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Safety and efficacy of selective RIPK1 inhibitor SIR1-365 in hospitalized patients with severe COVID-19: A multicenter, randomized, double-blind, phase 1b trial

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重症医学（英文） 2025年第1期5卷 70-78页

作者： Chavez-Tapia Norberto Sayeed Muneeba Ahsan Luxmi Shobha Kasper Douglas J. Xue Fenchao Shen Yang Fan Weiliang Yuan Wei Du Bin Obesity and Digestive Disease Unit Medica Sur Clinic and Foundation Mexico City Mexico Sindh Infectious Diseases Hospital and Research Centre Dow University of Health Sciences Karachi Sindh Pakistan Department of medicine Division of Infectious Disease University of Illinois School of Medicine OSF HealthCare System d/b/a Saint Francis Medical Center Peoria IL USA Sironax USA Inc. Edison NJ USA Medical Intensive Care Unit State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Beijing China

Background::Receptor-interacting protein kinase 1 (RIPK1), a serine/threonine protein kinase, is mainly activated by pro-inflammatory cytokines and pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its activation could result in apoptosis, necroptosis, or inflammation. This study was conducted to evaluate the safety and efficacy of a potent and selective inhibitor of RIPK1, SIR1-365, in hospitalized patients with severe coronavirus disease 2019 (COVID-19).Methods::This multicenter, randomized, double-blind, phase 1b study screened patients from December 18, 2020 until November 27, 2021. Adults hospitalized with severe COVID-19 (diagnosed ≤2 weeks before screening) were randomized 1:1 to receive oral placebo or SIR1-365 100 mg three times daily for ≤14 consecutive days, with standard-of-care. The primary objective was to evaluate SIR1-365 safety and tolerability. Secondary objectives included an assessment of SIR1-365 efficacy. Descriptive statistics were used to summarize safety. The study was not powered for efficacy testing. Relevant inferential statistical tests were used to aid interpretation of differences in clinical ***::Forty-five patients were randomized, 42 were treated. Eighteen patients experienced treatment-emergent adverse events (TEAEs) and 7 patients were ≥ grade 3. Fewer SIR1-365-treated vs. placebo-treated patients experienced TEAEs (30.4% vs. 57.9%) and serious TEAEs (13.0% vs. 26.3%) within 28 days of the first dose. There were no serious treatment-related TEAEs or deaths. Compare to placebo, SIR1-365 significantly increased arterial oxygenation from baseline to day 7 (least-squares mean change [standard error]: 109.4 [26.4] vs. -24.2 [23.6];P=0.0095), significantly reduced hospitalization duration after treatment (mean±standard deviation: [4.7±3.7] days vs. [8.6±5.6] days;P=0.0145) and respiratory failure incidence (8.3% vs. 38.1%;two-sided P=0.0291

关键词： COVID-19 Phase 1b trial Receptor-interacting protein 1 RIPK1 RIPK1 inhibitor SIR1-365

Seasonal influen e on miRNA expression dynamics of extracellular vesicles in equine follicular flui

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Journal of Animal Science and Biotechnology 2025年第1期 136-152页

作者： Jean M.Feugang Ahmed Gad Nico G.Menjivar Ghassan M.Ishak Samuel Gebremedhn Melba O.Gastal Notsile H.Dlamini Radek Prochazka Eduardo L.Gastal Dawit Tesfaye Department of Animal and Dairy Sciences Mississippi State University Animal Reproduction and Biotechnology Laboratory (ARBL) Department of Biomedical Sciences College of Veterinary Medicine and Biomedical Sciences Colorado State University Department of Animal Production Faculty of AgricultureCairo University Department of Surgery and Obstetrics College of Veterinary Medicine University of Baghdad Animal Science School of Agricultural Sciences Southern Illinois University J.R.Simplot Company Institute of Animal Physiology and Genetics Czech Academy of Sciences

