Analysis Of Clinical Database Research Articles

Repurposing gestrinone for tumor suppressor through P21 reduction regulated by JNK in gynecological cancer

Endometriosis has been shown to increase the risk of gynecological cancers. However, the effect of gestrinone, a clinical endometriosis drug, on gynecological cancers remains unclear. This study aimed to understand the effect of gestrinone on gynecological cancers. A retrospective study was conducted using the Longitudinal Health Insurance Database 2000 of the Taiwan National Health Insurance Research Database (NHIRD) to observe the risk of gynecological cancers. Medication records from the Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital CSMUH and cancer records from the Taiwan Cancer Registry were collected to analyze the correlation between gestrinone use and gynecological cancers. Subsequently, human cell lines were used to investigate the effect of gestrinone on gynecological cancers. A total of 8330 endometriosis patients were enrolled, and analyses revealed that endometriosis patients had a higher risk of developing ovarian and endometrial cancer. However, the rate of cervical cancer was not statistically different (P=0.249). Analyses of both the NHIRD and CSMUH databases revealed that gestrinone may reduce the risk of gynecological cancer. Cellular experiments verified the anticancer effects of gestrinone, which effectively and specifically inhibited the growth of HeLa cervical cancer cells, decreased P21 expression via JNK phosphorylation, and induced apoptosis. Combining the results of clinical database analysis and cell experiments, our findings prove that gestrinone has the potential to protect against cancer through regulation of the JNK-P21 axis. Repurposing the anticancer efficacy of gestrinone may be a strategy for targeted therapy in the future.

Protective role of cytoplasmic p21Cip1/Waf1 in apoptosis of CDK4/6 inhibitor‐induced senescence in breast cancer cells

Inhibition of CDK4/6 slows the cell cycle and induces senescence in breast cancer cells. However, senescent cancer cells promote invasion and metastasis. Several drugs reportedly target senescent cells, including ABT‐263 (navitoclax). We examined the effects of the CDK4/6 inhibitor abemaciclib and ABT‐263 on two human breast cancer cell lines. The abemaciclib and ABT‐263 combination additively decreased the viability of MDA‐MB‐231 cells, but not MCF‐7 cells. Also, the combination therapy‐induced caspase‐dependent apoptosis in MDA‐MB‐231 cells. Combination therapy with abemaciclib and ABT‐737, an ABT‐263 analog, significantly suppressed the in vivo growth of MDA‐MB‐231 with transient body‐weight loss. Given that p16Ink4a and p21Cip1/Waf1 are key factors in senescence and that both cell lines were negative for p16, the role of p21 in apoptosis of treated breast cancer cells was investigated. Although abemaciclib increased the cytoplasmic p21 level in both cell lines as a hallmark of senescence, the abemaciclib and ABT‐263 combination decreased it only in MDA‐MB‐231 cells. This decrease of p21 expression was relieved by caspase inhibition, and p21 was colocalized with caspase‐3 in the cytoplasm of MDA‐MB‐231 cells. Alternatively, small interfering RNA‐mediated knockdown of p21 rendered caspase‐3‐negative MCF‐7 cells susceptible to abemaciclib and ABT‐263, as well as TNF‐related apoptosis‐inducing ligand. Furthermore, a clinical database analysis showed that p21high breast cancer patients had a poorer prognosis compared to p21low patients. These results suggest that cytoplasmic p21 plays a protective role in apoptosis of CDK4/6 inhibitor‐induced senescent breast cancer cells.

Relation of substance use disorders to mortality, accident and emergency department attendances, and hospital admissions: A 13-year population-based cohort study in Hong Kong

BackgroundThe impact of substance use disorders (SUD) in an Asian population has not been fully explored. We aimed to assess the risk of mortality, accident and emergency (A&E) department attendances, and hospital admissions associated with SUD in a population-based cohort study. MethodPatients diagnosed with SUD in public A&E departments from 2004 to 2016 (N = 8,423) were identified in the Clinical Database Analysis and Reporting System of the Hong Kong Hospital Authority and 1:1 matched to patients without SUD by propensity score (N = 6,074 in each group). Relative risks of mortality, A&E attendances and hospital admissions were assessed using Cox regression and Hurdle negative binomial regression. ResultsPatients with SUD had higher mortality (hazard ratio=1.43; 95% confidence interval [CI]=1.26–1.62) and more often died from poisoning or toxicity and injuries. The odds ratio (OR) for A&E attendances and all-cause hospital admissions associated with SUD were 2.80 (95% CI=2.58–3.04) and 3.54 (95% CI=3.26–3.83), respectively. The impact of SUD on the above outcomes was greatest among school-aged individuals (≤ 21 years) and decreased with age. The relative risk of mental disorder-related hospital admissions was much higher than that for infections, respiratory diseases, and cardiovascular diseases. In patients with SUD, ketamine and amphetamine use were associated with increased A&E attendances than opioid use. ConclusionsSUD was associated with increased mortality, A&E attendances and hospital admissions, especially in school-aged individuals. Our findings suggest prioritising early treatment and preventive interventions for school-aged individuals and focusing on the management of comorbid mental disorders and the use of ketamine and amphetamine.

