Quasi-periodic X-ray eruptions years after a nearby tidal disruption event.

Quasi-periodic eruptions (QPEs) are luminous bursts of soft X-rays from the nuclei of galaxies, repeating on timescales of hours to weeks1-5. The mechanism behind these rare systems is uncertain, but most theories involve accretion disks around supermassive black holes (SMBHs) undergoing instabilities6-8 or interacting with a stellar object in a close orbit9-11. It has been suggested that this disk could be created when the SMBH disrupts a passing star8,11, implying that many QPEs should be preceded by observable tidal disruption events (TDEs). Two known QPE sources show long-term decays in quiescent luminosity consistent with TDEs4,12 and two observed TDEs have exhibited X-ray flares consistent with individual eruptions13,14. TDEs and QPEs also occur preferentially in similar galaxies15. However, no confirmed repeating QPEs have been associated with a spectroscopically confirmed TDE or an optical TDE observed at peak brightness. Here we report the detection of nine X-ray QPEs with a mean recurrence time of approximately 48 h from AT2019qiz, a nearby and extensively studied optically selected TDE16. We detect and model the X-ray, ultraviolet (UV) and optical emission from the accretion disk and show that an orbiting body colliding with this disk provides a plausible explanation for the QPEs.

First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase I dose exploration.

BACKGROUND: Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in ∼10%-15% of solid tumors. AMG 193, a CNS-penetrant methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, selectively induces synthetic lethality in MTAP-deleted tumor cells. Here, we report results of the completed monotherapy dose exploration evaluating AMG 193 in patients with MTAP-deleted solid tumors. PATIENTS AND METHODS: In this first-in-human, multicenter, open-label, phase I study, patients with advanced CDKN2A-deleted and/or MTAP-deleted solid tumors received AMG 193 orally [once (o.d.) or twice (b.i.d.) daily] continuously in 28-day cycles. Primary objectives were safety and tolerability assessed by dose-limiting toxicities and determination of the maximum tolerated dose; secondary objectives included pharmacokinetics and preliminary antitumor activity measured by RECIST v1.1. RESULTS: As of 23 May 2024, 80 patients in dose exploration received AMG 193 at doses 40-1600 mg o.d. or 600 mg b.i.d. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). Dose-limiting toxicities were reported in eight patients at doses ≥240 mg, including nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The maximum tolerated dose was determined to be 1200 mg o.d. Mean exposure of AMG 193 increased in a dose-proportional manner from 40 mg to 1200 mg. Among the efficacy-assessable patients treated at the active and tolerable doses of 800 mg o.d., 1200 mg o.d., or 600 mg b.i.d. (n = 42), objective response rate was 21.4% (95% confidence interval 10.3% to 36.8%). Responses were observed across eight different tumor types, including squamous/non-squamous non-small-cell lung cancer, pancreatic adenocarcinoma, and biliary tract cancer. At doses ≥480 mg, complete intratumoral PRMT5 inhibition was confirmed in paired MTAP-deleted tumor biopsies, and molecular responses (circulating tumor DNA clearance) were observed. CONCLUSIONS: AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on objective response rate and circulating tumor DNA clearance.

Dual blockade of IL-4 and IL-13 with dupilumab ameliorates sensorineural olfactory dysfunction in mice with eosinophilic sinonasal inflammation.

BACKGROUND: Dupilumab, an antibody that binds IL-4Rα and inhibits IL-4 and IL-13 signals, has demonstrated efficacy in chronic rhinosinusitis with nasal polyps (CRSwNP) primarily characterized by type 2 inflammation. Current evidence suggests that the rate of improvement in olfactory dysfunction with dupilumab exceeds that of nasal polyp reduction, yet the underlying mechanism remains undisclosed. We hypothesize that dupilumab may initially ameliorate sensorineural olfactory dysfunction. METHODOLOGY: Male BALB/c mice were intranasally administered ovalbumin and Aspergillus protease for 12 weeks to induce eosinophilic sinonasal inflammation. Dupilumab treatment was also administered. The mice underwent histological assessment, olfactory behavioural test, and gene expression profiling to identify neuroinflammatory markers within the olfactory bulb. RESULTS: Dupilumab treatment resulted in a reduction in the number of mucosal protruding lesions, as well as decreased infiltration of eosinophils and neutrophils, along with a decrease in olfactory sensory neuron injury. Furthermore, there was a downregulation in the mRNA expression related to microglia activation and neuroinflammation in the olfactory bulb. CONCLUSIONS: Dupilumab improves the sensorineural pattern of olfactory dysfunction in mice, potentially explaining why olfaction improves more rapidly than polyp reduction in patients with CRSwNP.

