Advances in immune checkpoint-based immunotherapies for multiple sclerosis: rationale and practice.

Beyond the encouraging results and broad clinical applicability of immune checkpoint (ICP) inhibitors in cancer therapy, ICP-based immunotherapies in the context of autoimmune disease, particularly multiple sclerosis (MS), have garnered considerable attention and hold great potential for developing effective therapeutic strategies. Given the well-established immunoregulatory role of ICPs in maintaining a balance between stimulatory and inhibitory signaling pathways to promote immune tolerance to self-antigens, a dysregulated expression pattern of ICPs has been observed in a significant proportion of patients with MS and its animal model called experimental autoimmune encephalomyelitis (EAE), which is associated with autoreactivity towards myelin and neurodegeneration. Consequently, there is a rationale for developing immunotherapeutic strategies to induce inhibitory ICPs while suppressing stimulatory ICPs, including engineering immune cells to overexpress ligands for inhibitory ICP receptors, such as program death-1 (PD-1), or designing fusion proteins, namely abatacept, to bind and inhibit the co-stimulatory pathways involved in overactivated T-cell mediated autoimmunity, and other strategies that will be discussed in-depth in the current review. Video Abstract.

The safety and efficacy of tislelizumab, alone or in combination with chemotherapy, for the treatment of non-small cell lung cancer: a systematic review of clinical trials.

BACKGROUND: Tislelizumab is an anti-programmed death-1 (PD-1) monoclonal antibody with a construction that enables it to have a higher affinity to its target. We aimed to evaluate tislelizumab's safety and efficacy for treating non-small cell lung cancer (NSCLC). METHODS: Embase, Scopus, PubMed, Web of Science, and Google Scholar were searched up to December 20, 2022. The review only included randomized controlled trials (RCTs) that evaluated the safety or efficacy of tislelizumab for treating patients with lung cancer. The revised Cochrane risk-of-bias tool (RoB2) was utilized to evaluate study quality. RESULTS: There were four RCTs identified, which included 1565 patients with confirmed locally advanced or metastatic squamous and/or non-squamous types of NSCLC. Treatment with tislelizumab was associated with better progression-free survival (PFS) and objective response rate (ORR), particularly when used in combination with chemotherapy. Almost all patients in both arms reported at least one treatment-emergent adverse event (TEAE). Decreased hematologic indexes accounted for more than 20% of the grade ≥ 3 TEAEs in the tislelizumab plus chemotherapy group. The proportion of TEAE that led to death in the tislelizumab plus chemotherapy arms ranged from 3.2 to 4.2%. Hypothyroidism, pneumonitis, and hyperglycemia were the most frequently noted immune-mediated adverse events in the tislelizumab group. CONCLUSIONS: Tislelizumab, whether used alone or in combination with chemotherapy, seems to demonstrate both a safety and efficacy as a treatment for NSCLC.

Radiological features of late-onset multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Late-onset multiple sclerosis (LOMS) is most commonly defined as the onset of the disease's presentations at age 50 or older. There is still much to discover about the radiological features of LOMS. The current study aims to assess the imaging features of LOMS, as well as the correlation between these findings and the clinical characteristics of these patients. METHOD: This study was conducted following the PRISMA statement. A systematic search was conducted through PubMed, Scopus, and EMBASE databases to identify the studies that have applied magnetic-resonance imaging (MRI) or other imaging methods to investigate the radiological findings, as well as the relationship between them and clinical findings of LOMS patients. The risk of bias was assessed using the Joanna Briggs Institute (JBI) checklists. Meta-analysis was conducted using the third version of the compressive meta-analysis software (CMA3). RESULTS: Our search identified 753 unique titles. Among them, 15 studies, including seven case-control, five case-series, and three cross-sectional studies, met the eligibility criteria. According to the quantitative synthesis, brain lesions were detected among 72.2% of LOMS patients (4 studies; 95% CI: 67.0% - 93.1%). In the context of spinal lesions, overall spinal cord involvement was 64.0% (8 studies; 95% CI: 42.5% - 81.1%). Based on the available evidence, supratentorial involvement was found in 82.7% of cases (3 studies; 95% CI: 17.4% - 99.1%), juxtacortical involvement in 34.1% (3 studies; 95% CI: 26.4% - 42.7%), infratentorial involvement in 51.3% (4 studies; 95% CI: 32.1% - 70.1%), and cerebellar involvement in 18.5% (3 studies; 95% CI: 13.9% - 24.1%). CONCLUSION: Based on the neuroimaging findings, we found that, given the heterogeneity of MS, LOMS patients have a high rate of spinal cord lesions and supratentorial involvement. The limited available evidence suggests that Barkhof criteria are the best compromise for the diagnosis of LOMS. There is still a need for future studies.