Suspension state and shear stress enhance breast tumor cells EMT through YAP by microRNA-29b.

Except for biochemical effects, suspension state (Sus) is proved to induce epithelial-mesenchymal transition (EMT) of circulating tumor cells (CTCs) mechanically. However, the difference between the effects of the mechanical microenvironment in capillaries (simplified as shear stress (SS) and Sus) and single Sus on EMT is unclear, nor the underlying mechanism. Here, breast tumor cells (BTCs) were loaded with Sus and SS to mimic the situation of CTCs stimulated by these two kinds of mechanics. It was demonstrated that the EMT of BTCs was enhanced by Sus and SS and the mechanotransductor yes-associated protein (YAP) was partially cytoplasmic stored with microRNA (miR)-29b decreased, which was detected by miR sequencing. Though it couldn't possess a feedback regulation, YAP promoted miR-29b expression and posttranscriptionally regulated BTCs EMT through miR-29b, where transforming growth factor β involved. Analysis of clinical database showed that high miR-29b expression was beneficial to high survival rate stabilizing its role of tumor suppressor. This study discovers the mechanism that Sus and SS promote BTCs EMT by YAP through miR-29b posttranscriptionally and highlight the potential of YAP and miR-29b in tumor therapy. The combination of suspension state and shear stress promotes transforming growth factor β involved epithelial-mesenchymal transition by yes-associated protein through microRNA-29b.

Use of omeprazole, the proton pump inhibitor, as a potential therapy for the capecitabine-induced hand-foot syndrome

Hand-foot syndrome (HFS), also known as palmar-plantar erythrodysesthesia (PPE), is a major side effect of capecitabine. Although the pathogenesis of HFS remains unknown, some studies suggested a potential involvement of inflammation in its pathogenesis. Proton pump inhibitors (PPIs) have been reported to have anti-inflammatory effects. In this study, we investigated the ameliorative effects of omeprazole, a PPI on capecitabine-related HFS in mice model, and a real-world database. Repeated administration of capecitabine (200 mg/kg, p.o., five times a week for 3 weeks) increased fluid content, redness, and tumor necrosis factor (TNF)-α substance of the mice hind paw. Co-administration of omeprazole (20 mg/kg, p.o., at the same schedule) significantly inhibited these changes induced by capecitabine. Moreover, based on the clinical database analysis of the Food and Drug Administration Adverse Event Reporting System, the group that has used any PPIs had a lower reporting rate of capecitabine-related PPE than the group that has not used any PPIs. (6.25% vs. 8.31%, p < 0.0001, reporting odds ratio (ROR) 0.74, 95% confidence interval (CI) 0.65–0.83). Our results suggest that omeprazole may be a potential prophylactic agent for capecitabine-induced HFS.

P155 Modelling calcinosis in systemic sclerosis through disease microenvironment-stem cell interactions: effect of novel therapeutic peptide RP832c

