[Completion rates of bundle treatment of among patients with sepsis shock in intensive care departments of hospitals in Jiangsu Province from 2016 to 2020 years].

Current clinical approaches for septic shock increasingly incorporate bundle treatment, a multi-component approach that uses a collection of tests and agents to assist in the identification and treatment of infection. The present study analyzed completion rates of 3 h and 6 h bundle treatment among patients with septic shock in intensive care units (ICUs) of hospitals in Jiangsu Province from 2016 to 2020, using data from the Jiangsu Provincial Intensive Care Medical Quality Control Center. Current approaches and factors affecting treatment completion were assessed.The completion rates of 3 h and 6 h bundle treatment in ICUs of all medical units in Jiangsu Province and in ICUs of hospitals of different levels were recorded. Analyses show that the completion rate of 3 h and 6 h bundle treatment for patients with septic shock in ICUs in Jiangsu Province increased year by year from 2016 to 2020.The completion rate of 3 h bundle treatment increased from 69.82% (3 604/5 162) to 82.47% (8 915/10 775) (all P<0.001). The completion rate of 6 h bundle treatment increased from 62.69% (3 236/5 162) to 72.54% (7 816/10 775) (all P<0.001). In addition, year by year, the completion rate of 3 h bundle treatment in ICUs in tertiary hospitals increased, from 69.80% (3 596/5 152) to 82.23% (7 375/8 969), while the completion rate of 6 h bundle treatment increased from 62.69% (3 230/5 152) to 72.18% (6 474/8 969) (all P<0.001). Completion rates in secondary hospitals also increased year by year, from 80.00% (8/10) to 85.27% (1 540/1 806) for 3 h treatment and from 60.00% (6/10) to 74.31% (1 342/1 806) (all P<0.001) for 6 h treatment. Completion rates for 3 h treatment in first-tier cities (83.99% (2 099/2 499)) and second-tier cities (84.68% (3 952/4 667)) was higher than in third-tier cities (79.36% (2 864/3 609)). The completion rate of 6 h bundle treatment gradually decreased in first-line (77.19% (1 929/2 499)), second-line (74.37% (3 471/4 667)), and third-line (66.94% (2 416/3 609)) cities (all P<0.001). The data collectively show that from 2016 to 2020, the completion rate of bundle treatment in septic shock patients in ICUs in Jiangsu Province improved significantly.

[Mechanism of circZNF609 targeting miR-153 to regulate the proliferation and apoptosis of diffuse large B-cell lymphoma].

