Elevated Aspartate Aminotransferase Research Articles

Persistent fever in acute hepatitis: think beyond acute viral hepatitis

Background Acute hepatitis due to various tropical infections can mimic the clinical picture of acute viral hepatitis(AVH), leading to increased morbidity and mortality. We aimed to identify clinical and laboratory parameters that could help to distinguish acute hepatitis due to tropical infections from AVH. Methods We retrospectively analyzed our database of 150 children (107 boys) with AVH and 50 children(34 boys)with acute hepatitis due to tropical infections between January 2013 and March 2023. Clinical features, investigations, complications and outcomes were compared. Results Hepatitis A (75%) was the commonest etiology of AVH while enteric fever (34%), dengue (26%), scrub typhus (20%) and leptospirosis (16%) constituted the majority of tropical infections. Persistent fever and skin rashes were found in 88% and 16% of patients respectively in the tropical infection group and none in the AVH group (p < 0.001). On univariate analysis, prodromal symptoms, clinically detectable jaundice, cholestatic pattern, total and direct bilirubin and liver enzymes were significantly higher in AVH while headache, myalgia, leukopoenia, thrombocytopenia, hyponatremia were significantly higher in tropical infections group (all p < 0.05). Multivariate analysis identified thrombocytopenia (Odds ratio [OR] 4.237) as an independent positive predictive factor and markedly elevated total bilirubin (OR 0.575), direct bilirubin (OR 0.498), aspartate aminotransferase (OR 0.841) and alanine aminotransferase (OR 0.863) as independent negative predictive factors for acute hepatitis due to tropical infections. Conclusion High index of suspicion for tropical infections is warranted in patients with persistent fever after the onset of jaundice, especially in the presence of skin rash and thrombocytopenia. SUMMARY Acute viral hepatitis and acute hepatitis due to tropical infections can have similar clinical and biochemical parameters. Milder degree of jaundice, lower elevation of serum transaminases and thrombocytopenia can be useful predictors for acute hepatitis due to tropical infections.

Tucidinostat Plus Exemestane as a Neoadjuvant in Early-Stage, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

To assess the efficacy and safety of tucidinostat plus exemestane as a neoadjuvant strategy in early-stage breast cancer. This prospective, open-label, single-arm phase II trial enrolled patients with stage II-III breast cancer with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative. Eligible patients received tucidinostat plus exemestane, and then breast-conserving surgery (BCS) or modified radical mastectomy. Among 20 enrolled patients, 3 of them achieved preoperative endocrine prognostic index (PEPI) score of 0. Additionally, complete cell cycle arrest was observed in 7, radiologic objective response rate in 10, and disease control rate in 20 patients, pathological complete response in 1 patient, and 5 patients performed BCS. Ki67 suppression from baseline to surgery was observed in 17 of patients, with the Ki67 change ratio of -73.5%. Treatment-emergent adverse event included neutropenia, leukopenia, thrombocytopenia, lymphopenia, hypoalbuminemia, aspartate aminotransferase elevation, glutamyl transpeptidase elevation, anemia, and alanine aminotransferase elevation. Despite the rate of PEPI score 0 was not high, tucidinostat plus exemestane as a neoadjuvant therapy might be well tolerated and showed promising clinical responses in patients with early hormone receptor-positive, HER2-negative breast cancer. To clarify the safety and efficacy of this strategy, further investigation is warranted. ChiCTR2100046678.

Toosendanin induces hepatotoxicity by restraining autophagy and lysosomal function through inhibiting STAT3/CTSC axis

Toosendanin (TSN) is the main active component in the traditional herb Melia toosendan Siebold & Zucc, which exhibits promising potential for development due to its diverse pharmacological properties. However, the hepatotoxicity associated with TSN needs further investigation. Previous research has implicated autophagy dysregulation in TSN-induced hepatotoxicity, yet the underlying mechanisms remain elusive. In this study, the mechanisms of signal transducer and activator of transcription 3 (STAT3) in TSN-induced autophagy inhibition and liver injury were explored using Stat3 knockout C57BL/6 mice and HepG2 cells. TSN decreased cell viability, increased lactate dehydrogenase (LDH) production in vitro, and elevated serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels as well as liver lesions in vivo, suggesting TSN had significant hepatotoxicity. TSN inhibited Janus kinase 2 (JAK2)/STAT3 pathway and the expression of cathepsin C (CTSC). Inhibition of STAT3 exacerbated TSN-induced autophagy inhibition and hepatic injury, whereas activation of STAT3 attenuated these effects of TSN. Mechanistically, STAT3 transcriptionally regulated the level of CTSC gene, which in turn affected autophagy and the process of liver injury. TSN-administered Stat3 knockout mice showed more severe hepatotoxicity, CTSC downregulation, and autophagy blockade than wildtype mice. In summary, TSN caused hepatotoxicity by inhibiting STAT3/CTSC axis-dependent autophagy and lysosomal function.