Abstract Background/Aims Systemic sclerosis (SSc) is a rare and progressive connective tissue disease that is more common in women in the third to fifth decades of life and is rare in children. Calcinosis cutis, the deposition of calcium deposits within the subcutaneous tissue, remains a challenging non-lethal complication of SSc. The development of calcinosis cutis is a poorly understood area and there are no functional mouse models or laboratory models for calcinosis in SSc. In this study we present clinical database analysis plus two potential in vitro models for examining calcinosis in the setting of SSc. Methods Clinical modelling through database analysis of n = 79 SSc patients with and without calcinosis was attempted. In tissue culture studies, the first model system utilised adipose-derived mesencyhmal stem cells (MSCs) stimulated with interstitial fluid from healthy controls or SSc patients (both n = 4). In a second model, macrophages from patients with SSc (n = 4 lines) were used to stimulate MSCs in co-culture. We examined the impact that this has on the deposition of calcium hydroxyapatite production after prolonged culture in osteogenic media, measured using a scale (scored 0-4) to describe the degree of alizarin red uptake. We also investigated the role of an inhibitor of TGFβ signalling, SB432542 (10µM), and RP832c,(10µM), a peptide therapy which targets and repolarises activated SSc macrophages via CD206, in reducing calcium hydroxyapatite production. Results Clinical database analysis demonstrated that 35% of patients had evidence of calcinosis, but the only significant factor between the calcinosis and non-calcinosis group was the presence of digital ulcerations (p = 0.0008). The tissue fluid based model of calcinosis demonstrated that on day 21 the blister fluid obtained from SSc patients induced a significant increase in calcium deposition as compared to the culture media alone (3.9 vs 2.5, p = 0.00071), whereas SB431542, reduced calcium production by SSc fluid treated cells (3.9 vs 3.0, p = 0.2147). In the cell based model, macrophages derived from SSc patients induced the production of mineralised deposits. Both the TGFβ inhibitor SB432542 and the RP832c peptide reduced calcinosis in this model (SB431542 0.5 vs 1.3 p = 0.0547, RP832c 0.2 vs 1.3 p = 0.0147). Conclusion Our understanding of the underlying pathogenesis of calcinosis within SSc remains poor leading to therapeutic challenges for clinicians. From this analysis, it appears that presence of digital ulceration is associated clinically with calcinosis, possibly implicating aberrant tissue repair or ischaemia. Both tissue culture models presented here may recreate certain aspects of calcinosis in patients with SSc and may provide a basis for further evaluation of therapeutic inhibitors. At present there are no therapies that have been consistently found to be effective but our data support a possible role for macrophage - mesenchymal stem cell interactions and for TGFβ. Disclosure B.G.T. Coumbe: None. S.N. Ahmad: None. G. Thomas: None. L. Borukhson: None. B. Ahmed Abdi: None. H. Lopez: None. C. Garvin: None. J. Jaynes: None. C. Yates: None. G. Martin: None. C. Denton: None. D. Abraham: None. R.J. Stratton: None.

Spinal or general anaesthesia for surgical repair of hip fracture and subsequent risk of mortality and morbidity: a database analysis using propensity score-matching.

Around 76,000 people fracture their hip annually in the UK at a considerable personal, social and financial cost. Despite longstanding debate, the optimal mode of anaesthesia (general or spinal) remains unclear. Our aim was to assess whether there is a significant difference in mortality and morbidity between patients undergoing spinal anaesthesia compared with general anaesthesia during hip fracture surgery. A secondary analysis examined whether a difference exists in mortality for patients with pre-existing cardiovascular disease or chronic obstructive pulmonary disease. This was a clinical database analysis of patients treated for hip fracture in Nottingham, UK between 2004 and 2015. Propensity score-matching was used to generate matched pairs of patients, one of whom underwent each mode of anaesthesia. Data were analysed using conditional logistic regression, with 7164 patients successfully matched. There was no difference in 30- or 90-day mortality in patients who had spinal rather than general anaesthesia (OR [95%CI] 0.97 [0.8-1.15]; p=0.764 and 0.93 [0.82-1.05]; p=0.247 respectively). Patients who had a spinal anaesthetic had a lower-risk of blood transfusion (OR [95%CI] 0.84 [0.75-0.94]; p=0.003) and urinary tract infection (OR [95%CI] 0.72 [0.61-0.84]; p<0.001), but were more likely to develop a chest infection (OR [95%CI] 1.23 [1.07-1.42]; p=0.004), deep vein thrombosis (OR [95%CI] 2.18 [1.07-4.45]; p=0.032) or pulmonary embolism (OR [95%CI] 2.23 [1.16-4.29]; p=0.016). The mode of anaesthesia for hip fracture surgery resulted in no significant difference in mortality, but there was a significant difference in several measures of postoperative morbidity.

