[Clinical characteristics of patients with rheumatic diseases and abnormal liver function].

Objective: To investigate the clinical characteristics of patients with rheumatic diseases and abnormal liver function, as well as determine the proportion and severity of liver function abnormalities. Methods: Cross-sectional study. Data were collected from patients registered in the Chinese Rheumatism Date Center from 2011 to 2021. The rheumatic diseases analyzed in this study were rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren syndrome (SS), ankylosing spondylitis (AS), and gout. Patient data, including demographic characteristics [ such as age, sex, body mass index,(BMI), and smoking history], liver function test results [including alanine aminotransferase (ALT), aspartate aminotransferase, alkaline phosphatase(ALP), and total bilirubin], and use of anti-rheumatic immune drugs and liver-protective drugs, were collected and compared between groups with normal and abnormal liver functions. In addition, the proportions of abnormal liver function were compared between sex and age groups. Results: A total of 116 308 patients were included in this study, including 49 659 with RA, 17 597 with SLE, 9 039 with SS, 11 321 with AS, and 28 692 with gout. The lowest proportion of liver function abnormalities was observed in patients with RA[11.02% (5 470/49 659)], followed by those with SS[17.97% (1 624/9 039)] and AS [18.22% (2 063/11 321) ], whereas patients with SLE [21.14% (3 720/17 597) ] and gout [28.73% (8 242/28 692)] exhibited the highest proportion of these abnormalities. Elevated ALT, mostly classified as grade 1, was the most commonly noted liver function abnormality, whereas elevated ALP was the least common. Some patients who took liver-protective drugs had normal liver function, with the lowest percentage observed in patients with gout [7.45% (36/483) ] and ranging from 21.7% to 30.34% in patients with RA, SLE, SS, and AS. The proportion of liver function abnormalities was higher in males than in females for all disease types [RA: 13.8%(1 368/9 906) vs. 10.3%(4 102/39 753); SLE: 33.6% (479/1 424) vs. 20.0% (3 241/16 173); SS: 25.4%(111/437) vs. 17.6%(1 513/8 602); AS: 20.1%(1 629/8 119) vs. 13.6% (434/3 202); and gout: 29.3% (8 033/27 394) vs. 16.1% (209/1 298)]. In RA, SLE, and AS, the proportions of liver function abnormalities were similar across all age groups. In SS, the proportion of liver function abnormalities increased with age [<40 years: 14.9%(294/1 979); 40-59 years: 18.1%(858/4 741); ≥60 years: 20.4%(472/2 319)], whereas a reversal of this trend was observed in gout [<40 years: 34.9%(4 294/12 320); 40-59 years: 25.5%(2 905/11 398);≥60 years: 21.0%(1 042/4 971)]. Conclusions: The proportions of combined liver function abnormalities in patients with rheumatologic diseases were high, and the utilization rates of liver-protective drugs were low. It is necessary to pay more attention to monitoring patients' liver function, timely administer liver-protective drugs, and optimize liver-protective regimens during the treatment of rheumatic diseases.

[Effect of out-hospital blood pressure management on prognosis of patients with acute aortic syndrome complicated with hypertension after TEVAR].

Objective: To investigate the influence of blood pressure control after discharge on prognosis of patients with acute aortic syndrome (AAS) complicated with hypertension who underwent thoracic endovascular aortic repair (TEVAR). Methods: This is a retrospective case analysis. Patients diagnosed with AAS complicated with hypertension and undergoing TEVAR in Northern Theater Command General Hospital from June 2002 to December 2021 were consecutively enrolled. Average systolic blood pressure (SBP) and the occurrence of endpoint events were recorded at one month, one year and every 2 years after TEVAR. According to the patients' average SBP, patients with average SBP<140 mmHg (1 mmHg=0.133 kPa) or<150 mmHg were divided into the target blood pressure achievement group, and the others were divided into target blood pressure non-achievement group. Endpoint events included all-cause death, aortic death, stroke, renal insufficiency, aortic related adverse events and a composite of these events (overall clinical adverse events), and re-accepting TEVAR. The incidence of endpoint events was compared between the two groups at each follow-up period. Results: A total of 987 patients were included, aged (55.7±11.7) years, including 779 male (78.9%). When the cutoff value was 140 mmHg, the rate of average target SBP achievement was 71.2% (703/987) at one month, 66.7% (618/927) during 1st to 12th month and 65.1% (542/832) from the first year to the third year after TEVAR. The proportion of patients taking≥2 antihypertensive agents was higher in the group of target blood pressure non-achievement group than the target blood pressure achievement group after TEVAR at 1 month (74.3% (211/284) vs.65.9% (463/703), P=0.010) and during 1st to 12th month (71.5% (221/309) vs. 63.6% (393/618), P=0.016). There were no statistical differences in the all-cause deaths, stroke, aortic related adverse events, and repeat TEVAR between the two groups (All P>0.05) during above follow-up periods. When the cutoff value was 150 mmHg, the rate of target SBP achievement was 89.3% (881/987) at one month, 85.2% (790/927) during 1st to 12th month and 85.6%(712/832) from the first year to the third year after TEVAR. The incidence of clinical total adverse events (8.8% (12/137) vs. 4.2% (33/790), P=0.021) and repeat TEVAR (4.4% (6/137) vs. 1.0% (8/790), P=0.003) in target blood pressure non-achievement group were significantly higher than the target blood pressure achievement group during 1st to 12th month after TEVAR. The incidence of all-cause deaths (5.8% (7/120) vs. 2.4% (17/712), P=0.037) in the target blood pressure non-achievement group was significantly higher than the target blood pressure achievement group from the first year to the third year follow-up period, but there were no statistical differences in the incidence of clinical total adverse events between the two group (P>0.05). Conclusion: Among TEVAR treated AAS patients complicated with hypertension, the average SBP more than 150 mmHg post discharge is associated with increased risk of adverse events. Ideal blood pressure control should be encouraged to improve the outcome of these patients.

