tbuckley/cabot-search huggingface dataset:
Vaspin: A Novel Biomarker Linking Gluteofemoral Body Fat and Type 2 Diabetes Risk
Authors: Harry Hezhou Wang, Michael Chong, Nicolas Perrot, James Feiner, Sibylle Hess, Salim Yusuf, Hertzel Gerstein, Guillaume Paré, Marie Pigeyre
Journal: Diabetes Care (2023)

OBJECTIVE To determine whether adiposity depots modulate vaspin levels and whether vaspin predicts type 2 diabetes (T2D) risk, through epidemiological and genetic analyses. RESEARCH DESIGN AND METHODS We assessed the relationship of plasma vaspin concentration with incident and prevalent T2D and adiposity-related variables in 1) the Prospective Urban and Rural Epidemiology (PURE) biomarker substudy (N = 10,052) and 2) the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial (N = 7,840), using regression models. We then assessed whether vaspin is causally associated with T2D and whether genetic variants associated with MRI-measured adiposity depots modulate vaspin levels, using two-sample Mendelian randomization (MR). RESULTS A 1-SD increase in circulating vaspin levels was associated with a 16% increase in incident T2D in the PURE cohort (hazard ratio 1.16; 95% CI 1.09–1.23; P = 4.26 × 10−7) and prevalent T2D in the ORIGIN cohort (odds ratio [OR] 1.16; 95% CI 1.07–1.25; P = 2.17 × 10−4). A 1-unit increase in BMI and triglyceride levels was associated with a 0.08-SD (95% CI 0.06–0.10; P = 2.04 × 10−15) and 0.06-SD (95% CI 0.04–0.08; P = 4.08 × 10−13) increase, respectively, in vaspin in the PURE group. Consistent associations were observed in the ORIGIN cohort. MR results reinforced the association between vaspin and BMI-adjusted T2D risk (OR 1.01 per 1-SD increase in vaspin level; 95% CI 1.00–1.02; P = 2.86 × 10−2) and showed that vaspin was increased by 0.10 SD per 1-SD decrease in genetically determined gluteofemoral adiposity (95% CI 0.02–0.18; P = 2.01 × 10−2). No relationships were found between subcutaneous or visceral adiposity and vaspin. CONCLUSIONS These findings support that higher vaspin levels are related to increased T2D risk and reduced gluteofemoral adiposity, positioning vaspin as a promising clinical predictor for T2D.
Efficacy and safety of MP1032 plus standard-of-care compared to standard-of-care in hospitalised patients with COVID-19: a multicentre, randomised double-blind, placebo-controlled phase 2a trial
Authors: Petra Sager, Astrid Kaiser, Sara Schumann, Beate Ludescher, Michael Niedermaier, Ivo Schmidt, Katharina Och, Christiane Dings, Thorsten Lehr, Wolfgang Brysch
Journal: The Lancet Regional Health - Europe (2023)

SARS-CoV-2 infections still have a significant impact on the global population. The existing vaccinations have contributed to reducing the severe disease courses, decreasing hospitalisations, and lowering the mortality rate. However, due to the variability of COVID-19 symptoms, the emergence of new variants and the uneven global distribution of vaccines there is still a great need for new therapy options. One promising approach is provided by host-directed therapies. We assessed here the efficacy and safety of MP1032, a host-directed anti-viral/anti-inflammatory drug in hospitalised patients with moderate to severe COVID-19. In a randomised, double-blind, placebo-controlled, Phase IIa study, patients were randomised 2:1 to receive either 300 mg MP032 bid + Standard-of-Care (SoC) or placebo bid + SoC for 28 days. Eligible patients were ≥18 years old, tested positive for SARS-CoV-2, and had moderate to severe COVID-19 symptoms. The study spanned 20 sites in six countries (Bulgaria, France, Hungary, Italy, Romania, Spain), assessing disease progression according the NIAID scale as the primary outcome on day 14. Secondary objectives included disease progression (day 28), disease resolution (days 14 and 28), mortality rate, COVID-19 related parameters and safety. Exposure-response analyses were performed, linking MP1032 to COVID-19 biomarkers (eGFR, D-dimer). 132 patients were enrolled to receive MP1032 + SoC (n = 87) or placebo + SoC (n = 45). The patients were all white or Caucasian with a mean (median) age of 60.5 (63) years. Overall, only 10 patients were vaccinated, 5 in each group. No significant risk difference of disease progression could be detected between groups on both day 14 (9.8% MP1032 vs. 11.6% placebo) and day 28 with MH common risk differences of −0.276% (95% CI, −11.634 to 11.081; p = 0.962) and 1.722% (95% CI, −4.576 to 8.019; p = 0.592), respectively. The treatment with MP1032 + SoC was safe and well-tolerated. Overall, 182 TEAEs including 10 SAEs were reported in 53.5% (46/86) of patients of the verum group and in 57.8% (26/45) of patients of the placebo group; the SAEs occurred in 5.8% (5/86) and 6.7% (3/45) of verum and placebo patients, respectively. None of the SAEs was considered as related. Despite the study's limitation in size and the variation in concurrent SoCs, these findings warrant further investigation of MP1032 as a host-directed anti-viral drug candidate. The study was funded by the COVID-19 Horizon Europe work programme and MetrioPharm AG.
