Combination therapy involving HSP90 inhibitors for combating cancer: an overview of clinical and preclinical progress.

The molecular chaperone heat shock protein 90 (HSP90) regulates multiple crucial signalling pathways in cancer by driving the maturation of key signalling components, thereby playing a crucial role in tumorigenesis and drug resistance in cancer. Inhibition of HSP90 results in metastable conformational collapse of its client proteins and their proteasomal degradation. Considerable efforts have been devoted to the development of small-molecule inhibitors targeting HSP90, and more than 20 inhibitors have been evaluated in clinical trials for cancer therapy. However, owing to disadvantages such as organ toxicity and drug resistance, only one HSP90 inhibitor has been approved for use in clinical settings. In recent years, HSP90 inhibitors used in combination with other anti-cancer therapies have shown remarkable potential in the treatment of cancer. HSP90 inhibitors work synergistically with various anti-cancer therapies, including chemotherapy, targeted therapy, radiation therapy and immunotherapy. HSP90 inhibitors can improve the pharmacological effects of the above-mentioned therapies and reduce treatment resistance. This review provides an overview of the use of combination therapy with HSP90 inhibitors and other anti-cancer therapies in clinical and preclinical studies reported in the past decade and summarises design strategies and prospects for these combination therapies. Altogether, this review provides a theoretical basis for further research and application of these combination therapies in the treatment of cancer.

Ligand-based pharmacophore modelling, structure optimisation, and biological evaluation for the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors.

Targeting Heat shock protein 90 (HSP90) C-terminus is an important strategy to develop HSP90 inhibitors without inducing heat shock response. The development of C-terminal inhibitors, however, is hampered by a lack of understanding regarding the interaction between the HSP90 C-terminus and the present inhibitors. We collected seven classical and structurally diverse HSP90 C-terminal inhibitors and constructed a ligand-based pharmacophore model. The subsequent virtual screening and structural optimisation led to the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors. 9 and 27 exhibited strong antitumour activity in vitro by inhibiting proliferation and inducing apoptosis in multiple cancer cell lines. These compounds disrupted the interaction between HSP90 C-terminus and peptidylprolyl isomerase D, exerting a stronger inhibitory effect than novobiocin. 27 significantly induced the degradation of HSP90 clients without triggering heat shock response. In an in vivo study using 4T1 mice breast cancer models, 9 showed a potent antitumour effect without obvious toxicity.

Application of Engineered Dendritic Cell Vaccines in Cancer Immunotherapy: Challenges and Opportunities.

OPINION STATEMENT: The primary objective of this study is to evaluate the effectiveness of cancer vaccines containing genetically modified dendritic cells (DCs) in inducing transformational immune responses. This paper sheds considerable light on DCs' function in advancing treatment techniques. This objective is achieved by thoroughly analyzing the many facets of DCs and their strategic integration into cancer treatment. Due to their role as immune response regulators, DCs can potentially enhance cancer treatment strategies. DCs have the potential to revolutionize immunotherapy, as shown by a comprehensive analysis of their numerous characteristics. The review deftly transitions from examining the fundamentals of preclinical research to delving into the complexities of clinical implementation while acknowledging the inherent challenges in translating DC vaccine concepts into tangible progress. The analysis also emphasizes the potential synergistic outcomes that can be achieved by combining DC vaccines with established pharmaceuticals, thereby emphasizing the importance of employing a holistic approach to enhance treatment efficacy. Despite the existence of transformative opportunities, advancement is hindered by several obstacles. The exhaustive analysis of technical complexities, regulatory dynamics, and upcoming challenges provides valuable insights for overcoming obstacles requiring strategic navigation to incorporate DC vaccines successfully. This document provides a comprehensive analysis of the developments in DC-based immunotherapy, concentrating on its potential to transform cancer therapy radically.

SOX17 Antagonizes the WNT Signaling Pathway and is Epigenetically Inactivated in Clear-Cell Renal Cell Carcinoma.