Objective: To investigate the molecular mechanism of circZNF609 targeting miR-153 to regulate the proliferation and apoptosis of diffuse large B-cell lymphoma. Methods: Fifty cases of lymphoma tissue from patients with diffuse large B-cell lymphoma who were diagnosed and treated in the First Affiliated Hospital of Zhengzhou University from July 2018 to December 2019 were collected. Thirty cases of normal lymph node tissues that were confirmed to be reactive hyperplasia by pathological diagnosis during the same period were selected as controls. Real time quantitative polymerase chain reaction (PCR) was used to detect the expression of circZNF609 in diffuse large B-cell lymphoma tissues and control hyperplasia lymph nodes. Diffuse large B-cell lymphoma OCI-LY19 cells were divided into control group (blank control), si-con group (transfected with siRNA control), si-ZNF609 group (transfected with circZNF609 siRNA), and si-ZNF609+ Anti-NC group (co-transfected with circZNF609 siRNA and inhibitor control) and si-ZNF609+ Anti-miR-153 group (co-transfected with circZNF609 siRNA and miR-153 inhibitor). Cell counting kit-8 (CCK-8) was used to detected proliferation, flow cytometry was used to detect cell cycle and apoptosis. Western blot was used to detect the protein expressions of C-caspase-3, cyclin D1, p21. The luciferase reporter system was used to identifie the relationship between circZNF609 and miR-153. Results: The expression level of circZNF609 in diffuse large B-cell lymphoma tissue was (1.44±0.22), higher than (0.37±0.14) in the control tissues (P<0.001). The cell survival rate of the si-ZNF609 group was (51.74±6.39)%, lower than (100.00±10.23)% of the control group and the (99.64±11.67)% of the si-con group (P<0.001). The proportion of cells in the G(0)/G(1) phase was (63.25±4.11)%, higher than (48.62±4.32)% of the control group and (47.12±3.20)% of the si-con group (P<0.001), the apoptosis rate was (13.36±1.42)%, higher than (3.65±0.47)% of the control group and (3.84±0.62)% of the si-con group (P<0.05). The expression levels of C-caspase-3 and p21 protein were (0.85±0.09) and (0.90±0.08), higher than (0.38±0.04) and (0.65±0.07) in the control group and (0.39±0.05) and (0.66±0.05) in the si-con group (P<0.001). The expression level of cyclin D1 protein was (0.40±0.03), lower than (0.52±0.06) of the control group and (0.53±0.04) of the si-con group (all P<0.001). CircZNF609 and miR-153 are mutually targeted. The cell survival rate of the si-ZNF609+ Anti-miR-153 group was (169.92±13.25)%, higher than (100.00±9.68)% of the si-ZNF609+ Anti-NC group (P<0.001), the ratio of cells in G(0)/G(1) phase and apoptosis rate were (52.01±3.62)% and (8.20±0.87)%, respectively, lower than (64.51±5.17)% and (14.03±1.17)% in the si-ZNF609+ Anti-NC group (P<0.001). The protein expression levels of C-caspase-3 and p21 were (0.42±0.06) and (0.52±0.06), lower than (0.80±0.07) and (0.92±0.10) of the si-ZNF609+ Anti-NC group (P<0.001). The protein expression level of cyclin D1 was (0.68±0.07), higher than (0.39±0.04) in the si-ZNF609+ Anti-NC group (P<0.001). Conclusion: Down-regulation of circZNF609 inhibits the proliferation of diffuse large B-cell lymphoma OCI-LY19 cells and induces apoptosis by targeting miR-153.

Clinical study and observation on the effect of hemoperfusion therapy treatment on central nervous system injury in patients with 2,4-dichlorophenoxyacetic acid poisoning.

OBJECTIVE: To evaluate the curative effect of hemoperfusion therapy on central nervous system injury in patients with 2,4-dichlorophenoxyacetic acid poisoning. PATIENTS AND METHODS: A total of 60 patients with 2,4-dichlorophenoxyacetic acid poisoning were enrolled in this study. They were admitted to the Emergency Department of Qinghai Provincial People's Hospital from 2015 to 2018 and were randomly divided into two groups by random number table method. One group was control group (routine treatment group), and the other group was the treatment group (hemoperfusion therapy was added on the basis of routine treatment). Glasgow coma score (GCS), APACHE II score, and MMSE score were used to evaluate the effects before treatment and 7 days after treatment. The results were statistically analyzed. RESULTS: After treatment, GCS in the treatment group was higher than that in the control group, while APACHE II score was lower than that in the control group, and MMSE score was significantly higher than that in the control group, with statistically significant difference (p<0.05). The effective rate in the control group was only 26.67%, and that in the treatment group was 86.67%, with statistically significant difference (c2=19.62, p<0.001). CONCLUSIONS: Hemoperfusion therapy can promote the recovery of central nervous system in patients with 2,4-dichlorophenoxyacetic acid poisoning, reduce the injury of other organs, and significantly reduce the mortality of patients.

[Application of radiomics captured from CT to predict the EGFR mutation status and TKIs therapeutic sensitivity of advanced lung adenocarcinoma].

