Thromboembolic risk in prostate cancer patients treated with PARP inhibitors: A systematic review and meta-analysis.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) have been associated with thrombotic events, although the association with thrombosis risk in different cancers remains poorly defined. METHODS: This meta-analysis included phase II and phase III clinical trials in which patients with metastatic prostate cancer were treated with PARPi either as monotherapy or in combination. The primary endpoints were the rates of thromboembolic events in prostate cancer patients. RESULTS: A total of 2210 and 1662 patients with prostate cancer were compared in the PARP inhibitor and control groups, respectively. 96 (4.3 %) and 37 (2.2 %) patients had thrombosis in the PARPi and control groups, respectively. PARPi had a statistically significant increased risk of thrombosis in prostate cancer patients (Odds Ratio (OR)=1.98, 95 % CI: 1.06-3.70, P=0.030). CONCLUSION: The heightened thrombotic risk associated with PARPi treatment in prostate cancer emphasizes the need for comprehensive management protocols to effectively reduce the risk and ensure safer outcomes.

Asymptomatic pyuria and bacteriuria are not risk factors for urinary tract infection in women with type 2 diabetes mellitus initiated SGLT2 inhibitors.

PURPOSE: Asymptomatic pyuria and bacteriuria are more prevalent in diabetic patients and may be associated with urinary tract infection (UTI). The aim of this study is to investigate the association between asymptomatic pyuria/bacteriuria at the initiation of SGLT2 inhibitor and UTI risk in female patients with type 2 diabetes. METHODS: The study was designed as a practical, single-center, prospective, cohort study. The female outpatients with type 2 diabetes initiated SGLT2 inhibitor were included. Patients who were symptomatic or treated in the past 3 months for urinary or genital tract infection, had a high risk for UTI were excluded. Hospitalization/antibiotic use for indications other than UTI were exclusion criteria during follow-up. All patients were followed up for 3 months. Pyuria and bacteriuria were exposure and, UTI was the outcome. Cumulative incidence and relative risk of UTI were analyzed for pyuria and bacteriuria. RESULTS: 143 female patients were included among 1132 female type 2 diabetic patients. 13 patients were excluded during follow-up. 41.5% of the patients (n = 54) had pyuria and 28.5% (n = 37) had bacteriuria. The cumulative incidence of UTI was 20% in the whole cohort, 25,9% (n = 14/54) in the pyuria group and 18.9% (n = 7/37) in the bacteriuria group. The relative risk of UTI was 1.64 (95% CI: 0.82-3.26, p = 0.15) for pyuria, 0.92 (95% CI: 0.42-2.01, p = 0.84) for bacteriuria, and 1.2 (95% CI: 0.47-3.08, p = 0.69) for pyuria plus bacteriuria. Adjusted odd ratios revealed similar results. CONCLUSIONS: Asymptomatic pyuria/bacteriuria at the initiation of SGLT2 inhibitors are not risk factors for UTI in women with type 2 diabetes.

Germline genetic variants in Turkish familial multiple myeloma/monoclonal gammopathy of undetermined significance cases.

Multiple myeloma (MM) is a haematological malignancy primarily affecting the elderly, with a striking male predilection and ethnic disparities in incidence. Familial predisposition to MM has long been recognized, but the genetic underpinnings remain elusive. This study aimed to investigate germline variants in Turkish families with recurrent MM cases. A total of 37 MM-affected families, comprising 77 individuals, were included. Targeted next-generation sequencing analysis yielded no previously reported rare variants. Whole exome sequencing analysis in 11 families identified rare disease-causing variants in various genes, some previously linked to familial MM and others not previously associated. Notably, genes involved in ubiquitination, V(D)J recombination and the PI3K/AKT/mTOR pathway were among those identified. Furthermore, a specific variant in BNIP1 (rs28199) was found in 13 patients across nine families, indicating its potential significance in MM pathogenesis. While this study sheds light on genetic variations in familial MM in Turkey, its limitations include sample size and the absence of in vivo investigations. In conclusion, familial MM likely involves a polygenic inheritance pattern with rare, disease-causing variants in various genes, emphasizing the need for international collaborative efforts to unravel the intricate genetic basis of MM and develop targeted therapies.

Clinical evaluation of DIAGNOVIR SARS-CoV-2 ultra-rapid antigen test performance compared to PCR-based testing.

