Pancreatic STAT5 activation promotes KrasG12D-induced and inflammation-induced acinar-to-ductal metaplasia and pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5 (STAT5) is a transcription factor implicated in the progression of various cancer types. However, its role in KRAS-driven pancreatic tumourigenesis remains unclear. DESIGN: We performed studies with LSL-Kras G12D; Ptf1a-Cre ERT (KCERT) mice or LSL-KrasG12D; LSL-Trp53R172H ; Pdx1-Cre (KPC) mice crossed with conditional disruption of STAT5 or completed deficiency interleukin (IL)-22. Pancreatitis was induced in mice by administration of cerulein. Pharmacological inhibition of STAT5 on PDAC prevention was studied in the orthotopic transplantation and patient-derived xenografts PDAC model, and KPC mice. RESULTS: The expression and phosphorylation of STAT5 were higher in human PDAC samples than control samples and high levels of STAT5 in tumour cells were associated with a poorer prognosis. The loss of STAT5 in pancreatic cells substantially reduces the KRAS mutation and pancreatitis-derived acinar-to-ductal metaplasia (ADM) and PDAC lesions. Mechanistically, we discovered that STAT5 binds directly to the promoters of ADM mediators, hepatocyte nuclear factor (HNF) 1ß and HNF4α. Furthermore, STAT5 plays a crucial role in maintaining energy metabolism in tumour cells during PDAC progression. IL-22 signalling induced by chronic inflammation enhances KRAS-mutant-mediated STAT5 phosphorylation. Deficiency of IL-22 signalling slowed the progression of PDAC and ablated STAT5 activation. CONCLUSION: Collectively, our findings identified pancreatic STAT5 activation as a key downstream effector of oncogenic KRAS signalling that is critical for ADM initiation and PDAC progression, highlighting its potential therapeutic vulnerability.

Effectiveness and safety of Moluodan in the treatment of precancerous lesions of gastric cancer: A randomized clinical trial.

OBJECTIVE: To investigate the clinical potential and safety of Moluodan to reverse gastric precancerous lesions. METHODS: Patients aged 18-70 years diagnosed with moderate-to-severe atrophy and/or moderate-to-severe intestinal metaplasia, with or without low-grade dysplasia, and negative for Helicobacter pylori were recruited in this randomized, double-blind, parallel-controlled trial. The primary outcome was the improvement of global histological diagnosis at 1-year follow-up endoscopy using the operative link for gastritis assessment, the operative link for gastric intestinal metaplasia assessment, and the disappearance rate of dysplasia. RESULTS: Between November 3, 2017 and January 27, 2021, 166 subjects were randomly assigned to the Moluodan group, 168 to the folic acid group, 84 to the combination group, and 84 to the high-dose Moluodan group. The improvement in global histological diagnosis was achieved in 60 (39.5%) subjects receiving Moluodan, 59 (37.8%) receiving folic acid, 26 (32.1%) receiving the combined drugs, and 36 (47.4%) receiving high-dose Moluodan. Moluodan was non-inferior to folic acid (95% confidence interval: -9.2 to 12.5; P = 0.02). High-dose Moluodan had a trend for better protective efficacy, though there was no statistical significance. The disappearance rate of dysplasia was 82.8% in the Moluodan group, which was superior to folic acid (53.9%; P = 0.006). No drug-related serious adverse events were observed. CONCLUSIONS: One pack of Moluodan three times daily for 1 year was safe and effective in reversing gastric precancerous lesions, especially dysplasia. Doubling its dose showed a better efficacy trend.

Fecal Signatures of Streptococcus anginosus and Streptococcus constellatus for Noninvasive Screening and Early Warning of Gastric Cancer.