Objective: To explore the ability of computed-tomography (CT) radiomic features to predict the Epidermal growth factor receptor (EGFR) mutation status and the therapeutic response of advanced lung adenocarcinoma to EGFR- Tyrosine kinase inhibitors (TKIs) treatment. Methods: A retrospective analysis was performed on 253 patients diagnosed as advanced lung adenocarcinoma, who underwent EGFR mutation detection, and those with EGFR sensitive mutation were treated with TKIs. Using the Lasso regression model and the 10 fold cross-validation method, the radiomic features of predicted EGFR mutation status and the screening of TKIs for sensitive populations were obtained. 715 radiomic features were extracted from unenhanced, arterial phase and venous phase, respectively. Results: The area under curve (AUC) values of the multi-phases including unenhanced, arterial phase and venous phase of the EGFR mutation status validation group were 0.763, 0.807 and 0.808, respectively. The number of radiomic features extracted from the multi-phases were 5, 18 and 23, respectively, which could distinguish the EGFR mutation status. The AUC values of the multi-phases of the EGFR-TKIs sensitive validation group were 0.730, 0.833 and 0.895, respectively. The number of radiomic features extracted from the multi-phases were 3, 7 and 22, respectively, which can be used to screen the superior population for TKIs treatment. The efficiency of radiomic features extracted from venous phase in predicting EGFR mutant status and EGFR-TKIs sensitivity was significantly superior than those of unenhanced and arterial phase. Conclusions: The radiomic features of CT scanning can be used as the radiomics biomarker to predict the EGFR mutation status of lung adenocarcinoma and to further screen the dominant population in TKIs therapy, which provides the basis for targeted therapy.

MiR-613 promotes cell proliferation and invasion in cervical cancer via targeting PTPN9.

OBJECTIVE: To investigate the potential effects of miR-613 on the development of cervical cancer (CC) and the relevant mechanism. PATIENTS AND METHODS: The expression level of miR-613 was detected in CC tissues and cells (siHa) by comparing with corresponding adjacent normal tissues and normal human embryonic kidney cells (293T). Luciferase assay was performed to evaluate the interaction between miR-613 and PTPN9. The effects of the miR-613 on siHa cells were determined by subsequent experiments including cell proliferation, invasion and migration. RESULTS: In our study, miR-613 was found up-regulated in CC tissues and the same result was found at cellular level. The potential target of miR-613 was analyzed by three public databases. We found that tyrosine-protein phosphatase non-receptor type 9 (PTPN9) was a direct target of miR-613, and Luciferase assays confirmed our hypothesis. The subsequent experiments showed that decreased expression of PTPN9 resulting from up-regulation of miR-613 could promote the cell proliferation, invasion and migration of CC cells. CONCLUSIONS: We showed the promotion function of miR-613 on CC by targeting PTPN9 and revealed that miR-613/PTPN9 axis might be a potential therapeutic target for the treatment of CC.

MST1 down-regulation in decreasing apoptosis of aortic dissection smooth muscle cell apoptosis.

OBJECTIVE: Elevated apoptosis of vascular smooth muscle cell (VSMC) is correlated with the occurrence of aortic dissection (AD). Mammalian ste20-like protein kinase 1 (MST1) is one important component of Hippo-YAP signal pathway for activation and cell apoptosis facilitation. Whether MST1 plays a role in AD pathogenesis is unclear yet. This study established an AD rat model to investigate the role of MST1 in regulating VSMC apoptosis and AD pathogenesis. MATERIALS AND METHODS: Cell apoptosis was compared between AD vascular tissues and normal rats, in addition to Caspase-3 activity, and expression of MST1, p-LATS1, p-YAP1, YAP1. In vitro cultured VSMCs from AD rats were treated with siRNA-MST1 to test apoptotic rate and Caspase-3 activity. AD model rats were treated with pGLVU6/GFP-MST1 for comparing MST1, p-LATS1, p-YAP1, and YAP1 expression, along with Caspase-3 activity, cell apoptosis, AD formation rate, diameter, and length. RESULTS: Compared to control group, AD rats had elevated vascular cell apoptosis, Caspase-3 activity, expressions of MST1, p-LATS1, and p-YAP1, plus lower YAP1 expression. siRNA interference of MST1 significantly inhibited apoptosis of in vitro cultured VSMC. shRNA lentivirus targeting MST1 pGLVU6/GFP-MST1 remarkably decreased expression of MST1, p-LATS1, and p-YAP1 in AD rat vascular tissues, increased YAP1 expression, decreased VSMC apoptosis, AD formation rate, AD diameter/length. CONCLUSIONS: MST1 up-regulation plays a role in facilitating VSMC apoptosis and AD pathogenesis. Down-regulation of MST1 decreased VSMC apoptosis and AD formation.

