Ultra-large scale virtual screening identifies a small molecule inhibitor of the Wnt transporter Wntless.

Wnts are lipid-modified glycoproteins that play key roles in both embryonic development and adult homeostasis. Wnt signaling is dysregulated in many cancers and preclinical data shows that targeting Wnt biosynthesis and secretion can be effective in Wnt-addicted cancers. An integral membrane protein known as Wntless (WLS/Evi) is essential for Wnt secretion. However, WLS remains undrugged thus far. The cryo-EM structure of WLS in complex with WNT8A shows that WLS has a druggable G-protein coupled receptor (GPCR) domain. Using Active Learning/Glide, we performed an ultra-large scale virtual screening from Enamine's REAL 350/3 Lead-Like library containing nearly 500 million compounds. 68 hits were examined after on-demand synthesis in cell-based Wnt reporter and other functional assays. ETC-451 emerged as a potential first-in-class WLS inhibitor. ETC-451 blocked WLS-WNT3A interaction and decreased Wnt-addicted pancreatic cancer cell line proliferation. The current hit provides a starting chemical scaffold for further structure or ligand-based drug discovery targeting WLS.

Low-to-Moderate Arsenic Exposure and Urothelial Tract Cancers with a Long Latent Period of Follow-Up in an Arseniasis Area.

BACKGROUND: Arsenic exposure can cause adverse health effects. The effects of long-term low-to-moderate exposure and methylations remain unclear. OBJECTIVE: This study aims to examine the association between low-to-moderate arsenic exposure and urothelial tract cancers while considering the effects of methylation capacity. METHODS: In this study, 5,811 participants were recruited from an arseniasis area in Taiwan for inorganic arsenic metabolite analysis. This follow-up study was conducted between August 1995 and December 2017. We identified 85 urothelial tract cancers in these participants, including 49 bladder and 36 upper urothelial tract cancer cases. A Cox proportional hazards model was employed. RESULTS: The analyses revealed a significant association between concentrations of inorganic arsenic in water > 100 ug/L and bladder cancer occurrence, with a hazard ratio (HR) of 4.88 (95% CI 1.35-17.61). A monotonic trend was observed between concentrations of inorganic arsenic in water (from 0 to > 100 ug/L) and the incidence of urothelial tract cancer, including bladder cancer (p < 0.05) and upper urothelial tract cancers (p < 0.05). Participants with a lower primary methylation index or higher secondary methylation index had a prominent effect. CONCLUSIONS: Rigorous regulations and active interventions should be considered for populations with susceptible characteristics.

Kinship analysis of type 2 diabetes mellitus familial aggregation in Taiwan.

BACKGROUND: Family disease history plays a vital role in type 2 diabetes mellitus (T2DM) risk. However, the familial aggregation of T2DM among different kinship relatives warrants further investigation. METHODS: This nationwide kinship relationship study collected 2000-2016 data of two to five generations of the Taiwanese population from the National Health Insurance Research Database. Approximately 4 million family trees were constructed from the records of 20, 890, 264 Taiwanese residents during the study period. T2DM was diagnosed on the basis of ICD-9-CM codes 250.x0 or 250.x2, with three consecutive related prescriptions. The Cox proportional hazard model was used for statistical analysis. RESULTS: Compared with their counterparts, individuals who had first-degree relatives with T2DM were more likely to develop T2DM during the follow-up period (hazard ratio [HR], 2.37-27.75), followed by individuals who had second-degree relatives with T2DM (HR, 1.29-1.88). T2DM relative risk was higher in those with an affected mother than in those with affected father. The HR for T2DM was 20.32 (95%CI = 15.64-26.42) among male individuals with an affected twin brother, whereas among female individuals with an affected twin sister, it was 60.07 (95%CI = 40.83-88.36). The HRs presented a dose-response relationship with the number of affected family members. CONCLUSION: The study suggests a significant familial aggregation of T2DM occurrence; these findings could aid in identifying the high-risk group for T2DM and designing early intervention strategies and treatment plans.

Combination of Thigh Circumference and Indices of Central Obesity Helps Predict Incident Chronic Kidney Disease: A 14-Year Prospective Cohort Study Using a Three-Dimensional Body Laser Scanner.

