Gut Dysbiosis Drives Inflammatory Bowel Disease Through the CCL4L2-VSIR Axis in Glycogen Storage Disease.

Patients with glycogen storage disease type Ib (GSD-Ib) frequently have inflammatory bowel disease (IBD). however, the underlying etiology remains unclear. Herein, this study finds that digestive symptoms are commonly observed in patients with GSD-Ib, presenting as single or multiple scattered deep round ulcers, inflammatory pseudo-polyps, obstructions, and strictures, which differ substantially from those in typical IBD. Distinct microbiota profiling and single-cell clustering of colonic mucosae in patients with GSD are conducted. Heterogeneous oral pathogenic enteric outgrowth induced by GSD is a potent inducer of gut microbiota immaturity and colonic macrophage accumulation. Specifically, a unique population of macrophages with high CCL4L2 expression is identified in response to pathogenic bacteria in the intestine. Hyper-activation of the CCL4L2-VSIR axis leads to increased expression of AGR2 and ZG16 in epithelial cells, which mediates the unique progression of IBD in GSD-Ib. Collectively, the microbiota-driven pathomechanism of IBD is demonstrated in GSD-Ib and revealed the active role of the CCL4L2-VSIR axis in the interaction between the microbiota and colonic mucosal immunity. Thus, targeting gut dysbiosis and/or the CCL4L2-VISR axis may represent a potential therapy for GSD-associated IBD.

Immunomodulatory Effect and Biological Significance of ß-Glucans.

ß-glucan, one of the homopolysaccharides composed of D-glucose, exists widely in cereals and microorganisms and possesses various biological activities, including anti-inflammatory, antioxidant, and anti-tumor properties. More recently, there has been mounting proof that ß-glucan functions as a physiologically active "biological response modulator (BRM)", promoting dendritic cell maturation, cytokine secretion, and regulating adaptive immune responses-all of which are directly connected with ß-glucan-regulated glucan receptors. This review focuses on the sources, structures, immune regulation, and receptor recognition mechanisms of ß-glucan.

Glycyrrhetinic acid suppresses breast cancer metastasis by inhibiting M2-like macrophage polarization via activating JNK1/2 signaling.

BACKGROUND: Breast cancer metastasis is leading cause of cancer death among women worldwide. Tumor-associated macrophages (TAMs) have been considered as potential targets for treating breast cancer metastasis because they promote tumor growth and development. Glycyrrhetinic acid (GA) is one of the most important phytochemicals of licorice which has shown promising anti-cancer efficacies in pre-clinical trials. However, the regulatory effect of GA on the polarization of TAMs remains elusive. PURPOSE: To investigate the role of GA in regulating the polarization of M2 macrophages and inhibiting breast cancer metastasis, and to further explore its underlying mechanisms of action. STUDY DESIGN: IL-4 / IL-13-treated RAW 264.7 and THP-1 cells were used as the M2-polarized macrophages in vitro. A 4T1 mouse breast cancer model and the tail vein breast cancer metastasis model were applied to study the effect of GA on breast cancer growth and metastasis in vivo. RESULTS: In vitro studies showed that GA significantly inhibited IL-4 / IL 13-induced M2-like polarization in RAW 264.7 and THP-1 macrophages without affecting M1-like polarization. GA strongly decreased the expression of M2 macrophage markers CD206 and Arg-1, and reduced the levels of the pro-angiogenic molecules VEGF, MMP9, MMP2 and IL-10 in M2 macrophages. GA also increased the phosphorylation of JNK1/2 in M2 macrophages. Moreover, GA significantly suppressed M2 macrophage-induced cell proliferation and migration in 4T1 cancer cells and HUVECs. Interestingly, the inhibitory effects of GA on M2 macrophages were abolished by a JNK inhibitor. Animal studies showed that GA significantly suppressed tumor growth, angiogenesis, and lung metastasis in BALB/c mice bearing breast tumor. In tumor tissues, GA reduced the number of M2 macrophages but elevated the proportion of M1 macrophages, accompanied by activation of JNK signaling. Similar results were found in the tail vein breast cancer metastasis model. CONCLUSION: This study demonstrated for the first time that GA could effectively suppress breast cancer growth and metastasis by inhibiting macrophage M2 polarization via activating JNK1/2 signaling. These findings indicate that GA could be served as the lead compound for the future development of anti-breast cancer drug.