Efficiency and Stability of Transarterial Chemoembolization Combined With or Without Lenvatinib for Unresectable Hepatocellular Carcinoma.

At present, there are relatively few reports on the treatment consisting of transarterial chemoembolization (TACE) combined with lenvatinib, and there is no unified conclusion on the curative effect. The objective of this research was to assess the efficacy and safety of combining TACE with lenvatinib for the treatment of unresectable hepatocellular carcinoma (uHCC). This study was a retrospective analysis of the patient's medical records. In this study, 249 patients (uHCC) in our hospital from 2020 to 2021 were divided into 2 groups, including the TACE-alone group (198 patients received TACE alone) and the TACE-LEN group (51 patients were treated with TACE combined with lenvatinib). According to the propensity score matching method, there were TACE-LEN group (51 patients) and TACE-alone group (51 patients). With the help of surgical experts, the overall survival (OS), progression-free survival (PFS), and tumor response (according to mRECIST) of the 2 groups were sorted and recorded, and then analyzed. Survival curves were established, the prognostic factors of OS and PFS were analyzed by univariate and multivariate analyses, and the independent prognostic factors were recorded. The adverse reactions of patients after treatment were recorded. The 1-year and 2-year OS rates were 50.98% and 19.48% for the TACE-LEN group, 27.45% and 8.55% for the TACE-alone group (P = .042), respectively. The PFS of patients in the TACE-LEN group was also longer (1-year PFS rate: 25.49% vs. 11.76%, 2-year PFS rate: 19.17% vs. 5.88%; P = .0069). The disease control rate (68.63% vs. 49.10%, P = .044) of the TACE-LEN group was significantly higher. In the subgroup analysis, the OS of the TACE-LEN group was better than TACE-alone group in patients with Barcelona Clinic Liver Cancer stage C (1-year OS rate: 44.44% vs. 17.14%, 2-year OS rate: 8.67% vs. 0%; P = .009). Factor analysis concluded that serum alkaline phosphatase and treatment protocol (TACE-LEN vs. TACE) were independent influencing factors of OS. The most common treatment-related AEs included decreased albumin (n = 28, 54.9%), hypertension (n = 23, 45.1%), elevated aspartate transaminase (n = 21, 41.2%) and elevated total bilirubin (n = 18, 35.2%) in TACE-LEN group. Compared with TACE monotherapy, TACE combined with lenvatinib effectively prolonged the OS time with a controllable safety profile for patients with uHCC.

Comparison of the effects of monounsaturated fatty acids and polyunsaturated fatty acids on the lipotoxicity of islets.

Monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) have been reported to combat saturated fatty acid (SFA)-induced cellular damage, however, their clinical effects on patients with metabolic diseases such as diabetes and hyperlipidemia are still controversial. Since comparative studies of the effects of these two types of unsaturated fatty acids (UFAs) are still limited. In this study, we aimed to compare the protective effects of various UFAs on pancreatic islets under the stress of SFA-induced metabolic disorder and lipotoxicity. Rat insulinoma cell line INS-1E were treated with palmitic acid (PA) with or without UFAs including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and oleic acid (OA) to determine cell viability, apoptosis, endoplasmic reticulum (ER) stress, and inflammatory. In vivo, male C57BL/6 mice were fed a 60% high-fat diet (HFD) for 12w. Then the lard in HFD was partially replaced with fish oil (FO) and olive oil (OO) at low or high proportions of energy (5% or 20%) to observe the ameliorative effects of the UFA supplement. All UFAs significantly improved PA-induced cell viability impairment in INS-1E cells, and their alleviation on PA induced apoptosis, ER stress and inflammation were confirmed. Particularly, OA had better effects than EPA, DHA, and AA on attenuating cellular ER stress. In vivo, the diets with a low proportion of UFAs (5% of energy) had limited effects on HFD induced metabolic disorder, except for a slight improved intraperitoneal glucose tolerance in obese mice. However, when fed diets containing a high proportion of UFAs (20% of energy), both the FO and OO groups exhibited substantially improved glucose and lipid metabolism, such as decrease in total cholesterol (TC), low-density lipoprotein (LDL), fasting blood glucose (FBG), and fasting blood insulin (FBI)) and improvement of insulin sensitivity evidenced by intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT). Unexpectedly, FO resulted in abnormal elevation of the liver function index aspartate aminotransferase (AST) in serum. Pathologically, OO attenuated HFD-induced compensatory hyperplasia of pancreatic islets, while this effect was not obvious in the FO group. Both MUFAs and PUFAs can effectively protect islet β cells from SFA-induced cellular lipotoxicity. In particular, both OA in vitro and OO in vivo showed superior activities on protecting islets function and enhance insulin sensitivity, suggesting that MUFAs might have greater potential for nutritional intervention on diabetes.

