Objective To design and synthesize novel Hsp90 inhibitors with dual functions of synergistically enhancing the antifungal activity of fluconazole （FLC） against drug-resistant fungi and anti-tumor activity based on the Hsp90 inhibitor Ganetespib. Methods The previous research found that Ganetespib had a good synergistic anti-resistant fungal activity with FLC, with a fractional inhibitory concentration index （FICI） of 0.023 to 0.039. In this study, structural modifications were made to Ganetespib by replacing its indole ring with a phenyl ring containing different substituents to design and synthesize a series of new compounds. The in vitro synergistic anti-resistant fungal activity against C. albicans 0304103 in combination with FLC, anti-tumor activity （against HEL, HL60 and A549 cells）, and Hsp90α inhibition activity were determined to explore their structure-activity relationship and mechanism of action. Results The chemical structures of 19 new compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. Most of the compounds exhibited strong Hsp90α inhibitory activity, good synergistic activity against drug-resistant fungi in combination with FLC and anti-tumor activity. The substitution of electron-donating groups on the benzene ring was beneficial to enhancing the synergistic activity against drug-resistant fungi in combination with FLC. Among them, compounds F3 and F5 showed excellent synergistic activity against drug-resistant fungi in combination with FLC （FICI were both 0.047） and anti-tumor activity （IC₅₀ were 0.025 to 0.15 μmol/L and 0.021 to 0.23 μmol/L respectively）, and could down-regulate the expression levels of drug resistance genes and efflux pump genes in fungi, inhibit the formation of fungal biofilms, and arrest the cell cycle of HEL cells at G0/G1 phase. Conclusion The novel Hsp90 inhibitors such as F3 and F5 could both effectively exert the dual activities of synergizing with FLC to combat drug-resistant fungi and fight against tumors, which provided a new idea for the development of new drugs with dual functions of synergizing with FLC to combat drug-resistant fungi and fight against tumors.

ObjectiveTo compare the brain imaging characteristics in patients with knee osteoarthritis (KOA) and low back pain (LBP) based on amplitude of low frequency fluctuation (ALFF) of functional magnetic resonance imaging. MethodsFrom August, 2015 to September, 2021, 16 KOA patients and 16 healthy subjects (controls 1) with similar age and gender were recruited from the communities of Fuzhou, Fujian. Other 27 patients with LBP and 32 healthy subjects (controls 2) with similar age and gender were obtained from the Openpain database. The ALFF were analyzed. KOA patients were assessed the pain with Brief Pain Inventory (BPI), and LBP patients were assessed with Visual Analogue Scale (VAS). The correlation between ALFF and pain scores was analyzed. ResultsCompared with their own controls, the ALFF decreased in the left anterior insula for both KOA and LBP patients. The ALFF decreased in the hippocampus and posterior cingulate cortex in KOA patients, while increased in LBP patients. ALFF in the left precuneus, left middle cingulate cortex and right periaqueductal gray matter decreased in KOA patients, and ALFF increased in the right precentral/postcentral gyrus. ALFF of bilateral anterior cingulate cortex, bilateral orbital anterior frontal cortex, left dorsolateral prefrontal cortex and right medial prefrontal cortex decreased in LBP patients, and ALFF increased in the right parahippocampal gyrus and right amygdala. ALFF of the left middle cingulate cortex negatively correlated with BPI score in KOA patients (r = -0.73, P = 0.003), and ALFF of the right hippocampus/amygdala positively correlated with VAS score in LBP patients (r = 0.73, P = 0.003). ConclusionThere are common and specific brain imaging features in different types of chronic pain. The alteration in the left anterior insula, hippocampus and posterior cingulate gyrus may be the common mechanism for KOA and LBP.

