Increase In AST Research Articles

Alanine Aminotransferase and Aspertate Aminotransaminase Activities in Wistar Rats Fed with Musa paradisiaca (Plantain) Stem Pulp in Aluminium Chloride Induced Hepatic Oxidative Stress

In this study, the effect of Musa paradisiaca (plantain) stem pulp on aluminium chloride (AlCl3) induced hepatotoxicity was studied. Fifteen (15) healthy female wistar rats after acclimatization for two weeks were randomly distributed to three (3) groups, with five (5) rats in each group. Group 1 served as control and received as control pelletized growers feed and distilled water throughout the experiment (14 days). Group 2 received 100mg/kg/body weight (b.w.) of aluminium chloride and was fed with pelletized growers feed and distilled water for 14 days and group 3 received 100mg/kgb.w of aluminium chloride and 2mL/kg of the juice gotten from M. paradisiaca and were also allowed free access to feed and water ad libitum for 14 days. Blood samples were collected via cardiac puncture and analyzed for AST, ALT, MDA and SOD. Results revealed that there was a significant increase in AST and ALT levels respectively from 67.83±1.39 to 173.40±0.81 and 43.73±1.00 to 128.24±0.68 after treatment with AlCl3 compared to control while administration of M. paradisiaca extract ameliorated the adverse effects of AlCl3 when compared to AlCl3 treated groups from 173.40±0.81 to 72.40±1.71 and 128.24±0.68 to 45.83±1.22 respectively. There was a significant decrease (P<0.05) in SOD level from 6.04± 0.49 to 2.56±0.86 of AlCl3 compared to control and a significant increase (P<0.05) from 2.56±0.86 to 6.00±1. 56 in SOD level was observed in M. paradisiaca treated groups when compared to AlCl3 treated group. It was also observed that there was a significant (P<0.05) from 401.09±0.10 to 1207.98±1.39 in MDA level after treatment with AlCl3 compared to control while there was a significant decrease (P<0.05) from 1207.98±1.39 to 388.83±31.15 in MDA level of M. paradisiaca treated groups when compared to the AlCl3 treated groups. It was observed that M. paradisiaca showed a mitigating effect on aluminium chloride-induced hepatotoxicity and thus justifying the hepatoprotective property of M. paradisiaca.

Evaluation of hepatotoxicity and nephrotoxicity induced by fenpyroximate in subchronic-orally exposed Wistar rats

Backgrounds Fenpyroximate (FEN) is an acaricide that inhibits the complex I of the mitochondrial respiratory chain. The aim of this work was to explore the hepatotoxic and nephrotoxic effects of FEN on Wistar rats. Methods The study involved five groups: a control group and four groups treated with FEN at 1, 2, 4, and 8 mg/Kg bw for 28 consecutive days. Histological examination and biochemical analysis of hepatic and renal biomarkers were performed. The malondialdehyde (MDA), protein carbonyl levels, and antioxidant enzymes activities were measured. Comet assay was conducted to explore FEN genotoxicity. Results FEN induced a disturbance of the hepatic and renal functions as evidenced by an increase in AST, ALT, ALP, creatinine, and uric acid levels and histopathological modifications in the two examined tissues. FEN increased hepatic and renal lipid peroxidation and protein oxidation. The activities of liver and kidney SOD, CAT, GPX , and GST are increased significantly in FEN-treated rats at doses of 2 and 4 mg/kg bw. However, with the dose of 8 mg/kg bw of FEN, these activities are decreased. Moreover, FEN increased DNA damage in a dose-dependent manner. Conclusion FEN was hepatotoxic and nephrotoxic very likely through induction of oxidative stress.

Bisphenol S induced dysregulations in liver; iron regulatory genes and inflammatory mediators in male Wistar rats.

Bisphenol S (BPS), an analog of bisphenol A (BPA), has been frequently detected in consumer products, food wrappers, plastics, and thermal papers. Since the liver is a hub of metabolic and detoxification pathways, thus intimately related to BPS presence in the environment and body. The current study was designed to investigate the effects of BPS administration in an animal model. Twenty-five male Wistar rats weighing 175 ± 25 g were randomly divided into control and treated groups. The control group was further divided into group I (no treatment) and group II (corn oil), whereas the treatment group was divided into D-I (40 mg/kg/day), D-II (200 mg/kg/day), and D-III (400 mg/kg/day) groups, getting oral doses of BPS for 15 days. Data analysis showed a significant statistical increase in hepatic enzymes ALT (33.4%), AST (25.4%), and ALP (529.6%) in the D-III group along with the development of hypercholesterolemia and hypertriglyceridemia in all BPS groups. Aberrant mRNA expressions of some key hepatic iron regulatory genes and inflammatory mediators were evident through qRT-PCR. Bisphenol S caused congestion of central vein from mild to moderate in hepatic sections. In conclusion, our investigation insinuates BPS intoxication potential and therefore may not be a safe alternative to BPA.

