Facial palsy induced by immune checkpoint blockade: A systematic analysis of clinical trials and a pharmacovigilance study of postmarketing data.

BACKGROUND: To estimate the risk of facial nerve palsy (FP) associated with immune checkpoint inhibitors (ICIs), and to describe its clinical features. METHODS: Data from randomized controlled trials (RCTs) and FDA Adverse Event Reporting System (FAERS) database were included. The primary outcome was the risk of FP events associated with ICIs. For data from RCTs, pooled analysis was performed by using risk ratios (RRs) with 95%CIs. In a separate retrospective pharmacovigilance study of FAERS, disproportionality was analyzed using the proportional reports reporting odds ratio (ROR) and information components (IC). RESULTS: A total of 21 RCTs (193,05 patients) were included, ICIs were associated with increased risk of FP (OR = 3.07, 95%CI:1.43-6.58). Results of subgroup analysis indicated that OR of ICI-related FP did not vary significantly by tumor type, ICIs treatment schedule, case of events, study design, median PFS and publication status. FAERS pharmacovigilance data identified 274 cases of FP related to ICIs therapy. ICIs were significantly associated with over-reporting frequencies of FP (ROR = 3.03, 95%CI:2.69-3.42; IC = 1.56, 95%CI:1.38-1.76). The median onset time of FP was 5.5 weeks, drug interruption was recorded in 78.0% of cases, with a positive dechallenge in 82.8 % of cases, and 71.7% of cases were recovered or recovering. CONCLUSIONS: These data suggest that ICIs were significantly associated with increased risk of FP in both trial settings and in clinical practice.

Type 1 diabetes with immune checkpoint inhibitors: A systematic analysis of clinical trials and a pharmacovigilance study of postmarketing data.

BACKGROUND: To estimate the risk of type 1 diabetes associated with immune checkpoint inhibitor (ICI-T1DM), and to describe its clinical features. METHODS: ICI-T1DM events in randomized clinical trials (RCTs) available in electronic databases were systematically reviewed. The primary outcome was the summary risk of T1DM related to ICIs, a meta-analysis was conducted to obtain Peto odds ratios (ORs) with 95 % CIs. In pharmacovigilance study, ICI-T1DM cases were extracted from FAERs. Disproportionality analyses were performed by calculating reporting odds ratio (ROR) and information components (IC). RESULTS: A total of 29 RCTs (20,234 patients) were included, treatment with ICIs significantly increased the risk of all-grade ICI-T1DM (OR: 4.54, 95 % CI: 2.66-7.72), and high-grade (grade 3 or above) ICI-T1DM (OR: 4.26, 95 % CI: 2.12-8.58). No significant differences among subgroup analyses were observed: ICIs treatment schedule, tumor type, case of events (T1DM vs F-T1DM), study design (double blind vs open label) or median PFS (PFS favours ICIs vs PFS favours Control). A total of 978 case reports form FAERS was extracted, treatment with ICIs significantly increased the reporting of ICI-T1DM (n = 978; ROR = 38.45, 95 %CI:35.70-41.41; IC = 4.77, 95 %CI:4.43-5.14). In cases with available data, the median latency period was 10.4 weeks, drug interruption was recorded in 82.3 % of cases, with a positive dechallenge in 76 % of cases, and death was recorded as outcome in 3.6 % of reports. CONCLUSIONS: Both data from clinical trials and postmarketing suggested that ICIs was associated with increased risk of ICI-T1DM. As ICIs gain greater clinical use, practitioners must be aware of ICI-T1DM events.

ZEB2/TWIST1/PRMT5/NuRD Multicomplex Contributes to the Epigenetic Regulation of EMT and Metastasis in Colorectal Carcinoma.

(1) Background: The EMT plays a crucial role in tumor metastasis, which is the major cause for colorectal carcinoma-related mortality. However, the underlying regulators and mechanisms of EMT in CRC metastasis are still poorly understood; (2) Methods: The transcriptional regulators of EMT in CRC and their functions were examined using RT2212PCR, Western blotting, and luciferase reporter assay. The components of ZEB2/TWIST1 complex and their mutual interactions were identified via affinity purification, mass spectrometry, co-immunoprecipitation, and pull-down experiments. The functional mechanisms of ZEB2/TWIST1/PRMT5/NuRD axis were determined by chromatin immunoprecipitation and luciferase reporter assay. The contribution of ZEB2/TWIST1/PRMT5/NuRD complex in the CRC metastasis was investigated using wound healing, transwell assay, and in vivo xenograft mouse model; (3) Results: We found that ZEB2 and TWIST1 were both significantly upregulated in CRC tissues and EMT of CRC cells. ZEB2 could recruit TWIST1 to the E-cadherin promoter and synergistically repressed its transcription. In addition, ZEB2 physically interacted with TWIST1, PRMT5, and the nucleosome remodeling and deacetylase (NuRD) complex to form a novel repressive multicomplex, leading to epigenetic silencing of E-cadherin in CRC cells. Notably, the combined inhibition of ZEB2 and TWIST1 and epigenetic inhibition markedly reduced CRC metastasis in mice; (4) Conclusions: We revealed for the first time that ZEB2 could recruit TWIST1, PRMT5, and NuRD to form a repressive multicomplex and epigenetically suppresses the transcription of E-cadherin, thereby inducing the EMT process and metastasis in CRC. Our results also confirmed the therapeutic potential of epigenetic inhibitors in CRC.

