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Background Human MAD1 mitotic arrest deficient-like 1 (MAD1L1) and MAD2 mitotic arrest deficient-like 1 (MAD2L1) are two interactive proteins playing important roles in maintaining spindle checkpoint function. This study examined the functional relevance of missense coding single nucleotide polymorphisms (SNPs) in MAD1L1 and MAD2L1 and their association with susceptibility to lung cancer. Methods SNPs in the MAD2L1 coding region were discovered by sequencing and impact of MAD1L1 and MAD2L1 variants on spindle checkpoint function was examined by flow cytometry and mitotic index assay. The associations of MAD1L1 and MAD2L1 variants with lung cancer were analysed in a case-control cohort of 1000 patients and 1000 controls. ORs and 95% CIs were estimated by logistic regression. Results A novel C-to-A SNP at codon 84 of MAD2L1 (Leu84Met substitution) was discovered. Cells expressing MAD2L1-84Met and MAD1L1-558His had impaired spindle checkpoint function, with a lower 4N-DNA content and mitotic index when treated with nocodazole. Case-control analysis showed that the MAD2L1 Leu84Met SNP was associated with increased risk of lung cancer in an allele dose dependent manner, with the ORs being 2.55 (95% CI 1.95 to 3.33) for the Leu/Met and 2.68 (95% CI 2.05 to 3.48) for the Met/Met genotype compared with the Leu/Leu genotype. The MAD1L1 558 His/His genotype was also associated with 1.4-fold elevated lung cancer risk compared with the Arg/Arg genotype. Conclusion These results suggest that genetic variants in MAD1L1 and MAD2L1 confer susceptibility to lung cancer, which might result from reduced spindle checkpoint function due to attenuated function of MAD1L1 and/or MAD2L1. [ABSTRACT FROM AUTHOR]

Tumor growth and metastasis require that tumor cells must have either the potential to shift genetically or epigenetically between proliferative and invasive phenotypes or both phenotypes simultaneously. In the present study, we demonstrated that neuroblastoma growth and invasion were distinct processes that were carried out by proliferative and invasive phenotypes of tumor cells, respectively. Two subpopulations from human neuroblastoma cell line were isolated: highly invasive (HI) cells and low-invasive (LI) cells. HI and LI cells had different proliferative rate and metastatic ability in vitro and in vivo. In addition, they had distinct activated signal pathways and sensitivities to chemotherapy drugs. Affymetrix microarray and quantitative reverse transcriptase–polymerase chain reaction revealed that visinin-like protein-1 (VSNL-1) mRNA in HI cells was significantly higher than that in LI cells. We also observed that VSNL-1 was over-expressed in tumor specimens from patients with distant organ metastases compared with those without metastases. Furthermore, the invasive and proliferative phenotypes of neuroblastoma cells could be exchanged by regulation of VSNL-1 expression in vitro and in vivo. Up-regulation of VSNL-1 potentiated the anoikis-resistant ability of neuroblastoma cell. The expression of anoikis inhibitor TrkB, intracellular adhesion molecule 1, major histocompatibility complex class I, CD44 and CD44v6 was associated with VSNL-1 level. These results suggested that distinct roles of proliferative and invasive phenotypes contributed to neuroblastoma progression and strongly demonstrated that VSNL-1 played a very important role in neuroblastoma metastasis. [ABSTRACT FROM AUTHOR]

The P53 tumor suppressor pathway plays an important role in cancer development. The auto-regulatory feedback mechanism of the P53 and MDM2 expression is critical in keeping proper tumor suppressor function of this pathway. This study examined the effect of P53 Arg72Pro variants on transactivation of polymorphic MDM2 promoter (T309G) and their associations with risk of developing gastric cardia adenocarcinoma (GCA) in a Chinese population. Luciferase assays consistently showed a significantly higher activity of the MDM2 309G promoter compared with the MDM2 309T promoter. In cells co-transfected with variant P53 cDNAs, P53-72Pro displayed a significantly higher ability to activate the MDM2 promoter than P53-72Arg. Genotype analyses in 500 GCA patients and 1000 controls showed that significantly increased risk for developing GCA was associated with the MDM2 309G and the P53 72Pro allele compared with the MDM2 309T and the P53 72Arg allele in an allele dose-dependent manner. A joint effect between the MDM2 and P53 polymorphisms in intensifying GCA risk was detected, with the odds ratio (OR) for the presence of both MDM2 390GG and P53 72Pro/Pro genotypes being 5.05 [95% confidence interval (CI), 2.50–10.20]. These results suggest that the P53 72Pro and MDM2 309G polymorphisms contribute to the risk of developing GCA. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about the impact of the interaction between RET and PHOX2B polymorphisms on risk of Hirschsprung's disease.

