Increase In AST Research Articles

Multiple organs injury and myocardial energy metabolism disorders induced by isoproterenol

The study sought to assess the detrimental effects of isoproterenol (ISO) on major organs and investigate the potential reversibility of these adverse reactions in mice. Male mice were divided into normal control, 0.2 mg/kg.d and 3.0 mg/kg.d ISO groups, and were subcutaneously administered of the respective doses for 14 consecutive days. Subsequently, a recovery period experiment was conducted, replicating the aforementioned procedure, followed by an additional 2-week recovery period for the mice. Following 14 consecutive days of administration, mice treated with ISO exhibited notable cardiac damage manifested by abnormal ECG patterns, dysregulated energy metabolism, elevated cardiac hypertrophy, and increased heart pathological score. Additionally, the administration of ISO resulted in liver and kidney damage, as evidenced by increased pathological score, serum albumin level, and urea level. Lung damage was also observed, indicated by an increase in lung pathological score. Furthermore, the administration of ISO at a dosage of 3.0 mg/kg.d resulted in a decrease in liver mass index, serum iron content, and an increase in lung mass index. After a 2-week recovery period, mice treated with ISO showed abnormalities in ECG patterns and dysregulated myocardial energy metabolism, accompanied by a decrease in serum iron content. Histopathological examinations revealed continued pathological changes in the heart and lung, as well as significant hemosiderin deposition in the spleen. Furthermore, the group treated with ISO at a dosage of 3.0 mg/kg.d showed an increase in serum AST and TP levels. In summary, the study demonstrates that both 0.2 mg/kg.d and 3.0 mg/kg.d doses of ISO can induce damage to the heart, liver, lung, kidney, and spleen, with the higher dose causing more severe injuries. After a 2-week withdrawal period, the liver, kidney, and thymus injuries caused by 0.2 mg/kg ISO shows signs of recovery, while damage to the heart, lung, and spleen persists. The thymus injury mostly recovers, with minimal kidney pathology, but significant damage to the heart, liver, and lung remains even after the withdrawal period for the 3.0 mg/kg ISO dose.

Links between gut microbiome, metabolome, clinical variables and non-alcoholic fatty liver disease severity in bariatric patients.

Bacterial species and microbial pathways along with metabolites and clinical parameters may interact to contribute to non-alcoholic fatty liver disease (NAFLD) and disease severity. We used integrated machine learning models and a cross-validation approach to assess this interaction in bariatric patients. 113 patients undergoing bariatric surgery had clinical and biochemical parameters, blood and stool metabolite measurements as well as faecal shotgun metagenome sequencing to profile the intestinal microbiome. Liver histology was classified as normal liver obese (NLO; n = 30), simple steatosis (SS; n = 41) or non-alcoholic steatohepatitis (NASH; n = 42); fibrosis was graded F0 to F4. We found that those with NASH versus NLO had an increase in potentially harmful E. coli, a reduction of potentially beneficial Alistipes putredinis and an increase in ALT and AST. There was higher serum glucose, faecal 3-(3-hydroxyphenyl)-3-hydroxypropionic acid and faecal cholic acid and lower serum glycerophospholipids. In NAFLD, those with severe fibrosis (F3-F4) versus F0 had lower abundance of anti-inflammatory species (Eubacterium ventriosum, Alistipes finegoldii and Bacteroides dorei) and higher AST, serum glucose, faecal acylcarnitines, serum isoleucine and homocysteine as well as lower serum glycerophospholipids. Pathways involved with amino acid biosynthesis and degradation were significantly more represented in those with NASH compared to NLO, with severe fibrosis having an overall stronger significant association with Superpathway of menaquinol-10 biosynthesis and Peptidoglycan biosynthesis IV. In bariatric patients, NASH and severe fibrosis were associated with specific bacterial species, metabolic pathways and metabolites that may contribute to NAFLD pathogenesis and disease severity.

Integration of pharmacodynamics and metabolomics to reveal rhubarb anthraquinone protection against nonalcoholic fatty liver disease rat model.

The objective of the present study was to investigate the effect of Rhubarb anthraquinone (RA) on a high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) rat model, and explore potential biomarker and metabolic pathways by using the metabolomics method. We established HFD rats as the NAFLD model. Forty Sprague-Dawley rats were randomly divided into a control group, model group, RA low-dose group, RA medium-dose group, and RA high-dose group, and evaluated the protective effect of RA on NAFLD by detecting biochemical indicators of serum and pathological changes of liver tissue. Investigating potential biomarkers and metabolic pathways connected with RA's protective effects against NAFLD by UHPLC-Q-TOF-MS untargeted metabolomics. The results showed that RA significantly reversed the increase of TG, TC, ALT, AST, and ALP (P < .05), the decrease of HDL-C (P < .05), and alleviated pathological conditions in NAFLD rats. Based on potential biomarker analysis, RA affected metabolic pathways such as fatty acids biosynthesis, bile acids biosynthesis, and pentose phosphate pathway, delaying the progression of NAFLD. RA improved blood lipid levels, liver function, and pathological conditions of NAFLD rats. Meanwhile, affected the metabolic pathways and regulated the synthesis of fatty acids and bile acids in NAFLD rats.

Enfortumab vedotin (EV) as monotherapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of stage I of a phase 2 trial.