Objective:To analyze the association between low-frequency variants of ARID1A gene and primary liver cancer using latent category model.Methods:The low-frequency variants of ARID1A gene was combined according to different functional areas, and the combined variables were analyzed by using the latent class model to obtain the latent variables. Then the logistic regression was used to analyze the association between low-frequency variants of ARID1A gene and primary liver cancer.Results:The low-frequency variants of ARID1A gene were divided into three categories by the latent class model. The class 1 was mainly unmutated population, the proportion was 94.2% (2 454/2 603). The class 2 was mainly transcriptional regulatory domain mutation, take 4.8% (124/2 603). The class 3 was dominantly exon mutation, about 1.0% (27/2 603). Using class 1 as a reference, it was found that mutations in the transcriptional regulatory domain could reduce the risk of liver cancer ( OR=0.601, 95% CI=0.364-0.992, P=0.046). Conclusion:The latent class model can identify low-frequency variants of gene associated with liver cancer and can be extended to more genetic association studies of low-frequency variants related to complex diseases.

Objective:To analyze the association between low-frequency variants of ARID1A gene and primary liver cancer using latent category model.Methods:The low-frequency variants of ARID1A gene was combined according to different functional areas, and the combined variables were analyzed by using the latent class model to obtain the latent variables. Then the logistic regression was used to analyze the association between low-frequency variants of ARID1A gene and primary liver cancer.Results:The low-frequency variants of ARID1A gene were divided into three categories by the latent class model. The class 1 was mainly unmutated population, the proportion was 94.2% (2 454/2 603). The class 2 was mainly transcriptional regulatory domain mutation, take 4.8% (124/2 603). The class 3 was dominantly exon mutation, about 1.0% (27/2 603). Using class 1 as a reference, it was found that mutations in the transcriptional regulatory domain could reduce the risk of liver cancer ( OR=0.601, 95% CI=0.364-0.992, P=0.046). Conclusion:The latent class model can identify low-frequency variants of gene associated with liver cancer and can be extended to more genetic association studies of low-frequency variants related to complex diseases.

ObjectiveTo investigate the association of the genetic variation of the long non-coding RNA HOX transcript antisense RNA (HOATIR) and gene-environment interaction with prognosis-related clinical features of liver cancer. MethodsA total of 923 patients with primary liver cancer Shunde Hospital of Southern Medical University were admitted to a hospital from October 2010 to October 2016 were enrolled in this study. TaqMan quantitative PCR was used to detect HOTAIR rs17105613 T＞C, rs12427129 C＞T, and rs3816153 G＞T genotypes. The chi-square test was used to analyze the difference in the distribution of clinical features of liver cancer, and the logistic regression model was used to analyze the influence of the genetic variation of HOTAIR on the TNM stage of liver cancer, portal vein tumor thrombus, and age of onset. ResultsAfter the adjustment for environmental factors, rs17105613 and rs3816153 were significantly associated with TNM stage in the recessive mode (P＜005), and there was a statistically significant multiplicative interaction between rs12427129 and smoking on the age of onset of liver cancer (P=0.029), as well as an additive interaction with critical statistical significance (P=0.092). ConclusionHOTAIR rs17105613 and rs3816153 may be associated with TNM stage of liver cancer. The interaction between rs12427129 and smoking may influence the age of onset of liver cancer. Therefore, the genetic variation of HOTAIR may promote the invasion and metastasis of hepatoma cells.

