Factors affecting tumor responders and predictive biomarkers of toxicities in cancer patients treated with immune checkpoint inhibitors

Cancer immunotherapy has brought a great revolution in the treatment of advanced human cancer. Immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have been widely administrated in the past years and demonstrated promising in a variety of malignancies. While some patients show benefit from ICIs, others do not respond or even develop resistance to these therapies. Among the responders, the treatments are consequently accompanied with immune-related adverse effects (irAEs), which are diverse in their effected organs, degree of severity and timing. Some of the toxicities are fatal and result in discontinuance of immunotherapy. The toxicity profile from anti-CTLA-4 to anti-PD-1/PD-L1 immunotherapies is distinct from those caused by conventional anticancer therapies, though their presentation may be similar. In order to better help clinicians recognize, monitor and manage irAEs in a growing population of cancer patients who are receiving ICI therapy, this article summarizes the FDA approved ICIs and focuses on (1) existing toxic evidence related to ICIs, (2) occurrence of irAEs, (3) factors influencing tumor responders treated with ICIs, (4) predictive biomarkers of irAEs, and (5) new potential mechanisms of resistance to ICI therapy.     

Predictive effect of PD-L1 expression for immune checkpoint inhibitor (PD-1/PD-L1 inhibitors) treatment for non-small cell lung cancer: A meta-analysis

BackgroundProgrammed death-ligand-1 (PD-L1) is a well-known predictive biomarker in non-small cell lung cancer (NSCLC) patients, however, its accuracy remains controversial. Here, we investigated the correlation between PD-L1 expression level and efficacy of its inhibitors, and hence assessed the predictive effect of PD-L1 expression.MethodsStudies that evaluated the efficacy of programmed death-1 (PD-1)/ PD-L1 inhibitors in advanced NSCLC patients according to tumor PD-L1 expression levels were searched for on Medline, Cochrane Library, and Embase. The pooled risk ratio (RR) and 95% confidence intervals (95% CIs) were calculated for the objective response rate (ORR) with overall survival (OS) and progression-free survival (PFS) were measured in terms of hazard ratio (HR) and the corresponding 95% CIs.Results1432 NSCLC patients from six randomized controlled trials (RCTs) were included and three PD-1/PD-L1 inhibitors (atezolizumab, nivolumab, and pembrolizumab) were used to treat the patients. A significantly higher ORR was observed in the high PD-L1 expression group compared to the low expression group (0.35 [95% CI, 0.30–0.40] vs 0.11 [95% CI, 0.09–0.14]). The results of the subgroup analysis, grouped by the type of drugs and antibodies which assess immune checkpoint inhibitors were identical with the pooled result. However, our study showed that PD-L1 expression was neither prognostic nor predictive of overall survival (OS) or progression-free survival (PFS) in patients treated with PD-1/PD-L1 inhibitors compared to chemotherapy.ConclusionsPD-L1 can be a predictive biomarker for ORR. Nevertheless, PD-L1 expression is not a good predictive tool for OS and PFS.     

Opportunities for overcoming tuberculosis: Emerging targets and their inhibitors

Tuberculosis (TB), an airborne infectious disease mainly caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of human morbidity and mortality worldwide. Given the alarming rise of resistance to anti-TB drugs and latent TB infection (LTBI), new targets and novel bioactive compounds are urgently needed for the treatment of this disease. We provide an overview of the recent advances in anti-TB drug discovery, emphasizing several newly validated targets for which an inhibitor has been reported in the past five years. Our review presents several attractive directions that have potential for the development of next-generation therapies.     