Assessment of liver function enzymes, MDA and GSH in the Sera of COVID-19 patients

A cluster of unexplained pneumonia cases was reported in Wuhan, China, in late December 2019. A new coronavirus was identified as the causative cause of this mysterious pneumonia a few days later. The World Health Organization has temporarily given this causal virus the designation of severe acute respiratory syndrome coronavirus 2 and the related infected disease as coronavirus disease 2019 (COVID-19). The primary objective of this study is to examine the liver efficiency and assess the oxidative stress status of COVID-19 patients by measuring liver function enzymes, glutathione and MDA. The study included 120 cases ranging from 20 to 60 years, divided into three groups, COVID-19 patients, recovered, and control groups. Group. The results obtained indicated a significant increase in ALT, AST, and ALP activity (p< 0.01) in patients compared to those recovering ​​and control. The results also indicated a significant increase in MDA in contrast to a significant decrease in the GSH activity of COVID-19 patients compared to recovered and healthy subjects. These results reflect the strong relationship between COVID-19 and impaired liver function as well as impaired oxidative stress / antioxidant balance.

Metformin protects against ethanol-induced liver triglyceride accumulation by the LKB1/AMPK/ACC pathway.

Hepatic lipid accumulation is one of the main pathological features of alcoholic liver disease (ALD). Metformin serves as an AMPK activator and has been shown to have lipids lowering effects in non-alcoholic fatty liver disease (NAFLD), but its role in ALD remains unclear. The purpose of this study was to explore the potential mechanism of metformin regulating lipid metabolism in ALD. In vitro and in vivo ALD models were established using AML12 cells and C57BL/6 mice, respectively. To determine the effect of metformin on ALD in vitro, the concentration of cellular triglyceride was examined by Nile red staining and a biochemical kit. To further reveal the role of metformin on ALD in vivo, liver tissues were examined by HE and oil red O staining, and the levels of ALT and AST in serum were determined via an automatic biochemical analyzer. The expression of mRNA and proteins were measured using qRT-PCR and Western blot, respectively. The role of the LKB1/AMPK/ACC axis on metformin regulating ethanol-induced lipid accumulation was evaluated by siRNA and AAV-shRNA interference. The results showed metformin reduced the ethanol-induced lipid accumulation in AML12 cells through activating AMPK, inhibiting ACC, reducing SREBP1c, and increasing PPARα. In addition, compared with control mice, metformin treatment inhibited ethanol-induced liver triglyceride accumulation and the increase of ALT and AST in serum. Interference with LKB1 attenuated the effect of metformin on ethanol-induced lipid accumulation both in vitro and in vivo. Metformin protects against lipid formation in ALD by activating the LKB1/AMPK/ACC axis.

Hematological and Biochemical Investigations of Green Synthesized Reduced Graphene Oxide Carbon Nanoparticles on Acetaminophen Induced Male Albino Rats.

The aim of this study is to evaluate the protective activity of green-synthesized Reduced graphene oxide carbon nanoparticles (RGO-CNP) from Asparagus racemosus (shatamuli) by hematological and biochemical assessments on acetaminophen induced uremic rats. 36 animals were divided into six groups including a control group, acetaminophen induced uremic group and nanoparticle treatment groups. Nanoparticle treated four groups were intraperitonealyco-administered RGO- CNP at doses of 0.5, 1.0, 2.0 and 4.0 mg/kg bw and acetaminophen at 500 mg/kg ofbw for 14 days respectively. Hematological analysis revealed that there was significant decrease (p<0.05) in Red Blood Cells (RBCs), Hemoglobin (Hb), with acetaminophen induced Group II. Co-administration of green synthesized RGO and acetaminophen on nanoparticle treating groups showed the effective protectivity and significant (p<0.05) recovery in the hematological alterations. Other hematological parameters including- WBC, Platelet, Hematocrit, MCH and MCHC remained within the reference range and no significant alterations were observed. There was a significant increase in plasma ALT, AST, serum urea and creatinine levels (p< 0.05) in uremic group (Group II) compare to control (Group I).The alterations were further resettled to the higher dose of RGO treated groups (Group V and VI). The other tested biochemical parameters ALP, total bilirubin, direct bilirubin, Serum triglyceride and cholesterol levels were not significantly altered when compared with control Group I. In conclusion, it is established that RGO possess protective response against acetaminophen induced toxicity as dose responsive manners, which is supported by haematological and biochemical observations. This promising effect suggests the potential applicability of RGO as therapeutics in drug delivery systems to reduce the toxicity.

Abstract CT196: Early results of a safety and efficacy study of allogeneic TruUCAR™ GC502 in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL)

