The causality between gut microbiota and ankylosing spondylitis: Insights from a bidirectional two-sample Mendelian randomization analysis.

BACKGROUND: The association between gut microbiota and ankylosing spondylitis (AS) has been reported in the literature; however, whether the two are correlative is unclear. METHODS: Single nucleotide polymorphisms associated with the gut microbiome composition and AS (968 AS cases and 336 191 controls) were obtained from published genome-wide association studies in this two-sample Mendelian randomization (MR) study. The causal relationship between gut microbiota and AS was estimated using the inverse-variance weighted method, and the robustness of our findings was confirmed through a comprehensive series of sensitivity analyses. RESULTS: Anaerotruncus (OR = 0.9984, 95% CI, 0.9968-0.9999, p = .0405) and Ruminococcaceae UCG002 (OR = 0.9989, 95% CI, 0.9979-0.9999, p = .0375) were protective against AS. Defluviitaleaceae (OR = 1.0015, 95% CI, 1.0005-1.0025, p = .0048), Butyricicoccus (OR = 1.0016, 95% CI, 1.0001-1.0032, p = .0429), Coprococcus 3 (OR = 1.0016, 95% CI, 1.0000-1.0032, p = .0463), and Defluviitaleaceae UCG011 (OR = 1.0016, 95% CI, 1.0005-1.0027, p = .0041) exhibited significant positive correlations with heightened susceptibility to AS. Reverse MR revealed that AS does not affect the gut microbial composition. CONCLUSION: Our study has established a genetically-based causal relationship between gut microbiota and AS. This finding suggests that we may be able to target and regulate specific bacterial groups in the gut to prevent and treat AS.

Transcriptomics and quantitative proteomics reveal changes after second stimulation of bone marrow-derived macrophages from lupus-prone MRL/lpr mice.

Innate immune memory can cause the occurrence and exacerbation of autoimmune diseases, and it is as well as being strongly associated with the pathogenesis of systemic lupus erythematosus (SLE), however, the specific mechanism remains to be further studied. We learned that IFN-γ stimulation generated innate immune memory in bone marrow-derived macrophages (BMDMs) and activated memory interferon-stimulated genes (ISGs). This research used IFN-γ and lipopolysaccharide (LPS) to treat BMDMs with lupus-prone MRL/lpr mice and showed that particular memory ISGs were substantially elevated in prestimulated macrophages. In order to identify the differentially expressed genes (DEGs), researchers turned to RNA-seq. GO and KEGG analysis showed that up-regulated DEGs were enriched in defense and innate immune responses, and were related to the expression of pattern recognition receptors (PRRs)-related pathways in macrophages. TMT-based proteome analysis revealed differentially expressed proteins (DEPs) up-regulated in BMDMs were abundant in metabolic pathways such as glucose metabolism. Our study found that after the secondary stimulation of MRL/lpr mice, the expression of PRRs in innate immune cells was changed, and IFN-related pathways were activated to release a large number of ISGs to promote the secondary response. At the same time, related metabolic modes such as glycolysis were enhanced, and epigenetic changes may occur. Therefore, SLE is brought on, maintained, and worsened by a variety of factors that work together to produce innate immune memory.

The convergence of aversion and reward signals in individual neurons of the mice lateral habenula.

The lateral habenula (LHb) and ventral tegmental area (VTA) are two structures closely connected, and they serve as aversion and reward junction of the brain, respectively. This study investigated whether single neurons in the LHb/VTA respond to both aversion and reward stimuli and how these neurons regulate aversion and reward processing. Using optogenetic combined with multi-channel recording of LHb / VTA neuronal discharge, we found that most single neurons in the LHb/ VTA respond to both aversion and reward stimuli. Interestingly, majority of neurons in LHb were aversion-activated and reward-inhibited neurons, consisting mainly of glutamatergic neurons, while most neurons in VTA were reward-activated and aversion-inhibited neurons, which inhibited by glutamatergic neurons in the LHb. Furthermore, optogenetic activation or inhibition of glutamatergic neurons in LHb and their terminals in VTA could induce aversive or reward behaviors. These results indicate that identical neurons in the LHb and VTA have different responses to reward and aversion stimuli. The aversion behaviors induced by activating LHb glutamatergic neurons may be due to its inhibition on reward-activated neurons in VTA. This study suggests that interplay between the LHb and VTA neurons may play a key role in regulating reward and aversion behaviors.

