696,071 results match your criteria inhibitor empagliflozin


Therapeutic review of cabotegravir/rilpivirine long-acting antiretroviral injectable and implementation considerations at an HIV specialty clinic.

Pharmacotherapy 2021 Jun 15. Epub 2021 Jun 15.

Indiana University Health, Indianapolis, Indiana, USA.

Cabotegravir/rilpivirine (CAB/RPV) was recently approved by the US Food and Drug Administration (FDA) as the first complete parenteral antiretroviral (ART) regimen for treatment of people living with HIV (PLWH). As a monthly intramuscular (IM) injection, this therapy constitutes a major departure from the traditional paradigm of oral therapy requiring (at least) daily administration that has defined HIV treatment for decades. Composed of a second-generation integrase inhibitor (INSTI) and nonnucleoside reverse transcriptase inhibitor (NNRTI), CAB/RPV has achieved high rates of sustained virologic suppression with a favorable safety profile for treatment-experienced PLWH following oral lead-in (OLI) during several clinical trials. Read More

View Article and Full-Text PDF

Tyrosine Kinase Inhibitor Sunitinib Delays Platelet-Induced Coagulation: Additive Effects of Aspirin.

Thromb Haemost 2021 Jun 15. Epub 2021 Jun 15.

Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.

Background:  Sunitinib is a multitarget tyrosine kinase inhibitor (TKI) used for cancer treatment. In platelets, sunitinib affects collagen-induced activation under noncoagulating conditions. We investigated (1) the effects of sunitinib on thrombus formation induced by other TK-dependent receptors, and (2) the effects under coagulating conditions. Read More

View Article and Full-Text PDF

Adjuvant versus Neoadjuvant Immunotherapy for Hepatocellular Carcinoma: Clinical and Immunologic Perspectives.

Semin Liver Dis 2021 Jun 15. Epub 2021 Jun 15.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Advancement in systemic therapy, particularly immune checkpoint inhibitor (ICI)-based combination regimens, has transformed the treatment landscape for patients with advanced hepatocellular carcinoma (HCC). The advancement in systemic therapy also provides new opportunities of reducing recurrence after curative therapy through adjuvant therapy or improving resectability through neoadjuvant therapy. Improved recurrence-free survival by adjuvant or neoadjuvant ICI-based therapy has been reported in other cancer types. Read More

View Article and Full-Text PDF

Human Neutrophil Elastase Mediates MUC5AC Hypersecretion via the Tumour Necrosis Factor-α Converting Enzyme-Epidermal Growth Factor Receptor Signalling Pathway in vivo.

ORL J Otorhinolaryngol Relat Spec 2021 Jun 15:1-9. Epub 2021 Jun 15.

Department of Otolaryngology, The First Affiliated Hospital of Nanchang University, Nanchang, China.

Objectives: The objective of this study is to examine the role of the tumour necrosis factor-α converting enzyme-epidermal growth factor receptor (TACE-EGFR) pathway in human neutrophil elastase (HNE)-induced MUC5AC mucin expression in mice.

Method: Four groups of mice, treated with HNE alone (HNE group), HNE plus TACE inhibitor (HNE + TAPI-2 group), HNE plus EGFR inhibitor (HNE + AG1478 group), and untreated (control group), were used in the experiment. Histopathological changes were monitored by haematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining. Read More

View Article and Full-Text PDF

Long Noncoding RNA GAS5 Targeting miR-221-3p/Cyclin-Dependent Kinase Inhibitor 2B Axis Regulates Follicular Thyroid Carcinoma Cell Cycle and Proliferation.

Pathobiology 2021 Jun 15:1-12. Epub 2021 Jun 15.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.

Introduction: Follicular thyroid carcinoma (FTC) is more aggressive than the most common papillary thyroid carcinoma (PTC). However, the current research on FTC is less than PTC. Here, we investigated the effects of long noncoding RNA (lncRNA) GAS5 and miR-221-3p in FTC. Read More

View Article and Full-Text PDF

Calcineurin Inhibitor Toxicity in Solid Organ Transplantation.

Pharmacology 2021 Jun 15:1-9. Epub 2021 Jun 15.

Department for Nephrology and Hypertension, University Hospital Insel Bern, Bern, Switzerland.