OBJECTIVE: Obesity, high body mass index, and visceral fat accumulation are associated with renal diseases. However, the association between body measurements and chronic kidney disease (CKD) is still unclear. METHODS: A cohort of 7,825 participants scheduled for follow-up of CKD was recruited from 2000 to 2008 in Taiwan. A questionnaire was developed to collect the basic demographics, lifestyle variables, personal disease history, and family disease history of the participants. A 3-dimensional body surface scanning system was used to take their body measurements. The participants underwent an average follow-up of 14.3 years for evaluation of the incidence of CKD. A multiple Cox regression model was built. RESULTS: Three body measurements, namely chest width (hazard ratio [HR] 1.059, 95% confidence interval [CI] 1.011-1.110), waist circumference (HR 1.017, 95% CI 1.006-1.029), and thigh circumference (HR 0.941, 95% CI 0.922-0.961), were significantly associated with CKD. Two combinations of body measurements, namely the waist-to-thigh ratio and chest-to-thigh ratio, were derived to predict the occurrence of CKD. Participants with the highest quartile of waist-to-thigh ratio and chest-to-thigh ratio had a 2.175-fold and 2.182-fold risk of developing CKD, respectively. CONCLUSIONS: This study suggests that along with central obesity, body limb measurements can be used as an indicator to predict the occurrence of CKD. The effects of limb measurements on CKD could help provide an innovative perspective regarding the intervention to be developed for the treatment of CKD and a preventive medicine for high-risk individuals. The association of thigh circumference with CKD warrants further investigation.

Structural model of human PORCN illuminates disease-associated variants and drug-binding sites.

Wnt signaling is essential for normal development and is a therapeutic target in cancer. The enzyme PORCN, or porcupine, is a membrane-bound O-acyltransferase (MBOAT) that is required for the post-translational modification of all Wnts, adding an essential mono-unsaturated palmitoleic acid to a serine on the tip of Wnt hairpin 2. Inherited mutations in PORCN cause focal dermal hypoplasia, and therapeutic inhibition of PORCN slows the growth of Wnt-dependent cancers. Based on homology to mammalian MBOAT proteins, we developed and validated a structural model of human PORCN. The model accommodates palmitoleoyl-CoA and Wnt hairpin 2 in two tunnels in the conserved catalytic core, shedding light on the catalytic mechanism. The model predicts how previously uncharacterized human variants of uncertain significance can alter PORCN function. Drugs including ETC-159, IWP-L6 and LGK-974 dock in the PORCN catalytic site, providing insights into PORCN pharmacologic inhibition. This structural model enhances our mechanistic understanding of PORCN substrate recognition and catalysis, as well as the inhibition of its enzymatic activity, and can facilitate the development of improved inhibitors and the understanding of disease-relevant PORCN mutants. This article has an associated First Person interview with the joint first authors of the paper.

Higher Leptin-to-Adiponectin Ratio Strengthens the Association Between Body Measurements and Occurrence of Type 2 Diabetes Mellitus.

Aim: This case-control study aimed to investigate the interrelations of body measurements and selected biomarkers in type 2 diabetes mellitus (T2DM). Methods: We recruited 98 patients with T2DM and 98 controls from 2016 to 2018 in Taiwan. Body measurements were obtained using a three-dimensional body surface scanning system. Four biomarkers related to insulin resistance, adipokines, and inflammation were assayed. A multiple logistic regression model was used to perform multivariable analyses. Results: Four body measurements, namely waist circumference (odds ratio, OR = 1.073; 95% confidence interval, CI = 1.017-1.133), forearm circumference (OR = 1.227; 95% CI = 1.002-1.501), thigh circumference (OR = 0.841; 95% CI = 0.73-0.969), and calf circumference (OR = 1.25; 95% CI = 1.076-1.451), were significantly associated with T2DM. Leptin (OR = 1.09; 95% CI = 1.036-1.146) and adiponectin (OR = 0.982; 95% CI = 0.967-0.997) were significantly associated with T2DM. Six body measurement combinations, namely body mass index, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, forearm-to-thigh ratio, and calf-to-thigh ratio (CTR), were significantly associated with T2DM. CTR had the strongest linear association with T2DM. Moderating effects of significant biomarkers, namely leptin and adiponectin, were observed. Participants with high leptin-to-adiponectin ratios and in the fourth CTR quartile were 162.2 times more prone to develop T2DM. Conclusions: We concluded that a combination of leptin and adiponectin modulated the strength of the association between body measurements and T2DM while providing clues for high-risk group identification and mechanistic conjectures of preventing T2DM.