Effect of COVID-19 outbreak on the treatment time of patients with acute ST-segment elevation myocardial infarction.

OBJECTIVE: To explore the effect of COVID-19 outbreak on the treatment time of patients with ST-segment elevation myocardial infarction (STEMI) in Hangzhou, China. METHODS: We retrospectively reviewed the data of STEMI patients admitted to the Hangzhou Chest Pain Center (CPC) during a COVID-19 epidemic period in 2020 (24 cases) and the same period in 2019 (29 cases). General characteristics of the patients were recorded, analyzed, and compared. Moreover, we compared the groups for the time from symptom onset to the first medical contact (SO-to-FMC), time from first medical contact to balloon expansion (FMC-to-B), time from hospital door entry to first balloon expansion (D-to-B), and catheter room activation time. The groups were also compared for postoperative cardiac color Doppler ultrasonographic left ventricular ejection fraction (LVEF),the incidence of major adverse cardiovascular and cerebrovascular events (MACCE),Kaplan-Meier survival curves during the 28 days after the operation. RESULTS: The times of SO-to-FMC, D-to-B, and catheter room activation in the 2020 group were significantly longer than those in the 2019 group (P < 0.05). The cumulative mortality after the surgery in the 2020 group was significantly higher than the 2019 group (P < 0.05). CONCLUSION: The pre-hospital and in-hospital treatment times of STEMI patients during the COVID-19 epidemic were longer than those before the epidemic. Cumulative mortality was showed in Kaplan-Meier survival curves after the surgery in the 2020 group was significantly different higher than the 2019 group during the 28 days.The diagnosis and treatment process of STEMI patients during an epidemic should be optimized to improve their prognosis.

Upregulation of programmed death ligand 1 by liver kinase B1 and its implication in programmed death 1 blockade therapy in non-small cell lung cancer.

AIMS: Liver kinase B1 (LKB1) deficiency is associated with reduced expression of programmed death ligand 1 (PD-L1) and inferior clinical outcomes of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC). This study aimed to investigate the mechanism by which LKB1 regulates PD-L1 expression and its role in programmed death 1 (PD-1) blockade therapy in NSCLC. MAIN METHODS: The impact of LKB1 on PD-L1 was assessed by western blot, qRT-PCR and immunohistochemistry in NSCLC. Activators/inhibitors of AMPK and NRF2 were applied to explore the mechanisms underlying the regulation of PD-L1 by LKB1. Efficiency of combined application of metformin and PD-1 blockade was evaluated in immunocompetent C57BL/6 mice. KEY FINDINGS: A remarkable positive correlation between LKB1 and PD-L1 expression was demonstrated in NSCLC tissues. Knockdown of LKB1 decreased PD-L1 in TC-1 cells, whereas overexpression of LKB1 increased PD-L1 in A549 cells. We further characterized that AMPK mediated the upregulation of PD-L1 by LKB1. Inhibition of AMPK or NRF2 markedly reduced PD-L1 in LKB1-intact NSCLC cells. In contrast, activation of AMPK or NRF2 reversed PD-L1 expression in LKB1-deficient NSCLC cells. Combined administration of metformin and anti-PD-1 antibody efficiently inhibited the growth of LKB1-intact tumors, whereas no obvious suppression was observed in LKB1-deficient tumors. SIGNIFICANCE: These findings demonstrated that LKB1 upregulates PD-L1 expression in NSCLC by activating the AMPK and KEAP1/NRF2 signaling. Activation of LKB1-AMPK with metformin improves the therapeutic effect of PD-1 blockade in NSCLC with wild-type LKB1.