152 Background: EV is an antibody-drug conjugate consisting of a fully human antibody directed against the extracellular domain of Nectin-4, which is conjugated to a microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker. In animal models of prostate cancer, metastatic lesions showed high membranous Nectin-4 expression (PMID: 30767361). We aimed to investigate EV in pts with mCRPC. Methods: This IRB-approved, investigator-initiated, single-arm, single-center, phase 2 study administered EV at 1.25 mg/kg IV on days 1, 8, and 15 of 28 days cycle. Key eligibility criteria: ≥18 years age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, performance status ≤ 1, adequate organ function, prior treatment (Rx) with ≥3 cycles of docetaxel and at least one androgen-receptor pathway inhibitor, received/refused all therapies shown to improve overall survival except cabazitaxel which is exclusionary. Primary objective: To assess antitumor activity of EV as determined by one of the following: 1) objective response by RECIST 1.1 in those with measurable disease, 2) confirmed conversion of circulating tumor cell count (CTC) to &lt;5/7.5 mL blood, 3) PSA decline of ≥ 50%, and 4) stable disease for ≥ 6 months per PCWG3 modified RECIST 1.1. Simon’s two-stage design was used. The null hypothesis (H0) that true response rate (RR) is 25% is tested against a one-sided alternative. In stage I if ≤3 responses were observed of 11 pts, the study will be stopped. Otherwise, 23 additional pts will be accrued (total 34). H0 will be rejected if ≥13 responses are observed in 34 pts (type I error rate 0.046, power 0.854 when true RR is 50%). Results: Herein, we present results of 11 pts treated on stage I of study. All pts were non-Hispanic white with median age of 72 years (range 43-78). Median number of prior systemic therapies in addition to castration: 5 (range 3-8). Median follow-up of the cohort was 9 months (range 1-13). 4/11 had RECIST measurable disease and 7/11 had CTC ≥5 at baseline. Overall 7/11 (64%) pts had protocol-defined response (5/11 PSA 50% responses, 3/4 objective response, 4/7 confirmed CTC response and 2/11 ≥ 6 months on Rx). Of the 9 pts who discontinued Rx, 8 discontinued due to disease progression (1 withdrew consent). Median number of completed cycles were 6 (range: 2-12) and median radiographic progression-free survival was 5.5 months (95% CI 5.3-not reached). Most common grade 3/4 treatment-related adverse events (TRAEs) were anemia, AST increase, dry skin, fatigue, hyperglycemia, rash, leucopenia (1 pt each) and nausea and decrease in neutrophil (2 pts each). 8 pts had dose interruptions and dose reductions. No Grade 5 TRAEs. Conclusions: EV showed promising efficacy and an acceptable safety profile in pts with heavily treated refractory mCRPC. Further enrollment in stage 2 of the trial is ongoing. Clinical trial information: NCT04754191 .

Ferroptosis participated in inhaled polystyrene nanoplastics-induced liver injury and fibrosis

The emerging contaminant nanoplastics (NPs) have received considerable attention. Due to their tiny size and unique colloidal properties, NPs could more easily enter the body and cross biological barriers with inhalation exposure. While NPs-induced hepatotoxicity has been reported, the hepatic impact of inhaled NPs was still unknown. To close this gap, a 40 nm polystyrene NPs (PS-NPs) inhalation exposure mice model was developed to explore the hepatotoxicity during acute (1 week), subacute (4 weeks), and subchronic period (12 weeks), with four exposure doses (0, 16, 40, and 100 μg/day). Results showed that inhaled PS-NPs caused a remarkable increase of ALT, AST, and ALP with a decrease of CHE, indicating liver dysfunction. Various histological abnormalities and significantly higher levels of inflammation in a dose- and time-dependent manner were observed. Moreover, after 4 weeks and 12 weeks of exposure, Masson staining and upregulated expression of TGF-β, α-SMA, and Col1a1 identified that inhaled PS-NPs exposure triggered the progression of liver fibrosis with the exposure time prolonged. From the mechanistic perspective, transcriptome analysis revealed that ferroptosis was involved in PS-NPs-induced liver hepatotoxicity, and key features of ferroptosis were detected, including persistent oxidative stress, iron overload, increased LPO, mitochondria damage, and the expression changes of GPX4, TFRC, and Ferritin. And in vitro and in vivo recovery tests showed that ferroptosis inhibitor Fer-1 treatment alleviated liver injury and fibrosis. The above results confirmed the critical role of ferroptosis in PS-NPs-induced hepatotoxicity. Furthermore, to better conclude our findings and understand the mechanistic causality within it, an adverse outcome pathway (AOP) framework was established. In total, this present study conducted the first experimental assessment of inhalation exposure to PS-NPs on the liver, identified that continuous inhaled PS-NPs could cause liver injury and fibrosis, and PS-NPs- ferroptosis provided a novel mechanistic explanation.

Physiological responses of oxidative damage, genotoxicity and hematological parameters of the toxic effect of neonicotinoid-thiamethoxam in Oreochromis niloticus

The purpose of investigation assessed the impacts of neonicotinoid thiamethoxam (TMX) at sublethal concentrations in hematological profile and renal function of Oreochromis niloticus. In the experiment, fish were exposed to TMX in four groups (0, 50, 100 and 150 ppm) for 7 days. At the end of the experiment, biochemical analysis of blood samples showed that the parameters indicating renal function showed a significant increase in serum enzymes ALT, AST, ALP and metabolites (BUN, urea, uric acid, creatinine and cortisol) concentrations, while albumin concentration decreased in a dose-dependent manner compared to the control group. In parallel with the decrease in Na+, K+ and Ca+2 in blood ion levels, there was a significant decrease in the activity of Na+/K+ ATPase, Ca+2 ATPase and AChE enzyme, levels of GSH and HSP70 in kidney tissue in TMX groups compared to the control group. It was determined that the toxic effect of TMX caused a significant increase in TBARS, PC, 8-OHdG levels, respectively. In conclusion, our study shows that TMX causes dose-dependent toxic effects, with knock-on effects on physiological processes regarding the hematological profile and renal function of O. niloticus.

