[Epidemiological characteristics of human respiratory syncytial virus (HRSV) among acute respiratory infection (ARI) cases in 16 provinces of China from 2009 to 2023].

Objective: To understand the epidemiological characteristics of human respiratory syncytial virus (HRSV) among acute respiratory infection (ARI) cases in 16 provinces of China from 2009 to 2023. Methods: The data of this study were collected from the ARI surveillance data from 16 provinces in China from 2009 to 2023, with a total of 28 278 ARI cases included in the study. The clinical specimens from ARI cases were screened for HRSV nucleic acid from 2009 to 2023, and differences in virus detection rates among cases of different age groups, regions, and months were analyzed. Results: A total of 28 278 ARI cases were enrolled from January 2009 to September 2023. The age of the cases ranged from<1 month to 112 years, and the age M (Q1, Q3) was 3 years (1 year, 9 years). Among them, 3 062 cases were positive for HRSV nucleic acid, with a total detection rate of 10.83%. From 2009 to 2019, the detection rate of HRSV was 9.33%, and the virus was mainly prevalent in winter and spring. During the Corona Virus Disease 2019 (COVID-19) pandemic, the detection rate of HRSV fluctuated between 6.32% and 18.67%. There was no traditional winter epidemic peak of HRSV from the end of 2022 to the beginning of 2023, and an anti-seasonal epidemic of HRSV occurred from April to May 2023. About 87.95% (2 693/3 062) of positive cases were children under 5 years old, and the difference in the detection rate of HRSV among different age groups was statistically significant (P<0.001), showing a decreasing trend of HRSV detection rate with the increase of age (P<0.001). Among them, the HRSV detection rate (25.69%) was highest in children under 6 months. Compared with 2009-2019, the ranking of HRSV detection rates in different age groups changed from high to low between 2020 and 2023, with the age M (Q1, Q3) of HRSV positive cases increasing from 1 year (6 months, 3 years) to 2 years (11 months, 3 years). Conclusion: Through 15 years of continuous HRSV surveillance analysis, children under 5 years old, especially infants under 6 months old, are the main high-risk population for HRSV infection. During the COVID-19 pandemic, the prevalence and patterns of HRSV in China have changed.

[Distribution of mosquito species and associated viruses in Hami City of Xinjiang Uygur Autonomous Region from 2019 to 2020].

OBJECTIVE: To investigate the distribution of mosquito species and their associated viruses, and identify Culex pipiens subspecies in Hami City, Xinjiang Uygur Autonomous Region. METHODS: Mosquitoes were captured using mosquito trapping lamps method in Yizhou District, Yiwu County, and Balikun County of Hami City in mi-July, 2019 and 2020. The species and subspecies of all captured mosquitoes were characterized. In addition, the flavivirus, alphavirus, bunyavirus, Japanese encephalitis virus, Liaoning virus, Tahyna virus, tick-borne encephalitis virus and West Nile virus were detected using reverse-transcription PCR assay in captured mosquitoes. RESULTS: A total of 1 496 mosquitoes were captured from Yizhou District, Yiwu County, and Balikun County of Hami City, belonging to 3 genus and 3 species. Cx. pipiens was the dominant mosquito species (986 mosquitoes, 65.91%), followed by Aedes caspius (457 mosquitoes, 30.55%), while Culiseta alaskaensis had the lowest number (53 mosquitoes, 3.54%). All captured Cx. pipiens mosquitoes were identified as Cx. pipiens pipiens based on the terminalia of male mosquitoes. RT-PCR assay tested negative for flavivirus, alphavirus, bunyavirus, Japanese encephalitis virus, Liaoning virus, Tahyna virus, tick-borne encephalitis or West Nile virus in captured Cx. pipiens mosquitoes. CONCLUSIONS: There were 3 species of mosquitoes in Hami City from 2019 to 2020, including Cx. pipiens, Ae. Caspius and C. alaskaensis, with Cx. pipiens as the dominant mosquito species, and all captured Cx. pipiens mosquitoes were Cx. pipiens pipiens; however, no arboviruses were detected.

[Analysis of common viral infection in surveillance cases of febrile respiratory syndrome in 9 provinces of China from 2009 to 2021].