Pre-Existing Immunity to a Nucleic Acid Contaminant-Derived Antigen Mediates Transaminitis and Resultant Diminished Transgene Expression in a Mouse Model of Hepatic Recombinant Adeno-Associated Virus-Mediated Gene Transfer.

Liver injury with concomitant loss of therapeutic transgene expression can be a clinical sequela of systemic administration of recombinant adeno-associated virus (rAAV) when used for gene therapy, and a significant barrier to treatment efficacy. Despite this, it has been difficult to replicate this phenotype in preclinical models, thereby limiting the field's ability to systematically investigate underlying biological mechanisms and develop interventions. Prior animal models have focused on capsid and transgene-related immunogenicity, but the impact of concurrently present nontransgene or vector antigens on therapeutic efficacy, such as those derived from contaminating nucleic acids within rAAV preps, has yet to be investigated. In this study, using Ad5-CMV_GFP-immunized immunocompetent BALB/cJ mice, and a coagulation factor VIII expressing rAAV preparation that contains green flourescent protein (GFP) cDNA packaged as P5-associated contaminants, we establish a model to induce transaminitis and observe concomitant therapeutic efficacy reduction after rAAV administration. We observed strong epitope-specific anti-GFP responses in splenic CD8+ T cells when GFP cDNA was delivered as a P5-associated contaminant of rAAV, which coincided and correlated with alanine and aspartate aminotransferase elevations. Furthermore, we report a significant reduction in detectable circulating FVIII protein, as compared with control mice. Lastly, we observed an elevation in the detection of AAV8 capsid-specific T cells when GFP was delivered either as a contaminant or transgene to Ad5-CMV_GFP-immunized mice. We present this model as a potential tool to study the underlying biology of post-AAV hepatotoxicity and demonstrate the potential for T cell responses against proteins produced from AAV encapsidated nontherapeutic nucleic acids, to interfere with efficacious gene transfer.

Association between liver enzymes and type 2 diabetes: a real-world study.

This study aimed to examine the association of liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl-transferase (GGT), with type 2 diabetes (T2D) risk, particularly their dose-response relationship. This cross-sectional study enrolled participants aged >20 years old who underwent physical examination at our local hospital from November 2022 to May 2023. A generalized additive model (GAM) was fit to assess the dose-response relationship between liver enzymes and T2D risk. Furthermore, data from the UK Biobank (n=217,533) and National Health and Nutrition Examination Survey (NHANES 2011-2018; n= 15,528) were analyzed to evaluate whether the dose-response relationship between liver enzymes and T2D differed by population differences. A total of 14,100 participants were included (1,155 individuals with T2D and 12,945 individuals without diabetes) in the analysis. GAM revealed a non-linear relationship between liver enzymes and T2D risk (P non-linear < 0.001). Specifically, T2D risk increased with increasing ALT and GGT levels (range, <50 IU/L) and then plateaued when ALT and GGT levels were >50 IU/L. Elevated AST within a certain range (range, <35 IU/L) decreased the risk of T2D, whereas mildly elevated AST (>35 IU/L) became a risk factor for T2D. The UK Biobank and NHANES data analysis also showed a similar non-linear pattern between liver enzymes and T2D incidence. Liver enzymes were non-linearly associated with T2D risk in different populations, including China, the UK, and the US. Elevated ALT and GGT levels, within a certain range, could increase T2D risk. More attention should be given to liver enzyme levels for early lifestyle intervention and early T2D prevention. Further studies are necessary to explore the mechanism of the non-linear association between liver enzymes and T2D risk.

Evaluation of clinically relevant serum proteins as biomarkers for monitoring COVID-19 severity, and end-organ damage among hospitalized unvaccinated patients