The regulatory effects of pomiferin dietary on nickel-induced hepatic injury in Sprague–Dawley rats; action mechanisms and signaling pathways

The new technological applications of nickel (Ni) raise concerns over its harmful effects on the environment and human health. Pomiferin isolated from Osage orange is evaluated in in vitro and in vivo laboratory bioassays. This study focused the effects of pomiferin on Ni-caused hepatic injury and its underlying mechanisms. With this aim, Sprague–Dawley rats received 10 mg/kg nickel chloride (NiCl2) for 7 d by intraperitoneal injections. Pomiferin was given orally once a day at different doses (75, 150, and 300 mg/kg) for 20 d after exposure to NiCl2. Animals were anesthetized and livers were carefully collected to evaluate oxidative stress, inflammation, vascular injury, and hepatic function. Also, immunofluorescence analysis of apoptosis and DNA damage was performed on rat hepatic tissues. NiCl2 increased MDA production while reducing SOD, CAT, and GPx activity. NiCl2 induced the production of inflammatory cytokines and also platelet activation in hepatic tissue. Moreover, there were significant increases in AST, ALT, and LDH levels. NiCl2 also caused significant pathological changes in hepatic. Additionally, it remarkably induced up-regulations of apoptotic marker and 8-OHdG expressions by immunofluorescence labeling in liver cells. Whereas, pomiferin significantly attenuated lipid peroxidation and increased antioxidant defense system in liver. Also, the use of pomiferin prevented deregulated inflammatory process by signaling pathways nuclear factor kappa B (NFκB)/COX-2/TNF-α/IL-1β/IL-6. In addition, pomiferin diminished histopathologic evidence of hepatic toxicity and significantly lower expressions of caspase 3 and 8-OHdG were observed in liver cells. Pomiferin seems to counteract the deleterious effects of NiCl2 on hepatic tissue through different cellular and signaling mechanisms.

The impact of epigallocatechin gallate, vitamin D, and D-chiro-inositol on early surgical outcomes of laparoscopic myomectomy: a pilot study.

A prospective investigation to assess the impact of 3months of treatment with epigallocatechin gallate (EGCG), vitamin D and D-chiro-inositol (DCI) in the treatment of uterine fibroids (UF) with laparoscopic myomectomy as evidenced by surgical outcomes and effect on liver function. Non-pregnant or lactating women aged between 30 and 40years were scheduled for laparoscopic myomectomy to treat symptoms or looking to conceive. After enrollment, patients were assigned to either (1) intervention group, assuming a total of 300mg EGCG, 50μg vitamin D, and 50mg DCI divided in 2 pills per day for 3months, or (2) control group, including untreated women scheduled to undergo laparoscopic myomectomy after 3months. 91 patients completed the study. The comparison of the surgical outcomes between the intervention (n = 44) and the control (n = 47) groups revealed that the treatment significantly reduces the duration of surgery (41.93 ± 7.56min vs 56.32 ± 10.63min, p < 0.001). Moreover, the treatment also reduced blood loss during surgery (149.09 ± 25.40mL vs 168.41 ± 21.34mL, p < 0.001), resulting in treated patients having higher Hb levels at discharge 11.27 ± 0.82mL vs 10.56 ± 0.82mL, p < 0.01). The surgery induced an increase in AST and in total bilirubin regardless of the assigned group, and the treatment induced no change in liver function. Our data suggest that EGCG plus vitamin D, and DCI could represent a safe option for women with UF scheduled for laparoscopic myomectomy, improving surgical outcomes without affecting liver functionality.

Ameliorative potential role of Rosmarinus officinalis extract on toxicity induced by etoposide in male albino rats.

The present work was showed to assess the effect of administration of rosemary extract on etoposide-induced toxicity, injury and proliferation in male rats were investigated. Forty male albino rats were arranged into four equal groups. 1st group, control; 2nd group, etoposide; 3rd group, co-treated rosemary & etoposide; 4th group, rosemary alone. In comparison to the control group, etoposide administration resulted in a significant increase in serum ALT, AST, ALP, total bilirubin, total protein, and gamma GT. In contrast; a significant decrease in albumin level in etoposide group as compared to G1. G3 revealed a significant decrease in AST, ALT, ALP, total protein and total bilirubin levels and a significant rise in albumin level when compared with G2. Serum levels of urea, creatinine, potassium ions, and chloride ions significantly increased; while sodium ions were significantly decreased in G2 when compared with G1. Also, there was an increase of MDA level for etoposide treated group with corresponding control rats. However, there was a remarkable significant decrease in SOD, GPX and CAT levels in G2 as compared to G1. There was a significant increase in serum hydrogen peroxide (H2O2) and Nitric oxide (NO) levels in group treated with etoposide when compared to control group. It was noticeable that administrated by rosemary alone either with etoposide had not any effect on the levels of H2O2 and Nitric oxide. Serum level of T3 and T4 was significantly increased in etoposide-administered rats in comparison with G1. The administration of rosemary, either alone or with etoposide, increased the serum levels of T3 and T4 significantly when compared to control rats. The gene expression analysis showed significant downregulation of hepatic SOD and GPx in (G2) when compared with (G1). The treatment with rosemary extract produced significant upregulation of the antioxidant enzymes mRNA SOD and GPx. MDA gene was increased in (G2) when contrasted with (G1). Treatment of the etoposide- induced rats with rosemary extract delivered significant decrease in MDA gene expression when compared with etoposide group. Rats treated with etoposide showed significant decline in hepatic Nrf2 protein expression, when compared with G1. While, supplementation of Etoposide- administered rats with the rosemary produced a significant elevation in hepatic Nrf2 protein levels. Additionally, the liver histological structure displayed noticeable degeneration and cellular infiltration in liver cells. It is possible to infer that rosemary has a potential role and that it should be researched as a natural component for etoposide-induced toxicity protection.