Objective: To understand the common viral infection among the surveillance cases of fever respiratory syndrome (FRS) in nine provinces in China. Methods: The research data were obtained from nine provinces (Anhui, Beijing, Guangdong, Hebei, Hunan, Jilin, Shandong, Shaanxi and Xinjiang) in the "Infectious Disease Surveillance Technology Platform Information Management System" of the Chinese Center for Disease Control and Prevention from January 2009 to June 2021. Finally, 8 243 FRS cases with nucleic acid detection results of eight viruses [human influenza virus (HIFV), human respiratory syncytial virus (HRSV), human adenovirus (HAdV), human parainfluenza virus (HPIV), human rhinovirus (HRV), human metapneumovirus (HMPV), human coronavirus (HCoV) and human Boca virus (HBoV)] were included in the study. The χ2 test/Fisher exact probability method was used to analyze the difference of virus detection rate in different age groups, regions and seasons. Results The M (Q1, Q3) age of 8 243 FRS cases was 4 (1, 18) years old, and 56.56% (4 662 cases) were children under 5 years old. Males accounted for 58.1% (4 792 cases) of all cases. All cases were from outpatient/emergency department (2 043 cases) and inpatient department (6 200 cases). The virus detection rates of FRS cases from high to low were HRSV, HIFV, HPIV, HRV, HAdV, HMPV, HCoV and HBoV. Two or more viruses were detected simultaneously in 524 cases, accounting for 15.66% of virus-positive cases. The difference of the virus detection rate in different age groups was statistically significant (all P values<0.05), and the virus detection rate in children<5 years old was higher (49.96%). The positive rate of any virus in south China was higher than that in north China (P<0.001). The virus-positive FRS cases were detected throughout the year. The detection rate of HRSV was higher in autumn and winter. The detection rate of HIFV was higher in winter. The detection rate of HMPV was higher in winter and spring. The detection rates of HPIV, HRV, HCoV and HBoV were higher in summer and autumn, while there was no significant difference in the detection rate of HAdV in different seasons. Compared with 2009-2019, the detection rate of any virus in 2020-2021 decreased from 41.37% to 37.86%. The detection rate of HIFV decreased sharply from 10.62% to 1.37%. The detection rate of HPIV decreased from 8.24% to 5.88%. The detection rate of HRV and HBoV increased from 5.43% and 1.79% to 9.67% and 3.19%, respectively. Conclusion: HRSV and HIFV infections are more common among FRS cases in nine provinces in China from 2009 to 2021, and the epidemiological characteristics of eight common respiratory viruses vary in different age groups, regions and seasons.

[Contribution of measles virus IgG antibody avidity assay to the identification of measles cases].

Objective: To evaluate the value of measles IgG antibody avidity assay in identifying the measles cases. Methods: Data from the Measles Surveillance Information System was used to collect laboratory confirmed or discarded cases in 2013-2015, and then tracing back the blood specimens from all measles network laboratories in Tianjin. Measles antibody avidity assay was used to detect and to redefine cases from the discarded ones. Results: A total of 326 measles cases including 267 laboratory-confirmed and 59 discarded cases were enrolled into this study, with 92.33% (301/326) of them aged ≥20 years. Result from the measles IgG antibody avidity assay showed that the ratio of high-avidity was 91.23%(52/57) of the discarded cases, which was significantly higher than 66.95% (158/236) of the laboratory confirmed cases (χ2=13.33, P<0.001). According to the case criterion, 15.25% (9/59) of the discarded cases were redefined as measles cases. Eight out of the nine cases were high-avidity with measles containing vaccine (MCV) vaccination history that named as SVF cases. One in nine cases with low-avidity was with typical clinical symptomatic measles but with no vaccination history of MCV. Conclusion: Measles IgG antibody avidity assay could provide reference serological evidence to reduce the error from those discarded cases caused by false negative results on IgM antibody, when diagnosing the measles cases.

[Clinical value of intact parathyroid hormone levels on the first day after total thyroidectomy on prediction for permanent hypoparathyroidism].

