tbuckley/cabot-search huggingface dataset:
Cardiac power output is associated with adverse outcomes in patients with preserved ejection fraction after transcatheter aortic valve implantation
Authors: Daisuke Miyahara, Masaki Izumo, Yukio Sato, Tatsuro Shoji, Mitsuki Yamaga, Yoshikuni Kobayashi, Takahiko Kai, Taishi Okuno, Shingo Kuwata, Masashi Koga, Yasuhiro Tanabe, Yoshihiro J Akashi
Journal:  (2024)

Abstract Aims Cardiac power output (CPO) measures cardiac performance, and its prognostic significance in heart failure with preserved ejection fraction (EF) has been previously reported. However, the effectiveness of CPO in risk stratification of patients with valvular heart disease and post-operative valvular disease has not been reported. We aimed to determine the association between CPO and clinical outcomes in patients with preserved left ventricular (LV) EF after transcatheter aortic valve implantation (TAVI). Methods and results This retrospective observational study included 1047 consecutive patients with severe aortic stenosis after TAVI. All patients were followed up for all-cause mortality and hospitalization for HF. CPO was calculated as 0.222 × cardiac output × mean blood pressure (BP)/LV mass, where 0.222 was the conversion constant to W/100 g of the LV myocardium. CPO was assessed using transthoracic echocardiography at discharge after TAVI. Of the 1047 patients, 253 were excluded following the exclusion criteria, including those with low LVEF, and 794 patients (84.0 [80.0–88.0] years; 35.8% male) were included in this study. During a median follow-up period of 684 (237–1114) days, the composite endpoint occurred in 196 patients. A dose-dependent association was observed between the CPO levels and all-cause mortality. Patients in the lowest CPO tertile had significantly lower event-free survival rates (log-rank test, P = 0.043). Multivariate Cox regression analysis showed that CPO was independently associated with adverse outcomes (hazard ratio = 0.561, P = 0.020). CPO provided an incremental prognostic effect in the model based on clinical and echocardiographic markers (P = 0.034). Conclusion CPO is independently and incrementally associated with adverse outcomes in patients with preserved LVEF following TAVI.
Semaglutide for weight loss in obese patients as an adjunctive treatment for hidradenitis suppurativa: its impact on disease control and quality of life
Authors: Daniel Lyons, Anusha Louly Nathan, Emily Pender, Gregg Murray, Conor Smith, Brian Kirby, Rosalind Hughes
Journal: British Journal of Dermatology (2024)

Hidradenitis suppurativa (HS) has a significant impact on patients’ quality of life (QoL) and mortality. We report the use of semaglutide and its impact on disease control and QoL in 30 patients with obesity attending an HS specialty clinic. These retrospective data suggest that the addition of semaglutide to standard HS treatments results in improvement in QoL and fewer HS flares. The retrospective nature of the study is a limitation. Placebo-controlled randomized clinical trials should be done in HS to assess the efficacy of semaglutide in this debilitating condition.
Protein N-glycans in Healthy and Sclerotic Glomeruli in Diabetic Kidney Disease
Authors: Dušan Veličković, John P. Shapiro, Samir V. Parikh, Brad Rovin, Robert D. Toto, Miguel A. Vazquez, Emilio D. Poggio, John F. O'Toole, John R. Sedor, Theodore Alexandrov, Sanjay Jain, Markus Bitzer, Jeffrey Hodgin, Marija Veličković, Kumar Sharma, Christopher R. Anderton
Journal: Journal of the American Society of Nephrology (2024)

Key Points Multiomics performed on diabetic kidney disease biopsies revealed five N -glycan signatures of sclerotic glomeruli that significantly differed compared with healthy glomeruli. Integrative spatial glycomics, proteomics, and transcriptomics revealed protein N -glycosylation characteristic of sclerotic glomeruli in diabetic kidney disease. Background Diabetes is expected to directly affect renal glycosylation; yet to date, there has not been a comprehensive evaluation of alterations in N -glycan composition in the glomeruli of patients with diabetic kidney disease (DKD). Methods We used untargeted mass spectrometry imaging to identify N -glycan structures in healthy and sclerotic glomeruli in formalin-fixed paraffin-embedded sections from needle biopsies of five patients with DKD and three healthy kidney samples. Regional proteomics was performed on glomeruli from additional biopsies from the same patients to compare the abundances of enzymes involved in glycosylation. Secondary analysis of single-nucleus RNA sequencing (snRNAseq) data were used to inform on transcript levels of glycosylation machinery in different cell types and states. Results We detected 120 N -glycans, and among them, we identified 12 of these protein post-translated modifications that were significantly increased in glomeruli. All glomeruli-specific N -glycans contained an N -acetyllactosamine epitope. Five N -glycan structures were highly discriminant between sclerotic and healthy glomeruli. Sclerotic glomeruli had an additional set of glycans lacking fucose linked to their core, and they did not show tetra-antennary structures that were common in healthy glomeruli. Orthogonal omics analyses revealed lower protein abundance and lower gene expression involved in synthesizing fucosylated and branched N -glycans in sclerotic podocytes. In snRNAseq and regional proteomics analyses, we observed that genes and/or proteins involved in sialylation and N -acetyllactosamine synthesis were also downregulated in DKD glomeruli, but this alteration remained undetectable by our spatial N -glycomics assay. Conclusions Integrative spatial glycomics, proteomics, and transcriptomics revealed protein N -glycosylation characteristic of sclerotic glomeruli in DKD.
Biomaterials‐Boosted Immunotherapy for Osteosarcoma
Authors: Chao Sun, Shuqiang Li, Jianxun Ding
Journal: Advanced Healthcare Materials (2024)

