Bile Ducts, Intrahepatic ; Dilatation, Pathologic ; Humans ; Synchrotrons

Objective To observe the development and progression of autophagy,and investigate the effect of autophagy on recovery of neurological dysfunction in rats after cerebral ischemia-reperfusion injury.Methods Preparation of middle cerebral artery occlusion (MCAO) models was performed by Longa method.(1) Forty-two SD rats were randomly assigned to blank control 1 group (n=9) and MCAO 1 group (n=33),and the rats of the MCAO 1 group were randomly divided into 6,12,48 and 72 h subgroups (n=6) and 24 h subgroup (n=9) according to the reperfusion times;the ultrastructural changes and autophagosome formation in hippocarnpal tissues of the blank control 1 group (n=3) and 24-h-reperfusion MCAO 1 subgroup (n=3) were observed under transmission electron microscope;the expressions of microtubule associated proteins light chain-3 (LC3)-Ⅱ,LC3-Ⅰ and Beclin-1 in the hippocampal tissues of each group (n=6) were detected by Western blotting.(2) Eighteen SD rats were randomly divided into blank control 2 group,MCAO 2 group and 3-methyladenine (3-MA,autophagy inhibitor) group (60 min prior to MCAO,injection of 10 μL [600 nmoL] 3-MA dilution into the lateral ventricle by stereotactic technique,n=6);the neurological rehabilitation of rats was analyzed by modified neurological severity scale (mNSS) one,3,5 and 7 d after reperfusion;the morphological changes and number of apoptotic cells in the hippocampal tissues were observed by HE staining 7 d after reperfusion.Results (1) The formation ofautophagy in the 24-h-reperfusion MCAO 1 subgroup was clearly observed under microscope;as compared with blank control 1 group,the ratio of LC3-Ⅱ/Ⅰ (excepted for 72-h-reperfusion MCAO 1 subgroup) and Beclin-1 expression in the hippocampus of 6,12,24 and 48-h-reperfusion MCAO 1 subgroups were significantly increased (P＜0.05);as compared with those in the 24-h-reperfusion MCAO 1 subgroup,the ratio of LC3-Ⅱ/Ⅰ and Beclin-1 expression in the hippocampus of 6,12,48 and 72-h-reperfusion MCAO 1 subgroups were significantly decreased (P＜ 0.05).(2) As compared with those the MCAO 2 group,the mNSS scores of 3-MA group were significantly decreased 3,5 and 7 d after surgery (P＜0.05);HE staining indicated that the injury of neurons in the hippocampus of 3-MA group was alleviated,and the number of apoptotic cells in the 3-MA group was significantly smaller than that in the MCAO 2 group ([14.00±2.10]/field vs.[37.83± 2.64]/field,P＜0.05).Conclusion Cerebral ischemia-reperfusion injury can activate autophagy,by which it can alleviate brain damage and improve its neurological dysfunction in rats after cerebral ischemia-reperfusion injury.

Objective:To explore the change in cerebral blood flow when healthy subjects swallow hot and ice water, and to verify the sensitivity of functional near-infrared spectroscopy (fNIRS) in identifying liquid temperatures while swallowing as a basis for applying it in diagnosis and intervention.Methods:Sixteen healthy subjects swallowed hot and ice water in randomized order while the process was recorded using fNIRS. The activation at rest and when swallowing hot and ice water was compared pairwise.Results:Compared with the resting state, 19 channels were activated during the swallowing of the hot and ice water. The common activated areas were S1, M1, PMC, SMA, Wernicke′s area, the somatosensory association cortex, the visual association cortex and the frontal eye field. However, the dorsal lateral prefrontal cortex was activated only when swallowing hot water, and the subcentral area was activated only when swallowing ice water. The SMA and PMC were significantly more activated when swallowing hot water than ice water.Conclusions:Multiple brain regions are activated and participate in regulating swallowing. The PMC and SMA areas can distinguish hot water from ice water swallowing.

Objective:To seek any correlation between cortical activity and the swallowing of dysphagia patients with infratentorial stroke, and to observe any effect of three-needle acupuncture of the tongue on such activity.Methods:Thirty infratentorial stroke survivors with dysphagia were randomly divided into a tongue three-needle group and a sham acupuncture group, each of 15. Functional near-infrared spectroscopy was used to monitor changes in the concentration of oxygenated hemoglobin (ΔHbO 2) at rest, during acupuncture (or sham acupuncture), during real or sham electro-acupuncture, and at rest after the acupuncture or sham acupuncture treatment. The Modified Rankin Scale, a Penetration-Aspiration Scale (PAS), and the Functional Oral Intake Scale were employed to assess overall functional disability and the swallowing of both groups. Results:At rest the average ΔHbO 2 concentrations recorded in the left primary motor cortex, the left dorsolateral prefrontal cortex and the left premotor cortex in both groups were positively correlated with the PAS scores. During the acupuncture ΔHbO 2 concentration in the right inferior frontal gyrus and the left middle temporal gyrus increased significantly in the tongue three-needle group. It decreased significantly in the left somatosensory cortex and the left primary motor cortex. Conclusion:Three-needle acupuncture of the tongue induces changes in cortical activity in infratentorial stroke survivors with dysphagia, suggesting a potential technique for improving disordered swallowing.