Adverse body measurements are superior to sarcopenia-associated measurements in predicting chronic diseases.

Few studies have demonstrated an association of sarcopenia-associated body measurements with chronic diseases through a comprehensive methodology. This study aims to examine the relationship between sarcopenia-associated body measurements and chronic diseases. This is a cohort study. We recruited 316 community dwellers, including 76 patients with sarcopenia and 240 controls, and obtained their body measurements associated with sarcopenia. We collected three-dimensional anthropometric body-surface measurements from 11,158 participants during 2000-2008 and followed up this cohort for 15 years to examine the association of these measurements with the risk of chronic diseases such as hypertension, type 2 diabetes mellitus (T2DM), heart disease, and nephrotic syndrome. Univariate analysis, canonical correlation, and Cox regression analysis were performed to explore the associations. Decreased waist width, upper left arm circumference, and left thigh circumference were significantly associated with sarcopenia. The adverse body measure score (ABMS) was derived by combining significant measurements, namely left upper arm circumference, waist width, and left thigh circumference, and used to predict the risk of hypertension, T2DM, heart diseases, and nephrotic syndrome. A positive association was observed between the ABMS and chronic diseases. Considering the first quartile of the ABMS as a reference, we determined hazard ratios of 2.259, 2.495, 1.332, and 1.595 for hypertension, T2DM, heart disease, and nephrotic syndrome, respectively, in the fourth quartile. Chronic diseases were more strongly associated with the ABMS than with sarcopenia-related body measurements alone. A high ABMS, which includes higher upper arm circumference, higher waist width, and lower thigh circumference, can significantly predict chronic diseases.

Joint effects of genomic markers and urinary methylation capacity associated with inorganic arsenic metabolism on the occurrence of cancers among residents in arseniasis-endemic areas: A cohort subset with average fifteen-year follow-up.

BACKGROUND: Chronic exposure to inorganic arsenic results in many cancers in susceptible persons. The metabolism of inorganic arsenic and genomic susceptibility are thought to be associated with cancer occurrence. METHODS: This study aims to examine the interaction of genomic susceptibility markers and urinary methylation capacity indicators involved in inorganic arsenic metabolism with all-cancer occurrence. This study conducted a follow-up on 96 residents to determine their urinary inorganic arsenic metabolites and genomic assay from an arseniasis area. Among them, 24 cancer developed. Multivariable Cox proportional hazards model was used to determine and estimate the candidate independent variables for cancer development. RESULTS: The residents with high inorganic arsenic exposure, high primary methylation index (PMI; MMA/InAs) (but lower secondary methylation index (SMI)), and non-heterogeneity type of genomic markers, including GSTO1, AS3MT, and MPO, tend to develop cancers. Subjects with higher PMI are at higher risk of developing cancers (HR = 1.66; 95% CI = 1.30-2.12). Cancer occurrence was greater among the CC type of GSTO1 (HR = 3.33; 95% CI = 1.11-10.00), CC type of AS3MT (HR = 19.21; 95% CI = 1.16-318.80), and AA type of MPO (HR = 13.40; 95% CI = 1.26-142.40). After adjusting confounders, a mutually moderating effect was revealed between genomic markers and methylation capacity on cancer occurrence. CONCLUSIONS: This study found the hypermethylation responses to inorganic arsenic exposure and an array of genomic markers may increase the susceptibility of a wide range of organ cancers. The findings indicated a high-risk arsenic-exposed population to develop cancers. The phenotype of arsenic metabolism and genomic polymorphism suggested a potential preventive strategy for arsenic carcinogenesis.

A Ras-LSD1 axis activates PI3K signaling through PIK3IP1 suppression.