Coronavirus Disease-19 (COVID-19) is a highly contagious infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The development of rapid antigen tests has contributed to easing the burden on healthcare and lifting restrictions by detecting infected individuals to help prevent further transmission of the virus. We developed a state-of-art rapid antigen testing system, named DIAGNOVIR, based on immune-fluorescence analysis, which can process and give the results in a minute. In our study, we assessed the performance of the DIAGNOVIR and compared the results with those of the qRT-PCR test. Our results demonstrated that the sensitivity and specificity of the DIAGNOVIR were 94% and 99.2%, respectively, with a 100% sensitivity and 96.97% specificity, among asymptomatic patients. In addition, DIAGNOVIR can detect SARS­CoV­2 with 100% sensitivity up to 5 days after symptom onset. We observed that the DIAGNOVIR Rapid Antigen Test's limit of detection (LoD) was not significantly affected by the SARS­CoV­2 variants including Wuhan, alpha (B1.1.7), beta (B.1.351), delta (B.1.617.2) and omicron (B.1.1.529) variants, and LoD was calculated as 8 × 102, 6.81 × 101.5, 3.2 × 101.5, 1 × 103, and 1 × 103.5 TCID50/mL, respectively. Our results indicated that DIAGNOVIR can detect all SARS-CoV-2 variants in just seconds with higher sensitivity and specificity lower testing costs and decreased turnover time.

Crizotinib efficacy and safety in patients with advanced NSCLC harboring MET alterations: A real-life data of Turkish Oncology Group.

Crizotinib is a multikinase inhibitor, effective in non-small cell lung cancer (NSCLC) harboring mesenchymal-epidermal transition (MET) alterations. Although small prospective studies showed efficacy and safety of crizotinib in NSCLC with MET alterations, there is limited real-life data. Aim of this study is to investigate real-life efficacy and safety of crizotinib in patients with advanced NSCLC harboring MET alterations. This was a retrospective, multicenter (17 centers) study of Turkish Oncology Group. Patients' demographic, histological data, treatment, response rates, survival outcomes, and toxicity data were collected. Outcomes were presented for the study population and compared between MET alteration types. Total of 62 patients were included with a median age of 58.5 (range, 26-78). Major histological type was adenocarcinoma, and 3 patients (4.8%) had sarcomatoid component. The most common MET analyzing method was next generation sequencing (90.3%). MET amplification and mutation frequencies were 53.2% (n = 33) and 46.8% (n = 29), respectively. Overall response rate and disease control rate were 56.5% and 74.2% in whole study population, respectively. Median progression free survival (PFS) was 7.2 months (95% confidence interval [CI]: 3.8-10.5), and median overall survival (OS) was 18.7 months (95% CI: 13.7-23.7), regardless of treatment line. Median PFS was 6.1 months (95% CI: 5.6-6.4) for patients with MET amplification, whereas 14.3 months (95% CI: 6.7-21.7) for patients with MET mutation (P = .217). Median PFS was significantly longer in patients who have never smoked (P = .040), have good performance score (P < .001), and responded to the treatment (P < .001). OS was significantly longer in patients with MET mutation (25.6 months, 95% CI: 15.9-35.3) compared to the patients with MET amplification (11.0 months; 95% CI: 5.2-16.8) (P = .049). In never-smokers, median OS was longer than smoker patients (25.6 months [95% CI: 11.8-39.3] vs 16.5 months [95% CI: 9.3-23.6]; P = .049). The most common adverse effects were fatigue (50%), peripheral edema (21%), nausea (29%) and diarrhea (19.4%). Grade 3 or 4 adverse effects were observed in 6.5% of the patients. This real-life data confirms efficacy and safety of crizotinib in the treatment of advanced NSCLC harboring MET alteration.

The relationship between clinicopathological parameters and PD-L1 expression level in advanced stage non-small cell lung cancer.

Introduction: Clinicopathological parameters related to programmed death ligand 1 (PD-L1) expression levels have been investigated in several studies. However, the results of these studies are conflicting and vary in different populations. This study aimed to investigate the relation of clinicopathological parameters with PD-L1 expression level in advanced stage non-small cell lung cancer patients. Materials and Methods: The patients diagnosed with non-small cell lung cancer were enrolled, retrospectively. The data of clinicopathological parameters was collected. Clinicopathological parameters in relation to PD-L1 expression levels (0%, 1-50%, and >50%) were analyzed as univariable and multivariable. Result: In total, 384 patients were enrolled. PD-L1 expression in tumor cells was between 1-50%, and >50% in 41.4%, and 23.4% of patients, respectively. There was no PD-L1 expression in 35.2% of the patients. In univariable analysis, we found that the parameters associated with PD-L1 expression levels revealed that metastatic site number, the subtype of cancer, diagnostic material type, platelet number, and LDH level were statistically significant. Adenocarcinoma frequency was higher in tumors that had PD-L1 expression >50% than in tumors that did not express PD-L1 and the difference was statistically significant (p= 0.04, coefficient= 0.3, 95% CI 0.09-0.94). Cytology as diagnostic material was significant in PD-L1 level 1-50% comparing to >50% (p= 0.02, coefficient= 2.2, 95% CI= 1.08-4.46). Conclusions: According to the results of our study, many of the clinicopathological parameters are not related to the PD-L1 level. The histological subtype and diagnostic material may affect the level of PD-L1 expression.