[Clinical characteristics and prognostic analysis of female patients with Stanford type B aortic dissection].

Objective: To explore the clinical characteristics and prognostic factors of female patients with Stanford type B aortic dissection. Methods: This is a single-centre retrospective study. Consecutive patients diagnosed with Stanford type B aortic dissection in General Hospital of Northern Theater Command from June 2002 to August 2021 were enrolled, and grouped based on sex. According to the general clinical conditions and complications of aortic dissection tear, patients were treated with thoracic endovascular aortic repair, surgery, or optimal medication. The clinical characteristics and aortic imaging data of the patients at different stages were collected, adverse events including all-cause deaths, stroke, and occurrence of aortic-related adverse events were obtained during hospitalization and within 30 days and at 1 and 5 years after discharge. According to the time of death, death was classified as in-hospital death, out-of-hospital death, and in-hospital death was divided into preoperative death, intraoperative death and postoperative death. According to the cause of death, death was classified as aortic death, cardiac death and other causes of death. Aortic-related adverse events within 30 days after discharge included new paraplegia, post-luminal repair syndrome, and aortic death; long-term (≥1 year after discharge) aortic-related adverse events included aortic death, recurrent aortic dissection, endoleak and distal ulcer events. The clinical characteristics, short-term and long-term prognosis was compared between the groups. Logistic regression analysis was used to explore the association between different clinical factors and all-cause mortality within 30 days in female and male groups separately. Results: A total of 1 094 patients with Stanford type B aortic dissection were enrolled, mean age was (53.9±12.1) years, and 861 (78.7%) were male and 233 (21.3%) were female. (1) Clinical characteristics: compared with male patients, female patients were featured with older average age, higher proportion of aged≥60 years old, back pain, anemia, optimal medication treatment, and higher cholesterol level; while lower proportion of smoking and drinking history, body mass index, calcium antagonists use, creatine kinase level, and white blood cell count (all P<0.05). However, there was no significant difference in dissection tear and clinical stage, history of coronary heart disease, diabetes, hypertension, and cerebrovascular disease between female and male patients (all P>0.05). (2) Follow-up result: compared with male patients, female patients had a higher rate of 30-day death [6.9% (16/233) vs. 3.8% (33/861), P=0.047], in-hospital death (5.6% (13/233) vs. 2.7% (23/861), P=0.027), preoperative death (3.9% (9/233) vs. 1.5% (12/861), P=0.023) and aorta death (6.0% (14/233) vs. 3.1% (27/861), P=0.041). The 1-year and 5-year follow-up results demonstrated that there were no significant differences in death, cerebrovascular disease, and aorta-related adverse events between the two groups (all P>0.05). (3) Prognostic factors: the results of the univariate logistic regression analysis showed that body mass index>24 kg/m2 (HR=1.087, 95%CI 1.029-1.149, P=0.013), history of anemia (HR=2.987, 95%CI 1.054-8.468, P=0.032), hypertension (HR=1.094, 95%CI 1.047-1.143, P=0.040) and troponin-T>0.05 µg/L (HR=5.818, 95%CI 1.611-21.018, P=0.003)were associated with an increased risk of all-cause mortality within 30 days in female patients. Conclusions: Female patients with Stanford type B aortic dissection have specific clinical characteristics, such as older age at presentation, higher rates of anemia and combined back pain, and higher total cholesterol levels. The risk of death within 1 month is higher in female patients than in male patients, which may be associated with body mass index, hypertension, anemia and troponin-T, but the long-term prognosis for both female and male patients is comparable.