Objective: To examine the value serum calcium and intact parathyroid hormone (iPTH) levels measured on the first day after total thyroidectomy on prediction for permanent hypoparathyroidism. Methods: Totally 546 patients with thyroid cancer and benign thyroid lesions who underwent total thyroidectomy at Department of General Surgery, Beijing Chaoyang Hospital, Capital Medical University from February 2008 to December 2018 were analyzed retrospectively. There were 158 males and 388 females aging (50.9±13.2) years (range: 19.0 to 79.2 years). Serum calcium and iPTH levels were collected before surgery, on the first day and 6 months after surgery. Logistic regression was used to analyze the correlation between each data and the occurrence of permanent hypoparathyroidism after surgery.The area under the receiver operating characteristic curve was used to evaluate the predictive power of iPTH for postoperative occurrence of permanent hypoparathyroidism. Results: Among the 546 cases of total thyroidectomy, 22 cases of permanent hypoparathyroidism occurred, with an incidence of 4.0% (22/546). Multivariate analysis showed that iPTH levels on the first day after total thyroidectomy (OR=2.932, 95%CI: 1.129 to 7.616, P=0.027) and serum calcium levels (OR=2.584, 95%CI: 1.017 to 6.567, P=0.046) were independent prognosis factors for postoperative permanent hypoparathyroidism. When the threshold value of iPTH at 24 hours after total thyroidectomy was 5.51 ng/L, the AUC was 0.956 (95%CI: 0.936 to 0.972, P=0.000), sensitivity was 100%, specificity was 85.1%, positive predictive value was 22%, negative predictive value was 100%. When the threshold value of serum calcium at 24 hours after total thyroidectomy was 1.93 mmol/L, the AUC was 0.733 (95%CI: 0.694 to 0.770, P=0.000), sensitivity was 63.6%, specificity was 78.1%, positive predictive value of 10.8% and negative predictive value of 98.1%. Conclusions: Serum iPTH and calcium levels on the first day after total thyroidectomy were related to the occurrence of permanent hypoparathyroidism postoperatively. The predictive value of iPTH level is higher than that of serum calcium level.

[Application of KeyPort access to transanal endoscopic mircrosurgery].

Objective: To explore the effectiveness of KeyPort access in transanal endoscopic mircrosurgery (TEM). Methods: A descriptive case series study was performed. Clinicopathological data of 20 patients undergoing KeyPort access TEM in Beijing Chaoyang Hospital of Capital Medical University from December 2016 to April 2018 were collected and analyzed retrospectively. Procedure of KeyPort access TEM: general anesthesia or combined spinal epidural anesthesia (CSEA); lithotomy or prone jack-knife position; anal dilation; placement of the KeyPortaccess; connection of TEM pneumoperitoneum device, light source and imaging equipment; placement of 5 mm dedicated endoscope; insufflation of CO2 with pressure of 1.6-2.0 kPa (12-15 mmHg); after rinsing the intestinal lumen, circular resection marginlabeled by the needle-shaped electrocautery;electric coagulation or ultrasonic knife used to perform a full-thickness resection with a 0.5 cm-1 cm margin along the marking line. Indications of KeyPort access TEM: (1) benign large sessile polyps which were difficult to resect under colonoscopy; (2) submucosal lesions with diameter <2 cm; (3) Tis and T1 stage rectal carcinoma without lymph node metastasis; (4) palliative resection of T2 stage rectal carcinoma without lymph node metastasis. Contraindications: (1) accompanying serious diseases without the tolerance of anesthesia and operation; (2) distance from lesion to anal verge >20 cm. Results: There were 10 males and 10 females with age of (63±15) years old and BMI of (24.5±3.3) kg/m(2). The diameter of the lesions was (2.0±1.3) cm, and the distance from lesion to anal verge was (6.2±2.2) cm. One patient had 3 lesions at different positions in rectum with diameters of 0.5 cm, 0.5 cm, and 1 cm, respectively. All operations were accomplished through the KeyPort access TEM and no case was transferred to other methods. The duration of surgery was 75 (30-220) minutes; intraoperative blood loss was 10 (0-30) ml. Two patients with rectal anterior wall lesions underwent full-thickness resection of the intestine wall reaching the peritoneal reflex with penetration into the peritonealcavity, and received suture closure immediately. For the patient with 3 rectal lesions, the 1.0 cm lesion received a full-thickness resection and the other 2 lesions received submucosal resection. No postoperative complication occurred. Postoperative pathology showed that there were 1 case of chronic inflammatory lesion, 4 cases of benign tumor, 3 cases of carcinoma in situ, 4 cases of neuroendocrine tumor, 6 cases of pT1 rectal cancer, 2 cases of pT2 rectal cancer (both invading the superficial muscle layer). The median hospital stay was 6 (3-7) days. The postoperative follow-up was (7.2±3.8) months. No postoperative complication or recurrence was observed. Conclusion: TEM with KeyPort access is safe, rapid and effective in the treatment of rectal tumors.