Abstract Introduction: CD19 targeted autologous CAR-T therapies have been approved for the treatment of r/r B-ALL and greatly improved outcome. However, some patients may not be eligible to receive autologous CAR-T. TruUCAR™ GC502 is an allogeneic, universal CAR-T product with CD19/CD7 dual directed CAR. Preclinical data of GC502 were reported at ASH 2021 (Abstract 148500). Here, we report early clinical results from a phase I open-label, non-randomized, prospective investigator initiate trial (IIT) of GC502 in r/r B-ALL patients. Methods: GC502 is manufactured using leukopaks from HLA-unmatched healthy donors. It contains a 4-1BB based CD19/CD7 dual directing CAR, a T cell enhancer, and genetically disrupted TRAC and CD7 loci to avoid GvHD and fratricide. Patients (pts) with r/r B-ALL were enrolled and treated with one of two different formulations (A or B) in escalating dose levels ranging from 1.0x107 (DL1) to 1.5x107 (DL2) cells/kg. Prior to infusion of GC502, pts received a Flu/Cy based lymphodepletion regimen. Adverse events, disease response and expansion kinetics were evaluated in this study. Results: To date, 4 pts (15-34 yrs) were enrolled from Sep. 2021 to Jan. 2022. All patients were heavily pretreated, and had received either autologous or donor derived CD19 or CD19-CD22 targeted CAR-T therapy. Baseline marrow blast levels ranged from 19.5% to 92% (median 48.1%). 1 pt had extramedullary involvement. At data cut-off (Jan. 28, 2022), all patients had received a single dose of GC502: 1 pt at DL 1 1.0x107cells/kg and 3 patients at DL 2 1.5x107cells/kg. At day 28 post CAR-T infusion, 2 out of 3 response evaluable patients had achieved CR/CRi; 1 pt achieved PR at month 1 and subsequently received HSCT on day 39. TEAEs presented as Gr 3 febrile neutropenia (2/3), Gr 4 thrombocytopenia (1/3) and Gr 3 anemia (3/3). All TEAE resolved after treatment with SOC. Non-hematological TEAE presented as Gr≤3 γ-GT increase (3/3), Gr≤3 AST increase (2/3) and Gr≤3 ALT increase (3/3). CRS presented as Gr 2 in 2 patients with formulation B. 2 pts received formulation A and experienced Gr 3 CRS with a duration of 7 and 10 days respectively (CRS was graded according ASTCT Consensus Grading). CRS in all pts was manageable and resolved after treatment with Ruxolitinib, SOC and supportive care. No ICANS or aGvHD were observed. The pt treated in DL 1 did not show adequate GC502 cellular expansion. Peak expansions of GC502 in peripheral blood were observed between week 1-2 in DL 2. Median peak CAR copies were 149,945 copies/ug DNA (range 10,849-195,400). Conclusions: TruUCAR™ GC502 demonstrated promising early results with a manageable safety profile. Robust CAR-T cell expansion was observed in DL2 at 1.5x107cells/kg in heavily pretreated r/r B-ALL patients, including those previously treated with CD19 CAR-T therapies. The study is ongoing and continues accruing patients. Citation Format: Shiqi Li, Xinxin Wang, Zhongtao Yuan, Lin Liu, Yu Li, Jia Liu, Jiaping He, Zhimin Li, Wei Zhao, Jianning Ge, Yajin Ni, Lianjun Shen, Wei Cao, Xi Zhang, Martina Sersch, Sanbin Wang. Early results of a safety and efficacy study of allogeneic TruUCAR™ GC502 in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT196.

Efficacy and safety of sintilimab plus XELOX as neoadjuvant therapy in patients with locally advanced gastric cancer: A single-arm open-label phase II trial.

e16091 Background: Neoadjuvant chemotherapies have been widely recommended by clinical guidelines for patients with locally advanced gastric cancer. However, the evidence of combining neoadjuvant chemotherapy with anti-programmed death 1 (anti-PD-1) antibody therapy for patients with locally advanced gastric cancer is inadequate. Thus, we conducted a single-arm phase II trial to evaluate the efficacy and safety of anti-PD-1 antibody sintilimab and XELOX regimen (capecitabine plus oxaliplatin) in patients with locally advanced gastric adenocarcinoma. Methods: Patients with locally advanced(cT3-4 N+ M0, CY0,P0) were enrolled and received four preoperative cycles of XELOX (oxaliplatin 130mg/m2, IV, d1 with capecitabine 1000mg/m2, bid, d1-d14, q21d) and sintilimab (200mg, IV, q21d). Surgery was performed within 3-4 weeks after completion preoperative therapy. After surgery, patients received four cycles of XELOX. The primary endpoint was the pathological complete response (pCR) rate and the secondary endpoints were major pathologic response (MPR) rate, R0 resection rate, safety, disease-free survival (DFS) and overall survival (OS). This clinical trial is registered at ChiCTR.gov.cn: ChiCTR2000030414. Results: From March 2020 to July 2021, 30 patients were enrolled, with median age 62 years (range30-72), males 18, cT3/T4: 8/22, cN1/2/3: 10/14/6, intestinal diffuse type (Lauren classification):17/13, ECOG PS 0/1/2: 19/8/3. There were 19(63.3%) patients with PD-L1 CPS≥1. All patients were available for preoperative response evaluation, the objective response (ORR) rate was 70.0% (95% CI, 50.6%-85.3%) and the disease control (DCR) rate was 100% (95% CI, 88.4%-100%). All (100%) achieved R0 resection. 10 patients (33.3%) achieved pCR (TRG 0) and 19 patients (63.3%) had MPR (TRG 0-1). Common treatment-related adverse events (TRAEs) were anemia (36.7%), leukopenia (36.7%), neutropenia (30.0%), diarrhea (26.6%), ALT increase (23.3%), AST increase (13.3%), thrombocytopenia (10.0%), vomiting (10.0%). The potential immune-related adverse events (irAEs) were dermatitis (6.7%), hypothyroidism (3.3%), pneumonia (10.0%). Most of the TRAEs and potential irAEs were grade 1 or 2. Grade3 TRAEs and irAEs included ALT increase (3.3%), AST increase (3.3%), dermatitis (3.3%). There were no severe complications and death related to the operation. The median postoperative hospital stay was 8 days (range6-23 days). Conclusions: Sintilimab plus XELOX as neoadjuvant therapy showed an encouraging pCR rate, MPR rate and manageable safety. This combination regimen might provide a new option for patients with locally advanced gastric cancer. Clinical trial information: ChiCTR2000030414.

First-in-human/phase I trial of PE0116 (4-1bb Ig G4 McAb) as single agent in patients with solid tumors progressed after lines of therapies in China.