Evaluating of some heart and liver enzymes in patients with myocardial infarction in Wasit.

The aim of the study was to evaluate some heart and liver enzymes in patients with myocardial infarction in Wasit . Myocardial infarction (MI) is a major cause of death and disability worldwideA heart attack, also known as myocardial infarction, occurs when blood flow to a section of the heart is cut off, resulting in the death of heart cells. This usually happens when a coronary artery becomes blocked due to the rupture of a vulnerable plaque made up of cholesterol, fatty acids, and white blood cells. The study took place in the cardiac resuscitation unit at Al-Zahra Teaching Hospital and Al-Karama Teaching Hospital in Wasit Governorate from November 2022 to January 2023. Its objective was to examine the significance of physiological, immunological indicators, and inflammatory biomarkers for accurately diagnosing, assessing risk, and predicting the future outcomes of patients with acute myocardial infarction. The study included 100 patients with acute myocardial infarction, including 71 men aged30-70 years, and 29 women aged 33-75 years. And 50 samples from the control, 28 samples from men and 22 samples from women, and they were divided into three age groups. The first group is 30-45 years old, the second group is 46-60 years old, and the third group is 61-75 years old. Taking into account the risk factors for acute myocardial infarction, which include Sex, age, high blood pressure, diabetes, smoking, and dyslexia. Lipid lipids through a questionnaire. The results of our study with regard to the diagnostic signs of myocardial infarction revealed a significant increase in troponin, myoglobin, and H-FABP, and a significant decrease in Creatine kinase. This study also indicated, regarding the results of liver enzymes, a significant increase in both AST and ALT at p≤ 0.5. Conclusions: In patients with AMI, The plasma level of significant increase in troponin, myoglobin, and H-FABP, and a significant decrease in Creatine kinase AST and ALT at p≤ 0.5.

Hepatoprotective effect of Swertiamarin from Cytarabine Induced Hepatotoxicity in Pregnant rats

Cytarabine (Ara-C) is a nucleoside analogue that is used to treat cancer as well as viral infections. It is hepatotoxic and induces oxidative stress. Swertiamarin (ST) is a natural antioxidant that protects the liver from hepatotoxicity caused by medication or toxicant exposure or pathological conditions. The purpose of this investigation was to see if ST could protect pregnant rats against Ara-C-induced hepatotoxicity. Pregnant rats were separated into six groups and given normal saline, Ara-C 25mg/kg, ST 100mg/kg, ST 200mg/kg, Ara-C 25mg/kg plus ST100 mg/kg, and Ara-C25mg/kg plus ST200 mg/kg from gestation day (GD8 to GD20) before being euthanized on GD21. Ara-C treatment resulted in a significant and dose-dependent decrease in weight gain, increased oxidative stress in pregnant rats by increasing MDA levels (p&lt;0.01) and decreasing CAT (p&lt;0.01), GSH (p&lt;0.01), GSH-Px (p&lt;0.01), and SOD (p&lt;0.01) levels, and an increase in enzyme markers AST (p&lt;0.01), ALT (p&lt;0.01), urea (p˂0.01) and creatinine levels (p˂0.01). Furthermore, significant vacuolization, poor tissue architecture, and the formation of pycnotic nuclei and dilated sinusoids were identified in the livers of Ara-C treated rats verses control rats. These data suggest that ST supplementation protects rats from hepatotoxicity caused by Ara-C prenatal exposure. Future research should look into the mechanisms involved in ST's protective impact against Ara-C-induced hepatotoxicity.

Risk Factors Affecting the Death of Hospitalized Patients with COVID-19 in the South of Iran

Background: Identifying effective factors in death caused by the infection of COVID-19 is one of the most worrisome issues in the globe. This study aims to investigate the frequency of risk factors leading to death in patients with COVID-19.&#x0D; Methods: This was a retrospective descriptive study done on 150 confirmed cases of COVID-19 in Imam Khomeini Hospital in Jiroft in 2019. Patients were included in the study by census method. The required information was extracted and recorded in the researcher's checklist; which included demographic and social characteristics of patients (age, gender, smoking, and opium consumption), underlying disease,test results (leukopenia, leukocytosis, neutropenia, decrease in albumin, increase in creatinine, ALT, AST, LDH and CRP), and the RT-PCR test.,. The researchers analyzed data using independent sample t-test, and chi-square by SPSS-V22.&#x0D; Results: The mean age of the patients was 72.19 ± 15.97. Most of those who died with COVID-19 were men. There was a statistically significant relationship between the use of drugs and the death of patients with COVID-19(P-value&lt;0.05). The average body mass index (BMI) of the confirmed patients was 31.14 ± 7.08 kg/m2 in the overweight group (P-value&lt;0.001). Moreover, there was a significant relationship between the risk factors CRP, ALB, AST, ALT, Cr, lym, Neut, WBC and inevitable death in patients with COVID-19(P-Value&lt;0.001). Regarding underlying diseases, diabetes, lung, and kidney diseases have been observed in most terminal patients (P-value&lt;0.001).&#x0D; Conclusion: Old age, male gender, high BMI, blood pressure, increased factors of CRP, AST, ALT, Cr, lym, Neut, WBC, and decreased ALB are among the risk factors leading to death in COVID-19 patients.&#x0D;

Study on the efficacy, safety, and biomarkers of nusinersen in type II and III spinal muscular atrophy in children.