Enabling ultra-low-voltage switching in BaTiO3.

Single crystals of BaTiO3 exhibit small switching fields and energies, but thin-film performance is considerably worse, thus precluding their use in next-generation devices. Here, we demonstrate high-quality BaTiO3 thin films with nearly bulk-like properties. Thickness scaling provides access to the coercive voltages (<100 mV) and fields (<10 kV cm-1) required for future applications and results in a switching energy of <2 J cm-3 (corresponding to <2 aJ per bit in a 10 × 10 × 10 nm3 device). While reduction in film thickness reduces coercive voltage, it does so at the expense of remanent polarization. Depolarization fields impact polar state stability in thicker films but fortunately suppress the coercive field, thus driving a deviation from Janovec-Kay-Dunn scaling and enabling a constant coercive field for films <150 nm in thickness. Switching studies reveal fast speeds (switching times of ~2 ns for 25-nm-thick films with 5-µm-diameter capacitors) and a pathway to subnanosecond switching. Finally, integration of BaTiO3 thin films onto silicon substrates is shown. We also discuss what remains to be demonstrated to enable the use of these materials for next-generation devices.

High-efficiency picosecond mode-locked laser using a thulium-doped nanoengineered yttrium-alumina-silica fiber as the gain medium.

We report the theoretical and experimental investigation of a self-starting mode-locked fiber laser with a nanoengineered Tm3+-doped yttrium-alumina-silica (YAS) fiber as the gain medium. The YAS fiber exhibits a higher capability of Tm3+ cluster elimination than commercial silica fibers. The Tm3+ fluorescence properties and YAS dispersion are well characterized. As a result, an efficient picosecond mode-locked fiber laser is demonstrated with a slope efficiency of 14.14% and maximum pulse energy of 1.27 nJ. To the best of our knowledge, this is the first mode-locked fiber laser based on a Tm3+-doped YAS fiber. The experimental observation is also supported by the numerical analysis.

Lifetime risks of hip fracture in patients with type 2 diabetic: Taiwan Diabetes Study.

This study is to estimate the lifetime risks of hip fracture in Chinese patients with type 2 diabetes. INTRODUCTION: The lifetime risks of hip fracture have not been reported across the age spectrum in male adults and female adults with type 2 diabetes. METHODS: A retrospective cohort study was conducted on 25275 men and 27953 women with type 2 diabetes aged 30-100 years old and participated in the National Diabetes Case Management Program in 2002-2004 in Taiwan. Sociodemographic factors, biomarkers, and comorbidity at the baseline and hip fracture events were analyzed with Cox proportional hazards regression models with age as the time scale. RESULTS: Significant differences in the lifetime risks of hip fracture were observed between men and women with type 2 diabetes. The cumulative lifetime incidences (%) of hip fracture at 50, 60, 65, 70, 75, 80, and 85 years old for men were 0.11, 0.40, 0.84, 1.84, 3.82, 8.53, and 16.72, respectively. The corresponding lifetime incidences (%) for women at 50, 60, 65, 70, 75, 80, and 85 years old were 0.05, 0.50, 1.36, 3.89, 9.56, 21.19, and 35.45, respectively. With competing risks, the significant multivariate-adjusted hazard ratio of developing hip fracture included smoking, alcohol drinking, duration of diabetes, type of oral hypoglycemic drugs use (no medication, sulfonylurea only, thiazolidinediones (TZD) only or TZD plus others, other single or multiple oral agents, insulin use, insulin plus oral hypoglycemic drug use), loop diuretics use, use of corticosteroids, normal weight or underweight, hyperlipidemia, and chronic obstructive pulmonary disease. CONCLUSIONS: The gender differences in lifetime hip fracture risk were significant. Thiazolidinediones and insulin use are factors with the greater magnitude of strength of association among those significantly associated with hip fracture.

Severe myocardial bridge presenting as paroxysmal atrioventricular block.