2640 Background: The 4-1BB co-stimulatory protein is an important modulator of the adaptive T Cell immune responses, and potentially a vital target for immunotherapies in oncology. HE0116 is a humanized agonist antibody to 4-1BB that promotes proliferation and activation of T cells. The FIH/phase Ia/Ib study was conducted to establish a maximum tolerated dose, identify dose-limiting toxicities (DLTs) and to assess safety, tolerability, and pharmacokinetics of HE0116 as single agent in patients with solid tumors who have progressed on standard of care (SoC) and experimental therapies. Methods: Patients (pts) with histologically confirmed solid tumors who progressed after prior SoC and experimental therapies were enrolled. A Fibonacci 3+3 design was employed for the phase 1a dose escalation of 9 dose levels. HE0116 was administered intravenously once in first 28-day cycle for PK analysis and DLT assessment. Pts continued HE0116 treatment every 3 weeks until experiencing an intolerable toxicity, disease progression or withdrawing consent. Results: As of January 25, 2022, 19 pts were enrolled in the dose-escalation phase). All pts had progressed on multiple lines of therapies, including but not limited to, chemotherapy, hormonal therapy, or/and immunotherapy. As defined in study protocol, pts received HE0116 intravenously at least once at six dose levels: 0.03 mg/kg (n = 1), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3), 1 mg/kg (n = 4), 2 mg/kg (n = 3), and 3 mg/kg (n = 5). One DLT of Grade (g) 4 platelets decrease was reported at 3 mg/kg, thus 3 new pts were added at this dose. The grade1 and grade2 HE0116 related adverse events (AEs) per CTCAE v5 that occurred ( < 10% frequency) were ALT and AST increase, platelet decrease, WBC decrease, anemia, hypokalemia, hyponatremia, hypoalbuminemia, hypothyroidism, or bone pain. Three SAE were reported: 1 g2 ascites, 1 g4 dyspnea, 1 g2 fever. To date there was one iPR at 1 mg/kg for a pt with advanced ovarian cancer with liver met after 6 cycles of treatment, and 4 iSD (1 in 2 mg/kg, 3 in 3 mg/kg) were recorded. Conclusions: HE0116 administrated intravenously every 3 weeks is well tolerated with minimal toxicities. Preliminary data are very encouraging as single agent HE0116 showed durable responses with 1 iPR, 4 iSD in several difficult to treat late-stage cancer pts. Dose escalation is ongoing as per study protocol. Phase II in select patient populations, and clinical investigation of the combination of HE0116 with CTLA-4 or PD-1 are warranted. Clinical trial information: CTR20201794.

Extended progression-free survival and long-term safety of nirogacestat in patients with desmoid tumors.

11545 Background: Desmoid tumors are rare, locally invasive, soft-tissue neoplasms that can cause significant morbidity and frequently recur despite surgery or radiation. The ongoing phase II trial of nirogacestat, a gamma-secretase inhibitor, in patients (pts) with recurrent, refractory desmoid tumors (NCT01981551), has reported disease stabilization and multiple partial responses as assessed by RECIST criteria (Kummar JCO 2017). Herein, we report long-term outcomes, tolerability, and safety of this study. Methods: A total of 17 pts enrolled in this open label, single arm, phase II study, completing accrual in 2014. Pts received 150 mg nirogacestat orally twice a day in continuous 3-week cycles. Objective treatment response was defined by RECIST 1.1 at cycle 1 and every 6 cycles thereafter using CT (affected area) per the primary study objective; optional MRI assessment was concurrently performed. Yearly CT scans of the chest, abdomen, and pelvis were performed on pts starting in 2016. Results: As of Dec. 31, 2021, 4/17 (23%) pts remain on nirogacestat treatment for over 7 years. The objective response rate has not changed since the 2017 publication [31.25% (5/16 evaluable patients), with an exact two-sided Clopper-Pearson 95% confidence interval of 11.0-58.7%], but the observed extended progression-free survival (PFS) is notable; no RECIST disease progression has been observed for any of the 16 evaluable patients at any point on study. Median time on treatment was 4.14 years (range: 0.17-7.99 years). Most common adverse events remain hypophosphatemia (13/17, 76%; 8 grade 3 [gr3], 5 gr2), diarrhea (13/17, 76%; 1 gr3, 4 gr2, 8 gr1), nausea (11/17, 65%; 11 gr1), AST increase (11/17, 65%; 1 gr2, 10 gr1), and lymphopenia (11/17, 65%; 2 gr2, 9 gr1); no pts required a dose reduction after the second year of therapy. Bone fractures (fx) were reported in 4 pts (3 female/1 male) during the first 4 years of treatment (1 hip fx, 1 rib fx, 2 metatarsal stress fxs). Two of these 4 pts experienced a further fx approximately 1 year later (contralateral metatarsal; hip). Both pts with hip fx were > 10 years post-menopausal. Given median age at enrollment (34 years; range: 20-69 years) and reported fx events, bone health was evaluated with findings in keeping with expected range for age. No secondary malignancies have been identified to date. Conclusions: No patients receiving nirogacestat have progressed after a median of more than 4 years of treatment. The long duration of responses and lack of tumor progressions observed in this trial has informed the design of a phase III trial in pts with progressing desmoid tumors (NCT03785964) that is currently underway. Clinical trial information: NCT01981551.

A phase II study of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma.