The impact of robotic surgery on quality of life, urinary and sexual function following total mesorectal excision for rectal cancer: a propensity score-matched analysis with laparoscopic surgery.

AIM: Quality of life (QoL) and functional outcomes are at risk of being impaired after rectal surgery, but there has been no large prospective study to thoroughly assess QoL according to surgical approach. We have investigated the impact of laparoscopic and robotic total mesorectal excision (TME) on QoL and functional outcomes. METHOD: Patients undergoing laparoscopic or robotic TME for rectal cancer between 2009 and 2013 were prospectively included in this questionnaire-based survey of QoL together with variations in urinary and sexual function. A propensity score analysis was retrospectively conducted to compare outcomes between groups in a cohort matched 1:1 for age, sex, body mass index, preoperative chemoradiation status and tumour height. The survey was performed preoperatively and 3, 6 and 12 months after surgery. RESULTS: Global health status/QoL was similar between the two groups for 130 matched pairs, but the robotic group showed better role, emotional and social functioning and experienced less fatigue and financial difficulty. International Prostatic Symptom Scores in men increased postoperatively, with significantly less impairment in the robotic group at 6 months. These scores were comparable to preoperative scores at 6 months in the robotic group and at 12 months in the laparoscopic group. Of 48 sexually active men in each group, International Index of Erectile Function-5 scores decreased postoperatively, returning to preoperative levels at 6 months in the robotic group and at 12 months in the laparoscopic groups. CONCLUSION: The robotic approach for TME was associated with less impairment of urinary and sexual function; QoL was comparable to the laparoscopic approach.

Clinical prognostic value of A FOXM1 related long non-coding RNA expression in gastric cancer.

OBJECTIVE: The aim of this study was to explore FOXM1-related LncRNA 1(FRLnc1) expression level in gastric cancer (GC) and demonstrate its association with the prognosis. PATIENTS AND METHODS: A total of 173 GC patients from Affiliated Hospital of Jining Medical University were enrolled in the study. GC tissue samples were quantified for FRLnc1 expression level using quantitative PCR (qPCR) method. The relevance between FRLnc1 expression and clinicopathological features was determined by x2-test. The association between FRLnc1 expression and overall survival was estimated by the Kaplan-Meier method. Multivariate and univariate analysis were performed to explore whether FRLnc1 was an independent prognostic factor for GC patients. RESULTS: We found that FRLnc1 expression was higher in GC tissues than corresponding adjacent tissues (p < 0.01). Increased FRLnc1 expression was associated with depth of tumor (p = 0.004), differentiation degree (p = 0.032), distant metastasis (p = 0.007), TNM stage (p = 0.006) and lymph node metastasis (p = 0.012). More importantly, Kaplan-Meier survival analysis demonstrated that overall patient survival for those with low FRLnc1 expression was significantly longer than those patients with high FRLnc1 expression (p < 0.001). Multivariate analysis suggested that FRLnc1 expression was an independent prognostic marker for survival in patients with GC. CONCLUSIONS: The data presented in this work firstly suggested that FRLnc1 may be a prognostic predictor in GC.

Analysis on application timing of IABP in emergency PCI treatment of patients with combined acute myocardial infarction and cardiac shock.

OBJECTIVE: To study the application timing and effect of intra-aortic balloon pump (IABP) in the emergency PCI treatment of patients with combined acute myocardial infarction (AMI) and cardiogenic shock (CS). PATIENTS AND METHODS: 84 cases of patients with combined AMI and CS under PCI in emergency treatment were randomly divided into the control group (n=42) and observational group (n=42). The control group underwent IABP again, after the invalidation of internal medicine drug treatment, while the observational group underwent IABP before the operation. We compared the effects of treatment. RESULTS: After the intervention, the averages of arterial pressure and urine volume were increased in both groups than before (p <0.05). The average of heart rate was decreased, and the improvement in the observational group was more significant (p <0.05). However, the mortality rate in the observational group during the perioperative period was decreased than the control group as well as, the success rate of off-respirator was significant (p <0.05). The comparison of IABP complication occurrence rate as well as the survival rate after 1-year follow-up between both groups was not significantly different. Additionally, whereas the NYHA grouping in two groups was gradually improved, the difference was not statistically significant between both groups. However, in the observational group, the LVEF after one-month follow-up was significantly higher than in the control group (p <0.05), but not when comparing 1-year. VEDd at each time point in two groups were also similar. CONCLUSIONS: The early IABP can improve hemodynamics of patients with combined AMI and CS under emergency PCI. It can reduce perioperative mortality rate, improve the success rate of off-respirator, but cannot increase IABP complication incidence rate while having little influence on the long-term survival rate and cardiac function indicator.