BACKGROUND & AIMS: Most patients with gastric cancer (GCa) are diagnosed at an advanced stage. We aimed to investigate novel fecal signatures for clinical application in early diagnosis of GCa. METHODS: This was an observational study that included 1043 patients from 10 hospitals in China. In the discovery cohort, 16S ribosomal RNA gene analysis was performed in paired samples (tissues and feces) from patients with GCa and chronic gastritis (ChG) to determine differential abundant microbes. Their relative abundances were detected using quantitative real-time polymerase chain reaction to test them as bacterial candidates in the training cohort. Their diagnostic efficacy was validated in the validation cohort. RESULTS: Significant enrichments of Streptococcus anginosus (Sa) and Streptococcus constellatus (Sc) in GCa tumor tissues (P < .05) and feces (P < .0001) were observed in patients with intraepithelial neoplasia, early and advanced GCa. Either the signature parallel test Sa∪Sc or single signature Sa/Sc demonstrated superior sensitivity (Sa: 75.6% vs 72.1%, P < .05; Sc: 84.4% vs 64.0%, P < .001; and Sa∪Sc: 91.1% vs 81.4%, P < .01) in detecting early GCa compared with advanced GCa (specificity: Sa: 84.0% vs 83.9%, Sc: 70.4% vs 82.3%, and Sa∪Sc: 64.0% vs 73.4%). Fecal signature Sa∪Sc outperformed Sa∪CEA/Sc∪CEA in the discrimination of advanced GCa (sensitivity: 81.4% vs 74.2% and 81.4% vs 72.3%, P < .01; specificity: 73.4% vs 81.0 % and 73.4% vs 81.0%). The performance of Sa∪Sc in the diagnosis of both early and advanced GCa was verified in the validation cohort. CONCLUSION: Fecal Sa and Sc are noninvasive, accurate, and sensitive signatures for early warning in GCa. (ClinicalTrials.gov, Number: NCT04638959).

Bipedicle Advancement Flap for Skin Coverage after Digital Mucous Cyst Excision: A Retrospective Study of 18 Cases.

OBJECTIVES: To assess the clinical outcomes of using a bipedicle advancement flap to cover the skin defects after digital mucous cyst (DMC) excision. METHODS: Data for 15 patients (18 fingers) with DMC, admitted to the Department of Orthopaedics and Surgery of the Affiliated Zhongshan Hospital of Dalian University from January 2016 to January 2018, were analyzed retrospectively. This study included 4 men and 11 women, with a mean age of 64 ± 7.8 years (range, 47-77 years). A total of 5 cases involved the thumb, 4 involved the index finger, 5 involved ithe middle finger, and 4 involved the ring finger. Among a total of 18 digital mucous cysts, 7 cases were in the left hand and 11 were in the right hand. Approximately 77.8% of cases had osteophytes. The cysts ranged in size from 0.5-1.0 cm to 0.7-1.2 cm. All patients underwent cyst and osteophyte excision and a bipedicle advancement flap to cover the resultant defect. The same surgical procedure was applied to all patients. Postoperative flap survival, healing, and infection were evaluated. The preoperative and postoperative ranges of motion (ROM) of the distal interphalangeal (DIP) and thumb interphalangeal joints (TIPJ) were recorded. Postoperative patient satisfaction was assessed by the visual analog scale (VAS, 0-10) during follow-up visits. The Shapiro-Wilk test was used to determine whether the data for the difference between the preoperative and postoperative ROM of the DIP/TIPJ were normally distributed or not. The homogeneity of variance was expressed as mean ± standard deviation. A paired t-test was used to compare the preoperative and postoperative ROM of the DIP/TIPJ. RESULTS: The patients were followed up for 20 ± 6.0 months (range, 12-36 months). All the flaps survived after surgery, and the incisions healed well. The sutures were removed 2 weeks postoperatively. No infections occurred and there was no cyst recurrence at follow up. After systemic physical therapy and functional exercises, the ROM of all the fingers was restored to the preoperative ROM by 1 month after surgery. The scores for patient satisfaction with surgery by means of the VAS were 8.5 ± 1.0 points, 2.8 ± 1.4 points, 2.0 ± 1.6 points, 1.5 ± 1.2 points, and 1.1 ± 1.3 points preoperatively, and 1, 3, 6, and 12 months postoperatively, respectively. The data for the difference between preoperative and postoperative VAS scores were normally distributed. There were significant differences between the preoperative and postoperative VAS scores. The preoperative DIP/TIPJ ROM was 71.7° ± 14.0°, and the postoperative ROM at 1, 3, 6, and 12 months were 69.3° ± 15.3°, 70.4° ± 12.7°, 71.5° ± 15.6°, and 71.8° ± 15.6°, respectively. The data for the difference between preoperative and postoperative ROM of the DIP/TIPJ were normally distributed. No difference was found between the preoperative and postoperative ROM. CONCLUSION: The bipedicle advancement flap provides a simple and effective technique for covering skin defects following DMC excision.

Transplantation of bone marrow mesenchymal stromal cells attenuates liver fibrosis in mice by regulating macrophage subtypes.