4519 Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). A phase II clinical study showed that RC48-ADC has a good effect on locally advanced or metastatic urothelial carcinoma with HER2-positive expression that failed standard chemotherapy. In the study, some patients with HER2-postive immunohistochemistry (IHC 2+) but negative FISH test still benefited from the treatment of RC48-ADC.This study was to evaluate the activity and safety of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma. Methods: This study is an open-label, single-center, single-arm, phase II trial. Eligibility criteria include: histologically confirmed urothelial carcinoma, HER2-negasitive (IHC 0 or 1+), ECOG PS 0-1,and treated with ≥1 prior systemic treatment. Patients received RC48-ADC 2mg/kg q2w until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. The primary objectives were activity (ORR) and safety. Second objectives included progress-free survival, disease control rate and overall survival. Results: As of February 2022(date cutoff),19 patients were enrolled. The median age was 64 years old(range:36-77). At baseline, there were 6 patients with HER2(IHC 0), and 13 patients with HER2(IHC 1+).Most patients (13/19) had visceral metastasis. 15(79%) patients had received≥2 lines treatment.At date cutoff, 19 patients were assessable for response. The objective response rate was 26.3% (95% CI:9.1%,51.2%) and the DCR was 94.7% (18/19). The mPFS was 5.5months (95% CI:3.9,6.8) and mOS was 16.4months (95% CI:7.1,21.7).All of the 6 patients with HER2(0) were SD in the study. The ORRs were 38% (5/13) in patients with HER2(IHC 1+),31% (4/13) in visceral metastasis,17% (1/6) in liver metastasis patients,27% (4/15) in patients post to ≥ 2 lines of treatment. Common treatment-related AEs were leukopenia (52.6%), hypoesthesia (47.4%),alopecia (47.4%), AST increase (42.1%), ALT increase (42.1%), and neutropenia (42.1%), fatigue (42.1%),nausea (26.3%), vomiting (15.8%).Most of these AEs were Grade 1 or 2. The AE of Grade 3 was neutropenia (10.5%). The SAE was CPK increased (5.3%). Conclusions: This study showed that RC48-ADC was safe and the ORR was 26.3% in HER-negative patients with locally advanced or metastatic urothelial carcinoma. The enrollment was completed and data will be updated later. Clinical trial information: NCT04073602.

A randomized phase Ib/II study of niraparib (nira) plus nivolumab (nivo) or ipilimumab (ipi) in patients (pts) with platinum-sensitive advanced pancreatic cancer (aPDAC).

4021 Background: Establishing alternatives to perpetual chemotherapy for pts with aPDAC has been proposed to address inevitable chemotherapy resistance and cumulative toxicity. Poly (ADP ribose) polymerase (PARP) inhibitors have shown clinical efficacy in this setting, and preclinical data suggest that the addition of immune checkpoint blockade (ICB) may offer synergistic tumor control. We performed a randomized, phase Ib/II study of nira plus anti-PD-1 (nivo) or nira plus anti-CTLA-4 (ipi) maintenance for pts with aPDAC who had not progressed after >4 mo of platinum-based therapy. Methods: After discontinuation of chemotherapy, pts were randomized 1:1 to nira 200mg PO daily plus either nivo 240mg IV q2 weeks (later amended to 480mg IV q4 weeks) or ipi 3mg/kg IV q3 weeks for four doses. Nira could be escalated to 300mg PO daily if tolerated. Pts were treated until progression or unacceptable toxicity. The primary endpoint was progression free survival at six months (PFS6) in each arm. Secondary endpoints included safety, OS, ORR, and outcomes by DNA damage repair (DDR) deficiencies. Pts were evaluable for safety if they had received > 1 dose of study treatment and for efficacy if they had also received > 1 follow-up imaging study. Based on historical data, the null hypothesis of PFS6 = 44% vs a 2-sided alternative hypothesis of PFS ≠ 44% was tested. 42 pts per arm provided 81% power for testing at a 5% significance level to detect inferior PFS6 < 27% or superior PFS6 > 61%. Results: As of Oct 2021, 91 pts were enrolled, of whom 84 were evaluable for efficacy (44 nira/nivo; 40 nira/ipi). The median potential follow-up was 23 mos. Most common treatment-related AEs were nira/nivo: thrombocytopenia (28%), arthralgia (25%), nausea (23%), and fatigue (23%) and nira/ipi: thrombocytopenia (45%), anemia (43%), fatigue (43%), nausea, (41%), AST increase (36%), rash (34%) and ALT increase (29%). 88% of AEs were grade 1-2. Efficacy results were: nira/nivo: PFS6 20.6% (95% CI 8.3-32.9, p = 0.0002), mPFS 1.9 mo and nira/ipi: PFS6 59.6% (95% CI 44.3-74.9, p = 0.045), mPFS 8.1 mo. Fifteen pts (8 nira/nivo; 7 nira/ipi) had pathogenic variants in BRCA or PALB2 . Excluding these: mPFS on nira/nivo was 1.9 mo (95% CI 1.8-1.9) and mPFS on nira/ipi was 7.6 mo (95% CI 4.0 – 11.1). Conclusions: In a randomized phase 1B/II study, nira/ipi as maintenance therapy met the primary endpoint of superior PFS6 while nira/nivo yielded inferior PFS6 for pts with aPDAC who had not progressed on first-line platinum-based chemotherapy. The benefit of nira/ipi maintenance persisted in pts without known DDR variants. Clinical trial information: NCT03404960. [Table: see text]