Background::Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer (TNBC). One of the immunosuppressive pathways involves programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment. Prior research has shown that MYC, a master transcription amplifier highly expressed in TNBC cells, can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy. This study aims to investigate the regulatory relationship between MYC and PD-L1, and whether a cyclin-dependent kinase (CDK) inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy. Methods::Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1. The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting. A patient-derived tumor xenograft (PDTX) model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression. Cell proliferation and migration were detected by 5-ethynyl-2′-deoxyuridine (EdU) cell proliferation and cell migration assays. Tumor xenograft models were established for in vivo verification. Results::A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells (TIICs). The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients. Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein. In addition, antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1. Conclusions::The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect, which might offer new insight for enhancing immunotherapy in TNBC.

Objective:To explore the relationship between cervical microecology and cervical squamous intraepithelial lesions (SIL).Methods:All subjects were recruited from the health care center or gynecology of the Affiliated Wuxi No.2 People′s Hospital of Nanjing Medical University from March to May of 2019, including 12 subjects normal cervix with 37-47 years old, 21 low-grade squamous intraepithelial lesion (LSIL) subjects with 39-48 years old, 5 high-grade squamous intraepithelial lesion (HSIL) subjects with 38-45 years old and 3 cervical squamous cell carcinoma subjects with 42-43 years old. All subjects were required to fill in a questionnaire, and performed cervical examination. Meanwhile, the microecology of cervical secretions was analyzed by the next generation sequencing (NGS) and the NGS results were analyzed by bioinformatics. Subjects were divided into human papilloma virus (HPV)-negative groups, low-risk HPV (lrHPV), 16/18 high-risk HPV (hrHPV) and other hrHPV infection groups based on HPV test results of NGS. The Venn diagram of data, microecology diversity, the relative abundance and co-occurrence of species, and the receiver operating characteristic (ROC) curve were analyzed.Results:A total of 909 species at the species level were obtained from the cervical secretions of all the subjects, and there was overlap among the groups. There was no significant difference in total HPV infection rate, 16/18 hrHPV infection rate and other hrHPV infection rates among subjects with different cervical lesions (all of P>0.05). Grouped by HPV infection, the 16/18 hrHPV-infected and other hrHPV-infected subjects had increased cervical microecology diversity ( U=39.00 and 43.00, all of P<0.05), and the relative abundance of Lactobacillus crispatus (L.crispatus) had no differences among the groups ( H=4.37, P=0.213 6). Grouped by cervical conditions, the cervical microecology diversity of the subjects with cervical lesions increased ( H=14.60, P=0.002 2), while the L.crispatus relative abundance decreased ( H=13.98, P=0.000 8). Among all the detected species, Mycoplasma, Chlamydia and Streptococcus B had a co-occurrence, while Lactobacillus iners, Gardnerella vaginalis, Atopobium vaginae, and Prevotella bivia had a co-occurrence. As the SIL diagnostic index, the area under the ROC curve (AUC) of the relative L.crispatus relative abundance was 0.874 [95% confidence interval ( CI):0.732-0.957]. L.crispatus combined with Lactobacillus jensenii (L.jensenii) and Mycoplasma had an AUC of 0.943 [95 %CI: 0.822-0.991] in the SIL diagnosis. Conclusions:The decreased L.crispatus relative abundance and the increased cervical microecology diversity may be related to HPV infection and cervical lesions; simplified NGS data may be helpful to the SIL diagnosis.