[Expression and regulatory role of ultraconserved long non-coding RNA uc.77 in lung cancer].

Objective: To investigate the effect and molecular mechanism of ultra-conservative long non-coding RNA uc.77 in lung cancer. Methods: Lung cancer tissues and adjacent normal tissues were obtained from 61 patients with lung cancer who were diagnosed with lung cancer and underwent surgery from 2014 to 2016 in the General Hospital of the Southern Theater Command of the People's Liberation Army. Real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to detect the uc.77 relative expressions in normal human bronchial epithelial cells 16HBE, lung cancer cell lines, and 61 pair lung cancer tissues. Uc.77 siRNA was transfected into lung cancer cells to interfere with the expression of uc.77, qRT-PCR was used to verify the interference effect, CCK8 method and clone formation experiment were used to detect cell proliferation ability, flow cytometry was used to detect apoptosis and cell cycle changes. H1299 cells transfected with uc.77 siRNA were injected into the subcutaneous right side of BALB/c nude mice to construct a tumor-bearing model for exploring the role of uc.77 on tumor growth. Western blot and qRT-PCR methods were used to detect the protein and mRNA expressions of p21. Results: The relative expression levels of uc.77 in lung cancer cell lines 95D, H1299, A549, H460, H446 and 16HBE-T were significantly higher than that of 16HBE cells (P<0.05). The uc.77 RNA expression levels of lung cancer tissues was significantly higher than that of the adjacent normal tissues (P<0.001). In addition, increased lncRNA uc.77 expression was significantly associated with big tumor size, lymph node metastasis and advanced TNM stage (P<0.05). After transfection with uc.77 siRNA, the expressions of uc.77 in H1299, 95-D and 16HBE-T cells were reduced (P<0.05), and the cell proliferation capacities were reduced at 48 hours and 72 hours (P<0.05). After transfection with uc.77 siRNA-1, the G(0)/G(1) phase cell ratio of H1299 siRNA-1 group [(71.86±3.46)%] was higher than those of H1299-control group [(47.62±5.48)%] and H1299 siRNA-NC group [(61.38±5.62)%, P<0.05], S phase cell ratio of H1299 siRNA-1 group [(14.99±3.61)%] was lower than those of H1299-control group [(34.95±7.05)%] and H1299 siRNA-NC group [(23.75±5.87)%, P<0.05], the apoptosis rate of H1299 siRNA-1 group [(4.90±1.80)%] was higher than those of H1299-control group [(3.30±0.80)%] and H1299 siRNA-NC group [(2.80±1.20)%, P<0.05], the colony formation rate of H1299 siRNA-1 group [(19.20±2.00)%] was lower than those of H1299 control group [(32.60±2.00)%] and H1299 siRNA-NC group [(34.40±1.00)%, P<0.05]. The results of the nude mice tumor formation experiment showed that the tumor volume of the H1299 siRNA-1 group was significantly lower than those of the H1299-control group and the H1299-negative control group (P<0.05), the average tumor weight of H1299 siRNA-1 group was significantly lower than those of H1299-control group and H1299-negative control group (P<0.05), tumor cell growth marker Ki-67 in the H1299 siRNA-1 group showed weak positive, and Ki-67 in the H1299-control group and H1299-negative control group showed positive. The result of qRT-PCR analysis showed that the mRNA expression level of p21 in H1299 siRNA-1 group (2.57±0.45) was higher than those in H1299 control group (1.00±0.00, P=0.001) and H1299 siRNA-NC group (1.52±0.37, P=0.009). The result of western blotting analysis also showed that the expression of p21 protein level in H1299 siRNA-1 group increased. Conclusions: The expression of ultraconserved long non-coding RNA uc.77 is elevated in lung cancer cell lines and lung cancer tissues. Silencing the expression of ultraconservative long noncoding RNA uc.77 can inhibit tumor growth, and blocking uc.77 expression may be a potential therapeutic target for lung cancer.

[Clinical characteristics and risk factors of periventricular-intraventricular hemorrhage in extremely low birth weight infants].