BackgroundThe extensive variability and conflicting information in Coronavirus Disease 2019 (COVID-19) patient data have made it difficult for the medical community to gain a comprehensive understanding and develop clear, reliable guidelines for managing COVID-19 cases. As the world uncovers the diverse side effects of the pandemic, the pursuit of knowledge about COVID-19 has become crucial. The present study aimed to evaluate some clinically relevant serum proteins, providing analysis of the obtained results to employ them in the diagnosis, prognosis, and disease monitoring among COVID-19 patients.MethodsSamples were collected from 262 COVID-19 unvaccinated hospitalized patients. Measurement of certain serum proteins, namely C-reactive protein (CRP), ferritin, D-dimer, procalcitonin, interleukin-6 (IL-6), serum creatinine (SCr), alanine transaminase (ALT), aspartate transaminase (AST) was done using standard methods. Statistical analysis was performed on the obtained data and the results were correlated to the severity and prognosis.ResultsThe calculated Mortality rate was found to be 30% with a higher percentage observed among females. The results showed elevation in serum CRP, ferritin, D-dimer, and procalcitonin in most of the patients, also some patients had elevated SCr, ALT, and AST levels indicating end-organ damage. The statistical analysis displayed a strong correlation between serum levels of CRP and ferritin, between D-dimer and ferritin, and between ferritin and procalcitonin. No significant difference was observed between male and female patients’ serum levels of the tested serum proteins. A significant correlation between increased serum procalcitonin and mortality was observed.ConclusionThe levels of measured serum proteins were impacted by SARS-CoV-2 infection. Serum ferritin, CRP, D-dimer, and procalcitonin are good predicting tools for end-organ damage and acute kidney impairment in COVID-19. Procalcitonin is a strong indicator of severity and mortality in hospitalized COVID-19 patients.

Toxicity evaluation of processing Evodiae fructus based on intestinal microbiota.

With the development of healthcare services, drug efficacy, and safety have become the focus of drug use, and processing alters drug toxicity and efficacy, exploring the effects of processing on Evodiae fructus (EF) can guide the clinical use of drugs. Fifty male Kunming mice were randomly divided into the control group (CCN), raw small-flowered EF group (CRSEF), raw medium-flowered EF group (CRMEF), processing small-flowered EF group (CPSEF), and processing medium-flowered EF group (CPMEF). The CRSEF, CRMEF, CPSEF, and CPMEF groups were gavaged with aqueous extracts of raw small-flowered EF dry paste (RSEF), medium-flowered EF dry paste (RMEF), processing small-flowered EF dry paste (PSEF) and processing medium-flowered EF dry paste (PMEF), respectively, for 21 days at 5 times the pharmacopeial dosage. Upon concluding the experiment, histopathological sections of liver and kidney tissues were examined. Additionally, levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine (SCr), and blood urea nitrogen (BUN) were determined. DNA from the intestinal contents of the mice was extracted, and 16S rRNA full-length high-throughput sequencing was performed. After fed EF 21 days, mice exhibited a decreasing trend in body weight. Comparative analysis with the CCN group revealed an upward trend in SCr, BUN, AST, and ALT levels in both CRSEF and CRMEF groups. The CRMEF group displayed notably elevated BUN and AST levels, with an observed increasing trend in Scr and ALT. Kidney sections unveiled cellular edema and considerable inflammatory cell infiltrates, whereas significant liver damage was not evident. Compared with CRSEF, Bun levels were significantly lower while AST levels were significantly higher in the CPMEF group. Additionally, the intestinal microbiota diversity and the relative abundance of Psychrobacter decreased significantly, and the relative abundance of Staphylococcus, Jeotgalicoccus, and Salinicoccus increased significantly in the CPMEF group. AST, ALT, and SCr were positively correlated with Staphylococcus, Jeotgalicoccus, and Salinicoccus. In conclusion, PMEF significantly increased harmful bacteria (Staphylococcus, Jeotgalicoccus, and Salinicoccu) and decreased beneficial bacteria. SEF with 5 times the clinical dose showed nephrotoxicity and SEF nephrotoxicity decreased after processing, but EF hepatotoxicity was not significant, which may be due to insufficient dose concentration and time.

Hepatic and renal lesions in sheep intoxicated with Urochloa hybrid Mulato II in Argentina.

A flock of 48 sheep in Argentina grazing on a pasture of hybrid Urochloa (formerly Brachiaria) Mulato II (Urochloa ruziziensis × Urochloa decumbens × Urochloa brizantha) developed facial dermatitis, severe jaundice, and weakness after brief physical activity. Blood biochemistry of 3 animals revealed azotemia, elevated aspartate aminotransferase activity, and increased direct, indirect, and total bilirubin concentrations. The urine was markedly turbid and contained large concentrations of bile pigments and protein. At autopsy of 2 animals, there was severe jaundice and subcutaneous submandibular edema. The livers were enlarged, intensely yellow, and had a marked acinar pattern. Gallbladders were distended, and the kidneys were diffusely dark in one animal and yellow-green in the other. Microscopically, there was lymphoplasmacytic and histiocytic cholangiohepatitis with abundant crystals in the lumen of bile ducts and in the cytoplasm of macrophages. The proximal and distal convoluted renal tubules had protein casts in their lumens, and crystals were observed in the lumen and epithelial cells. Lectin histochemistry showed strong affinity for Arachis hypogaea agglutinin in hepatic macrophages. In the one sheep that was tested for heavy metals, copper concentrations in the liver and kidney were within the RIs. Despite the immediate change of pasture, morbidity and mortality were 100% within 3 mo. The association between the consumption of this pasture, and the clinical, biochemical, pathology, and lectin histochemistry findings confirmed intoxication with Urochloa hybrid Mulato II. To our knowledge, intoxication by this hybrid of Urochloa has not been reported previously.