Tissue mechanics modulate PCNP expression in oral squamous cell carcinomas with different differentiation.

Background: PEST-containing nuclear protein (PCNP), a novel zinc finger protein, participates in cell cycle regulation. Previous studies have confirmed that PCNP plays a role in mediating cellular development and invasion in a variety of cancer types. However, the relationship between PCNP expression and the occurrence and development of oral squamous cell carcinoma (OSCC) requires further exploration. In this study, we used biological atomic force microscopy to examine the histomorphological and mechanical properties of OSCC to explore the relationship between PCNP expression and differentiation of OSCC. Methods: Seventy-seven OSCC samples with varying degrees of differentiation were selected for hematoxylin and eosin staining, immunohistochemistry, and cellular mechanical measurement. The expression of PCNP and the mechanical properties such as stiffness and roughness of the tissue interface in OSCC samples were investigated. The Kaplan-Meier survival curve was utilized to assess the relationship of PCNP expression with patient survival. Results: The level of PCNP was significantly higher in well-differentiated OSCC than in moderately and poorly differentiated OSCC (P < 0.001). High expression of PCNP was specifically associated with higher tumor differentiation, lack of lymph node metastasis, and lower tumor node metastasis stage (all P < 0.05). Patients with high PCNP expression had a higher survival rate than those with low PCNP expression. The average variation of stiffness within a single tissue ranged from 347 kPa to 539 kPa. The mean surface roughness of highly, moderately, and poorly differentiated OSCC and paraneoplastic tissues were 795.53 ± 47.2 nm, 598.37 ± 45.76 nm, 410.16 ± 38.44 nm, and 1010.94 ± 119.07 nm, respectively. Pearson correlation coefficient demonstrated a positive correlation between PCNP expression and tissue stiffness of OSCC (R = 0.86, P < 0.001). Conclusion: The expression of PCNP was positively correlated with patient survival, tumor differentiation, and mechanical properties of tissue interfaces. PCNP is a potential biomarker for the early diagnosis and staging of OSCC. Furthermore, determination of the mechanical properties of the tissue interface could provide further useful information required for the detection and differentiation of OSCC.

The behavioural and neuropathologic sexual dimorphism and absence of MIP-3α in tau P301S mouse model of Alzheimer's disease.

BACKGROUND: Tau hyper-phosphorylation has been considered a major contributor to neurodegeneration in Alzheimer's disease (AD) and related tauopathies, and has gained prominence in therapeutic development for AD. To elucidate the pathogenic mechanisms underlying AD and evaluate therapeutic approaches targeting tau, numerous transgenic mouse models that recapitulate critical AD-like pathology have been developed. Tau P301S transgenic mice is one of the most widely used mouse models in AD research. Extensive studies have demonstrated that sex significantly influences AD pathology, behavioral status, and therapeutic outcomes, suggesting that studies using mouse models of AD must consider sex- and age-related differences in neuropathology, behavior, and plasma content. METHOD: We systematically investigated differences in tau P301S transgenic mice (PS19 line) and wildtype littermates of different sex behavioral performance, tau neuropathology, and biomarkers in plasma and brain. RESULTS: Male P301S transgenic mice exhibited significant changes in weight loss, survival rate, clasping, kyphosis, composite phenotype assessment, nest building performance, tau phosphorylation at Ser202/Thr205, and astrocyte activation compared to that of wild-type littermates. In contrast, female P301S transgenic mice were only sensitive in the Morris water maze and open field test. In addition, we characterized the absence of macrophage-inflammatory protein (MIP-3α) and the upregulation of interferon (IFN)-γ, interleukin (IL)-5, and IL-6 in the plasma of P301S transgenic mice, which can be served as potential plasma biomarkers in P301S Tg mice. Male P301S transgenic mice expressed more monokine induced by IFN-γ (MIG), tumor necrosis factor-α (TNF-α), IL-10, and IL-13 than those of female P301S mice. CONCLUSION: Our findings highlight sexual dimorphism in the behavior, neuropathology, and plasma proteins in tau P301S transgenic AD mice, indicating that the use of male P301S transgenic mice may be more suitable for assessing anti-phosphorylated tau therapeutic strategies for AD and related tauopathies, and the MIP-3α may be a new potential plasma biomarker.