Biomarkers for immune checkpoint therapy targeting programmed death 1 and programmed death ligand 1.

Rapidly increasing usages of immune checkpoint therapy for cancer treatment, particularly monoclonal antibodies that target programmed cell death-1 (PD-1) and its ligand PD-L1, have been achieved due to startling durable therapeutic efficacy with limited toxicity. The therapeutics significantly prolonged the overall survival and progression free survival of patients across multiple cancer types. However, the objective response rate of patients receiving this kind of treatment is substantially low. Therefore, it is of great importance to exploit reliable biomarkers that can robustly predict the therapeutic effects. Several biomarkers have been characterized for the selection of patients, which is mainly based on immunological and genetic criteria. Herein, we focus on the current progress regarding the biomarkers for anti-PD-1/PD-L1 therapy.

Recent Findings in the Regulation of Programmed Death Ligand 1 Expression.

With the recent approvals for the application of monoclonal antibodies that target the well-characterized immune checkpoints, immune therapy shows great potential against both solid and hematologic tumors. The use of these therapeutic monoclonal antibodies elicits inspiring clinical results with durable objective responses and improvements in overall survival. Agents targeting programmed cell death protein 1 (PD-1; also known as PDCD1) and its ligand (PD-L1) achieve a great success in immune checkpoints therapy. However, the majority of patients fail to respond to PD-1/PD-L1 axis inhibitors. Expression of PD-L1 on the membrane of tumor and immune cells has been shown to be associated with enhanced objective response rates to PD-1/PD-L1 inhibition. Thus, an improved understanding of how PD-L1 expression is regulated will enable us to better define its role as a predictive marker. In this review, we summarize recent findings in the regulation of PD-L1 expression.

Role of DNA hypomethylation in lateral habenular nucleus in the development of depressive-like behavior in rats.

BACKGROUND: Lateral habenula nucleus (LHb) has recently been noted for its role in stress-induced depressive disorder. Yet little is known about the mechanisms by which external stimuli or depression induces pathological alteration in the LHb. METHODS: Chronic unpredictable mild stress (CUMS) was employed to model depressive-like behaviors in adult rats. We examined expressions of DNA methyltransferases (Dnmts) mRNA and protein and global DNA methylation levels in LHb of CUMS-induced depressive rats. Then 5-aza-2'-deoxycytidine (5-aza), a Dnmts inhibitor, was infused into the LHb of native rats to test the effects of hypomethylation in the LHb. The gene expressions in the LHb and the levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in dorsal raphe nucleus (DRN) were examined in 5-aza infusion rats by quantitative real-time PCR and high performance liquid chromatography, respectively. RESULTS: Rats were exposed to CUMS for 21 days and depressive-like behaviors were induced as expected. We observed significant decrease in mRNA and protein expressions of Dnmt1 and DNA hypomethylation in LHb of depressive rats. These phenomenon suggests that CUMS-induced depressive-like behaviors are related with DNA hypomethylation in the LHb. Local 5-aza infusion into LHb of native rat resulted in global DNA hypomethylation in the LHb and induced depressive-like behaviors which are featured with lack of interest and investment in the environment, behavioral despair and anhedonia. Moreover, DNA hypomethylation in the LHb increased transcription of ß calcium/calmodulin dependent protein kinase II and glutamate receptor 1 in the LHb and attenuated the levels of 5-HT and 5-HIAA in the DRN. Our data suggested that alteration of DNA methylation in the LHb may control 5-HT neuronal activity in the DRN to regulate emotional state. CONCLUSIONS: DNA hypomethylation in the LHb is involved in the development of depressive-like behavior and suitable methylation state contributes to the emotional stabilization.

HNF6 promotes tumor growth in colorectal cancer and enhances liver metastasis in mouse model.