Efficacy and safety of direct oral anticoagulants versus warfarin in the treatment of cerebral venous sinus thrombosis.

BACKGROUND: Given the evolving application and promising outcomes of direct oral anticoagulants (DOACs) in various thromboembolic conditions, we aimed to compare the efficacy and safety of DOACs with warfarin in the post-acute treatment of cerebral venous sinus thrombosis (CVST) using clinical and radiological parameters. METHODS: A total of 140 CVST patients were enrolled, with 95 receiving warfarin and 45 receiving DOACs as post-acute treatment. Clinical and imaging parameters of the patients in follow-up visits were investigated, including the last modified Rankin Scale (mRS), venous thromboembolic events, CVST recurrence, mortality rate, recanalization status, and hemorrhagic events, to compare the efficacy and safety of treatment between the two groups. RESULTS: At baseline, patients' assessments using two prognostic scores, ISCVT-RS and IN-REvASC, revealed that there was no statistically significant difference in the distribution of prognostic risk categories between the warfarin and DOACs groups. Following acute therapy, patients in the warfarin and DOACs groups were followed up for the median of 359 and 325 days, respectively. Analysis to compare the efficacy of warfarin and DOACs revealed no significant difference in last mRS scores, CVST recurrence rate, venous thromboembolic events, and recanalization status between the two groups. Additionally, there was no statistically significant difference in the risk of hemorrhagic events between warfarin and DOACs groups. CONCLUSION: Our findings show that DOACs have comparable safety and efficacy in the post-acute treatment of CVST patients; however, large-scale randomized controlled trials are required to validate our findings.

Viruses and thrombocytopenia.

Thrombocytopenia, characterized by a decrease in platelet count, is a multifaceted clinical manifestation that can arise from various underlying causes. This review delves into the intriguing nexus between viruses and thrombocytopenia, shedding light on intricate pathophysiological mechanisms and highlighting the pivotal role of platelets in viral infections. The review further navigates the landscape of thrombocytopenia in relation to specific viruses, and sheds light on the diverse mechanisms through which hepatitis C virus (HCV), measles virus, parvovirus B19, and other viral agents contribute to platelet depletion. As we gain deeper insights into these interactions, we move closer to elucidating potential therapeutic avenues and preventive strategies for managing thrombocytopenia in the context of viral infections.

The efficacy of hemiepiphysiodesis for idiopathic knee coronal angular deformity by reconstruction plate and screw: A pilot study.

Background: Angular deformities of the lower extremities are among the most common findings in pediatric orthopedics. Alteration of the mechanical axis in the lower extremity affects the cosmetic appearance and may lead to gait disturbances, knee discomfort, patellar maltracking with or without pain, and early joint osteoarthritis. In the current study, we aimed to investigate the efficacy of 3-hole 3.5 mm reconstruction plates in tension-band temporary hemiepiphysiodesis for correcting idiopathic knee coronal angular deformities. Methods: The surgical procedure was performed using an extraperiosteal tension band plate (a 3-hole reconstruction plate) and two 3.5 mm cortical screws to treat idiopathic knee coronal angular deformity in children. The location of the hemiepiphysiodesis was determined based on the type of angular deformity present. Postoperative follow-ups were conducted through x-rays to measure the medial proximal tibial angle and lateral distal femoral angle of the limbs. Statistical analysis was then performed to evaluate the efficacy of the surgical treatment based on the rate of alignment change exhibited. Results: The study included 14 patients (25 limbs) with genu valgum deformity who underwent temporary hemiepiphysiodesis on both the distal femur and proximal tibia, with 16 proximal tibias and 15 distal femurs being corrected. The correction rate for genu valgum was found to be 0.59° per month for both proximal tibial and distal femoral hemiepiphysiodesis. Six patients (12 limbs) were also identified with genu varum deformity, and the correction rates for proximal tibial lateral hemiepiphysiodesis and distal femoral lateral hemiepiphysiodesis were 0.85° and 0.15° per month, respectively. During a mean follow-up duration of 11 ± 5.7 months, only one case of physeal plate closure was observed, and there were no other significant complications. Conclusion: Temporary hemiepiphysiodesis with a 3-hole R-plate and two cortical screws takes advantage of physiological physeal growth to successfully treat idiopathic angular deformities with low complication rates.