Osteosarcoma (OS) is a primary malignant bone tumor that emanates from mesenchymal cells, commonly found in the epiphyseal end of long bones. The highly recurrent and metastatic nature of OS poses significant challenges to the efficacy of treatment and negatively affects patient prognosis. Currently, available clinical treatment strategies primarily focus on maximizing tumor resection and reducing localized symptoms rather than the complete eradication of malignant tumor cells to achieve ideal outcomes. The biomaterials-boosted immunotherapy for OS is characterized by high effectiveness and a favorable safety profile. This therapeutic approach manipulates the tumor microenvironments at the cellular and molecular levels to impede tumor progression. This review delves into the mechanisms underlying the treatment of OS, emphasizing biomaterials-enhanced tumor immunity. Moreover, it summarizes the immune cell phenotype and tumor microenvironment regulation, along with the ability of immune checkpoint blockade to activate the autoimmune system. Gaining a profound comprehension of biomaterials-boosted OS immunotherapy is imperative to explore more efficacious immunotherapy protocols and treatment options in this setting.
Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease?
Authors: Maximilian Huttasch, Michael Roden, Sabine Kahl
Journal: Metabolism (2024)

Metabolic dysfunction-associated steatotic liver disease (MASLD) closely associates with obesity and type 2 diabetes. Lifestyle intervention and bariatric surgery aiming at substantial weight loss are cornerstones of MASLD treatment by improving histological outcomes and reducing risks of comorbidities. Originally developed as antihyperglycemic drugs, incretin (co-)agonists and SGLT2 inhibitors also reduce steatosis and cardiorenovascular events. Certain incretin agonists effectively improve histological features of MASLD, but not fibrosis. Of note, beneficial effects on MASLD may not necessarily require weight loss. Despite moderate weight gain, one PPARγ agonist improved adipose tissue and MASLD with certain benefit on fibrosis in post-hoc analyses. Likewise, the first THRβ-agonist was recently provisionally approved because of significant improvements of MASLD and fibrosis. We here discuss liver-related and metabolic effects induced by different MASLD treatments and their association with weight loss. Therefore, we compare results from clinical trials on drugs acting via weight loss (incretin (co)agonists, SGLT2 inhibitors) with those exerting no weight loss (pioglitazone; resmetirom). Furthermore, other drugs in development directly targeting hepatic lipid metabolism (lipogenesis inhibitors, FGF21 analogs) are addressed. Although THRβ-agonism may effectively improve hepatic outcomes, MASLD treatment concepts should consider all cardiometabolic risk factors for effective reduction of morbidity and mortality in the affected people.
Therapeutic avenues in bone repair: Harnessing an anabolic osteopeptide, PEPITEM, to boost bone growth and prevent bone loss
Authors: Jonathan W Lewis, Kathryn Frost, Georgiana Neag, Mussarat Wahid, Melissa Finlay, Ellie H Northall, Oladimeji Abudu, Samuel Kemble, Edward T Davis, Emily Powell, Charlotte Palmer, Jinsen Lu, G Ed Rainger, Asif J Iqbal, Myriam Chimen, Ansar Mahmood, Simon W Jones, James R Edwards, Amy J Naylor, Helen M McGettrick
Journal: Cell Reports Medicine (2024)

