ObjectiveTo investigate the effect and underlying mechanism of the Wulao Qisun prescription on pathological new bone formation in ankylosing spondylitis （AS）. MethodsSynovial fibroblasts were isolated from the hip joints of AS patients and observed under a microscope to assess cell morphology. The cells were identified using immunofluorescence staining. The isolated AS fibroblasts were divided into blank group， low drug-containing serum group， medium drug-containing serum group， high drug-containing serum group， and positive drug group. After drug intervention， cell proliferation was measured using the cell counting kit-8 （CCK-8） assay to observe fibroblast growth and determine the optimal intervention time. Alkaline phosphatase （ALP） activity was measured using the alkaline phosphatase assay. Protein expression of osteocalcin （OCN）， osteopontin （OPN）， and runt-related transcription factor 2 （Runx2） was detected by Western blot. The mRNA expression levels of Wnt5a， β-catenin， and Dickkopf-1 （DKK-1） were measured by real-time quantitative polymerase chain reaction （Real-time PCR）. ResultsCompared with the blank group， each drug-containing serum group of Wulao Qisun prescription and the positive drug group inhibited the proliferation of AS fibroblasts and reduced ALP expression （P<0.01）. Compared with the blank group， the low drug-containing serum group of Wulao Qisun prescription downregulated β-catenin mRNA expression （P<0.05）. The medium and high drug-containing serum groups and the positive drug group significantly downregulated Wnt5a and β-catenin mRNA expression （P<0.05， P<0.01）， with the positive drug group showing the most pronounced effect （P<0.01）. The high drug-containing serum group and the positive drug group significantly upregulated DKK-1 mRNA expression （P<0.01）. Compared with the blank group， the low drug-containing serum group of Wulao Qisun prescription inhibited the expression of OPN and Runx2 proteins （P<0.05， P<0.01）， while the medium and high drug-containing serum groups and the positive drug group inhibited the expression of OCN， OPN， and Runx2 proteins （P<0.05， P<0.01）. ConclusionThe Wulao Qisun prescription can inhibit the proliferation and osteogenic differentiation of AS fibroblasts， thereby delaying the formation of pathological new bone in AS. The possible mechanism involves the regulation of Wnt/β-catenin-related gene expression， further inhibiting the transcription of downstream target genes.

Objective To investigate the effects of dapagliflozin on inflammatory cytokines, blood glucose control and cardiac function in elderly with preserved ejection fraction heart failure (HFpEF) combined with type 2 diabetes. Methods A total of 80 elderly HFpEF patients with type 2 diabetes mellitus were randomly divided into control group (40 cases) and study group (40 cases). The control group received hypoglycemic and anti-heart failure standard therapy, and the study group received hypoglycemic and anti-heart failure standard therapy and dapagliflozin therapy. Both groups were treated for 6 months. The levels of inflammatory factors, blood glucose control, myocardial markers, exercise endurance [6 min walking distance (6MWD)], cardiac ultrasound related indexes and adverse drug reactions were compared between the two groups. Results After 6 months of treatment, serum interleukin-6 (IL-6), hypersensitive C-reactive protein (hs-CRP) and tumor necrosis factor (TNF)-α in the study group were significantly lower than those in the control group (P<0.05); the glycated hemoglobin (HbA1c), fasting blood glucose (FPG), amino terminal B-type brain natriuretic peptide precursor (NT-proBNP) and hypersensitive troponin (hs-TNT) of the study group were significantly lower than those of the control group (P<0.05); the 6MWD and left ventricular ejection fraction (LVEF) of the study group were higher than those of the control group, and the left ventricular end-diastolic diameter (LVEDD), right atrial and right ventricular diameter, left atrial and left ventricular diameter, right ventricular wall thickness and pulmonary artery pressure of the study group were significantly lower than those of the control group (P<0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P>0.05). Conclusion The use of dapagliflozin in the treatment of elderly HFpE patients complicated with type 2diabetes can effectively control their blood sugar level, reduce inflammation, improve exercise endurance, and improve patients' heart function without increasing adverse drug reactions.