Effectiveness of exercise interventions in the management of cancer-related fatigue: a systematic review of systematic reviews.

BACKGROUND: Cancer-related fatigue is a widely prevalent global public health concern with serious consequences. Increasing evidence suggests the effectiveness of exercise intervention in treating cancer-related fatigue, but there is a lack of a summary of relevant literature on the same to help reach a clear consensus. OBJECTIVE: To summarize evidence regarding the efficacy of exercise interventions to reduce cancer fatigue, as determined in systematic reviews (SRs) and/or meta-analyses (MAs). METHOD: From inception to September 2022, PubMed (1948-2022), Embase (1974-2022), Cochrane Library (1993-2022), CINAHL (1937-2022), Web of Science (1997-2022), China Knowledge Resource Integrated Database (1999-2022), Wanfang Database (1993-2022), and Chinese Biomedical Database (1994-2022) were searched for inclusion to the study. Two reviewers independently extracted the data from the included articles. AMSTAR II was to evaluate the methodological quality of the reviews. RESULTS: A total of 46 systematic reviews were assessed for data on exercise intervention in reducing cancer-related fatigue among cancer patients. In addition, some studies have reported adverse events during the exercise intervention period. The quality of the included systematic review was found to be low or critically low. CONCLUSIONS: The present systematic review of systematic reviews supports exercise intervention for reducing cancer-related fatigue. Further higher-quality studies are warranted to improve the level of evidence for exercise interventions for application in the treatment of cancer-related fatigue.

Evaluation and comparison of adaptive immunity through analyzing the diversities and clonalities of T-cell receptor repertoires in the peripheral blood.

The adaptive immune system plays an important role in defending against different kinds of diseases, including infection and cancer. There has been a longtime need for a simple method to quantitatively evaluate the potency of adaptive immunity in our bodies. The tremendously diversified T-cell receptor (TCR) repertoires are the foundation of the adaptive immune system. In this study, we analyzed the expressed TCRß repertoires in the peripheral blood of 582 healthy donors and 60 cancer patients. The TCR repertoire in each individual is different, with different usages of TCR Vß and Jß genes. Importantly, the TCR diversity and clonality change along with age and disease situation. Most elder individuals and cancer patients have elevated numbers of large TCRß clones and reduced numbers of shared common clones, and thus, they have very low TCR diversity index (D50) values. These results reveal the alteration of the expressed TCRß repertoire with aging and oncogenesis, and thus, we hypothesize that the TCR diversity and clonality in the peripheral blood might be used to evaluate and compare the adaptive immunities among different individuals in clinical practice.

Human umbilical cord-derived mesenchymal stem cells ameliorate experimental colitis by normalizing the gut microbiota.