Myeloid cells pave the metastatic road in breast cancer.
Authors: Daniel E. Michaud, Jennifer L. Guerriero
Journal: Cancer Research (2023)

Abstract Current immunotherapeutic approaches are tailored towards biomarkers and mechanisms presented in the primary tumor microenvironment, yet few are designed against targets that arise in the metastatic site. In a recent Cancer Discovery article, Yofe and colleagues spatially and temporally mapped the evolving breast tumor metastatic environment within the lung at single cell resolution to identify immunologic cell types and mechanisms underlying the formation of metastatic nodules. The authors identified myeloid cell, monocyte, and neutrophil phenotypes as the most significant differences between the primary tumor and metastatic site. The authors also revealed the existence of a metastases-specific population of macrophages expressing Trem2 in both human and murine models that exhibit immunosuppressive features. Interestingly, Trem2+ macrophages are enriched at the invasive border of metastatic nodules compared to the metastatic core, suggesting they play an exclusionary role within the site. Characterization of the pre-metastatic lung in conjunction with pseudo-time lineage analysis revealed that Fn1+ monocytes precede metastasis formation and are the likely source of Trem2+ macrophages in developed nodules. This study supports the characterization of metastatic immune microenvironments to identify novel immunotherapeutic targets that may not exist within the primary site but play a significant role in patient outcome.
Artemisinins: Promising drug candidates for the treatment of autoimmune diseases
Authors: Xu Gao, Xian Lin, Qingwen Wang, Jian Chen
Journal: Medicinal Research Reviews (2023)

Abstract Autoimmune diseases are characterized by the immune system's attack on one's own tissues which are highly diverse and diseases differ in severity, causing damage in virtually all human systems including connective tissue (e.g., rheumatoid arthritis), neurological system (e.g., multiple sclerosis) and digestive system (e.g., inflammatory bowel disease). Historically, treatments normally include pain‐killing medication, anti‐inflammatory drugs, corticosteroids, and immunosuppressant drugs. However, given the above characteristics, treatment of autoimmune diseases has always been a challenge. Artemisinin is a natural sesquiterpene lactone initially extracted and separated from Chinese medicine Artemisia annua L., which has a long history of curing malaria. Artemisinin's derivatives such as artesunate, dihydroartemisinin, artemether, artemisitene, and so forth, are a family of artemisinins with antimalarial activity. Over the past decades, accumulating evidence have indicated the promising therapeutic potential of artemisinins in autoimmune diseases. Herein, we systematically summarized the research regarding the immunoregulatory properties of artemisinins including artemisinin and its derivatives, discussing their potential therapeutic viability toward major autoimmune diseases and the underlying mechanisms. This review will provide new directions for basic research and clinical translational medicine of artemisinins.