[Expression discordances and clinical values of ER, PR, HER-2 and Ki-67 in primary and metastatic breast cancer].

Objective: To investigate the expression discordances of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor2 (HER-2) and Ki-67 in primary and metastatic breast cancer specimens and explore the clinical significances. Methods: Biopsies of metastatic lesions were performed in 203 patients with breast cancer recurrence and metastasis indicated by physical examination and/or imaging examination. We confirmed pathological properties and assessed the expressions of ER, PR, HER-2 and Ki-67 in primary and metastatic lesions, their relationships with prognosis were also analyzed. Results: Biopsy failed in 3 patients, the pathology and immunohistochemitry results of metastatic lesions were not obtained. One person was diagnosed as tuberculosis and another was primary lung cancer. Among the 198 cases of primary and metastatic lesions, the discordance rates of ER, PR, HER-2 and Ki-67 were 27.3%, 34.3%, 11.8% and 15.1%, respectively.The expressions of ER, HER-2 and Ki-67 were not significantly different between the primary and metastatic lesions, however, the expressions of PR were more likely to turn negative in the metastases (P<0.001). The disease-free survival (DFS) of patients with ER, PR positive, HER-2 negative and low expression of Ki-67 in metastatic lesion was much longer (P<0.05). Conclusions: The expressions of ER, PR, HER-2 and Ki-67 in metastatic lesions are associated with the prognosis of breast cancer patients.Their expression discordances between primary and metastatic lesions can guide the treatment and evaluate the risks of recurrence and prognosis.

[The application of measles specific IgM and IgG antibody detection in classification measles vaccine failure, Tianjin].

Objective: To study the application of measles specific IgM and IgG antibody detection in classification of primary vaccination failure (PVF) and secondary vaccination failure (SVF). Methods: Measles surveillance information system was used to collect measles confirmed cases in Tianjin, 2013-2015, and their blood specimens were collected, totally 284 cases were enrolled. Measles IgM and IgG were detected with enzyme-linked immunosorbent assay (ELISA), and the relative avidity index (RAI) was used to express the result of measles avidity. Measles IgM, IgG and IgM/IgG was analyzed with receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC) as evaluation indicators. In addition, compared with a measles outbreak (26 cases) of a middle school in Tianjin in 2016, for making further verification on the diagnostic value of vaccination failure with IgM, IgG and IgM/IgG. Results: The age of cases ranged was 0-58 years old, the interval median (P(25), P(75)) of serum collection after rash onset was 2 (1, 4) days. The positive rate of measles IgM and IgG in acute phase specimens were 76.06% (216 cases) and 88.38% (251 cases). According to the ROC curve analysis, the area under the ROC curve (AUC) of IgM, IgG and IgM/IgG were 0.753, 0.891 and 0.952, indicating that IgM/IgG was the best index to distinguish PVF and SVF. The best cut off value for IgM/IgG was 0.06, the sensibility and specificity were 88.75% and 86.63%. When IgM/IgG >1, 96.30% cases were low-avidity (RAI <40%), only 1 case was equivocal response (RAI: 40%-60%). 97.14% cases were high-avidity (RAI >60%) when IgM/IgG <0.01, only 3 cases were equivocal response (RAI 40%-60%). The threshold of IgM/IgG was used to verify the measles outbreak of a middle school in Tianjin, 2016. In the acute phase specimens, 100% (26 cases) of IgM/IgG were <0.06, 84.62% (22 cases) of IgM/IgG were <0.01. Conclusion: The detection of measles IgM and IgG with ELISA, and IgM/IgG is a valuable diagnostic tool to distinguish PVF and SVF.

[Correlation analysis on meteorological factors regarding the incidence of hand, foot and mouth disease in Xinjiang Uygur Autonomous Region, 2011-2018].