The upper-limb volumetric changes in breast cancer survivors with axillary web syndrome.

Whether upper-limb swelling is associated with axillary web syndrome (AWS) is unknown. We recruited unilateral breast cancer (BC) patients who were scheduled for surgical intervention and lymph node dissection. The pre-operative assessment and post-operative assessment 3-4 weeks after surgery evaluated the upper-limb circumferential measurements, segmental limb volume, pain scores, grasp, shoulder range of motion (ROM), shoulder muscle power and quality-of-life scores. In the control group, the peri-elbow volume and upper-arm volume were significantly higher post-operatively than pre-operatively. In the AWS group, no significant difference was found. In comparison with the control group, the AWS group had significantly more pain, less active ROM in shoulder abduction and a lower upper-limb volume at 0-10 cm proximal to the lateral epicondyle. The incidence of lymphedema was 9.9% and was not associated with AWS. AWS is a common morbidity of lymph node dissection and causes significant pain and restricted shoulder abduction in the affected limb in BC survivors. This study is the first to investigate post-operative upper-limb volumetric changes in BC survivors with and without AWS. Our findings are of great value for the clinical effect of AWS in BC survivors, for patient education, and for developing diagnostic tools for detecting AWS.

Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice.

In humans, the composition of gut commensal bacteria is closely correlated with obesity. The bacteria modulate metabolites and influence host immunity. In this study, we attempted to determine whether there is a direct correlation between specific commensal bacteria and host metabolism. As mice aged, we found significantly reduced body weight and fat mass in Atg7ΔCD11c mice when compared with Atg7f/f mice. When mice shared commensal bacteria by co-housing or feces transfer experiments, body weight and fat mass were similar in both mouse groups. By pyrosequencing analysis, Bacteroides acidifaciens (BA) was significantly increased in feces of Atg7ΔCD11c mice compared with those of control Atg7f/f mice. Wild-type C57BL/6 (B6) mice fed with BA were significantly more likely to gain less weight and fat mass than mice fed with PBS. Of note, the expression level of peroxisome proliferator-activated receptor alpha (PPARα) was consistently increased in the adipose tissues of Atg7ΔCD11c mice, B6 mice transferred with fecal microbiota of Atg7ΔCD11c mice, and BA-fed B6 mice. Furthermore, B6 mice fed with BA showed elevated insulin levels in serum, accompanied by increased serum glucagon-like peptide-1 and decreased intestinal dipeptidyl peptidase-4. These finding suggest that BA may have potential for treatment of metabolic diseases such as diabetes and obesity.

[Survey of continuous renal replacement therapy application status].

Objective: To investigate the condition of implementation of continuous renal replacement therapy (CRRT) in quality control center of critical care medicine. Methods: Questionnaire mails were issued to all of the quality control respondents to survey the application of CRRT in June 2015 from Jiangsu quality control center of critical care medicine. Results: Among the 69 quality control respondents, 62 were equipped with CRRT devices, and in 58 of which patients were treated with CRRT. There were 195 doctors and 253 nurses in 62 quality control respondents attended CRRT training at or above the provincial level; the proportions of hospitals in southern, central and northern regions of Jiangsu were 63%, 79% and 86% respectively with trained doctors (more than 2), and 34%, 38% and 43% respectively with trained nurses (more than 3). The preferred material for CRRT filter were AN69 and acrylic, accounting for 48% and 45% respectively. The average life span was less than 12 h for 21% filters, 12-24 h for 34% filters, and more than 72 h for only 2% filters. Manual displacement liquids were currently mainly used in our province, accounting for 75%. Heparin is the most frequently used anticoagulants, accounting for 48%. Citrate and low molecular weight heparin used for anticoagulation accounted for 31% and 21% respectively. Bleeding was the most common clinical complication (43%) in patients with CRRT, followed by low temperature (22%). The average hospitalization expenses for patients with CRRT amounted to 69 643 yuan RMB per person, in which the cost for CRRT accounted for 19 525 yuan RMB per person. Conclusion: The application of CRRT varies in filter materials, anticoagulants, replacement frequencies and dilution mode. Bleeding is the most common clinical complication in patients with CRRT. Besides, the proportion of trained doctors and nurses at the provincial level is still very low. It will be improved with intensive training and reasonable implementation for us to prolong the lifespan of the filters and reduce the cost for patients with CRRT.