BACKGROUND: Crohn's disease (CD) is a chronic non-specific inflammatory bowel disease. Current CD therapeutics cannot fundamentally change the natural course of CD. Therefore, it is of great significance to find new treatment strategies for CD. Preclinical and clinical studies have shown that mesenchymal stromal cells (MSCs) are a promising therapeutic approach. However, the mechanism by which MSCs alleviate CD and how MSCs affect gut microbes are still unclear and need further elucidation. METHODS: We used 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce experimental colitis in mice and analysed the microbiota in faecal samples from the control group, the TNBS group and the TNBS + MSC group with faecal 16S rDNA sequencing. Subsequent analyses of alpha and beta diversity were all performed based on the rarified data. PICRUStII analysis was performed on the 16S rRNA gene sequences to infer the gut microbiome functions. RESULTS: MSC Treatment improved TNBS-induced colitis by increasing survival rates and relieving symptoms. A distinct bacterial signature was found in the TNBS group that differed from the TNBS + MSC group and controls. MSCs prevented gut microbiota dysbiosis, including increasing α-diversity and the amount of Bacteroidetes Firmicutes and Tenericutes at the phylum level and decreasing the amount of Proteobacteria at the phylum level. MSCs alleviated the increased activities of sulphur and riboflavin metabolism. Meanwhile some metabolic pathways such as biosynthesis of amino acids lysine biosynthesis sphingolipid metabolism and secondary bile acid biosynthesis were decreased in the TNBS group compared with the control group and the TNBS + MSC group CONCLUSIONS: Overall, our findings preliminarily confirmed that colitis in mice is closely related to microbial and metabolic dysbiosis. MSC treatment could modulate the dysregulated metabolism pathways in mice with colitis, restoring the abnormal microbiota function to that of the normal control group. This study provides insight into specific intestinal microbiota and metabolism pathways linked with MSC treatment, suggesting a new approach to the treatment of CD.

A pH-sensitive supramolecular nanosystem with chlorin e6 and triptolide co-delivery for chemo-photodynamic combination therapy.

The combination of Ce6, an acknowledged photosensitizer, and TPL, a natural anticancer agent, has been demonstrated as a useful strategy to reinforce the tumor growth suppression, as well as decrease the systemic side effects compared with their monotherapy. However, in view of the optimal chemo-photodynamic combination efficiency, there is still short of the feasible nanovehicle to steadily co-deliver Ce6 and TPL, and stimuli-responsively burst release drugs in tumor site. Herein, we described the synergistic antitumor performance of a pH-sensitive supramolecular nanosystem, mediated by the host-guest complexing between ß-CD and acid pH-responsive amphiphilic co-polymer mPEG-PBAE-mPEG, showing the shell-core structural micelles with the tight ß-CD layer coating. Both Ce6 and TPL were facilely co-loaded into the spherical supramolecular NPs (TPL+Ce6/NPs) by one-step nanoprecipitation method, with an ideal particle size (156.0 nm), acid pH-responsive drug release profile, and enhanced cellular internalization capacity. In view of the combination benefit of photodynamic therapy and chemotherapy, as well as co-encapsulation in the fabricated pH-sensitive supramolecular NPs, TPL+Ce6/NPs exhibited significant efficacy to suppress cellular proliferation, boost ROS level, lower MMP, and promote cellular apoptosis in vitro. Particularly, fluorescence imaging revealed that TPL+Ce6/NPs preferentially accumulated in the tumor tissue area, with higher intensity than that of free Ce6. As expected, upon 650-nm laser irradiation, TPL+Ce6/NPs exhibited a cascade of amplified synergistic chemo-photodynamic therapeutic benefits to suppress tumor progression in both hepatoma H22 tumor-bearing mice and B16 tumor-bearing mice. More importantly, lower systemic toxicity was found in the tumor-bearing mice treated with TPL+Ce6/NPs. Overall, the designed supramolecular TPL+Ce6/NPs provided a promising alternative approach for chemo-photodynamic therapy in tumor treatment.