Determinants of Tricuspid Regurgitation Progression and Its Implications for Adequate Management
Authors: Ander Arteagoitia Bolumburu, Juan Manuel Monteagudo Ruiz, Patricia Mahia, Esther Pérez David, Teresa González, Marta Sitges, Chi-Hion Li, David Alonso, Fernando Carrasco, Manuel Luna Morales, Antonio Adeba, Jesús María de la Hera, José Luis Zamorano
Journal: JACC. Cardiovascular imaging (2023)
Zinc prevents vaginal candidiasis by inhibiting expression of an inflammatory fungal protein
Authors: Elena Roselletti, Eva Pericolini, Alexandre Nore, Peter Takacs, Bence Kozma, Arianna Sala, Francesco De Seta, Manola Comar, Jane Usher, Gordon D. Brown, Duncan Wilson
Journal: Science Translational Medicine (2023)

Candida causes an estimated half-billion cases of vulvovaginal candidiasis (VVC) every year. VVC is most commonly caused by Candida albicans , which, in this setting, triggers nonprotective neutrophil infiltration, aggressive local inflammation, and symptomatic disease. Despite its prevalence, little is known about the molecular mechanisms underpinning the immunopathology of this fungal infection. In this study, we describe the molecular determinant of VVC immunopathology and a potentially straightforward way to prevent disease. In response to zinc limitation, C. albicans releases a trace mineral binding molecule called Pra1 (pH-regulated antigen). Here, we show that the PRA1 gene is strongly up-regulated during vaginal infections and that its expression positively correlated with proinflammatory cytokine concentrations in women. Genetic deletion of PRA1 prevented vaginal inflammation in mice, and application of a zinc solution down-regulated expression of the gene and also blocked immunopathology. We also show that treatment of women suffering from recurrent VVC with a zinc gel prevented reinfections. We have therefore identified a key mediator of symptomatic VVC, giving us an opportunity to develop a range of preventative measures for combatting this disease.
Ex vivo tissue perturbations coupled to single-cell RNA-seq reveal multilineage cell circuit dynamics in human lung fibrogenesis
Authors: Niklas J. Lang, Janine Gote-Schniering, Diana Porras-Gonzalez, Lin Yang, Laurens J. De Sadeleer, R. Christoph Jentzsch, Vladimir A. Shitov, Shuhong Zhou, Meshal Ansari, Ahmed Agami, Christoph H. Mayr, Baharak Hooshiar Kashani, Yuexin Chen, Lukas Heumos, Jeanine C. Pestoni, Eszter Sarolta Molnar, Emiel Geeraerts, Vincent Anquetil, Laurent Saniere, Melanie Wögrath, Michael Gerckens, Mareike Lehmann, Ali Önder Yildirim, Rudolf Hatz, Nikolaus Kneidinger, Jürgen Behr, Wim A. Wuyts, Mircea-Gabriel Stoleriu, Malte D. Luecken, Fabian J. Theis, Gerald Burgstaller, Herbert B. Schiller
Journal: Science Translational Medicine (2023)

Pulmonary fibrosis develops as a consequence of failed regeneration after injury. Analyzing mechanisms of regeneration and fibrogenesis directly in human tissue has been hampered by the lack of organotypic models and analytical techniques. In this work, we coupled ex vivo cytokine and drug perturbations of human precision-cut lung slices (hPCLS) with single-cell RNA sequencing and induced a multilineage circuit of fibrogenic cell states in hPCLS. We showed that these cell states were highly similar to the in vivo cell circuit in a multicohort lung cell atlas from patients with pulmonary fibrosis. Using micro-CT-staged patient tissues, we characterized the appearance and interaction of myofibroblasts, an ectopic endothelial cell state, and basaloid epithelial cells in the thickened alveolar septum of early-stage lung fibrosis. Induction of these states in the hPCLS model provided evidence that the basaloid cell state was derived from alveolar type 2 cells, whereas the ectopic endothelial cell state emerged from capillary cell plasticity. Cell-cell communication routes in patients were largely conserved in hPCLS, and antifibrotic drug treatments showed highly cell type-specific effects. Our work provides an experimental framework for perturbational single-cell genomics directly in human lung tissue that enables analysis of tissue homeostasis, regeneration, and pathology. We further demonstrate that hPCLS offer an avenue for scalable, high-resolution drug testing to accelerate antifibrotic drug development and translation.
Treatment outcomes and risk factors for an unsuccessful outcome among patients with highly drug-resistant tuberculosis in Ukraine
Authors: Ole Skouvig Pedersen, Tetiana Butova, Valeriy Kapustnyk, Valerii Miasoiedov, Mykhailo Kuzhko, Leonid Hryshchuk, Svitlana Kornaha, Natalia Borovok, Olena Raznatovska, Andrii Fedorec, Artemii Bogomolov, Mykhaylo Tkhorovskiy, Oleksandra Akymenko, Iurii Klymenko, Olena Kulykova, Zhanna Karpenko, Tetiana Shapoval, Nataliia Chursina, Natalia Kondratyuk, Olha Parkhomenko, Inna Sazonenko, Mykola Ostrovskyy, Iryna Makoida, Lyubov Markovtsiy, Vasyl Skryp, Victoriya Lubenko, Nataliia Hrankina, Leonid Bondarenko, Valentyna Hlynenko, Victor Næstholt Dahl, Dmytro Butov
Journal: Clinical Microbiology and Infection (2023)

To describe demographics, clinical features, and treatment outcomes of patients with highly drug-resistant tuberculosis (TB) in Ukraine, and to evaluate risk factors for an unsuccessful outcome.