Safety and tolerability of Empagliflozin use during the holy month of Ramadan by fasting patients with type 2 diabetes: A prospective cohort study

BackgroundType 2 Diabetes Mellitus (T2DM) patients are exposed to a 7.5 times higher risk of hypoglycemia while fasting during Ramadan. Relevant diabetes guidelines prioritize the use of SGLT2 inhibitors over other classes. There is a great need to enrich data on their safe and effective use by fasting patients at greater risk of hypoglycemia. Therefore, this study aims to assess the safety and tolerability of Empagliflozin in T2DM Muslim patients during Ramadan.MethodologyA prospective cohort study was conducted for adult Muslim T2DM patients. Patients who met the inclusion criteria were categorized into two sub-cohorts based on Empagliflozin use during Ramadan (Control versus Empagliflozin). The primary outcomes were the incidence of hypoglycemia symptoms and confirmed hypoglycemia. Other outcomes were secondary. All patients were followed up to eight weeks post-Ramadan. A propensity score (PS) matching and Risk Ratio (RR) were used to report the outcomes.ResultsAmong 1104 patients with T2DM who were screened, 220 patients were included, and Empagliflozin was given to 89 patients as an add-on to OHDs. After matching with PS (1:1 ratio), the two groups were comparable. The use of other OHDs, such as sulfonylurea, DPP4 inhibitors, and Biguanides, was not statistically different between the two groups. The risk of hypoglycemia symptoms during Ramadan was lower in patients who received Empagliflozin than in the control group (RR 0.48 CI 0.26, 0.89; p-value = 0.02). Additionally, the risk of confirmed hypoglycemia was not statistically significant between the two groups (RR 1.09 CI 0.37, 3.22; p-value = 0.89).ConclusionEmpagliflozin use during Ramadan fasting was associated with a lower risk of hypoglycemia symptoms and higher tolerability. Further randomized control trials are required to confirm these findings.     

Total glucosides of paeony for the treatment of rheumatoid arthritis: A methodological and reporting quality evaluation of systematic reviews and meta-analyses

ObjectiveTo assess the methodological, reporting and evidence quality of systematic reviews and meta-analyses of total glucosides of paeony (TGP) for rheumatoid arthritis (RA).MethodsWe comprehensively searched the literature in numerous databases from inception to July 29th, 2020. Two appraisers collected data and assessed the methodological and reporting quality of the included reviews by revised A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) tool and the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA), respectively. The level of evidence quality was evaluated by employing the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) scale.ResultsEleven relevant articles were collected. The results from AMSTAR-2 showed that the methodological quality of all included reviews was critically low; no authors met the standard of those critical domains (0%), particularly in item 2, item 4 and item 7. The PRISMA scores ranged from 16.5 to 25, and one meta-analysis almost conformed to the PRISMA structure. According to GRADE, the 11 studies included 59 outcomes: 27 had very low quality, 22 had low quality, 10 had moderate quality, and none had high quality evidence. The most prominent downgrading factors were risk of bias, followed by publication bias, inconsistency, imprecision, and indirectness.ConclusionsAlthough included studies summarized that TGP was effective and safe in the treatment of RA, the methodological and reporting quality and the quality of evidence was poor overall; decision-makers should be prudent when using TGP in treating RA patients. High-quality and multicenter studies investigating TGP for RA are urgently needed.     

The use of dietary supplements for mental health among the Saudi population: A cross-sectional survey

IntroductionDespite limited evidence about the efficacy and safety of dietary supplements (DSs) for improving mental health, people with or without mental disorders often tend to use them, especially during the ongoing COVID-19 pandemic. Previous studies focused on DS use for maintaining or improving overall health; Therefore, this study aimed to assess the prevalence of DSs for mental health among the SA population and to determine the factors that affect their use.MethodsThis cross-sectional study was based on an online survey of Saudi Arabian participants between July and August 2021 with an anonymous, self-completed questionnaire distributed using convenience sampling. The questionnaire included queries related to demographic information, DS use assessment, and mental health evaluation using the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder 7-item (GAD-7), questionnaire, and the Insomnia Severity Index (ISI).ResultsIn total, 443 participants from various regions of Saudi Arabia completed the questionnaire. The prevalence of DS use in the Saudi population was 44%. Vitamin D (28%) and melatonin (20%) were the most commonly reported DSs used for mental health. The odds of DS use were three times higher in responders with previous mental health diagnoses (OR: 2.972; 95% CI: 1.602–5.515). Furthermore, the chances of using DSs almost doubled in patients with sub-threshold and moderate to severe insomnia (OR: 1.930; 95% CI: 1.191–3.126 and OR: 2.485; 95% CI: 1.247–4.954, respectively).ConclusionResponders diagnosed by a specialist with psychiatric disorders or current insomnia had a higher chance of using DSs. Thus, healthcare providers must provide evidence-based information regarding DSs for mental health improvement and encourage the public to consult healthcare professionals before self-medicating for mental health problems.     