SWOG 1609 cohort 48: anti-CTLA-4 and anti-PD-1 for advanced gallbladder cancer.

Most patients with advanced gallbladder cancer are treated with multiagent chemotherapy. Immune checkpoint inhibitors offer the possibility of a durable response with less toxicity. This prospective, multicenter, open-label study was designed to evaluate the anticancer activity of nivolumab plus ipilimumab in patients with advanced gallbladder cancer. Nineteen patients with advanced gallbladder cancer refractory to ≥1 previous therapy received nivolumab 240mg intravenously every 2weeks and ipilimumab 1mg/kg intravenously every 6weeks until disease progression or unacceptable toxicity. The primary end point was confirmed radiographic overall response rate (ORR) (complete response [CR]+partial response [PR] confirmed on subsequent scan); secondary end points included unconfirmed overall response, clinical benefit rate (confirmed and unconfirmed responses+stable disease >6months), progression-free survival, overall survival, and toxicity. The confirmed ORR was 16% (CR, n=1 [5%]; PR, n=2 [11%]); all were microsatellite stable, and the confirmed CR had undetectable programmed death-ligand 1 by immunohistochemistry. The unconfirmed ORR and clinical benefit rates were both 32%. The median duration of response was 14.8months (range, 4-35.1+ months). The 6-month progression-free survival was 26% (95% CI, 12-55). The median overall survival was 7.0months (95% CI, 3.9-19.1). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was 1 possibly related death (sepsis with attendant hepatic failure). Ipilimumab plus nivolumab was well tolerated and showed modest efficacy with durable responses in previously treated patients with advanced gallbladder cancer. NCT02834013 (ClincialTrials.gov). This prospective study assessed the efficacy and safety of nivolumab plus ipilimumab in 19 patients with advanced gallbladder cancer refractory to previous therapy. The combination demonstrated modest efficacy with a 16% confirmed overall response rate, durable responses, and manageable toxicities, suggesting potential benefits for this challenging patient population.

Additional nodules detected using EOB-MRI in patients with resectable single hepatocellular carcinoma: an implication for active treatment strategy.

Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOBMRI) further enhances the identification of additional hepatic nodules compared with computed tomography (CT) alone; however, the optimal treatment for such additional nodules remains unclear. We investigated the long-term oncological effect of aggressive treatment strategies for additional lesions identified using EOB-MRI in patients with hepatocellular carcinoma (HCC). Data from 522 patients diagnosed with solitary HCC using CT between January 2008 and December 2012 were retrospectively reviewed. Propensity score-matched (PSM) analysis was used to compare the oncologic outcomes between patients with solitary HCC and those with additional nodules on EOB-MRI after aggressive treatment (resection or radiofrequency ablation [RFA]). Among the 383 patients included, 59 had additional nodules identified using EOB-MRI. Compared with patients with solitary HCC, those with additional nodules on EOB-MRI had elevated total bilirubin, aspartate transaminase, and alanine transaminase; had a lower platelet count, higher MELD score, and highly associated with liver cirrhosis (P<0.05). Regarding long-term outcomes, 59 patients with solitary HCC and those with additional nodules after PSM were compared. Disease-free survival (DFS) and overall survival (OS) were comparable between the two groups (DFS, 60.4 vs. 44.3 months, P=0.071; OS, 82.8 vs. 84.8 months, P=0.986). The aggressive treatment approach, either resection or RFA, for patients with additional nodules identified on EOBMRI was associated with long-term survival comparable with that for solitary HCC. However, further studies are required to confirm these findings.