The existing suite of therapies for bone diseases largely act to prevent further bone loss but fail to stimulate healthy bone formation and repair. We describe an endogenous osteopeptide (PEPITEM) with anabolic osteogenic activity, regulating bone remodeling in health and disease. PEPITEM acts directly on osteoblasts through NCAM-1 signaling to promote their maturation and formation of new bone, leading to enhanced trabecular bone growth and strength. Simultaneously, PEPITEM stimulates an inhibitory paracrine loop: promoting osteoblast release of the decoy receptor osteoprotegerin, which sequesters RANKL, thereby limiting osteoclast activity and bone resorption. In disease models, PEPITEM therapy halts osteoporosis-induced bone loss and arthritis-induced bone damage in mice and stimulates new bone formation in osteoblasts derived from patient samples. Thus, PEPITEM offers an alternative therapeutic option in the management of diseases with excessive bone loss, promoting an endogenous anabolic pathway to induce bone remodeling and redress the imbalance in bone turnover.
Transcriptomic and spatial dissection of human ex vivo right atrial tissue reveals proinflammatory microvascular changes in ischemic heart disease
Authors: Suvi Linna-Kuosmanen, Eloi Schmauch, Kyriakitsa Galani, Johannes Ojanen, Carles A. Boix, Tiit Örd, Anu Toropainen, Prosanta K. Singha, Pierre R. Moreau, Kristiina Harju, Adriana Blazeski, Åsa Segerstolpe, Veikko Lahtinen, Lei Hou, Kai Kang, Elamaran Meibalan, Leandro Z. Agudelo, Hannu Kokki, Jari Halonen, Juho Jalkanen, Jarmo Gunn, Calum A. MacRae, Maija Hollmén, Juha E.K. Hartikainen, Minna U. Kaikkonen, Guillermo García-Cardeña, Pasi Tavi, Tuomas Kiviniemi, Manolis Kellis
Journal: Cell Reports Medicine (2024)

Cardiovascular disease plays a central role in the electrical and structural remodeling of the right atrium, predisposing to arrhythmias, heart failure, and sudden death. Here, we dissect with single-nuclei RNA sequencing (snRNA-seq) and spatial transcriptomics the gene expression changes in the human ex vivo right atrial tissue and pericardial fluid in ischemic heart disease, myocardial infarction, and ischemic and non-ischemic heart failure using asymptomatic patients with valvular disease who undergo preventive surgery as the control group. We reveal substantial differences in disease-associated gene expression in all cell types, collectively suggesting inflammatory microvascular dysfunction and changes in the right atrial tissue composition as the valvular and vascular diseases progress into heart failure. The data collectively suggest that investigation of human cardiovascular disease should expand to all functionally important parts of the heart, which may help us to identify mechanisms promoting more severe types of the disease.
Socioeconomic Status Transition Throughout Life and Risk of Dementia
Authors: Ryoto Sakaniwa, Kokoro Shirai, Dorina Cadar, Tami Saito, Katsunori Kondo, Ichiro Kawachi, Andrew Steptoe, Hiroyasu Iso
Journal: JAMA Network Open (2024)

Socioeconomic status (SES) is associated with dementia. However, the role of SES transitions in dementia is less explored; such evidence would be useful to understand whether social mobility is associated with healthy longevity at older ages.
Iberdomide increases innate and adaptive immune cell subsets in the bone marrow of patients with relapsed/refractory multiple myeloma
Authors: Oliver Van Oekelen, Michael Amatangelo, Manman Guo, Bhaskar Upadhyaya, Adam P. Cribbs, Geoffrey Kelly, Manishkumar Patel, Seunghee Kim-Schulze, Erin Flynt, Alessandro Lagana, Sarah Gooding, Miriam Merad, Sundar Jagganath, William E. Pierceall, Udo Oppermann, Anjan Thakurta, Samir Parekh
Journal: Cell Reports Medicine (2024)

Iberdomide is a potent cereblon E3 ligase modulator (CELMoD agent) with promising efficacy and safety as a monotherapy or in combination with other therapies in patients with relapsed/refractory multiple myeloma (RRMM). Using a custom mass cytometry panel designed for large-scale immunophenotyping of the bone marrow tumor microenvironment (TME), we demonstrate significant increases of effector T and natural killer (NK) cells in a cohort of 93 patients with multiple myeloma (MM) treated with iberdomide, correlating findings to disease characteristics, prior therapy, and a peripheral blood immune phenotype. Notably, changes are dose dependent, associated with objective response, and independent of prior refractoriness to MM therapies. This suggests that iberdomide broadly induces innate and adaptive immune activation in the TME, contributing to its antitumor efficacy. Our approach establishes a strategy to study treatment-induced changes in the TME of patients with MM and, more broadly, patients with cancer and establishes rational combination strategies for iberdomide with immune-enhancing therapies to treat MM.
Targeting WEE1 enhances the antitumor effect of KRAS-mutated non-small cell lung cancer harboring TP53 mutations
Authors: Koji Fukuda, Shinji Takeuchi, Sachiko Arai, Shigeki Nanjo, Shigeki Sato, Hiroshi Kotani, Kenji Kita, Akihiro Nishiyama, Hiroyuki Sakaguchi, Koshiro Ohtsubo, Seiji Yano
Journal: Cell Reports Medicine (2024)