The evaluation of adverse drug reactions in Saudi Arabia: A retrospective observational study

PurposeThis study aimed to assess the type, severity, seriousness, reasons, and outcomes of adverse drug reactions (ADRs) in the reports submitted to the regional spontaneous ADR database.MethodsA retrospective observational study was conducted to analyze all the Tabuk Health Affairs hospitals in Saudi Arabia submitted to SFDA from January 2020 to December 2020. The database was structured according to the Saudi ADR form’s fields. The Naranjo algorithm was used to assess the causes of the ADRs (sFDA, 2022).ResultsFor 1 year, 2,349 ADR reports, along with 242 suspected drugs for 4,114 reactions, were submitted to SFDA. We found more males than females had ADRs (56.1% vs. 43.8%, P < 0.05).Antimicrobial drugs (26.9%), hematologic drugs (19.7%), and neuropsychiatric drugs (12.9%) were responsible for most ADRs. Most of the reactions were associated with the use of ciprofloxacin (7.7%), followed by the combination of lopinavir and ritonavir (4.1%). Two deaths resulted from salbutamol and cefazolin use. Based on the results of the Naranjo assessment of causality, cardiovascular events (9.9%) exhibited the highest score (≥9) for a causal relationship with the suspected drugs, followed by dermatological events (9.5%).ConclusionsThe spontaneous report database is an important and valuable source of aftermarket authorization safety information. In our study, most drugs used as antimicrobial, cardiovascular, and hematologic therapies were associated with a higher risk of developing severe and serious events. We recommend monitoring and using medications optimally to ensure patient safety.     

The role of JAK/STAT signaling pathway and its inhibitors in diseases

The JAK/STAT signaling pathway is an universally expressed intracellular signal transduction pathway and involved in many crucial biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation. It provides a direct mechanism for extracellular factors-regulated gene expression. Current researches on this pathway have been focusing on the inflammatory and neoplastic diseases and related drug.The mechanism of JAK/STAT signaling is relatively simple. However, the biological consequences of the pathway are complicated due to its crosstalk with other signaling pathways. In addition, there is increasing evidence indicates that the persistent activation of JAK/STAT signaling pathway is closely related to many immune and inflammatory diseases, yet the specific mechanism remains unclear. Therefore, it is necessary to study the detailed mechanisms of JAK/STAT signaling in disease formation to provide critical reference for clinical treatments of the diseases.In this review, we focus on the structure of JAKs and STATs, the JAK/STAT signaling pathway and its negative regulators, the associated diseases, and the JAK inhibitors for the clinical therapy.     

Screening and identification of potential MERS-CoV papain-like protease (PLpro) inhibitors; Steady-state kinetic and Molecular dynamic studies

MERS-CoV belongs to the coronavirus group. Recent years have seen a rash of coronavirus epidemics. In June 2012, MERS-CoV was discovered in the Kingdom of Saudi Arabia, with 2,591 MERSA cases confirmed by lab tests by the end of August 2022 and 894 deaths at a case-fatality ratio (CFR) of 34.5% documented worldwide. Saudi Arabia reported the majority of these cases, with 2,184 cases and 813 deaths (CFR: 37.2%), necessitating a thorough understanding of the molecular machinery of MERS-CoV. To develop antiviral medicines, illustrative investigation of the protein in coronavirus subunits are required to increase our understanding of the subject. In this study, recombinant expression and purification of MERS-CoV (PLpro), a primary goal for the development of 22 new inhibitors, were completed using a high throughput screening methodology that employed fragment-based libraries in conjunction with structure-based virtual screening. Compounds 2, 7, and 20, showed significant biological activity. Moreover, a docking analysis revealed that the three compounds had favorable binding mood and binding free energy. Molecular dynamic simulation demonstrated the stability of compound 2 (2-((Benzimidazol-2-yl) thio)-1-arylethan-1-ones) the strongest inhibitory activity against the PLpro enzyme. In addition, disubstitutions at the meta and para locations are the only substitutions that may boost the inhibitory action against PLpro. Compound 2 was chosen as a MERS-CoV PLpro inhibitor after passing absorption, distribution, metabolism, and excretion studies; however, further investigations are required.     