BACKGROUND: SRY-box containing gene 17 (SOX17) was reported to be a candidate tumor suppressor gene in multiple tumors. Little is known about its role in clear-cell renal cell carcinoma (ccRCC). This study aims to identify the epigenetic regulation and tumor-suppressive function of SOX17 in ccRCC. PATIENTS AND METHODS: Fifty-five human ccRCC tissue samples, ten adjacent non-malignant kidney tissue samples, 20 paired paraffin section tissues and seven RCC cell lines were obtained. Immunohistochemistry (IHC) and real-time PCR were used to examine the expression of the target genes at the mRNA and protein levels. The methylation of SOX17 was analyzed using methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS) assay. The functions of SOX17 were examined by using CCK8, colony formation, wound healing assay and Matrigel invasion assays. Luciferase assay was used to analyze the function of SOX17 in the WNT signaling pathway. RESULTS: We investigated the SOX17 expression in ccRCC tissues and adjacent non-malignant kidney tissues using PCR and IHC. The expression of SOX17 was lower in ccRCC tissues. Next, we analyzed the DNA promoter methylation of SOX17 in 55 human ccRCC tissues, 10 adjacent non-malignant kidney tissues and RCC cell lines using MSP. DNA methylation of the SOX17 promoter region occurred in 60% of ccRCC tissues and 10% of adjacent non-malignant kidney tissues. In vitro experiments showed that SOX17 suppressed the proliferation of RCC cells. Furthermore, SOX17 inhibited the migration of RCC cells as shown in the wound healing and migration assays. In addition, we found that SOX17 overexpression affected the WNT signaling pathway by downregulating c-myc and cyclinD1. CONCLUSION: In summary, our study showed that SOX17 is downregulated in ccRCC and the loss of SOX17 expression is regulated via epigenetic mechanisms in ccRCC. In addition, SOX17 negatively regulates the WNT signaling pathway and function as a tumor suppressor in ccRCC.

AATF is Overexpressed in Human Bladder Cancer and Regulates Chemo-Sensitivity Through Survivin.

OBJECTIVE: Dysregulation of apoptosis antagonizing transcription factor (AATF) has been reported to be closely associated with human cancers. However, its involvement in human bladder cancer (BC) remains unexplored. This study aimed to investigate the clinical significance and biological roles of AATF in human bladder cancers. METHODS: AATF protein expression was examined in 107 cases of bladder cancer tissues using immunohistochemistry. AATF plasmid transfection and small interfering RNA (siRNA) knockdown were performed in T24 and 5637 cell lines. CCK-8, colony formation, annexin V/PI, JC-1 staining, and Western blotting were carried out to investigate the biological roles and underlying mechanisms of AATF in bladder cancer cells. RESULTS: Our results showed that AATF expression was upregulated in human bladder cancer specimens and correlated with T stage. Analysis of the Oncomine database showed elevation of AATF mRNA in BC tissues. The Cancer Genome Atlas (TCGA) data suggested that high AATF expression correlated with poor patient survival. Western blotting showed that AATF protein expression was higher in BC cell lines compared to normal bladder transitional epithelial cell line SV-HUC-1. CCK-8 and colony assays showed that ectopic AATF expression upregulated cell growth rate and colony numbers. CCK-8, annexin V/propidium iodide (PI), JC-1 assays and Western blotting showed that AATF overexpression decreased cisplatin sensitivity, downregulated cisplatin-induced apoptosis and upregulated mitochondrial membrane potential, with decreased cytochrome c and cleaved-PARP expression. AATF siRNA knockdown showed the opposite effects. Mechanistically, AATF overexpression upregulated cyclin E and Survivin at both mRNA and protein levels. The decreased cisplatin sensitivity/apoptosis induced by ectopic AATF were reversed after treatment with Survivin inhibitor YM155. CONCLUSION: Our results showed that AATF was overexpressed in human bladder cancers and promoted malignant behavior by regulating cyclin E and Survivin, indicating AATF could serve as a malignant biomarker and potential therapeutic target in BC.

Diagnosis and Treatment of Renal Cell Carcinoma During Pregnancy.