The time span for the approval of nusinersen to treat SMA remains short. Most studies on the efficacy and safety of this drug within clinical trials, are lacking real-world research data. This study is based on real-world studies of SMA patients in children with type II and III SMA and is committed to objectively evaluating the effectiveness and safety of this drug. A retrospective analysis was conducted on the clinical data of 18 children with type II and III SMA from January 2022 to June 2023. The motor function assessment scale, SMN protein, platelet, liver and kidney function, and other laboratory indicators of all patients before and after treatment were collected for statistical analysis. After load dose treatment (after 64 days of treatment), compared with baseline, the Revised Upper Limb Module (RULM) of SMA patients showed significant improvement (improvement rate: 44%), confirming the short-term effectiveness of the drug. The increase in cerebrospinal fluid SMN protein was greater in patients with significant improvement in motor function than in patients without improvement in motor function. Compared with baseline, there was no significant increase in AST and ALT levels in SMA patients, indicating that the drug had almost no effect on the liver. After each treatment, thrombocytopenia and partial urinary protein positivity may occur, but it could recover before the next treatment. This indicates that nusinersen is potentially harmful to platelet and renal function, although the effect is weak and reversible. Nusinersen has shown good efficacy and overall safety, but platelets and urinary protein are still indicators that require long-term monitoring. The increase in cerebrospinal fluid SMN protein was greater in patients with significant improvement in motor function than in patients without improvement in motor function.

The structure of gastrointestinal tract pathology in patients receiving hemodialysis treatment

BACKGROUND. Hemodialysis patients are characterized by a wide range of concomitant diseases, including cardiovascular, bone mineral, nutritional, cognitive, various metabolic disorders and anemia. Meanwhile, gastrointestinal tract disorders in these patients remains largely unexplored. Patients receiving treatment with programmed hemodialysis are characterized by a wide range of concomitant diseases, including cardiovascular, bone mineral, nutritional, cognitive, various metabolic disorders and anemia. Meanwhile, the pathology of the gastrointestinal tract in this category of patients remains largely unexplored.AIM: to investigate the structure of digestive diseases in patients receiving hemodialysis treatment.PATIENTS AND METHODS. This study included 180 hemodialysis patients. The median age was 60[47;68] years. Gastrointestinal Symptoms Questionnaire (GSQ) was used to evaluate gastrointestinal symptoms over the last month. The results of abdomen ultrasound, gastroscopy, colonoscopy, and complex laboratory examination were also analyzed.RESULTS. The overall prevalence of gastrointestinal symptoms was 77.2 % (139/180). The most frequent complaints were constipation (46.8 %) and abdominal pain (41 %). The most common stool frequency was one bowel action per day. The third, fourth, fifth type of stool according to the Bristol Stool Form Scale were noted by the majority of participants. Abdominal ultrasound revealed diffuse liver changes in 115 (63.9 %), signs of cirrhosis – in 7(3.9 %) patients. Ultrasound pathology of the gallbladder was represented by anomalies of its shape in 11.1 %, signs of chronic cholecystitis – in 10 %, stones (sludge) – in 7.2 %, polyps – in 2.2 % of patients. Diffuse changes in pancreatic parenchyma, steatosis, pseudocysts and dilatation of the main pancreatic duct were diagnosed respectively in 39(21,7 %), 21(11,7 %), 10(5,6 %) and 3(1.7 %) hemodialysis patients. According to 154 gastroscopies, the most common endoscopic finding in the stomach was chronic gastritis, detected in 86(55.8 %) of the subjects. Erosive gastritis was diagnosed in 22(14.3 %), gastric ulcer – in 3(2.0 %) patients. Endoscopic duodenal pathology was represented by erythematous duodenitis in 53(34.4 %), erosive duodenitis in 15(9.7 %), ulcer in 2(1.3 %), duodenal bulb abnormalities in 23(14.9 %) patients. Combined gastric and duodenal lesions were found in 88(57.1 %) patients. Сolonoscopy was performed in 56 patients, of whom 15 (26.8 %) had signs of colitis (mainly sigmoiditis), 2(3.6 %) – diverticulitis, 10(17.9 %) – diverticulosis, 12(21.4 %) – colon polyps, 8(14.3 %) – angiodysplasia mucosa, in 3(5.4 %) – dolichocolon. Despite the abundance of gastrointestinal symptoms and instrumental findings, no significant deviations in laboratory parameters (including an increase in AST, ALT, total bilirubin, amylase, lipase) were found.CONCLUSION. Hemodialysis patients are characterized by a high prevalence of gastrointestinal symptoms and various pathological changes in the gastrointestinal tract, the diagnosis and treatment of which require an individual multidisciplinary approach.