Rectal tube drainage reduces major anastomotic leakage after minimally invasive rectal cancer surgery.

AIM: Anastomotic leakage is the most serious complication following low anterior resection for rectal cancer and is a major cause of postoperative morbidity and mortality. The object of the present study was to investigate whether rectal tube drainage can reduce anastomotic leakage after minimally invasive rectal cancer surgery. METHOD: Three hundred and seventy-four patients who underwent laparoscopic or robotic LAR for tumours located ≤ 15 cm above the anal verge between 1 April 2012 and 31 October 2014 were assessed retrospectively. Of these, 107 with intermediate risk of anastomotic leakage received transanal rectal tube drainage. The rectal tube group was matched by propensity score analysis with patients not having rectal tube drainage, giving 204 patients in the study. Covariates for propensity score analysis included age, sex, body mass index, tumour height from the anal verge and preoperative chemoradiation. RESULTS: Patient demographics, tumour location, preoperative chemoradiation and operative results were similar between the two groups. The overall leakage rate was 10.8% (22/204), with no significant difference between the rectal tube group (9.8%) and the nonrectal tube group (11.8%, P = 0.652). Of the patients with anastomotic leakage, major leakage requiring reoperation developed in 11.8% of those without and 3.9% of those with a rectal tube. On multivariate analysis, age over 65 years and nonuse of a rectal tube were found to be independent risk factors for major anastomotic leakage. CONCLUSION: Rectal tube placement may be a safe and effective method of reducing the rate of major anastomotic leakage, alleviating the clinical course of leakage following minimally invasive rectal cancer surgery.

[Mutation status of epidermal growth factor receptor and KRAS gene in non-small cell lung cancers at Xuanwei regions of Yunnan Province].

OBJECTIVE: To investigate the mutation status of epidermal growth factor receptor (EGFR) and KRAS gene in patients with non-small cell lung cancer (NSCLC) in Xuanwei, Yunnan and to correlate the mutation status with clinicopathologic features. METHODS: Mutation status of exons 18, 19, 20 and 21 of EGFR, and codons 12, 13 of KRAS in 63 cases of NSCLC were analyzed by gene sequencing and ARMS-Taqman probe method. Correlation with patients' clinicopathological characteristics was performed. RESULTS: EGFR and KRAS mutations were present in 55.6% (35/63) and 6.3% (4/63), respectively. EGFR gene mutations were present, including exon 18 G719X in 14.3% (5/35), exon 19 in 14.3% (5/35), exon 20 S768I and T790M in 20.0% (7/35), exon 21 L858R in 31.4% (11/35), exon 18 G719X and exon 20 S768I double mutation in 17.1% (6/35), and exon 20 T790M and exon 21 L858R double mutation in 2.9% (1/35). KRAS mutations were seen in codon 12 in 3 of 4 cases, and codon 13 in 1 of 4 cases. EGFR mutations were mutually exclusive with KRAS mutations. According to statistic analysis, EGFR mutations were associated with the histological types of NSCLC(P<0.05), but without correlation with patient's gender, age, smoking status and lymph node metastasis(P>0.05). KRAS mutations in NSCLC had no correlation with the clinical pathologic characteristics of the patients. CONCLUSIONS: A higher frequency of EGFR exon 18 G719X and 20 exon S768I mutations are found in the patients in Xuanwei, Yunnan. EGFR mutations are associated with histologic types of NSCLC, but without correlation with patient's gender, age, smoking status and lymph node metastasis. KRAS mutation in NSCLC has no correlation with the clinicopathologic characteristics of the patients.