Isolation and purification of immune cells from the liver

Isolating and purifying liver immune cells are crucial for observing the changes in intrahepatic immune responses during the development of liver diseases and exploring the potential immunological mechanisms. Therefore, the aim of this study was to provide an optimal protocol for isolating immune cells with a high yield and less damage. We compared mechanical dissection and collagenase digestion, and the results were represented by the proportion of lymphocytes, Kupffer cells and neutrophils. The apoptosis rates of liver immune cells resulted by different isolation protocols were compared by Annexin V-staining using flow cytometric analysis. Our data indicated that the enzymatic digestion in vitro was more efficient than the mechanical dissection in vitro with a suitable collagenase IV concentration of 0.01%, and the purification of liver immune cells by a one-step density gradient centrifugation in 33% Percoll had the definite advantage of a higher proportion of the target cells. We also provided evidence that enzymatic digestion in vitro method was superior to collagenase digestion in situ for liver T lymphocytes, NK cells and NKT cells isolation and purification. This protocol was also validated in human liver samples. In conclusion, we developed an optimal protocol for isolating and purifying immune cells from mouse and human liver samples in vitro by 0.01% collagenase IV and 33% Percoll density gradient centrifugation with the advantages of higher cell yields and viability. This method provides a basis for further studying liver immune cells and liver immunity with a wide range of applications.     

A guide to oral vaccination: Highlighting electrospraying as a promising manufacturing technique toward a successful oral vaccine development

Most vaccines approved by regulatory bodies are administered via intramuscular or subcutaneous injections and have shortcomings, such as the risk of needle-associated blood infections, pain and swelling at the injection site. Orally administered vaccines are of interest, as they elicit both systemic and mucosal immunities, in which mucosal immunity would neutralize the mucosa invading pathogen before the onset of an infection. Hence, oral vaccination can eliminate the injection associated adverse effects and enhance the person's compliance. Conventional approaches to manufacturing oral vaccines, such as coacervation, spray drying, and membrane emulsification, tend to alter the structural proteins in vaccines that result from high temperature, organic and toxic solvents during production. Electrohydrodynamic processes, specifically electrospraying, could solve these challenges, as it also modulates antigen release and has a high loading efficiency. This review will highlight the mucosal immunity and biological basis of the gastrointestinal immune system, different oral vaccine delivery approaches, and the application of electrospraying in vaccines development.     

Adipokines as targets in musculoskeletal immune and inflammatory diseases

Adipokines are the principal mediators in adipose signaling. Nevertheless, besides their role in energy storage, these molecules can be produced by other cells, such as immune cells or chondrocytes. Given their pleiotropic effects, research over the past few years has also focused on musculoskeletal diseases, showing that these adipokines might have relevant roles in worsening the disease or improving the treatment response. In this review, we summarize recent advances in our understanding of adipokines and their role in the most prevalent musculoskeletal immune and inflammatory disorders.     

Nonsteroidal Anti-inflammatory Drugs Utilization Patterns and Risk of Adverse Events due to Drug-Drug Interactions among Elderly Patients: A Study from Jordan