Evaluation of Hemotoxic, Hepatotoxic and Nephrotoxic Potential of Profenofos-based Insecticide in Freshwater Labeo rohita Fish at Low Concentrations

Profenofos, an organophosphate, is a major pollutant that pollutes freshwater bodies, causing significant impacts on fish health. Objective: Present study was performed to assess the toxicological impacts of pesticide profenofos on hematological, biochemical and histological alterations in different organs of Labeo rohita. Methods: Fish were divided in three groups. Group one was treated as control while second and third groups were exposed to 0.6 mg/L and 1.2 mg/L profenofos respectively for 28 days. Results: Results revealed that MCV, MCHC, MCH, RDW-SD, PCT, PDW, HGB, RBC and HCT levels were significantly reduced. WBC, RDW, PLT, MPV, neutrophils, lymphocytes, monocytes and eosinophils were increased as compared to pesticide free group. Biochemical results showed significant increase in cholesterol, triglycerides, AST, albumin, A/G ratio, HDL T3, T4, blood glucose, creatinine and urea levels were documented while levels of LDL, VLDL, ALT, total proteins, globulin, TSH and blood urea nitrogen (BUN) decreased significantly in exposed fish. Furthermore, histological changes in kidney, gills and liver of fish showed degenerative effects after exposure to profenofos in both concentrations. Conclusions: The present study concluded that profenofos resulted in widespread toxic effects on aquatic organisms specially fish.

A Phase 1 Study of Adding Pitavastatin to Venetoclax-Based Therapy in AML and CLL/SLL

Statins (HMG-CoA-reductase inhibitors) are drugs used widely for the treatment of high cholesterol and are generally well-tolerated. There has been increasing interest in repurposing statins for oncology based on the recognition that many cancer cells are “addicted” to the mevalonate biosynthetic pathway (Iannelli et al, 2017; Juarez and Fruman 2021). We have shown that statins increase expression of the pro-apoptotic BCL2 family member PUMA (Lee at al, 2018). We have strong pre-clinical evidence that statins improve responses to the BCL2 inhibitor venetoclax (VEN) in cell line models and ex vivo primary patient specimens from patients with both chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) (Lee et al, 2018). Additionally, retrospective review of patients enrolled into the early clinical trials of VEN in CLL revealed improved responses to VEN (complete remission [CR] and progression-free survival) in the patients who were concurrently on a statin medication (Lee et al, 2018). These retrospective analyses may underestimate the potential of statins for leukemia therapy, as the statin drugs most commonly prescribed for hypercholesterolemia are not pharmacologically optimized for oncology (Abdullah et al., 2018). We developed a phase 1 study of adding pitavastatin (PIT) to VEN-based therapy in patients with AML and CLL/small lymphocytic lymphoma (SLL) (NCT04512105). AML patients were eligible if receiving induction therapy with azacitidine (AZA) and VEN per standard of care. CLL/SLL patients could receive either VEN with obinutuzumab (O) or rituximab. A 3+3 design was employed. Dose level 1 was PIT 2 mg daily, and dose level 2 (DL2) was 4 mg daily. These doses are consistent with the doses used for the treatment of hypercholesterolemia. Those enrolling at DL2 had a creatinine clearance of 60 mL/min or higher based on the prescribing information for pitavastatin. Patients already on statins for the treatment for hypercholesterolemia were allowed; these patients stopped their prescribed statin for 72 hours prior to initiation of PIT. PIT started after patients completed VEN ramp-up and had been on a stable VEN dose for at least 5 days. Primary objectives were assessing safety and tolerability and determining the recommended phase 2 dose of PIT in combination with VEN-based therapies. Secondary objectives included CR rates. Exploratory objectives included performing BH3 profiling on pretreatment and post-treatment blood samples to assess whether add-on treatment with PIT increases apoptotic priming, as seen in preclinical models (Lee et al, 2018). 14 patients signed informed consent. 6 were deemed ineligible. 2 withdrew consent prior to starting PIT therapy. 6 patients received PIT on study. 2 patients had AML and received AZA+VEN. 2 patients had CLL, and 2 patients had SLL. The CLL/SLL patients all received VEN+O. Grade 1 myalgia was reported in one subject on the 4mg PIT dose. 1 patient experienced a grade 1 increase in AST on the 4mg dose. Another patient had grade 1 elevation in bilirubin and alkaline phosphatase at the 4 mg dose. Grade 3-4 toxicities included leukopenia, neutropenia (1 case of febrile neutropenia, grade 3), anemia, and thrombocytopenia. Cycle 1 was defined as the dose-limiting toxicity (DLT) period, and no hematologic toxicities occurred during the DLT period. 1 patient had grade 3 pancreatitis, but this was felt to be unrelated to therapy or disease (also outside the DLT period). No grade 5 toxicities occurred while on study therapy. Toxicities were overall felt to be similar to patients receiving VEN-based therapy in standard clinical practice. All evaluable patients (n=5) achieved clinical CR. 1 patient with SLL is awaiting re-staging at the time of this abstract. Correlative studies are ongoing. In 2 patient peripheral blood samples analyzed, the % blasts (for an AML sample) and % CD5+ B-cells (for a CLL sample) were reduced 24 hours after PIT dosing compared to prior to any treatment and before PIT/after VEN ramp-up. Based on the tolerability of PIT and encouraging clinical outcomes, a phase 2 study is being planned to better assess the efficacy of adding PIT to VEN-based therapies in AML and CLL/SLL.

Effects of testosterone replacement on lipid profile, hepatotoxicity, oxidative stress, and cognitive performance in castrated wistar rats.

