells displayed reduced lysine(K)63-linked and increased K48-linked AKT1 levels. RESULTS: Supporting experimental data, we found that rs9321, a variant in a GC-enriched region of the UCHL1 gene, is associated with reduced methylation (n=5133), increased UCHL1 gene expression in lungs (n=815), and reduced cardiac index in patients (n=796). In addition, Gadd45α (an established demethylating gene) knockout mice ( Gadd45α −/− ) exhibited reduced lung vascular UCHL1 and AKT1 expression along with attenuated hypoxic pulmonary hypertension. CONCLUSIONS: Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.
Correction: Antibody–Peptide Epitope Conjugates for Personalized Cancer Therapy
Authors: Songfa Zhang, Chuan Yan, David G. Millar, Qiqi Yang, James M. Heather, Adam Langenbucher, Laura T. Morton, Sean Sepulveda, Eric Alpert, Lauren R. Whelton, Dominique T. Zarrella, Mei Guo, Eleanor Minogue, Michael S. Lawrence, Bo R. Rueda, David R. Spriggs, Weiguo Lu, David M. Langenau, Mark Cobbold
Journal: Cancer Research (2024)

In the original version of this article (1), there was an error in Fig. 3A.Specifically, incorrect representative images were used to show merged fluorescence and brightfield of zebrafish with injection of uncleavable APECs at day 7 and after therapy.
Abstract PO5-13-02: BRCA mutational profiles of endocrine-resistant breast cancer
Authors: Emelie Karlsson, Caroline Schagerholm, Stephanie Robertson, Hosein Toosi, Emmanouil Sifakis, Johan Hartman
Journal: Cancer Research (2024)

Abstract Background Around 75% of breast cancer (BC) patients have tumors expressing the treatment-predictive biomarker estrogen receptor α (ER) and are consequently offered endocrine therapy. One-third of these patients develop endocrine resistance, a majority with tumors that retain ER expression. For most cases, the resistance mechanism is still unknown, but mutational activity is a suggested mechanism. Germline BRCA mutations are well-known in BC and are found in approximately 23% of patients with triple-negative BC and in 5% of patients with ER+ BC. However, less is certain about the somatic variants, though studies have shown prevalences of around 3% in BC. This study aimed to examine the somatic BRCA mutational profiles of endocrine-resistant paired primary and relapse tumors. Methods A retrospective cohort of verified endocrine-resistant BC patients was collected at Karolinska University Hospital in Stockholm, Sweden. Patients diagnosed in 2008-2012 with an ER+ and human epidermal growth factor receptor 2 (HER2) negative primary tumor and a following ER+ and HER2- relapse tumor within five years of ongoing endocrine therapy were included (N=63). DNA was extracted from archived formalin-fixed paraffin-embedded relapse and primary tumor tissue and analyzed by panel sequencing. Tumor-free lymph nodes were used as germline normal samples. Results The analysis showed somatic BRCA mutational activity in 38.1% of the patients. Variants were present in 20.3% of primary tumors and 30.4% of relapse tumors. BRCA1 mutations were present in 11.9% of primary tumors and 21.4% of relapse tumors. BRCA2 variations were, in turn, seen in 11.9% of primary tumors and 14.3% of relapse tumors. The frequency of patients that had alterations in both the primary and relapse tumors was 3.2% for BRCA1 and BRCA2 respectively. Conclusion This study of a unique endocrine-resistant BC cohort shows a high presence and varying distribution of somatic BRCA mutations in both primary and even higher in relapse tumors. These results suggest that mutational testing for possible further treatment decisions may be relevant for patients exhibiting endocrine resistance, especially in the advanced setting. Citation Format: Emelie Karlsson, Caroline Schagerholm, Stephanie Robertson, Hosein Toosi, Emmanouil Sifakis, Johan Hartman. BRCA mutational profiles of endocrine-resistant breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-13-02.
Abstract PO4-28-02: Adipocyte Progenitor-Mediated Effects on Mammary Cancer Cells
Authors: Jacqulene Sunder Singh, Purna Joshi, Emma Unger
Journal: Cancer Research (2024)