Atezolizumab combined with chemotherapy in the first-line treatment of extensive-stage small cell lung cancer: a real-life data of the Turkish Oncology Group.

PURPOSE: Atezolizumab has been shown to be effective and safe in randomized trial in the first-line treatment of extensive-stage small cell lung cancer (SCLC). However, there are limited real-life data on atezolizumab. In this study, we aimed to determine the real-life efficacy and safety of atezolizumab combined with chemotherapy in the first-line treatment of extensive-stage SCLC. METHODS: This trial is a retrospective multicenter study of the Turkish Oncology Group, which included extensive-stage SCLC patients who received atezolizumab combined with chemotherapy in a first-line treatment. The characteristics of the patients, treatment and response rates, and PFS and OS are presented. Factors associated with PFS and OS were analyzed by univariate and multivariate analysis. RESULTS: A total of 213 patients at the 30 oncology centers were included. The median number of chemotherapy cycle was 5 (1-8) and atezolizumab cycle was 7 (1-32). After median 11.9 months of follow-up, median PFS and OS was 6.8 months (95%CI 5.7-7.8), and 11.9 months (95%CI 11-12.7), respectively. The ORR was 61.9%. ECOG-PS (p = 0.002) and number of metastatic sites (p = 0.001) were associated with PFS and pack-year of smoking (p = 0.05), while ECOG-PS (p = 0.03) and number of metastatic sites (p = 0.001) were associated with OS. Hematological side effects were common and toxicities were manageable. CONCLUSION: This real-life data confirm the efficacy and safety of atezolizumab in combination with chemotherapy in first-line treatment of extensive-stage SCLC.

Glucagon-like peptide-1 receptor agonist treatment of high carbohydrate intake-induced metabolic syndrome provides pleiotropic effects on cardiac dysfunction through alleviations in electrical and intracellular Ca2+ abnormalities and mitochondrial dysfunction.

The pleiotropic effects of glucagon-like peptide-1 receptor (GLP-1R) agonists on the heart have been recognised in obese or diabetic patients. However, little is known regarding the molecular mechanisms of these agonists in cardioprotective actions under metabolic disturbances. We evaluated the effects of GLP-1R agonist liraglutide treatment on left ventricular cardiomyocytes from high-carbohydrate induced metabolic syndrome rats (MetS rats), characterised with insulin resistance and cardiac dysfunction with a long-QT. Liraglutide (0.3 mg/kg for 4 weeks) treatment of MetS rats significantly reversed long-QT, through a shortening the prolonged action potential duration and recovering inhibited K+ -currents. We also determined a significant recovery in the leaky sarcoplasmic reticulum (SR) and high cytosolic Ca2+ -level, which are confirmed with a full recovery in activated Na+ /Ca2+ -exchanger currents (INCX ). Moreover, the liraglutide treatment significantly reversed the depolarised mitochondrial membrane potential (MMP), increased production of oxidant markers, and cellular acidification together with the depressed ATP production. Our light microscopy analysis of isolated cardiomyocytes showed marked recoveries in the liraglutide-treated MetS group such as marked reverses in highly dilated T-tubules and SR-mitochondria junctions. Moreover, we determined a significant increase in depressed GLUT4 protein level in liraglutide-treated MetS group, possibly associated with recovery in casein kinase 2α. Overall, the study demonstrated a molecular mechanism of liraglutide-induced cardioprotection in MetS rats, at most, via its pleiotropic effects, such as alleviation in the electrical abnormalities, Ca2+ -homeostasis, and mitochondrial dysfunction in ventricular cardiomyocytes.

Trastuzumab ± Capecitabine Maintenance After the First-Line Treatment of HER2-Positive Advanced Gastric Cancer: Retrospective Observational Real-Life Data of Turkish Oncology Group.