Androgen deficiency is associated with multiple biochemical and behavioral disorders. This study investigated the effects of testosterone replacement and Spirulina Platensis association on testosterone deficiency-induced metabolic disorders and memory impairment. Adult male rats were randomly and equally divided into four groups and received the following treatments for 20 consecutive days. non-castrated rats received distilled water. Castrated group received distilled water. Testosterone treated group: castrated rats received 0.20 mg of testosterone dissolved in corn oil by subcutaneous injection (i.p.). Spirulina co-treated group: castrated rats received 0.20 mg of testosterone (i.p.) dissolved in corn oil followed by 1000 mg/kg of Spirulina per os. Data showed that castration induced an increase in plasma ALT, AST, alkaline phosphatase (PAL), cholesterol, and triglycerides level. Castrated rats showed a great elevation in SOD and CAT activities and MDA and H2O2 levels in the prostate, seminal vesicles, and brain. Testosterone deficiency was also associated with alteration of the spatial memory and exploratory behaviour. Testosterone replacement either alone or with Spirulina combination efficiently improved most of these biochemical parameters and ameliorated cognitive abilities in castrated rats. Testosterone replacement either alone or in combination with Spirulina improved castration-induced metabolic, oxidative, and cognitive alterations.

Chia seeds and coenzyme Q10 alleviate iron overload induced hepatorenal toxicity in mice via iron chelation and oxidative stress modulation

Iron overload (IOL) can cause hepatorenal damage due to iron-mediated oxidative and mitochondrial damage. Remarkably, combining a natural iron chelator with an antioxidant can exert greater efficacy than monotherapy. Thus, the present study aimed to evaluate the efficacy of Chia and CoQ10 to chelate excess iron and prevent hepatorenal oxidative damage in IOL mice. Male Swiss albino mice (n = 49) were randomly assigned to seven groups: control, dietary Chia, CoQ10, IOL, IOL + Chia, IOL + CoQ10, and IOL + Chia + CoQ10. Computational chemistry indicates that the phytic acid found in the Chia seeds is stable, reactive, and able to bind to up to three iron ions (both Fe2+ and Fe3+). IOL induced a significant (P < 0.05) increase in serum iron, ferritin, transferrin, TIBC, TSI, RBCs, Hb, MCV, MCH, WBCs, AST, ALT, creatinine, and MDA. IOL causes a significant (P < 0.05) decrease in UIBC, platelets, and antioxidant molecules (GSH, SOD, CAT, and GR). Also, IOL elicits mitochondrial membrane change depolarization, and DNA fragmentation and suppresses mitochondrial DNA copies. Furthermore, substantial changes in hepatic and renal tissue, including hepatocellular necrosis and apoptosis, glomerular degeneration, glomerular basement membrane thickening, and tubular degeneration, were observed in the IOL group. Dietary Chia and CoQ10 induced significant (P < 0.05) amelioration in all the mentioned parameters. They can mostly repair the abnormal architecture of hepatic and renal tissues induced by IOL, as signified by normal sinusoids, normal central veins, and neither glomerular damage nor degenerated tubules. In conclusion, the combined treatment with Chia + CoQ10 exerts more pronounced efficacy than monotherapy in hepatorenal protection via chelating excess iron and improved cellular antioxidant status and hepatorenal mitochondrial function in IOL mice.

CTIM-32. A PARALLEL COHORT PHASE 2 STUDY OF REGORAFENIB PLUS NIVOLUMAB FOR RECURRENT OR METASTATIC SOLID TUMORS: RESULTS IN PATIENTS WITH GLIOBLASTOMA MULTIFORME (GBM) OR ANAPLASTIC ASTROCYTOMA (AA)

Abstract INTRODUCTION The multikinase inhibitor regorafenib improved overall survival (OS) versus lomustine in relapsed GBM in the randomized phase 2 REGOMA study. The aim of this study was to evaluate the efficacy of regorafenib combined with nivolumab in this setting (NCT04704154). METHODS Patients aged ≥ 18 years with recurrent GBM/AA (WHO 2016 classification) after radiotherapy plus temozolomide, and an ECOG performance status (PS) of 0/1, received oral regorafenib 90 mg/day on days 1–21 and intravenous nivolumab 480 mg on day 1 of each 28-day cycle. If tolerated, the regorafenib dose could be escalated to 120 mg/day from cycle 2. Prior regorafenib treatment or immunotherapy was not allowed. The primary endpoint was objective response rate (ORR) using RANO criteria. Secondary endpoints included progression-free survival (PFS), OS, and safety (MedDRA; CTCAE v5.0). RESULTS Of the 36 patients enrolled, 30 were treated and were eligible for analysis. Median age was 60 years, 63% had an ECOG PS of 1, and 90% had GBM (10% AA). All patients discontinued treatment as of the primary analysis (March 9, 2023). One patient had a best-overall partial response (ORR; 3%) and nine (30%) had stable disease. Median number of cycles of regorafenib and nivolumab infusions was three. Median PFS (RANO) was 2.7 months (80% CI 1.8, 7.3) and 6-month PFS was 31.5%. Median OS was 8.0 months (80% CI 4.6, 12.4) and 12-month OS was 33.7%. Thirteen patients (43%) had grade 3/4 treatment-emergent adverse events (TEAEs), which were drug-related in 12 patients (40%). The most common drug-related grade 3/4 TEAEs were AST increase (13%), ALT increase (10%), and hypertension (10%). There were no immune-mediated serious TEAEs or drug-related grade 5 TEAEs. CONCLUSION The efficacy results of this study do not support further evaluation of regorafenib combined with nivolumab in GBM/AA. The safety profile was acceptable and manageable.