Chest pain complicated with electrocardiographic changes is not an uncommon scenario in emergency departments, which should be examined cautiously. We describe a 51-years-old man with a myocardial bridge of coronary artery presenting with simultaneous Mobitz type I atrioventricular block on electrocardiography. Echocardiography excluded valvular abnormality and systolic/diastolic dysfunction. Coronary angiography confirmed the diagnosis of a myocardial bridge at the middle segment of the left anterior descending artery, involving the most dominant septal perforator branch with marked systolic compression. The patient underwent coronary artery bypass grafting surgery and was followed up uneventfully at the outpatient department with medical treatment of diltiazem and clopidogrel. The present case is being reported to highlight that clinicians should be alert to such a congenital abnormality as a potential cause of repeated myocardial infarction and conduction abnormality.

Visit-to-visit blood pressure variability and hip fracture risk in older persons.

We investigated the association between blood pressure variability measured by the coefficient of variation (CV) of blood pressure and hip fracture in older persons with diabetes. After excluding patients with acute complications and comorbidities, a positive association with similar magnitude of strength was found between BP variability and hip fracture, compared with that in the original analysis. INTRODUCTION: Hypertension is a risk factor of osteoporosis and hip fracture, but studies have yet to investigate whether blood pressure variability measured by the CV of blood pressure can predict hip fracture in older persons with diabetes. METHODS: We conducted a retrospective cohort study on 21,160 patients who suffered from type 2 diabetes (age ≥ 50 years) and participated in the National Diabetes Care Management Program in Taiwan. The patients' 1-year variability in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the baseline and subsequent hip fracture incidence for 8.2 years were analyzed. RESULTS: There were 937 recorded incident hip fractures. SBP-CV and DBP-CV were classified based on their tertiles. After multivariate adjustment was conducted, SBP-CV found to be a predictor of hip fracture, and its hazard ratio was 1.18 (95% CI 1.00-1.40) for the third tertile compared with the first tertile. CONCLUSIONS: Our study suggests SBP stability is a predictor for hip fracture incidence in older persons with type 2 diabetes.

Photoinduced antibacterial activity of NRC03 peptide-conjugated dopamine/nano-reduced graphene oxide against Staphylococcus aureus.

In recent years, several drugs have become relatively easy to obtain with the rapid development of the economy and improvement in people's living standards. However, pathogenic bacteria have evolved strains that are resistant to certain drugs, such as antibiotics. Peptides are generally considered to be safe, have high tolerance to drugs, and are easy to manufacture. However, peptides are easily decomposed in complex biological environments. To solve this problem, many studies have modified peptides on the surface of nanomaterials to increase their functionality, biocompatibility, and stability. Meanwhile, nanomaterials have exhibited good absorption of near-infrared (NIR) light. When the NIR laser is focused on nanomaterials, photons are absorbed and the energy of the photons is converted into heat. Low-toxicity NRC03 peptide-conjugated dopamine/nano-reduced-graphene oxide (NRC03-DA/nRGO) nanomaterials are synthesized in this study for antibacterial testing using photothermal technology. The strains used in this study were Gram-positive Staphylococcus aureus (S. aureus). Our results indicated that the synthesized NRC03-DA/nRGO exhibits good absorption of NIR light and high photothermal conversion efficiency. Moreover, the synthesized NRC03-DA/nRGO inhibits the growth and survival of S. aureus. When the NRC03 peptide is modified on the surface of DA/nRGO, its biological stability is improved and the photothermal effect generated by NIR light produces additive effects, thereby indicating potential antibacterial applications.

[The role and mechanism of 2-deoxyglucose in reversing osimertinib-acquired resistance of non-small cell lung cancer cell line].