Renal cell carcinoma during pregnancy is extremely rare, but it is the commonest urological malignancy reported in pregnancy. Currently, no uniform domestic or international diagnostic or treatment criteria exist for these patients, so their diagnosis and treatment are challenging for urologists. The health and reproductive needs of these patients have improved in recent years because of the continuous development of medical technology. This article reviews the epidemiology, risk factors, diagnosis, treatment, and prognosis of renal cell carcinoma during pregnancy.

BCAT1 Overexpression Promotes Proliferation, Invasion, and Wnt Signaling in Non-Small Cell Lung Cancers.

INTRODUCTION: Dysregulation of BCAT1 has been implicated in carcinogenesis. However, its clinical significance and biological roles in human non-small cell lung cancer (NSCLC) are not clear. METHODS: Immunohistochemistry was used to examine the protein expression of BCAT1 in 107 cases of lung cancer tissues. Biological roles and potential mechanisms of BCAT1 were examined using MTT, colony formation assay, Matrigel invasion assay, Western blot, RNA-sequencing, and luciferase reporter assay. RESULTS: We found BCAT1 was upregulated in 60 of 107 lung cancer tissues and correlated with nodal metastasis, advanced stages and short overall survival. The Cancer Genome Atlas (TCGA) and ONCOMINE data analyses also indicated that BCAT1 was elevated in human NSCLC tissues. BCAT1 protein was higher in lung cancer cell lines than in normal bronchial epithelial cell line. BCAT1 overexpression increased the cell growth rate, colony numbers and invasion abilities in both BEAS-2B and H1299 cell lines, while BCAT1 siRNA decreased the cell proliferation rate, colony numbers, and inhibited invasion. RNA-sequencing (RNA-seq) and Gene Set Enrichment Analysis (GSEA) analyses indicated that BCAT1 overexpression activated Wnt/Myc signaling. Western blot revealed that BCAT1 increased protein expression of MMP7, cyclin D1, c-Myc, and decreased E-cadherin and p27 in the BEAS-2B and H1299 cell lines. Further experiments showed that BCAT1 overexpression elevated Wnt reporter luciferase activity and increased activate ß-catenin protein while downregulating p-ß-catenin protein expression. BCAT1 knockdown showed the opposite effects. TCGA data analysis suggested positive correlations between BCAT1 and c-Myc, cyclin D1, and MMP7 mRNA. Blockage of Wnt signaling using an inhibitor (ICG-001) downregulated c-Myc, cyclin D1, MMP7 expressions and abolished the upregulating effects of BCAT1 on these proteins. CONCLUSION: In summary, our data showed that BCAT1 was overexpressed in human NSCLCs. BCAT1 facilitated cell proliferation and invasion possibly through regulation of the Wnt signaling pathway.

RASSF6 Is Downregulated In Human Bladder Cancers And Regulates Doxorubicin Sensitivity And Mitochondrial Membrane Potential Via The Hippo Signaling Pathway.

BACKGROUND: The present study aimed to investigate the clinicopathological significance and biological roles of RASSF6 in human bladder cancers. MATERIALS AND METHODS: Immunohistochemistry and Western blots were used to examine the protein expression of RASSF6 in bladder cancer tissues. Biological roles of RASSF6 were examined using MTT, colony formation assay, Matrigel invasion assay, cell cycle analysis, AnnexinV/PI staining and JC-1 staining. Western blot analysis was used to examine the potential mechanism. RESULTS: We found that RASSF6 was downregulated in 73 of 138 bladder cancer specimens, which correlated with advanced stages. RASSF6 overexpression decreased the cell growth rate and inhibited invasion ability in T24 cell line. Downregulation of RASSF6 using siRNA increased the cell proliferation rate and promoted invasion in 5637 cell line. Cell cycle studies showed that RASSF6 overexpression suppressed the process of cell cycle progression. RASSF6 overexpression also increased the cellular response to doxorubicin (DOX) treatment. AnnexinV/PI staining showed that RASSF6 overexpression promoted DOX-induced apoptosis with increased cytochrome c and cleavage of caspase-3 and caspase-9. We also showed that RASSF6 overexpression downregulated the mitochondrial membrane potential, while RASSF6 depletion showed the opposite effect. Western blot analysis demonstrated that RASSF6 overexpression repressed p-Rb and Bcl-xL while upregulating p21 expression. In addition, we found that RASSF6 overexpression affected the Hippo signaling pathway by downregulating YAP. Depletion of YAP downregulated Bcl-xL expression and abolished the effect of RASSF6 on Bcl-xL. Depletion of YAP also upregulated the level of apoptosis and downregulated mitochondrial membrane potential. YAP siRNA abolished the effects of RASSF6 on DOX-induced apoptosis and loss of mitochondrial membrane potential. CONCLUSION: Taken together, our results showed that RASSF6 was downregulated in bladder cancers. RASSF6 inhibited cell proliferation and invasion, as well as the progression of cancer, by regulating DOX sensitivity and mitochondrial membrane potential, possibly via the Hippo signaling pathway.