PI3K Interacting Protein 1 (PIK3IP1) is a suppressor of the PI3K/Akt/mTOR pathway. We previously reported that activated Ras suppresses PIK3IP1 expression to positively regulate the PI3K pathway in cancer cells. Using doxycycline-inducible PIK3IP1, here we confirm that reversing the effect of Ras by inducing expression of PIK3IP1 suppresses Ras-induced anchorage-independent growth, supporting the central role of PIK3IP1 in transformation. However, the molecular mechanisms by which Ras-activation that causes loss of PIK3IP1 expression are unknown. We find that Ras activity represses PIK3IP1 expression via the recruitment of lysine-specific demethylase 1 (LSD1) to the PIK3IP1 gene promoter and enhancer, resulting in erasure of active histone marks. These studies demonstrate cross-activation of Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways, where Ras decommissions PIK3IP1 gene expression by enhancing LSD1 and its corepressor activities to suppress PIK3IP1 transcription.

RATES AND RISK FACTORS FOR RECURRENCE OF RETINOPATHY OF PREMATURITY AFTER LASER OR INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR MONOTHERAPY.

PURPOSE: To determine the rates and risk factors of recurrent retinopathy of prematurity (ROP) treated by laser photocoagulation, intravitreal bevacizumab (IVB) monotherapy, or intravitreal ranibizumab (IVR) monotherapy. METHODS: In this retrospective cohort study, consecutive infants with Type 1 ROP who received laser, IVB, or IVR treatments were followed for at least 75 weeks of postmenstrual age. Data analysis was performed between March 2010 and February 2017 in Chang Gung Memorial Hospital, Linkou, Taiwan. RESULTS: A total of 176 infants (340 eyes) were included in this study. The mean follow-up was 197.3 ± 110 weeks. All of the baseline demographic and ROP characteristics among the laser, IVB, and IVR groups were similar. The overall recurrence rate after treatment was 44 of 340 eyes (12.9%). The IVB group had a recurrence rate of 10.0%, followed by the laser group (18.0%) and the IVR group (20.8%); however, these rates were not significantly different (P = 0.0528). Compared with the laser group, the IVB and IVR groups exhibited recurrence at later ages (43.4 ± 3.5 weeks for the IVB group, 42.3 ± 2.0 weeks for the IVR group, and 39.5 ± 2.8 weeks for the laser group; P = 0.0058). The mean interval of recurrence from initial treatment in the laser group was 3.6 ± 1.4 weeks compared with 8.8 ± 3.9 weeks and 8.3 ± 1.6 weeks in the IVB and IVR groups, respectively (P = 0.0001). Overall, the independent risk factors of recurrence included an early postmenstrual age at initial treatment (P = 0.0160), Zone I (P = 0.0007), low Apgar score (P = 0.0297), and multiple births (P = 0.0285). There was no significant difference in progression to retinal detachment among the three groups (laser: 3/61, 4.9%; IVB: 2/231, 0.9%;and IVR: 1/48, 2.1%; P = 0.2701). CONCLUSION: Laser, IVR, and IVB are effective for Type 1 ROP. Retinopathy of prematurity recurrence requiring re-treatment was encountered as late as 50 weeks of postmenstrual age after IVB or IVR but earlier after laser. Longer follow-up for infants treated with anti-vascular endothelial growth factor is needed, especially in patients with significant risk factors such as an early postmenstrual age at initial treatment, Zone I ROP, low Apgar score, and multiple births.

Factors associated with adverse drug reaction occurrence and prognosis, and their economic impacts in older inpatients in Taiwan: a nested case-control study.