G9a and histone deacetylases are crucial for Snail2-mediated E-cadherin repression and metastasis in hepatocellular carcinoma.

Functional E-cadherin loss, a hallmark of epithelial-mesenchymal transition (EMT), is important for metastasis. However, the mechanism of Snail2 in hepatocellular carcinoma (HCC) EMT and metastasis remains unclear. Here, we showed that Snail2 was upregulated in primary HCC, and significantly increased during transforming growth factor-ß-induced liver cell EMT. Snail2-overexpressing and knockdown cell lines have been established to determine its function in EMT in HCC. H3K9 methylation was upregulated and H3K4 and H3K56 acetylation were downregulated at the E-cadherin promoter in Snail2-overexpressing cancer cells. Furthermore, Snail2 interacted with G9a and histone deacetylases (HDACs) to form a complex to suppress E-cadherin transcription. Snail2 overexpression enhanced migration and invasion in HCC cells, whereas G9a and HDAC inhibition significantly reversed this effect. Moreover, Snail2 overexpression in cancer cells increased tumor metastasis and shortened survival time in mice, whereas G9a and HDAC inhibitors extended survival. Our study not only reveals a critical mechanism underlying the epigenetic regulation of EMT but also suggests novel treatment strategies for HCC.

Snail2 induced E-cadherin suppression and metastasis in lung carcinoma facilitated by G9a and HDACs.

Snail2 is a repressor of E-cadherin during carcinogenesis; however, the specific mechanisms involved in this process remain largely unknown. Here, we determined that Snail2 was highly increased during TGF-ß-induced EMT process in lung cells. H3K9 methylation was up-regulated and H3K4/H3K56 acetylation were down-regulated at the E-cadherin promoter. Snail2 interacted with G9a and HDACs to exert suppression of E-cadherin transcription. Overexpression of Snail2 enhanced the migration and invasion ability, whereas G9a and HDACs inhibition significantly reversed this effect. Our study demonstrated the importance of G9a- and HDACs-mediated regulation during Snail2-induced E-cadherin repression and metastasis during LC progression.

Epigenetic suppression of E-cadherin expression by Snail2 during the metastasis of colorectal cancer.

BACKGROUND: The transcription factor Snail2 is a repressor of E-cadherin expression during carcinogenesis; however, the specific mechanisms involved in this process in human colorectal cancer (CRC) remain largely unknown. METHOD: We checked the expression of Snail2 in several clinical CRC specimens. Then, we established Snail2-overexpressing and knockdown cell lines to determine the function of Snail2 during EMT and metastasis processes in CRC. In addition, we used luciferase reporter assay to explore how Snail2 inhibits the expression of E-cadherin and induces EMT. RESULTS: We found that the expression of Snail2 was higher in clinical specimens of colorectal cancer (CRC) compared to non-cancerous tissues. Overexpression of Snail2 induced migration and metastatic properties in CRC cells in vitro and in vivo. Furthermore, overexpression of Snail2 promoted the occurrence of the epithelial-mesenchymal transition (EMT), downregulating the expression of E-cadherin and upregulating that of vimentin. Specifically, Snail2 could interact with HDAC6 and then recruited HDAC6 and PRC2 to the promoter of E-cadherin and thus inhibited the expression of E-cadherin, promoting EMT and inducing invasion and metastasis of CRC. CONCLUSION: Our study reveals that Snail2 might epigenetically suppress the expression of E-cadherin during CRC metastasis.

Risk of severe pulmonary embolism in cancer patients receiving bevacizumab: Results from a meta-analysis of published and unpublished data.

To evaluate the association between severe pulmonary embolism events and bevacizumab, we conducted the first meta-analysis evaluating the incidence and risk of pulmonary embolism associated with bevacizumab-based therapy. We searched PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov up to September 2016 for randomized controlled trials comparing bevacizumab with no bevacizumab on cancer patients. Incidence rates, relative risks, and 95% confidence intervals were calculated using fixed- or random-effects models. The primary end point was the association of bevacizumab with pulmonary embolism. Subgroup analyses were performed according to tumor type, dose, and publication status. In total, 23 randomized controlled trials were included. For patients receiving bevacizumab, the overall incidence of severe pulmonary embolism events was 1.76% (95% confidence interval = 1.25%-2.27%). Cancer patients treated with bevacizumab did not increase the risk of pulmonary embolism events (relative risk = 1.00, 95% confidence interval = 0.80-1.25). No significant differences in pulmonary embolism incidence or risk among subgroup analyses were observed. No evidence of publication bias was observed. This study suggested that bevacizumab may not increase the risk of pulmonary embolism in cancer patients.