Analysis of the association of ANO3/MUC15, COL4A4, RRBP1, and KLK1 polymorphisms with COPD susceptibility in the Kashi population.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a complex, multifactorial, polygenic disease. The rate of occurrence of COPD in the Kashi population (Uyghur) is significantly higher than that observed nationwide. The identification of COPD-related genes in the Chinese Uyghur population could provide useful insights that could help us understand this phenomenon. Our previous whole-exome sequencing study of three Uyghur families with COPD demonstrated that 72 mutations in 55 genes might be associated with COPD; these included rs15783G > A in the anoctamin 3 (ANO3) gene/mucin 15 (MUC15) gene, rs1800517G > A in the collagen type IV alpha 4 chain (COL4A4) gene, rs11960G > A in the ribosome binding protein 1 (RRBP1) gene, and rs5516C > G in the kallikrein 1 (KLK1) gene. This case-control study aimed to further validate the association of the four mutations with COPD in the Chinese Uyghur population. METHODS: Sanger sequencing was used for the genotyping of four polymorphisms (ANO3/MUC15 rs15783, COL4A4 rs1800517, RRBP1 rs11960, and KLK1 rs5516) in 541 unrelated Uyghur COPD patients and 534 Uyghur healthy controls. We then conducted stratified analyses based on the smoking status and airflow limitation severity, to explore the correlation between selected gene polymorphisms and COPD. RESULTS: ANO3/MUC15 rs15783 and KLK1 rs5516 polymorphisms could significantly reduce COPD risk (p < 0.05), but COL4A4 rs1800517 and RRBP1 rs11960 polymorphisms were not correlated with COPD in the entire population. In a stratified analysis of smoking status, non-smokers with the ANO3/MUC15 rs15783G/G genotype (OR = 0.63, p = 0.032) or COL4A4 rs1800517 allele G (OR = 0.80, p = 0.023) had a reduced risk of COPD. Smokers with the RRBP1 rs11960A/G genotype had a lower risk of COPD (OR = 0.41, p = 0.025). The KLK1 rs5516G > C polymorphism was associated with a decreased risk of COPD (OR < 1, p < 0.05), irrespective of the smoking status of individuals. No significant association with COPD severity was observed in individuals with these four polymorphisms (p > 0.05). CONCLUSION: We identified four previously unreported mutations (ANO3/MUC15 rs15783, COL4A4 rs1800517, RRBP1 rs11960, and KLK1 rs5516) that might decrease the COPD risk in individuals with different smoking statuses in the Chinese Uyghur population. Our findings provide new light for the genetic risk factors associated with the occurrence of COPD.

[Analysis of SLC25A13 gene variants in 16 infants with intrahepatic cholestasis caused by citrin protein deficiency].

OBJECTIVE: To explore the characteristics of SLC25A13 gene variants in 16 infants with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). METHODS: The infants were subjected to high-throughput DNA sequencing for coding exons and flanking regions of the target genes. Suspected variants were verified by Sanger sequencing and bioinformatic analysis. RESULTS: Among the 16 NICCD cases, 15 were found to harbor pathogenic variants. Among these, IVS14-9A>G, c.1640G>A, c.762T>A, c.736delG, c.1098Tdel and c.851G>A were previously unreported. CONCLUSION: Six novel SLC25A13 variants were found by high-throughput sequencing, which has enriched the spectrum of SLC25A13 gene variants and provided a basis for genetic counseling and prenatal diagnosis.

SMAD3 rs36221701 T>C polymorphism impacts COPD susceptibility in the Kashi population.

Small mother against decapentaplegic (SMAD) family member 3 (SMAD3) is well correlated with the inflammatory response of chronic obstructive pulmonary disease (COPD). A previous study indicated that the single nucleotide polymorphism (SNP) rs36221701 of SMAD3 was related to the risk of inflammatory disease. Hence, given the pathogenesis of COPD is intently associated with smoking and gene polymorphism, this study aims to analyze the relationship between SMAD3 rs36221701 and COPD susceptibility, and to explore whether the interaction is related to smoking status. We studied the association between the rs36221701 and rs34307601 of SMAD3 and COPD susceptibility, a total of 541 COPD patients and 534 controls of the Uyghur population were recruited at the First People's Hospital and the village of Kashi. The interrelation of the two SNPs with the risk of COPD was determined by calculating odds ratio (OR) and 95% confidence interval (95% CI). We found a significant association between the rs36221701 and COPD risk in the non-smoking population. TC genotype showed a significant decreased association with COPD risk (OR = 0.59, 95% CI = 0.41-0.83, P < 0.05), but CC genotype can increased the COPD risk (OR > 1, P < 0.05). In addition, COPD susceptibility was not related to the genetic variations in the rs34307601 (P > 0.05). In conclusion, we confirmed that the SMAD3 rs36221701 may be associated with COPD susceptibility in the Chinese Uyghur population, especially among non-smokers. Our data provide new light for the relationship between SMAD3 gene polymorphisms and COPD susceptibility in the Chinese Uyghur population.