Diagnosis of Kidney Renal Cell Tumor through Clinical data mining and CT scan image processing: A Survey

This study deals with the systematic study of the mining of data and medical image-based CAD to classify or predict Kidney Renal (KRCC) tumors. Kidney tumors are of different types having different characteristics and have different methodologies to classify or predict tumor and its stages. KRCC is the most common type of cancer of the kidney, but there are others. Several factors may increase the risk of a person developing KRCC disease like smoking, obesity, High blood pressure, and many more. In almost all cases, only a single kidney is affected, but in rare cases, both can be affected by KRCC. As cancer grows, it may invade structures near the kidney, such as surrounding fatty tissue, veins, renal gland, or the liver. It might also spread to other parts of the body, such as the lungs or bones. It becomes essential to detect the KRCC tumor and classify it at the early stage to assist the pathologist in identifying the cause and severity of the tumor and in monitoring treatment. The pathologist examines the kidney diseases by using two different modes of data (Medical images and clinical databases). In this study, we reviewed different CAD tools to classify or predict KRCC tumor and its stages. For this study, two groups of methods that are data mining and medical image processing methods are selected. These methods allow the accurate quantification and classification of KRCC tumors from the clinical tools. Computer-assisted medical image and clinical database analysis show excellent potential for tumor diagnosis and monitoring.

Quantitative Analysis of Multi-components in Curcuma xanthorrhiza by Single Marker

Rotavirus is one of the most important causative agents of gastroenteritis in both infants and children worldwide, resulting in a high mortality and burden of disease, mainly in low-income, developing countries. Oral rehydration therapy with zinc supplementation is currently the recommended way to prevent death from diarrheal dehydration. In this study, we aimed to estimate the effectiveness of zinc supplementation in combination therapy of patients with suspected rotavirus infection in Indonesia. The perspective of this pharmacoeconomic study refer to the economic vantage point of cost-of-illness analysis. Achievement of this goal was possible with the construction of a decision tree model and determination of decision rules for inclusion of zinc supplementation into the combination therapy. The input parameters of the model were hospitalization days of patients stratified by the presence or absence of rotavirus infection as well as the additional inclusion of zinc supplementation. The criterion for prediction and decision making was the global rotavirus prevalence. The feature of the simulation was that the costs were expressed as relative to each other, which allowed to unify the proposed methodology. Retrospective analysis of clinical database of Indonesian patients with acute diarrhea has shown that zinc supplementation would be rational in case of rotavirus prevalence among these patients is higher than 81.5%. It was shown that additional zinc supplementation would be costeffective with probability of 0.62 and 0.53 – in the positive range of cost ratio variation or if costs for less than 43% of baseline therapy per day costs on an average.

MiR-137 promotes anoikis through modulating the AKT signaling pathways in Pancreatic Cancer.

Anoikis resistance is a fundamental feature of the survival of metastatic cancer cells during cancer progression. However, the mechanisms underlying anoikis resistance in pancreatic cancer (PC) are still unclear. MicroRNA-137 (miR-137) is a tumor suppressor that inhibits the proliferation and invasion of cancer cells through targeting multiple oncogenes. However, the effects and molecular mechanism of miR-137 on anoikis of PC are still unclear. Here we demonstrated that miR-137 was downregulated after the induction of anoikis model in time dependent. Function assays revealed that miR-137 promoted the pancreatic cancer cells anoikis in vitro and vivo. According to bioinformation analysis of clinical databases, we predicted that paxillin (PXN) was a target of miR-137. Further, TCGA analysis revealed that PXN was closely associated with the development of PC. Through loss-of-function studies, we demonstrated that PXN was a functional target of miR-137 on anoikis of PC cells. Moreover, we found that PXN promoted the activation of the AKT signaling pathways which was involving in the cancer cells anoikis. Together, our findings reveal that miR-137 plays a novel role during anoikis and may serve as a potential target for the detection and treatment of PC.

From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB).

BackgroundRecessive dystrophic epidermolysis bullosa (RDEB) is an inherited genetic disorder characterized by recurrent and chronic open wounds with significant morbidity, impaired quality of life, and early mortality. RDEB patients demonstrate reduction or structural alteration type VII collagen (C7) owing to mutations in the gene COL7A1, the main component of anchoring fibrils (AF) necessary to maintain epidermal-dermal cohesion. While over 700 alterations in COL7A1 have been reported to cause dystrophic epidermolysis bullosa (DEB), which may be inherited in an autosomal dominant (DDEB) or autosomal recessive pattern (RDEB), the incidence and prevalence of RDEB is not well defined. To date, the widely estimated incidence (0.2–6.65 per million births) and prevalence (3.5–20.4 per million people) of RDEB has been primarily characterized by limited analyses of clinical databases or registries.MethodsUsing a genetic modelling approach, we use whole exome and genome sequencing data to estimate the allele frequency of pathogenic variants. Through the ClinVar and NCBI database of human genome variants and phenotypes, DEB Register, and analyzing premature COL7A1 termination variants we built a model to predict the pathogenicity of previously unclassified variants. We applied the model to publicly available sequences from the Exome Aggregation Consortium (ExAC) and Genome Aggregation Database (gnomAD) and identified variants which were classified as pathogenic for RDEB from which we estimate disease incidence and prevalence.ResultsGenetic modelling applied to the whole exome and genome sequencing data resulted in the identification of predicted RDEB pathogenic alleles, from which our estimate of the incidence of RDEB is 95 per million live births, 30 times the 3.05 per million live birth incidence estimated by the National Epidermolysis Bullosa Registry (NEBR). Using a simulation approach, we estimate a mean of approximately 3,850 patients in the US who may benefit from COL7A1-mediated treatments in the US.ConclusionWe conclude that genetic allele frequency estimation may enhance the underdiagnosis of rare genetic diseases generally, and RDEB specifically, which may improve incidence and prevalence estimates of patients who may benefit from treatment.