Clinical and biomarker analyses of hepatic arterial infusion chemotherapy plus lenvatinib and PD-1 inhibitor for patients with advanced intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with a dismal prognosis and few effective therapeutic approaches. This study aimed to investigate the efficacy, safety, and predictive biomarkers of hepatic arterial infusion chemotherapy (FOLFOX-HAIC) in combination with lenvatinib and PD-1 inhibitor for patients with advanced iCCA. Locally advanced or metastatic iCCA patients receiving the triple combination therapy of lenvatinib, PD-1 inhibitor, and FOLFOX-HAIC were included in this retrospective study. Primary endpoint was the progression-free survival, evaluated using the RECIST criterion. The secondary endpoints included overall survival, objective response rate, and safety. Whole exome and RNA sequencing of tumor biopsy tissues were performed for biomarker exploration. Between May, 2019 and December 2022, a total of 46 patients were included in this study. The primary endpoint showed a median progression-free survival of 9.40 months (95% CI: 5.28-13.52), with a 6-month progression-free survival rate of 76.1%. The median overall survival was 16.77 months (95% CI, 14.20-19.33), with an objective response rate of 47.8% and disease control rate of 91.3% per RECIST. In addition, 4.3% and 8.7% of patients achieved complete response of all lesions and intrahepatic target lesions per mRECIST, respectively. The most common treatment-related adverse events were neutropenia, thrombocytopenia, elevated aspartate aminotransferase and alanine aminotransferase level. Furthermore, integrated analysis of genetic, transcriptomic, and immunohistochemistry data revealed that pre-existing immunity (high expression level of immune-related signatures and intra-tumoral CD8+ T cell density) in baseline tumor tissues was associated with superior clinical benefits. However, the evaluation of tumor mutation burden did not show potential predictive value in this triple combination. FOLFOX-HAIC in combination with lenvatinib and PD-1 inhibitor demonstrated a promising antitumor activity with manageable safety profiles in patients with advanced iCCA. Moreover, our study also revealed new perspectives on potential biomarkers for clinical efficacy.

Acute Poisoning of Benzodiazepines Among Patients Admitted to Loghman Hakim Hospital

Background: Benzodiazepines have been highly prescribed by physicians and have attracted public attention due to their high safety. These drugs have sedative, hypnotic, anti-anxiety, and anti-seizure properties. However, these drugs are also widely used for suicide. The present study was designed and implemented to determine the distribution of patients poisoned with benzodiazepines in terms of clinical and demographic characteristics. Methods: Investigation of poisoning with benzodiazepines in one year in the poisoning department of Loghman Medical Center in Tehran City, Iran, was carried out as a descriptive-prospective study. In this research, 458 poisoned patients were studied to collect data on their age, gender, drug dosage, type of drug, duration of hospitalization, blood analysis results, and mortality. Results: The majority of patients poisoned with benzodiazepines were women (62.2%). The mean age of people was 31.67 years. The most frequently used drugs were clonazepam and alprazolam. Other drugs used with benzodiazepines were propranolol, methadone, and acetaminophen. The death rate was 1.7%. The incidence of hypoglycemia and creatinine above 1.3 was 8.53% and 11.3%, respectively. Hyperglycemia was 10.6%. There were 11, 80, and 178 cases of elevated alanine transaminase, aspartate aminotransferase, and alkaline phosphatase, respectively. Conclusion: Benzodiazepines have the potential to cause liver and kidney damage and changes in insulin secretion and blood sugar. This issue should be considered when dealing with a poisoned patient to prevent serious injuries.

Antioxidant and antiproliferative effects of Teucrium polium extract: computational and in vivo study in rats

The current study aimed to assess the antioxidant and antiproliferative effects of teucrium polium extract: computational and in vivo study in rats. Three groups of animals: Group (i) constitute the control group; Group (ii) HeLa group received an intrafemoral inoculation of HeLa cells and Group (iii) constitue the combination between HeLa + T. polium. The plant was administered by gavage. Our results revealed that HeLa cell injection showed an elevation in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TB), creatinine, urea, calcium and phosphorus. The pretreatment with the plant extract reduced the level of these parameters. Injection of HeLa cells showed a significant decrease in phosphorus and calcium respectively. However, the pretreatment by T. polium modulated the level of these two minerals. Rats treated with HeLa cells line showed an increase in the level of lipid peroxidation as evaluated by the TBARS substances, at the same time, a significant decreases in SOD, CAT and GPx activities were noted in the HeLa group compared to the control. On the other hand, pretreatment with the plant improved the level of these enzymes. Our results revealed that T.polium has a therapeutic effect on some health problems. HeLa cell line induced a small infiltration in liver and kidney. T. polium reduced the damage in both liver and kidney, but did not reveal any proliferation of tumor cells from trabecular bone tissue. The computational study revealed that T. polium compound bound with high free binding energies and established promising network of molecular interactions with COX-2 and TNF-α macromolecules.

Relationship of shift work with liver enzyme abnormalities and nonalcoholic fatty liver disease: A retrospective cohort study of Thai workers in Bangkok, Thailand