L2pB1 Cells Contribute to Tumor Growth Inhibition.

Natural IgM (nIgM) antibodies play critical roles in cancer immunosurveillance. However, the role of B-1 B cells, the lymphocytes that produce nIgM, remains to be elucidated. L2pB1 cells, a subpopulation of B-1 B cells, have a unique poly-self-reactive nIgM repertoire and are capable of phagocytosis, potent antigen presentation, and immunomodulation. Using an inducible knock-in and knockout mouse model, we investigated the effect of the loss of L2pB1 cells in a B16F10 melanoma model. Our results show active tumor infiltration of L2pB1 cells in wild type mice, and conversely, depletion of L2pB1 cells results in larger tumor mass and increased angiogenesis. In vitro analysis revealed that L2pB1 cells contribute to the growth inhibition of melanoma cells in both 2D cell culture and 3D tumor spheroids. Similar effects were observed in an MC38 murine colon cancer model. Moreover, our data suggest that one of the ways that L2pB1 cells can induce tumor cell death is via lipoptosis. Lastly, we tested whether L2pB1 cell-derived monoclonal nIgM antibodies can specifically recognize tumor spheroids. Nine of the 28 nIgM-secreting L2pB1 clones demonstrated specific binding to tumor spheroids but did not bind control murine embryonic fibroblasts. Our study provides evidence that L2pB1 cells contribute to cancer immunity through their unique nIgM repertoire, tumor recognition, and lipoptosis. Taken together, because of their ability to recognize common features of tumors that are independent of genetic mutations, L2pB1 cells and their nIgM could be potential candidates for cancer treatment that can overcome tumor heterogeneity-associated drug resistance.

Effects of solar radiation on photosynthetic physiology of barren stalk differentiation in maize.

Barren stalks and kernel abortion are the major obstacles that hinder maize production. After many years of inbreeding, our group produced a pair of barren stalk/non-barren stalk near-isogenic lines SN98A/SN98B. Under weak light stress, the barren stalk rate is up to 98 % in SN98A but zero in SN98B. Therefore, we consider that SN98A is a weak light-sensitive inbred line whereas SN98B is insensitive. In the present study, the near-isogenic lines SN98A/SN98B were used as test materials to conduct cytological and photosynthetic physiological analyses of the physiological mechanism associated with the differences in maize barren stalk induced by weak light stress. The results showed that weak light stress increased the accumulation of reactive oxygen species (ROS), decreased the function of chloroplasts, destroyed the normal rosette structure, inhibited photosynthetic electron transport, and enhanced lipid peroxidation. The actual photochemical quantum efficiency for PSI (Y(I)) and PSII (Y(II)), relative electron transfer rate for PSI (ETR(I)) and PSII (ETR(II)), and the P700 activities decreased significantly in the leaves of SN98A and SN98B under weak light stress, where the decreases were greater in SN98A than SN98B. After 10 days of shading treatment, the O2·- production rate, H2O2 contents, the yield of regulated energy dissipation (Y(NPQ)), the donor side restriction for PSI (Y(ND)) and the quantum efficiency of cyclic electron flow photochemistry were always higher in SN98A than SN98B, and the antioxidant enzyme activities were always lower in SN98A than those in SN98B. These results show that SN98B has a stronger ability to remove ROS at its source, and maintain the integrity of the structure and function of the photosynthetic system. This self-protection mechanism is an important physiological reason for its adaptation to weak light.

The rs74794265 SNP of the SREK1 Gene is Associated with COPD in Kashi, China.