The clinical development of Kirsten rat sarcoma virus (KRAS)-G12C inhibitors for the treatment of KRAS-mutant lung cancer is limited by the presence of co-mutations, intrinsic resistance, and the emergence of acquired resistance. Therefore, innovative strategies for enhancing apoptosis in KRAS-mutated non-small cell lung cancer (NSCLC) are urgently needed. Through CRISPR-Cas9 knockout screening using a library of 746 crRNAs and drug screening with a custom library of 432 compounds, we discover that WEE1 kinase inhibitors are potent enhancers of apoptosis, particularly in KRAS-mutant NSCLC cells harboring TP53 mutations. Mechanistically, WEE1 inhibition promotes G2/M transition and reduces checkpoint kinase 2 (CHK2) and Rad51 expression in the DNA damage response (DDR) pathway, which is associated with apoptosis and the repair of DNA double-strand breaks, leading to mitotic catastrophe. Notably, the combined inhibition of KRAS-G12C and WEE1 consistently suppresses tumor growth. Our results suggest targeting WEE1 as a promising therapeutic strategy for KRAS-mutated NSCLC with TP53 mutations.
Alarmin S100A8 imparts chemoresistance of esophageal cancer by reprogramming cancer-associated fibroblasts
Authors: Xinjie Chen, Guoyu Cheng, Liang Zhu, Tianyuan Liu, Xinyu Yang, Rucheng Liu, Zhengjie Ou, Shaosen Zhang, Wen Tan, Dongxin Lin, Chen Wu
Journal: Cell Reports Medicine (2024)

Chemotherapy remains the first-line treatment for advanced esophageal cancer. However, durable benefits are achieved by only a limited subset of individuals due to the elusive chemoresistance. Here, we utilize patient-derived xenografts (PDXs) from esophageal squamous-cell carcinoma to investigate chemoresistance mechanisms in preclinical settings. We observe that activated cancer-associated fibroblasts (CAFs) are enriched in the tumor microenvironment of PDXs resistant to chemotherapy. Mechanistically, we reveal that cancer-cell-derived S100A8 triggers the intracellular RhoA-ROCK-MLC2-MRTF-A pathway by binding to the CD147 receptor of CAFs, inducing CAF polarization and leading to chemoresistance. Therapeutically, we demonstrate that blocking the S100A8-CD147 pathway can improve chemotherapy efficiency. Prognostically, we found the S100A8 levels in peripheral blood can serve as an indicator of chemotherapy responsiveness. Collectively, our study offers a comprehensive understanding of the molecular mechanisms underlying chemoresistance in esophageal cancer and highlights the potential value of S100A8 in the clinical management of esophageal cancer.
Medicare Coverage and Patient Out-of-Pocket Costs for Cardiovascular-Kidney-Metabolic Medications
Authors: Grant M. Young, Kannu Bansal, Ralph J. Riello, Katherine A. A. Clark, Sanket S. Dhruva, Kamil F. Faridi, Nihar R. Desai
Journal: JAMA Network Open (2024)

This cross-sectional study evaluates the association between Medicare coverage and patient out-of-pocket costs for cardiovascular-kidney-metabolic medications.
The interplay between metabolic adaptations and diet in cancer immunotherapy
Authors: Lena Espelage, Natalie Wagner, Jan-Malte Placke, Selma Ugurel, Alpaslan Tasdogan
Journal: Clinical Cancer Research (2024)

Abstract Over the past decade, cancer immunotherapy has significantly advanced through the introduction of immune checkpoint inhibitors and the augmentation of adoptive cell transfer to enhance the innate cancer defense mechanisms. Despite these remarkable achievements, some cancers exhibit resistance to immunotherapy, with limited patient responsiveness and development of therapy resistance. Metabolic adaptations in both immune cells and cancer cells have emerged as central contributors to immunotherapy resistance. In the last few years, new insights emphasized the critical role of cancer and immune cell metabolism in animal models and patients. During therapy, immune cells undergo important metabolic shifts crucial for their acquired effector function against cancer cells. However, cancer cell metabolic rewiring and nutrient competition within tumor microenvironment (TME) alters many immune functions, affecting their fitness, polarization, recruitment, and survival. These interactions have initiated the development of novel therapies targeting tumor cell metabolism and favoring antitumor immunity within the TME. Furthermore, there has been increasing interest in comprehending how diet impacts the response to immunotherapy, given the demonstrated immunomodulatory and antitumor activity of various nutrients. In conclusion, recent advances in preclinical and clinical studies have highlighted the capacity of immune-based cancer therapies. Therefore, further exploration into the metabolic requirements of immune cells within the TME holds significant promise for the development of innovative therapeutic approaches that can effectively combat cancer in patients.
Irene Salinas: The joy of continuous growth and learning
Authors: Lucie Van Emmenis
Journal: The Journal of Experimental Medicine (2024)