PURPOSE: In the ToGA trial for HER2-positive advanced gastric cancer, cisplatin plus fluoropyrimidine was given for 6 cycles; trastuzumab was given until disease progression. However, there is a lack of real-life data about trastuzumab maintenance after 6 cycle chemotherapy. This study aims to present real-life data of trastuzumab ± capecitabine maintenance after 6 cycles of platinum, fluoropyrimidine, and trastuzumab in non-progressive patients. METHODS: This is a retrospective multicenter study of the Turkish Oncology Group. A total of 35 HER2-positive, inoperable locally advanced, recurrent, or metastatic gastric adenocarcinoma patients being non-progressive at the end of 6 cycle chemotherapy and being given trastuzumab ± capecitabine as maintenance treatment were included from sixteen oncology centers. Baseline characteristics, objective tumor responses, progression free and overall survival data, and toxicities were determined. RESULTS: About 68% of the patients were given CF, and 32% were given FOLFOX with trastuzumab as the first-line treatment. The best response in 6 cycle chemotherapy was complete 8 (22%), partial 24 (68%), and stable disease 3 (8%). All patients had trastuzumab maintenance (median cycle 13; range 7-51), and 49% of the patients had capecitabine with trastuzumab (median capecitabine cycle 6; range 2-30). The median PFS of the patients was 12.0 months (95% CI 10.3-13.7), and median OS was 17.4 months (95% CI 15.2-19.5). There were 2 patients with grade 1 cardiotoxicity. CONCLUSION: Trastuzumab maintenance ± capecitabine after 6 cycles of trastuzumab plus combined chemotherapy treatment revealed efficacy and safety in non-progressive HER2-positive advanced gastric cancer.

Efficacy and tolerability of vismodegib treatment in locally advanced and metastatic basal cell carcinoma: Retrospective real-life data.

The study aims to evaluate the vismodegib treatment in local advanced (laBCC) and metastatic (mBCC) basal cell carcinoma. The data of 29 patients were retrospectively reviewed. The clinical and histopathological features of the patients and adverse events of vismodegib were recorded. Overall survival (OS) and progression-free survival (PFS) were evaluated with Kaplan-Meier analysis. The median follow-up period was 17 months (range: 1.6-57.3), and the median age at diagnosis 73 years (range: 39-88). The most common disease location was head and neck (86.2%), and the most common non-skin sites of disease were lymph nodes (13.8%), bone (13.8%), lung (6.9%), and brain (6.9%). Three (10.3%) patients had Gorlin's syndrome. The number of metastatic patients was 5 (17.2%). With vismodegib treatment, the complete response rate was 27.6%, partial response 55.2%, and stable response 10.3%. Treatment responses were most frequently seen within 2 months from the beginning of vismodegib. The median OS was 43.3 ± 9.0 months (25.6-61.1) for all patients. The median PFS in the laBCC was 15.7 ± 1.8 months (12.2-19.3), and 12.1 ± 4.6 months (2.9-21.2) in the mBCC. In the univariable analysis for the OS, only the treatment after the vismodegib was statistically significant, showing chemotherapy was better comparing to no treatment or surgery. The most common adverse events were fatigue-58.6%, muscle spasms-48.3%, alopecia-13.8%, and weight loss-13.8%. This real-life data study shows that vismodegib treatment in locally advanced and metastatic BCC was well tolerated and effective.

Topical aloe vera for the treatment of cetuximab-related acneiform rash in colorectal cancer: A case report.

INTRODUCTION: Colorectal cancer is one of the most common cancers in the world. Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor which provides survival benefit when combined with chemotherapy in RAS wild type metastatic colorectal cancer. Cutaneous toxicities associated with cetuximab have a significant impact on patient quality of life, treatment continuation and healthcare resource utilization. CASE REPORT: A 60-year-old male patient presented with fatigue, weight loss and abdominal pain. Two closely located malignant polypoid lesions were detected in the sigmoid colon, and pathological examination revealed colonic adenocarcinoma.Management and outcome: Thorax, abdominal and pelvic computed tomography showed metastases. FOLFOX chemotherapy and cetuximab were started. The patient developed acneiform rash firstly in his face, although prophylactic vitamin K1 0.1% containing cream was given. He was given mild potency topical corticosteroid and doxycycline. The lesions progressed to his front and back body. He did not want to use topical vitamin K1 cream, topical steroid and doxycycline tablets. Instead, he wanted to use aloe vera extract which he produced from the leaves of the plant. Patient's lesions were regressed significantly. DISCUSSION: The most common and earliest skin toxicity is acneiform rash which affects 60 to 80% of the patients. In this case, cetuximab-related severe acneiform rash was effectively treated by topical aloe vera. Topical aloe vera may be used in the management of cetuximab-related cutaneous toxicities without any side effect.