A systematic review of the safety and efficacy of monoclonal antibodies for progressive multiple sclerosis.

BACKGROUND: Progressive multiple sclerosis (PMS) is a debilitating condition characterized by progressively worsening symptoms. Monoclonal antibodies are novel therapies for MS, but their safety and efficacy in the progressive form have not been comprehensively studied. In this systematic review, we aimed to evaluate the available evidence regarding monoclonal antibody treatment for PMS. METHODS: After registration of the study protocol in PROSPERO, we systematically searched three major databases for clinical trials involving monoclonal antibodies administration for PMS treatment. All the retrieved results were imported into the EndNote reference manager. After removing the duplicates, two independent researchers did the study selection and data extraction. The risk of bias was assessed using the Joanna Briggs Institute (JBI) checklist. RESULTS: Of the 1846 studies in the preliminary search, 13 clinical trials investigating monoclonal antibodies (Ocrelizumab, Natalizumab, Rituximab, and Alemtuzumab) in PMS patients were included. Ocrelizumab was significantly effective in reducing clinical disease progression measures in primary PMS patients. The results for Rituximab were not completely reassuring and only showed significant changes for some endpoints on MRI and clinical measures. Natalizumab decreased the relapse rate and improved MRI features for secondary PMS patients, but not clinical endpoints. The studies on Alemtuzumab treatment revealed conflicting outcomes, with improvements observed in MRI endpoints but clinical worsening in patients. Additionally, among the studied adverse events, upper respiratory infections, urinary tract infections, and nasopharyngitis were frequently reported. CONCLUSION: Based on our findings, Ocrelizumab is the most efficient monoclonal antibody for primary PMS, although it is associated with a higher risk of infection. While other monoclonal antibodies did not show significant promise in treating PMS, more research is necessary.

Diagnostic value of an increase in central venous pressure during SBT for prediction of weaning failure in mechanically ventilated patients: A cross-sectional study.

Background: Timely and successful extubation is an essential step forward in clinical practice to minimize complications of mechanical ventilation and unsuccessful weaning processes. Thus, research into predictive factors of weaning outcome to optimize spontaneous breathing trial (SBT) precision before extubation is critical in intensive care practices. In this study, we aimed to investigate the predictive factors of the weaning outcome before and during SBT in mechanically ventilated patients. Methods: In this cross-sectional study, 159 mechanically ventilated patients who were eligible for SBT were enrolled. Of these patients, 140 had successful extubation, whereas the remainder failed. Each patient's PaCO2 and PaO2 levels, respiratory rate (RR), SpO2, mean arterial pressure (MAP), heart rate (HR), and central venous pressure (CVP) values at the start of SBT, 3 min later, and at the end of SBT were measured. These values, along with the patients' clinical characteristics, were then investigated to determine if there was any correlation between these variables and the weaning outcome. Results: Our analysis revealed that increase in CVP, independent of hemoglobin (Hb) concentration, PaO2, SpO2, duration of mechanical ventilation (MV), length of intensive care unit (ICU) stay, and SBT process, as well as underlying disease, was positively correlated with extubation/weaning failure. While age, gender, vital signs (MAP, RR, and HR), sequential organ failure assessment (SOFA), and acute physiology and chronic health evaluation (APACHE) scores had no significant correlation with patients' extubation outcomes. Conclusion: According to our findings, integrating CVP assessment into SBT besides routine indices measurement and monitoring can be considered for the prediction of weaning outcome in critically ill mechanically ventilated patients.

The current landscape of CAR T-cell therapy for solid tumors: Mechanisms, research progress, challenges, and counterstrategies.

The successful outcomes of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic cancers have increased the previously unprecedented excitement to use this innovative approach in treating various forms of human cancers. Although researchers have put a lot of work into maximizing the effectiveness of these cells in the context of solid tumors, few studies have discussed challenges and potential strategies to overcome them. Restricted trafficking and infiltration into the tumor site, hypoxic and immunosuppressive tumor microenvironment (TME), antigen escape and heterogeneity, CAR T-cell exhaustion, and severe life-threatening toxicities are a few of the major obstacles facing CAR T-cells. CAR designs will need to go beyond the traditional architectures in order to get over these limitations and broaden their applicability to a larger range of malignancies. To enhance the safety, effectiveness, and applicability of this treatment modality, researchers are addressing the present challenges with a wide variety of engineering strategies as well as integrating several therapeutic tactics. In this study, we reviewed the antigens that CAR T-cells have been clinically trained to recognize, as well as counterstrategies to overcome the limitations of CAR T-cell therapy, such as recent advances in CAR T-cell engineering and the use of several therapies in combination to optimize their clinical efficacy in solid tumors.