Caspase-9 inhibition triggers Hsp90-based chemotherapy-mediated tumor intrinsic innate sensing and enhances antitumor immunity
Authors: Jingyang Li, Xiaoyu Han, Mayu Sun, Weida Li, Guanghuan Yang, Huiyi Chen, Bao Guo, Jingquan Li, Xiaoguang Li, Hui Wang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Antineoplastic chemotherapies are dramatically efficient when they provoke immunogenic cell death (ICD), thus inducing an antitumor immune response and even tumor elimination. However, activated caspases, the hallmark of most cancer chemotherapeutic agents, render apoptosis immunologically silent. Whether they are dispensable for chemotherapy-induced cell death and the apoptotic clearance of cells in vivo is still elusive. Methods A rational cell-based anticancer drug library screening was performed to explore the immunogenic apoptosis pathway and therapeutic targets under apoptotic caspase inhibition. Based on this screening, the potential of caspase inhibition in enhancing chemotherapy-induced antitumor immunity and the mechanism of actions was investigated by various cells and mouse models. Results Heat shock protein 90 (Hsp90) inhibition activates caspases in tumor cells to produce abundant genomic and mitochondrial DNA fragments and results in cell apoptosis. Meanwhile, it hijacks Caspase-9 signaling to suppress intrinsic DNA sensing. Pharmacological blockade or genetic deletion of Caspase-9 causes tumor cells to secrete interferon (IFN)-β via tumor intrinsic mitochondrial DNA/the second messenger cyclic GMP–AMP (cGAS) /stimulator of interferon genes (STING) pathway without impairing Hsp90 inhibition-induced cell death. Importantly, both Caspase-9 and Hsp90 inhibition triggers an ICD, leading to the release of numerous damage-associated molecular patterns such as high-mobility group box protein 1, ATP and type I IFNs in vitro and remarkable antitumor effects in vivo. Moreover, the combination treatment also induces adaptive resistance by upregulating programmed death-ligand 1 (PD-L1). Additional PD-L1 blockade can further overcome this acquired immune resistance and achieve complete tumor regression. Conclusions Blockade of Caspase-9 signaling selectively provokes Hsp90-based chemotherapy-mediated tumor innate sensing, leading to CD8 + T cell-dependent tumor control. Our findings implicate that pharmacological modulation of caspase pathway increases the tumor-intrinsic innate sensing and immunogenicity of chemotherapy-induced apoptosis, and synergizes with immunotherapy to overcome adaptive resistance.
Deletion of the protein tyrosine phosphatase PTPN22 for adoptive T cell therapy facilitates CTL effector function but promotes T cell exhaustion
Authors: Alexandra Rose Teagle, Patricia Castro-Sanchez, Rebecca J Brownlie, Nicola Logan, Simran S Kapoor, David Wright, Robert J Salmond, Rose Zamoyska
Journal: Journal for ImmunoTherapy of Cancer (2023)

Adoptive cell therapy (ACT) is a promising strategy for treating cancer, yet it faces several challenges such as lack of long-term protection due to T cell exhaustion induced by chronic TCR stimulation in the tumor microenvironment. One benefit of ACT, however, is that it allows for cellular manipulations, such as deletion of the phosphotyrosine phosphatase non-receptor type 22 (PTPN22), which improves CD8
Tumor cell-intrinsic SETD2 inactivation sensitizes cancer cells to immune checkpoint blockade through the NR2F1-STAT1 pathway
Authors: Xufen Zheng, Yuxiang Luo, Yangjie Xiong, Xiaoxiao Liu, Chunling Zeng, Xiaojing Lu, Xiaofang Wang, Yumei Cheng, Simin Wang, Haoqi Lan, Kai Wang, Zhonghui Weng, Wenbo Bi, Xinxin Gan, Xiaona Jia, Linhui Wang, Yuexiang Wang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Cancer immunotherapies can induce durable tumor regression, but most patients do not respond. SETD2 mutation has been linked to the efficacy of immune checkpoint inhibitors (ICIs) immunotherapy. The functional importance of the SETD2 inactivation and how to modulate immunotherapy response remains unclear. Methods To explore the function of SETD2 in immunotherapy, knockout and subsequent functional experiments were conducted. Bulk RNA-seq, ATAC-seq, Chip-seq and single-cell RNA-seq were performed to dissect the mechanism and explore the immune microenvironment of mouse tumor. Flow cytometry was used to assess