Hepatocyte nuclear factor 6 (HNF6), as a transcription factor, has been reported to be involved in cell proliferation, carcinogenesis, and tumor metastasis. Here, we demonstrated the role of HNF6 in tumor growth and liver metastasis in colorectal cancer (CRC). Through bioinformatics and clinical samples analysis, we found HNF6 messenger RNA was upregulated both in CRC primary sites and liver metastases, and its high expression indicated poor survival in CRC patients. In vitro studies confirmed that HNF6 promoted cell proliferation and colony formation. What is more, in mouse models, the xenografts grew significantly faster and liver metastasis rate was nearly 45% higher in mice injected with HNF6-overexpressing cells. Further mechanism exploration showed that HNF6 expression affected cell adhesion and conferred resistance to anoikis in CRC cells. Taken together, HNF6 expression was upregulated in CRC and closely correlated with poor survival. HNF6 promoted CRC cell proliferation and tumor growth, and may contribute to liver metastasis via conferring cell resistance to anoikis.

PARP-1 inhibitors sensitize HNSCC cells to APR-246 by inactivation of thioredoxin reductase 1 (TrxR1) and promotion of ROS accumulation.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Mutations of TP53 may reach 70% - 85% in HNSCC patients without human papillomavirus (HPV) infection. Recurrence rate remains particularly high for HNSCC patients with mutations in the TP53 gene although patients are responsive to surgery, irradiation, and chemotherapy early in the treatment. p53-Reactivation and Induction of Massive Apoptosis-1 (PRIMA-1) and its methylated analogue PRIMA-1Met (also known as APR-246) are quinuclidine compounds that rescue the DNA-binding activity of mutant p53 (mut-p53) and restore the potential of wild-type p53. In the current report, we demonstrated that inhibition of poly (ADP-ribose) polymerase-1 (PARP-1) with 6(5H)-phenanthridinone (PHEN) and N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N, N-dimethylamino) acetamide hydrochloride (PJ34) sensitizes UMSCC1, UMSCC14, and UMSCC17A, three HNSCC cell lines to the treatment of APR-246. PHEN enhances APR-246-induced apoptosis, but not programmed necrosis or autophagic cell death in HNSCC cells. The PARP-1 inhibition-induced sensitization of HNSCC cells to APR-246 is independent of TP53 mutation. Instead, PARP-1 inhibition promotes APR-246-facilitated inactivation of thioredoxin reductase 1 (TrxR1), leading to ROS accumulation and DNA damage. Overexpression of TrxR1 or application of antioxidant N-acetyl-L-cysteine (NAC) depletes the ROS increase, reduces DNA damage, and decreases cell death triggered by APR-246/PHEN in HNSCC cells. Thus, we have characterized a new function of PARP-1 inhibitor in HNSCC cells by inactivation of TrxR1 and elevation of ROS and provide a novel therapeutic strategy for HNSCC by the combination of PARP-1 inhibitors and APR-246.

Piperlongumine and p53-reactivator APR-246 selectively induce cell death in HNSCC by targeting GSTP1.

TP53 mutations frequently occur in head and neck squamous cell carcinoma (HNSCC) patients without human papillomavirus infection. The recurrence rate for these patients is distinctly high. It has been actively explored to identify agents that target TP53 mutations and restore wild-type (WT) TP53 activities in HNSCC. PRIMA-1 (p53-reactivation and induction of massive apoptosis-1) and its methylated analogue PRIMA-1Met (also called APR-246) were found to be able to reestablish the DNA-binding activity of p53 mutants and reinstate the functions of WT p53. Herein we report that piperlongumine (PL), an alkaloid isolated from Piper longum L., synergizes with APR-246 to selectively induce apoptosis and autophagic cell death in HNSCC cells, whereas primary and immortalized mouse embryonic fibroblasts and spontaneously immortalized non-tumorigenic human skin keratinocytes (HaCat) are spared from the damage by the co-treatment. Interestingly, PL-sensitized HNSCC cells to APR-246 are TP53 mutation-independent. Instead, we demonstrated that glutathione S-transferase pi 1 (GSTP1), a GST family member that catalyzes the conjugation of GSH with electrophilic compounds to fulfill its detoxification function, is highly expressed in HNSCC tissues. Administration of PL and APR-246 significantly suppresses GSTP1 activity, resulting in the accumulation of ROS, depletion of GSH, elevation of GSSG, and DNA damage. Ectopic expression of GSTP1 or pre-treatment with antioxidant N-acetyl-L-cysteine (NAC) abrogates the ROS elevation and decreases DNA damage, apoptosis, and autophagic cell death prompted by PL/APR-246. In addition, administration of PL and APR-246 impedes UMSCC10A xenograft tumor growth in SCID mice. Taken together, our data suggest that HNSCC cells are selectively sensitive to the combination of PL and APR-246 due to a remarkably synergistic effect of the co-treatment in the induction of ROS by suppression of GSTP1.