Background Ovarian follicular fluid(FF) is a dynamic environment that changes with the seasons,affecting follicle development,ovulation,and oocyte *** in the follicles release tiny particles called extracellular vesicles(EVs)containing vital regulatory molecules,such as microRNAs(miRNAs).These miRNAs are pivotal in facilitating communication within the follicles through diverse signaling and information transfer ***-coupled miRNA signaling is implicated to be associated with ovarian function,follicle and oocyte growth and response to various environmental ***,we investigated how seasonal variations directly influence the ovulatory and anovulatory states of ovarian follicles and how are they associated with follicular fluid EV-coupled miRNA dynamics in *** Ultrasonographic monitoring and follicular fluid aspiration of preovulatory follicles in horses during the anovulatory(spring:non-breeding) and ovulatory(spring,summer,and fall:breeding) seasons and subsequent EV isolation and miRNA profiling identified significant variation in EV-miRNA cargo *** identified 97 miRNAs with differential expression among the groups and specific clusters of miRNAs involved in the spring transition(miR-149f-200b,-206,-221,-328,and-615) and peak breeding period(including miR-143,-192,-451,-302b,-100,and let-7c):Bioinformatic analyses showed enrichments in various biological functions,e.g.,transcription factor activity,transcription and transcription regulation,nucleic acid binding,sequence-specific DNA binding,p53 signaling,and post-tran slational *** analyses revealed distinct sets of significantly up-and down-regulated miRNAs associated with spring anovulatory(Cluster 1) and summer ovulation-the peak breeding season(Clusters 4 and 6).Conclusions The findings from the current study shed light on the dynamics of FF-EV-coupled miRNAs in relation to equine ovulatory and anovulatory seasons,and their roles in understanding the me

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Critical role of OX40 signaling in the TCR-independent phase of human and murine thymic Treg generation

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Cellular & Molecular Immunology 2019年第2期16卷 138-153页

作者： Prabhakaran Kumar Alejandra Marinelarena Divya Raghunathan Vandhana K Ragothaman Shikha Saini Palash Bhattacharya Jilao Fan Alan L Epstein Ajay V Maker Bellur S Prabhakar Department of Microbiology and Immunology University of Illinois-College of MedicineChicagoILUSA Department of Pathology University of Southern California Keck School of MedicineLos AngelesCAUSA Department of Surgery Division of Surgical OncologyUniversity of Illinois-College of MedicineChicagoILUSA

Regulatory T cells(Tregs)play a pivotal role in immune-tolerance,and loss of Treg function can lead to the development of *** Tregs generated in the thymus substantially contribute to the Treg pool in the periphery,where they suppress self-reactive effector T cells(Teff)***,we showed that OX40L(TNFSF4)is able to drive selective proliferation of peripheral Tregs independent of canonical antigen presentation(CAP-independent)in the presence of low-dose ***,we hypothesized that OX40 signaling might be integral to the TCR-independent phase of murine and human thymic Treg(tTreg)*** of tTregs is a two-step process:Strong T-cell receptor(TCR)signals in combination with co-signals from the TNFRSF members facilitate tTreg precursor selection,followed by a TCR-independent phase of tTreg development in which their maturation is driven by ***,we investigated whether OX40 signaling could also play a critical role in the TCR-independent phase of tTreg ***40−/−mice had significantly reduced numbers of CD25−Foxp3low tTreg precursors and CD25+Foxp3+mature tTregs,while OX40L treatment of WT mice induced significant proliferation of these cell *** to tTeff cells,OX40 was expressed at higher levels in both murine and human tTreg precursors and mature *** ex vivo cultures,OX40L increased tTreg maturation and induced CAP-independent proliferation of both murine and human tTregs,which was mediated through the activation of AKT-mTOR *** novel findings show an evolutionarily conserved role for OX40 signaling in tTreg development and proliferation,and might enable the development of novel strategies to increase Tregs and suppress autoimmunity.

关键词： Thymic Tregs OX40L IL-2 Treg proliferation maturation

Multiaxially-stretchable kirigami-patterned mesh design for graphene sensor devices

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Nano Research 2020年第5期13卷 1406-1412页

作者： Hyo Chan Lee Ezekiel YHsieh Keong Yong SungWoo Nam Department of Mechanical Science and Engineering University of Illinois at Urbana–ChampaignUrbanaIllinois 61801USA Department of Materials Science and Engineering University of Illinois at Urbana–ChampaignUrbanaIllinois 61801USA Materials Research Laboratory University of Illinois at Urbana–ChampaignUrbanaIllinois 61801USA Micro and Nanotechnology Laboratory University of Illinois at Urbana–ChampaignUrbanaIllinois 61801USA Carle illinois college of medicine University of Illinois at Urbana–ChampaignChampaignIllinois 61820USA