Objective: To analyze the clinical characteristics and risk factors of periventricular-intraventricular hemorrhage (PIVH) in extremely low birth weight infants (ELBWI). Methods: From January 2019 to January 2022, the clinical data of 238 ELBWI admitted to the intensive care unit of Henan Provincial Children's Hospital within 1 week after birth and regular head color ultrasound examination were retrospective reviewed. The infants were divided into PIVH group and non-PIVH group according to whether PIVH occurred. The incidence and time of PIVH were described, and the differences in basic clinical features, perinatal conditions, postnatal treatment and complications between the two groups were compared. The risk factors of PIVH in ELBWI were further explored by multivariate binary logistic regression analysis. Results: Among 238 ELBWI (146 males and 92 females), 82 cases (34.5%) developed PIVH, including 28 cases (11.8%) of severe PIVH and 54 cases (22.7%) of mild PIVH. Among the 82 cases of PIVH, 68 cases occurred within 3 days after birth. Gestational age [(27.4±1.5) weeks vs (27.8±1.5) weeks, P=0.012], gestational diabetes mellitus [0 vs 9.0%(14/156), P=0.005], fibrinogen (FIB) [(1.8±0.5) g/L vs (2.7±0.9) g/L, P=0.012] were lower in PIVH group than in non-PIVH group. However, intrauterine distress [46.3%(38/82) vs 11.5%(18/156), P<0.001], birth asphyxia [85.4%(70/82) vs 62.8%(98/156), P<0.001], patent ductus arteriosus (PDA) [65.9%(54/82) vs 51.3%(80/156）, P=0.017], failure to withdraw invasive ventilator within 1 week [82.9%(14/82) vs 67.3%(105/156), P=0.010], use of vasoactive drugs within 1 week [28.0%(23/82) vs 15.4%(24/156), P=0.020], acidosis [28.0%(23/82) vs 12.2%(19/156), P=0.002], and hemorrhagic disease [18.3%(15/82) vs 7.1%(11/156), P=0.008] were higher in PIVH group than in non-PIVH group. Multivariate binary logistic regression analysis found that the risk factors for PIVH in ELBWI were acidosis (OR=2.257, 95%CI: 1.104-4.614, P=0.026), use of vasoactive drugs within 1 week (OR=2.274, 95%CI: 1.148-4.504, P=0.018), bleeding disorders (OR=2.583, 95%CI: 1.075-6.206, P=0.034) use of vasoactive drugs within 1 week (OR=2.301, 95%CI: 1.153-4.591, P<0.001). Conclusions: The incidence of PIVH in ELBWI is high, which mostly occurs within 3 days after birth. Acidosis, hemorrhagic disease, use of vasoactive agents within 1 week and failure to evacuate invasive ventilators within 1 week may increase the risk of PIVH in ELBWI.

Effect of Hepatocyte Targeting Nanopreparation Syringopicroside on Duck Hepatitis B Virus and Evaluation of Its Safety.

Syringopicroside is a kind of iridoid monomer compound isolated from Syringa oblata exhibiting a potent effect against hepatitis B virus (HBV). The therapeutic effect and safety of syringopicroside-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (SYR-NP) were studied on the model of HBV-infected ducklings and on cultured HepG2.2.15 cells. HBV DNA in ducklings was assessed by fluorescence quantitative PCR. In HepG2.2.15 cells, the content of HBsAg and HBeAg were assayed. Acute toxicity of SYR-NP was studied in ICR mice in 12 h and 7 days after SYR-NP administration. The serum levels of HBV DNA in ducklings treated with SYR-NP in a high dose was significantly lower than in the control. In HepG2.2.15 cells treated with different doses of SYR-NP, the concentrations of HBsAg and HBeAg were significantly below the control. Acute toxicity test showed high safety of SYR-NP. Thus, SYR-NP can inhibit replication of HBV DNA and protect the liver tissue.

Aligning tumor mutational burden (TMB) quantification across diagnostic platforms: phase II of the Friends of Cancer Research TMB Harmonization Project.

BACKGROUND: Tumor mutational burden (TMB) measurements aid in identifying patients who are likely to benefit from immunotherapy; however, there is empirical variability across panel assays and factors contributing to this variability have not been comprehensively investigated. Identifying sources of variability can help facilitate comparability across different panel assays, which may aid in broader adoption of panel assays and development of clinical applications. MATERIALS AND METHODS: Twenty-nine tumor samples and 10 human-derived cell lines were processed and distributed to 16 laboratories; each used their own bioinformatics pipelines to calculate TMB and compare to whole exome results. Additionally, theoretical positive percent agreement (PPA) and negative percent agreement (NPA) of TMB were estimated. The impact of filtering pathogenic and germline variants on TMB estimates was assessed. Calibration curves specific to each panel assay were developed to facilitate translation of panel TMB values to whole exome sequencing (WES) TMB values. RESULTS: Panel sizes >667 Kb are necessary to maintain adequate PPA and NPA for calling TMB high versus TMB low across the range of cut-offs used in practice. Failure to filter out pathogenic variants when estimating panel TMB resulted in overestimating TMB relative to WES for all assays. Filtering out potential germline variants at >0% population minor allele frequency resulted in the strongest correlation to WES TMB. Application of a calibration approach derived from The Cancer Genome Atlas data, tailored to each panel assay, reduced the spread of panel TMB values around the WES TMB as reflected in lower root mean squared error (RMSE) for 26/29 (90%) of the clinical samples. CONCLUSIONS: Estimation of TMB varies across different panels, with panel size, gene content, and bioinformatics pipelines contributing to empirical variability. Statistical calibration can achieve more consistent results across panels and allows for comparison of TMB values across various panel assays. To promote reproducibility and comparability across assays, a software tool was developed and made publicly available.