Predictive factors of rapidly progressive-interstitial lung disease in patients with clinically amyopathic dermatomyositis.

Clinically amyopathic dermatomyositis (CADM) is a unique subset of dermatomyositis, showing a high incidence of lung involvements. The aim of this study is to identify risk factors, other than melanoma differentiation-associated protein (MDA)-5, for developing rapidly progressive-interstitial lung disease (RP-ILD) in patients with CADM. Forty CADM patients, in whom 11 patients developed RP-ILD, were enrolled. Clinical features and laboratory findings were compared between the patients with and without RP-ILD. We found that skin ulceration, CRP, serum ferritin, anti-MDA5 Ab, and lymphocytopenia were significantly associated with ILD. Multivariate logistic regression analysis indicated that anti-MDA5 Ab(+), elevated CRP, and decreased counts of lymphocyte were independent risk factors for RP-ILD, which can provide a precise predict for RP-ILD in CADM patients. When anti-MDA5 Ab(+) was removed from the multivariate regression model, using skin ulcerations, elevated serum ferritin and decreased counts of lymphocyte can also precisely predict RP-ILD. Except for MDA-5, more commonly available clinical characteristics, such as skin ulcerations, serum ferritin, and count of lymphocyte may also help to predict prognosis in CADM.

Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death.

Blockade of fatty acid synthase (FASN), a key enzyme involved in de novo lipogenesis, results in robust death of ovarian cancer cells. However, known FASN inhibitors have proven to be poor therapeutic agents due to their ability to induce cachexia. Therefore, we sought to identify additional targets in the pathway linking FASN inhibition and cell death whose modulation might kill ovarian cancer cells without the attendant side effects. Here, we show that the initiator caspase-2 is required for robust death of ovarian cancer cells induced by FASN inhibitors. REDD1 (also known as Rtp801 or DDIT4), a known mTOR inhibitor previously implicated in the response to FASN inhibition, is a novel caspase-2 regulator in this pathway. REDD1 induction is compromised in ovarian cancer cells that do not respond to FASN inhibition. Inhibition of FASN induced an ATF4-dependent transcriptional induction of REDD1; downregulation of REDD1 prevented orlistat-induced activation of caspase-2, as monitored by its cleavage, proteolytic activity and dimerization. Abrogation of REDD1-mediated suppression of mTOR by TSC2 RNAi protected FASN inhibitor-sensitive ovarian cancer cells (OVCA420 cells) from orlistat-induced death. Conversely, suppression of mTOR with the chemical inhibitors PP242 or rapamycin-sensitized DOV13, an ovarian cancer cell line incapable of inducing REDD1, to orlistat-induced cell death through caspase-2. These findings indicate that REDD1 positively controls caspase-2-dependent cell death of ovarian cancer cells by inhibiting mTOR, placing mTOR as a novel upstream regulator of caspase-2 and supporting the possibility of manipulating mTOR to enhance caspase-2 activation in ovarian cancer.

Potent anti-tumour activity of a novel conditionally replicating adenovirus for melanoma via inhibition of migration and invasion.

BACKGROUND: Conditionally replicating adenoviruses (CRAds) represent a novel class of oncological therapeutic agents. One strategy to ensure tumour targeting is to place the essential viral genes under the control of tumour-specific promoters. Ki67 has been selected as a cancer gene therapy target, as it is expressed in most malignant cells but is barely detectable in most normal cells. This study aimed to investigate the effects of a Ki67 promoter-controlled CRAd (Ki67-ZD55-IL-24) on the proliferation and apoptosis of melanoma cells. METHODS: Melanoma cells were independently treated with Ki67-ZD55-IL-24, ZD55-IL-24, Ki67-ZD55, and ZD55-EGFP. The cytotoxic potential of each treatment was assessed using cell viability measurements. Cell migration and invasion were assayed using cell migration and invasion assays. Apoptosis was assayed using the annexin V-FITC assay, western blotting, reverse transcriptase PCR (RT-PCR), haematoxylin and eosin (H&E) staining, and the TUNEL assay. RESULTS: Our results showed that Ki67-ZD55-IL-24 had significantly enhanced anti-tumour activity as it more effectively induced apoptosis in melanoma cells than the other agents. Ki67-ZD55-IL-24 also caused the most significant inhibition of cell migration and invasion of melanoma cells. Furthermore, apoptosis was induced more effectively in melanoma xenografts in nude mice. CONCLUSIONS: This strategy holds promising potential for the further development of an effective approach to treat malignant melanoma.

