In vivo genotoxicity assessment of N-(-9 acridinyl)-b-alanine hydrochloride (S-300) using a validated Pig-a mutagenesis assay.

BACKGROUND: N-(-9 acridinyl)-b-alanine hydrochloride (S-300) is the main byproduct of red blood cell (RBC) amustaline/glutathione(GSH) pathogen reduction, currently undergoing phase III US clinical trials following successful European studies(1-3). Phosphatidylinositol glycan, class A (Pig-a) X-linked gene mutagenesis is a validated mammalian in vivo mutation assay for genotoxicity, assessed as clonal loss of glycosylphosphatidylinositol-linked CD59 cell-surface molecules on reticulocytes (RETs) and RBCs. METHODS: Male Sprague-Dawley rats received continuous infusion of S-300 up to the maximum feasible dose (240 mg/kg/day-limited by solubility and volume) for 28 days. Positive controls received a known mutagen by oral gavage on Days 1-3. Plasma levels of S-300 were assessed by HPLC before, during and after infusion. CD59-negative RBCs and RETs were enumerated in pre-dose and Day 28 samples, using a flow cytometric method. Outcome was evaluated by predetermined criteria using concurrent and historical controls. Toxicity was assessed by laboratory measures and necropsy. RESULTS: S-300 reached maximum, dose-dependent levels (3-15 µmol/L) within 2-8 h that were sustained for 672 h and undetectable 2 h after infusion. Circulating RET levels indicated a lack of hematopoietic toxicity. Necropsy revealed minimal-mild observations related to poor S-300 solubility at high concentrations. Pig-a assessment met the preset acceptability criteria and revealed no increase in mutant RBCs or RETs. CONCLUSIONS: Maximum feasible S-300 exposure of rats by continuous infusion for 28 days was not genotoxic as assessed by an Organization for Economic Cooperation and Development-compliant, mammalian, in vivo Pig-a gene mutation assay that meets the requirements of International Conference on Harmonization (ICH) S2(R1) and FDA guidances on genotoxicity testing.

The pharmacologic and toxicologic characterization of the potent and selective KRAS G12D inhibitors ERAS-4693 and ERAS-5024.

Two potent and selective KRASG12D inhibitors, ERAS-4693 and ERAS-5024, were generated as possible clinical candidates to treat patients harboring G12D mutations in solid tumors. Both molecules exhibited strong anti-tumor activity in the KRASG12D mutant PDAC xenograft mouse models while ERAS-5024 also showed tumor growth inhibition when administered on an intermittent dosing regimen. Acute dose-limiting toxicity consistent with an allergic reaction was observed for both molecules shortly after administration at doses just above those which demonstrated anti-tumor activity, indicative of a narrow therapeutic index. A series of studies were subsequently conducted to identify a common underlying mechanism for the observed toxicity, including CETSA® (Cellular Thermal Shift Assay) as well as several functional off-target screens. Both ERAS-4693 and ERAS-5024 were identified to agonize MRGPRX2 which has been linked to pseudo-allergic reactions. In vivo toxicologic characterization of both molecules included repeat-dose studies in the rat and dog. Dose-limiting toxicities were observed in both species with ERAS-4693 and ERAS-5024 and plasma exposure levels at the maximum tolerated doses were generally below that which caused strong anti-tumor activity, supporting the initial observation of a narrow therapeutic index. Additional overlapping toxicities included a reduction in reticulocytes and clinical pathological changes suggestive of an inflammatory response. Furthermore, increases in plasma histamine were observed in dogs administered ERAS-5024, supporting the hypothesis that MRGPRX2 agonism may be the cause of the pseudo-allergic reaction. This work highlights the importance of balancing both the safety and efficacy of KRASG12D inhibitors as this class of molecules begins to enter clinical development.

Treatment of Acute Graft-versus-Host Disease in Liver Transplant Recipients.

Acute graft-versus-host disease (aGvHD) is a rare complication of liver transplantation associated with high morbidity and mortality. Death typically occurs due to complications related to severe infection, shock, and multiorgan failure. The clinical presentation involves dysfunction of multiple organ systems with overlapping symptoms that often results in a diagnostic delay. As there are a limited number of cases reported in the literature, there are no clear guidelines for treatment. Many different therapeutic measures have been utilized that target various immune system pathways, but steroids remain the first line of therapy. We report on two patients who developed aGvHD after liver transplantation who were treated with ruxolitinib, a novel Janus kinase 1/2 (JAK) inhibitor that has been shown to improve outcomes in steroid refractory cases of aGvHD after allogenic hematopoietic stem cell transplantation. We reviewed the literature to discuss various therapeutic options currently available for aGvHD after liver transplantation.

Lifestyle Interventions to Improve Glycemic Control in Adults with Type 2 Diabetes Living in Low-and-Middle Income Countries: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (RCTs).

Alongside glucose lowering therapy, clinical guidelines recommend lifestyle interventions as cornerstone in the care of people living with type 2 diabetes (T2DM). There is a specific need for an up-to-date review assessing the effectiveness of lifestyle interventions for people with T2DM living in low-and-middle income countries (MICs). Four electronic databases were searched for RCTs published between 1990 and 2020. T2DM, lifestyle interventions, LMICs and their synonyms were used as search terms. Data codebooks were developed and data were extracted. Narrative synthesis and meta-analysis were conducted using random effects models to calculate mean differences (MD) and standardized mean differences (SMD) and 95% confidence intervals (CI). Of 1284 articles identified, 30 RCTs (n = 16,670 participants) met the inclusion criteria. Pooled analysis revealed significant improvement in HBA1c (MD -0.63; CI: -0.86, -0.40), FBG (SMD -0.35; CI: -0.54, -0.16) and BMI (MD -0.5; CI: -0.8, -0.2). In terms of intervention characteristics, those that included promoted self-management using multiple education components (e.g., diet, physical activity, medication adherence, smoking cessation) and were delivered by healthcare professionals in a hospital/clinic setting were deemed most effective. However, when interpreting these results, it is important to consider that most included studies were evaluated as being of low quality and there was a significant amount of intervention characteristics heterogeneity. There is a need for further well-designed studies to inform the evidence base on which lifestyle interventions are most effective for glycemic control in adults with T2DM living in LMICs.

Mycobacterium haemophilum infection in a renal transplant patient with inflammatory bowel disease.

A 61-year-old immunosuppressed renal transplant patient with inflammatory bowel disease presented with tender pink nodules on the trunk and extremities. An initial biopsy was suggestive of metastatic Crohn disease, but after disease persistence, a second biopsy revealed disseminated Mycobacterium haemophilum. Atypical mycobacterial infections should be considered in immunosuppressed patients. This case highlights the complexities of diagnosing such infections in patients with an underlying granulomatous condition and the particular growth requirements of M. haemophilum.

A history of the Robert M. Zollinger Chair of Surgery.

The senior director of medical center development and alumni affairs at the Ohio State University and a development officer at the Ohio State University Office of Medical Center and Health Sciences Development describe the origins of the endowed Robert M. Zollinger Chair of Surgery and the recipients of the professorship.