A Verdict for Glimepiride: Effective and Not Guilty of Cardiovascular Harm.

Amazingly, whether sulfonylureas pose unacceptable risks compared with other treatments for diabetes has been debated for nearly 50 years. Ever since increased mortality was associated with tolbutamide in the University Group Diabetes Program (UGDP) (1), a warning of potential cardiovascular risk for drugs in this class has been mandated. Their tendency to cause both nonsevere and severe hypoglycemia worries patients and providers alike, who fear that hypoglycemia may precipitate serious cardiovascular events. Despite these concerns, sulfonylureas continue to be widely used for type 2 diabetes because they reliably improve glycemic control, lack symptomatic side effects other than hypoglycemia, and are very inexpensive. A recent commentary in Diabetes Care questioned whether the modern drugs in this class—glimepiride and gliclazide—deserve the shadow of guilt cast over them by studies of older sulfonylureas (2). They are conveniently dosed once daily and are less likely to cause hypoglycemia than the older agents, especially glyburide (also called glibenclamide). Unlike glyburide, they do not oppose ischemic preconditioning, a cardioprotective mechanism (3), and meta-analytic evidence suggests they are associated with lower rates of cardiovascular events than glyburide (4). Up to now, high-quality evidence to resolve the risk-versus-benefit debate has been lacking. Epidemiologic analyses of clinical databases and meta-analyses of short-term clinical studies comparing a sulfonylurea with placebo or an active comparator have shown conflicting results (5–8). Some studies comparing sulfonylureas with metformin suggest higher cardiovascular risk with sulfonylureas (9), but it is unclear whether this is because sulfonylureas are harmful or metformin is protective. Experience in the UK Prospective Diabetes Study (UKPDS) favors the latter interpretation. Over 10 years of randomized comparison with a conventional lifestyle-based regimen in the UKPDS, basal insulin or a sulfonylurea did not alter cardiovascular outcomes, whereas metformin reduced cardiovascular and all-cause mortality (10). But because metformin is preferred as …

Pharmacoeconomic Rationale of Zinc Supplementation In The Management of Acute Diarrhea In Children With Rotavirus Infection In Indonesia

Rotavirus is one of the most important causative agents of gastroenteritis in both infants and children worldwide, resulting in a high mortality and burden of disease, mainly in low-income, developing countries. Oral rehydration therapy with zinc supplementation is currently the recommended way to prevent death from diarrheal dehydration. In this study, we aimed to estimate the effectiveness of zinc supplementation in combination therapy of patients with suspected rotavirus infection in Indonesia. The perspective of this pharmacoeconomic study refer to the economic vantage point of cost-of-illness analysis. Achievement of this goal was possible with the construction of a decision tree model and determination of decision rules for inclusion of zinc supplementation into the combination therapy. The input parameters of the model were hospitalization days of patients stratified by the presence or absence of rotavirus infection as well as the additional inclusion of zinc supplementation. The criterion for prediction and decision making was the global rotavirus prevalence. The feature of the simulation was that the costs were expressed as relative to each other, which allowed to unify the proposed methodology. Retrospective analysis of clinical database of Indonesian patients with acute diarrhea has shown that zinc supplementation would be rational in case of rotavirus prevalence among these patients is higher than 81.5%. It was shown that additional zinc supplementation would be costeffective with probability of 0.62 and 0.53 – in the positive range of cost ratio variation or if costs for less than 43% of baseline therapy per day costs on an average.

Lasting DNA Damage and Aberrant DNA Repair Gene Expression Profile Are Associated with Post-Chronic Cadmium Exposure in Human Bronchial Epithelial Cells.