Calcineurin inhibitors (CNIs) have a substantial role in maintaining immunosuppression after solid organ transplantation (SOT). These drugs have a narrow therapeutic window, and individual doses and drug treatment monitoring are necessary. Still, a substantial proportion of patients suffer from short- or long-term calcineurin inhibitor toxicity (CNT), including kidney function impairment, hypertension, neurotoxicity, and metabolic disturbances. Read More

View Article and Full-Text PDF

Clinical Efficacy of Ponatinib in Philadelphia-Positive T-Cell Acute Lymphoblastic Leukemia with Extramedullary Involvement.

Acta Haematol 2021 Jun 15:1-5. Epub 2021 Jun 15.

Istituto di Ematologia "Seràgnoli" IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

T-cell acute lymphoblastic leukemia (T-ALL) is a rare entity in the adult acute leukemia setting. Translocation (9;22)(q34;q11) and BCR-ABL1 rearrangement are occasionally found in T-ALL and have been reported in no more than 100 cases in the literature (most of which are chronic myeloid leukemia blast crisis). Here, we report the remarkable effectiveness of third-generation tyrosine-kinase inhibitor ponatinib in obtaining hematological and metabolic remission, in a patient with Philadelphia chromosome-positive de novo T-ALL and outcomes of a therapeutic strategy containing chemotherapy intensification, nelarabine, and allogeneic hematopoietic stem cell transplantation. Read More

View Article and Full-Text PDF

EML4-ALK fusion variant.3 and co-occurrent PIK3CA E542K mutation exhibiting primary resistance to three generations of ALK inhibitors.

Cancer Genet 2021 May 28;256-257:131-135. Epub 2021 May 28.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

The ALK inhibitors are promising therapeutic agents against lung cancer harboring ALK fusion genes and are currently under development up to the third generation. However, its therapeutic effects are reported to be affected by differences in ALK variants and co-occurrent mutations. Materials and Methods; We experienced an autopsy case of an ALK-positive lung cancer patient who showed primary resistance to three generations of ALK inhibitors. Read More

View Article and Full-Text PDF

"Clicking" fragment leads to novel dual-binding cholinesterase inhibitors.

Bioorg Med Chem 2021 Jun 7;42:116269. Epub 2021 Jun 7.

National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland; National Centre for Nuclear Research, 05-400 Otwock-Świerk, Poland.

Cholinesterase inhibitors are potent therapeutics in the treatment of Alzheimer's disease. Among them, dual binding ligands have recently gained a lot of attention. We discovered novel dual-binding cholinesterase inhibitors, using "clickable" fragments, which bind to either catalytic active site (CAS) or peripheral anionic site (PAS) of the enzyme. Read More

View Article and Full-Text PDF

Synthetic fluorescent MYC probe: Inhibitor binding site elucidation and development of a high-throughput screening assay.

Bioorg Med Chem 2021 Jun 6;42:116246. Epub 2021 Jun 6.

Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States. Electronic address:

We report the discovery of a fluorescent small molecule probe. This probe exhibits an emission increase in the presence of the oncoprotein MYC that can be attenuated by a competing inhibitor. Hydrogen-deuterium exchange mass spectrometry analysis, rationalized by induced-fit docking, suggests it binds to the "coiled-coil" region of the leucine zipper domain. Read More

View Article and Full-Text PDF

Progress in the study of D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) reversing multidrug resistance.

Colloids Surf B Biointerfaces 2021 Jun 8;205:111914. Epub 2021 Jun 8.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, PR China. Electronic address:

Currently, multidrug resistance (MDR) is one of the major reasons for failure in clinical cancer chemotherapy. Overexpression of the ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which significantly increases the efflux of anticancer drugs from tumor cells, enhances MDR. In the past few decades, four generations of P-gp inhibitors have appeared. Read More

View Article and Full-Text PDF

Thromboembolic events associated with immune checkpoint inhibitors: A real-world study of data from the food and drug administration adverse event reporting system (FAERS) database.

Int Immunopharmacol 2021 Jun 12;98:107818. Epub 2021 Jun 12.

Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, Beijing 100020, China. Electronic address:

Background: Although there have been a few studies reporting thromboembolic events (TEEs) in patients treated with immune checkpoint inhibitors (ICIs), the detailed profile of the TEEs and the prothrombotic effects of ICIs remain mostly unknown.