BackgroundWorldwide, the prescribing pattern of the Nonsteroidal Anti-inflammatory Drugs (NSAIDs) has increased. They are considered highly effective medications in controlling various conditions including inflammatory diseases. They are associated with various adverse effects including gastrointestinal bleeding and ulcer and renal toxicity though. These adverse effects are generally potentiated when NSAIDs are co-prescribed with other drugs that share similar adverse effects and toxicities. Developing severe side effects from NSAIDs is more prone among elderly patients. Hence, it is crucial to evaluate prescribing pattern of these agents to prevent/decrease the number of unwanted side effects caused by NSAIDs.AimThe aim of this study is to assess the prescribing pattern of NSAIDs among elderly and the co-prescribing of NSAIDs and different interacting drugs, which could lead to more incidences of NSAIDs-induced toxicities among Jordanian elderly patients.Settings and MethodologyA multicenter retrospective study was performed during a three months period in Jordan. The study involves a total number of (n = 5916) elderly patient’s records obtained from Four governmental hospitals in Jordan.ResultsA total number of (n = 20450) drugs were prescribed and dispensed for patient. NSAIDs drugs prescribing percentage was 10.3% of total medications number. Aspirin was the most commonly prescribed NSAIDs among patients (70.4%), followed by Diclofenac sodium in all dosage forms (25.1%) and oral Ibuprofen (3.1%. In addition, Aspirin was the highest NSAIDs co-prescribed with ACEI (e.g., Enalapril), ARBs (e.g. Candesartan and Losartan), Diuretics (Furosemide, Indapamide, Hydrochlorothiazide, Amiloride, and Spironolactone), Warfarin and antiplatelets (Clopidogreal and Ticagrelor) followed by Diclofenac and other NSAIDs.ConclusionNSAIDs prescribing rate among elderly patients was high. Additionally the co-prescribing of NSAIDs especially Aspirin with other agents, which contributes to NSAIDs nephrotoxicity and gastrointestinal toxicity, were high. Strict measurements and action plans should be taken by prescribers to optimize the medical treatment in elderly through maximizing the benefits and decreasing the unwanted side effects.     

FVIII at the crossroad of coagulation,bone and immune biology: Emerging evidence of biological activities beyond hemostasis

Hemophilia A is an X-linked hereditary disorder that results from deficient coagulation factor VIII (FVIII) activity, leading to spontaneous bleeding episodes, particularly in joints and muscles. FVIII deficiency has been associated with altered bone remodeling, dysregulated macrophage polarization, and inflammatory processes that are associated with the neoformation of abnormal blood vessels. Treatment based on FVIII replacement can lead to the development of inhibitors that render FVIII concentrate infusion ineffective. In this context, hemophilia has entered a new therapeutic era with the development of new drugs, such as emicizumab, that seek to restore the hemostatic balance by bypassing pathologically acquired antibodies. We discuss the potential extrahemostatic functions of FVIII that may be crucial for defining future therapies in hemophilia.     

Protective effects of maternal administration of curcumin and hesperidin in the rat offspring following repeated febrile seizure: Role of inflammation and TLR4

Neuroinflammation has a key role in seizure generation and perpetuation in the neonatal period, and toll-like receptor 4 (TLR4) pathway has a prominent role in neuroinflammatory diseases. Administration of antioxidants and targeting TLR4 in the embryonic period may protect rat offspring against the next incidence of febrile seizure and its harmful effects. Curcumin and hesperidin are natural compounds with anti-inflammatory and antioxidant properties and have an inhibitory action on TLR4 receptors. We evaluated the effect of maternal administration of curcumin and hesperidin on infantile febrile seizure and subsequent memory dysfunction in adulthood.Hyperthermia febrile seizure was induced on postnatal days 9–11 on male rat pups with 24 h intervals, in a Plexiglas box that was heated to ~45 °C by a heat lamp. We used enzyme-linked immunosorbent assay, Western blotting, malondialdehyde (MDA), and glutathione (GSH) assessment for evaluation of inflammatory cytokine levels, TLR4 protein expression, and oxidative responses in the hippocampal tissues. For assessing working memory and long-term potentiation, the double Y-maze test and Schaffer collateral-CA1 in vivo electrophysiological recording were performed, respectivelyOur results showed that curcumin and hesperidin decreased TNF-α, IL-10, and TLR4 protein expression and reversed memory dysfunction. However, they did not provoke a significant effect on GSH content or amplitude and slope of recorded fEPSPs in the hippocampus. In addition, curcumin, but not hesperidin, decreased interleukin-1β (IL-1β) and MDA levels.These findings imply that curcumin and hesperidin induced significant protective effects on febrile seizures, possibly via their anti-inflammatory and antioxidant properties and downregulation of TLR4.