Direct Measurement of the Astrophysical

Fluorine is one of the most interesting elements in nuclear astrophysics, where the ^{19}F(p,α)^{16}O reaction is of crucial importance for Galactic ^{19}F abundances and CNO cycle loss in first generation Population III stars. As a day-one campaign at the Jinping Underground Nuclear Astrophysics experimental facility, we report direct measurements of the essential ^{19}F(p,αγ)^{16}O reaction channel. The γ-ray yields were measured over E_{c.m.}=72.4-344 keV, covering the Gamow window; our energy of 72.4 keV is unprecedentedly low, reported here for the first time. The experiment was performed under the extremely low cosmic-ray-induced background environment of the China JinPing Underground Laboratory, one of the deepest underground laboratories in the world. The present low-energy S factors deviate significantly from previous theoretical predictions, and the uncertainties are significantly reduced. The thermonuclear ^{19}F(p,αγ)^{16}O reaction rate has been determined directly at the relevant astrophysical energies.

[Effectiveness of 23-valent pneumococcal polysaccharide vaccine on adult pneumococcal disease].

Streptococcus pneumoniae (Spn) will cause various pneumococcal diseases when host has a weak immune system. The World Health Organization ranks it as one of the 12 key pathogens causing heavy burden of disease. At present, the drug resistance of Spn is rising, and vaccination is an important and effective strategy to decrease the burden of disease. The 23-valent pneumococcal polysaccharide vaccine (PPV23) is a preventive vaccine for adults that covers 65% to 91% of Spn isolates worldwide. Accumulating evidence have confirmed the effectiveness of PPV23 in decreasing the incidence, hospitalization, mortality, and economic burden of pneumococcal diseases in adults. The burden of pneumococcal diseases in China is heavy, but the adult vaccination rate is low. Here, we review the prevalence of adult pneumococcal diseases, the preventive and protective effects and benefits of PPV23 vaccine on high-risk population, especially the elderly individuals. We hope this review can provide references and new ideas for adult PPV23 vaccination programs in China.

[Cellular immunity evaluation of five mycobacterium tuberculosis recombinant proteins and their compositions].

Objective: The cellular immunity of 5 Mycobacterium tuberculosis recombinant proteins and their compositions was evaluated. Method: A total of 88 fresh venous blood from peripheral heparin anticoagulant population, 42 of which were from tuberculosis patients treated by The Tuberculosis Prevention and Treatment Center of Changping District, Beijing, and 46 of healthy volunteers were provided by the Infection Diseases of Chinese Center for Disease Control and Prevention. Healthy volunteers without a history of tuberculosis exposure and any clinical signs and symptoms. Using the Mycobacterium tuberculosis standard strain H37Rv DNA as a template, complete genes of the selected 5 recombinant proteins Rv3874, Rv3875, Rv2031c, Rv1411c and Rv3418c by PCR amplified; 5 recombinant proteins were cloned, expressed and purified as stimulants by genetic recombination and protein purification techniques, and the effector T cell enzyme-linked immunospot assay (ELISPOT) was used to detect cellular immunity in the population. Results: The recombinant proteins Rv3874, Rv3875, Rv2031c, Rv1411c and Rv3418c were successfully cloned, expressed and purified; And the sensitivities were 50.00%, 71.43%, 69.04%, 73.81% and 76.19%, and the specificities were 86.96%, 76.09%, 71.74%, 39.13% and 36.96%. In addition, the positive predictive value, negative predictive value, area under the curve and Youden index were 52.46% to 77.78%, 62.96% to 74.47%, 0.511 to 0.754 and 0.129 to 0.475, respectively. Except for Rv1411c and Rv3418c, the number of spot-forming cell (SFC) detected by Rv3874, Rv3875 and Rv2031c in tuberculosis patients was higher than healthy volunteers, and the differences were statistically significant (P<0.001). Among the 26 compositions composed of 5 recombinant proteins, the sensitivity was 80.95% to 95.24%, and the specificity was 68.89% to 24.44%. As the number of recombinant proteins in the composition increases, the sensitivity gradually increased, but the specificity decreased. Conclusion: The recombinant proteins of Mycobacterium tuberculosis Rv3874, Rv3875 and Rv2031c have strong ability to stimulate T cells to produce immune response, and have certain antigenicity. The efficacy of Rv1411c and Rv3418c alone as diagnostic antigens is not ideal, and the composition composed of multi-component antigens has certain application value. This article provides experimental evidence for the immune diagnosis of tuberculosis and the preparation of new anti-tuberculosis vaccines.