Objective: To study the correlation between meteorological factors and the incidence of hand, foot and mouth disease (HFMD) in Xinjiang Uygur Autonomous Region (Xinjiang) so as to provide scientific evidence for the early warning, prediction, prevention and control of HFMD. Methods: Data on HFMD surveillance and related population was collected from the China Information System for Disease Control and Prevention from 2011 to 2018. Meteorological data was obtained from http://www.tianqihoubao.com. Correlation analysis on meteorological factors and the incidence of HFMD in Xinjiang was conducted, using the Excel 2007, SPSS 17.0, and Spatial Distribution Map by ArcGIS 10.2 software. Results: HFMD usually occurred between April and July. Numbers of patients reached the top in May and June. Temperature was positively correlated with the incidence of HFMD (r=0.370, P<0.01) while precipitation was positively correlated with the incidence of HFMD (r=0.747, P<0.01). The temperature threshold appeared as 5 ℃-35 ℃ for the incidence of HFMD. Interval period was one month between the peak of both the incidence of HFMD and the precipitation. A power function relationship (y=0.009 4x(2.332 9), R(2)=0.898 9) was noticed between the precipitation and the incidence of HFMD. Conclusions: The incidence of HFMD was closely related to the meteorological factors including temperature and precipitation in Xinjiang during 2011-2018. Our findings have provided evidence for the development of early warning system on HFMD in Xinjiang.

[A clinical analysis of 123 cases of primary empty sella].

Objective: This study was conducted to analyze the clinical characteristics and pituitary function of patients with primary empty sella (PES). Methods: The clinical data from 123 hospitalized adult patients with PES from January 2010 to May 2016 were retrospectively studied. Results: (1) The average age of the 123 (male 43, female 80) PES patients was (59.2±13.6) years (ranging 24-92 years), among whom 61% patients were in the age group between 50-69 years. (2) The symptoms of the patients included fatigue (56.1%), headache (34.1%), nausea and vomiting (17.9%), gonadal dysfunction (17.1%), visual disturbance (5.7%) and hypopituitarism crisis (3.3%). (3) Hypopituitarism was found in 66 of the 123 patients. Among them, 36.6%, 31.7% and 17.1% were central hypoadrenalism, hypogonadism, and hypothyroidism, respectively.The percentage of hypopituitarism in complete PES was significantly higher than that in partial PES (P<0.05). (4) Sixteen patients were concomitant with other autoimmune diseases including 11 patients with Graves' disease and 2 with Cushing's syndrome due to adrenal adenoma. Conclusions: The incidence of hypopituitarism in PES was 53.7%, in which the pituitary-adrenal axis hypofunction was more common. An overall evaluation of the pituitary function was essential for the patients who had headache and fatigue, or with suspected PES. The patients with hypopituitarism should be given hormone replacement therapy in time and followed up afterword.

[Epidemiology of pertussis in adults and related factors in Tianjin, 2005-2014].

OBJECTIVE: To understand the epidemiological characteristics of pertussis in adults and related factors in Tianjin. METHODS: Descriptive epidemiological analysis was conducted by using the epidemiological data of pertussis in adults in Tianjin during 2005-2014. The transmission routes of family cluster cases were analyzed. ELISA was conducted to detect pertussis immunity levels in adults aged 18-83 years. RESULTS: The pertussis cases in adults accounted for 28.57%(252/882)of the total cases in Tianjin , the annual incidence of pertussis in adults was 0.16/100 000. The highest incidence was 0.46/100 000 in 2013. The age specific proportion of the cases was highest in age group 21-30 years(36.12%, 91/252). Three household transmission routes of pertussis were identified, the major one was adult-to-infant(77.78%,98/126). The parents were the infection sources of 81.64% of infant cases(80/98). Of the 904 study subjects, the average positive rate of antibody against pertussis was 55.20%(95%CI: 51.96%-58.44%). There were significant differences in antibody positive rate among different age groups(P= 0.015), and which had the linear correlation with the reported annual incidence(r=0.98, P=0.003)and showed upward trend(χ(2)=11.79, P=0.001). CONCLUSION: The study indicated that adults have become the population at high risk for pertussis and the major infection sources for infants in Tianjin. The positive rate of antibody against pertussis was low in adults. It is suggested to conduct pertussis vaccination in adults.

Effect of an on-hip load-carrying belt on physiological and perceptual responses during bimanual anterior load carriage.