Objective: To explore the role and mechanism of 2-deoxyglucose (2-dg) in reversing osimertinib- acquired resistance of non-small cell lung cancer(NSCLC)cell line. Methods: The NSCLC line H1975 (purchased from the American Type Culture Collection) was conducted by induction method in vitro to construct the osimertinib-resistance NSCLC cell line H1975-OR. The osimertinib-resistance of H1975-OR cell line was examined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony-formation assay, Ki67 incorporation assay and the expression of apoptosis-related protein. The glycolysis level was assayed by the lactic acid production measured in the culture medium supernatant of H1975 and H1975-OR. The expression of glycolysis key enzymes (HK2, GLUT1, P-PKM2) and apoptosis-related protein (BIM, Bcl-2) were detected by Western blot. The cells were divided into control group, 2-deoxyglucose (4 mmol/L) monotherapy group, osimertinib (3 µmol/L) monotherapy group and 2-deoxyglucose (4 mmol/L)+ osimertinib (3 µmol/L) combination therapy group, then the apoptosis rate of cells was measured by flow cytometry to evaluate the pro-apoptotic ability of drugs. Date were analyzed by Independent-Samples t-test using SPSS 16.0 statistical software. Results: The glycolysis level of osimertinib-sensitive cell line H1975 was lower than that of osimertinib-resistance cell line H1975-OR [the yield of lactic acid, respectively, was (21.0±0.9) and (26.5±2.8) mmol·L(-1)·10(4)cells(-1), P<0.05]. The osimertinib- acquired resistance of H1975-OR could be reversed by 4 mmol/L 2-deoxyglucose(the IC(50) value of osimertinib in H1975-OR cell line decreased from (7.0±1.9) µmol/L to (1.4±0.1) µmol/L, which was close to the IC(50) value of osimertinib in H1975 cell line (1.0±0.2) µmol/L. The apoptosis rate of H1975-OR was significantly higher in 2-deoxyglucose + osimertinib combination therapy group (26.7±2.4)%, compared to control group (5.1±0.7)%, 2-deoxyglucose monotherapy group (6.1±2.5)% and osimertinib monotherapy group (11.4±2.7)%(all P<0.05). The expression of pro-apoptotic protein BIM in H1975-OR was significantly higher in 2-deoxyglucose+ osimertinib combination therapy group (177.8±28.1)% and the expression of anti-apoptotic protein Bcl-2 in H1975-OR was significantly lower in 2-deoxyglucose+ osimertinib combination therapy group (24.6±5.2)%, compared to control group (100±0)%, all P<0.05. Conclusion: 2-deoxyglucose can reverse the acquired resistance of NSCLC cell line to osimertinib, which may be related to the inhibition of cell glycolysis and the induction of apoptosis.

Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase-conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives. Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials.gov (NCT 01287585).

Risk score prediction model for dementia in patients with type 2 diabetes.

BACKGROUND AND PURPOSE: No study has established a prediction dementia model in the Asian populations. This study aimed to develop a prediction model for dementia in Chinese type 2 diabetes patients. METHODS: The retrospective cohort study included 27 540 Chinese type 2 diabetes patients (aged 50-94 years) enrolled in the Taiwan National Diabetes Care Management Program. Participants were randomly allocated into derivation and validation sets at a 2:1 ratio. Cox proportional hazards regression models were used to identify risk factors for dementia in the derivation set. Steps proposed by the Framingham Heart Study were used to establish a prediction model with a scoring system. RESULTS: The average follow-up was 8.09 years, with a total of 853 incident dementia cases in the derivation set. The dementia risk score summed up the individual scores (from 0 to 20). The areas under the curve of 3-, 5- and 10-year dementia risks were 0.82, 0.79 and 0.76 in the derivation set and 0.84, 0.80 and 0.75 in the validation set, respectively. CONCLUSIONS: The proposed score system is the first dementia risk prediction model for Chinese type 2 diabetes patients in Taiwan.

AFP role in predicting recurrence of hepatocellular carcinoma after living donor liver transplantation in HCV patients.

HCC is one of the leading causes of death worldwide. Liver transplantation including living donor transplantation is the best available treatment. We have analyzed our experience with LDLT in patients with HCC and HCV in order to determine if alpha feto-protein (AFP) is a better predictor of recurrence than the tumor burden. We have identified all patients with HCV related liver disease and HCC who have undergone LDLT in one center during the period from December 2000 to December 2014. Outcomes from the prospective database were compared for patients who met Milan criteria (single tumor ≤5 cm, maximum of 3 total tumors with none >3 cm) or not. Uni- and multi-variable analyses of factors influencing recurrence free survival (RFS) were performed. A total of 142 patients with HCC and HCV associated liver disease underwent LDTL during the study period. RFS was 96.4% at 1 years, 91.8% at 3 years and 91.8% at 5 years. Gender, model for End-Stage Liver disease (MELD), pre-transplant therapy, AFP level, tumor number, total tumor size were predictors of recurrence on univariable analysis. On multivariable analysis MELD score (Hazard ratio (HR) 1.16) and Log10 AFP (HR 3.14) were predictors of RFS. In the ROC curve analysis with an AUC of 0.76 the optimal cut-off value of AFP was 26ng/mL. In conclusion MELD score and pre-transplant AFP predict recurrence after LDLT for HCC with HCV infection.