A metaphyseal fracture rat model for mechanistic studies of osteoporotic bone healing.

Most osteoporotic fractures occur at metaphyseal regions of long bones. The present study proposed a clinically relevant animal model that satisfied: i) induction of osteoporosis, ii) unilateral complete osteotomy at metaphysis, iii) internal fixation. 6 months old female Sprague-Dawley rats (n = 64) were randomly divided into the ovariectomised-metaphyseal osteotomy (OVX, n = 32) and metaphyseal osteotomy (SHAM, n = 32) groups. The metaphyseal-osteotomy model was created with a plate-fixation of the osteotomy and assessed by X-ray, micro-computed tomography, histomorphometry and mechanical testing at weeks 1, 3 and 6. X-ray results showed complete healing of metaphyseal osteotomy at week 6. Histology showed 3 stages of metaphyseal healing. Stage 1 was characterised by fibrous tissue, consisting of disorganised orientation of collagen fibres, and infiltration of immune cells. At stage 2, a transitional zone consisting of maturing fibrous tissue and differentiating mesenchymal cells with early trabecular bone formation and disorganised woven bone were observed. During stage 3, cortical bone ends unified and woven bone underwent transformation to lamellar bone. OVX group healing was significantly delayed when compared to SHAM samples. The study demonstrated that healing of osteoporotic osteotomy at the metaphyseal region was delayed in terms of radiography, histomorphometry and mechanical strength. These quantitative evaluations, along with histological features, may provide key references for future studies. The animal model may provide additional clinical relevance as most osteoporotic fracture in humans occurs at metaphyseal regions.

[Prospective controlled observation ofeffect of adjuvant chemotherapy onsurvival and prognosis ofhigh-risk upper tract urothelial carcinoma patients underwent radical nephroureterectomy].

Objective: To assess the oncologic outcomes of radical nephroureterectomy (RNU) combined with adjuvant chemotherapy (ACT) in patients with high risk upper tract urothelial carcinoma (UTUC). Methods: From January 2014, all high-risk UTUC patients after RNU surgery were enrolled in this prospective comparative trial. And these patients were randomized to ACT group (Gemcitabine+Cisplatin three weeks regimen) and observing group. Cox proportional hazard modeling and Kaplan-Meier analysis were used to determine overall survival (OS), cancer specific survival (CSS) and disease-free survival (PFS) in the cohort. Results: The median follow-up duration was36 months (range: 6-54) in the ACT group (n=94) and 30 months (range: 6-54) in the observing group (n=82). Oncologic outcomes of RNU treated high-risk UTUC patients were improved much significantly by ACT: OS [P=0.0397, HR: 1.39(0.91-1.75)], CSS [P=0.0255, HR: 1.26(1.07-1.45)] and PFS [P=0.0033, HR: 3.78(3.13-4.55)]. The further analysis in lymph node positive cohort displayed that median times of oncologic events were prolonged in the ACT group compared with the observing group: OS (26.8mon vs 36.3mon, P=0.0255), CSS (28.2mon vs39.3mon, P=0.0197) and PFS (11.4mon vs 31.9mon, P=0.0018). Additionally in T3/4 cohort, the significant growth in the median times of OS (20.6mon vs 32.2mon, P=0.0183), CSS (21.9mon vs 38.4mon, P=0.0226) and PFS (13.9mon vs 36.3mon, P=0.0217) were observed in ACT group. Conclusion: ACT could play the important synergistic role in improving the OS, CSS and PFS of high-risk UTUC patients after RNU.

[Derepression of CXCR7 indicates resistance to enzalutamide in castration resistant prostate cancer].

Objective: To investigate the effect of the derepression of chemokine receptor-7 (CXCR7) in prostatic tissues from patients with Castration Resistant Prostate Cancer (CRPC) on the resistance to enzalutamide (Enza). Methods: During the period of January 2015 to December 2017 all CRPC cases who underwent radical radiotherapy or androgen deprivation therapy (ADT) were evaluated. After prostatic puncture biopsy, the tissues were treated for immunostaining with CXCR7. Cox proportional hazard modeling and Kaplan-Meier analysis were used to determine PSA Progression-Free Survival (PSAP-FS) and Clinical or Radiographic Progression-Free Survival (CRP-FS) in the cohort. At last, PSA response rates and progression outcomes in CXCR7 negative cases and CXCR7 positive cases were analyzed. Results: Total 39 CRPC patients were enrolled in this study. And 23 cases derepress CXCR7, 16 cases negatively express CXCR7. The median follow-up duration was 12 months (range: 6-18) in the cohort. Chi-square analysis confirmed that PSA response rates after Enza treatment were significantly associated with CXCR7 derepression (χ(2)=22.129, P=0.000 06). Compared with CXCR7 positive expression group, CXCR7 negative expression group displayed improved median PSAP-FS (4.4 mon vs 11.7 mon, P=0.040 8) and CRP-FS (5.2 mon vs 13.1 mon, P=0.036 2) after Enza treatment. Conclusion: Derepression of CXCR7 in CRPC patients may be associated with resistance to enzalutamide. This protein may be novel target for treatment of CRPC.