Presents a response to a letter to the editor on gene polymorphisms.

The coronavirus disease 2019 (COVID-19) has caused a global pandemic, resulting in considerable morbidity and mortality. Tocilizumab, an inhibitor of IL-6, has been widely repurposed as a treatment of severely ill patients without robust evidence supporting its use. In this study, we aimed to systematically describe the effectiveness of treatment and prevention of the cytokine storms in COVID-19 patients with tocilizumab. In this multicentered retrospective and observational cohort study, 65 patients with COVID-19 receiving tocilizumab and 130 not receiving tocilizumab were propensity score matched at a ratio of 2:1 based on age, sex, and comorbidities from January 20, 2020 to March 18, 2020 in Wuhan, China. After adjusting for confounding, the detected risk for in-hospital death was lower in the tocilizumab group versus nontocilizumab group (hazard ratio = 0.47; 95% confidence interval = 0.25-0.90; p = 0.023). Moreover, use of tocilizumab was associated with a lower risk of acute respiratory distress syndrome (odds ratio = 0.23; 95% confidence interval = 0.11-0.45; p < 0.0001). Furthermore, patients had heightened inflammation and more dysregulated immune cells before treatment, which might aggravate disease progression. After tocilizumab administration, abnormally elevated IL-6, C-reactive protein, fibrinogen, and activated partial thromboplastin time decreased. Tocilizumab may be of value in prolonging survival in patients with severe COVID-19, which provided a novel strategy for COVID-19-induced cytokine release syndrome. Our findings could inform bedside decisions until data from randomized, controlled clinical trials become available. [ABSTRACT FROM AUTHOR]

Mouse gene inactivation has shown that the transcription factor Sox11 is required for mouse palatogenesis. However, whether Sox11 is primarily involved in the regulation of palatogenesis still remains elusive. In this study, we explored the role of Sox11 in palatogenesis by analyzing the developmental mechanism in cleft palate formation in mutants deficient in Sox11. Sox11 is expressed both in the developing palatal shelf and in the surrounding structures, including the mandible. We found that cleft palate occurs only in the mutant in which Sox11 is directly deleted. As in the wild type, the palatal shelves in the Sox11 mutant undergo outgrowth in a downward direction and exhibit potential for fusion and elevation. However, mutant palatal shelves encounter clefting, which is associated with a malpositioned tongue that results in physical obstruction of palatal shelf elevation at embryonic day 14.5 (E14.5). We found that loss of Sox11 led to reduced cell proliferation in the developing mandibular mesenchyme via Cyclin D1, leading to mandibular hypoplasia, which blocks tongue descent. Extensive analyses of gene expression in Sox11 deficiency identified FGF9 as a potential candidate target of Sox11 in the modulation of cell proliferation both in the mandible and the palatal shelf between E12.5 and E13.5. Finally we show, using in vitro assays, that Sox11 directly regulates the expression of Fgf9 and that application of FGF9 protein to Sox11-deficient palatal shelves restores the rate of BrdU incorporation. Taken together, the palate defects presented in the Sox11 loss mutant mimic the clefting in the Pierre Robin sequence in humans. [ABSTRACT FROM AUTHOR]