Abstract Treatment challenges in breast cancer arise from significant heterogeneity found within breast tumors and the surrounding microenvironment. The tumor microenvironment presents a complex ecosystem which comprises diverse stromal cells including immune, endothelial and fibroblast cell lineages and the extracellular matrix that support tumor progression. Adipocytes represent an abundant cell population in the normal breast and prior studies have reported a crosstalk between adipocytes and mammary cancer cells. De-differentiation of adipocytes into adipocyte progenitor-like cells is linked to a pro-tumorigenic microenvironment in mouse mammary tumors. We have previously demonstrated that adipocyte progenitors in the murine mammary stroma have the capacity to generate epithelial lineages during mammary epithelial growth. The influence of adipocyte progenitors in the mammary tumor microenvironment is not known. In this study, we investigated the effects of adipocyte progenitors on mammary cancer cells and their interactions using the 3T3-L1 adipocyte precursor (AP) cell line and the EO771 syngeneic mammary cancer (MCa) cell line. AP and MCa cell lines were co-cultured, after which MCa cell growth, invasion and migration were assessed using established in vitro assays. MCa cells cultured alone were also exposed to AP-conditioned media to determine whether secreted factors derived from APs could modulate MCa cells. AP cells were found to alter the behavior of MCa cells, affecting their cell proliferation, migration, and cellular phenotype. This work infers the potential of adipocyte progenitors to regulate mammary cancer growth and progression, which warrants further investigation into their fate and role in vivo during mammary tumorigenesis. Keywords: breast cancer, adipocyte progenitors, tumor microenvironment Citation Format: Jacqulene Sunder Singh, Purna Joshi, Emma Unger. Adipocyte Progenitor-Mediated Effects on Mammary Cancer Cells [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-28-02.
Abstract PS18-03: The Association between Food Deserts, Food Swamps, and Postmenopausal Breast Cancer Mortality in the United States
Authors: Malcolm Bevel, Meng-Han Tsai, April Parham, Sydney Andrzejak, Samantha Jones, Justin Moore
Journal: Cancer Research (2024)

Abstract Purpose: Breast cancer (BRCA), the 4th leading cause of cancer death in the United States (U.S.), is one of 13 obesity-related cancers. Healthy food consumption is a protective factor shown to decrease obesity risk and postmenopausal BRCA mortality, respectively. However, residing in geographical areas with no access to healthy food options (food deserts) or unhealthy food options (food swamps) reduces access to healthy foods and has been severely understudied. We examined the relationship between residing in food swamps and deserts with postmenopausal BRCA mortality. Methods: We conducted an ecological analysis utilizing 2010 – 2020 Center for Disease Control and Prevention postmenopausal BRCA mortality data (restricted to 45+ years old) and aggregated 2012 – 2020 data from the U.S. Department of Agriculture Food Environment Atlas data. Food swamp score (FS) was calculated as the ratio of fast-food and convenience stores to grocery stores and farmer’s markets. Food desert score (FD) was calculated as the proportion of residents living more than one mile (urban) or 10 miles (rural) from a grocery store and household income ≤ 200% of the federal poverty threshold. We categorized FD and FS to low, moderate, or high; higher scores indicated counties with poorer healthy food resources. Multilevel generalized mixed effects models were used to estimate the mentioned association. Results: 2,280 counties/county equivalents with high postmenopausal BRCA mortality rates had higher percentage of non-Hispanic (NH)-Black population (5.80 vs. 2.08), poverty rates (17.2 vs. 14.2), and high food swamp scored areas (39.0 vs. 24.5) versus counties/county equivalents with low postmenopausal BRCA mortality rates (p-value &amp;lt; 0.0001). After adjusting for age, percentage of NH-Blacks per county, and poverty rate, we found 42% increased odds of having high postmenopausal BRCA mortality rates among U.S. counties/county equivalents with high food swamp scores (adjusted odds ratio [AOR] = 1.42; 95% CI: 1.14 – 1.78). Conclusions: Sampled U.S. counties with the poorest food swamp environment had significantly increased odds of postmenopausal BRCA mortality. We suggest that local policymakers and community stakeholders should employ sustainable approaches at combating obesity and BRCA by increasing healthier accessible food sources (e.g. creating more walkable neighborhoods and community gardens). Citation Format: Malcolm Bevel, Meng-Han Tsai, April Parham, Sydney Andrzejak, Samantha Jones, Justin Moore. The Association between Food Deserts, Food Swamps, and Postmenopausal Breast Cancer Mortality in the United States [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS18-03.