BACKGROUND: Kashi city is situated near the Taklamakan desert and has a high incidence rate of chronic obstructive pulmonary disease (COPD). In this study, we aimed to explore the relationship between the SNP of the SREK1 gene locus rs74794265 and the susceptibility to COPD among the Uyghur population in Kashi, XinJiang, China. METHODS: A total of 541 patients with COPD and 534 control subjects were included in this study. Sanger sequencing was used to analyze the SNP of the SREK1 gene locus rs74794265 site. The distribution of genotypes in different genetic models between the case and control group were analyzed by logistic regression analysis after adjusting for age, sex, and smoking history. RESULTS: The SREK1 gene SNP locus rs74794265 included two genotypes, namely, C/C and C/T, of which C/C was the wildtype; The risk of COPD was significantly lower in patients with heterozygous C/T in rs74794265 [p=0.0236, OR=0.3677 (0.1547-0.8742)], and the allele frequency of T was also significantly lower in the patient group [p=0.0245, OR=0.3728 (0.1577-0.8811)]. The heterozygous C/T of rs74794265 among non-smoking COPD patients was significantly lower than other COPD patients [p=0.0298, OR=0.3217 (0.1156-0.8949)], and there was no significant correlation of the heterozygous C/T genotype in smokers. CONCLUSION: We found that the rs74794265 heterozygous C/T genotype significantly reduces the risk of COPD. The C/T genotype is likely a protective factor for COPD in the Kashi region. We speculate that the occurrence of COPD in this area is probably more related to desert climate condition and genetic factors than smoking status.

Cross-species higher sensitivities of FcγRIIIA/FcγRIV to afucosylated IgG for enhanced ADCC.

BACKGROUND: Expressing afucosylated human IgG1 antibodies with Chinese hamster ovary (CHO) cells deficient of α-(1,6)-fucosyltransferase (FUT8) is being more and more accepted as a routine method to enhance antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies, especially for anti-cancer regimens. However, in pre-clinical studies relying on disease models other than mice and primates, e.g., those underrepresented species for infectious diseases, it is less clear whether such afucosylated antibodies can demonstrate enhanced therapeutic index. This is because the orthologues of human FcγRIIIA or mouse FcγRIV from those species have not been well characterized. METHODS: We set up a luciferase-based ADCC assay with Jurkat reporter cells expressing FcγRIIIA/FcγRIV from human, mouse, rat, hamster, guinea pig, ferret, rabbit, cat, dog, pig and monkey, and also produced human, mouse, hamster, rabbit and pig IgG from wild type and Fut8-/- CHO cells or hybridomas. RESULTS: We confirmed that enhanced stimulation through FcγRIIIA/FcγRIV by afucosylated IgG, as compared with wild type IgG, is a cross-species phenomenon. CONCLUSIONS: Thus, efficacy and toxicology studies of the next generation afucosylated therapeutic IgG and Fc fusion proteins in these underrepresented animal models should be expected to generate translatable data for treating human diseases, leading to the expanded applications of this new class of glycoengineered biologics.

Infliximab treatment of glycogenosis Ib with Crohn's-like enterocolitis: A case report.

BACKGROUND: Glycogen storage disease type Ib (GSD-Ib) is a glycogen metabolism disorder that leads to the manifestations of inflammatory bowel disease (IBD), especially Crohn's disease (CD)-like colitis. Although biological agents are effective for treating CD, their application in the treatment of GSD-Ib with CD-like colitis has been rarely reported. CASE SUMMARY: A 13-year-old Han male was diagnosed with GSD-Ib with CD. The patient was treated with granulocyte colony-stimulating factor. When he had symptoms of CD-like colitis, he was continuously pumped with enteral nutrition and administered oral mesalazine for 2 wk; however, the symptoms did not improve significantly. Hence, infliximab (IFX) was administered. Hitherto, the patient has been followed up for 1 year, and no clinical manifestations have been observed. After 6 mo of treatment (fifth IFX treatment), the disease activity index and all inflammatory indexes decreased, and a review of the colonoscopy data showed that the ulcers appeared smooth. CONCLUSION: In this study, the patient was successfully treated with IFX. In cases of GSD-Ib, IBD should be highly considered.

Lung-resident memory B cells protect against bacterial pneumonia.