Shift work, particularly night shift work, has several detrimental health outcomes. This retrospective study investigated the associations of shift work with the incidence rates of liver enzyme abnormalities and nonalcoholic fatty liver disease (NAFLD) using the annual health check-up database between 2009 and 2016 and self-administered questionnaires from two large organizations in Thailand. Among 10,205 participants, 3620 eligible participants, classified into three subgroups by their shift work status, were followed up until abnormal liver outcomes were observed. The incidence rate of abnormal outcomes was calculated, and Cox proportional hazard models were used to assess the associations. Current shift work was not associated with abnormal liver outcomes, including elevated alanine aminotransferase and aspartate aminotransferase levels, elevated lipid accumulation product (e-LAP), and elevated hepatic steatosis index (e-HSI). However, when the frequencies and duration of shift work were investigated, the duration of shift work was associated with NAFLD outcomes. Healthcare personnel with 10–20 years of shift work experience had a higher risk of e-LAP (adjusted hazard ratio [HR] = 1.31, 95% confidence interval [CI] = 1.04–1.65), while workers with more than 20 years of shift work had a lower risk of e-LAP (adjusted HR = 0.77, 95% CI–0.62–0.97). Nonhealthcare shift workers with fewer than 10 years of work exposure had a higher risk of e-HSI (adjusted HR = 4.30, 95% CI = 1.28–14.47). In summary, the shift work status was not associated with liver abnormalities, but the duration of shift work was associated with NAFLD.

Durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial

We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue sarcoma (STS). In this single-arm phase 2 trial (NCT03798106), treatment consisted of pazopanib 800 mg orally once a day and durvalumab 1500 mg once every 3 weeks. Primary outcome was overall response rate (ORR) and secondary outcomes included progression-free survival (PFS), overall survival, disease control rate, immune-related response criteria, and safety. The ORR was 30.4% and the trial met the pre-specified endpoint. The median PFS was 7.7 months (95% confidence interval: 5.7–10.4). The common treatment-related adverse events of grades 3–4 included neutropenia (9 [19.1%]), elevated aspartate aminotransferase (7 [14.9%]), alanine aminotransferase (5 [10.6%]), and thrombocytopenia (4 [8.5%]). In a prespecified transcriptomic analysis, the B lineage signature was a significant key determinant of overall response (P = 0.014). In situ analysis also showed that tumours with high CD20+ B cell infiltration and vessel density had a longer PFS (P = 6.5 × 10−4) than those with low B cell infiltration and vessel density, as well as better response (50% vs 12%, P = 0.019). CD20+ B cell infiltration was identified as the only independent predictor of PFS via multivariate analysis. Durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile.

Levilactobacillus brevis MZ384011 and Levilactobacillus brevis MW362779 can mitigate lead induced hepato-renal damage by regulating visceral dispersion and fecal excretion.

Heavy metal pollution is a global issue. Current study provides evidence on Pb toxicity ameliorative potential and safe nature of Levilactobacillus brevis MZ384011 (S1) and Levilactobacillus brevis MW362779 (S2), isolated from carnivore gut and human milk, respectively. In a 60-days experiment, the rats were distributed into six groups. G-I, G-V and G-VI were kept on normal diet, while GII-IV were fed on lead nitrate (500mg/kg) supplemented food, throughout experiment. After confirmation of Pb toxicity in GII-IV at 15th day, S1 was orally administered to G-III and G-V while S2 was given to G-IV and G-VI at a dose of 1 × 109 CFU/animal/day. On day 60 of experiment, positive control (G-II) displayed significant reduction in body weight, total protein, albumin, globulin, mineral profile, erythrocyte count, hemoglobin, hematocrit and hematological indices and elevation in leukocyte count, alanine aminotransferase, aspartate aminotransferase, bilirubin, uric acid and creatinine along with alterations in hepato-renal architecture. With reference to G-II, the G-III and G-IV displayed significant improvement in all aforementioned parameters, 40-60% reduction in tissue Pb levels (blood, liver, kidney and adipose tissue) and elevation in fecal Pb contents (p = 0.000). The groups V and VI did not show any sign of toxicity. The findings confirm that strains are safe for biological application and can reverse Pb toxicity by facilitating fecal Pb excretion and reducing its systemic dispersal. To best of our information this is the first report on Pb toxicity ameliorative role of Levilactobacillus brevis from human milk, the safest source.

Fruquintinib combined with sintilimab as a second-line therapy for advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC): A phase II, single-arm, prospective study.