BACKGROUND: Liver fibrosis is a key phase that will progress to further injuries such as liver cirrhosis or carcinoma. This study aimed to investigate whether transplantation of bone marrow mesenchymal stromal cells (BM-MSCs) can attenuate liver fibrosis in mice and the underlying mechanisms based on the regulation of macrophage subtypes. METHODS: A liver fibrosis model was induced by intraperitoneal (i.p.) injection of CCl4 twice per week for 70 days, and BM-MSCs were intravenously transplanted twice on the 60th and 70th days. Immunohistology and gene expression of liver fibrosis and macrophage subtypes were analyzed. Mouse RAW264.7 cells and JS1 cells (hepatic stellate cell strain) were also used to explore the underlying mechanisms of the effects of BM-MSCs on liver fibrosis. RESULTS: After transplantation of BM-MSCs, F4/80+CD206+-activated M2 macrophages and matrix metalloproteinase 13 (MMP 13) expression were significantly increased while F4/80+iNOS+-activated M1 macrophages were inhibited in liver tissue. Gene expression of IL-10 was elevated while IL12b, IFN-γ, TNF-α, and IL-6 gene expression were decreased. ΤGF-ß1 and collagen-1 secretions were reduced while caspase-3 was increased in JS1 cells treated with BM-MSC-conditioned media. BM-MSCs effectively suppressed the expression of α-SMA, Sirius red, and collagen-1 in the liver, which are positively correlated with fibrosis and induced by CCl4 injection. CONCLUSIONS: Taken together, we have provided the first demonstration that BM-MSC transplantation can promote the activation of M2 macrophages expressing MMP13 and inhibition of M1 macrophages to further inhibit hepatic stellate cells (HSCs), which play synergistic roles in attenuating liver fibrosis.

Uncontacted tire explosion causing trauma to bilateral lower extremities: A case report.

It is uncommon for tire explosion related injuries on the lower extremity. The bilateral lower extremities were injured by tire explosion when the patient was seated in a bus. She sustained an open fracture with partial bone loss in the right calcaneus (a comminuted fracture in the right ankle joint) and a closed comminuted fracture in the left tibia and fibula. This damage was caused by uncontacted tire explosion, thanks to a thick floor between the exploded tire and the patient's feet. This type of injury on lower extremity caused by uncontacted tire explosion was uncommon.

Predictors and outcome of acute kidney injury after transcatheter aortic valve implantation: a systematic review and meta-analysis.

AIMS: The aim of this systematic review and meta-analysis was to investigate the predictors and outcome of acute kidney injury (AKI) after transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: There were 35 articles recruiting 13,256 patients included in our study. Hypertension (odds ratio [OR] 1.92, 95% CI: 1.44 to 2.56), diabetes mellitus (OR 1.33, 95% CI: 1.20 to 1.47), peripheral artery disease (OR 1.28, 95% CI: 1.14 to 1.45) and a left ventricular ejection fraction <40% (OR 1.50, 95% CI: 1.19 to 1.88) were identified as significant independent predictors of AKI. In addition to the aforementioned comorbidities, procedure-related/post-TAVI factors such as transapical access (OR 1.68, 95% CI: 1.44 to 1.97), major bleeding (OR 1.82, 95% CI: 1.37 to 2.40) and transfusion (OR 1.30, 95% CI: 1.12 to 1.51) were also associated with a higher risk of AKI. Importantly, the risk of short-term all-cause death increased progressively with the aggravating severity of AKI (OR, 30 days: stage 1: 3.41; stage 2: 4.0; stage 3: 11.02; one year: stage 1: 1.95; stage 2: 2.82; stage 3: 7.34), as determined by a univariate analysis. After eliminating confounders, AKI remained linked to a higher risk for both short-term (30 days: HR 2.12, 95% CI: 1.59 to 2.83) and long-term (≥3 years: HR 1.37, 95% CI: 1.27 to 1.48) all-cause mortality. CONCLUSIONS: The reason for the occurrence of AKI was multifactorial, including baseline characteristics, procedure-related and post-TAVI factors. It appeared that even stage 1 AKI exerted detrimental effects on survival within one year, and AKI was also independently linked to mortality beyond three years.

Value of CT angiography in reducing the risk of hemorrhage associated with mini-percutaneous nephrolithotomy.