Lung-resident memory B cells (BRM cells) are elicited after influenza infections of mice, but connections to other pathogens and hosts - as well as their functional significance - have yet to be determined. We postulate that BRM cells are core components of lung immunity. To test this, we examined whether lung BRM cells are elicited by the respiratory pathogen pneumococcus, are present in humans, and are important in pneumonia defense. Lungs of mice that had recovered from pneumococcal infections did not contain organized tertiary lymphoid organs, but did have plasma cells and noncirculating memory B cells. The latter expressed distinctive surface markers (including CD69, PD-L2, CD80, and CD73) and were poised to secrete antibodies upon stimulation. Human lungs also contained B cells with a resident memory phenotype. In mice recovered from pneumococcal pneumonia, depletion of PD-L2+ B cells, including lung BRM cells, diminished bacterial clearance and the level of pneumococcus-reactive antibodies in the lung. These data define lung BRM cells as a common feature of pathogen-experienced lungs and provide direct evidence of a role for these cells in pulmonary antibacterial immunity.

Prevalence and Risk Factors of Chronic Obstructive Pulmonary Disease in Kashi Region, Northwestern China.

OBJECTIVE: To investigate the prevalence and the risk factors of COPD in the Uyghur population in the Kashi region. METHODS: From August 2018 to March 2019, we recruited participants of Uyghur ethnicity and aged ≥40 years old from the Kashi region using a combined cluster sampling and random sampling method. We collected potential risk factors using questionnaire, and conduced lung function using a portable pulmonary function instrument. RESULTS: A total of 2963 participants were included in this analysis, of whom 1268 were males and 1695 were females. There were 504 participants with COPD, generating a prevalence of 17.01%. With the increase of age, the prevalence of COPD in different genders increased significantly. The results of different regions were χ2= 627.89, p < 0.01, indicating significant differences in the prevalence in different regions. Among them, based on the existing survey data, it is speculated that Shache county has the highest crude prevalence, but the sample size needs to be further expanded. The participants with high age, smoking, lower BMI, high waist circumference, systolic blood pressure, fried cooking and barbecue share more COPD than those who partake of fruits and vegetables in this study. CONCLUSION: The prevalence of COPD among the Uyghur population in the Kashi region is higher than the national rural average. Among them, high age, smoking, low BMI, high waist circumference, high systolic blood pressure, cooking methods that may be stir-fried and deep-fried barbecue are risk factors for COPD, and vegetable and fruit intake may be a protective factor for COPD.

Electroacupuncture Attenuates Morphine Tolerance in Rats with Bone Cancer Pain by Inhibiting PI3K/Akt/JNK1/2 Signaling Pathway in the Spinal Dorsal Horn.

PURPOSE: Morphine is often used for the treatment of moderate and severe cancer pain, but long-term use can lead to morphine tolerance. Methods for effectively inhibiting morphine tolerance and the related mechanism of action are of great significance for the treatment of cancer pain. Previous studies have shown that electroacupuncture (EA) can inhibit the occurrence of morphine tolerance, but the mechanism is not yet clear. The aim of the present study was to explore the signaling pathway by which EA attenuates the development of bone cancer pain (BCP)-morphine tolerance (MT). MATERIALS AND METHODS: Changes in the paw withdrawal threshold (PWT) of rats with bone cancer pain-morphine tolerance were observed in a study of EA combined with intrathecal injection of a PI3K inhibitor (LY294002) or agonist (insulin-like growth factor-1 [IGF-1]). We also tested the protein expression of phosphorylated phosphatidylinositol 3-kinase (p-PI3K), phosphorylated protein kinase B (p-Akt), phosphorylated c-Jun NH2-terminal kinase 1/2 (p-JNK1/2), and ß-arrestin2 in the L4-6 spinal dorsal horn of rats. RESULTS: The protein expression of p-PI3K, p-Akt, p-JNK1/2, and ß-arrestin2 was upregulated in the L4-6 spinal dorsal horn of rats with bone cancer pain and bone cancer pain-morphine tolerance. EA delayed the occurrence of morphine tolerance in rats with bone cancer pain and downregulated the protein expression of p-PI3K, p-Akt, p-JNK1/2, and ß-arrestin2 in the L4-6 spinal dorsal horn of rats with bone cancer pain-morphine tolerance. Intrathecal injection of LY294002 attenuated the development of morphine tolerance and downregulated the protein expression of p-Akt, p-JNK1/2, and ß-arrestin2 in the spinal dorsal horn of rats with bone cancer pain-morphine tolerance. In addition, the inhibitory effect of EA on morphine tolerance was reversed by IGF-1. CONCLUSION: The mechanism underlying the ability of EA to attenuate morphine tolerance may be associated with inhibition of the PI3K/Akt/JNK1/2 signaling pathway.