FIBROMYALGIA - CHARACTERISTICS AND PROOF OF PAIN

Fibromyalgia is a disease that remains unrecognized due to ignorance and misinterpretation of symptoms. This article presents a clinical case from the medical practice of Fibromyalgia, while characterizing the pain syndrome and the necessary tests to prove the diagnosis. The clinical case concerned a patient with lumbar pain syndrome who did not respond to non-steroidal anti-inflammatory drugs. No connection has been established with the diseases provided for in the differential diagnosis, such as disc herniation, acute arterial insufficiency, rheumatoid arthritis. The laboratory tests performed are normal, except for a slight increase in AST of about 200 U / l, as well as high CRP values. No instrumental studies such as endophotonic emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRT) and electroencephalogram (EEG) were performed. The case describes a modified symptom in the elderly. Modified symptoms are experienced differently by patients. In this case, our own (from the doctor’s experience) paradigm was used for diagnosis. The paradigm consists of four main steps, which are: description of the specifics of each symptom; two aspects of the diagnosis: what is and what is not; the symptoms form a whole which represents the diagnosis with a logical connection and sequence and analysis of small deviations and nuances - a way of accurate diagnosis. The burning nature of the pain, the presence of painful nodules in the lumbar and scapular areas bilaterally, point to myositis. Various non-steroidal anti-inflammatory drugs have been administered in various forms (oral, topical and injectable), with no effect. As a last resort, a tricyclic antidepressant, amitriptyline, was included, which showed that the pain disappeared within a month. The presence of a mental component in the field of rheumatic disease, the effect of amitriptyline pain and the presence of sore spots at the predilection sites, led to the disease “Fibromyalgia”. Diagnosis of fibromyalgia is necessary to comply with two conditions clinical analysis of pain with the detection of painful points and instrumental nuclear magnetic resonance imaging to demonstrate dysfunction of the central nervous system and electroencephalogram for sleep disorders. To improve the diagnostic process, it is necessary in practice to apply tests of hormones and neurotransmitters.

Physiological alteration and the expression of fibrogenesis-proinflammatory genes in hepatocellular carcinoma patients with chronic hepatitis C and onset metabolic syndrome: a preliminary report at Saiful Anwar General Hospital Malang

Hepatocellular carcinoma (HCC) is one type of cancer that is included in the fifth order of cancer that causes death in the world. The highest incidence of liver cancer is found in men. Liver function related to the metabolism of various endogenous and exogenous substances is prone to chronic inflammatory stimulation, one of which is hepatitis C virus (HCV) infection. TGF-β1, NOX4, and TNF-α are three potential genes responsible for regulating chronic inflammation and fibrogenesis. This study aims to describe the profile of potential fibrogenesis and inflammation genes that play a role in the progression of HCC due to chronic hepatitis C. This type of research is a descriptive study with a quantitative approach that was carried out using Quantitative Real-Time PCR analysis. The results of serological tests in the male gender group showed that the average fasting body glucose level was 85.22 mg/dL, total cholesterol 242 mg/dL, triglyceride 158.44 mg/dL, HDL-C 18.56 mg/dL, and LDL-C 172 mg/dL. In the female gender group, the data obtained on average levels of fasting blood glucose 82.33l mg.dL, total cholesterol 350 mg/dL, triglyceride 181 mg/dL, HDL-C 29 mg/dL, and LDL-C 190 mg/dL. All gender groups also showed an increase in AST and ALT levels that had exceeded normal limits. The expression of fibrosis-related genes, namely TGF-β1 was 5.8x higher in male patients than female patients. The NOX4 gene also showed almost the same thing, namely, its expression level was 1.2 times higher in male patients. From the expression of the proinflammatory cytokine TNF-, it is also known that in male patients, the expression level is 2x times higher than in female patients. The difference in expression levels in the two groups involved a repressive mechanism of estrogen. Increased expression levels of TGF-β1, NOX4, and TNF- genes are thought to involve the activity of the HCV core protein, which then induces several signaling pathways such as NF-κB and SMAD3. From these results, the expression levels of TGF-β1, NOX4, and TNF- as the main regulators of chronic inflammation and fibrosis can describe the progression of HCC and can be used as initial data on the profile of inflammation and fibrogenesis in HCC cases that have previously been exposed to HCV infection.

Experimental assessment of the toxicity of a cardiac drug based on a phosphodiesterase-3 inhibitor and ethylmethylhydroxypyridine succinate