Efficacy and safety of veliparib plus chemotherapy for the treatment of lung cancer: A systematic review of clinical trials.

BACKGROUND: As a poly-ADP ribose polymerase (PARP) inhibitor, veliparib has been identified as a potential therapeutic agent for lung cancer. The present study aimed to conduct a systematic review of clinical trials investigating the efficacy and safety of veliparib for treating lung cancer. METHODS: PubMed, Scopus, the Web of Science, and Google Scholar were systematically searched up to October 30, 2022. Only randomized controlled trials (RCTs) evaluating the efficacy or safety of veliparib in the treatment of lung cancer patients were included. Studies were excluded if they were not RCTs, enrolled healthy participants or patients with conditions other than lung cancer, or investigated therapeutic approaches other than veliparib. The Cochrane risk-of-bias tool was used for quality assessment. RESULTS: The seven RCTs (n = 2188) showed that patients treated with a combination of veliparib and chemotherapy had a significantly higher risk of adverse events, when compared to the control arm. There was no statistically significant difference in overall survival (OS) between those treated with veliparib plus chemotherapy and those receiving the standard therapies. Only two trials demonstrated an improvement in progression-free survival (PFS), and only one study found an increase in objective response rate (ORR). Furthermore, adding veliparib to standard chemotherapy showed no benefit in extending the duration of response (DoR) in any of the studies. CONCLUSIONS: Only a small number of studies have found veliparib to be effective, in terms of improved OS, PFS, and ORR, while the majority of studies found no benefit for veliparib over standard treatment.

Spectrum and Burden of Influenza Infection: An Approach to Identify Predictors of Morbidity and Mortality Rate from the Patients of the Northwest of Iran.

Background: The objective of this research is to analyze influenza-induced complications, symptoms, and the interaction of morbidity and mortality rates in hospitalized influenza cases based on age-sex dispersion, influenza virus subtype, prescribed medications, and underlying conditions. Materials and Methods: We performed this retrospective study using a dataset of 10,517 hospitalized individuals, including 3,101 laboratory-confirmed influenza cases from patients of all ages who had attended hospitals in the Northwest of Iran due to respiratory complications. Results: The most prevalent strain which circulated annually was influenza A/H3N2. In contrast to previous studies, our findings suggested that influenza A/H1N1 has the highest mortality rate and the most severe complications.Regardless of virus type/subtype, the most susceptible age group for influenza was 0-9 years old in both males and females. Meanwhile the high-risk age group among males was 50-59 years old and among females were over 80 age group (mortality rate ≈ 20%). Chronic obstructive pulmonary disease (COPD) (32%) and cardiovascular disease (CVD) (30%) were the most prevalent active underlying diseases among the patients who died, with the latter being more prevalent in males over the age of 70. Patients with a history of chemotherapy had the highest mortality rate. Patients who were prescribed a combination of antibiotics and antivirals had better outcomes with lowest mortality rate. Conclusion: Our findings demonstrated that annual influenza seasons are often marked by changes in influenza types and subtypes, with variations in the severity. Development of a standardized set of arrays that best correspond with infections, can be useful in guiding diagnostic and therapeutic decisions.

The Basis and Advances in Clinical Application of Cytomegalovirus-Specific Cytotoxic T Cell Immunotherapy for Glioblastoma Multiforme.

A high percentage of malignant gliomas are infected by human cytomegalovirus (HCMV), and the endogenous expression of HCMV genes and their products are found in these tumors. HCMV antigen expression and its implications in gliomagenesis have emerged as a promising target for adoptive cellular immunotherapy (ACT) strategies in glioblastoma multiforme (GB) patients. Since antigen-specific T cells in the tumor microenvironments lack efficient anti-tumor immune response due to the immunosuppressive nature of glioblastoma, CMV-specific ACT relies on in vitro expansion of CMV-specific CD8+ T cells employing immunodominant HCMV antigens. Given the fact that several hurdles remain to be conquered, recent clinical trials have outlined the feasibility of CMV-specific ACT prior to tumor recurrence with minimal adverse effects and a substantial improvement in median overall survival and progression-free survival. This review discusses the role of HCMV in gliomagenesis, disease prognosis, and recent breakthroughs in harnessing HCMV-induced immunogenicity in the GB tumor microenvironment to develop effective CMV-specific ACT.