cell surface antigen and intratumoral T cell levels. Results We comprehensively determine the effect of SETD2 inactivation in ICIs therapy and elucidate the mechanistic impact on tumor immunity. Murine syngeneic tumors harboring Setd2 inactivation are sensitive to ICIs. By bulk and single-cell RNA-seq, we further reveal that SETD2 inactivation reprograms intratumoral immune cells and inflames the tumor microenvironment, which is characterized by high infiltration of T cells and enhanced antigen presentation to activate CD8 + T cell-mediated killing. Mechanistically, via an integrated multiomics analysis using ATAC-seq, ChIP-seq and RNA-seq, we demonstrate that SETD2 inactivation reduces NR2F1 transcription by impairing H3K36me3 deposition and chromatin accessibility, which activates the STAT1 signaling pathway to promote chemokines and programmed cell death protein-1 (PD-1) expression and enhance antigen presentation. All these regulatory mechanisms synergistically promote the effects of anti-programmed cell death ligand 1 immunotherapy in Setd2 -knockout syngeneic mouse models. The SETD2-NR2F1-STAT1 regulatory axis is conserved in human and murine cancers. Finally, cancer patients harboring SETD2 mutations who received ICIs show increased durable clinical benefits and survival. Conclusions These findings provide novel insights into the biology of SETD2 inactivation regulation and reveal a new potential therapeutic biomarker for ICIs immunotherapy in various refractory cancers.
iPSC-derived natural killer cells expressing the FcγR fusion CD64/16A can be armed with antibodies for multitumor antigen targeting
Authors: Kristin M Snyder, Kate J Dixon, Zachary Davis, Martin Hosking, Geoffrey Hart, Melissa Khaw, Anders Matson, Ryan Bjordahl, Bryan Hancock, Soheila Shirinbak, Jeffrey S Miller, Bahram Valamehr, Jianming Wu, Bruce Walcheck
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Antibody therapies can direct natural killer (NK) cells to tumor cells, tumor-associated cells, and suppressive immune cells to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). This antigen-specific effector function of human NK cells is mediated by the IgG Fc receptor CD16A (FcγRIIIA). Preclinical and clinical studies indicate that increasing the binding affinity and avidity of CD16A for antibodies improves the therapeutic potential of ADCC. CD64 (FcγRI), expressed by myeloid cells but not NK cells, is the only high affinity IgG Fc receptor and is uniquely capable of stably binding to free monomeric IgG as a physiological function. We have reported on the generation of the FcγR fusion CD64/16A, consisting of the extracellular region of CD64 and the transmembrane and cytoplasmic regions from CD16A, retaining its signaling and cellular activity. Here, we generated induced pluripotent stem cell (iPSC)-derived NK (iNK) cells expressing CD64/16A as a potential adoptive NK cell therapy for increased ADCC potency. Methods iPSCs were engineered to express CD64/16A as well as an interleukin (IL)-15/IL-15Rα fusion (IL-15RF) protein and differentiated into iNK cells. iNK cells and peripheral blood NK cells were expanded using irradiated K562-mbIL21-41BBL feeder cells and examined. NK cells, ovarian tumor cell lines, and therapeutic monoclonal antibodies were used to assess ADCC in vitro, performed by a DELFIA EuTDA assay or in real-time by IncuCyte assays, and in vivo. For the latter, we developed a xenograft mouse model with high circulating levels of human IgG for more physiological relevance. Results We demonstrate that (1) iNK-CD64/16A cells after expansion or thaw from cryopreservation can be coupled to therapeutic antibodies, creating armed iNK cells; (2) antibody-armed iNK-CD64/16A cells can be redirected by added antibodies to target new tumor antigens, highlighting additional potential of these cells; (3) cytokine-autonomous activity by iNK-CD64/16A cells engineered to express IL-15RF; and that (4) antibody-armed iNK-CD64/16A cells thawed from cryopreservation are capable of sustained and robust ADCC in vitro and in vivo, as determined by using a modified tumor xenograft model with high levels of competing human IgG. Conclusions iNK cells expressing CD64/16A provide an off-the-shelf multiantigen targeting platform to address tumor heterogeneity and mitigate antigen escape.