Integrated Drug Expression Analysis for leukemia: an integrated in silico and in vivo approach to drug discovery.

Screening for drug compounds that exhibit therapeutic properties in the treatment of various diseases remains a challenge even after considerable advancements in biomedical research. Here, we introduce an integrated platform that exploits gene expression compendia generated from drug-treated cell lines and primary tumor tissue to identify therapeutic candidates that can be used in the treatment of acute myeloid leukemia (AML). Our framework combines these data with patient survival information to identify potential candidates that presumably have a significant impact on AML patient survival. We use a drug regulatory score (DRS) to measure the similarity between drug-induced cell line and patient tumor gene expression profiles, and show that these computed scores are highly correlated with in vitro metrics of pharmacological activity. Furthermore, we conducted several in vivo validation experiments of our potential candidate drugs in AML mouse models to demonstrate the accuracy of our in silico predictions.

Eradication of hepatitis C virus profoundly prolongs survival in hepatocellular carcinoma patients receiving transarterial chemoembolization.

Adjuvant pegylated interferon plus ribavirin treatment (PegIFN/RBV) reduces recurrence and prolongs survival in early stage hepatocellular carcinoma (HCC) patients with chronic hepatitis C (CHC) infection receiving resection or ablation. However, the impact of antiviral therapy in intermediate and advanced stage of CHC-HCC patients is uncertain. This study aimed to investigate the impact PegIFN/RBV treatment on recurrence-free interval and survival in patients with HCC receiving transarterial chemoembolization (TACE). From 2010 to 2013, 274 CHC patients from a 1073 patient-based cohort composed of freshly diagnosed HCC and receiving TACE treatment the Chang Gung Memorial Hospital, Linkou Medical Center were recruited. Propensity score matching (PSM) (age, gender, AST to Platelet Ratio Index (APRI), tumour size, tumour number and Child-Turcotte-Pugh score) with the ratio 1:2 for patients with and without PegIFN/RBV treatment was performed. Statistics were performed with SPSS V.20 (IBM, USA). After matching, 153 patients were analysed and 27 patients (17.6%) achieved sustained virologic response (SVR). The 2-year cumulative overall survival rate and recurrence-free survival rate among patients with SVR, non-SVR, and untreated were 85.2% vs 58.3% vs 69.6% (P=.001) and 73.3% vs 53.8% vs 58.5% (P=.013). By Cox regression analysis, non-SVR, untreated, increase CTP score and nonresponder to TACE were independent factors related to mortality. The SVR achieved by PegIFN/RBV treatment markedly improves survival and reduces tumour recurrence in CHC-HCC patients receiving TACE treatment after complete response.

Severe hypoglycemia and hip fracture in patients with type 2 diabetes: a nationwide population-based cohort study.

Hypoglycemia is a major concern in glycemic control. Using the Taiwan National Health Insurance Research Database, we found that the risk of hip fracture was associated with emergency or hospitalization visits of severe hypoglycemia in patients with type 2 diabetes; greater visits were associated with higher incidence of hip fracture. INTRODUCTION: The objective of the study was to assess the risk of hip fracture among patients with type 2 diabetes mellitus (T2DM) and severe hypoglycemia. METHODS: Using the National Health Insurance Research database in Taiwan, we identified 2588 patients with T2DM who had developed severe hypoglycemia from 2001 to 2009. A comparison cohort who had never developed severe hypoglycemia was frequency matched at a ratio of approximately 1:2. Multivariate Cox proportional hazard regression analysis was used to evaluate the risk of hip fracture. RESULTS: During a median follow-up period of 3.9 years, there were 219 hip fracture events in 5173 comparison cohorts and 148 hip fracture events in 2588 hypoglycemia cohorts. The incidence of hip fracture was higher in patients with severe hypoglycemia than without severe hypoglycemia (17.19 vs. 8.83 per 1000 person-years; adjusted HR 1.71, 95% CI = 1.35-2.16). Approximately half of the individuals developed hip fracture within 2 years from the first occurrence of severe hypoglycemia. There was a significant associated trend towards increased hip fracture risk with increasing average visit of severe hypoglycemia per year (p for trend <0.001). Medication analysis showed that patients taking sulfonylurea alone, insulin alone, and insulin secretagogues combined with insulin had a higher associated risk to develop hip fracture. CONCLUSIONS: Severe hypoglycemia was associated with a higher risk to develop hip fracture. The more the visits of severe hypoglycemia per year indicated the higher associated risk in patients with T2DM. Fall is likely an important reason for severe hypoglycemia in relation to increased risk of hip fracture.