Methods: Data from January 2004 to December 2019 in the FAERS database were retrieved. We investigated the clinical characteristics of the TEEs and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare ICIs with the full database and other anti-cancer agents. Read More

View Article and Full-Text PDF

Tumor progress intercept by intervening in Caveolin-1 related intercellular communication via ROS-sensitive c-Myc targeting therapy.

Biomaterials 2021 Jun 7;275:120958. Epub 2021 Jun 7.

College of Pharmaceutical Science, Zhejiang University, Hangzhou, 310058, China. Electronic address:

Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) play an important role in the development of tumors by secreting a variety of cytokines or directly communicating with tumor cells, making TAMs-targeted therapeutic strategies very attractive. It has been reported that oncogene c-Myc is related to every aspect of the oncogenic process of tumor cells and the alternative activation of macrophages. Hence, we constructed a glycolipid nanocarrier containing ROS-responsive peroxalate linkages (CSOPOSA) for ROS-triggered release of drugs and further modified it with Ex 26 (Ex 26-CSOPOSA), a selective sphingosine 1-phosphate receptor 1 (S1PR1) antagonist, to achieve the dual-targeted delivery of the c-Myc inhibitor JQ1 via S1PR1, which is overexpressed on both tumor cells and TAMs, thereby inducing apoptosis of tumor cells, and blocking M2 polarization of macrophages. Read More

View Article and Full-Text PDF

Restoring NAD by NAMPT is essential for the SIRT1/p53-mediated survival of UVA- and UVB-irradiated epidermal keratinocytes.

J Photochem Photobiol B 2021 Jun 12;221:112238. Epub 2021 Jun 12.

DHC Corporation Laboratories, Division 2, 2-42 Hamada, Mihama-ku, Chiba 261-0025, Japan.

Nicotinamide adenine dinucleotide (NAD) is a crucial coenzyme in energy production. The imbalance of NAD synthesis has been found to trigger age-related diseases, such as metabolic disorders, cancer, and neurodegenerative diseases. Also, UV irradiation induces NAD depletion in the skin. Read More

View Article and Full-Text PDF

Knockdown of CDK5 down-regulates PD-L1 via the ubiquitination-proteasome pathway and improves antitumor immunity in lung adenocarcinoma.

Transl Oncol 2021 Jun 12;14(9):101148. Epub 2021 Jun 12.

Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 Huaihai West Road, Shanghai 200030, PR China. Electronic address:

Although immunotherapy (anti-PD-1/PD-L1 antibodies) has been approved for clinical treatment of lung cancer, only a small proportion of patients respond to monotherapy. Hence, understanding the regulatory mechanism of PD-L1 is particularly important to identify optimal combinations. In this study, we found that inhibition of CDK5 induced by shRNA or CDK5 inhibitor leads to reduced expression of PD-L1 protein in human lung adenocarcinoma cells, while the mRNA level is not substantially altered. Read More

View Article and Full-Text PDF

Proton pump inhibitors and the risk of colorectal cancer.

Authors:
Tomoyuki Kawada

Clin Res Hepatol Gastroenterol 2021 Jun 12:101730. Epub 2021 Jun 12.

Department of Hygiene and Public Health, Nippon Medical School, Japan. Electronic address:

View Article and Full-Text PDF

Loss of hepatocyte identity following aberrant YAP activation: a key mechanism in alcoholic hepatitis.

J Hepatol 2021 Jun 12. Epub 2021 Jun 12.

Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France. Electronic address:

Background & Aims: Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, because understanding of the molecular drivers leading to death are not well understood. This study evaluates the Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration.

Method: The Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcoholic cirrhosis and in control livers, using RNA-Seq, real-time PCR, Western blot, immunohistochemistry (IHC) and transcriptome analysis after laser microdissection. Read More

View Article and Full-Text PDF

Preclinical evidence of synergism between atovaquone and chemotherapy by AMPK-dependent mitochondrial dysfunction.

Eur J Pharmacol 2021 Jun 12:174256. Epub 2021 Jun 12.

Department of Pulmonary and Critical Care Medicine, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China. Electronic address:

Chemoresistance has been associated with increased reliance on mitochondrial functions in many cancers, including lung cancer. Atovaquone is an anti-malaria drug and mitochondrial inhibitor. In this work, we attempted to explore whether atovaquone can be repurposed for lung cancer treatment to overcome chemoresistance. Read More

View Article and Full-Text PDF

Increase in brain L-lactate enhances fear memory in diabetic mice: involvement of glutamate neurons.