Ureteral stent placement and percutaneous nephrostomy in the management of hydronephrosis secondary to cervical cancer.

OBJECTIVE: This study aimed to evaluate the efficacy of ureteral stent placement for the treatment of hydronephrosis secondary to cervical cancer and analyze factors that may predict failure of ureteral stent placement and the differences between ureteral stent placement and percutaneous nephrostomy. STUDY DESIGN: Clinical data of patients with cervical cancer complicated with hydronephrosis admitted to our hospital from July 2008 to August 2018 were retrospectively analyzed. To evaluate the efficacy of ureteral stent placement and percutaneous nephrostomy in the management of hydronephrosis secondary to cervical cancer. RESULTS: A total of 89 patients were analyzed. A ureteral stent was successfully placed in 60 patients. Indwelling stent failed in 29 patients, and then percutaneous nephrostomy was performed. Both surgical procedures were safe and effective. There was a significant correlation between the success rate of ureteral stent placement and the degree of hydronephrosis and the length of the ureteral obstruction. There was no significant difference in the incidence of complications following ureteral stent placement and percutaneous nephrostomy, while there were significant differences between the two treatment modalities in terms of surgical time, hospitalization time, and surgical cost. CONCLUSION: Ureteral stent placement is the preferred method for the treatment of hydronephrosis secondary to cervical cancer. However, in patients with more severe hydronephrosis and ureteral obstruction >3 cm in length, percutaneous nephrostomy may be more appropriate.

The comparation of effects and security of double-J stent retention and ureteroscopy lithotripsy in the treatment of symptomatic ureteral calculi during pregnancy.

OBJECTIVE: To describe the efficacy of double-J stent retention and ureteroscopy lithotripsy, we performed a study to evaluate the management of symptomatic ureteral calculi during pregnancy. MATERIALS AND METHODS: From January 2005 and June 2015, 53 pregnant women with symptomatic ureteral calculi were admitted and treated in our hospital. According to the treatment techniques, there were divided into two groups: double-J stent retention group (30 cases) and ureteroscopy lithotripsy group (23 cases). We collected the characteristics and treatment outcome of the patients. RESULTS: Double-J stent retention was performed on 30 patients. And the stents were successfully inserted in 25 patients (83.3%). 4 cases got complication in double-J group (16%). The mean operating time, medical cost and hospitalization time of double-J group were 20.6 min, 1632 yuan and 1.3 days. Ureteroscopy lithotripsy was performed on 23 patients. 20 patients were operated successfully (87.0%). 2 cases got complication in ureteroscopy group (10.0%). The mean operating time, medical cost and hospitalization time of ureteroscopy group were 41.5 min, 2792 yuan and 6.0 days. CONCLUSION: In summary, both double-J stent retention and ureteroscopy lithotripsy are effective and safe in the managation of ureteral calculi during pregnancy.

Knockdown of fibrous sheath interacting protein 1 expression reduces bladder urothelial carcinoma cell proliferation and induces apoptosis via inhibition of the PI3K/AKT pathway.