Periarticular fracture of the shoulder is a common type of fractures in the elderly. Postoperative adverse events such as internal fixation failure, humeral head ischemic necrosis and upper limb dysfunction occur frequently, which seriously endangers the exercise and health of the elderly. Compared with the fracture with normal bone mass, the osteoporotic periarticular fracture of the shoulder is complicated with slow healing and poor rehabilitation, so the clinical management becomes more difficult. At present, there is no targeted guideline or consensus for this type of fracture in China. In such context, experts from Youth Osteoporosis Group of Chinese Orthopedic Association, Orthopedic Expert Committee of Geriatrics Branch of Chinese Association of Gerontology and Geriatrics, Osteoporosis Group of Youth Committee of Chinese Association of Orthopedic Surgeons and Osteoporosis Committee of Shanghai Association of Chinese Integrative Medicine developed the Chinese expert consensus on the diagnosis and treatment of osteoporotic periarticular fracture of the shoulder in the elderly ( version 2023). Nine recommendations were put forward from the aspects of diagnosis, treatment strategies and rehabilitation of osteoporotic periarticular fracture of the shoulder, hoping to promote the standardized, systematic and personalized diagnosis and treatment concept and improve functional outcomes and quality of life in elderly patients with osteoporotic periarticular fracture of the shoulder.

Objective:To explore the clinical value of adjuvant therapy in patients with T3 gallbladder cancer (GBC) who have undergone R0 resection.Methods:Clinical and pathological data from 415 patients with T3 GBC who underwent surgical treatment in 7 tertiary centers in China from January 2013 to December 2018 were collected,including 251 males and 164 females,aged (61±11)years (range: 26 to 88 years). Depending on whether to receive adjuvant therapy after radical resection,the patients were divided into the radical resection group alone (group A, n=358) and the radical resection combined with the postoperative adjuvant therapy group (group B, n=57). The general data of the two groups were matched 1∶1 by propensity score matching method,and the caliper value was 0.02.Clinicopathological characteristics,overall survival and disease-free survival of the two groups were compared.The Cox regression model was used for multivariate analysis,and patients with at least one or more independent risk factors were classified as high-risk clinicopathological subtypes. Subgroup analysis was performed to assess the clinical value of adjuvant therapy after radical resection in patients with high-risk clinicopathological subtypes. Results:After the matching,there were 42 patients in each of the two groups. The incidence of gallbladder cancer and the number of dissected lymph nodes in group B after cholecystectomy were higher than those in group A ( χ 2=9.224,2.570,both P<0.05). There were no significant differences in overall survival rate and disease-free survival rate between the two groups before and after matching (all P>0.05). The results of the univariate and multivariate analysis showed that CA19-9>39 U/ml,nerve invasion,tumor location (liver side or bilateral),TNM stage ⅢB to ⅣB ,poorly differentiated tumor were independent prognostic factors of overall survival and disease-free survival of patients with T3 stage gallbladder cancer (all P<0.05).Three hundred and twenty-nine patients(79.3%) had high-risk clinicopathological subtypes,and the median survival time after curative resection with and without adjuvant therapy was 17 months and 34 months respectively,and the 3-year and 5-year overall survival rates were respectively 40.0%,21.3% and 46.0%,46.0% ( χ 2=4.042, P=0.044);the median disease-free survival time was 9 months and 13 months,and the 3-year and 5-year disease-free survival rates were 23.4%,13.6% and 30.2%,18.2% ( χ 2=0.992, P=0.319). Conclusions:Postoperative adjuvant therapy following radical surgery did not yield significant improvements in the overall survival and disease-free survival rates of patients diagnosed with T3 gallbladder cancer. However, it demonstrated a significant extension in the overall survival rate for patients presenting high-risk clinicopathological subtypes.

Objective:To explore the clinical value of adjuvant therapy in patients with T3 gallbladder cancer (GBC) who have undergone R0 resection.Methods:Clinical and pathological data from 415 patients with T3 GBC who underwent surgical treatment in 7 tertiary centers in China from January 2013 to December 2018 were collected,including 251 males and 164 females,aged (61±11)years (range: 26 to 88 years). Depending on whether to receive adjuvant therapy after radical resection,the patients were divided into the radical resection group alone (group A, n=358) and the radical resection combined with the postoperative adjuvant therapy group (group B, n=57). The general data of the two groups were matched 1∶1 by propensity score matching method,and the caliper value was 0.02.Clinicopathological characteristics,overall survival and disease-free survival of the two groups were compared.The Cox regression model was used for multivariate analysis,and patients with at least one or more independent risk factors were classified as high-risk clinicopathological subtypes. Subgroup analysis was performed to assess the clinical value of adjuvant therapy after radical resection in patients with high-risk clinicopathological subtypes. Results:After the matching,there were 42 patients in each of the two groups. The incidence of gallbladder cancer and the number of dissected lymph nodes in group B after cholecystectomy were higher than those in group A ( χ 2=9.224,2.570,both P<0.05). There were no significant differences in overall survival rate and disease-free survival rate between the two groups before and after matching (all P>0.05). The results of the univariate and multivariate analysis showed that CA19-9>39 U/ml,nerve invasion,tumor location (liver side or bilateral),TNM stage ⅢB to ⅣB ,poorly differentiated tumor were independent prognostic factors of overall survival and disease-free survival of patients with T3 stage gallbladder cancer (all P<0.05).Three hundred and twenty-nine patients(79.3%) had high-risk clinicopathological subtypes,and the median survival time after curative resection with and without adjuvant therapy was 17 months and 34 months respectively,and the 3-year and 5-year overall survival rates were respectively 40.0%,21.3% and 46.0%,46.0% ( χ 2=4.042, P=0.044);the median disease-free survival time was 9 months and 13 months,and the 3-year and 5-year disease-free survival rates were 23.4%,13.6% and 30.2%,18.2% ( χ 2=0.992, P=0.319). Conclusions:Postoperative adjuvant therapy following radical surgery did not yield significant improvements in the overall survival and disease-free survival rates of patients diagnosed with T3 gallbladder cancer. However, it demonstrated a significant extension in the overall survival rate for patients presenting high-risk clinicopathological subtypes.