[Oncologic outcomes of high-risk upper tract urothelial carcinoma patients undergoing radical nephroureterectomy combined with adjuvant chemotherapy].

Objective: To assess the oncologic outcomes of radical nephroureterectomy (RUN) combined with adjuvant chemotherapy (ACT) in patients with high risk upper tract urothelial carcinoma (UTUC). Methods: One-hundred-thirty-four individuals with high-risk UTUC who underwent RUN with or without ACT were evaluated. Cox proportional hazard model and Kaplan-Meier analysis were used to determine overall and cancer specific survival in the cohort. Results: The median follow-up duration was 24 months (range: 6-36) in the RUN group (n=61) and 18 months (range: 6-36) in the RUN+ACT group (n=73). Median time of overall survival (OS) and cancer specific survival (CSS) showed much better in RUN+ACT group than in RUN group, but the differences were not reached the significant standard. The further analysis in lymph node positive cohort displayed that median times of oncologic events were prolonged in the RUN+ACT group compared with the RUN group: OS (30.1 mon vs 18.0 mon, P=0.083) and CSS (29.2 mon vs 18.6 mon, P=0.047). Additionally in T3/T4 cohort, the significant growth in the median times of OS (25.2 mon vs 12.6 mon, P=0.038) and CSS (31.3 mon vs 18.9 mon, P=0.044) were observed in combination treatment group. Conclusion: ACT could play the important synergistic role in improving the OS and CSS of RUN treated UTUC patients with lymph node-positive or stage of T3/T4.

[Mechanism of androgen in improving erectile dysfunction in castrated rats by regulating androgen receptor/vascular endothelial growth factor].

Objective: To explore the mechanism of androgen in improving erectile dysfunction in castrated rats. Methods: Forty 8-week-old male Sprague-Dawley (SD) rats were randomly divided into 4 groups:normal control group (Group A); castration group (Group B, in which rats were castrated); intervention groups (group C and D), in which rats were treated with different concentrations of testosterone undecanoate orally every day at 10 mg/kg (low dose) and 20 mg/kg (high dose), respectively after being castrated. Animals in group A and B were given 0.9% NS instead. After 8-week treatment, the level of serum testosterone, intra cavernous pressure (ICP) and mean arterial pressure (MAP) were detected, and the expression of androgen receptor (AR)and vascular endothelial growth factor (VEGF) were detected in the penis by Immunohistochemistry and Western blot. Results: The level of serum testosterone was significantly lower in group B [(1.3±0.6) nmol/L] than in group A [(17.1±1.5) nmol/L] (P<0.05).After testosterone supplementation, serum testosterone levels in group C [(8.7±1.2) nmol/L] and group D [(15.5±1.6) nmol/L] were higher than that in group B (all P<0.05). Max ICP/MAP of group C and D were higher than that in group B (all P<0.05). Immunohistochemistry and Western blot showed that the expression levels of AR and VEGF in group B were significantly lower than those in group A, C and D, and group D > group C (all P<0.05). Conclusion: Androgen replacement therapy with testosterone undecanoate can improve the erectile function of castrated rats by protecting the integrity of endothelial cells through AR/VEGF pathway.

[Activation of HIF-1α/ß-catenin signal pathway leads to radioresistance of prostate cancer cells].