BACKGROUND: FSIP1 plays a vital role in tumorigenesis and cancer progression. In bladder cancer, FSIP1 overexpression was associated with poor prognosis of bladder urothelial carcinoma. In this study, we investigated whether FSIP1 is essential in the progression of bladder cancer and the mechanism by which it mediates this effect. METHODS: FSIP1 expression was knocked down in bladder cancer cells using lentiviral-mediated short hairpin RNA (shRNA). FSIP1 expression was detected using Western blotting, immunohistochemistry (IHC), and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The effects of FSIP1 knockdown on tumor cells were assessed using colony formation, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and flow cytometry (FCM) apoptosis assays in vitro and BALB/c nude mouse xenograft model in vivo. RESULTS: The findings suggested that FSIP1 protein was highly expressed in bladder cancer cell lines. Knockdown of FSIP1 resulted in reduced tumor cell viability, cell cycle arrest at G0/G1 phase and apoptosis of bladder cancer cell lines (P<0.05). Moreover, knockdown of FSIP1 expression suppressed the tumor formation and growth of bladder cancer xenografts (P<0.05). At the gene level, knockdown of FSIP1 expression downregulated the activity of the PI3K/AKT signaling pathway. CONCLUSION: This study demonstrated that knockdown of FSIP1 suppressed bladder cancer cell malignant behaviors in vitro and in vivo through the inhibition of the PI3K/AKT signaling pathway, suggesting that targeting FSIP1 could be further evaluated as a potential therapeutic strategy in bladder cancer.

Derlin-1 overexpression confers poor prognosis in muscle invasive bladder cancer and contributes to chemoresistance and invasion through PI3K/AKT and ERK/MMP signaling.

Derlin-1 has been found to be overexpressed in several human cancers. However, its clinical significance and biological roles in bladder cancer remain unexplored. Here, we found that Derlin-1 was upregulated in 38.6% (58/150) cases of cancer samples. The rate of Derlin-1 overexpression was higher in muscle invasive bladder cancer (MIBC) than non-muscle invasive bladder cancer (NMIBC) (p=0.0079). Derlin-1 was a predicting factor for poor patient prognosis. Derlin-1 depletion inhibited while its overexpression facilitated cell invasion and colony formation. In addition, Derlin-1 overexpression induced cisplatin resistance while its depletion sensitized cancer cells to cisplatin. Further analysis demonstrated that Derlin-1 activated AKT phosphorylation and upregulated Bcl-2 expression. Blockage of AKT signaling by LY294005 abolished the effects of Derlin-1 on Bcl-2 and cisplatin resistance. Immunoprecipitation indicated Derlin-1 interacted with p110α subunit of PI3K. In addition, we showed that Derlin-1 depletion downregulated and its overexpression upregulated cell MMP-2/9 expression and ERK phosphorylation. Derlin-1 mediated upregulation of MMP-2/9 could be blocked by ERK inhibitor. In conclusion, our study demonstrated that Derlin-1 is overexpressed in bladder cancer and promotes malignant phenotype through ERK/MMP and PI3K/AKT/Bcl-2 signaling pathway.

Upregulation of endoplasmic reticulum stress is associated with diaphragm contractile dysfunction in a rat model of sepsis.

Sepsis often causes diaphragm contractile dysfunction. Endoplasmic reticulum (ER) stress has been implicated in muscle contractile dysfunction. However, it remains unknown if ER stress occurs in the diaphragm during sepsis. In the present study, rats were divided into 4 groups and received placebo or one of three durations of endotoxin treatment (24, 48 h and 7 days). Isometric contractile force of the diaphragm was measured and lung wet-to-dry ratio (W/D) was calculated. Hematoxylin and eosin (H&E) staining of lung tissue was performed and electron microscopy assessed ER damage in the diaphragm during sepsis. The mRNA and protein expression of glucose­regulated protein 78 kDa (GRP78), glucose-regulated protein 94 kDa (GRP94), C/EBP homologous protein (CHOP), endoplasmic reticulum protein 44 (ERP44), protein disulfide-isomerase like protein (ERP57) and protein disulfide isomerase family A member 4 (ERP72) in diaphragm muscles were measured using reverse transcription­quantitative polymerase chain reaction and western blot analysis. The level of cleaved caspase-12 was analyzed by western blot analysis. The results demonstrated that sepsis increased lung W/D. H&E staining revealed that sepsis caused alveolar congestion, hemorrhage and rupture. Swollen and distended ER was observed using electron microscopy during sepsis and decreased diaphragm contractile function was also observed. The expression levels of ER stress markers (GRP78, GRP94, CHOP, ERP44, ERP57 and ERP72) and the level of cleaved caspase­12 were significantly elevated in septic rats compared with control rats, particularly in the 48 h group. In conclusion, the present study indicated that weakened diaphragm contraction and damaged ER in septic rats was associated with increased expression of ER stress markers.