Brain Res 2021 Jun 12:147560. Epub 2021 Jun 12.

Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.

Previous reports suggest that diabetes mellitus is associated with psychiatric disorders, including depression and anxiety, but the mechanisms involved are unknown. We have reported that streptozotocin (STZ)-induced diabetic mice show enhancement of conditioned fear memory. To clarify the mechanisms through which diabetes affects conditioned fear memory, the present study investigated the role of L-lactate and glutamatergic function in enhancement of conditioned fear memory in diabetes. Read More

View Article and Full-Text PDF

CTPS forms the cytoophidium in zebrafish.

Exp Cell Res 2021 Jun 12:112684. Epub 2021 Jun 12.

School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom. Electronic address:

Cytidine triphosphate synthase (CTPS) catalyzes the rate-limiting step of de novo CTP biosynthesis. An intracellular structure of CTPS, the cytoophidium, has been found in many organisms including prokaryotes and eukaryotes. Formation of the cytoophidium has been suggested to regulate the activity and stability of CTPS and may participate in certain physiological events. Read More

View Article and Full-Text PDF

Inhibiting microRNA-424 in bone marrow mesenchymal stem cells-derived exosomes suppresses tumor growth in colorectal cancer by upregulating TGFBR3.

Arch Biochem Biophys 2021 Jun 12:108965. Epub 2021 Jun 12.

Oncology Department, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 North Baoshan Road, Yunyan District, Guiyang, 550001, Guizhou, China. Electronic address:

Objective: MicroRNAs (miRNAs) have been demonstrated to be differently expressed in colorectal cancer (CRC) and were identified as biomarkers and therapeutic targets for CRC. We aimed to identify the effect of microRNA-424 (miR-424) on process of CRC.

Methods: Exosomes were obtained from bone marrow mesenchymal stem cells (BMSCs). Read More

View Article and Full-Text PDF

Identification and validation of selective deubiquitinase inhibitors.

Cell Chem Biol 2021 Jun 2. Epub 2021 Jun 2.

Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Deubiquitinating enzymes (DUBs) are a class of isopeptidases that regulate ubiquitin dynamics through catalytic cleavage of ubiquitin from protein substrates and ubiquitin precursors. Despite growing interest in DUB biological function and potential as therapeutic targets, few selective small-molecule inhibitors and no approved drugs currently exist. To identify chemical scaffolds targeting specific DUBs and establish a broader framework for future inhibitor development across the gene family, we performed high-throughput screening of a chemically diverse small-molecule library against eight different DUBs, spanning three well-characterized DUB families. Read More

View Article and Full-Text PDF

Retrospective study of treatment patterns and outcomes post-lenalidomide for multiple myeloma in Canada.

Eur J Haematol 2021 Jun 15. Epub 2021 Jun 15.

Cross Cancer Institute, University of Alberta, Canada.

Lenalidomide is an important component of initial therapy in newly-diagnosed multiple myeloma, either as maintenance therapy post-autologous stem cell transplantation (ASCT) or as first-line therapy with dexamethasone for patients' ineligible for ASCT (non-ASCT). This retrospective study investigated treatment patterns and outcomes for ASCT-eligible and -ineligible patients who relapsed after lenalidomide as part of first-line therapy, based on data from the Canadian Myeloma Research Group Database for patients treated between January 2007 and April 2019. Among 256 patients who progressed on lenalidomide maintenance therapy, 28. Read More

View Article and Full-Text PDF

Neutrophil degranulation biomarkers characterize restrictive echocardiographic pattern with diastolic dysfunction in patients with diabetes.

Eur J Clin Invest 2021 Jun 15:e13640. Epub 2021 Jun 15.

First Clinic of internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132, Genoa, Italy.

Objective: investigating the potential association between neutrophils degranulation and patterns of myocardial dysfunction in a cohort of patients with type 2 diabetes mellitus (T2DM).

Background: Two distinct phenotypes of diabetic cardiomyopathy have been described: a restrictive phenotype with diastolic dysfunction (restrictive/DD) and a dilative phenotype with systolic dysfunction (dilative/SD). However, the underlying determinants of these two patterns are not yet recognized METHODS: In this single-center, observational, cross-sectional study 492 patients were recruited. Read More

View Article and Full-Text PDF

Using darolutamide in advanced prostate cancer: How I Do It.

