The influenza A virus (IAV), renowned for its high contagiousness and potential to catalyze global pandemics, poses significant challenges due to the emergence of drug-resistant strains. Given the critical role of RNA polymerase in IAV replication, it stands out as a promising target for anti-IAV therapies. In this study, we identified a novel C-3-substituted oleanolic acid benzyl amide derivative, A5, as a potent inhibitor of the PA_C-PB1_N polymerase subunit interaction, with an IC₅₀ value of 0.96 ± 0.21 μmol/L. A5 specifically targets the highly conserved PA_C domain and demonstrates remarkable efficacy against both laboratory-adapted and clinically isolated IAV strains, including multidrug-resistant strains, with EC₅₀ values ranging from 0.60 to 1.83 μmol/L. Notably, when combined with oseltamivir, A5 exhibits synergistic effects both in vitro and in vivo. In a murine model, dose-dependent administration of A5 leads to a significant reduction in IAV titers, resulting in a high survival rate among treated mice. Additionally, A5 treatment inhibits virus-induced Toll-like receptor 4 activation, attenuates cytokine responses, and protects against IAV-induced inflammatory responses in macrophages. In summary, A5 emerges as a novel inhibitor with high efficiency and broad-spectrum anti-influenza activity.

{L-End}Objective To investigate the current status of long working hours of food-delivery workers from food-delivery platform, and analyze its impact on their health such as occupational stress, depressive symptoms, insomnia symptoms, fatigue accumulation, and life satisfaction. {L-End}Methods A total of 2 145 food-delivery workers from two food-delivery platforms in Guangzhou City were selected as the research subjects using convenience sampling method. The occupational stress, depressive symptoms, insomnia symptoms, fatigue accumulation, and life satisfaction were investigated using the Core Occupational Stress Scale, Patient Health Questionnaire-9 items, Self-sleep Management Questionnaire, Self-diagnosis Questionnaire of Fatigue Accumulation of Workers, and World Health Organization Five-item Well Being Index. {L-End}Results The median and the 25th and 75th percentiles of weekly working hours were 63 (49,77) hours. And 92.2% (1 978/2 145) of workers, who worked more than 40 hours per week, were long working hours workers. While 70.1% (1 504/2 145) workers, who worked 55 hours or more per week, were ultra-long working hours workers. The detection rate of occupational stress, depressive symptoms, insomnia symptoms, fatigue accumulation, and low life satisfaction was 30.1%, 27.5%, 34.7%, 40.8%, and 75.1%, respectively. The longer the weekly working hours of the research subjects, the higher the detection rate of occupational stress and fatigue accumulation (all P<0.01). The results of multivariate logistic regression analysis showed that ultra-long working hours (weekly working hours ≥55 hours) was the influencing factor of occupational stress and fatigue accumulation after excluding the influence of confounding factors among workers (all P<0.05). {L-End}Conclusion The food-delivery workers of food-delivery platforms generally work long hours. Ultra-long working hours is a risk factor for occupational stress and fatigue accumulation among these workers.

OBJECTIVETo compare the expressions of hypoxia-inducible factor 1 alpha(HIF-1α) and Semaphorin 4D(Sema4D) in colorectal carcinoma and normal colorectal tissues, and to investigate their correlation and clinical significance.

METHODSThe expressions of HIF-1α and Sema4D were examined in 86 cases of colorectal carcinoma and 52 normal colorectal tissues by SP immunohistochemical staining. Correlation between these two expressions and association of the expressions with clinicopathological characters and prognosis were analyzed.

