The effect and safety of CDK4/6 inhibitors combined endocrine therapy on HR+, HER2-breast cancer: a meta-analysis of randomized controlled trials

Introduction: The purpose of this meta-analysis is to evaluate the efficacy and safety of cyclin-dependent kinase4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) on hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer (BC). Material and methods: A search was conducted in the PubMed, Embase, Web of Science, and Cochrane Library databases before July 2022. Results: A total of 19 studies comprising 19,004 patients were eligible for this meta-analysis. This meta-analysis found that for unresectable locally advanced or metastatic HR+, HER2– BC, CDK4/6i combined with ET can significantly improve the progression-free survival (PFS) (hazard ratio = 0.59, p < 0.001), overall survival (OS) (hazard ratio = 0.77, p < 0.001), objective response rate (ORR) [risk ratio (RR) = 1.32, p = 0.001)], disease control rate (DCR) (RR = 1.10, p < 0.001), and clinical benefit response (CBR) (RR = 1.15, p = 0.001). For early HR+, HER2- BC, CDK4/6i combined with ET improved ORR (RR = 1.14, p = 0.05) and invasive disease free survival (iDFS) (hazard ratio = 0.87, p = 0.045) but had no effect on pathologic complete response (pCR) (RR = 1.75, p = 0.33), distant recurrence free survival (DRFS) (hazardratio = 0.83, p = 0.311), and OS (hazard ratio = 1.08, p = 0.705). Conclusion: CDK4/6i combined with ET can improve the prognosis of patients with unresectable locally advanced or metastatic HR+, HER2– BC, but it has no obvious effect on patients with early HR+, HER2– BC. It is generally safe and manageable

Human Hemoglobin Subunit Beta Functions as a Pleiotropic Regulator of RIG-I/MDA5-Mediated Antiviral Innate Immune Responses

Hemoglobin is an important oxygen-carrying protein and plays crucial roles in establishing host resistance against pathogens and in regulating innate immune responses. The hemoglobin subunit beta (HB) is an essential component of hemoglobin, and we have previously demonstrated that the antiviral role of the porcine HB (pHB) is mediated by promoting type I interferon pathways. Thus, considering the high homology between human HB (hHB) and pHB, we hypothesized that hHB also plays an important role in the antiviral innate immunity. In this study, we characterized hHB as a regulatory factor for the replication of RNA viruses by differentially regulating the RIG-I- and MDA5-mediated antiviral signaling pathways. Furthermore, we showed that hHB directly inhibited MDA5-mediated signaling by reducing the MDA5-double-stranded RNA (dsRNA) interaction. Additionally, hHB required hHB-induced reactive oxygen species (ROS) to promote RIG-I-mediated signaling through enhancement of K63-linked RIG-I ubiquitination. Taken together, our findings suggest that hHB is a pleiotropic regulator of RIG-I/MDA5-mediated antiviral responses and further highlight the importance of the intercellular microenvironment, including the redox state, in regulating antiviral innate immune responses. IMPORTANCE Hemoglobin, the most important oxygen-carrying protein, is involved in the regulation of innate immune responses. We have previously reported that the porcine hemoglobin subunit beta (HB) exerts antiviral activity through regulation of type I interferon production. However, the antiviral activities and the underlying mechanisms of HBs originating from other animals have been poorly understood. Here, we identified human HB (hHB) as a pleiotropic regulator of the replication of RNA viruses through regulation of RIG-I/MDA5-mediated signaling pathways. hHB enhances RIG-I-mediated antiviral responses by promoting RIG-I ubiquitination depending on the hHB-induced reactive oxygen species (ROS), while it blocks MDA5-mediated antiviral signaling by suppressing the MDA5-dsRNA interaction. Our results contribute to an understanding of the crucial roles of hHB in the regulation of the RIG-I/MDA5-mediated signaling pathways. We also provide novel insight into the correlation of the intercellular redox state with the regulation of antiviral innate immunity

Table_2_The relationship between tobacco and breast cancer incidence: A systematic review and meta-analysis of observational studies.docx

