Chimeric antigen receptor-based natural killer cell immunotherapy in cancer: from bench to bedside.

Immunotherapy has rapidly evolved in the past decades in the battle against cancer. Chimeric antigen receptor (CAR)-engineered T cells have demonstrated significant success in certain hematologic malignancies, although they still face certain limitations, including high costs and toxic effects. Natural killer cells (NK cells), as a vital component of the immune system, serve as the "first responders" in the context of cancer development. In this literature review, we provide an updated understanding of NK cell development, functions, and their applications in disease therapy. Furthermore, we explore the rationale for utilizing engineered NK cell therapies, such as CAR-NK cells, and discuss the differences between CAR-T and CAR-NK cells. We also provide insights into the key elements and strategies involved in CAR design for engineered NK cells. In addition, we highlight the challenges currently encountered and discuss the future directions in NK cell research and utilization, including pre-clinical investigations and ongoing clinical trials. Based on the outstanding antitumor potential of NK cells, it is highly likely that they will lead to groundbreaking advancements in cancer treatment in the future.

Associations between gastro-oesophageal reflux disease and a range of diseases: an umbrella review of systematic reviews and meta-analyses.

OBJECTIVE: Numerous meta-analyses have revealed the association between gastro-oesophageal reflux disease (GORD) and a range of diseases; however, the certainty of the evidence remains unclear. This study aimed to summarise and assess the certainty of evidence derived from meta-analyses. METHODS: Embase, PubMed, Web of Science, Cochrane Databases of Systematic Reviews, CNKI and Wangfang databases from their inception to 22 February 2020 were queried for systematic reviews and meta-analyses on the association between GORD and various diseases. The methodological quality of the included studies was assessed using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2), and evidence certainty was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Statistical analysis was conducted using Stata V.15. RESULTS: Ten publications with associations between GORD and different types of diseases were included. There was high heterogeneity (I2 >75%) among seven independent meta-analyses. Evidence for publication bias in two independent meta-analyses was also observed. According to the AMSTAR 2 approach, the methodological quality was high for 20% of meta-analyses, moderate for 10%, low for 40% and critically low for 30%. Based on GRADE approach, the certainty of evidence was high for the association between GORD and higher risk of chronic obstructive pulmonary disease (COPD) exacerbation (OR 5.37; 95% CI 2.71 to 10.64) and higher prevalence of oesophageal adenocarcinoma (OR 4.57; 95% CI 3.89 to 5.36), and it was moderate for the association between GORD and higher chronic rhinosinusitis prevalence (OR 2.16; 95% CI 1.37 to 3.48). CONCLUSION: The association between GORD and a range of diseases was extensively studied, and our findings revealed a high certainty of evidence of the association between GORD and an increased risk of COPD exacerbation as well as increased prevalence of oesophageal adenocarcinoma. Further investigations using systematic reviews and meta-analyses of high methodological quality that include prospective large cohort studies and adjusted confounders are warranted. PROSPERO REGISTRATION NUMBER: CRD42019122264.

BIIB021: A novel inhibitor to heat shock protein 90-addicted oncology.

Heat shock protein 90 is induced in response to the cell stress. Its overexpression has been reported in many cancers with poor prognosis. It acts as a chaperone to the client proteins, especially the activated oncoproteins in malignancies to protect them from degradation. Heat shock protein 90 inhibition represented anti-cancer effects in many studies. Previous natural product-based compounds are limited by their association with target toxicities. BIIB021 is an orally available, fully synthetic novel small-molecule heat shock protein 90 inhibitor that has shown strong antitumor activities in a large number of preclinical models and is now under clinical investigation. This review will summarize its therapeutic effects and highlight the prospect of targeting heat shock protein 90 in the cancer therapy.

The association between MTHFR gene C677T polymorphism and ALL risk based on a meta-analysis involving 17,469 subjects.

