Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair.Among the elements that lead to DDP resistance,O6-methylguanine(O6-MG)-DNA-meth-yltransferase(MGMT),a DNA-repair enzyme,performs a quintessential role.In this study,we clarify the significant involvement of MGMT in conferring DDP resistance in CRC,elucidating the underlying mechanism of the regulatory actions of MGMT.A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study,and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo.Conversely,in cancer cells,MGMT overexpression abolishes their sensi-tivity to DDP treatment.Mechanistically,the interaction between MGMT and cyclin dependent kinase 1(CDK1)inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1.Meanwhile,to achieve nonhomologous end joining,MGMT interacts with XRCC6 to resist chemotherapy drugs.Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation,and several Wnt inhibitors can repress drug-resistant cells.In summary,our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.

Objective To establish an ideal modeling method for diarrhea predominant irritable bowel syndrome(IBS-D)with anxiely and depression in rats,and to provide a basis for the clinical study of IBS-D.Methods 60 rats were used in this study.(1)At first,20 rats were randomly divided into blank,3%acetic acid enema,4%acetic acid enema,and 5%acetic acid enema groups.After the modeling and observation period,the diarrhea status and the degree of colon injury caused by different modeling concentrations were observed by diarrhea related index and colon histopathology.(2)After the optimal modeling concentration was assessed,40 rats were randomly divided into control(a),acetic acid enema(b),acetic acid+binding(c),and acetic acid+binding+tail clip(d)groups and correspondingly treated for 8 days.After the treatments,the general condition,diarrhea-related index,open field test(OFT)score,and colonic histopathology of rats were evaluated.Results(1)Compared with the blank group,the fecal trait score of 4%acetic acid enema group was increased on days 1 to 3 after intervention(P＜0.001),and gradually decreased on days 4 to 7 after intervention.After 1 week,there was no significant difference between the fecal trait score and that of the blank group(P＞0.05).Body weight was lower(P＜0.01),fecal water content was higher(P＜0.001).Compared with blank group,body weight of the 5%acetic acid enema group was decreased(P＜0.001),the fecal trait score and diarrhea index were increased(P＜0.01).No significant difference was found between 3%acetic acid enema and blank groups.The pathological colon tissue showed that,compared with the blank group,the mucosal structure of the 4%acetic acid enema group was complete with a small amount of inflammatory cell infiltration,and the pathological tissue score showed no significant difference(P＞0.05),whereas the 5%acetic acid enema had a medium to large amount of inflammatory cell infiltration,and the pathological tissue score was increased(P＜0.01).(2)Compared with group a,group b had lower body weight(P＜0.001),and higher fecal trait score,fecal water content and diarrhea index(P＜0.01).Compared with a and b groups,the body weight of c and d groups was lower(P＜0.001),the fecal traits score,fecal water content,and diarrhea index were increased(P＜0.01),and the colon running time was decreased(P＜0.01).Compared with group c,Fecal water content in group D was higher(P＜0.001).In the OFT score,compared with a and b groups,the OFT distance,standing times,and upright times in c and d groups were lower(P＜0.05).Compared with c,the OFT distance,standing times,and upright times in d group were lower(P＜0.05).The pathological tissue of colon showed that the mucosal structure of the four groups was complete,and there were different degrees of inflammatory cell infiltration.The pathological tissue scores of groups c and d were higher than those of groups a and b(P＜0.05).Conclusions The 4%acetic acid concentration is appropriate for IBS-D modeling.After superposition and binding,the IBS-D diarrhea and internal hypersensitivity characteristic state can be better simulated.After superposition of a tail clip,the IBS-D model of liver stagnation and spleen deficiency can be established successfully.