OBJECTIVE: Older patients are likely to have higher disease complexity and more drug prescriptions of which are associated with a higher incidence of adverse drug reactions (ADR). This study aimed to investigate factors associated with ADR occurrence, prognosis and medical expenses in older inpatients. DESIGN: A nested case-control study. SETTING: A medical centre located in north Taiwan. PARTICIPANTS: 539 reported ADR cases from a patient cohort containing 108 548 older inpatients were collected from 2006 to 2012. There were 1854 non-ADR matched controls; a maximum of 1:5 matched by age, sex and principal diagnosis were collected. EXPOSURE: Polypharmacy, the number of drugs prescribed, comorbidities and the admission department were factors associated with ADRs, as well as subsequent poor prognosis, length of stay and medical expenses. PRIMARY AND SECONDARY OUTCOME MEASURES: ADR occurrence and poor prognosis (mortality, discharge against medical advice in critical conditions, or admitted to intensive care unit) were the primary outcomes. Additional medical expenses and the length of hospital stay were the secondary outcomes. RESULTS: The admission department, number of comorbidities and number of drug prescriptions before ADRs were associated with ADR occurrence among older inpatients. ADR severity was a significant prognostic factor among ADR cases. The multivariate-adjusted OR of 1.63 (95% CI 1.36 to 1.95) for poor prognosis was found as the number of comorbidities increased. Patients prescribed ≥11 drugs including psychoactive drugs showed 2.45-fold (95% CI 1.40 to 4.28) poorer prognosis than other patients. ADRs caused the addition of US$1803.8, US$360.8 and 5.6 days in total medical expenses, drug expenses and length of stay among affected older inpatients, respectively. CONCLUSIONS: The number of comorbidities and polypharmacy including the use of psychoactive drugs has significant impacts on ADR occurrence and prognosis among older inpatients. The findings provide clues for future prescription modification and patient's safety improvement in geriatric care.

Prodrugs of the cancer cell selective anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131) are orally efficacious in a mouse model of resistant colon cancer.

A131 (1) possesses a unique cancer cell selective dual mechanism of action where cancer cells are killed but normal cells only undergo growth arrest and are able to regrow after removal of 1. SAR studies of 1 indicate that only the specific structure of 1 elicits the full pharmacological effect. However, application of 1 in mouse models of cancer has been hampered by its low solubility and stability when given orally. In this work we describe the study of various prodrugs based on modification of the indole nitrogen. A range of acyl analogues were prepared as prodrugs which were shown to undergo degradation to the parent drug in plasma. A preferred prodrug fully elicited the pharmacological effects of 1 in cells and led to high aqueous solubility suitable for oral administration. In a mouse model of paclitaxel-resistant colon cancer, compound 10, as a TFA salt, showed 76% tumor growth inhibition when administered at an oral dose of 80 mg/kg twice a day.

Predicting Type 2 Diabetes Mellitus Occurrence Using Three-Dimensional Anthropometric Body Surface Scanning Measurements: A Prospective Cohort Study.

BACKGROUND: An accurate and comprehensive anthropometric measure for predicting type 2 diabetes mellitus (T2DM) has not yet been depicted. METHODS: A total of 8450 nondiabetic participants were recruited during 2000-2010 in Taiwan. The cohort was followed up to the end of 2013, over an average of 8.87 years. At recruitment, participants completed a questionnaire related to basic demographics, lifestyle variables, personal disease history, and family disease history. 3D body surface scanning was used to obtain 35 anatomical measurements. A Cox proportional hazard model was used to conduct multivariable analyses. RESULTS: A total of 2068 T2DM cases at an incidence rate of 27.59 × 10-3 (year-1) were identified during the follow-up period. Multivariable-adjusted hazard ratios (HRs) demonstrated that neck circumference (NC) (HR = 1.048; 95% CI = 1.033-1.064), waist width (WW) (HR = 1.061; 95% CI = 1.040-1.081), and left thigh circumference (TC) (HR = 0.984; 95% CI = 0.972-0.995) were significant predictors of the occurrence of T2DM. While dividing body measurement into median high/low groups, an increased risk of T2DM was observed among participants with a larger NC and smaller TC (HR = 1.375; 95% CI = 1.180-1.601) and a larger WW and smaller TC (HR = 1.278; 95% CI = 1.085-1.505) relative to other participants. CONCLUSIONS: This study suggests that as well as using traditional waist and TC measurements, NC can be used as an indicator to provide an early prediction of developing T2DM, while providing clues for future mechanistic investigations of T2DM.

Discovery of the cancer cell selective dual acting anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131).