Activation of Akt signaling in prostate induces a TGFß-mediated restraint on cancer progression and metastasis.

Mutations in the PTEN tumor suppressor gene are found in a high proportion of human prostate cancers, and in mice, Pten deletion induces high-grade prostate intraepithelial neoplasia (HGPIN). However, progression from HGPIN to invasive cancer occurs slowly, suggesting that tumorigenesis is subject to restraint. We show that Pten deletion, or constitutive activation of the downstream kinase AKT, activates the transforming growth factor (TGF)ß pathway in prostate epithelial cells. TGFß signaling is known to have a tumor suppressive role in many cancer types, and reduced expression of TGFß receptors correlates with advanced human prostate cancer. We demonstrate that in combination either with loss of Pten or expression of constitutively active AKT1, inactivation of TGFß signaling by deletion of the TGFß type II receptor gene relieves a restraint on tumorigenesis. This results in rapid progession to lethal prostate cancer, including metastasis to lymph node and lung. In prostate epithelium, inactivation of TGFß signaling alone is insufficient to initiate tumorigenesis, but greatly accelerates cancer progression. The activation of TGFß signaling by Pten loss or AKT activation suggests that the same signaling events that have key roles in tumor initiation also induce the activity of a pathway that restrains disease progression.

The deubiquitinating enzyme DUBAI stabilizes DIAP1 to suppress Drosophila apoptosis.

Deubiquitinating enzymes (DUBs) counteract ubiquitin ligases to modulate the ubiquitination and stability of target signaling molecules. In Drosophila, the ubiquitin-proteasome system has a key role in the regulation of apoptosis, most notably, by controlling the abundance of the central apoptotic regulator DIAP1. Although the mechanism underlying DIAP1 ubiquitination has been extensively studied, the precise role of DUB(s) in controlling DIAP1 activity has not been fully investigated. Here we report the identification of a DIAP1-directed DUB using two complementary approaches. First, a panel of putative Drosophila DUBs was expressed in S2 cells to determine whether DIAP1 could be stabilized, despite treatment with death-inducing stimuli that would induce DIAP1 degradation. In addition, RNAi fly lines were used to detect modifiers of DIAP1 antagonist-induced cell death in the developing eye. Together, these approaches identified a previously uncharacterized protein encoded by CG8830, which we named DeUBiquitinating-Apoptotic-Inhibitor (DUBAI), as a novel DUB capable of preserving DIAP1 to dampen Drosophila apoptosis. DUBAI interacts with DIAP1 in S2 cells, and the putative active site of its DUB domain (C367) is required to rescue DIAP1 levels following apoptotic stimuli. DUBAI, therefore, represents a novel locus of apoptotic regulation in Drosophila, antagonizing cell death signals that would otherwise result in DIAP1 degradation.

Very small photoluminescent gold nanoparticles for multimodality biomedical imaging.

An original synthesis method based on X-ray irradiation produced gold nanoparticles (AuNPs) with two important properties for biomedical research: intense visible photoluminescence and very high accumulation in cancer cells. The nanoparticles, coated with MUA (11-mercaptoundecanoid acid), are very small (1.4 nm diameter); the above two properties are not present for even slightly larger sizes. The small MUA-AuNPs are non-cytotoxic (except for very high concentrations) and do not interfere with cancer cell proliferation. Multimodality imaging using visible light fluorescence and X-ray microscopy is demonstrated by tracing the nanoparticle-loaded tumor cells.