The Cochrane risk of bias assessment tool 2 (RoB 2) versus the original RoB: A perspective on the pros and cons.

Background and Aims: Critical appraisal or risk of bias assessment is a fundamental part of systematic reviews that clarifies the degree to which included research articles are qualified and reliable. Version 2 of the Cochrane tool for assessing the risk of bias in randomized trials (RoB 2), the updated version of the first tool, was released in 2019. Here, we have compared these two versions of Cochrane risk of bias assessment tools and highlighted the pros and cons of RoB 2. Methods: Statistical analysis and methodology is not applicable to this article as no new data were created or analyzed in this study. Results: The overall approach in RoB 2 is that by answering some signaling questions after the specification of results, effects of interest, and sources of information, an overall judgment for the quality of each study is reached. Accordingly, in the original version of the Cochrane RoB tool, the judgment can be in three different conclusions, including low, unclear, and high risk of bias. The most prominent difference in bias domains is the removal of "other bias" domain being replaced by "overall bias" judgment. Also, the most common presentation types of Cochrane risk of bias assessments are the "summary" and "graph" which are generated by Review Manager, web-based applications, or packages in R software. Conclusion: The RoB 2 tool, compared to the original RoB, has improved and is the recommended version by the Cochrane Collaboration for quality assessment of randomized controlled trials. It is recommended to consider funding source, duration of follow-up, declaration of data availability, the status of baseline characteristics between groups, and sample size calculation methods in further revisions of the Cochrane risk of bias assessment tools.

SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury.

Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria, and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of ischemic injury and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 (Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2-/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitor reduced cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in cardiac response to injury and the progression of cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy and injury by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of these disorders.

Clinical efficacy and safety of bispecific antibodies for the treatment of solid tumors: a systematic review and meta-analysis.

INTRODUCTION: Immunotherapy is a promising and progressing treatment approach for cancer. Bispecific antibodies (BsAbs) are antibody constructs that can bind to two different epitopes. The dual-specificity of BsAbs improves their efficacy compared to monoclonal antibodies. AREAS COVERED: Although BsAbs have achieved excellent therapeutic effects in hematologic cancers, no systematic review with meta-analysis evaluated their efficacy in solid tumors. In the present systematic review and meta-analysis, we aimed to establish the clinical efficacy and safety of BsAbs in solid tumors. EXPERT OPINION: BsAbs are not associated with significantly better safety or efficacy outcomes than conventional therapies. BsAb was not associated with improvement in overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). However, BsAb increased the rate of stable disease (SD) significantly. Also, BsAb substantially increased the OS and PFS and resulted in a higher frequency of DCR for uveal melanoma. Furthermore, the safety analysis showed no obvious difference in the rate of any adverse events (AEs), grade ≥3 AEs, serious AEs, and AEs leading to treatment discontinuation in the intervention group compared to controls. Further high-quality randomized controlled trials on BsAbs in solid tumors are highly recommended.

Pleural CEA, CA-15-3, CYFRA 21-1, CA-19-9, CA-125 discriminating malignant from benign pleural effusions: Diagnostic cancer biomarkers.

INTRODUCTION: There is a need for a rapid, accurate, less-invasive approach to distinguishing malignant from benign pleural effusions. We investigated the diagnostic value of five pleural tumor markers in exudative pleural effusions. METHODS: By immunochemiluminescence assay, we measured pleural concentrations of tumor markers. We used the receiver operating characteristic curve analysis to assess their diagnostic values. RESULTS: A total of 281 patients were enrolled. All tumor markers were significantly higher in malignant pleural effusions than benign ones. The area under the curve of carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 15-3, cytokeratin fragment 19 (CYFRA) 21-1, CA-19-9, and CA-125 were 0.81, 0.78, 0.75, 0.65, and 0.65, respectively. Combined markers of CEA + CA-15-3 and CEA + CA-15-3 + CYFRA 21-1 had a sensitivity of 87% and 94%, and specificity of 75% and 58%, respectively. We designed a diagnostic algorithm by combining pleural cytology with pleural tumor marker assay. CEA + CYFRA 21-1 + CA-19-9 + CA-15-3 was the best tumor markers panel detecting 96% of cytologically negative malignant pleural effusions, with a negative predictive value of 98%. CONCLUSIONS: Although cytology is specific enough, it has less sensitivity in identifying malignant pleural fluids. As a result, the main gap is detecting malignant pleural effusions with negative cytology. CEA was the best single marker, followed by CA-15-3 and CYFRA 21-1. Through both cytology and suggested panels of tumor markers, malignant and benign pleural effusions could be truly diagnosed with an accuracy of about 98% without the need for more invasive procedures, except for the cohort with negative cytology and a positive tumor markers panel, which require more investigations.