[Clinical characteristics and gene variants of patients with infantile intrahepatic cholestasis].

OBJECTIVE: To explore the clinical characteristics and genetic findings of patients with infantile intrahepatic cholestasis. METHODS: The clinical data were collected in children who were admitted to the Department of Gastroenterology in Children's Hospital, Capital Institute of Pediatrics from June 2017 to June 2019 and were suspected of inherited metabolic diseases. Next generation sequencing based on target gene panel was used for gene analysis in these children. Sanger sequencing technology was used to verify the genes of the members in this family. RESULTS: Forty patients were enrolled. Pathogenic gene variants were identified in 13 patients (32%), including SLC25A13 gene variation in 3 patients who were diagnosed with citrin deficiency, JAG1 gene variation in 3 patients who were diagnosed with Alagille syndrome, ABCB11 gene variation in 3 patients who were diagnosed with progressive familial intrahepatic cholestasis type 2, HSD3B7 gene variation in 1 patient who was diagnosed with congenital bile acid synthesis defect type 1, AKR1D1 gene variation in 1 patient who was diagnosed with congenital bile acid synthesis defect type 1, NPC1 gene variation in 1 patient who was diagnosed with Niemann-Pick disease, and CFTR gene variation in 1 patient who was diagnosed with cystic fibrosis. CONCLUSIONS: The etiology of infantile intrahepatic cholestasis is complex. Next generation sequencing is helpful in the diagnosis of infantile intrahepatic cholestasis.

Whole-Exome Sequencing Implicates the USP34 rs777591A > G Intron Variant in Chronic Obstructive Pulmonary Disease in a Kashi Cohort.

Genetic factors are important factors in chronic obstructive pulmonary disease (COPD) onset. Plenty of risk and new causative genes for COPD have been identified in patients of the Chinese Han population. In contrast, we know considerably little concerning the genetics in the Kashi COPD population (Uyghur). This study aims at clarifying the genetic maps regarding COPD susceptibility in Kashi (China). Whole-exome sequencing (WES) was used to analyze three Uyghur families with COPD in Kashi (eight patients and one healthy control). Sanger sequencing was also used to verify the WES results in 541 unrelated Uyghur COPD patients and 534 Uyghur healthy controls. WES showed 72 single nucleotide variants (SNVs), two deletions, and small insertions (InDels), 26 copy number variants (CNVs), and 34 structural variants (SVs), including g.71230620T > A (rs12449210T > A, NC_000,016.10) in the HYDIN axonemal central pair apparatus protein (HYDIN) gene and g.61190482A > G (rs777591A > G, NC_000002.12) in the ubiquitin-specific protease 34 (USP34) gene. After Sanger sequencing, we found that rs777591"AA" under different genetic models except for the dominant model (adjusted OR = 0.8559, 95%CI 0.6568-1.115, p > .05), could significantly reduce COPD risk, but rs12449210T > A was not related to COPD. In stratified analysis of smoking status, rs777591"AA" reduced COPD risk significantly among the nonsmoker group. Protein and mRNA expression of USP34 in cigarette smoke extract-treated BEAS-2b cells increased significantly compared with those in the control group. Our findings associate the USP34 rs777591"AA" genotype as a protector factor in COPD.