Selective targeting of cancer cells over normal cells is a key objective of targeted therapy. However few approaches achieve true mechanistic selectivity resulting in debilitating side effects and dose limitation. In this work we describe the discovery of A131 (4a), a new agent with an unprecedented dual mechanism of action targeting both mitosis and autophagy. Compound 4a was first identified in a phenotypic screen in which HeLa cells treated with 4a manifested mitotic arrest along with formation of multiple vesicles. Further investigations showed that 4a causes an increase in mitotic marker pH3 and autophagy marker LC3. Importantly 4a induces cell death in cancer cells while sparing normal cells which regrow after 4a is removed. Dual activities against pH3 and LC3 markers are required for cancer cell selectivity. An extensive SAR investigation confirmed 4a as the optimal dual inhibitor with potency against a panel of 30 cancer cell lines (average antiproliferative GI50 1.5 µM). In a mouse model of paclitaxel-resistant colon cancer, 4a showed 74% tumor growth inhibition when administered at a dose of 20 mg/kg IP twice a day.

Chest width, waist circumference, and thigh circumference are predictors of dementia.

OBJECTIVE: Few studies have investigated the relationship between specific body measures and dementia. METHODS: Three-dimensional anthropometric body surface scanning data containing 38 body measures were collected from 6831 participants from the health examination department of a medical center in Taiwan during 2000 to 2008, and 236 dementia cases were identified during the 10-year follow-up. A multiple Cox regression analysis was performed. RESULTS: Specific body measures, namely chest width (hazard ratio [HR] = 0.90; 95% confidence interval [CI] = 0.83-0.98), and right thigh circumference (HR = 0.93; 95% CI = 0.90-0.96), were protective predictors to dementia occurrence. Waist circumference (HR = 1.03; 95% CI = 1.02-1.05) was a risk factor in dementia occurrence. Among the combinations, dementia risk was higher in participants with a larger waist circumference and a smaller right thigh circumference, with the highest HR of 2.49 (95% CI = 1.54-4.03). CONCLUSION: The body measures provide clues for future applications and scientific merits in both clinical and preventive medicine.

Lifestyle characteristics as moderators of the effectiveness of weight control interventions among semiconductor workers.

BACKGROUND: Workers in high technology industry are experiencing stressful environment and have been ranked as a high risk group for adverse health effects. The effectiveness of worksite health promotion is important for occupational health. This study is to investigate the effect of health interventions on body measurement changes while examining the role of their lifestyle factors. METHODS: A total of 904 participants aged over 30 years were recruited from 14 semiconductor worksites in Taiwan from 2011 to 2015. A multi-settings, quasi-experimental study was conducted that assigned participants into two intervention programs, including exercise program and diet-plus-exercise program. The outcomes include the changes of body weight, waist circumference, body mass index (BMI), and biophysiological indicators. Lifestyle variables include alcohol consumption, cigarette smoking, and regular exercise. Multiple linear regression analyses were performed to test the association. RESULTS: The findings have demonstrated that one kilogram body weight reduction is associated with a decrease of 0.58 mmHg SBP (p < 0.001), 0.29 mmHg DBP (p < 0.001), 3.33 mg/dL triglyceride (p < 0.001), 0.96 mg/dL total cholesterol (p < 0.001), and 0.68 mg/dL LDL (p < 0.001). The diet-plus-exercise group had more significant effect on both weight changes and biophysiological changes than exercise-only group (p < 0.001). Lifestyle factors, including cigarette smoking, alcohol consumption, and regular exercise, were significant moderators of the effectiveness of health interventions. CONCLUSIONS: Both exercise and diet interventions are important to the effectiveness of health promotion in occupational sectors. Lifestyle modifications are vital for weight control programs in improving body shape changes and biophysiological indicators.

Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality.

Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally upregulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway. Strikingly, Ras activation overrides a131-induced PIK3IP1 upregulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131's ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras˧PIK3IP1˧PI3K signaling network.

Opposing Activities of Aurora B Kinase and B56-PP2A Phosphatase on MKlp2 Determine Abscission Timing.

After cleavage furrow ingression during cytokinesis, nascent daughter cells remain connected by an intercellular bridge (ICB) and the midbody [1, 2]. The midbody becomes an assembly platform for ESCRT complexes that split apart the plasma membrane (PM) anchored to the ICB and complete abscission, which is the final step of cell division [3-5]. Aurora B governs abscission by regulating its timing as a checkpoint [6-10]. However, the underlying mechanisms for this process remain unknown. Here, we reveal the mechanism controlling abscission through integration of Aurora B kinase and B56-bound PP2A phosphatase activities on the kinesin motor protein MKlp2. We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton at the ICB through its previously uncharacterized lipid association motif (LAM). MKlp2 recruits Aurora B to the ICB [11-15]. In turn, Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878. Strikingly, a phospho-resistant MKlp2 S878A mutant overcomes Aurora-B-mediated abscission blockade. Thus, abscission is determined by the balance of Aurora B and B56-PP2A activities on MKlp2 S878 within the LAM. Together, these findings establish a key mechanism for Aurora B regulation of abscission in mammalian cells.