Objective: To evaluate the influence of enhanced recovery after surgery (ERAS) nursing model for perioperative patients in orthopedic surgery on complications. Methods: Computer-based search of electronic databases the Cochrane Library, PubMed, Embase, Web of Science, CNKI, WF and CBM Database to search for randomized controlled trials on the application of ERAS nursing models in orthopaedic patients at domestic and foreign before March 16, 2018, data were selected and screened according to the inclusion and exclusion criteria. RevMan 5.3 was used for meta-analysis of the included studies. Results: A total of 25 RCTs were included in the study and a total of 2 412 patients were included. Meta-analysis showed that the incidence of deep venous thrombos[RR=0.38, 95%CI(0.24, 0.61), P<0.01], and incidence of pulmonary infection[RR=0.26, 95% CI (0.10, 0.67), P=0.005], incidence of urinary tract infections[RR=0.28, 95%CI(0.10,0.78), P=0.01], incidence of constipation [RR=0.30, 95% CI (0.17,0.56), P=0.0001], The incidence of bloating [RR=0.35, 95%CI(0.13, 0.95), P=0.04], they were lower in the experimental group than in routine care, they were statistically significant. Incidence of incision infection [RR=0.75, 95% CI(0.17, 3.27), P= 0.70], incidence of pressure sores [RR=0.34, 95% CI(0.09, 1.27), P=0.11], incidence of nausea and vomiting [RR=0.81, 95% CI(0.52, 1.25), P=0.34] were not statistically significant; postoperative hospital stay, hospitalization costs, and patient satisfaction were statistically significant. Conclusions Compared with routine care, the ERAS nursing model can promote the recovery of orthopedic patients during perioperative period, reduce postoperative deep venous thrombosis, constipation, pulmonary infection, urinary tract infection, postoperative hospital stay, hospitalization costs, and patient satisfaction. All have a positive impact, but more multicentre and large sample clinical trials are needed for validation.

Objective: To investigate the serum angiopoietin-Ⅱ (Ang Ⅱ) levels in acute pancreatitis (AP) patients and the relationship between AngⅡ levels and the disease severity of AP based on the new Atlanta classification criteria. Methods: Seventy-seven patients with AP who were treated in the Affiliated Baiyun Hospital of Guizhou Medical University were included in this prospective study. According to the revised Atlanta classification, the modified Mashall scoring system was used to divided patients into AP with the persistent organ failure(POF) group and without POF group, and the CECT was used to divided patients into AP with pancreatic necrosis(PN) group and without PN group. The levels of AP 72 h after admission of two groups were compared with t test, and Spearman analysis was used to analyze the correlation between common severity indicators and Ang Ⅱ. The receiver operating characteristic (ROC) was performed to analyze the area under curve(AUC), sensitivity and specificity of Ang Ⅱ in predicting POF and PN. Results: According to the modified Mashall scoring system, there were 18 patients (23.38%) in POF group and 59 patients (76.62%) in without POF group. According to CECT, 22 patients (28.57%)were in PN group and 55 patients(71.43%) in without PN group. The Ang Ⅱ of the POF and PN groups was significantly higher than those without POF and PN groups (P=0.001, 0.011) on day 1 on admission. The cut-off value was 126.44 μg/L, and the AUC, sensitivity and specificity for predicting POF were 0.739, 83.3% and 68.4%, which was significantly better than that of traditional predictive indicators, such as C-reaction protein (CRP), procalcitonin (PCT), blood urea nitrogen (BUN), bedside index for severity in AP (BISAP) score and Ranson score. When the cut-off value was 130.90 μg/L, the AUC, sensitivity and specificity for predicting PN were 0.703, 77.3% and 73.6%, respectively, which was significantly better than that of all traditional single indicator. The predicted value was less than PCT and CRP 2 or 3 day after admission. In addition, the Ang Ⅱlevel 1 day after admission was closely related to the Ranson score, BISAP score, and PCT level which was commonly used indicators of AP severity. Conclusions Under the new Atlanta classification criteria, Ang Ⅱ is superior to the traditional predictive indicators commonly used for predicting POF, and is a better single biochemical indicator for predicting PN in clinic.

Objective To design and prepare 13 ,15-cycloimides chlorin p6 (1) ,a class of chlorin related antitumor photo-sensitizers ,which contain a more stable six-membered cyclic imide comparing to the exocyclic anhydride ring of purpurin-18 (2) .Compounds (1) exhibit strong absorption at long wavelengths near λmax 700 nm to take full advantage of greater tissue penetration .Methods Pheophorbide a (3) was obtained by acid hydrolysis of chlorophyll a ,which was from crude chlorophyll extracts of Chinese traditional herb named Silkworm excrement .Purpurin-18 (2) was prepared by air oxidation and alkali open loop simultaneously on five-membered beta-keto carboxylic ester ring of pheophorbide a (3) .Finally ,the target compounds 1a~1j were synthesized via condensation of its anhydride ring with various amines including carboxyl-protected amino acids . Results Target compounds 1a~1j were successfully synthesized in yields ranged from 32 .6% to 65 .2% .Their structures were confirmed by elemental analysis ,ESI-MS and 1 H NMR spectra .Conclusion Treatment of purpurin-18 (2) with amines can produce target compounds 1a~1j .The starting raw material was inexpensive and readily available .The reaction conditions were mild and workup was convinient .