332 Background: The KEYNOTE-061 trial showed that anti-PD-1 monotherapy did not improve overall survival compared to chemotherapy in the second-line treatment of advanced GC/GEJC. Preclinical and clinical data have demonstrated the synergistic anti-tumor effect of fruquintinib, a highly selective oral VEGFR 1/2/3 inhibitor, in combination with immune checkpoint inhibitors (ICIs). Additionally, the phase III study (NCT03223376) of fruquintinib combined with paclitaxel in second-line GC/GEJC has yielded positive topline results. This study aims to assess the safety and efficacy of fruquintinib combined with sintilimab (an anti-PD-1 antibody) as a second-line therapy for GC/GEJC. Methods: In this phase II, open-label trial (NCT05625737), patients (pts) aged 18-75 years who were HER2-negative and had failed first-line standard therapy were enrolled. Eligible pts received fruquintinib at 4mg/day orally on days 1-14 and sintilimab at 200 mg intravenously on day 1, with treatment repeated every 3 weeks. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. An optimal Simon two-stage design was employed: if more than 1 pt achieved objective responses in the first stage (n = 7), the study would proceed to the second stage and enroll an additional 19 pts; otherwise, the study would be terminated. Results: At data cut-off (August 31, 2023), 7 pts were enrolled in the first stage and additional 7 pts in the second stage. Pts characteristics included: median age 50 (range 33–71); 29% male; 57% with ECOG PS 1; 57% with peritoneal metastasis, and 71% having previously received immunotherapy. Of the 12 pts evaluable for tumor response, 4 achieved partial responses, and 4 had stable disease, resulting in a confirmed ORR of 33.3% (95% CI: 9.9-65.1%) and a DCR of 66.7% (95% CI: 34.9-90.0%). The median PFS was 5.09 months (95% CI: 2.69–NA), while OS results were pending maturity. Grade 1-2 treatment-emergent adverse events (TEAEs) occurred in ≥20% of pts, including decreased white blood cell count (36%), hypertriglyceridemia (29%), abdominal pain (29%), decreased lymphocyte count (21%), and elevated aspartate transaminase and alanine transaminase (21%). Grade 3/4 TEAEs occurred in only one patient, consisting of increased blood bilirubin levels, aspartate transaminase elevation, and alanine transaminase elevation. No treatment-related deaths were reported. Conclusions: The combination of fruquintinib and sintilimab as a second-line therapy has demonstrated promising anti-tumor activity and an acceptable safety profile in pts with advanced GC/GEJC. The trial is ongoing, and further data analysis and reporting are anticipated. Clinical trial information: NCT05625737 .

Perioperative lenvatinib combined with tislelizumab plus transcatheter arterial chemoembolization in resectable hepatocellular carcinoma with high-risk of recurrence: A prospective, single-arm, phase 2 trial.

503 Background: Early recurrence is common after surgery for hepatocellular carcinoma (HCC) and associated with poor prognosis. There is no standard of care neoadjuvant therapy. The combinations of lenvatinib, anti-PD-1 antibodies and transcatheter arterial chemoembolization (TACE) (triple therapy) has shown better trend in tumor response and survival outcomes on unresectable HCC. This study aims to explore the efficacy and safety of triple therapy in the neoadjuvant therapy of resectable HCC patients with high-risk of recurrence. Methods: This prospective, single-arm, phase 2 trial (ChiCTR2100048249) enrolled patients with primary resectable HCC who had not received prior anti-tumor therapy. TACE will be performed once on Day 1. Tislelizumab (an anti-PD-1 antibody, 200 mg) intravenously once every 3 weeks and lenvatinib (bodyweight ≥ 60 kg, 12 mg; &lt; 60 kg, 8 mg) orally daily was initiated within 7-10 days after TACE treatment. Surgery was performed 8 weeks after treatment. After 4-8 weeks of surgery, patients continued to receive tislelizumab and lenvatinib for 6 months. Primary endpoint was relapse-free survival (RFS). Secondary endpoints were objective response rate (ORR) by mRECIST, major pathological reactions, R0 resection rates, overall survival, and adverse events (AE). Results: From April 2022 to June 2023, 29 patients (median age, 54 years) from ten Chinese hospitals were enrolled, all Child-Pugh A and ECOG PS 0, mostly males (79.3%) and HBV infection (93.1%). According to mRECIST, the ORR was 89.7% (26/29, CR 4, PR 22), and the DCR was 96.7% (28/29). No grade 3 or above AE were observed. The most common AE were rash (4/29, 13.8%), thrombocytopenia (3/29, 10.3%), fatigue (3/29, 10.3%), elevated aspartate aminotransferase (2/29, 6.9%), elevated alanine aminotransferase (2/29, 6.9%), and hypertension (2/29, 6.9%). In 29 patients, 26 patients had received surgical treatment (R0 resection rates were 100%), 20 patients (20/26, 76.9%) achieved major pathological reaction (necrosis &gt; 90%), and 4 patients (4/26, 15.4%) achieved complete pathological response. 2 patient (6.9%) refused surgery. 1 patient (3.4%) developed disease progression and lost the chance of surgery. After a median follow-up of 8.0 months (interquartile range 4.6-12.3 months), one patient died of severe pneumonia caused by COVID-19 infection 9.9 months after operation. Tumor recurrence was detected in 3 patients. The 6- and 12-month RFS rates were 90% and 82.5%, respectively. Median RFS and overall survival were not reached. Conclusions: Lenvatinib, tislelizumab, and TACE were safe and showed promising efficacy as a neoadjuvant therapy for resectable HCC with high risk of recurrence. Clinical trial information: ChiCTR2100048249.