SIRT6 belongs to the conserved NAD⁺-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD⁺. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC₅₀ of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

Objective:To study the impact of number and location of metastatic lymph nodes on prognosis of patients after radical resection for intrahepatic cholangiocarcinoma (ICC).Methods:A retrospective study was conducted on 105 patients who underwent radical resection and lymphadenectomy for ICC at the First Affiliated Hospital of Xi’an Jiaotong University from January 2010 to December 2020. There were 49 males and 56 females, with age of (58±10) years old. These patients were divided into 2 groups using the TNM staging (8th edition) into the N0 stage group ( n=62) and N1 stage group ( n=43). Using the NMLN staging, those with 0, 1-2, and >3 number of metastatic lymph nodes (NMLN) were divided into 3 groups: the stage 0 group ( n=62), stage 1 group ( n=24), and stage 2 group ( n=19). Of the 43 patients with lymph node metastasis, they were divided into 2 groups according to whether the lymph node metastasis was limited to the first lymph node station: the first station metastasis group ( n=11) and the non-first station metastasis group ( n=32). The general data, extent of lymph node dissection, pathological examinations, and postoperative survival outcomes of these patients were collected. Determination of risk factors for prognosis of ICC after radical resection was carried out. Results:The median number of lymph node harvested, or the detection of N0 and N1 staging were 6 (3, 8) and 6 (3, 10), respectively. There were no significant differences between the two groups ( Z=-1.10, P>0.05). Overall survival of patients in the N0 stage group was better than the N1 stage group (32.0 vs. 9.0 months, χ 2=23.99, P<0.001). The median survival times of patients in the stage 0, stage 1 and stage 2 groups were 32.0, 14.0 and 6.0 months, respectively. There was a significant difference in overall survival among the 3 groups (χ 2=32.18, P<0.001). The time-dependent receiver operating characteristic curves showed that NMLN staging had better prognostic predictive ability than the N staging. The median survival times of the first station metastasis group and the non-first station metastasis group were 18.0 and 7.0 months, respectively. There was no significant difference between the two groups (χ 2=2.21, P>0.05). Multivariate analysis showed that tumor carbohydrate antigen 125>35.0 U/ml ( HR=4.297, 95% CI:2.418-7.634), hepatolithiasis ( HR=2.713, 95% CI:1.499-4.911), T4 staging ( HR=2.934, 95% CI:1.478-5.825), NMLN stage 1 ( HR=2.759, 95% CI:1.500-5.077) and NMLN stage 2 ( HR=7.376, 95% CI:3.553-15.312) were independent risk factors affecting prognosis of ICC after radical resection ( P<0.05). Conclusion:Lymph node metastasis was an important poor prognostic risk factor after radical resection of intrahepatic cholangiocarcinoma. The prognosis of ICC patients was related to the NMLN, but it was not related to the location of metastatic lymph nodes.

Post-stroke cognitive impairment （PSCI） refers to a series of syndromes from mild cognitive impairment to dementia caused by stroke. The mitogen-activated protein kinases （MAPK）signaling pathway is a key pathway for transmitting cellular signals in mammals ，and p 38 is a classic branch of it. p 38 MAPK signaling pathway is involved in various pathophysiological processes such as cell growth ，differentiation，apoptosis and inflammatory response in central nervous system diseases. At present ，great progress has been made in clinical and basic experimental studies on prevention and treatment of PSCI by traditional Chinese medicine （TCM），but there is a lack of relevant systematic summary. Therefore ，this article summarizes the role of p 38 MAPK signaling pathway in PSCI and the pharmacological research progress of TCM in prevention and treatment of PSCI through p 38 MAPK signaling pathway.