Downregulation of miR-133b predict progression and poor prognosis in patients with urothelial carcinoma of bladder.

We found microRNA-133b (miR-133b) was downregulated in urothelial carcinoma of the bladder (UCB) tissues, and it could inhibit the proliferation and induce apoptosis in UCB cells. Consequently, we intend to explore the clinical significance of miR-133b in UCB patients. Expression of miR-133b in 146 UCB specimens and matched adjacent non-neoplastic bladder tissues were measured by quantitative real-time polymerase chain reaction. The overall survival (OS) curve and progression-free survival (PFS) curve were plotted using the Kaplan-Meier method. Prognostic factors for OS and PFS were identified by univariate and multivariate analyses using the Cox proportional hazards regression model. The expression of miR-133b was significantly downregulated in UCB tissues compared with those in adjacent non-neoplastic bladder tissues (P < 0.001). Among UCB patients, low expression of miR-133b significantly correlated with aggressive clinicopathological features. Multivariate analysis indicated that the expression of miR-133b was the independent prognostic factors for predicting PFS (RR: 2.97; 95% CI: 1.78-6.44; P = 0.009) and OS (RR: 4.23; 95% CI: 1.51-11.8; P = 0.011) in patients with UCB. Our study demonstrated that downregulation of miR-133b associated with aggressive clinicopathological features and predicted unfavorable prognosis in patients with UCB, might serve as feasible biomarker for clinical outcome of UCB patients after surgery and potential therapeutic target in the future.

TRIM29 Overexpression Promotes Proliferation and Survival of Bladder Cancer Cells through NF-κB Signaling.

PURPOSE: TRIM29 overexpression has been reported in several human malignancies and showed correlation with cancer cell malignancy. The aim of the current study is to examine its clinical significance and biological roles in human bladder cancer tissues and cell lines. MATERIALS AND METHODS: A total of 102 cases of bladder cancer tissues were examined for TRIM29 expression by immunohistochemistry. siRNA and plasmid transfection were performed in 5637 and BIU-87 cell lines. Cell Counting Kit-8, flow cytometry, western blot, and real-time polymerase chain reaction were performed to examine its biological roles and mechanism in bladder cancer cells. RESULTS: We found that TRIM29 overexpression showed correlation with invading depth (p=0.0087). Knockdown of TRIM29 expression in bladder cancer cell line 5637 inhibited cell growth rate and cell cycle transition while its overexpression in BIU-87 cells accelerated cell proliferation and cell cycle progression. TRIM29 overexpression also inhibited cell apoptosis induced by cisplatin. In addition, we demonstrated that TRIM29 depletion decreased while its overexpression led to upregulated expression of cyclin D1, cyclin E, and Bcl-2. We also showed that TRIM29 knockdown inhibited protein kinase C (PKC) and nuclear factor κB (NF-κB) signaling while its overexpression stimulated the PKC and NF-κB pathways. BAY 11-7082 (NF-κB inhibitor) partly attenuated the effect of TRIM29 on expression of cyclin and Bcl-2. Treatment with PKC inhibitor staurosporine resulted in ameliorated TRIM29 induced activation of NF-κB. CONCLUSION: The current study demonstrated that TRIM29 upregulates cyclin and Bcl family proteins level to facilitate malignant cell growth and inhibit drug-induced apoptosis in bladder cancer, possibly through PKC-NF-κB signaling pathways.

High levels of positive end-expiratory pressure preserve diaphragmatic contractility during acute respiratory distress syndrome in rats.