Dysregulation of Survivin-Targeting microRNAs in Autoimmune Diseases: New Perspectives for Novel Therapies.

It has been well established that the etiopathogenesis of diverse autoimmune diseases is rooted in the autoreactive immune cells' excessively proliferative state and impaired apoptotic machinery. Survivin is an anti-apoptotic and mitotic factor that has sparked a considerable research interest in this field. Survivin overexpression has been shown to contribute significantly to the development of autoimmune diseases via autoreactive immune cell overproliferation and apoptotic dysregulation. Several microRNAs (miRNAs/miRs) have been discovered to be involved in survivin regulation, rendering the survivin-miRNA axis a perspective target for autoimmune disease therapy. In this review, we discuss the role of survivin as an immune regulator and a highly implicated protein in the pathogenesis of autoimmune diseases, the significance of survivin-targeting miRNAs in autoimmunity, and the feasibility of targeting the survivin-miRNA axis as a promising therapeutic option for autoimmune diseases.

Survivin; a novel therapeutic target that correlates with survival of autoreactive T lymphocytes obtained from patients with ankylosing spondylitis.

Ankylosing spondylitis (AS) is progressive immune-mediated arthritis. Persistent autoreactivity of T cells with an up-regulated Survivin expression is strongly implicated in AS immunopathogenesis. Besides, Survivin can inhibit proapoptotic caspase 9 activations. Moreover, microRNAs are small non-coding RNAs that are dysregulated in various diseases, in which their altered expression could modulate Survivin expression. The primary goal of this study was to assess the role of Survivin and its-targeting microRNAs in the immunopathogenesis of AS disease. For this aim, peripheral blood mononuclear cells (PBMCs) were isolated from 15 patients with AS and healthy matched controls using Ficoll-Hypaque. T cells were obtained using the magnetic-activated cell sorting (MACS) method. After that, the expression levels of Survivin, Caspase 9, and specific miRNAs were determined using qT-qPCR. Also, the expression of Survivin and Caspase 9 at protein levels was determined by western blotting. Then, the isolated T cells were co-cultured with interleukin (IL)-2 and muromonab-CD3 (OKT-3) for active-induced cell death (AICD) induction, Survivin siRNA for inhibition of Survivin expression, and their combination to assess the implication of Survivin expression in autoreactive T lymphocytes' resistance to apoptosis by determining the rate of apoptosis by Flowcytometry assay. The results showed that Survivin was up-regulated while Caspase 9 was downregulated in patients with AS. It was also revealed that microRNAs that directly or indirectly target the Survivin mRNA were dysregulated in patients with AS. It was also revealed that T cells obtained from AS patients were more resistant to apoptosis induction than those obtained from healthy people. In summary, the results obtained from this study showed that dysregulation of Survivin and Survivin-targeting miRNAs in T lymphocytes obtained from AS patients contribute to their resistance to apoptosis, suggesting the future development of targeted therapies for AS.

Vitamin supplementation as a potential adjunctive therapeutic approach for COVID-19: biological and clinical plausibility.

The recent pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19) has introduced itself into the human population in the 21st century after the coronavirus diseases SARS-CoV and Middle East respiratory syndrome (MERS-CoV). Major investigations are underway worldwide in the search for pharmaceutical interventions for COVID-19 and many agents are administered in off-label routes. Several cases are under study to check or restrict clinical manifestations of COVID-19. According to the fact that the efficacy of some micro-nutrients like vitamins is proven to treat or prevent infectious diseases because of their antimicrobial and immunomodulatory activity, the potential role of vitamins in the COVID-19 treatment or prevention must be considered.

Extrapulmonary Clinical Manifestations in COVID-19 Patients.

COVID-19 manifestations in symptomatic patients can be in the form of pneumonia, acute respiratory syndrome, and multiple organ dysfunction as well. Renal complications, gastrointestinal dysfunctions, endocrine system disorders, myocardial dysfunction and arrhythmia, neurological dysfunctions, dermatological symptoms, hematological manifestations, and thromboinflammation are among the reported extrapulmonary complications. Moreover, the presence of coagulopathy, excessive and dysregulated immune responses, and autoimmunity by COVID-19 patients is considerable. The pathogenesis of infection entails the entry of the virus via receptors on cells, principally angiotensin-converting enzyme 2 receptors. Direct virus damage coupled with indirect effects of viral infection including thromboinflammation, dysfunction of the immune system, and dysregulation of the renin-angiotensin system leads to multiple organ failure. This review outlines the extrapulmonary organ-specific complications and their pathophysiology and epidemiology.