Combination of trastuzumab and taxane-containing intensified chemotherapy in first-line treatment of HER2-positive advanced gastric cancer.

PURPOSE: Taxane-containing combinations are recommended for the first-line therapy of advanced gastric cancer. It is not known which chemotherapy regimen is the best with trastuzumab for HER2-positive patients. The aim of this study was to compare taxane-containing intensified chemotherapy versus standard chemotherapy in combination with trastuzumab in the first-line treatment of HER2-positive advanced gastric adenocarcinoma. METHODS: This study is a retrospective multicenter study of the Turkish Oncology Group. A total of 130 HER2-positive patients with inoperable locally advanced, recurrent, or metastatic gastric adenocarcinoma being given chemotherapy plus trastuzumab as the first-line treatment were included from 16 different oncology centers. Trastuzumab combination with intensified chemotherapy including taxane or standard chemotherapy was compared in terms of progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: There were 108 patients in the standard and 22 patients in the intensified chemotherapy group. PFS of the standard and intensified group were 5.6 months (95% confidence interval [CI] 4.8-6.4) and 5.3 months (95% CI 2.6-8), respectively (p = 0.70). OS of the standard and intensified group were 11.1 months (95% CI 8.3-13.9) and 15.2 months (95% CI 12.7-17.7), respectively (p = 0.03). Repeated analysis excluding patients given any previous therapy revealed similar results. The intensified group had more fever and febrile neutropenia. CONCLUSION: Trastuzumab combination with intensified chemotherapy provides better OS in first-line treatment of HER2-positive advanced gastric cancer. Further large-scale studies should be performed in HER2-positive patients.

Thyroid dysfunctions in adult patients after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Thyroid dysfunction (TD) is one of the major endocrinopathies shown after allogeneic hematopoietic stem cell transplantation over the long term. The incidence and the risk factors for TD have varied widely. PATIENTS AND METHODS: Two hundred and fifty-nine patients with pre-transplant normal thyroid function tests who survived at least 1 year after allo-HSCT between 2006-2016 were included in the study. RESULTS: Sixty-four patients (25%) developed TD at median of 34 months (range, 1-112 months). Hypothyroidism was detected in 32 patients (12%): 5 patients had primary hypothyroidism, and subclinical hypothyroidism occurred in 27 patients. 18 patients (7%) were diagnosed with hyperthyroidism: 2 patients (0.07%) were treated for primary hyperthyroidism, and 16 patients (6%) were followed for subclinical hyperthyroidism. Euthyroid sick syndrome occurred in 14 cases. None of the patients with thyroid dysfunction developed secondary thyroid malignancy. Receiving high-dose TBI (P = .001) was found to be significant risk for hypothyroidism; older age than median (P = .01) and pre-transplant active disease (P < .0001) were related to hyperthyroidism. CONCLUSIONS: Thyroid dysfunction, mostly hypothyroidism, is a long-term complication after allo-HSCT in 25% of patients. Older age, pre-transplant active disease, and receiving TBI are among the risk factors. Sustained long-term monitoring of thyroid function test should be considered post allo-HSCT.

Mean platelet volume and response to the first line therapy in newly diagnosed adult immune thrombocytopenia patients: a retrospective study

Background/aim: Immune thrombocytopenia (ITP) is treated by corticosteroids and/or intravenous immune globulin as the first line treatment when necessary. Mean platelet volume (MPV) is a marker of platelet production and function. In this study, we aimed to search the relationship between the MPV and the treatment response in ITP patients and it was hypothesized that MPV can be used as a predictor of the response. Materials and methods: The 70 newly diagnosed adult primary ITP patients and 70 of healthy people were included. MPV between ITP and healthy population, MPV in the diagnosis and after the treatment between the responders and the nonresponders were compared. Results: The responders had significantly higher MPV and the nonresponders had significantly lower MPV than the healthy population (11.09 and 10.21 fL, P = 0.03; 9.38 and 10.21 fL, P = 0.001). MPV in the diagnosis was significantly higher in the responders than the nonresponders (11.09 and 9.38 fL, P = 0.005). MPV significantly changed after the treatment in the responders (11.09 to 9.32 fL, P = 0.004). Conclusion: MPV can be used as a predictor of early response to the first line treatment in newly diagnosed adult primary ITP patients.