CLDN6 promotes chemoresistance through GSTP1 in human breast cancer.

BACKGROUND: Claudin-6 (CLDN6), a member of CLDN family and a key component of tight junction, has been reported to function as a tumor suppressor in breast cancer. However, whether CLDN6 plays any role in breast cancer chemoresistance remains unclear. In this study, we investigated the role of CLDN6 in the acquisition of chemoresistance in breast cancer cells. METHODS: We manipulated the expression of CLDN6 in MCF-7 and MCF-7/MDR cells with lv-CLDN6 and CLDN6-shRNA and investigated whether CLDN6 manipulation lead to different susceptibilities to several chemotherapeutic agents in these cells. The cytotoxicity of adriamycin (ADM), 5-fluorouracil (5-FU), and cisplatin (DDP) was tested by cck-8 assay. Cell death was determined by DAPI nuclear staining. The enzyme activity of glutanthione S-transferase-p1 (GSTP1) was detected by a GST activity kit. Then lv-GSTP1 and GSTP1-shRNA plasmids were constructed to investigate the potential of GSTP1 in regulating chemoresistance of breast cancer. The TP53-shRNA was adopted to explore the regulation mechanism of GSTP1. Finally, immunohistochemistry was used to explore the relationship between CLDN6 and GSTP1 expression in breast cancer tissues. RESULTS: Silencing CLDN6 increased the cytotoxicity of ADM, 5-FU, and DDP in MCF-7/MDR cells. Whereas overexpression of CLDN6 in MCF-7, the parental cell line of MCF-7/MDR expressing low level of CLDN6, increased the resistance to the above drugs. GSTP1 was upregulated in CLDN6-overexpressed MCF-7 cells. RNAi -mediated silencing of CLDN6 downregulated both GSTP1 expression and GST enzyme activity in MCF-7/MDR cells. Overexpresssion of GSTP1 in CLDN6 silenced MCF-7/MDR cells restored chemoresistance, whereas silencing GSTP1 reduced the chemoresistance due to ectopic overexpressed of CLDN6 in MCF-7 cells. These observations were also repeated in TNBC cells Hs578t. We further confirmed that CLDN6 interacted with p53 and promoted translocation of p53 from nucleus to cytoplasm, and both the expression and enzyme activity of GSTP1 were regulated by p53. Clinicopathologic analysis revealed that GSTP1 expression was positively associated with CLDN6 in human breast cancer samples. CONCLUSION: High expression of CLDN6 confers chemoresistance on breast cancer which is mediated by GSTP1, the activity of which is regulated by p53. Our findings provide a new insight into mechanisms and strategies to overcome chemoresistance in breast cancer.

BEX2 promotes tumor proliferation in colorectal cancer.