Objective:To examine the correlation between perineural invasion and clinicopathological factors and the role of perineural invasion on the prognosis of patients with curatively resected gallbladder carcinoma.Methods:The clinicopathological and follow-up data of 548 patients with gallbladder carcinoma who underwent radical surgery from the First Affiliated Hospital of Xi′an Jiaotong University from January 2013 to December 2020 were analyzed retrospectively. There were 173 males and 375 females,with age( M(IQR)) of 62(14)years(range:30 to 88 years). The correlations between perineural invasion and the clinicopathological features were analyzed. The relationship between prognosis and clinicopathological factors were further analyzed. The survival curve was drawn using the Kaplan-Meier method. The univariate analysis and multivariate analysis were done using the Log-rank test and Cox proportional hazard model respectively. Results:Radical resection was performed in 548 cases,including 59 cases(10.8%) with perineural invasion. The results of univariate analysis showed that perineural invasion was related to serum bilirubin level,serum carcinoembryonic antigen(CEA) level,CA19-9 level,T stage,lymph node metastasis,liver invasion,vessel invasion and tumor location(all P<0.05).The results of multivariate analysis showed that jaundice,high-level serum CA19-9,high-level serum CEA,T4 stage,vessel invasion and tumor located in the neck or cystic duct of the gallbladder were independent risk factors of perineural invasion in gallbladder carcinoma. Survival of 367 patients in T3-T4 stages were analyzed. The prognosis of gallbladder carcinoma patients with perineural invasion was significantly worse than that of patients without perineural invasion(median survival time:12.0 months vs. 34.7 months, P<0.01). Univariate analysis showed that perineural invasion,gallbladder stones,gallbladder polyps,CA125,CEA,CA19-9,serum bilirubin level,tumor location,N stage,liver invasion and pathological differentiation were independent risk factors affecting prognosis of patients with gallbladder carcinoma(all P<0.05). The results of Cox proportional hazard model showed that perineural invasion,N stage,liver invasion,gallbladder stones,pathological differentiation were independent risk factors affecting prognosis of patients with gallbladder carcinoma(all P<0.05). Conclusions:Jaundice,high-level serum CA19-9,high-level serum CEA,T4 stage,vessel invasion and tumor located in the neck or cystic duct of the gallbladder are independent risk factors for perineural invasion of gallbladder carcinoma. Perineural invasion is one of the independent risk factors affecting the prognosis of T3-T4 stage gallbladder carcinoma.

Objective:To examine the correlation between perineural invasion and clinicopathological factors and the role of perineural invasion on the prognosis of patients with curatively resected gallbladder carcinoma.Methods:The clinicopathological and follow-up data of 548 patients with gallbladder carcinoma who underwent radical surgery from the First Affiliated Hospital of Xi′an Jiaotong University from January 2013 to December 2020 were analyzed retrospectively. There were 173 males and 375 females,with age( M(IQR)) of 62(14)years(range:30 to 88 years). The correlations between perineural invasion and the clinicopathological features were analyzed. The relationship between prognosis and clinicopathological factors were further analyzed. The survival curve was drawn using the Kaplan-Meier method. The univariate analysis and multivariate analysis were done using the Log-rank test and Cox proportional hazard model respectively. Results:Radical resection was performed in 548 cases,including 59 cases(10.8%) with perineural invasion. The results of univariate analysis showed that perineural invasion was related to serum bilirubin level,serum carcinoembryonic antigen(CEA) level,CA19-9 level,T stage,lymph node metastasis,liver invasion,vessel invasion and tumor location(all P<0.05).The results of multivariate analysis showed that jaundice,high-level serum CA19-9,high-level serum CEA,T4 stage,vessel invasion and tumor located in the neck or cystic duct of the gallbladder were independent risk factors of perineural invasion in gallbladder carcinoma. Survival of 367 patients in T3-T4 stages were analyzed. The prognosis of gallbladder carcinoma patients with perineural invasion was significantly worse than that of patients without perineural invasion(median survival time:12.0 months vs. 34.7 months, P<0.01). Univariate analysis showed that perineural invasion,gallbladder stones,gallbladder polyps,CA125,CEA,CA19-9,serum bilirubin level,tumor location,N stage,liver invasion and pathological differentiation were independent risk factors affecting prognosis of patients with gallbladder carcinoma(all P<0.05). The results of Cox proportional hazard model showed that perineural invasion,N stage,liver invasion,gallbladder stones,pathological differentiation were independent risk factors affecting prognosis of patients with gallbladder carcinoma(all P<0.05). Conclusions:Jaundice,high-level serum CA19-9,high-level serum CEA,T4 stage,vessel invasion and tumor located in the neck or cystic duct of the gallbladder are independent risk factors for perineural invasion of gallbladder carcinoma. Perineural invasion is one of the independent risk factors affecting the prognosis of T3-T4 stage gallbladder carcinoma.