Aim To explore the effects of putative receptor protein related to ATI (APJ) homodimer on the behaviors-the proliferation, migration and tube formation of human umbilical vein endothelial cells (HU-VECs). Methods HUVECs at logarithmic growth stage were randomly divided into PBS, Apelin-13 + TM1 (APJ monomer group) and Apelin-13 + PBS group (APJ homodimer group). Western blot and Matrix-Assisted Laser Desorption/Ionization Time of Fligh Mass Spectrometry (MALDI-TOF MS) were used to detect the expression of APJ and APJ homodimer in HUVECs, respectively. Real-Time Cell Analyzers (RT-CA) was used to detect the concentration of the maximum effect of Apelin-13. Cell viability was detected by CCK-8. The cell migration ability was detected by scratch test, and the number of tubes formed on matri-gel that made artificial basement membrane was counted. Results Western blot and MALDI-TOF MS showed that APJ and APJ homodimer were expressed in HUVECs. The EC50 of Apelin-13 was 2.26 x 10

OBJECTIVES: To explore the effect of acupuncture and moxibustion on intestinal flora in the rats with diarrhea-predominant irritable bowel syndrome (IBS-D) based on 16S rDNA technique. METHODS: Ten rats were randomized from 58 SPF-grade male SD rats to be the blank group. The remained 48 rats were prepared to be IBS-D models by the modified method of acetic acid enema combined with binding tail-clip stress. Forty successfully-modeled rats were randomly divided into a model group, an acupuncture group, a moxibustion group and a western medication group, with 10 rats in each one. In the acupuncture group, the needle was inserted at bilateral "Zusanli" (ST 36) and remained for 15 min in each rat. In the moxibustion group, the suspending moxibustion was delivered at bilateral "Zusanli" (ST 36) for 15 min. The rats in the western medication group were given pinaverium bromide suspension (10 mL/kg) by intragastric administration. The above interventions were performed once daily for consecutive 14 days. The body mass and the score of fecal trait were compared before and after modeling, as well as after intervention in each group. Fecal water content, diarrhea index and colon transit time (CTT) were measured after modeling and intervention in the rats of each group separately. After intervention, the colonic morphology of rats in each group was observed, and using 16S rDNA technique, the intestinal flora was detected. RESULTS: After modeling, compared with the blank group, the body mass and CTT were reduced (P<0.01); fecal trait scores, fecal water contents and diarrhea index increased (P<0.01) in the other 4 groups. After intervention, the body mass and CTT of the rats decreased (P<0.01), and fecal trait score, fecal water content and diarrhea index increased (P<0.01) in the model group compared with those in the blank group. In the acupuncture group, the moxibustion group and the western medication group, when compared with the model group, the body mass and CTT were elevated (P<0.01), while fecal trait scores, fecal water contents and diarrhea index declined (P<0.01). Compared with the western medication group, fecal water content decreased in the acupuncture group and the moxibustion group (P<0.05), while CTT increased in the acupuncture group (P<0.01), the body mass increased and fecal trait score was dropped in the moxibustion group (P<0.05). The colonic mucosa structure was clear and complete, and there was no obvious inflammatory cell infiltration in the blank group. The mild interstitial edema of intestinal mucosa was presented with the infiltration of few inflammatory cells in the model group. There was the infiltration of few inflammatory cells in the mucosa of the acupuncture group, the moxibustion group and the western medication group. Compared with the blank group, the indexes of Richness, Chao1, ACE and Shannon decreased in the model group (P<0.05). Indexes of Richness, Chao1 and ACE increased in the acupuncture group and the moxibustion group (P<0.05), and the Richness index in the western medication group increased (P<0.05) when compared with those in the model group. The relative abundance of Bacteroidetes, Proteobacteria and Prevotella increased (P<0.05), and that of Firmicutes and Muribaculaceae decreased (P<0.05) in the model group compared with those in the blank group. When compared with the model group, the relative abundance of Bacteroidetes, Proteobacteria and Prevotella was reduced (P<0.05), while that of Firmicutes and Muribaculaceae increased (P<0.05) in the acupuncture group, the moxibustion group and the western medication group; and that of Actinobacteria and Bifidobacterium increased in the acupuncture group and the moxibustion group (P<0.05). Compared with the blank group, the relative abundance of lipopolysaccharide (LPS) biosynthesis was elevated (P<0.05), and that of folate biosynthesis, lipoic acid metabolism, zeatin biosynthesis, ubiquinone and other terpenoid quinone biosynthesis decreased (P<0.05) in the model group. The relative abundance of LPS biosynthesis was dropped (P<0.05), and that of folate biosynthesis, lipoic acid metabolism, zeatin biosynthesis, ubiquinone and other terpenoid quinone biosynthesis increased (P<0.05) in the acupuncture group, the moxibustion group and the western medication group compared with those of the model group. CONCLUSIONS Either acupuncture or moxibustion can relieve the symptoms of IBS-D and protect intestinal mucosa, which may be associated with regulating the structure of intestinal flora and promoting nutrient metabolism and biosynthesis.
Rats ; Male ; Animals ; Irritable Bowel Syndrome/therapy* ; Moxibustion/methods* ; Rats, Sprague-Dawley ; Gastrointestinal Microbiome ; Lipopolysaccharides ; Thioctic Acid ; Ubiquinone ; Zeatin ; Acupuncture Therapy ; Diarrhea/therapy* ; Terpenes ; Water ; Folic Acid ; Acupuncture Points