Cadmium (Cd) is a widespread environmental pollutant and carcinogen. Although the exact mechanisms of Cd-induced carcinogenesis remain unclear, previous acute/chronic Cd exposure studies have shown that Cd exerts its cytotoxic and carcinogenic effects through multiple mechanisms, including interference with the DNA repair system. However, the effects of post-chronic Cd exposure remain unknown. Here, we establish a unique post-chronic Cd-exposed human lung cell model (the “CR0” cells) and investigate the effects of post-chronic Cd exposure on the DNA repair system. We found that the CR0 cells retained Cd-resistant property even though it was grown in Cd-free culture medium for over a year. The CR0 cells had lasting DNA damage due to reduced DNA repair capacity and an aberrant DNA repair gene expression profile. A total of 12 DNA repair genes associated with post-chronic Cd exposure were identified, and they could be potential biomarkers for identifying post-chronic Cd exposure. Clinical database analysis suggests that some of the DNA repair genes play a role in lung cancer patients with different smoking histories. Generally, CR0 cells were more sensitive to chemotherapeutic (cisplatin, gemcitabine, and vinorelbine tartrate) and DNA damaging (H2O2) agents, which may represent a double-edged sword for cancer prevention and treatment. Overall, we demonstrated for the first time that the effects of post-chronic Cd exposure on human lung cells are long-lasting and different from that of acute and chronic exposures. Findings from our study unveiled a new perspective on Cd-induced carcinogenesis—the post-chronic exposure of Cd. This study encourages the field of post-exposure research which is crucial but has long been ignored.

The influence of nimodipine and vasopressors on outcome in patients with delayed cerebral ischemia after spontaneous subarachnoid hemorrhage.

Delayed cerebral ischemia (DCI) is a major factor contributing to the inferior outcome of patients with spontaneous subarachnoid hemorrhage (SAH). Nimodipine and induced hypertension using vasopressors are an integral part of standard therapy. Consequences of the opposite effect of nimodipine and vasopressors on blood pressure on patient outcome remain unclear. The authors report the detailed general characteristics and influence of nimodipine and vasopressors on outcome in patients with SAH. The authors performed a 2-center, retrospective, clinical database analysis of 732 SAH patients treated between 2008 and 2016. Demographic and clinical data such as age, sex, World Federation of Neurosurgical Societies (WFNS) grade, BMI, Fisher grade, history of arterial hypertension and smoking, aneurysm location, C-reactive protein (CRP) level, and detailed dosage of vasopressors and nimodipine during the treatment period were evaluated. Clinical outcome was analyzed using the modified Rankin Scale (mRS) 6 months after treatment. Univariate and multivariate regression analyses were performed. Additionally, mean arterial pressure (MAP), age, nimodipine, and vasopressor dose cutoff were evaluated with regard to outcome. The level of significance was set at ≤ 0.05. Follow-up was assessed for 397 patients, 260 (65.5%) of whom achieved a good outcome (defined as an mRS score of 0-3). Univariate and multivariate analyses confirmed that nimodipine (p = 0.049), age (p = 0.049), and CRP level (p = 0.002) are independent predictors of good outcome. WFNS grade, Fisher score, hypertension, initial hydrocephalus, and total vasopressor dose showed significant influence on outcome in univariate analysis, and patient sex, smoking status, BMI, and MAP showed no significant association with outcome. A subgroup analysis of patients with milder initial SAH (WFNS grades I-III) revealed that initial hydrocephalus (p = 0.003) and CRP levels (p = 0.001) had significant influence on further outcome. When evaluating only patients with WFNS grade IV or V, age, CRP level (p = 0.011), vasopressor dose (p = 0.030), and nimodipine dose (p = 0.049) were independent predictors of patient outcome. Patients with an MAP < 93 mm Hg, a nimodipine cutoff dose of 241.8 mg, and cutoff total vasopressor dose of 523 mg had better outcomes. According to the authors' results, higher doses of vasopressors can safely provide a situation in which the maximum dose of nimodipine could be administered. Cutoff values of the total vasopressor dose were more than 3 times higher in patients with severe SAH (WFNS grade IV or V), while the nimodipine cutoff remained similar in patients with mild and severe SAH. Hence, it seems encouraging that a maximum nimodipine dosage can be achieved despite the need for a higher vasopressor dose in patients with SAH.

Multiple primary cancers associated with endometrial and ovarian cancers: An analysis based upon the Japan Autopsy Annual Database from 2002 to 2010.