RESULTSThe positive rates of HIF-1α and Sema4D protein in colorectal carcinoma tissues were significantly higher than those in normal colorectal tissues(58.1% vs. 7.7%, χ(2)=34.624, P<0.01; 60.5% vs. 11.5%, χ(2)=31.839, P<0.01). HIF-1α and Sema4D protein expressions were closely associated with colorectal carcinoma histological types(P=0.003, P=0.010), TNM staging (P=0.003, P=0.017) and lymphatic metastasis (P=0.003, P=0.020), and a significant correlation was observed between the expressions of HIF-1α and Sema4D protein (r=0.567, P<0.01). The 5-year overall survival rate was 37%. Univariate analysis showed that 5-year survival rates of patients with positive and negative HIF-1α protein expression were 24% and 56%(P=0.003), and those with positive and negative Sema4D protein expression were 23% and 59%(P=0.001). Multivariate Cox analysis showed that expression of Sema4D was an independent prognostic factor of colorectal cancer patients(P=0.026), while expression of HIF-1α was not(P=0.501).

CONCLUSIONCombined detection of HIF-1α and Sema4D has the potential to predict the development trend of colorectal carcinoma and prognosis of patients.

Antigens, CD ; metabolism ; Colorectal Neoplasms ; metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Lymphatic Metastasis ; Neoplasm Staging ; Prognosis ; Semaphorins ; metabolism ; Survival Rate

BACKGROUNDHypoxia promotes tumor angiogenesis and hypoxia-inducible factor-1 alpha (HIF-1α) plays a pivotal role in this process. Recently identified pro-angiogenic factor, semaphorin4D (Sema4D) also promotes angiogenesis and enhances invasive proliferation in some tumors. Furthermore, tumor-associated macrophages (TAMs) can increase the expression of HIF-1α and Sema4D in cancer cells and thus influence tumor growth and progression. The purpose of this study was to evaluate the effect of TAMs on the expression of Sema4D and HIF-1α and the impact of biologic behavior in colon cancer cells.

METHODSImmunohistochemistry was used to analyze HIF-1α and Sema4D expression in 86 curatively resected colon cancer samples and 52 normal colon tissues samples. The relationship between their expression and clinicopathological factors was analyzed. Furthermore, macrophage-tumor cell interactions, such as metastasis, angiogenesis, were also studied using in vitro co-culture systems. Statistical analysis was performed using SPSS 17.0 software (SPSS Inc., USA). Differences between two groups were analyzed with Student's t test.

RESULTSHIF-1α (58%) and Sema4D (60%) were expressed at a significantly higher level in tumors than in normal tissues (P < 0.01, for both). Furthermore, HIF-1α and Sema4D expression was significantly correlated with lymphatic metastasis, specific histological types and TNM stages (P < 0.05), but not with age and tumor size (P > 0.05). Sema4D expression was correlated with that of HIF-1α (r = 0.567, P < 0.01). TAMs markedly induced HIF-1α and Sema4D expression in colon cancer cells and subsequently increased their migration and invasion.

CONCLUSIONSHIF-1α and Sema4D expression are closely related to lymphatic metastasis, specific histological types and TNM stages in colon cancer. Furthermore, TAMs promote migration and invasion of colon cancer cells and endothelial tube formation, possibly through up-regulation of HIF-1α and Sema4D.

Adult ; Aged ; Antigens, CD ; genetics ; metabolism ; Cell Line, Tumor ; Colonic Neoplasms ; genetics ; metabolism ; Female ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; genetics ; metabolism ; Immunohistochemistry ; Macrophages ; immunology ; metabolism ; Male ; Middle Aged ; Neoplasm Metastasis ; genetics ; pathology ; Semaphorins ; genetics ; metabolism