SIRT2 inhibition protects against cardiac hypertrophy and heart failure.

Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of heart failure (HF) and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 ( Sirt2 -/- ) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2 -/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitors reduces cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in the progression of HF and cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of this disorder.

Clinical safety and efficacy of bispecific antibody in the treatment of solid tumors: A protocol for a systematic review.

BACKGROUND: Cancers are among the most common causes of mortality and morbidity. Recently, bispecific antibodies (BsAbs) have been used for cancer treatment. The aim of this systematic review and meta-analysis will be to determine the safety and efficacy of BsAbs in the treatment of solid tumors. METHODS: We will search five electronic databases, PubMed, EMBASE, Scopus, Web of Science, and CENTRAL, in addition to Clinical-Trials.gov and metaRegister of controlled trials and backward and forward citation searching of included studies. Eligible studies will be controlled clinical trials evaluating safety and/or efficacy of BsAbs in adult patients with solid tumors. The primary outcomes will be the incidence of safety and efficacy measures. Title and/or abstract screening, full text reviewing, data collection, and quality assessment will be done by two reviewers. We will use The Cochrane Collaboration's risk of bias tool 2 (RoB2) to assess the quality of included studies. If I-square heterogeneity was greater than 40%, we will implement random effect model. Subgroup analysis and meta-regression will be undertaken if applicable. The metaprop command of STATA will be used to calculate frequency of AEs. Funnel plot, Egger's and Peter's tests will be utilized to evaluate publication bias in case of including at least ten studies. We will use sensitivity analysis to evaluate the effects of funding sources and continuity correction on effects size. CONCLUSIONS: The findings of the present study will provide information on safety and efficacy of BsAbs for physicians and researchers in the management of solid tumors. TRIAL REGISTRATION: Registration on PROSPERO CRD42021227879 Also, important protocol amendments will be stated on PROSPERO registration.

Monoclonal antibodies in diabetic retinopathy.

INTRODUCTION: Diabetic retinopathy (DR), as one of the main complications of diabetes, is among the leading causes of blindness and visual impairment worldwide. AREAS COVERED: Current clinical therapies include photocoagulation, vitrectomy, and anti-vascular endothelial growth factor (VEGF) therapies. Bevacizumab and ranibizumab are two monoclonal antibodies (mAbs) inhibiting angiogenesis. Intravitreal ranibizumab and bevacizumab can decrease the rate of blindness and retinal thickness, and improve visual acuity whether as monotherapy or combined with other treatments. They can increase the efficacy of other treatments and decrease their adverse events. Although administered intravitreally, they also might enter the circulation and cause systemic effects. This study is aimed to review our current knowledge about mAbs, bevacizumab and ranibizumab, in DR including superiorities, challenges, and limitations. Meanwhile, we tried to shed light on new ideas to overcome these limitations. Our latest search was done in April 2021 mainly through PubMed and Google Scholar. Relevant clinical studies were imported. EXPERT OPINION: Future direction includes detection of more therapeutic targets considering other components of DR pathophysiology and shared pathogenesis of DR and neurodegenerative diseases, such as Parkinsons disease and Alzheimers disease, the treat-and-extend regimen, and new ways of drug delivery and other routes of ocular drug administration.

Adverse events associated with immune checkpoint inhibitors in patients with breast cancer: A systematic review and meta-analysis.