ObjectiveTo screen the risk factors of osteoporosis in perimenopausal women， and to provide direction for timely prevention and treatment. MethodsUsing multilevel stratified random sampling method， the perimenopausal women were investigated by questionnaire survey， and the determination of bone mineral density （BMD） and the levels of several important hormones. ResultsA total of 720 valid questionnaires were received. Among 720 perimenopausal women， 173 had osteoporosis and 547 had no osteoporosis. Univariate analysis of the influencing factors of osteoporosis showed that the levels of parathyroid hormone （PTH）， Estradiol （E₂）， body mass index （BMI）， age， time of last period and age of menopause were significantly different among perimenopausal women in the prevalence of osteoporosis（χ²=4.23， 4.86， 16.06， 21.04， 10.52， 13.02； P<0.05）.Logistic regression analysis showed that the increase of PTH （OR=2.70， P<0.05）and menopause （OR=1.76， P<0.05） were the risk factors of osteoporosis . Higher BMI（OR=0.65， P<0.05）， higher personal monthly income（OR=0.72， P<0.05）， longer sunshine time（OR=0.69， P<0.05）， were the protective factors against osteoporosis. ConclusionThe increase of PTH levels and menopause are the risk factors for osteoporosis in women. Perimenopausal women should be monitored for bone mineral density and appropriate intervention. Necessary treatment measures should be taken for the patients with osteopenia and osteoporosis.

Objective: To examine the clinical effect of simple muscle packing through transnasal sphenoid approach in the treatment of intrasellar arachnoid cyst. Methods: The clinical data of 11 patients with intrasellar arachnoid cyst treated by transnasal sphenoidal approach with simple muscle packing at the Neurosurgery Department of the First Affiliated Hospital of Zhengzhou University from January 2014 to February 2020 were retrospectively analyzed. There were 5 males and 6 females, with a median age of 48 years (range: 23 to 75 years). The clinical manifestations included headache in 6 cases, dizziness in 4 cases, hypo-libido in 1 case, disturbance of consciousness in 1 case, visual impairment in 7 cases and mixed pituitary dysfunction in 5 cases. The enlargement of the sellar fossa was seen in the preoperative MRI images. The enhanced MRI images showed that the cyst wall of the intrasellar arachnoid cyst was not enhanced, and the compression and thinning of the sellar base was seen in the CT images. In 9 cases, the cyst extended suprasellar and the sellar septum was "arched". In 7 cases, the cyst compressed the optic chiasm upward. The cyst walls of all patients were incised through the nasal sphenoid approach under the endoscope, and the muscle was packed after sufficient drainage. The postoperative symptoms, pituitary endocrine function and recurrence of patients were followed up. Results: MRI images of the sellar region in all patients showed significant reduction or disappearance of cysts. Intracranial infection occurred in 1 case and electrolyte disorder in 2 cases, which were relieved after symptomatic treatment. No cerebrospinal fluid rhinorrhea occurred. Postoperative clinical symptoms were completely relieved in 6 cases and partially relieved in 5 cases. Pituitary endocrine function recovered completely in 2 cases and improved significantly in 4 cases. All patients were followed up for 10 to 40 months. One patient found to have a partial recurrence of the cyst 3 months after surgery. Because there were no new symptoms appeared, the follow-up was continued without second operation. Conclusion: Transnasal sphenoidal approach is a feasible method for the treatment of intrasellar arachnoid cyst.
Adult ; Aged ; Arachnoid Cysts/surgery* ; Endoscopy ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Muscles ; Retrospective Studies ; Sella Turcica ; Young Adult