Authors:
Joelle Hamilton

Can J Urol 2021 Jun;28(3):10673-10677

Urology Centers of Alabama, Homewood, Alabama, USA.

Darolutamide is a nonsteroidal androgen inhibitor FDA approved for the treatment of castration-resistant non-metastatic prostate cancer (nmCRPC). After decades of offering androgen deprivation therapy (ADT) alone or first-generation androgen receptor blockers for patients whose PSA was rising despite castrate levels of testosterone, there are now three different treatment options to add to ADT. These include apalutamide approved in February 2018, enzalutamide FDA approved in June 2018, and darolutamide approved July 2019. Read More

View Article and Full-Text PDF

Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design.

Chem Rev 2021 Jun 15. Epub 2021 Jun 15.

Instituto de Biología Molecular y Celular de Rosario (IBR), CONICET, Universidad Nacional de Rosario, Ocampo y Esmeralda S/N, 2000 Rosario, Argentina.

Antimicrobial resistance is one of the major problems in current practical medicine. The spread of genes coding for resistance determinants among bacteria challenges the use of approved antibiotics, narrowing the options for treatment. Resistance to carbapenems, last resort antibiotics, is a major concern. Read More

View Article and Full-Text PDF

Discovery and Optimization of a Novel 2-Pyrazolo[3,4-d]pyrimidine Derivative as a Potent Irreversible Pan-Fibroblast Growth Factor Receptor Inhibitor.

J Med Chem 2021 Jun 15. Epub 2021 Jun 15.

The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.

Fibroblast growth factor receptors (FGFRs) have become promising therapeutic targets in various types of cancers. In fact, several selective irreversible inhibitors capable of covalently reacting with the conserved cysteine of FGFRs are currently being evaluated in clinical trials. In this article, we optimized and discovered a novel lead compound with remarkable inhibitory effects against FGFR (1-3), which is a derivative of 2-pyrazolo[3,4-d]pyrimidine. Read More

View Article and Full-Text PDF

Screening a Library of FDA-Approved and Bioactive Compounds for Antiviral Activity against SARS-CoV-2.

ACS Infect Dis 2021 Jun 15. Epub 2021 Jun 15.

School of Public Health, Division of Infectious Diseases and Vaccinology, University of California, Berkeley, Berkeley, California 94720, United States.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has emerged as a major global health threat. The COVID-19 pandemic has resulted in over 168 million cases and 3.4 million deaths to date, while the number of cases continues to rise. Read More

View Article and Full-Text PDF

Kidney outcomes using a sustained ≥40% decline in eGFR: A meta-analysis of SGLT2 inhibitor trials.

Clin Cardiol 2021 Jun 15. Epub 2021 Jun 15.

Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: A recent meta-analysis of sodium-glucose cotransporter 2 (SGLT2) inhibitor outcome trials reported that SGLT2 inhibitors were associated with reduction in the risk of adverse composite kidney outcomes, with moderate heterogeneity across the trials; however, the endpoints were defined differently across the trials.

Hypothesis: The apparent heterogeneity of the meta-analysis of kidney composite outcomes of SGLT2 inhibitor trials will be substantially reduced by using a consistent assessment of sustained ≥40% decline in eGFR/chronic kidney dialysis/transplantation/renal death across trials.

Methods: We performed a meta-analysis of kidney composite outcomes from the four SGLT2 cardiovascular outcome trial programs conducted in general type 2 diabetes mellitus populations, which included, as a surrogate of progression to kidney failure, a sustained ≥40% decline in eGFR along with kidney replacement therapy and kidney death. Read More

View Article and Full-Text PDF

The association between neurohormonal therapy and mortality in older adults with heart failure with reduced ejection fraction.

J Am Geriatr Soc 2021 Jun 15. Epub 2021 Jun 15.

The Dartmouth Institute, Geisel School of Medicine, Hanover, New Hampshire, USA.

Background/objectives: Neurohormonal therapy, which includes beta-blockers and angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (ACEi/ARBs), is the cornerstone of heart failure with reduced ejection fraction (HFrEF) treatment. While neurohormonal therapies have demonstrated efficacy in randomized clinical trials, older patients, which now comprise the majority of HFrEF patients, were underrepresented in those original trials. This study aimed to determine the association between short- (30 day) and long-term (1 year) mortality and the use of neurohormonal therapy in HFrEF patients, across the age spectrum. Read More

View Article and Full-Text PDF