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism is closely related to the acute lymphoblastic leukaemia (ALL) indicated by many previous epidemiologic studies. However, their conclusions were still conflicting. METHODS: Our aim is to evaluate their associations using a more comprehensive updated meta-analysis. Electronic searches were conducted to select published studies prior to February, 2016. RESULTS: Totally, 39 case-control studies including 6551 ALL cases and 10,918 controls were selected in current meta-analysis. The association was detected significantly between MTHFR C677T polymorphism and ALL reducing susceptibility. CONCLUSIONS: Our results indicate that the MTHFR C677T polymorphism may be a promising ALL biomarker and studies to explore the protein levels of the variants and their functional role are required for the definitive conclusions.

Lower Expression of SPRY4 Predicts a Poor Prognosis and Regulates Cell Proliferation in Colorectal Cancer.

BACKGROUND/AIMS: Colorectal cancer (CRC) is the third most common type of cancer worldwide. Sprouty proteins are modulators of mitogeninduced signal transduction processes and therefore can influence the process of cancerogenesis. The encoded protein of Sprouty homolog 4 (SPRY4) is associated with various human cancers. However, its biological role and clinical significance in CRC development and progression are unknown. METHODS: The aim of this study was to evaluate the expression and biological role of SPRY4 in colorectal cancer. qRT-PCR was performed to investigate the expression of SPRY4 in tumor tissues and corresponding non tumor colorectal tissues from 70 patients. The effect of SPRY4 on proliferation was evaluated by MTT and colony formation assays. CRC cells transfected with SPRY4 were injected into nude mice to study the effect of SPRY4 on tumorigenesis in vivo. RESULTS: The lower expression of SPRY4 was remarkably correlated with deep tumor invasion and advanced TNM stage. Multivariate analyses revealed that SPRY4 expression served as an independent predictor for overall survival. Using 5-aza treatment, we also observed that SPRY4 expression can be affected by DNA methylation. Further experiments revealed that overexpressed SPRY4 significantly inhibited CRC cell proliferation both in vitro and in vivo. CONCLUSION: Our study demonstrated that SPRY4 is involved in the development and progression of colorectal cancer by regulating cell proliferation and shows that SPRY4 may be a potential diagnostic and prognostic target in patients with colorectal cancer.

Relationships between micronutrient losses in sweat and blood pressure among heat-exposed steelworkers.

We aimed to examine the effect of micronutrient losses through sweat on blood pressure (BP) among heat-exposed steelworkers. A total of 224 heat-exposed male steelworkers from an ironworks facility were evaluated in July 2012. We measured the Wet Bulb Globe Temperature Index to evaluate the level of heat stress in the workplace. We collected sweat from the workers during an eight-hour work, and then we measured the micronutrients in the sweat. We also measured the BP of each worker. The results revealed that vitamin C, potassium, and calcium losses in sweat were positively correlated with systolic (SBP) and diastolic (DBP) blood pressure (all P<0.05). A linear stepwise regression analysis revealed that potassium, and calcium losses in sweat adversely affected SBP and DBP (all P<0.05). An analysis of covariance showed that SBP increased when potassium or calcium losses in sweat were >900 mg, or >100 mg, respectively. Further, DBP increased when potassium or calcium losses in sweat were >600 mg or >130 mg, respectively. Therefore, vitamin C, potassium, and calcium losses in sweat may adversely effect BP. To help steelworkers maintain healthy BP, facilities with high temperatures should try to lower environmental temperatures to reduce vitamin C, potassium, and calcium losses in sweat. Additionally, heat-exposed steelworkers may need to increase their dietary intakes of vitamin C, potassium, and calcium. Further research is needed to confirm these findings and support these recommendations.

Zebrafish xenotransplantation as a tool for in vivo cancer study.

Zebrafish represents a powerful model for cancer research. Particularly, the xenotransplantation of human cancer cells into zebrafish has enormous potential for further evaluation of cancer progression and drug discovery. Various cancer models have been established in adults, juveniles and embryos of zebrafish. This xenotransplantation zebrafish model provides a unique opportunity to monitor cancer proliferation, tumor angiogenesis, metastasis, self-renewal of cancer stem cells, and drug response in real time in vivo. This review summarizes the use of zebrafish as a model for cancer xenotransplantation, and highlights its advantages and disadvantages.

Mitochondrial membrane potential and reactive oxygen species in cancer stem cells.