Objective To compare the expressions of hypoxia-inducible factor 1 alpha (HIF-1α) and Semaphorin 4D (Sema4D) in colorectal carcinoma and normal colorectal tissues, and to investigate their correlation and clinical significance. Methods The expressions of HIF-1α and Sema4D were examined in 86 cases of colorectal carcinoma and 52 normal colorectal tissues by SP immunohistochemical staining. Correlation between these two expressions and association of the expressions with clinicopathological characters and prognosis were analyzed. Results The positive rates of HIF-1α and Sema4D protein in colorectal carcinoma tissues were significantly higher than those in normal colorectal tissues (58.1% vs. 7.7%, χ2=34.624,P<0.01; 60.5% vs. 11.5%, χ2=31.839, P<0.01). HIF-1α and Sema4D protein expressions were closely associated with colorectal carcinoma histological types (P=0.003,P=0.010), TNM staging (P=0.003,P=0.017) and lymphatic metastasis (P=0.003,P=0.020), and a significant correlation was observed between the expressions of HIF-1α and Sema4D protein (r=0.567, P<0.01). The 5-year overall survival rate was 37%. Univariate analysis showed that 5-year survival rates of patients with positive and negative HIF-1α protein expression were 24% and 56%(P=0.003), and those with positive and negative Sema4D protein expression were 23% and 59%(P=0.001). Multivariate Cox analysis showed that expression of Sema4D was an independent prognostic factor of colorectal cancer patients(P=0.026), while expression of HIF-1α was not(P=0.501). Conclusion Combined detection of HIF-1α and Sema4D has the potential to predict the development trend of colorectal carcinoma and prognosis of patients.

Objective To compare the expressions of hypoxia-inducible factor 1 alpha (HIF-1α) and Semaphorin 4D (Sema4D) in colorectal carcinoma and normal colorectal tissues, and to investigate their correlation and clinical significance. Methods The expressions of HIF-1α and Sema4D were examined in 86 cases of colorectal carcinoma and 52 normal colorectal tissues by SP immunohistochemical staining. Correlation between these two expressions and association of the expressions with clinicopathological characters and prognosis were analyzed. Results The positive rates of HIF-1α and Sema4D protein in colorectal carcinoma tissues were significantly higher than those in normal colorectal tissues (58.1% vs. 7.7%, χ2=34.624,P<0.01; 60.5% vs. 11.5%, χ2=31.839, P<0.01). HIF-1α and Sema4D protein expressions were closely associated with colorectal carcinoma histological types (P=0.003,P=0.010), TNM staging (P=0.003,P=0.017) and lymphatic metastasis (P=0.003,P=0.020), and a significant correlation was observed between the expressions of HIF-1α and Sema4D protein (r=0.567, P<0.01). The 5-year overall survival rate was 37%. Univariate analysis showed that 5-year survival rates of patients with positive and negative HIF-1α protein expression were 24% and 56%(P=0.003), and those with positive and negative Sema4D protein expression were 23% and 59%(P=0.001). Multivariate Cox analysis showed that expression of Sema4D was an independent prognostic factor of colorectal cancer patients(P=0.026), while expression of HIF-1α was not(P=0.501). Conclusion Combined detection of HIF-1α and Sema4D has the potential to predict the development trend of colorectal carcinoma and prognosis of patients.