Cognitive impairment and hippocampal atrophy in chronic kidney disease.

BACKGROUND: Cognition impairment is well known in patients with chronic kidney disease (CKD). The relationship between brain structure and cognitive performance in CKD patients is still under investigation. The study aimed to quantitatively assess the relationship between brain structure and cognitive performance in patients with CKD. METHODS: We recruited 39 patients with CKD and 39 age- and sex-matched control participants from a tertiary medical center. All participants underwent 3-T MRI scan neuropsychological assessments, and renal function tests. FreeSurfer software was used for imaging processing and analysis, including measurement of cortical thickness and gray matter (GM) and white matter volumes. RESULTS: Compared with control subjects (73.1±7.5 years old), patients with CKD (76.4±8.4 years old) had significantly lower scores on the Mini-Mental State Examination, and forward digit span test (P<.01). Patients with CKD had smaller cerebral GM volume, hippocampus, and decreased cortical thickness (P<.01) relative to the control group. Estimated glomerular filtration rate (eGFR) was correlated with cognitive performance, cortical thickness, GM volume, and hippocampal volume (P<.001). Linear regression analysis revealed that eGFR and GM volume were independently negatively associated with cognitive performance (P<.001), while eGFR and age were negatively associated with cortical thinning and GM volume after controlling for confounding factors. CONCLUSIONS: This study demonstrated that impaired kidney function is associated not only with poor cognitive performance, but also with small cerebral GM volume and reduced cortical thickness.

[Effect and mechanism of silibinin on the inhibition of ALK positive NSCLC cells by sensitizing crizotinib].

Objective: To explore the synergistic effect of silibinin combined with crizotinib on anaplastic lymphoma kinase positive (ALK+ ) non-small cell lung cancer (NSCLC) cells and its mechanism. Methods: H2228 and H3122 cells were treated with silibinin, crizotinib alone or in combination. Cell proliferation was measured by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and colony formation assay. Migration or invasion ability was tested by wound healing assay or transwell assay, respectively. Expressions of E-Cadherin and vimentin protein were examined by immunofluorescence staining. The protein expressions of ALK, p-ALK, E-Cadherin and Vimentin were detected by western blotting.The anti-cancer effect of silibinin combined with crizotinib in vivo was determined by subcutaneously injecting 2×10(6) H2228 cells into immunodeficient nude mice. Results: The result of MTT assay showed that the cell viability of H2228 or H3122 treated with 100 µmol/L silibinin was (88.38±4.10)% or (72.27±3.62)%, respectively, marginally decreased compared with that of the control. The 50% inhibitory concentration (IC(50)) of H2228 cells treated with crizotinib alone or combined with 100 µmol/L silibinin was (917.10±7.75) nmol/L or (238.73±7.67) nmol/L, respectively. The IC(50) of H3122 cells treated with crizotinib alone or combined with 100 µmol/L silibinin was (472.50±15.70) nmol/L or (206.10±12.01) nmol/L, respectively. The IC(50s) of H2228 and H3122 cells were significantly decreased by combined treatment of crizotinib and silibinin compared to crizotinib treatment alone (P<0.01). When compared with the control group, colony forming ratios of H2228 cells were (83.34±2.72)% in 100 µmol/L silibinin treatment group, (69.42±3.06)% in 400 nmol/L crizotinib treatment group and (27.32±1.42)% in combined treatment group. When compared with the control group, colony forming ratios of H3122 cells were (84.45±5.67)% in 100 µmol/L silibinin treatment group, (45.02±5.83)% in 400 nmol/L crizotinib treatment group and (17.43±3.83)% in combined treatment group. Silibinin combined with crizotinib treatment significantly inhibited the colony formation ability of H2228 and H3122 cells (P<0.01). Migration and invasion results showed that combined treatment of crizotinib and silibinin markedly inhibited the migration and invasion ability of H2228 cells (P<0.01). Western blot results indicated that treated with silibinin alone or in combination of crozitinib for 48 hours, the protein level of E-cadherin in H2228 cells was upregulated, while the expressions of p-ALK and vimentin were downregulated, without obvious alteration of ALK protein expression. In the xenograft model, the mean tumor weight was (9.40±2.58)g in crizotinib treatment group and (4.58±1.07)g in the combined treatment group. The inhibitory effect of tumor growth in vivo of combined treatment was significantly superior to that of crizotinib treatment alone (P<0.05). Conclusion: Silibinin enhances the inhibitory effect of crizotinib on ALK positive NSCLC cells, which may be associated with suppression of ALK activity and mesenchymal-epithelial transition.