PURPOSE: To evaluate the clinical value of computed tomography angiography (CTA) in reducing the risk of hemorrhage associated with mini-percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: A total of 158 patients with renal or ureter stones who had undergone mini-percutaneous nephrolithotomy were retrospectively enrolled into this study from May of 2011 to April of 2014. Group 1 (65 patients) underwent computed tomography angiography, and Group 2 (93 patients) underwent non-contrast CT. The clinical characteristics of the patients and hemorrhagic complications were recorded. The hematologic complications (transfusion rate, and preoperative and postoperative hemoglobin values) were assessed. RESULTS: There were no statistically significant differences in age, body mass index(BMI), stone diameter, operative time, stone-free rate, and hospital stay between the 2 groups. In group 2, 1 patient (1.1%) developed a renal arteriovenous fistula and was treated with embolus therapy. In addition, Group 2 showed significantly drop in hemoglobin (3.6 g/dL vs. 2.4 g/dL, respectively; P < 0.001) and more transfusions (9.7% vs. 1.5%, respectively; P < 0.05) compared with Group 1. CONCLUSION: The study showed that patients who underwent computed tomography angiography prior to percutaneous nephrolithotomy had lower drop of hemoglobin and needed less transfusions. These findings may suggest that the use of computed tomography angiography may reduce the risk of bleeding during percutaneous nephrolithotomy.

Value of CT angiography in reducing the risk of hemorrhage associated with mini-percutaneous nephrolithotomy

ABSTRACTPurpose:To evaluate the clinical value of computed tomography angiography (CTA) in reducing the risk of hemorrhage associated with mini-percutaneous nephrolithotomy (PCNL).Materials and Methods:A total of 158 patients with renal or ureter stones who had undergone mini-percutaneous nephrolithotomy were retrospectively enrolled into this study from May of 2011 to April of 2014. Group 1 (65 patients) underwent computed tomography angiography, and Group 2 (93 patients) underwent non-contrast CT. The clinical characteristics of the patients and hemorrhagic complications were recorded. The hematologic complications (transfusion rate, and preoperative and postoperative hemoglobin values) were assessed.Results:There were no statistically significant differences in age, body mass index(BMI), stone diameter, operative time, stone-free rate, and hospital stay between the 2 groups. In group 2, 1 patient (1.1%) developed a renal arteriovenous fistula and was treated with embolus therapy. In addition, Group 2 showed significantly drop in hemoglobin (3.6 g/dL vs. 2.4 g/dL, respectively; P <0.001) and more transfusions (9.7% vs. 1.5%, respectively; P <0.05) compared with Group 1.Conclusion:The study showed that patients who underwent computed tomography angiography prior to percutaneous nephrolithotomy had lower drop of hemoglobin and needed less transfusions. These findings may suggest that the use of computed tomography angiography may reduce the risk of bleeding during percutaneous nephrolithotomy.

[Ten significantly differentially expressed genes in prostate cancer: Screening and verification].

OBJECTIVE: To screen and verify differentially expressed genes in prostate cancer. METHODS: Using DNA microarray, we screened differentially expressed genes in prostate cancer tissue and its adjacent tissue followed by verification by PCR. RESULTS: A total of 1 444 genes were found to be differentially expressed (differentiation ≥ 1.5-fold; P≤ 0.05) in the prostate cancer tissue, of which 769 (53%) were up-regulated and 675 (47%) down-regulated. Fifty percent of the differentially expressed genes showed a 1.5- to 2-fold differentiation, including 396 up-regulated and 182 down-regulated ones. Additionally, 308 up-regulated and 334 down-regulated genes exhibited a >2- to 5-fold, 46 up-regulated and 78 down-regulated genes a > 5- to 10-fold, and 19 up-regulated and 81 down-regulated genes a > 10-fold differentiation. Verification by subjecting 15 most significantly up-regulated and another 15 most markedly down-regulated genes to quantitative real-time PCR (qRT-PCR) showed that most of the genes had a transcriptional profile similar to that in the microarray data, with a Pearson correction coefficient of 0.83 between the microarray data and qRT-PCR results. Totally, 10 significantly differentially expressed genes were identified. CONCLUSION: DNA microarray analysis provides reliable information on differentially expressed genes in prostate cancer and benign tissues. The 10 significantly differentially expressed genes verified by qRT-PCR could possibly become new bio-markers and specific molecules for tumor identification.

Effect of MUC1 siRNA on drug resistance of gastric cancer cells to trastuzumab.

Trastuzumab is the first molecular targeting drug to increase the overall survival rate in advanced gastric cancer. However, it has also been found that a high intrinsic or primary trastuzumab resistance exists in some proportion of gastric cancer patients. In order to explore the mechanism of resistance to trastuzumab, firstly we investigated the expression of MUC1 (membrane-type mucin 1) in gastric cancer cells and its relationship with drug-resistance. Then using gene-silencing, we transfected a siRNA of MUC1 into drug-resistant cells. The results showed the MKN45 gastric cell line to be resistant to trastuzumab, mRNA and protein expression of MUC1 being significantly upregulated. After transfection of MUC1 siRNA, protein expression of MUC1 in MKN45cells was significantly reduced. Compared with the junk transfection and blank control groups, the sensitivity to trastuzumab under MUC1 siRNA conditions was significantly increased. These results imply that HER2-positive gastric cancer cell MKN45 is resistant to trastuzumab and this resistance can be cancelled by silencing expression of the MUC1 gene.