Objective To compare the efficacy of XELOX and FOLFOX4 in the treatment of locally advanced unresectable gastric cancer. Methods The clinical data of 72 patients with gastric cancer who were admitted to the Shandong Provincial Hospital from July 2006 to October 2009 were prospectively analyzed. Of all the patients, 3 lost follow-up, and 69 patients with locally advanced unresectable gastric cancer were randomly divided into XELOX group ( n = 36 ) and FOLFOX4 group ( n = 33 ) according to the random number table.All patients received chemotherapy for six weeks. The efficacy of the two regimens were evaluated by the multidiscipline team six weeks later. The cell cycle of patients with complete or partial remission and received surgical treatment was detected by flow cytometry. All data were analyzed using the Pearson chi-square test, Levene test or t test. Results The curative rates of XELOX and FOLFOX4 were 53% (19/36) and 52% (17/33), respectively,with no significant difference between the two groups ( x2= 0. 01 , P ＞ 0. 05 ). The incidences of nausea and vomiting, phlebitis and hand-foot syndrome were 25% (9/36), 6% (2/36) and 19% (7/36) in the xELOX group, and 55% ( 18/33), 39% (13/33) and 3% (1/33) in the FOLFOX4 group, respectively, with significant difference between the two groups ( x2 = 6.31, 11.59, 4.53, P ＜ 0.05 ). Nineteen patients in the XELOX group and 17 patients in the FOLFOX4 group received surgical resection of the gastric cancer, and no complications such as anastomotic leakage and hemorrhage occurred postoperatively. In the XELOX group, the s-phase fraction (SPF),proliferation index (PI) and G2/M of the gastric cancer cells were 5.89% ± 0.79%, 9.22% ± 1.99% and 5.19% ± 1. 66% after neoadjuvant chemotherapy, which were significantly lower than 6.76% ± 1.21%, 10.44% ±2.12% and 6. 04% ± 0. 57% before neoadjuvant chemotherapy, while the ratio of gastric cancer cells in the G0/G1 phase after neoadjuvant chemotherapy was 90.39% ±4.78%, which was significantly higher than 87.54%±6.34% before neoadjuvant chemotherapy (x2 =3.61, 2.52, 2. 15, 2.91, P ＜0.05). In the FOLFOX4group, the SPF, PI and G2/M of the gastric cancer cells were 6.09% ± 0.96%, 10.65 % ± 2.47% and 4.88% ±0.87% after neoadjuvant chemotherapy, which were significantly lower than 7.15% ± 1.45%, 11.87% ± 2.33%and 5.67% ± 1.03% before neoadjuvant chemotherapy, while the ratio of gastric cancer cells in the G0/G1 phase after neoadjuvant chemotherapy was 91.45% ± 5.22%, which was significantly higher than 88.01% ± 4.23%before neoadjuvant chemotherapy ( x2 = 3.50, 2.06, 3.37, 2.94, P ＜ 0.05 ). There was a significant difference in PI between XELOX group and FOLFOX4 group after neoadjuvant chemotherapy ( x2 = 2.66, P ＜ 0.05 ).Conclusions XELOX and FOLFOX4 are safe and effective in the treatment of locally advanced unresectable gastric cancer, and they can significantly restrain the proliferation of gastric cancer cells. XELOX regimen is more effective than FOLFOX4 regimen.

Objective To investigate the role of hypoxia inducible factor-1α (HIF-1α) and von Hippel-Lindau (VHL) in murine endochondral ossification. Methods The knockout of HIF-1α or VHL gene in murine osteoblasts was accomplished by conditional knockout technique at 4th, 8th and 12th week, and the differences between wild-type group and knock-out group in endochondral ossification were detected by HE staining, micro-CT scanning, trabecular bone area measurement, calcium content measurement, tetracycline fluorescence labeling, Real-time PCR and Western blotting. Results After knockout of HIF-1α gene in osteoblasts, the expression of vascular endothelial growth factor ( VEGF) reduced, the rate of new bone formation stepped down, the content of calcium became less, and the trabecular bone volume decreased (P <0.05) . After knockout of VHL gene in osteoblasts, the expression of VEGF increased, the rate of new bone formation stepped up, the content of calcium became more, and the trabecular bone volume was promoted (P < 0.001). Conclusion During murine endochondral ossification, VHL/HIF-1α signal pathway promotes angiogenesis through the stimulation of VEGF expression, which subsequently accelerates osteogenesis.

OBJECTIVE To explore the rational application of aminoglycosides antibiotics.METHODS We randomly selected 520 patients' records of applying aminoglycosides antibiotics from Jan to Dec in 2007.Types of antibiotics,dosages,usage,ways of delivery and periods and combination of medicines were analyzed.RESULTS Out of the 520 cases,the oldest patient was 89 year and the youngest one was 7 years.The application rate of amikacin was the highest(35.6%),which was delivered mainly by iv,the combination of medicines accounted for 92.7%.CONCLUSIONS The application of aminoglycosides antibiotics in our hospital is basically rational.In some cases the improper antibiotics are used and the duration is a little longer,which should be supervised.