Peptic Ulcer Disease in Living Liver Donors: A Longitudinal Population-Based Study.

The objective of this nationwide cohort study was to investigate the risk of peptic ulcer disease (PUD) in living liver donors (LDs). A total of 1333 LDs and 5332 matched nondonors were identified during 2003-2011. Hospitalized patients identified as LDs were assigned to the LD cohort, and the non-LD comparison cohort comprised age- and sex-matched nondonors. Cumulative incidences and hazard ratios (HRs) were calculated. The overall incidence of PUD was 1.74-fold higher in the LD cohort than in the non-LD cohort (2.14 vs. 1.48 per 1000 person-years). After adjustment for age, sex, monthly income and comorbidities, we determined that the LD cohort exhibited a higher risk of PUD than did the non-LD cohort (adjusted HR 1.74, 95% confidence interval [CI] 1.45-2.09). The incidence of PUD increased with age; the risk of PUD was 2.53-fold higher in patients aged ≥35 years (95% CI 2.14-2.99) than in those aged ≤34 years. LDs with comorbidities of osteopathies, chondropathies and acquired musculoskeletal deformities exhibited a higher risk of PUD (adjusted HR 3.93, 95% CI 2.64-5.86) compared with those without these comorbidities. LDs are associated with an increased risk of PUD after hepatectomy.

Vinflunine-gemcitabine versus vinflunine-carboplatin as first-line chemotherapy in cisplatin-unfit patients with advanced urothelial carcinoma: results of an international randomized phase II trial (JASINT1).

BACKGROUND: There is no standard first-line chemotherapy for advanced urothelial carcinoma (aUC) in cisplatin-ineligible (cisplatin-unfit) patients. The study assessed the efficacy and tolerability profile of two vinflunine-based cytotoxic regimens in this setting. PATIENTS AND METHODS: Patients with aUC a creatinine clearance (CrCl) of <60 but ≥30 ml/min, performance status 0 or 1 and no prior chemotherapy for advanced disease were randomized (1 : 1). They received vinflunine 250 or 280 mg/m(2) (based on baseline CrCl) on day 1, plus either gemcitabine [750 mg/m(2) escalated to 1000 mg/m(2) in cycle 2 if no toxicity grade (G) ≥2 on days 1 and 8 (VG) or plus carboplatin area under the curve 4.5 day 1 (VC) every 21 days]. To detect a 22% improvement in each arm compared with H0 (41%) in the primary end point, disease control rate (DCR = complete response + partial response + stable disease), 31 assessable patients per arm were required (α = 5%, ß = 20%). RESULTS: Sixty-nine patients were enrolled (34 VG, 35 VC). Less G3/4 haematological adverse events (AEs) were reported with VG: neutropaenia was seen in 38% (versus 68% with VC) and febrile neutropaenia in 3% (versus 14% with VC) of patients. No major differences were observed for non-haematological AEs. DCR was 77% in both groups; overall response rate (ORR) was 44.1% versus 28.6%, with a median progression-free survival of 5.9 versus 6.1 months and median OS of 14.0 versus 12.8 months with VG and VC, respectively. CONCLUSION: Both vinflunine-based doublets offer a similar DCR, ORR and OS. The better haematological tolerance favours the VG combination, which warrants further study. CLINICALTRIALS.GOV PROTOCOL IDENTIFIER: NCT 01599013.