Objective:To investigate the effects of dexmedetomidine on the myocardial electrical conduction velocity and the expression and distribution of connexin 43 (Cx43) in rats.Methods:Healthy adult Sprague-Dawley rats of both sexes, weighing 270-330 g, were used.Twelve isolated rat hearts successfully perfused in the Langendorff apparatus were divided into 2 groups ( n=6 each) using a random number table method: control group (group C) and dexmedetomidine group (group D). The hearts were perfused for 15 min with K-H solution, and then the hearts were continuously perfused for 30 min with 37 ℃ K-H solution in group C and with K-H solution containing dexmedetomidine 50 ng/ml in group D. Programmed electrical stimulation was performed after the end of perfusion, the activation latency was recorded, and the electrical conduction velocity of myocardial tissues was calculated, and then the left ventricular myocardial tissues were obtained for determination of the expression and distribution of myocardial Cx43 protein by immunohistochemistry method. Results:Compared with group C, the activation latency was significantly prolonged, the electrical conduction velocity was reduced, and the expression of Cx43 was down-regulated in group D ( P<0.05). Cx43 protein was mostly distributed in intercalated discs at both ends of cells in group C, and there was a tendency for the proteins localized at end-to-end contact sites of ventricular cardiomyocytes to localize at side-to-side contact sites, and the distribution was messy in group D. Conclusions:Dexmedetomidine causes arrhythmia probably through down-regulating the expression of Cx43 protein, changing its distribution, and reducing myocardial electrical conduction velocity in rats.

Objective To forecast the future burden and its attributable risk factors of infective endocarditis (IE). Method We analyzed the disease burden of IE and its risk factors from 1990 to 2019 using the Global Burden of Disease 2019 database and projected the disease burden from 2020 to 2030 using a Bayesian age-period-cohort model. Results By 2030, the incidence of IE will increase uncontrollably on a global scale, with developed countries having the largest number of cases and developing countries experiencing the fastest growth. The affected population will be predominantly males, but the gender gap will narrow. The elderly in high-income countries will bear the greatest burden, with a gradual shift to middle-income countries. The incidence of IE in countries with middle/high-middle social-demographic indicators (SDI) will surpass that of high SDI countries. In China, the incidence rate and the number of IE will reach 18.07 per 100,000 and 451,596 in 2030, respectively. IE-associated deaths and heart failure will continue to impose a significant burden on society, the burden on women will increase and surpass that on men, and the elderly in high-SDI countries will bear the heaviest burden. High systolic blood pressure has become the primary risk factor for IE-related death. Conclusions This study provides comprehensive analyses of the disease burden and risk factors of IE worldwide over the next decade. The IE-associated incidence will increase in the future and the death and heart failure burden will not be appropriately controlled. Gender, age, regional, and country heterogeneity should be taken seriously to facilitate in making effective strategies for lowering the IE disease burden.
Male ; Humans ; Female ; Aged ; Global Burden of Disease ; Bayes Theorem ; Global Health ; Risk Factors ; Cost of Illness ; Endocarditis ; Heart Failure