Objective To improve the synthesis process of chlorine f (1).Methods A "one-pot"method was applied to prepare Photosensitizer component (1),using pheophorbide a (3) as raw material by oxidating and cracking of the E-ring of (3) with bubbling oxygen in alcoholic solution of potassium hydroxide at 0 ℃ followed by refluxing in nitrogen atmosphere.In order to obtain the optimal synthetic procedure,the orthogonal experimental design of L9 (34 ) was adopted to investigate three different levels of four main factors i.e.ring opening reaction time,alcoholic variety,alkali concentration and refluxing reaction time.Results The target compound (1) was optimizedly synthesized through treatment of raw material (3) with bubbling oxy-gen in 25% ethanol solution of potassium hydroxide at 0℃ for 30 min,followed by refluxing in nitrogen atmosphere for 20 min in yield of 40.8%.Conclusion The procedure developed has some advantages of simple and safty operation,and high synthetic yield.

OBJECTIVETo investigate the relationship between homocysteine (Hcy), von willebrand factor (vWF), soluble intercellular adhesion molecule-1 (sICAM-1) and the risk of cardio-cerebrovascular events among Inner Mongolians.

METHODSA survey was conducted among 2 589 Inner Mongolians from May 2002 to June 2003, and they were followed up for about ten years. The 182 individuals who developed cardio-cerebrovascular events in the cohort were defined as cases and those whose age, gender and residence 1:1 matched to cases were selected from the individuals who did not developed cardio-cerebrovascular events as controls. Then, a nested case-control study was used to analyze the relationship between Hcy, vWF and sICAM-1 and risk of cardio-cerebrovascular events. Conditonallogistic regression analysis was used to calculate OR values and 95% CI.

RESULTSThe cases had a higher baseline blood pressure, higher prevalence of hypertension and family history of hypertension compared to controls (all P values < 0.05), however, there were no significantly different between TC, TG, LDL-C, HDL-C, FBG, smoking and drinking rates (all P values > 0.05). The M (P(25)-P(75)) of Hcy were 10.68 (7.84-14.98) and 10.02 (6.64-13.94) µmol/L, vWFs were 10.88 (8.14-14.58) and 10.42 (7.97-13.50) mg/L, sICAM-1 were 336.48 (260.68-409.87) and 335.12 (269.87-409.87) ng/ml. They were not significantly different between the two groups (Z values were 0.89, 0.94 and 0.29, respectively, all P values >0.05). After adjustment for the family history of hypertension, hypertension, TC, FPG, BMI, smoking and drinking rate, the conditional logistic regression showed that OR (95% CI) of risk of cardio-cerebrovascular events were 1.00 (0.52-1.93), 2.37 (1.25-4.49), and 0.81 (0.45-1.47) for the participants with increased Hcy, vWF, and sICAM-1, compared with those with normal Hcy, vWF, and sICAM-1, respectively.

CONCLUSIONIn the Inner Mongolians, increased vWF at baseline may increase the risk of cardio-cerebrovascular events, and increased Hcy and sICAM-1 were not significantly associated with the risk of cardio-cerebrovascular events.

Cardiovascular Diseases ; Case-Control Studies ; Cytokines ; Homocysteine ; Humans ; Hypertension ; Intercellular Adhesion Molecule-1 ; Logistic Models ; Prevalence ; Risk ; Risk Factors ; Stroke ; von Willebrand Factor