An updated meta-analysis of fatal adverse events caused by bevacizumab therapy in cancer patients.

BACKGROUND: The risk of fatal adverse events (FAEs) due to bevacizumab-based chemotherapy has not been well described; we carried out an updated meta-analysis regarding this issue. METHODS: An electronic search of Medline, Embase and The Cochrane Central Register of Controlled Trials was conducted to investigate the effects of randomized controlled trials on bevacizumab treatment on cancer patients. Random or fixed-effect meta-analytical models were used to evaluate the risk ratio (RR) of FAEs due to the use of bevacizumab. RESULTS: Thirty-four trials were included. Allocation to bevacizumab therapy significantly increased the risk of FAEs; the RR was 1.29 (95% CI:1.05-1.57). This association varied significantly with tumor types (P=0.002) and chemotherapeutic agents (P=0.005) but not with bevacizumab dose (P=0.90). Increased risk was seen in patients with non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer. However, FAEs were lower in breast cancer patients treated with bevacizumab. In addition, bevacizumab was associated with an increased risk of FAEs in patients who received concomitant agents of taxanes and/or platinum. CONCLUSION: Compared with chemotherapy alone, the addition of bevacizumab was associated with an increased risk of FAEs among patients with special tumor types, particularly when combined with chemotherapeutic agents such as platinum.

Meta-analysis of long-term vitamin D supplementation on overall mortality.

INTRODUCTION: It has been suggested that vitamin D is effective to prevent mortality. However, there is no consistent conclusion that the effects of vitamin D supplementation on all-cause mortality are associated with duration of treatment. We conducted a meta-analysis regarding this issue in an effort to provide a more robust answer. METHODS: A comprehensive search in a number of databases, including MEDLINE, Embase and The Cochrane Central Register of Controlled Trials, was conducted for collecting randomized controlled trials (RCTs) on vitamin D supplementation preventing mortality. Two investigators independently screened the literature according to the inclusive and exclusive criteria and the relative data were extracted. Data analysis was performed by using Review Manager 5.0 software. RESULTS: Data from forty-two RCT s were included. Vitamin D therapy significantly decreased all-cause mortality with a duration of follow-up longer than 3 years with a RR (95% CI) of 0.94 (0.90-0.98). No benefit was seen in a shorter follow-up periods with a RR (95% CI) of 1.04 (0.97-1.12). Results remain robust after sensitivity analysis. The following subgroups of long-term follow-up had significantly fewer deaths: female only, participants with a mean age younger than 80, daily dose of 800 IU or less, participants with vitamin D insufficiency (baseline 25-hydroxyvitamin D level less than 50 nmol/L) and cholecalciferol therapy. In addition, the combination of vitamin D and calcium significantly reduced mortality and vitamin D alone also had a trend to decrease mortality in a longer time follow up. CONCLUSIONS: The data suggest that supplementation of vitamin D is effective in preventing overall mortality in a long-term treatment, whereas it is not significantly effective in a treatment duration shorter than 3 years. Future studies are needed to identify the efficacy of vitamin D on specific mortality, such as cancer and cardiovascular disease mortality in a long-term treatment duration.

Oral adjuvant clodronate therapy could improve overall survival in early breast cancer: results from an updated systematic review and meta-analysis.

OBJECT: The aim of this study was to evaluate the effectiveness of clodronate in the adjuvant therapy of early breast cancer on patient survival. METHODS: We performed a literature search to identify studies that investigated the effects of clodronate treatment on early breast cancer. Random and fixed-effect meta-analytical models were used where indicated and between-study heterogeneity was assessed. The primary study end-points were overall survival. Secondary end-points were bone metastasis-free survival and non-skeletal metastasis (mainly visceral metastases) free survival. RESULTS: Four randomised controlled trials met the inclusion criteria. Risk ratio (95% confidence interval (CI)) of overall survival was 0.84 (0.56-1.26); risk ratio (95% CI) of bone metastasis-free survival was 0.77 (0.58-1.02); risk ratio (95% CI) of non-bone metastasis-free survival was 0.89 (0.61-1.30). Outcomes after sensitivity analysis were: risk ratio (95% CI) of overall survival was 0.71 (0.52-0.96); risk ratio (95% CI) of bone metastasis-free survival was 0.70 (0.56-0.86); risk ratio (95% CI) of non-bone metastasis-free survival was 0.76 (0.64-0.92). CONCLUSION: Compared with the control arm, adjuvant treatment with clodronate may improve the overall survival, bone metastasis-free survival and non-bone metastasis-free (mainly visceral metastases) survival in patients with early breast cancer. However, further meta-analyses involving all known randomised trials with analysis of sub-groups by age or menopausal status, accessing original trial data, should be performed.