Manual load carriage continues to be a major contributor of musculoskeletal injury. This study investigates the physiological and subjective effects of an on-hip load-carrying belt (HLCB) during bimanual anterior load carriage. Fifteen healthy male participants walked on a level ground treadmill at 4.5 km/h for 5 min carrying 5, 10 and 15 kg loads with hands and arms in front of the body, with and without using the HLCB (WD and ND). Heart rate, normalized oxygen uptake, minute ventilation and, central and peripheral ratings of perceived exertion were the dependent variables. The mean heart rate, normalized oxygen uptake, minute ventilation and peripheral rating of perceived exertion increased significantly with load under both WD and ND conditions. At a load of 15 kg, the mean heart rate, normalized oxygen uptake, minute ventilation and peripheral rating of perceived exertion were significantly lower by 6.6%, 8.0%, 11.8% and 13.9% respectively in WD condition when compared to the ND condition. There was no significant difference between WD and ND conditions with 5 or 10 kg load. It can be concluded that the HLCB could reduce a person's physiological and peripheral perceptual responses when walking on a level ground treadmill at 4.5 km/h with a load of 15 kg. Using a HLCB or similar device is therefore recommended for bimanual anterior load carriage for loads of 15 kg or probably larger.

Expression of transforming growth factor-ß1 and connective tissue growth factor in congenital biliary atresia and neonatal hepatitis liver tissue.

We investigated the expression of transforming growth factor-ß1 (TGF-ß1) and connective tissue growth factor (CTGF) in the liver tissue of infants with congenital biliary atresia and neonatal hepatitis, as well as the relationship between the expression of the two factors and liver fibrosis. Thirty-six infants who met the cholestasis criteria were classified into congenital biliary atresia and neonatal hepatitis groups. All specimens were stained with hematoxylin and eosin and Masson's trichrome, and the degree of liver fibrosis was assessed. The scope and level of CTGF and TGF-ß1 expression in the different specimens was evaluated by immunohistochemistry and observation. Liver fibrosis in the congenital biliary atresia group was more advanced than that in the neonatal hepatitis group, and the difference was significant (P < 0.01). In the neonatal hepatitis patients, CTGF and TGF-ß1 were mainly expressed in the hepatocytes, while they were expressed in both hepatocytes and biliary epithelial cells in the congenital biliary atresia patients, and in these patients the expression was significantly stronger than in the neonatal hepatitis patients (P < 0.01). With the aggravation of hepatic fibrosis, CTGF and TGF-ß1 expression levels in liver tissue gradually increased, and their expression levels were significantly correlated (P < 0.01). Liver fibrosis is present in both congenital biliary atresia and neonatal hepatitis patients. The gradual increase of CTGF and TGF-ß1 expression levels in liver tissue is associated with liver fibrosis. Early expression of CTGF and TGF-ß1 in biliary epithelial cells may be involved in the pathogenesis of congenital biliary atresia.

Identification and Genetic Diversity of Formae Speciales of Setosphaeria turcica in China.

Setosphaeria turcica is an important pathogen that causes northern leaf blight of corn and sorghum. In total, 188 isolates were isolated from diseased leaves of maize and sorghum in China. However, differences in morphology were not apparent among S. turcica isolates derived from different hosts. The formae speciales were identified as S. turcica. f. sp. zeae and S. turcica. f. sp. sorghi. Universally primed polymerase chain reaction (UP-PCR) analysis led to the conclusion that genetic differences were present among these formae speciales and divided these isolates into five clades. The isolates of each clade belonged to the same forma specialis, and different formae speciales were assigned to different clades. The results of the present study demonstrated that pathogenic specialization of the S. turcica isolate correlated more closely with genetic diversity than geographical distribution. Therefore, combined with assays for pathogenicity, UP-PCR analysis yields an enhanced understanding of the formae speciales of S. turcica.

Protein kinase D1 inhibits breast cancer cell invasion via regulating matrix metalloproteinase expression.

