Inosine, gut microbiota, and cancer immunometabolism.

This article briefly reviews cancer immunity and the role of gut microbiota in carcinogenesis, followed by an understanding of mechanisms by which inosine is involved in cancer immunometabolism. The immune system plays a paradoxical role in cancer treatment. Antitumor immunity depends on the T-cell priming against tumor antigens, whereas inflammatory mediators trigger the protumor signaling in the tumor microenvironment. Studies link the microbiome with metabolism and immunity-two main factors implicated in carcinogenesis. Gut microbiota has been shown to affect both antitumor immunity and protumor immune signaling. There is mounting evidence that the human microbiome can play a role in the immunotherapeutic effects, both response and resistance. Inosine-5'-monophosphate dehydrogenase (IMPDH) is a highly conservative enzyme widely expressed in mammals. Cell signaling pathways use molecular inosine, a crucial secondary metabolite in purine metabolism and a molecular messenger. Recent research has identified inosine as a critical regulator of immune checkpoint inhibition (ICI) therapeutic response in various tumor types. Some bacterial species were found to produce inosine or its metabolite hypoxanthine and induce T-helper 1 differentiation and effector functions via the inosine-A2AR-cAMP-PKA pathway upon ICI therapy. Also, inosine acts as a substitute carbon source for T-cell metabolism in glucose-restricted environments, i.e., the tumor microenvironment, assisting T-cell proliferation and differentiation while enhancing sensitivity to ICI, reinforcing the notion that inosine metabolism might contribute to antitumor immunity. Also, inosine is a potent agonist of the adenosine receptor, A2AR, and A2AR signaling can affect T-cell responses and antitumor immunity, making the inosine-A2AR pathway blockage a candidate for cancer treatment. Further research is required to investigate inosine as a cancer immunometabolism therapy.

Efficacy and Safety of the Fixed-Dose Versus Variable-Dose of 4-PCC for Vitamin K Antagonist Reversal: A Comprehensive Systematic Review and Meta-Analysis.

BACKGROUND: The optimal dosing strategy of four-factor prothrombin complex concentrate (4F-PCC) for vitamin K antagonists (VKAs) reversal is unknown. METHODS: We conducted systematic search on the PubMed, SCOPUS, and Embase databases from inception to December 2020 for clinical studies that compared the fixed-dose versus variable-dose of 4-PCC for VKAs reversal with at least one reported clinical outcome. The treatment effects were expressed as relative ratios (RR) with 95% confidence intervals (CIs) and pooled by a random-effects model. RESULTS: Ten studies, including 988 patients, were included. Fixed-dose 4-PCC was associated with lower rate of mortality (RR= 0.65, 95% CI 0.47 to 0.9, p= 0.009), comparable rate of thromboembolic event (TEE) (RR= 1.10, 95%CI 0.44 to 2.80, p= 0.826), and lower goal INR reached (RR= 0.87, 95%CI 0.78 to 0.96, p= 0.007). Less 4-PCC cumulative dose, shorter duration of order-to-needle time, similar hospital length of stay, the comparable time required for INR reversal, higher post-4-PCC INR, and a higher need for additional dose were observed in fixed-dose. CONCLUSIONS: The use of a fixed-dose of 4-PCC may be considered an effective and safe dosing strategy for VKAs reversal in various clinical situations. However, further well-designed, controlled studies should be conducted focusing on clinical outcomes to determine the optimal dose of 4-PCC for VKAs reversal.

Comparing safety of proton-pump inhibitors versus H2-receptor antagonists in kidney transplant recipients: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Multiple studies have been conducted to compare the safety of proton-pump inhibitors (PPIs) and H2-receptor antagonists (H2RAs) as acid-suppressive treatment in kidney transplant recipients with conflicting results. This systematic review and meta-analysis aimed to evaluate the risk of adverse effects in kidney transplant patients receiving PPIs compared to those treated with H2RAs. METHODS: A systematic search was performed on the databases from inception to June 2021. The treatment effects were expressed as odds ratio (OR), weighted mean differences (WMD) and their 95% confidence intervals (CI) and pooled by a random-effects model. RESULTS AND DISCUSSIONS: Eight studies, consisting 4,844 patients, were included. Patients were followed for a mean duration of 23.57 months after transplantation. Compared with H2RAs, PPIs exposure was associated with similar rate of biopsy-proven acute rejection (BPAR) (OR = 1.05, 95% CI 0.83-1.34, p = 0.67), mortality (OR = 1.31, 95% CI 0.56-3.07, p = 0.533), graft loss (OR = 1.06, 95% CI 0.59-1.93, p = 0.842), Clostridioides difficile infection (OR = 1.37, 95% CI 0.49-3.85, p = 0.545) and pneumonia (OR = 1.83, 95% CI 0.95-3.52, p = 0.072). The estimated glomerular filtration rate (eGFR) at 12 months was lower in patients who received PPIs than those treated with H2RAs (WMD = -1.01, 95% CI -1.89 to -0.12 ml/min/1.73m2 , p = 0.02). The PPI-treated kidney transplant patients experienced higher rate of antibody-mediated rejection (AMR) (OR = 1.87, 95% CI 1.03-3.04, p = 0.039) and hypomagnesemia (OR = 2.16, 95% CI 1.46-3.20, p Ë‚ 0.001). WHAT IS NEW AND CONCLUSIONS: Compared with H2RAs, PPIs were not associated with higher risks of BPAR, mortality, graft loss or infection-related outcomes. However, taking PPIs was associated with higher rates of AMR and hypomagnesemia, and lower eGFR at one year after transplantation. Further well-controlled studies are needed to assess the impact of acid-suppressive strategy on long-term outcomes in KTRs.