Objective:To systematically review the effect of preoperative pulmonary rehabilitation on postoperative pulmonary complications in patients with lung cancer.Methods:The randomized controlled trials of preoperative pulmonary rehabilitation for lung cancer published in the past 10 years were retrieved in China Biomedical Literature Database, China National Knowledge Infrastructure, VIP, WanFang Data, PubMed, Embase, Web of Science, Cochrane Library and Wiley Online Library. The search limit was from January 1, 2010 to January 1, 2021. The quality evaluation and data extraction of the included article were carried out, and the Meta-analysis of the outcome indicators of postoperative pulmonary complications was conducted.Results:A total of 12 articles were included. Meta-analysis showed that the incidence of postoperative pulmonary complications in the intervention group was lower than that in the control group, and the difference was statistically significant [ RR=0.42, 95% CI (0.32, 0.55) , P<0.01]. Subgroup analysis was performed according to the duration of intervention, and the results showed that when the intervention duration was one week, the difference between the intervention group and the control group was statistically significant [ RR=0.36, 95% CI (0.24, 0.55) , P<0.01], when the intervention duration was more than one week, the difference between the intervention group and the control group was statistically significant [ RR=0.48, 95% CI (0.33, 0.68) , P<0.01) ]. Subgroup analysis was conducted with different evaluation time after operation, and the results showed that when the evaluation time was one month, the difference between the intervention group and the control group was statistically significant [ RR=0.48, 95% CI (0.34, 0.68) , P<0.01], when the evaluation time was more than one month, there was no significant difference between the intervention group and the control group [ RR=0.39, 95% CI (0.08, 1.85) , P=0.24]. Except for pneumonia or pulmonary infection, atelectasis, and bronchopleural fistula, there was no significant difference in the incidence of postoperative pulmonary complications in patients with lung cancer ( P>0.05) . Conclusions:Exercise that includes breathing training for at least one week is a common intervention for preoperative pulmonary rehabilitation. Preoperative pulmonary rehabilitation is beneficial to reduce the overall and one month postoperative pulmonary complications after lung cancer surgery, but the impact on postoperative pulmonary complications evaluated for more than one month and specific complications requires further study.

Objective This study aimed to determine the association of hyperlipidemia with clinical endpoints among hospitalized patients with COVID-19, especially those with pre-existing cardiovascular diseases (CVDs) and diabetes. Methods This multicenter retrospective cohort study included all patients who were hospitalized due to COVID-19 from 21 hospitals in Hubei province, China between December 31, 2019 and April 21, 2020. Patients who were aged < 18 or ≥ 85 years old, in pregnancy, with acute lethal organ injury (e.g., acute myocardial infarction, severe acute pancreatitis, acute stroke), hypothyroidism, malignant diseases, severe malnutrition, and those with normal lipid profile under lipid-lowering medicines (e.g., statin, niacin, fenofibrate, gemfibrozil, and ezetimibe) were excluded. Propensity score matching (PSM) analysis at 1:1 ratio was performed to minimize baseline differences between patient groups of hyperlipidemia and non-hyperlipidemia. PSM analyses with the same strategies were further conducted for the parameters of hyperlipidemia in patients with increased triglyceride (TG), increased low-density lipoprotein cholesterol (LDL-C), and decreased high-density lipoprotein cholesterol (HDL-C). Mixed-effect Cox model analysis was performed to investigate the associations of the 28-days all-cause deaths of COVID-19 patients with hyperlipidemia and the abnormalities of lipid parameters. The results were verified in male, female patients, and in patients with pre-existing CVDs and type 2 diabetes. Results Of 10 945 inpatients confirmed as COVID-19, there were 9822 inpatients included in the study, comprising 3513 (35.8%) cases without hyperlipidemia and 6309 (64.2%) cases with hyperlipidemia. Based on a mixed-effect Cox model after PSM at 1:1 ratio, hyperlipidemia was not associated with increased or decreased 28-day all-cause death [adjusted hazard ratio (
Adult ; Aged ; Aged, 80 and over ; COVID-19/therapy* ; Cardiovascular Diseases/complications* ; Case-Control Studies ; Cause of Death ; China/epidemiology* ; Diabetes Mellitus, Type 2/complications* ; Female ; Hospitalization ; Humans ; Hyperlipidemias/complications* ; Male ; Middle Aged ; Propensity Score ; Proportional Hazards Models ; Retrospective Studies ; Risk Factors