PURPOSE: This study aimed to explore the role of protein kinase D1 (PKD1) in breast cancer invasion. MATERIALS AND METHODS: The relative expression of PKD1mRNA and protein in human invasive breast cancer tissue samples and normal samples, as well as breast cancer cell lines, were detected. Constitutively-active PKD1 and PKD1 specific shRNA were expressed in the MD-MB-231 and MCF-7 cells, respectively. The role of PKD1 in the invasive behavior of breast cancer cell line was evaluated by matrix metalloproteinase (MMP) expression. RESULTS: The results showed that PKD1, as a serine/threonine kinase, is downregulated significantly in invasive ductal carcinoma and metastatic invasive ductal carcinoma tissue than the normal tissue and the low expression of PKD1 is also found in breast cancer cell line MD-MB-231. The MMP2 and MMP9 expression in PKD1 constitutively-active MD-MB-231 cells and MCF-7 knockdown cells were decreased and increased respectively. CONCLUSION: The authors confirmed that PKD1 was downregulated in invasive breast cancer. PKD1 can negatively regulate the MMP expression and may serve as a potential therapeutic target.

The A3 adenosine receptor agonist CF502 inhibits the PI3K, PKB/Akt and NF-kappaB signaling pathway in synoviocytes from rheumatoid arthritis patients and in adjuvant-induced arthritis rats.

The A(3) adenosine receptor (A(3)AR) is over-expressed in inflammatory cells and was defined as a target to combat inflammation. Synthetic agonists to this receptor, such as IB-MECA and Cl-IB-MECA, exert an anti-inflammatory effect in experimental animal models of adjuvant- and collagen-induced arthritis. In this study we present a novel A(3)AR agonist, CF502, with high affinity and selectivity at the human A(3)AR. CF502 induced a dose dependent inhibitory effect on the proliferation of fibroblast-like synoviocytes (FLS) via de-regulation of the nuclear factor-kappa B (NF-kappaB) signaling pathway. Furthermore, CF502 markedly suppressed the clinical and pathological manifestations of adjuvant-induced arthritis (AIA) in a rat experimental model when given orally at a low dose (100 microg/kg). As is typical of other G-protein coupled receptors, the A(3)AR expression level was down-regulated shortly after treatment with agonist CF502 in paw and in peripheral blood mononuclear cells (PBMCs) derived from treated AIA animals. Subsequently, a decrease in the expression levels of protein kinase B/Akt (PKB/Akt), IkappaB kinase (IKK), I kappa B (IkappaB), NF-kappaB and tumor necrosis factor-alpha (TNF-alpha) took place. In addition, the expression levels of glycogen synthase kinase-3 beta (GSK-3beta), beta-catenin, and poly(ADP-ribose)polymerase (PARP), known to control the level and activity of NF-kappaB, were down-regulated upon treatment with CF502. Taken together, CF502 inhibits FLS growth and the inflammatory manifestations of arthritis, supporting the development of A(3)AR agonists for the treatment of rheumatoid arthritis.

Doxorubicin loaded pH-sensitive micelle targeting acidic extracellular pH of human ovarian A2780 tumor in mice.

The purpose of this study was to examine the efficacy of a chemotherapeutic drug, doxorubicin (DOX), loaded in pH-sensitive micelles poly(l-histidine) (M(n):5K)-b-PEG (M(n):5K) micelles. The micelles were designed to target the acidic extracellular pH of solid tumors. Studies of pH-dependent cytotoxicity, growth rate of the tumor, pharmacokinetics and biodistribution were conducted. In vitro DOX uptake upon A2780 cells by incubating the cells in a pH 6.8 complete medium at a concentration of 20 microg DOX/ml in the micelle formulation was more than five times that of pH 7.4 condition for initial 20 min. In vivo pharmacokinetic data showed that AUC (area under concentration curve) and half life time (t(1/2)) (plasma half life) of DOX in the pH sensitive micelles increased about 5.8- and 5.2-fold of free DOX in phosphate buffered saline (PBS), respectively. It appeared that DOX in the pH-sensitive micelles preferentially accumulated in the tumor site. The distributions at 12 h post injection in other organs including liver, kidney, spleen, lung and heart were not significantly different from those of DOX in PBS at a 6 mg DOX/kg dose. The in vivo test of anti-tumor activity was performed with human ovarian carcinoma A2780 which was subcutaneously xenografted in female nu/nu athymic mice. The pH-sensitive micelle formulation significantly retarded tumor growth rate without serious body weight loss. The triggered drug release by the reduced tumor pH is believed to be a major mechanism of the observed efficacy after passive accumulation of the micelles by EPR effect. This may have resulted in a local high dose of drug in the tested solid tumor.