Recent genome-wide association studies have identified single-nucleotide polymorphism (SNPs) within the SLC22A3 (solute carrier family 22 member 3) gene associated with coronary heart disease (CHD) in the Caucasian population. We performed molecular analysis to investigate the potential role of SLC22A3 variants in CHD. Our study showed that the common polymorphism rs3088442 G → A, which is localized in the 3' UTR of the SLC22A3 gene, was associated with a decreased risk of CHD in the Chinese population by a case control study. In silico analysis indicated that G → A substitution of SNP rs3088442 created a putative binding site for miR-147 in the SLC22A3 mRNA. By overexpressing miR-147 or inhibiting endogenous miR-147, we demonstrated that SNP rs3088442 G → A recruited miR-147 to inhibit SLC22A3 expression. Moreover, SLC22A3 deficiency significantly decreased LPS-induced monocytic inflammatory response by interrupting NF-κB and MAPK signaling cascades in a histamine-dependent manner. Notably, the expression of SLC22A3A was also suppressed by LPS stimulus. Our findings might indicate a negative feedback mechanism against inflammatory response by which SLC22A3 polymorphisms decreased the risk of CHD. [ABSTRACT FROM AUTHOR]

Background: A recent genome-wide study (GWAS) has identified GPC5 as a promising susceptibility gene for Lung cancer in never smokers (LCINS). However, the most significant single nucleotide polymorphism (SNP) in this GWAS, rs2352028, has yielded controversial results. The aim of this study was to clarify the relationship between rs2352028 and LCINS. Considering that rs2352028 might be largely marker-SNP correlated to causative variants, two predicted functional SNPs, rs3759452 and rs7322083, were additionally investigated in this study. Methods: A hospital based case-control study including 298 cases and 599 controls in a never-smoking Chinese Han population was conducted, and then a meta-analysis combining our data and published data was performed to verify the findings. Results: The SNP rs3759452, predicted to potentially change transcription factor binding site of GPC5, was significantly associated with LCINS risk (odds ratio for dominant model = 1.55, 95% confidence interval = 1.14-2.12). Nevertheless, no significant evidence was showed for rs2352028, both in our case- control study and the meta-analysis including 13 studies of 2342 LCINS cases and 13,398 never-smoking controls. Further subgroup meta-analysis according to population ethnicity and cancer histology also reported no significant association of rs2352028. Conclusions: The association conferring rs3759452 further supports the value of GPC5 in susceptibility to LCINS. Nevertheless, comprehensive analyses are warranted to dissect the functional mechanism underpinning rs3759452. [ABSTRACT FROM AUTHOR]

The heat shock protein Hsp70 is crucial for regulating cellular homeostasis in stressed cells. Although the tumorigenic potential and prognostic applications of Hsp70 have been widely investigated, it remains unclear whether genetic variations of the human isoforms HSPA1L, HSPA1A, and HSPA1B are associated with cancer risk and prognosis. In this study, we genotyped six tagSNPs in these genes in 1,152 paired patients with lung cancer and controls, and then validated the results in additional cohorts of 1,781 patients with lung cancer and 1,038 controls. In addition, we evaluated the associations of these tagSNPs with survival in 330 patients with advanced non-small cell lung cancer (NSCLC) with additional validation in another 331 patients with advanced NSCLC. Functions of the risk variants identified were investigated using cell-based reporter assays. We found that the HSPA1B rs6457452T allele was associated with increased lung cancer risk compared with the rs6457452C allele in both data sets and also pooled analysis (adjusted OR = 1.41; P = 2.8 x 10-5). The HSPA1B rs2763979TT genotype conferred poor survival outcomes for patients with advanced NSCLC in two independent cohorts and pooled analysis [adjusted hazard ratio (HR) = 1.80, 1.61, and 1.66; P = 0.013, 0.036, and 0.002, respectively]. Lastly, we also found that the rs2763979T and rs6457452T alleles were each sufficient to reduce expression of transcriptional reporter constructs, when compared with the rs2763979C and rs6457452C alleles, respectively. Taken together, our findings define that functional HSPA1B variants are associated with lung cancer risk and survival. These Hsp70 genetic variants may offer useful biomarkers to predict lung cancer risk and prognosis. [ABSTRACT FROM AUTHOR]