Objective:To analyze the efficacy and safety of the biological agent infliximab (IFX) in the treatment of pediatric Crohn′s disease.Methods:A total of 86 children with Crohn′s disease who had received IFX in three hospitals (Ruijin Hospital, Ruijin Hospital North and Shanghai Children's Hospital) in Shanghai from January 2007 to December 2017 were included in this retrospective study. The efficacy of IFX was assessed by comparing clinical and laboratory data before and after IFX treatment. Student t test, Mann-Whitney U test or chi-square test were used to analyze the data of the two groups. Logistic reggression analysis were used to analyze the effects of variables such as age, clinical characteristics, disease behavior and combined medications on the efficacy and safety of IFX. Results:Among the 86 children with Crohn′s disease in the study, 50 were males and 36 females. The IFX treatment was initiated at 12.0 (7.1, 13.6) years of age, and the follow-up period was 94.1 (47.8, 185.5) weeks. Efficacy analysis showed that in the induction remission phase, the clinical response rate was 97% (79/81) and the remission rate was 74% (60/81). In the maintenance remission phase, the clinical response rate was 75% (51/68) and the remission rate was 68% (46/68). After 34 weeks of treatment with IFX, pediatric Crohn′s disease activity index (PCDAI) (5 (0, 10) vs. 36 (26, 45)), C-reactive protein (3 (1, 8) vs. 8 (3, 31) mg/L), erythrocyte sedimentation rate (10 (6, 10) vs. 35 (20, 50) mm/1 h), platelet ( (327±107)×10 9vs. (438±159) ×10 9/L), albumin ((37±6) vs. (30±6) g/L), hemoglobin ((116±16) vs. (103±18) g/L), change of body weight (-0.5±1.2 vs. -1.0±0.9), anemia (29% (20/68) vs. 75% (51/68)), and perianal disease (13/21 vs. 0) were significantly improved (all P<0.05). By the end of 34 weeks of IFX treatment, 25% (17/68) of children experienced secondary loss of response to IFX. Logistic reggression analysis showed that PCDAI>30 was positively correlated with secondary loss of response ( OR=3.823, 95% CI 1.015 -15.328, P=0.048), and combined with azathioprine was conducive to maintaining efficacy of IFX ( OR=0.440, 95% CI 0.106 -1.033, P=0.044). The IFX-related adverse events included infusion reactions in 17% (15/86) and infections in 42% (36/86) of children. Analysis showed that age<6 years was a risk factor for infusion reactions (χ 2=6.556, P=0.010), and combined use of steroids (χ 2=5.230, P=0.022) may increase the incidence of infection. Conclusions:IFX is effective in the treatment of pediatric Crohn′s disease with favorable safety. Reducing secondary loss of response to IFX is an urgent issue that need to be addressed. At the same time, it is necessary to pay close attention to the adverse events during IFX treatment.

OBJECTIVE：To rapidly evaluate the effectiveness ，safety and economics of Ginkgo biloba extract（EGb）in the treatment of Alzheimer ’s disease （AD）patients，and to provide evidence-based reference for clinical drug selection and decision. METHODS：Retrieved from PubMed ，Embase，Cochrane Library ，Web of Science ，CNKI，CBM，Wanfang database ，health technology assessment （HTA）organization websites and database during the inception to Aug. 10，2020，HTA reports ，systematic reviews/Meta-analysis，and pharmacoeconomic studies of EGb versus placebo in the treatment of AD were collected. After literature screening and data extration ，HTA checklist ，AMSTAR-2 scale and CHEERS scale were used respectively to evaluate the literature quality of the included HTA report ，systematic review/Meta-analysis and pharmacoeconomics studies. The conclusion of the included studies were summarized by using qualitative description. RESULTS ：A total of 9 literatures were included ，involving 8 systematic reviews and 1 economic studies. In terms of effectiveness ，there was no statistical significance in MMSE score of EGb group，ADAS-Cog score of 120 mg EGb group ，compared with placebo group （P＞0.05）. Dementia Quality of Life （DQoL）score of EGb group was significantly higher than that of placebo group. The scores of short cognitive aptitude tests ，neuropsychiatric inventory（NPI），NPI caregiver version score ，ADAS-Cog score of 160 mg EGb group and 240 mg EGb group were significantly lower than those of control group （P＜0.05）. ADL scores of patients were inconsistent ；ADL scores of EGb group were significantly lower than those o f placebo group （P＜0.05），or there was no significant diff erence between 2 groups（P＞0.05）； . subgroup analysis by dose showed that there was no RDY2019-39） significant difference in ADL score between 120 mg EGb group and placebo group （P＞0.05）；ADL score of 240 mg E-mail：renxiaolei83@126.com EGb group were signicantly lower than that of placebo group （P＜0.05）. Subgroup analysis of clinical global impression 010-88325751。E-mail：lyi1267@126.com change （CGIC） score showed that there was no significant difference in CGIC score between EGb group and placebo group after receiving ＜200 mg EGb and 26 weeks of treatment （P＞ 0.05）；CGIC score of EGb group was significantly higher than that of placebo group after receiving ＞200 mg EGb and 24 weeks of treatment （P＜0.05）. In terms of safety ，there was no statistical significance in the incidence of ADR or the incidence of severe ADR between EGb group and placebo group （P＞0.05）. Subgroup analysis by dose showed that the incidence of ADR in 240 mg EGb group was significantly higher than placebo group （P＜0.05）. Economically ，EGb treatment for AD is cost-effective ，which could indirectly save the nursing costs of AD patients. CONCLUSIONS ：The efficacy of EGb in the treatment of AD is uncertain ， and the safety and economy are good.