In wearable electronics,significant research has gone into imparting stretchability and flexibility to otherwise rigid electronic components while maintaining their electrical *** far,this has been achieved through various geometric modifications of the rigid conductive components themselves,such as with microcracked,buckled,or planar meander ***,strategic placement of these resulting components within the overall devices,such as embedding them at the neutral plane,has been found to further enhance mechanical stability under ***,these strategies are still limited in performance,failing to achieve fully strain-insensitive electrical performance under biaxial stretching,twisting,and mixed strain ***,we developed a new platform for wearable,motion artifact-free sensors using a graphene-based multiaxially stretchable kirigami-patterned mesh *** normalized resistance change of the electrodes and graphene embedded in the structure is smaller than 0.5%and 0.23%under 180°torsion and 100%biaxial strain,***,the resistance change is limited to 5%under repeated stretching-releasing cycles from 0%to 100%biaxial *** addition,we investigated the deformation mechanisms of the structure with finite element *** on the simulation results,we derived a dimensionless geometric parameter that enables prediction of stretchability of the structure with high ***,as a proof-of-concept,we demonstrated a biaxially-stretchable graphene-based sensor array capable of monitoring of temperature and glucose level with minimized motion-artifacts.

关键词： kirigami mesh strain-insensitive wearable graphene glucose

Phytochemical study of Illicium angustisepalum and its biological activities

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Acta Pharmaceutica Sinica B 2017年第4期7卷 485-490页

作者： Karina M. Szymulanska-Ramamurthy Ming Zhao Chun-Tao Che Department of Medicinal Chemistry and Pharmacognosy College of Pharmacy University of Illinois at Chicago Jiangsu Collaborating Innovation Center of Chinese medicine Resources Industrialization College of Pharmacy Nanjing University of Chinese Medicine

Sixteen compounds, including two new natural products(1 and 2), were obtained from the twigs of Illicium angustisepalum. The structures were elucidated based on NMR, MS, IR data and optical rotation values. Compounds 4,5,6 and 8 displayed moderate antibacterial activities against clinical isolates; compounds 4,5,8,9 and 15 protected neural cells against oxidative stress; and compounds 10 and 14 exhibited anti-acetylcholinesterase activity.

关键词： Illicium angustisepalum Chemical ingredients Antibacterial Neuroprotection Anti-acetylcholinesterase

Of ethnicity, environment, and microbiota

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Cellular & Molecular Immunology 2019年第2期16卷 106-108页

作者： Sundararajan Jayaraman Department of Surgery University of Illinois College of Medicine at PeoriaPeoriaILUSA

Elie Metchnikoff’s lecture illustrated that‘men were free from microbes at birth and within tenth and seventeenth hour of birth the surface of skin,mucous membranes,respiratory passages,and more abundantly the digestive organs became peopled with microbes derived from the air or water’.1 It is interesting to note that the revised ratio of human cells to the number of bacteria in the body is 1:1,which is further tipped towards the human cell mass following each defecation.

关键词： organs respiratory revised

Therapeutic options for the management of pancreatic cancer

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World Journal of Gastroenterology 2014年第32期20卷 11142-11159页

作者： Maria L Rossi Azeem A Rehman Christopher S Gondi Department of medicine University of Illinois College of MedicinePeoria Peoria IL 61656-1649 United States

Since its initial characterization, pancreatic ductal adenocarcinoma has remained one of the most devastating and difficult cancers to treat. Pancreatic cancer is the fourth leading cause of death in the United States, resulting in an estimated 38460 deaths annually. With few screening tools available to detect this disease at an early stage, 94% of patients will die within five years of diagnosis. Despite decades of research that have led to a better understanding of the molecular and cellular signaling pathways in pancreatic cancer cells, few effective therapies have been developed to target these pathways. Other treatment options have included more sophisticated pancreatic cancer surgeries and combination therapies. While outcomes have improved modestly for these patients, more effective treatments are desperately needed. One of the greatest challenges in the future of treating this malignancy will be to develop therapies that target the tumor microenvironment and surrounding pancreatic cancer stem cells in addition to pancreatic cancer cells. Recent advances in targeting pancreatic stellate cells and the stroma have encouraged researchers to shift their focus to the role of desmoplasia in pancreatic cancer pathobiology in the hopes of developing newer-generation therapies. By combining novel agents with current cytotoxic chemotherapies and radiation therapy and personalizing them to each patient based on specific biomarkers, the goal of prolonging a patient’s life could be achieved. Here we review the most effective therapies that have been used for the treatment of pancreatic cancer and discuss the future potential of therapeutic options.