BACKGROUND: Breast cancer is one of the most prevalent cancers with a high rate of mortality. Immune checkpoint inhibitors (ICIs) have shown promising results in breast cancer treatment. However, the incidences of adverse events (AEs) and immune-related AEs (irAEs) due to ICIs have not been investigated comprehensively. We aimed to determine any-grade and grade 3-5 AEs and irAEs of ICIs compared to the control group which were other conventional therapies in adults with breast cancer. METHODS: We included controlled clinical trials that involved ICIs in adults with breast cancer to assess AEs and irAEs of ICIs. We systematically searched PubMed, EMBASE, Scopus, Web of Science, the Cochrane Central Register of Controlled Trials, Clinical-Trials.gov, and metaRegister of Controlled Trials up to March 12, 2021. Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) was used for quality assessment. RESULTS: Nine studies, including 4687 participants met our inclusion criteria. Rash and infusion reaction were the two most frequent irAEs of any-grade and grade 3-5. Among irAEs, hyperthyroidism had the most prominent difference between the two groups in favor of ICIs followed by hypothyroidism and adrenal insufficiency. Among grade 3-5 and any-grade non-immune AEs, increased aspartate aminotransferase (RR = 1.91; 95% CI, 1.11-3.28) and cough (RR = 1.32; 95%CI, 1.11-1.57) had the highest RRs in favor of ICIs, respectively. The frequencies of overall any-grade and grade 3-5 irAEs were higher in the ICI group. CONCLUSION: The results showed that all the AEs and irAEs of all the categories were more prevalent with ICIs.

Targeted therapy strategies against SARS-CoV-2 cell entry mechanisms: A systematic review of in vitro and in vivo studies.

Due to the rapidly spreading of novel coronavirus disease (COVID-19) worldwide, there is an urgent need to develop efficient vaccines and specific antiviral treatments. Pathways of the viral entry into cells are interesting subjects for targeted therapy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The present study aims to provide a systematic evaluation of the most recent in vitro and in vivo investigations targeting SARS-CoV-2 cell entry. A systematic search was carried out in major medical sources, including MEDLINE (through PubMed), Web of Science, Scopus, and EMBASE. Combinations of the following search terms were used: SARS-CoV-2, in vitro, in vivo, preclinical, targeted therapy, and cell entry. A modified version of the Consolidated Standards of Reporting Trials and Systematic Review Centre for Laboratory Animal Experimentation assessment tools were applied for evaluating the risk of bias of in vitro and in vivo studies, respectively. A narrative synthesis was performed as a qualitative method for the data synthesis of each outcome measure. A total of 2,649 articles were identified through searching PubMed, Web of Science, Scopus, EMBASE, Google Scholar, and Biorxiv. Finally, 22 studies (one in vivo study and 21 in vitro studies) were included. The spike (S) glycoprotein of the SARS-CoV-2 was the main target of investigation in 19 studies. SARS-CoV-2 can enter into the host cells through endocytosis or independently. SARS-CoV-2 S protein utilizes angiotensin-converting enzyme 2 or CD147 as its cell-surface receptor to attach host cells. It consists of S1 and S2 subunits. The S1 subunit mediates viral attachment to the host cells, while the S2 subunit facilitates virus-host membrane fusion. The cleavage of the S1-S2 protein, which is required for the conformational changes of the S2 subunit and processing of viral fusion, is regulated by the host proteases, including cathepsin L (during endocytosis) and type II membrane serine protease (independently). Targeted therapy strategies against SARS-CoV-2 cell entry mechanisms fall into four main categories: strategies targeting virus receptors on the host, strategies neutralizing SARS-CoV-2 spike protein, strategies targeting virus fusion to host cells, and strategies targeting endosomal and non-endosomal dependent pathways of virus entry. Inhibition of the viral entry by targeting host or virus-related components remains the most potent strategy to prevent and treat COVID-19. Further high-quality investigations are needed to assess the efficacy of the proposed targets and develop specific antivirals against SARS-CoV-2.

Development and clinical application of bispecific antibody in the treatment of colorectal cancer.

INTRODUCTION: Treatment of colorectal cancer as one of the most commonly diagnosed and a frequent cause of cancer-related deaths is of great challenges in health-related issues. AREAS COVERED: Immunotherapy is the fourth pillar of cancer treatment which provides more novel therapeutic options with expanding investigational potentials. One of the modalities in immunotherapy is the use of bispecific antibodies. Despite demonstrating many promising roles, it still needs more advanced studies to identify the actual pros and cons. In this review, the application of bispecific antibody in the treatment of colorectal cancer has been explained, based on preclinical and clinical studies. The literature search was conducted mainly through PubMed in June and September 2019. EXPERT OPINION: Bispecific antibody is in its early stages in colorectal cancer treatment, requiring modern technologies in manufacturing, better biomarkers and more specific target antigens, more studies on individual genetic variations, and conducting later phase clinical trials and systematic reviews to achieve better survival benefits.