Cancer stem cells (CSCs) are believed as the initiators of the occurrence, development and recurrence of malignant tumors. Targeting this unique cell population would provide a less toxic approach than regular chemotherapeutic agents that kill bulk rapid proliferating tumor cells and also normal cells which divide rapidly. To date, major research effort has been aimed at identifying and eradicating CSC population. The metabolism heterogeneity of mitochondria in CSCs shows a big promise for cancer research. Of them, mitochondrial membrane potential (Δψm), reflecting the functional status of the mitochondrion is proved to be highly related to cancer malignancy. Reactive oxygen species, mainly produced from mitochondria, are also increased in many types of cancer cells. However, their statuses in CSCs remain poorly understood. Here we shall review the mitochondrial membrane potential and reactive oxygen species of CSCs and propose the novel potential targets for cancer therapy.

Genetic 135G/C polymorphism of RAD51 gene and risk of cancer: a meta-analysis of 28,956 cases and 28,372 controls.

The RAD51 gene is essential for the repair of damaged DNA related to tumor development. Although a number of genetic studies have attempted to link the 135G/C polymorphism of RAD51 gene to the risk of cancer, the results were inconclusive. The present study aimed at investigating the pooled association using the more comprehensive meta-analysis. The PubMed, EBSCO, and BIOSIS databases were searched to identify eligible studies which were published in English before March 2014. Data were extracted using standardized methods. The association was assessed by odds ratio (OR) with 95 % confidence interval (CI). Begg's test was used to measure publication bias. Sensitivity analyses were also performed to assess the stability of the results. A total of 45 eligible studies with 28,956 patients and 28,372 controls were included in this meta-analysis. Overall, significant association was detected between 135G/C polymorphism and increased cancer risk (C allele vs. G allele: OR 1.23, 95 % CI 1.18-1.28; CC vs. GG: OR 2.41, 95 % CI 2.12-2.74; CC vs. CG: OR 3.86, 95 % CI 3.41-4.37; recessive model: OR 3.57, 95 % CI 3.19-4.00). In further stratified analysis, significantly elevated cancer risk was observed among Caucasians but not Asians. Subgroup analysis by different cancers also showed their significant associations in breast cancer, hematologic malignances, ovarian cancer, colorectal cancer and endometrial cancer, but not in head and neck cancer. Our results indicated that the RAD51 135G/C polymorphism was a candidate for susceptibility of cancer. The effect of the variants on the expression levels and the possible functional role of the variants in different cancers should be addressed in further studies.

[Effect of method of soothing liver and regulating qi on expression of gastrin and somatostatin in hypothalamus, castric antrum of functional dyspepsia rats].

OBJECTIVE: To explore the effects of the method of soothing the liver and regulating qi on expression of gastrin and somatostatin in hypothalamus and gastric antrum of functional dyspepsia model rats. METHOD: The 32 rats were randomly divided into normal group, model group, Chaihu Shugansan group and domperidone group (n = 8). The functional dyspepsia model was established by constantly squeezing their tails and mean while saline, Chaihu Shugansan decoction and domperidone suspension were administered respectively to 4 groups by gavage. The expression of gastrin and somatostatin in hypothalamus and gastric antrum of rats by immunohistochemical were detected 3 weeks later. RESULT: The expression of GAS in the hypothalamus and gastric antrum of model group were less than those of normal group (P < 0.05, P < 0.01), while the expression of SS in the hypothalamus and gastric antrum in Model group were significantly increased than those of normal group (P < 0.01). The expression of GAS and SS in gastric antrum of Chaihu Shugansan group and domperidone group were increased and decreased respectively, and the differences were significant (P < 0.05, P < 0.01). There were no obvious difference about expression of GAS, SS in the hypothalamus between domperidone group and model group. GAS expression in hypothalamus of Chaihu Shugansan group were increased than those of normal group but there was no obvious difference in SS expression in hypothalamus between Chaihu Shugansan group and model group. CONCLUSION: The method of soothing the liver and regulating qi can increase GAS expression in central and peripheral and decrease SS expression in peripheral gastric antrum, which may be one of its therapeutic mechanisms on functional dyspepsia.