Sweet's syndrome under ipilimumab therapy and a brief comparison of the cases in literature.

INTRODUCTION: Ipilimumab is an anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody. Ipilimumab has shown improvement in overall survival in patients with advanced melanoma. Because ipilimumab activates the immune system against the tumor, ipilimumab is associated with adverse events related to immune system activation. Immune-associated side effects are frequently seen in the gastrointestinal system and skin. Sweet's syndrome (SS) is an uncommon inflammatory disorder. Some drugs or malignancy can cause SS. Only a few case reports have been reported of ipilimumab-associated SS. CASE: A 53-year-old female with metastatic melanoma was treated with ipilimumab. After the fourth cycle, she developed painful lesions on her legs and hands. The pathologic biopsy of the lesions revealed neutrophilic dermatosis consistent with SS.Management and outcome: The patient was treated with 60 mg/day of prednisone for four days, nonsteroidal anti-inflammatory drugs and inhaler bronchodilator and steroid. She had symptomatic relief at the beginning of treatment. The prednisone doses were quickly tapered every three days. When the patient was treated with 10 mg/day of prednisone for three days, the skin nodules recurred. Prednisone 40 mg per day was re-started and then a slower taper by decreasing by 10 mg/day every week was instituted. After one-month treatment the prednisone dose was given as a 5 mg doses for one week and then stopped. No new lesions recurred after slower taper of prednisone. CONCLUSION: Herein we report a case presented with SS under ipilimumab therapy. Melanoma patients treated with ipilimumab can develop SS. The clinicians should be aware of this condition.

Regulation of the unfolded protein response through ATF4 and FAM129A in prostate cancer.

Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. Using systemic unbiased gene expression and proteomic analyses, we identified a novel direct ATF4 target gene, family with sequence similarity 129 member A (FAM129A), which is critical in mediating ATF4 effects on prostate tumorigenesis. Interestingly, FAM129A regulated both PERK and eIF2α in a feedback loop that differentially channeled the UPR output. ATF4 and FAM129A protein expression is increased in patient PCa samples compared with benign prostate. Importantly, in vivo therapeutic silencing of ATF4-FAM129A axis profoundly inhibited tumor growth in a preclinical PCa model. These data support that one of the canonical UPR branches, through ATF4 and its target gene FAM129A, is required for PCa growth and thus may serve as a novel therapeutic target.

A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats.

BACKGROUND: Metabolic syndrome (MetS) is a prevalent risk factor for cardiac dysfunction. Although SGLT2-inhibitors have important cardioprotective effects in hyperglycemia, their underlying mechanisms are complex and not completely understood. Therefore, we examined mechanisms of a SGLT2-inhibitor dapagliflozin (DAPA)-related cardioprotection in overweight insulin-resistant MetS-rats comparison with insulin (INSU), behind its glucose-lowering effect. METHODS: A 28-week high-carbohydrate diet-induced MetS-rats received DAPA (5 mg/kg), INSU (0.15 mg/kg) or vehicle for 2 weeks. To validate MetS-induction, we monitored all animals weekly by measuring body weight, blood glucose and HOMO-IR index, electrocardiograms, heart rate, systolic and diastolic pressures. RESULTS: DAPA-treatment of MetS-rats significantly augmented the increased blood pressure, prolonged Q-R interval, and low heart rate with depressed left ventricular function and relaxation of the aorta. Prolonged-action potentials were preserved with DAPA-treatment, more prominently than INSU-treatment, at most, through the augmentation in depressed voltage-gated K+-channel currents. DAPA, more prominently than INSU-treatment, preserved the depolarized mitochondrial membrane potential, and altered mitochondrial protein levels such as Mfn-1, Mfn-2, and Fis-1 as well as provided significant augmentation in cytosolic Ca2+-homeostasis. Furthermore, DAPA also induced significant augmentation in voltage-gated Na+-currents and intracellular pH, and the cellular levels of increased oxidative stress, protein-thiol oxidation and ADP/ATP ratio in cardiomyocytes from MetS rats. Moreover, DAPA-treatment normalized the increases in the mRNA level of SGLT2 in MetS-rat heart. CONCLUSIONS: Overall, our data provided a new insight into DAPA-associated cardioprotection in MetS rats, including suppression of prolonged ventricular-repolarization through augmentation of mitochondrial function and oxidative stress followed by improvement of fusion-fission proteins, out of its glucose-lowering effect.