BEX2 has been suggested to promote the tumor growth in breast cancer and glioblastoma, while inhibit the proliferation of glioma cells. Thus, the role of BEX2 in tumor was still in debate. Additionally, the biological functions of BEX2 in colorectal cancer (CRC) have not yet been clarified. Here, we reported that BEX2 was overexpressed in advanced CRC from both the GSE14333 database and fresh CRC tissue specimens, and positively correlated with clinical staging. Knockdown of BEX2 significantly decreased the in vitro proliferation of SW620 colorectal cancer cells, suppressed subcutaneous xenograft growth and enhanced the survival of mice with cecal tumors. These effects were mainly mediated by the JNK/c-Jun pathway. Knockdown of BEX2 inhibited JNK/c-Jun phosphorylation, while BEX2 overexpression activated JNK/c-Jun phosphorylation. Moreover, the administration of the JNK-specific inhibitor SP600125 to SW620 with BEX2 overexpression abolished the effect of BEX2 on SW620 cell proliferation. This study reveals that BEX2 promotes colorectal cancer cell proliferation via the JNK/c-Jun pathway, suggesting BEX2 as a potential candidate target for the treatment of CRC.

LKB1 is a DNA damage response protein that regulates cellular sensitivity to PARP inhibitors.

Liver kinase B1 (LKB1) functions as a tumor suppressor encoded by STK11, a gene that mutated in Peutz-Jeghers syndrome and in sporadic cancers. Previous studies showed that LKB1 participates in IR- and ROS-induced DNA damage response (DDR). However, the impact of LKB1 mutations on targeted cancer therapy remains unknown. Herein, we demonstrated that LKB1 formed DNA damage-induced nuclear foci and co-localized with ataxia telangiectasia mutated kinase (ATM), γ-H2AX, and breast cancer susceptibility 1 (BRCA1). ATM mediated LKB1 phosphorylation at Thr 363 following the exposure of cells to ionizing radiation (IR). LKB1 interacted with BRCA1, a downstream effector in DDR that is recruited to sites of DNA damage and functions directly in homologous recombination (HR) DNA repair. LKB1 deficient cells exhibited delayed DNA repair due to insufficient HR. Notably, LKB1 deficiency sensitized cells to poly (ADP-ribose) polymerase (PARP) inhibitors. Thus, we have demonstrated a novel function of LKB1 in DNA damage response. Cancer cells lacking LKB1 are more susceptible to DNA damage-based therapy and, in particular, to drugs that further impair DNA repair, such as PARP inhibitors.

Water-soluble ginseng oligosaccharides protect against scopolamine-induced cognitive impairment by functioning as an antineuroinflammatory agent.

BACKGROUND: Panax ginseng root is used in traditional oriental medicine for human health. Its main active components such as saponins and polysaccharides have been widely evaluated for treating diseases, but secondary active components such as oligosaccharides have been rarely studied. This study aimed to assess the impact of water-soluble ginseng oligosaccharides (WGOS), which were isolated from the warm-water extract of Panax ginseng root, on scopolamine-induced cognitive impairment in mice and its antineuroinflammatory mechanisms. METHODS: We investigated the impact of WGOS on scopolamine-induced cognitive impairment in mice by using Morris water maze and novel object recognition task. We also analyzed the impact of WGOS on scopolamine-induced inflammatory response (e.g., the hyperexpression of proinflammatory cytokines IL-1ß and IL-6 and astrocyte activation) by quantitative real-time polymerase chain reaction and glial fibrillary acid protein (GFAP) immunohistochemical staining. RESULTS: WGOS pretreatment protected against scopolamine-induced learning and memory deficits in the Morris water maze and in the novel object recognition task. Furthermore, WGOS pretreatment downregulated scopolamine-induced hyperexpression of proinflammatory cytokines interleukin (IL)-1ß and IL-6 mRNA and astrocyte activation in the hippocampus. These results indicate that WGOS can protect against scopolamine-induced alterations in learning and memory and inflammatory response. CONCLUSION: Our data suggest that WGOS may be beneficial as a medicine or functional food supplement to treat disorders with cognitive deficits and increased inflammation.

Why depression and pain often coexist and mutually reinforce: Role of the lateral habenula.