A thorough analysis of multiple primary cancers (MPC) could provide important information as to the pathogenesis of human malignancies. Analysis of MPC using clinical databases has been performed, but little has been done using autopsy cases. Therefore, in this study, we first retrospectively analyzed MPC associated with endometrial and ovarian cancers using the Japan Autopsy Annual Database. The Japan Autopsy Annual Database from 2002 to 2010 was established by the Japanese Society of Pathology, Tokyo, Japan. Among the 164 211 autopsy cases registered, 9142 were cases of primary cancers. The patients with endometrial cancer-associated MPC did have a lower risk of harboring colorectal cancer (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.45-0.89) but had a higher risk of ovarian cancer (OR, 3.15; 95% CI, 2.11-4.71). Those with ovarian cancer-associated MPC had a lower risk of harboring gallbladder cancer including bile ductal cancer (OR, 0.47; 95% CI, 0.27-0.80) but a higher risk of harboring breast (OR, 1.69; 95% CI, 1.20-2.38) and endometrial cancers (OR, 3.48; 95% CI, 2.33-5.20). Both endogenous and exogenous factors are associated with the incidence of MPC. Results of our present study based on Japanese Autopsy Base first demonstrated that female hormones had a strong influence on the incidence of MPC. This study also demonstrated that the analysis of MPC using an autopsy database could have advantages over clinical database analysis.

Systematic Lab Knowledge Integration for Management of Lipid Excess in High-Risk Patients: Rationale and Design of the SKIM LEAN Project.

SKIM LEAN aims at exploiting Electronic Health Records (EHRs) to integrate knowledge derived from routine laboratory tests with background analysis of clinical databases, for the identification and early referral to specialist care, where appropriate, of patients with hypercholesterolemia, who may be inadequately controlled according to their cardiovascular (CV) risk level. SKIM LEAN addresses gaps in care that may occur through the lack of coordination between primary and specialist care, incomplete adherence to clinical guidelines, or poor patient's compliance to the physician's prescriptions because of comorbidities or drug side effects. Key project objectives include: (1) improved health professionals' competence and patient empowerment through a two-tiered educational website for general practitioners (GPs) and patients, and (2) implementation of a hospital-community shared care pathway to increase the proportion of patients at high/very-high CV risk (Familial Hypercholesterolemia, previous CV events) who achieve target LDL cholesterol (LDL-C) levels. Thanks to a close collaboration between clinical and information technology partners, SKIM LEAN will fully exploit the value of big data deriving from EHRs, and filter such knowledge using clinically-derived algorithms to risk-stratify patients. Alerts for GPs will be generated with interpreted test results. GPs will be able to refer patients with uncontrolled LDL-C within the shared pathway to the lipid or secondary prevention outpatient clinics of NIG hospital. Metrics to verify the project achievements include web-site visits, the number of alerts generated, numbers of patients referred by GPs, the proportion of secondary prevention patients who achieve LDL-C <100 mg/dl or a >50% decrease from baseline.

Abstract 175: Mechanical transduction mediated by Integrin-ILK dependent actin dynamics drives stem-plasticity leading experimental metastatic colonization of prostate cancer leading experimental metastatic colonization of prostate cancer

Abstract Incurable bone metastasis is a main cause of death in prostate cancer. Metastasis is believed to be initiated by a small subpopulation of cancer cells termed tumor initiating cells (TICs) or cancer stem-like cells (CSCs). One of the key steps of the metastatic cascade is metastatic colonization of circulating tumor cells/clusters (CTCs) in a distant niche from circulation. From clinical database analysis, a significant up regulation of genes related to cell-ECM interaction was observed in prostate cancer patients derived CSCs, implying that the enhanced focal adhesion ability and its correlated cytoskeleton remodeling of CSCs plays a critical role in regulating metastatic colonization. However, due to a lack of tools to visualize the low amount of disseminated CSCs at high imaging resolution, it remains unknown how those cells behave when they interact with the stromal compartment at the inception of metastatic colonization. Hereby, we intravenously injected osteotropic prostate cancer cells with fluorescently-labeled F-actin into transparent zebrafish embryos to monitor single cell dynamics during metastatic colonization. In this model we observed a highly dynamic actin-based cytoskeletal remodeling in ALDHhi CSCs that controls extravasation and metastatic colonization. Transcriptome analysis revealed that this cytoskeleton remodeling was regulated by the focal adhesion factors: Integrinβ1 and integrin linked kinase (ILK). Genetic targeting of Integrinβ1 and ILK significantly inhibited expression of pluripotency genes, ALDH activity, metastatic colonization and outgrowth, suggesting the Integrinβ1-ILK axis as a key metastatic regulator that drives stem-like properties of CSCs during metastasis. Further in vitro and in vivo analysis showed that the Integrinβ1-ILK axis controls prostate cancer stem plasticity by generating contractile force through small GTPase-CDC42 and invadopodia regulator-N-wasp when the cells physically interact with the ECM. This mechanical transduction further activates mechanical sensor YAP/TAZ in a hippo-independent manner and promotes the expression of pluripotency genes that support metastatic initiation. Interference with this process by blocking CDC42-N-wasp signaling significantly attenuated mechanical transduction, impaired YAP/TAZ nuclear translocation and eventually inhibited metastatic initiation. Taken together, this study indicates a fundamental role of the mechanical transduction between ECMs and CSCs mediated by integrin/ILK dependent cytoskeleton remodeling at metastatic onset and outgrowth. Pharmacological targeting of this process may be a potent approach to attenuate the formation of prostate cancer metastasis on clinic. Citation Format: Lanpeng Chen, Stefano Coppola, Nick Landman, Arwin Groenewoud, Thomas Schmidt, B.Ewa Snaar-Jagalska. Mechanical transduction mediated by Integrin-ILK dependent actin dynamics drives stem-plasticity leading experimental metastatic colonization of prostate cancer leading experimental metastatic colonization of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 175.