关键词： Pancreatic cancer Pancreatic cancer stem cells Microenvironment Surgical resection Neoadjuvant therapy Adjuvant therapy Chemotherapy Radiation Personalized therapy

A novel approach in preventing vascular leakage and angiogenesis in wet age-related macular degeneration

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Neural Regeneration Research 2022年第8期17卷 1751-1752页

作者： Kaori H.Yamada Department of Pharmacology and Regenerative medicine Department of Ophthalmology and Visual SciencesUniversity of Illinois College of MedicineChicagoILUSA

Vascular leakage and angiogenesis in diseases:The vascular system carries blood throughout the body to supply oxygen and nutrients to tissues and remove waste from *** of the vascular system worsens many *** this perspective,vascular function in blinding eye diseases,current therapies,and our developing approach will be *** blood vessels are composed of the monolayer of the endothelial cells,and the outer layer made by pericytes and smooth muscle cells provide structural support and shape to the *** monolayers function as a *** barrier function of endothelial monolayers controls plasma protein uptake and the infiltration of immune cells by regulating adherence of cell-cell *** leakage causes unwanted plasma leak,accumulation of immune cells,and tissue inflammation.

关键词： degeneration approach remove

Progression from low-grade dysplasia to malignancy in patients with Barrett's esophagus diagnosed by two or more pathologists

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World Journal of Gastroenterology 2016年第39期22卷 8831-8843页

作者： Harsha Moole Jaymon Patel Zohair Ahmed Abhiram Duvvuri Sreekar Vennelaganti Vishnu Moole Sowmya Dharmapuri Raghuveer Boddireddy Pratyusha Yedama Naveen Bondalapati Achuta Uppu Prashanth Vennelaganti Srinivas Puli Department of medicine University of Illinois College of Medicine at Peoria Division of Gastro-enterology and Hepatology Kansas City Veteran Affairs Medical Center Department of medicine Apogee Medical Group Department of medicine NTR University of Health Sciences Department of medicine Barnes Jewish Christian Medical Group Christian Hospital Department of medicine Albert Einstein College of Medicine Division of Gastroenterology and Hepatology University of Kansas Medical Center Division of Gastroenterology and Hepatology University of Illinois College of Medicine at Peoria

AIM To evaluate annual incidence of low grade dysplasia(LGD) progression to high grade dysplasia(HGD) and/or esophageal adenocarcinoma(EAC) when diagnosis was made by two or more expert *** Studies evaluating the progression of LGD to HGD or EAC were included. The diagnosis of LGD must be made by consensus of two or more expert gastrointestinal pathologists. Articles were searched in Medline, Pubmed, and Embase. Pooled proportions were calculated using fixed and random effects model. Heterogeneity among studies was assessed using the I2 statistic. RESULTS Initial search identified 721 reference articles, of which 53 were selected and reviewed. Twelve studies(n = 971) that met the inclusion criteria were included in this analysis. Among the total original LGD diagnoses in the included studies, only 37.49% reached the consensus LGD diagnosis after review by two or more expert pathologists. Total follow up period was 1532 patient-years. In the pooled consensus LGD patients, the annual incidence rate(AIR) of progression to HGD and or EAC was 10.35%(95%CI: 7.56-13.13) and progression to EAC was 5.18%(95%CI: 3.43-6.92). Among the patients down staged from original LGD diagnosis to No-dysplasia Barrett's esophagus, the AIR of progression to HGD and EAC was 0.65%(95%CI: 0.49-0.80). Among the patients down staged to Indefinite for dysplasia, the AIR of progression to HGD and EAC was 1.42%(95%CI: 1.19-1.65). In patients with consensus HGD diagnosis, the AIR of progression to EAC was 28.63%(95%CI: 13.98-43.27). CONCLUSION When LGD is diagnosed by consensus agreement of two or more expert pathologists, its progression towards malignancy seems to be at least three times the current estimates, however it could be up to 20 times the current estimates. Biopsies of all Barrett's esophagus patients with LGD should be reviewed by two expert gastroenterology pathologists. Follow-up strict surveillance programs should be in place for these patients.

关键词： Barrett’s esophagus Low grade dysplasia High grade dysplasia Esophageal adenocarcinoma Annual incidence of progression Systematic review Meta-analysis