Objective: To investigate the role of hypoxia-inducible factor-1α (HIF-1α) and ß-catenin in radioresistance of prostate cancer (PCa) cells. Method: Two PCa cell lines, LNCaP and C4-2B, were grouped as: negative control (no treatment), HIF-1α overexpression group (transfected with HIF-1α plasmids), and ß-catenin silencing group (transfected with HIF-1α plasmids and ß-catenin-shRNA). Cell proliferation, cycle, invasion, and radiosensitivity were measured under normal or hypoxic condition. Radiosensitivity was tested in two mice PCa models (the LNCaP orthotopic BALB/c-nu mice model and the C4-2B subcutaneous SCID mice model). Results: In both LNCaP and C4-2B cells, HIF-1α transfection led to an enhanced ß-catenin nuclear translocation, while ß-catenin silencing inhibited the ß-catenin nuclear translocation. Enhanced ß-catenin nuclear translocation caused by HIF-1α overexpression resulted in enhanced cell proliferation and invasion, altered cell cycle distribution, reduced apoptosis, and improved non-homologous-end-joining (NHEJ) repair under irradiation condition. In vivo imaging of orthotopic models showed that HIF-1α overexpression LNCaP cells produced tumors with 3-fold volume (P=0.003 1) and 2-fold wet weight (P=0.039 4) than those by negative control cells at day 21, and ß-catenin silencing cells aberrantly reduced both tumor volume (P=0.000 3) and wet weight (P=0.017 5) than HIF-1α overexpression cells. In addition, C4-2B subcutaneous models showed similar tumor promotion effects induced by HIF-1α overexpression (tumor volume: P=0.000 1 and wet weight: P=0.047 3) and suppressive effects by ß-catenin silencing (tumor volume: P<0.000 1 and wet weight: P=0.022 1) as LNCaP orthotopic xenograft with regard to tumor volume and wet weight. Conclusions: HIF-1α overexpression enhanced ß-catenin nuclear translocation, which led to the activation of the ß-catenin/NHEJ signaling pathway and increased cell proliferation, invasion, and DNA repair. These results suggest that HIF-1α overexpression led to radioresistance of PCa cells.

[Long-term oncologic outcomes of localized high-risk prostate cancer undergoing brachytherapy combined with external-beam radiation therapy and maximal androgen blockade].

Objective: To investigate the oncologic outcome and PSA kinetics of localized high-risk prostate cancer (PCa) patients treated with combination strategy of radiation therapy (RT) and maximal androgen blockade (MAB). Methods: We retrospectively reviewed the clinical data of 320 localized PCa patients undergoing RT+ MAB from 2001 to 2015. And radiation treatment protocol consisted of permanent prostate brachytherapy (PPB) at 110 Gy and EBRT at 45 Gy/23 fractions. Results: The median follow-up time was 90 (range: 12-186) months. And 117 (36.6%) cases underwent MAB + external-beam radiotherapy (EBRT), and other 203 (63.4%) cases received MAB+ EBRT+ PPB. Multivariate Cox regression analyses showed that PSA kinetics were positive indicators of oncologic outcomes. Furthermore, PSA kinetics were aberrantly improved by supplemental PPB to MAB+ EBRT as following, PSA nadir (1.3±0.7)µg/L vs(0.11±0.06)µg/L, time of PSA decrease to nadir (7.5±1.8)months vs (3.2±2.1)months, PSA doubling time (15.6±4.2)months vs (22.6±6.1)months, PSA decreasing amplitude (84.6±6.2)%vs(95.8±3.4)%. Additionally, the median time of several important oncologic events in MAB+ EBRT+ PPB group were also prolonged than that in MAB+ EBRT group as following, overall survival (12.3 years vs 9.1 years, P<0.001), biochemical recurrence-free survival (9.8 years vs 6.5 years, P<0.001), skeletal-related event (10.4years vs 8.2 years, P<0.001), and cytotoxic chemotherapy (11.6 years vs 8.8 years, P=0.007). Conclusion: MAB+ EBRT+ PPB is extremely effective combination strategy for localized high-risk PCa patients, and PPB plays the important synergistic role in improving PSA kinetics, which are independent predictor for oncologic outcomes.

[Primary culture and functional identification of distal pulmonary artery smooth muscle cells in mice].

Objective: To establish a method of isolation and primary culture of mice distal pulmonary artery smooth muscle cells (PASMCs) and identify the functional properties. Methods: PASMCs were harvested from the distal pulmonary artery (PA) tissue of mice by enzymatic digestion of collagenaseⅠand papain; and the growth characteristics were observed under inverted microscope and identified by Immunofluorescence technique. Effects on the intracellular calcium ion concentration of distal PASMCs were detected by Fura-2-AM fluorescent probe tracer under a fluorescence microscope in Krebs solution containing clopiazonic acid (CPA) and nifedipin (Nif). Results: PASMCs density reached approximately to 80% in a typical valley-peak-like shape after 6 days. Cell α-smooth muscle actin (α-SMA) immunofluorescence identified that 95% of the cultured cells were PASMCs. More than 95% PASMCs responded well to calcium-potassium Krebs solution (potassium ion concentration of 60 mmol/L) and showed a rapid increase in basal [Ca(2+) ](i) after 1 minute's perfusion (Δ[Ca(2+) ](i)>50), which demonstrated that the voltage-dependent calcium channels (VDCC) of distal PASMCs were in good function; after the perfusion of calcium Krebs, calcium-free/calcium-Krebs containing CPA and Nif, distal PASMCs showed two typical peaks, indicated the full function of store-operated calcium channel (SOCC) in distal PASMCs. Conclusion: This experiment successfully established a stable and reliable mice distal PASMCs model and the study of pulmonary vascular diseases could benefit from its higher purity and better functional condition.