The study aimed to establish the parameters of chronic toxicity of the newly developed drug based on phosphodiesterase-3 inhibitor and ethylmethylhydroxypyridine succinate in experiments on laboratory animals. The analysis was performed on white sexually mature young male Wistar rats weighing 170–185 g. Four groups of white rats were formed. The first experimental group was administered Bendamine based on a phosphodiesterase-3 inhibitor and ethylmethylhydroxypyridine succinate at a therapeutic dose. Rats of the second experimental group were injected with the experimental drug in a 5-fold dose. Rats of the third experimental group were administered the drug in a 10-fold dose. The fourth group served as control. The study of chronic toxicity of Bendamine in white rats indicates that long-term 30-day administration in therapeutic doses or 5-fold dose does not cause clinical signs of poisoning, as evidenced by the physiological limits of fluctuations in the studied morphological and biochemical parameters of blood rats. Prolonged administration of Bendamine to rats in a 10-fold dose is accompanied by a slight suppression of the body's physiological state, as indicated by a decrease in total erythrocytes and hemoglobin by 10.1 % against an increase in white blood cells by 59.8% (P < 0.001). In addition, there was a decrease in the functional state of the liver, as evidenced by a probable reduction in total protein by 8.0% and urea – by 13.5 %, as well as an increase in ALT, AST, and alkaline phosphatase by 31.6 %, 7.4 %, and 53.9% respectively. Probable changes in the coefficients of liver and spleen mass have been established. When administered intramuscularly to rats with the drug Bendamine for 30 days, the macroscopic and microscopic structure of the studied internal organs is preserved in all groups of animals. The second experimental group revealed reversible moderate histostructural changes in the liver and kidneys. In rats treated with ten times the therapeutic dose of the drug, histologically found hemodynamic disorders and alterations in dystrophic nature, mainly of protein origin, with focal localization in the parenchyma of the liver, kidneys, and myocardium, which in most cases are reversible and result from the compensatory response. Macroorganism on the introduction of a high dose of the study drug.

TELOMERE LENGTH AS A BIOLOGICAL MARKER FOR ASSESSING THE SERIOUSNESS OF PNEUMONIA OF VARIOUS ETIOLOGIES

Abstract. The results of the features of the clinical course of pneumonia of various etiologies are presented, taking into account the epigenetic indicator of the human body, such as telomere length. We examined 102 male military personnel who were treated at the hospital therapy clinic of the Military Medical Academy named after S. M. Kirov. The patients were divided into two groups: group I of 63 people aged 37,3±6,7 years with pneumonia caused by a new coronavirus infection; Group II - 39 men aged 41.4±5.3 years with bacterial pneumonia of various etiologies. Patients were examined and treated according to the standard scheme. In the group of severe viral pneumonia, a significantly larger volume of lung parenchymal damage was determined, a decrease in saturation to 91,3±1,6% (p=0,003); myocardial damage: an increase in troponin T up to 15,6±5,3 ng/l (p=0.001), an increase in total CPK, AST and ALT compared with patients of group II. In group I, evaluating the results of hemogram parameters, attention is drawn to the tendency to thrombocytopenia (172±29x109/l, p=0,03), the tendency to leukopenia (4.1±1,2x109/l) in severe disease. There was a significant increase in CRP, D-dimer and ferritin in severe viral pneumonia in men of group I, which can be characterized as coagulopathy associated with the risk of developing arterial and venous thrombosis because of microthrombovasculitis. Telomeres are specialized functional complexes that are located at the ends of chromosomes and protect them from fusion with each other, which preserves the integrity of the eukaryotic cell genome. Telomere length is an important characteristic of a person’s overall health. It is associated with such characteristics as longevity or the affinity of the human body to various diseases, such as type 2 diabetes mellitus, hypertension, coronary heart disease, and others. In this scientific study, change in length lomer in patients with pneumonia of various etiologies. The most pronounced shortening of telomere length was found in patients with severe viral pneumonia (significant shortening of telomere length by more than 2000 base pairs), compared with bacterial pneumonia. The identified changes can be used to predict an unfavorable outcome of pneumonia caused by a new coronavirus infection, for example, the development of such a formidable complication as a “cytokine storm”. The obtained preliminary results make it possible to consider telomere length as a specific biological marker for assessing the severity of pneumonia caused by the SARS-CoV-2 virus.

CHANGES IN SOME HAEMATOLOGICAL AND BIOCHEMICAL PARAMETERS IN LOCAL BLACK GOATS DURING PREGNANCY

The present study was aimed to assess and determine the effects of pregnancy on some biochemical and haematological parameters. This experiment was conducted using 16 pregnant of known gestational period and 4 non-pregnant does raised at commercial farm. Results revealed a non-significant differences between pregnant and non-pregnant does for all studied traits. With the advances of pregnancy, it was noticed an increase (P<0.05) in PCV, Hb, AST, ALT, Glucose and Cholesterol and a decrease in total protein and globulin. In conclusion, it can be indicated that physiological status impacts the traits under consideration.

First data for sotorasib in patients with pancreatic cancer with KRAS p.G12C mutation: A phase I/II study evaluating efficacy and safety

360490 Background: KRAS mutation is present in 90% of pancreatic ductal adenocarcinomas with p.G12C accounting for 1% to 2% of these mutations. Sotorasib, a small molecule that specifically and irreversibly inhibits KRASG12C, has been investigated in the CodeBreaK100 trial in patients with KRASG12C-mutated advanced solid tumors. Herein, we report on the largest dataset evaluating efficacy and safety of a KRASG12C inhibitor in patients with pretreated KRASG12C-mutated pancreatic cancer. Methods: CodeBreaK100 (NCT03600883) is an international, single arm, phase I/II study evaluating the efficacy and safety of sotorasib in patients with KRASG12C-mutated advanced solid tumors with ≥ 1 prior systemic therapy unless intolerant or ineligible for available therapies. The primary efficacy endpoint is confirmed objective response rate (ORR), assessed by blinded independent central review (BICR) per RECIST 1.1. Secondary endpoints include duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: As of November 1, 2021, 38 patients with pancreatic cancer (mean age: 65 years, 76.3% male) from the combined phase I/II study received sotorasib 960 mg once daily. Stage IV disease was present in 55.3% of patients at diagnosis, and in all patients at enrollment. Baseline ECOG scores were 0, 1, or 2 in 31.6%, 57.9%, and 10.5% of patients, respectively. Most patients (79%) had ≥ 2 prior lines of therapy (median: 2 [range: 1-8]). Median treatment duration was 4.1 months with a median follow-up of 16.8 months. Eight patients had confirmed partial response by BICR with a resulting ORR of 21.1% (95% CI: 9.55%-37.32%). DCR was 84.2% (Table 1). Treatment-related adverse events (TRAEs) of any grade occurred in 16 (42.1%) patients. Grade ≥ 3 TRAEs occurred in 6 patients: diarrhea (2); fatigue (2); abdominal pain, ALT increase, AST increase, pleural effusion, and pulmonary embolism (1 each). No TRAEs were fatal or resulted in sotorasib discontinuation. Conclusions: Sotorasib demonstrated clinically meaningful anticancer activity and tolerability in patients with heavily pretreated KRASG12C-mutated advanced pancreatic cancer, who have limited treatment options and poor prognosis. Clinical trial information: NCT03600883. [Table: see text]