Predictive factors for hospitalization of nonurgent patients in the emergency department.

Nonurgent emergency department (ED) patients are a controversial issue in the era of ED overcrowding. However, a substantial number of post-ED hospitalizations were found, which prompted for investigation and strategy management. The objective of this study is to identify risk factors for predicting the subsequent hospitalization of nonurgent emergency patients. This was a retrospective study of a database of adult nontrauma ED visits in a medical center for a period of 12 months from January 2013 to December 2013. Patient triages as either Taiwan Triage and Acuity Scale (TTAS) level 4 or 5 were considered "nonurgent." Basic demographic data, primary and secondary diagnoses, clinical parameters including blood pressure, heart rate, body temperature, and chief complaint category in TTAS were analyzed to determine if correlation exists between potential predictors and hospitalization in nonurgent patients.A total of 16,499 nonurgent patients were included for study. The overall hospitalization rate was 12.47 % (2058/16,499). In the multiple logistic regression model, patients with characteristics of males (odds ratio, OR = 1.37), age more than 65 years old (OR = 1.56), arrival by ambulance (OR = 2.40), heart rate more than 100/min (OR = 1.47), fever (OR = 2.73), and presented with skin swelling/redness (OR = 4.64) were predictors for hospitalization. The area under receiver-operator calibration curve (AUROC) for the prediction model was 0.70. Nonurgent patients might still be admitted for further care especially in male, the elderly, with more secondary diagnoses, abnormal vital signs, and presented with dermatologic complaints. Using the TTAS acuity level to identify patients for diversion away from the ED is unsafe and will lead to inappropriate refusal of care for many patients requiring hospital treatment.

Long-Term and Interactive Effects of Pay-For-Performance Interventions among Diabetic Nephropathy Patients at the Early Chronic Kidney Disease Stage.

Chronic kidney disease (CKD) is a major health problem worldwide because of the aging population and lifestyle changes. One of the important etiologies of CKD is diabetes mellitus (DM). The long-term effects of pay-for-performance (P4P) on disease progression have not been thoroughly examined.This study is a retrospective population-based patient cohort design to examine the continuous effects of diabetes and CKD P4P interventions. This study used the health insurance claims database to conduct a longitudinal analysis. A total of 32,084 early CKD patients with diabetes were extracted from the outpatient claims database from January 2011 to December 2012, and the follow-up period was extended to August 2014. A 4-group matching design, including both diabetes and early CKD P4P interventions, with only diabetes P4P intervention, with only early CKD P4P intervention, and without any P4P interventions, was performed according to their descending intensity. The primary outcome of this study was all-cause mortality and the causes of death. The statistical methods included a Chi-squared test, ANOVA, and multi-variable Cox regression models.A dose-response relationship between the intervention groups and all-cause mortality was observed as follows: comparing to both diabetes and early CKD P4P interventions (reference), hazard ratio (HR) was 1.22 (95% confidence interval [CI], 1.00-1.50) for patients with only a diabetes P4P intervention; HR was 2.00 (95% CI, 1.66-2.42) for patients with only an early CKD P4P intervention; and HR was 2.42 (95% CI, 2.02-2.91) for patients without any P4P interventions. The leading cause of death of the total diabetic nephropathy patient cohort was infectious diseases (34.32%) followed by cardiovascular diseases (17.12%), acute renal failure (1.50%), and malignant neoplasm of liver (1.40%).Because the earlier interventions have lasting long-term effects on the patient's prognosis regardless of disease course, an integrated early intervention plan is suggested in future care plan designs. The mechanisms regarding the effects of P4P intervention, such as health education on diet control, continuity of care, and practice guidelines and adherence, are the primary components of disease management programs.