[Synergetic killing effects of external magnetic fields combined with porphyrin-dextran magnetic nanoparticles on the human bladder cancer cells].

OBJECTIVE: To study the synergetic killing effects of external magnetic fields combined with the photodynamic action of porphyrin-dextran iron oxide magnetic nanoparticles (PDMN) on human bladder cancer cells in vitro. METHODS: The PDMN were produced by using the chemical co-precipitation and redox process and the physicochemical properties were characterized. Methyl thiazolyl tetrazolium (MTT) and flow cytometry were used to determine the effects of photodynamic therapy of PDMN combined with external pulsed electromagnetic fields (5 mT) on killing human bladder cancer BIU-87 cells respectively. RESULTS: The diameters of PDMN were 10-15 nm and the saturation magnetization was 0.20 emu/g. Effective diameter of PDMN was 94.8 nm. PDMN could remarkably inhibit the proliferation and induce the obvious apoptosis of BIU-87 cells, and the rates of growth inhibition and apoptosis were (17.61±2.73)% and (24.53±5.74)% respectively. Moreover, external pulsed electromagnetic fields (5 mT) could also suppress the proliferation and induce apoptosis of BIU-87 cells. Furthermore, the photodynamic action of PDMN combined with external magnetic fields significantly inhibited the proliferation and promote apoptosis of BIU-87 cells, and the rates of growth inhibition and apoptosis was (28.11±4.25)% and (24.53±5.74)%, respectively, which were significantly higher than those of other groups (P<0.01). CONCLUSION: The chemical modified photodynamic action of PDMN could effectively inhibit proliferation and induce apoptosis of BIU-87 cells. Moreover, these effects on BIU-87 cells could be strengthened by the combination with external magnetic fields.

[Establishment and preliminary application of multiplex PCR for detecting the microsatellite markers in silkies].

In order to obtain the stable PCR combinations for silkies genetic analysis, multiplex PCR was used and its reaction condition was optimized. Five combinations of multiplex PCR with good effects were obtained from eighteen microsatellite markers. Three of them were quadruplex-PCRs, and two were triplex-PCRs. The products of multiplex PCR were further combined into three sets for the electrophoresis on ABI 3100-Avant Genetic Analyzer. The results suggested that the eighteen microsatellite markers could be successfully applied to the silkies genetic analysis.

[The population genetic structure analysis via microsatellite loci in new Silkies laying breeds].

Twenty microsatellite markers selected from the chicken GENBANK were analyzed for polymorphism in two new Silkies laying breeds. Allele frequencies were tested by the auto scan on ABI 3100-Avant Genetic Analyzer. The results suggested that the optimization test of multiplex PCR was successful and 18 pairs of microsatellite DNA markers were polymorphic. The average number of alleles detected by a pair of primers was 7.444. The average value of PIC was 0.669. The average observation population heterzygosity of the 18 markers was 0.3962, and the average expected population heterzygosity of the 18 markers was 0.7301. The number of bands tested on the auto scan was higher than that based on band presence or absence on gel, thus it was more suitable for genetic population analysis.

Demographic determinants for change in activities of daily living: a cohort study of the elderly people in Beijing.

To describe changes in activities of daily living (ADL) of community-dwelling Beijing elderly people, observed for 8 years, and to identify the demographic characteristics that predict the functional change. Four sets of interview data from 1992 to 2000 were used to evaluate changes among Beijing elderly aged 55 years and over. Results revealed that prevalence of disability increased from 3.9% to 7.1% during the 8 years of follow-up with the average increasing rate of disability was 0.41% per year. Meanwhile an increasing likelihood of recovery from disability is observed with age and time. Women, aged 75 or more, experienced higher disability than men though it was in the opposite for younger ages. In addition, certain demographic subgroups (such as women, unmarried, illiterate and living in non urban area) appeared to be at higher risk for ADL impaired. The patterns of ADL change is in both the direction of improvement and declination. Demographic variables emerged as a significant predictor in estimating functional outcomes. Furthermore, it is recommended that the demarcation factor for the evaluation of ADL should be 75 years of age.