Suppression of Oxidative Stress and Proinflammatory Cytokines Is a Potential Therapeutic Action of Ficus lepicarpa B. (Moraceae) against Carbon Tetrachloride (CCl4)-Induced Hepatotoxicity in Rats.

Local tribes use the leaves of Ficus lepicarpa B. (Moraceae), a traditional Malaysian medicine, as a vegetable dish, a tonic, and to treat ailments including fever, jaundice and ringworm. The purpose of this study was to look into the possible therapeutic effects of F. lepicarpa leaf extract against carbon tetrachloride (CCl4)-induced liver damage in rats. The DPPH test was used to measure the antioxidant activity of plants. Gas chromatography-mass spectrometry was used for the phytochemical analysis (GCMS). Six groups of male Sprague-Dawley rats were subjected to the following treatment regimens: control group, CCl4 alone, F. lepicarpa 400 mg/kg alone, CCl4 + F. lepicarpa 100 mg/kg, CCl4 + F. lepicarpa 200 mg/kg and CCl4 + F. lepicarpa 400 mg/kg. The rats were euthanized after two weeks, and biomarkers of liver function and antioxidant enzyme status were assessed. To assess the extent of liver damage and fibrosis, histopathological and immunohistochemical examinations of liver tissue were undertaken. The total phenolic content and the total flavonoid content in methanol extract of F. lepicarpa leaves were 58.86 ± 0.04 mg GAE/g and 44.31 ± 0.10 mg CAE/g, respectively. F. lepicarpa’s inhibitory concentration (IC50) for free radical scavenging activity was reported to be 3.73 mg/mL. In a dose-related manner, F. lepicarpa was effective in preventing an increase in serum ALT, serum AST and liver MDA. Histopathological alterations revealed that F. lepicarpa protects against the oxidative stress caused by CCl4. The immunohistochemistry results showed that proinflammatory cytokines (tumour necrosis factor-α, interleukin-6, prostaglandin E2) were suppressed. The antioxidative, anti-inflammatory, and free-radical scavenging activities of F. lepicarpa can be related to its hepatoprotective benefits.

S-Acetyl-Glutathione Attenuates Carbon Tetrachloride-Induced Liver Injury by Modulating Oxidative Imbalance and Inflammation.

Liver fibrosis, depending on the stage of the disease, could lead to organ dysfunction and cirrhosis, and no effective treatment is actually available. Emergent proof supports a link between oxidative stress, liver fibrogenesis and mitochondrial dysfunction as molecular bases of the pathology. A valid approach to protect against the disease would be to replenish the endogenous antioxidants; thus, we investigated the protective mechanisms of the S-acetyl-glutathione (SAG), a glutathione (GSH) prodrug. Preliminary in vitro analyses were conducted on primary hepatic cells. SAG pre-treatment significantly protected against cytotoxicity induced by CCl4. Additionally, CCl4 induced a marked increase in AST and ALT levels, whereas SAG significantly reduced these levels, reaching values found in the control group. For the in vivo analyses, mice were administered twice a week with eight consecutive intraperitoneal injections of 1 mL/kg CCl4 (diluted at 1:10 in olive oil) to induce oxidative imbalance and liver inflammation. SAG (30 mg/kg) was administered orally for 8 weeks. SAG significantly restored SOD activity, GSH levels and GPx activity, while it strongly reduced GSSG levels, lipid peroxidation and H2O2 and ROS levels in the liver. Additionally, CCl4 induced a decrease in anti-oxidants, including Nrf2, HO-1 and NQO-1, which were restored by treatment with SAG. The increased oxidative stress characteristic on liver disfunction causes the impairment of mitophagy and accumulation of dysfunctional and damaged mitochondria. Our results showed the protective effect of SAG administration in restoring mitophagy, as shown by the increased PINK1 and Parkin expressions in livers exposed to CCl4 intoxication. Thus, the SAG administration showed anti-inflammatory effects decreasing pro-inflammatory cytokines TNF-α, IL-6, MCP-1 and IL-1β in both serum and liver, and suppressing the TLR4/NFkB pathway. SAG attenuated reduced fibrosis, collagen deposition, hepatocellular damage and organ dysfunction. In conclusion, our results suggest that SAG administration protects the liver from CCl4 intoxication by restoring the oxidative balance, ameliorating the impairment of mitophagy and leading to reduced inflammation.