BackgroundThe effect of tobacco on breast cancer (BC) is controversial. The purpose of this study was to investigate the relationship between tobacco and BC.MethodsA search was conducted in PubMed, EBSCO, Web of Science and Cochrane Library databases before February 2022. The adjusted odd ratio (OR) and corresponding 95% confidence interval (CI) were used to examine the relationship between active or passive smoking and BC risk.ResultsA total of 77 articles composed of 2,326,987 participants were included for this meta-analysis. Active (OR=1.15, 95% CI=1.11-1.20, pConclusionSmoking (active and passive) increased the risk of BC in women. The effect of smoking on BC was influenced by smoking-related factors (duration, intensity, years of quitting), population-related factors (fertility status), and BC subtypes.Systematic Review Registrationidentifier CRD42022322699.</p

Table_1_The relationship between tobacco and breast cancer incidence: A systematic review and meta-analysis of observational studies.docx

BackgroundThe effect of tobacco on breast cancer (BC) is controversial. The purpose of this study was to investigate the relationship between tobacco and BC.MethodsA search was conducted in PubMed, EBSCO, Web of Science and Cochrane Library databases before February 2022. The adjusted odd ratio (OR) and corresponding 95% confidence interval (CI) were used to examine the relationship between active or passive smoking and BC risk.ResultsA total of 77 articles composed of 2,326,987 participants were included for this meta-analysis. Active (OR=1.15, 95% CI=1.11-1.20, pConclusionSmoking (active and passive) increased the risk of BC in women. The effect of smoking on BC was influenced by smoking-related factors (duration, intensity, years of quitting), population-related factors (fertility status), and BC subtypes.Systematic Review Registrationidentifier CRD42022322699.</p

Table_3_The relationship between tobacco and breast cancer incidence: A systematic review and meta-analysis of observational studies.docx

BackgroundThe effect of tobacco on breast cancer (BC) is controversial. The purpose of this study was to investigate the relationship between tobacco and BC.MethodsA search was conducted in PubMed, EBSCO, Web of Science and Cochrane Library databases before February 2022. The adjusted odd ratio (OR) and corresponding 95% confidence interval (CI) were used to examine the relationship between active or passive smoking and BC risk.ResultsA total of 77 articles composed of 2,326,987 participants were included for this meta-analysis. Active (OR=1.15, 95% CI=1.11-1.20, pConclusionSmoking (active and passive) increased the risk of BC in women. The effect of smoking on BC was influenced by smoking-related factors (duration, intensity, years of quitting), population-related factors (fertility status), and BC subtypes.Systematic Review Registrationidentifier CRD42022322699.</p

Efficacy and safety of SGLT-2i in overweight/obese, non-diabetic individuals: a meta-analysis of randomized controlled trials

Introduction: Sodium-glucose cotransporter 2 inhibitor (SGLT-2i) has been shown to decrease blood glucose levels in type 2 diabetes mellitus (T2DM) patients and potentially yield additional benefits in weight loss. This meta-analysis aimed to investigate the efficacy and safety of giving SGLT-2i to overweight/obese, non-diabetic individuals. Material and methods: The search was underpinned by PubMed, Cochrane Central Register of Controlled Trials, Web of Science, and Springer to identify English-language papers on randomized controlled trials (RCTs) on the use of SGLT-2i in overweight/obese, nondiabetic individuals published in and before March 2021, to study its effectiveness and safety. Results were evaluated by weighted mean difference (WMD), standardized mean difference (SMD), risk ratio (RR), and 95% confidence interval (CI). Results: We reviewed 13 papers and compared the SGLT-2i group with the control group (other drugs and placebo) and found that SGLT-2i reduced weight (WMD = –1.33, p = 0.002) and waist circumference (WMD = –1.94, p = 0.03) in overweight/obese, non-diabetic individuals. The use of SGLT-2i is more effective than other interventions in terms of weight loss ≥ 5% (RR = 2.04, p &lt; 0.001), but not in terms of weight loss ≥ 10% (RR = 1.83, p = 0.22). In addition, there were no significant changes in other metabolic parameters, like fasting plasma glucose (FPG), lipids, blood pressure, etc. SGLT-2i increased the risk of infections in urinary tract (RR = 1.91, p = 0.009) andreproductive system (RR = 4.09, p &lt; 0.001). Conclusions: SGLT-2i is a promising candidate to reduce weight and waist circumference to a limited extent in overweight/obese, nondiabetic individuals. Generally, it is safe and effective. However, it potentially increased the risk of urogenital infections, which cannot be ignored