Effects of pulmonary rehabilitation on exercise capacity and disease impact in patients with chronic obstructive pulmonary disease and obesity

ObjectivesTo explore the influence of obesity on outcomes of exercise capacity and disease impact in patients with chronic obstructive pulmonary disease (COPD) in response to pulmonary rehabilitation (PR) and to compare outcomes to those of normal weight and overweight counterparts. DesignSecondary data analysis of clinical database. SettingSt. James’s Hospital, Dublin, Ireland. Participants155 participants with a primary diagnosis of COPD who completed a PR programme between 2012 and 2014. Main Outcome MeasuresExercise capacity evaluated using the Six Minute Walk Test (6MWT) and the COPD Assessment Test (CAT) evaluated disease impact. ResultsWalking distance in the 6MWT improved significantly [mean difference of 55m (95% CI: 42 to 68; p<0.001)] and similarly [F(2, 92)=1.434, p=0.24] across all BMI categories, although the level of improvement reached clinical significance in the normal/underweight and overweight categories only. Disease impact on the CAT score improved across all body mass index (BMI) classifications by 2.3 points (95% CI: 0.9 to 3.6; p<0.050) which reached clinical significance and did not vary across BMI categories [F(2, 80)=0.534, p=0.58]. ConclusionExercise capacity and self-report disease impact of individuals with COPD improved similarly in response to PR irrespective of BMI.

TMEM74 promotes tumor cell survival by inducing autophagy via interactions with ATG16L1 and ATG9A

Autophagy is a highly inducible system of intracellular degradation that occurs in lysosomes or vacuoles. Transmembrane 74 (TMEM74) has been shown to induce autophagy. However, the mechanism by which TMEM74 stimulates autophagy and the impacts of TMEM74-induced autophagy on tumor cell survival remain unclear. In this study, TMEM74 was shown to increase the autophagic flux process in different tumor cell lines. Further investigations revealed that TMEM74 interacts with ATG16L1 and ATG9A. Moreover, distinctive from the common autophagy models, it is found that TMEM74-related autophagy is independent of BECN1/PI3KC3 complex and ULK1, and TMEM74 may initiate and promote autophagy directly via interactions with ATG16L1 and ATG9A responsible for the nucleation and elongation respectively. Considering the ultimate outcome of TMEM74-induced autophagy in tumor cells, TMEM74-triggered autophagy induces a pro-survival effect on tumor cells, particularly cells under metabolic stress, consistent with alteration of a series of signal pathways. Intriguingly, TMEM74 itself can be downregulated through the autophagic process, which indicates that a potential self-regulatory loop exists so as to maintain an appropriate level of autophagy, avoiding excessive autophagy to commit tumor cells to death. According to the clinical database analysis, the high expression of TMEM74 significantly shortens the surviving periods of patients in several specific cancers indicating that TMEM74 itself can be treated as an effective potential target with clinical values to prolong surviving periods of cancer patients in the future. In conclusion, our study reveals a new mechanism by which autophagy is stimulated by a novel positive modulator through a unique pathway and demonstrates a novel connection between autophagy and cell survival, which undoubtedly serves to broaden our understanding of autophagy.