The interrelation of depression and pain is increasingly coming under scrutiny. Although the lateral habenula (LHb) is widely implicated in the pathogenesis of depression and pain, its role in the interaction of depression and pain remains unknown. Thus, the aim of current study was to investigate the role of LHb in rat depression-pain comorbidity. Single extracellular firing recording and immunofluorescence methods were used to compare firing rates and c-Fos expression of the LHb neurons in normal and model rats. Following subcutaneous injection of formalin into the hind paw to simulate natural pain, we assessed pain behavior in rats subjected to the chronic, unpredictable mild stress procedure (CUMS, a model of depression). Pain sensitivity in the model rats was increased over that of controls. These rats showed a significant increase in the firing activity of LHb neurons compared with normal rats. Significantly, about 73% of neurons with high discharge frequency in LHb of model rats were pain-activated neurons (PANs), and the firing rates of PANs were inhibited by intraperitoneal injection of a tricyclic antidepressant, clomipramine. Immunofluorescence showed that the percentage of c-Fos positive cells in LHb was significantly increased in rats receiving CUMS alone, rats receiving pain stimulation alone, and rats receiving both CUMS and pain stimulation, but especially the last. The interaction effect was inhibited by injection of clomipramine. The LHb lesion can improve both depression-like behavior and pain sensitivity in depression model rats with pain. These suggest that hyperactivity of the LHb neurons contributes to depression-pain comorbidity in rats.

Association between MutL homolog 1 polymorphisms and the risk of colorectal cancer: a meta-analysis.

PURPOSE: As one of the most essential components of mismatch repair system, MutL homolog 1 (MLH1) plays an increasingly implicated role in initiation and promotion of colorectal carcinogenesis, with germ-line mutations in different loci. However, whether a single genetic variant in MLH1 could predict the risk of cancer was still under doubt and recent studies yielded inconsistent results. Therefore, this meta-analysis aimed at investigating the association between MLH1 single-nucleotide polymorphisms (SNPs) and colorectal cancer (CRC) risks. METHODS: A systematic literature search of PubMed, MEDLINE, Web of Science and BIOSIS databases was performed to obtain all available SNPs and studies. We focused on three SNPs (rs1800734, rs1799977 and rs63750448) with the most included studies and conducted overall and subgroup analyses after data extraction. RESULTS: A total of 37,347, 29,114 and 2722 patients in case and control groups were meta-analyzed in four genetic models (AA vs. BB, AB vs. BB, AA+AB vs. BB and AA vs. BB+AB) for each SNP. The overall results suggested that the mutation in rs63750447 predicted a higher CRC risk (AB vs. BB: OR 2.283, 95 % CI 1.612-3.232, P = 0.000; AA+AB vs. BB: OR 2.291, 95 % CI 1.618-3.244, P = 0.000), while rs1800734 and rs1799977 were not associated with CRC risks. Subgroup analysis according to study area, quality score and genotyping technique revealed the similar results. CONCLUSIONS: As the first meta-analysis reporting the association between rs63750448 and CRC risk, the A allele substitution might be a risk factor for CRC. Additionally, there was no persuasive evidence showing that SNPs of rs1800734 and rs1799977 were related to CRC susceptibility.

[Association between the quality of sleep and the occurrence of diabetes among people with impaired glucose regulation].

OBJECTIVE: To understand the association between people under impaired glucose regulation (IGR) with poor quality of sleep and the occurrence of diabetes. METHODS: Based on a cohort of 1136 persons with IGR, the present study would include information on the duration of sleep and severity of insomnia. The cohort was followed for two years and the outcomes of impaired glucose regulation were summarized. Poisson regression was employed to analyze the relationship between the quality of sleep and the occurrence of diabetes. RESULTS: After the confounders were adjusted, when compared with 7 - 9 h sleep duration, the less than 7 h sleep duration showed a RR value of 1.77 (P < 0.001) while more than 9 h sleep duration had a RR value of 1.45 (P = 0.067). When compared data from people having less than 14 scores of the Insomnia Severity Index (ISI), those people with more than 14 scores had a RR value of 1.58 (P < 0.001). CONCLUSION: Causal relationship between the quality of sleep and the occurrence of diabetes did exist among the IGR population while the poor quality of sleep might increase the risk of diabetes at the end of the two-year following-up program.