D-4'-thioadenosine derivatives as highly potent and selective agonists at the human A3 adenosine receptor.

4'-Thionucleoside derivatives as potent and selective A3 adenosaine receptor agonists were synthesized, starting from D-gulono-gamma-lactone via D-thioribosyl acetate as a key intermediate, among which the 2-chloro-N6-methyladenosine-5-methyluronamide showed the most potent and selective binding affinity (Ki = 0.28 +/- 0.09 nM) at the human A3 adenosine receptor.

Neoceptor concept based on molecular complementarity in GPCRs: a mutant adenosine A(3) receptor with selectively enhanced affinity for amine-modified nucleosides.

Adenosine A(3) receptors are of interest in the treatment of cardiac ischemia, inflammation, and neurodegenerative diseases. In an effort to create a unique receptor mutant that would be activated by tailor-made synthetic ligands, we mutated the human A(3) receptor at the site of a critical His residue in TM7, previously proposed to be involved in ligand recognition through interaction with the ribose moiety. The H272E mutant receptor displayed reduced affinity for most of the uncharged A(3) receptor agonists and antagonists examined. For example, the nonselective agonist 1a was 19-fold less potent at the mutant receptor than at the wild-type receptor. The introduction of an amino group on the ribose moiety of adenosine resulted in either equipotency or enhanced binding affinity at the H272E mutant relative to wild-type A(3) receptors, depending on the position of the amino group. 3'-Amino-3'-deoxyadenosine proved to be 7-fold more potent at the H272E mutant receptor than at the wild-type receptor, while the corresponding 2'- and 5'-amino analogues did not display significantly enhanced affinities. An 3'-amino-N(6)-iodobenzyl analogue showed only a small enhancement at the mutant (K(i) = 320 nM) vs wild-type receptors. The 3'-amino group was intended for a direct electrostatic interaction with the negatively charged ribose-binding region of the mutant receptor, yet molecular modeling did not support this notion. This design approach is an example of engineering the structure of mutant receptors to recognize synthetic ligands for which they are selectively matched on the basis of molecular complementarity between the mutant receptor and the ligand. We have termed such engineered receptors "neoceptors", since the ligand recognition profile of such mutant receptors need not correspond to the profile of the parent, native receptor.

Allosteric modulation of A(3) adenosine receptors by a series of 3-(2-pyridinyl)isoquinoline derivatives.

Allosteric modulators of A(1) and A(2A) adenosine receptors have been described; however, for the A(3) adenosine receptor, neither an allosteric site nor a compound with allosteric effects has been described. In this study, the allosteric modulation of human A(3) adenosine receptors by a series of 3-(2-pyridinyl)isoquinoline derivatives was investigated by examining their effects on the dissociation of the agonist radioligand, [(125)I]N(6)-(4-amino-3-iodobenzyl)-5'-N-methylcarboxamidoadenosine (I-AB-MECA), from the receptor. Several 3-(2-pyridinyl)isoquinoline derivatives, including VUF5455, VUF8502, VUF8504, and VUF8507, slowed the dissociation of the agonist radioligand [(125)I]I-AB-MECA in a concentration-dependent manner, suggesting an allosteric interaction. These compounds had no effect on the dissociation of the radiolabeled antagonist [(3)H]PSB-11 from the A(3) adenosine receptor, suggesting a selective enhancement of agonist binding. By comparison, compounds of similar structure (VUF8501, VUF8503, VUF8505), the classical adenosine receptor antagonist CGS15943 and the A(1) receptor allosteric enhancer PD81723 did not significantly influence the dissociation rate of [(125)I]I-AB-MECA. The effect of agonist on forskolin-induced cAMP production was significantly enhanced by VUF5455. When the subtype-selectivity of the allosteric enhancement was tested the compounds had no effect on the dissociation of either [(3)H]N(6)-[(R)-phenylisopropyl]adenosine from the A(1) adenosine receptor or [(3)H]CGS21680 from the A(2A) adenosine receptor. Probing of structure-activity relationships suggested that a carbonyl group is essential for allosterism but preferred only for competitive antagonism. The presence of a 7-methyl group decreased the competitive binding affinity without a major loss of the allosteric enhancing activity, suggesting that the structural requirements for allosteric enhancement might be distinct from those for competitive antagonism.