A First-in-Human Phase 1 Study of the Menin-KMT2A (MLL1) Inhibitor JNJ-75276617 in Adult Patients with Relapsed/Refractory Acute Leukemia Harboring KMT2A or NPM1 Alterations

Background: Relapsed/refractory (R/R)acute leukemia withalterations in KMT2A (also called MLL1; 9-15% of adult AML, 10% of ALL) or NPM1 (30% of adult AML) are often associated with poor outcomes. Pre-clinical studies demonstrated the relevance of the menin-KMT2A protein-protein interaction in sustaining leukemic cells with KMT2A and NPM1 alterations (Kuhn 2016). JNJ-75276617 is a potent and selective inhibitor of the interaction between the scaffolding protein menin and the methyltransferase KMT2A with preclinical activity in KMT2A-rearranged or NPM1-mutated leukemic cell lines and primary leukemia patient samples in vitro and in vivo (Kwon 2022). We report initial data investigating JNJ-75276617 in adult participants (pts) with R/R acute leukemia harboring KMT2A alterations (rearrangements, amplifications, or partial tandem duplications) or NPM1 mutations. Methods: 75276617ALE1001 (NCT04811560) is an ongoing Phase 1, multicenter, open-label, dose-finding study. Pts in dose escalation receive JNJ-75276617 orally on a 28-day cycle. As of 8 April 2023, multiple dose levels ≥15 mg have been explored on either a daily or twice daily (BID) dosing schedule. AEs were graded by CTCAE v5.0. Responses were investigator-assessed per ELN2017. Preliminary safety, efficacy and PD data are reported herein, with a focused review of the efficacy in higher dose levels with ≥3 pts dosed. Results: Fifty-eight pts received JNJ-75276617. The median age was 63 (range: 19-83) years; 56 pts (97%) had R/R AML and 2 (3%) had R/R ALL. The median number of prior lines of treatment was 2 (range: 1-7), including 10 (17%) pts with a prior allogeneic stem cell transplant. A KMT2A or NPM1 alteration was present in 33 (57%) and 25 (43%) pts, respectively. Thirty (52%) pts experienced ≥1 treatment-related AE (TRAE); most commonly differentiation syndrome (DS) (8 [14%]). Grade ≥3 TRAEs were observed in 17 (29%) pts; those reported in ≥2 pts were neutropenia (6 [10%]), anemia and thrombocytopenia (4 [7%] each), DS (3 [5%]), and ALT and AST increase (2 [3%] each). Dose limiting toxicities (DLTs) were observed in 5 (9%) pts, with DS (2 [3%]) as the only DLT reported in ≥2 pts. In 26 (63%) of the 41 pts with disease evaluation data, there was a reduction in bone marrow (BM) disease burden ( Figure 1). Of these, a ≥50% decrease in BM blasts was observed in 16 (39%) pts. In the highest dose level with ≥3 pts (90 mg BID; n=8), the ORR (≥PR) was 50% (n=4), with all responders ongoing ( Figure 2). These responders (2 NPM1-, 2 KMT2A-altered) achieved CR (1 pt), CRh (1 pt), and CRi (2 pts). In a review of higher dose levels with ≥3 pts (≥45 mg BID; n=20), the ORR was 40% (n=8), with 7 responders ongoing ( Figure 2). These responders (5 NPM1-, 3 KMT2A-altered) achieved CR (3 pts), CRh (1 pt), CRi (3 pts), and PR (1 pt); median (range) time to first response (≥PR) 1.81 mos (1.0-3.3; n=8); time to CR, CRh, or CRi 1.77 mos (1.0-3.3; n=7); and time to CR 2.79 mos (1.8-2.9; n=3). Across all cohorts there were 12 responders, including 1 MRD negative CR. One responder discontinued treatment for allogeneic transplant; however, 8 responders continue on treatment, including 2 pts in cycle 9. Preliminary PD data from unfractionated BM and/or PBMCs in paired samples among responders (n=12) show biologic activity as indicated by reduction in expression (mean fold change from baseline calculated as [on-tx-baseline]/baseline [range]) of menin-KMT2A target genes ( MEIS1 -0.42 [-1.0-9.0]; HOXA9 -0.03 [-1.0-21.7]; FLT3 18.6 [-1.0-425]) and induction of genes associated with differentiation ( ITGAM 55.0 [-0.93-1467]; MNDA 5.9 [-1.0-83.5]). Compared to baseline, the percentage of KMT2A-altered cells or NPM1 variant allele frequency (VAF) was reduced in responders, with a decrease in KMT2A-altered cells by break-apart FISH probe from 59.2% at baseline to 8.1% post-treatment and in NPM1 VAF using a myeloid gene NGS panel from 13.1% at baseline to 2.8% post-treatment. Conclusions: Dose escalation in 75276617ALE1001 is ongoing with the RP2D(s) yet to be determined. Pts in dose expansion will receive JNJ-75276617 at the identified RP2D(s). Preliminary results of this FIH Phase 1 study demonstrate that JNJ-75276617 monotherapy has an acceptable safety profile, encouraging antileukemic activity, and emerging biologic activity consistent with the proposed mechanism of action in pts with R/R acute leukemia harboring KMT2A or NPM1 alterations.