Irene Salinas is a professor in the Department of Biology, University of New Mexico. Her lab uses multiple animal models to study nasal immunity and neuroimmune interactions in the olfactory-central nervous system axis in response to microorganisms. We recently spoke with Irene about her current work, her diversity, equity, and inclusion (DEI) work, and how her leadership style has changed over the years.
Correction: Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect
Authors: Tamara Kögl, Hsin-Fang Chang, Julian Staniek, Samuel C.C. Chiang, Gudrun Thoulass, Jessica Lao, Kristoffer Weißert, Viviane Dettmer-Monaco, Kerstin Geiger, Paul T. Manna, Vivien Beziat, Mana Momenilandi, Szu-Min Tu, Selina J. Keppler, Varsha Pattu, Philipp Wolf, Laurence Kupferschmid, Stefan Tholen, Laura E. Covill, Karolina Ebert, Tobias Straub, Miriam Groß, Ruth Gather, Helena Engel, Ulrich Salzer, Christoph Schell, Sarah Maier, Kai Lehmberg, Tatjana I. Cornu, Hanspeter Pircher, Mohammad Shahrooei, Nima Parvaneh, Roland Elling, Marta Rizzi, Yenan T. Bryceson, Stephan Ehl, Peter Aichele, Sandra Ammann
Journal: The Journal of Experimental Medicine (2024)
Airway-occluding Mucus Plugs and Cause-specific Mortality in COPD
Authors: Sofia K. Mettler, Sushilkumar Sonavane, Scott Grumley, Hrudaya P. Nath, Andrew C. Yen, Carrie Pistenmaa, Pietro Nardelli, Raul San Jose Estepar, Michael H. Cho, Alejandro A. Diaz
Journal: American Journal of Respiratory and Critical Care Medicine (2024)
Genome-wide identification of replication fork stalling/pausing sites and the interplay between RNA Pol II transcription and DNA replication progression
Authors: Patricia Rojas, Jianming Wang, Giovanni Guglielmi, Martina Mustè Sadurnì, Lucas Pavlou, Geoffrey Ho Duen Leung, Vijay Rajagopal, Fabian Spill, Marco Saponaro
Journal: Genome biology (2024)

DNA replication progression can be affected by the presence of physical barriers like the RNA polymerases, leading to replication stress and DNA damage. Nonetheless, we do not know how transcription influences overall DNA replication progression.
Biologically informed NeuralODEs for genome-wide regulatory dynamics
Authors: Intekhab Hossain, Viola Fanfani, Jonas Fischer, John Quackenbush, Rebekka Burkholz
Journal: Genome biology (2024)

Abstract Background Gene regulatory network (GRN) models that are formulated as ordinary differential equations (ODEs) can accurately explain temporal gene expression patterns and promise to yield new insights into important cellular processes, disease progression, and intervention design. Learning such gene regulatory ODEs is challenging, since we want to predict the evolution of gene expression in a way that accurately encodes the underlying GRN governing the dynamics and the nonlinear functional relationships between genes. Most widely used ODE estimation methods either impose too many parametric restrictions or are not guided by meaningful biological insights, both of which impede either scalability, explainability, or both. Results We developed PHOENIX, a modeling framework based on neural ordinary differential equations (NeuralODEs) and Hill-Langmuir kinetics, that overcomes limitations of other methods by flexibly incorporating prior domain knowledge and biological constraints to promote sparse, biologically interpretable representations of GRN ODEs. We tested the accuracy of PHOENIX in a series of in silico experiments, benchmarking it against several currently used tools. We demonstrated PHOENIX’s flexibility by modeling regulation of oscillating expression profiles obtained from synchronized yeast cells. We also assessed the scalability of PHOENIX by modeling genome-scale GRNs for breast cancer samples ordered in pseudotime and for B cells treated with Rituximab. Conclusions PHOENIX uses a combination of user-defined prior knowledge and functional forms from systems biology to encode biological “first principles” as soft constraints on the GRN allowing us to predict subsequent gene expression patterns in a biologically explainable manner.