NEW FINDINGS: What is the central question of this study? Higher levels of positive end-expiratory pressure (PEEP) have recently been used in patients with acute respiratory distress syndrome (ARDS). In normal physiological conditions, the ability of the diaphragm to generate pressure is reduced when the lung volume is elevated beyond its functional residual capacity. It is unknown whether higher levels of PEEP will have a negative impact on diaphragmatic contraction in the presence of the pathophysiology of ARDS. What is the main finding and its importance? Mechanical ventilation with higher levels of PEEP reduced lung injury, improved diaphragmatic contractility and increased the expression of both dihydropyridine receptor and ryanodine receptor in the diaphragms of rats with ARDS. Higher levels of positive end-expiratory pressure (PEEP) have recently been used in patients with acute respiratory distress syndrome (ARDS). In normal physiological conditions, the ability of the diaphragm to generate pressure is reduced when the lung volume is elevated beyond its functional residual capacity. Thus, it is critical to understand whether higher levels of PEEP will have a negative impact on diaphragmatic contraction in the presence of the pathophysiology of ARDS. This study was designed to determine whether higher levels of PEEP reduce diaphragmatic contractility in a rat model of ARDS generated using i.p. lipopolysaccharide. Forty rats were randomly assigned to the following five groups: a control group with no special treatment; an ARDS group with no mechanical ventilation; and three ARDS groups with mechanical ventilation with PEEP at 0, 5 or 10 cmH2 O, respectively. We found that mechanical ventilation with PEEP reduced lung injury, improved diaphragmatic contractility and increased the expression of both dihydropyridine receptor and ryanodine receptor in the diaphragms of rats with ARDS. These changes were most significant at a PEEP of 10 cmH2 O among all applied levels of PEEP. In conclusion, using a rat ARDS model, this study confirmed that diaphragmatic contractility was preserved by mechanical ventilation with high levels of PEEP.

Sclerotherapy for rare bleeding stomal varices after ileal conduit urinary diversion: an effective and noninvasive method.

INTRODUCTION: Bleeding stomal varices after ileal conduit urinary diversion are rare, but they can develop in patients with portal venous hypertension caused by cirrhosis. CASE PRESENTATION: We report the case of a 68-year-old man who developed stomal haemorrhage two months after radical cystectomy and ileal conduit urinary diversion to treat invasive bladder cancer. Alcoholic cirrhosis and portal venous hypertension were considered to be the causes of varices and bleeding. We chose to control the stomal varices using sclerotherapy. The stomal varices disappeared and no bleeding recurred during one year of follow up. CONCLUSION: We believe that sclerotherapy is a suitable treatment for bleeding stomal varices.

Comparative assessment of surgeons' task performance and surgical ergonomics associated with conventional and modified flank positions: a simulation study.

BACKGROUND: Flank position is extensively used in retroperitoneoscopic urological practice. Most surgeons follow the patients' position in open approaches. However, surgical ergonomics of the conventional position in the retroperitoneoscopic surgery is poor. We introduce a modified position and evaluated task performance and surgical ergonomics of both positions with simulated surgical tasks. METHODS: Twenty-one novice surgeons were recruited to perform four tasks: bead transfer, ring transfer, continuous suturing, and cutting a circle. The conventional position was simulated by setting an endo-surgical simulator parallel to the long axis of a surgical desk. The modified position was simulated by rotating the simulator 30° with respect to the long axis of the desk. The outcome measurements include task performance measures, kinematic measures for body alignment, surface electromyography, relative loading between feet, and subjective ratings of fatigue. RESULTS: We observed significant improvements in both task performance and surgical ergonomics parameters under the modified position. For all four tasks, subjects finished tasks faster with higher accuracy (p < 0.005 or < 0.001). For ergonomics part: (1) The angle between the upper body and the head was decreased by 7.4 ± 1.7°; (2) The EMG amplitude collected from shoulders and left lumber was significantly lower (p < 0.05); (3) Relative loading between feet was more balanced (p < 0.001); (4) Manual-action muscles and postural muscles are rated less fatiguing according to the questionnaire (p < 0.05). CONCLUSIONS: Conventional position of patient in retroperitoneoscopic upper urinary tract surgery is associated with poor surgical ergonomics. With a simulated surgery, we demonstrated that our modified position could significantly improve task performance and surgical ergonomics. Further studies are still warranted to validate these benefits for both patients and surgeons.