A systematic review and meta-analysis of the impact of cornelian cherry consumption on blood lipid profiles.

Polyphenolic and flavonoid compounds are claimed to improve blood lipid profiles and to provide protective effects against cardiovascular disease. For this reason, we conducted a systematic review and meta-analysis of studies that comprehensively investigated the effects of cornelian cherry supplementation on lipid profiles in rat models. Up to December 2020, 855 articles were screened, and finally, seven articles were selected as eligible for the meta-analysis. This meta-analysis revealed that cornelian cherry supplementation significantly decreased low-density lipoprotein (LDL) (WMD = -6.38 mg/dl; 95% CI, -9.93 to-2.84; p < .001), triglyceride (TG) (WMD = -52.36 mg/dl; 95% CI, -80.50 to -24.22; p < .005), and cholesterol level (WMD = -37.16 mg/dl; 95% CI, -51.19 to -23.13; p < .005) in treated rats compared with control groups. A nonsignificant increase in high-density lipoprotein (HDL) level was observed (WMD = 4.21 mg/dl; 95% CI, -3.25 to 11.66; p = .268). These results suggest that cherry supplementation may have health effects by modifying lipid profiles. However, there is a need for more well-controlled human clinical trials to make more definitive conclusions about the potential health benefits of cherry supplementation.

Treatment of toxoplasmic encephalitis with the combination of clindamycin plus azithromycin in an HIV-infected patient: A case report.

The existence of alternative oral therapies could help clinicians to treat toxoplasmic encephalitis (TE) in the HIV patients. The combination of azithromycin and clindamycin may serve as an effective treatment for TE in HIV-infected patients.

Interferon therapy in patients with SARS, MERS, and COVID-19: A systematic review and meta-analysis of clinical studies.

Concern regarding coronavirus (CoV) outbreaks has stayed relevant to global health in the last decades. Emerging COVID-19 infection, caused by the novel SARS-CoV2, is now a pandemic, bringing a substantial burden to human health. Interferon (IFN), combined with other antivirals and various treatments, has been used to treat and prevent MERS-CoV, SARS-CoV, and SARS-CoV2 infections. We aimed to assess the clinical efficacy of IFN-based treatments and combinational therapy with antivirals, corticosteroids, traditional medicine, and other treatments. Major healthcare databases and grey literature were investigated. A three-stage screening was utilized, and included studies were checked against the protocol eligibility criteria. Risk of bias assessment and data extraction were performed, followed by narrative data synthesis. Fifty-five distinct studies of SARS-CoV2, MERS-CoV, and SARS-CoV were spotted. Our narrative synthesis showed a possible benefit in the use of IFN. A good quality cohort showed lower CRP levels in Arbidol (ARB) + IFN group vs. IFN only group. Another study reported a significantly shorter chest X-ray (CXR) resolution in IFN-Alfacon-1 + corticosteroid group compared with the corticosteroid only group in SARS-CoV patients. In a COVID-19 trial, total adverse drug events (ADEs) were much lower in the Favipiravir (FPV) + IFN-α group compared with the LPV/RTV arm (P = 0.001). Also, nausea in patients receiving FPV + IFN-α regimen was significantly lower (P = 0.03). Quantitative analysis of mortality did not show a conclusive effect for IFN/RBV treatment in six moderately heterogeneous MERS-CoV studies (log OR = -0.05, 95% CI: (-0.71,0.62), I2 = 44.71%). A meta-analysis of three COVID-19 studies did not show a conclusive nor meaningful relation between receiving IFN and COVID-19 severity (log OR = -0.44, 95% CI: (-1.13,0.25), I2 = 31.42%). A lack of high-quality cohorts and controlled trials was observed. Evidence suggests the potential efficacy of several combination IFN therapies such as lower ADEs, quicker resolution of CXR, or a decrease in inflammatory cytokines; Still, these options must possibly be further explored before being recommended in public guidelines. For all major CoVs, our results may indicate a lack of a definitive effect of IFN treatment on mortality. We recommend such therapeutics be administered with extreme caution until further investigation uncovers high-quality evidence in favor of IFN or combination therapy with IFN.