Effect of wetting on nucleation and growth of D2 in confinement.

We have performed a computational study to determine how the wetting of liquid deuterium to the walls of the material influences nucleation. We present the development of a pair-wise interatomic potential that includes zero-point motion of molecular deuterium. Deuterium is used in this study because of its importance to inertial confinement fusion and the potential to generate a superfluid state if the solidification can be suppressed. Our simulations show that wetting dominates undercooling compared to the pore geometries. We observe a transition from heterogeneous nucleation at the confining wall to homogeneous nucleation at the bulk of the liquid (and intermediate cases) as the interaction with the confining wall changes from perfect wetting to non-wetting. When nucleation is heterogeneous, the temperature needed for solidification changes by 4 K with decreasing deuterium-wall interaction, but it remains independent (and equal to the one from bulk samples) when homogeneous nucleation dominates. We find that growth and quality of the resulting microstructure also depends on the magnitude of liquid deuterium-wall interaction strength.

Clinical impact of coexisting retinopathy and vascular calcification on chronic kidney disease progression and cardiovascular events.

BACKGROUND AND AIMS: Retinopathy and vascular calcification (VC) are representative markers of microvascular and macrovascular dysfunction in patients with chronic kidney disease (CKD). However, their relationship and combined effects on clinical outcomes remain undetermined. METHODS AND RESULTS: We included 523 patients with nondialysis-dependent CKD stage 3-5 who had been examined with fundus photography for diabetic or hypertensive retinopathy. Simple radiographs were analyzed for the presence of VC. The clinical significance of VC of the abdominal aorta and iliofemoral artery (apVC) and retinopathy was evaluated in terms of the rate of renal function decline and composite of any cardiovascular event or death. CKD patients with retinopathy showed higher prevalence of apVC than those without retinopathy (25.6% vs. 12.5%, P < 0.001).The presence of retinopathy was independently associated with apVC (OR 2.13, 95% CI 1.31, 3.49). In multivariate analysis, compared with subjects with neither apVC nor retinopathy, the coexistence of both apVC and retinopathy were independently associated with rapid renal function decline (ß = -1.51; 95% CI -2.40, -0.61), whereas apVC or retinopathy alone were not. Compared with subjects with neither apVC nor retinopathy, the HRs for composite end points were 1.05 (95% CI 0.48, 2.27), 1.79 (95% CI 1.14, 2.80), and 2.07 (95% CI 1.17, 3.67) for patients with apVC only, those with retinopathy only, and those with both apVC and retinopathy, respectively. CONCLUSION: The coexistence of VC and retinopathy was independently associated with CKD progression and cardiovascular events or deaths, and its combined effect was stronger than any separate condition.

Biological Behavior of Osteoblast Cell and Apatite Forming Ability of the Surface Modified Ti Alloys.

Titanium as one kind of biomaterials comes in direct contact with the body, making evaluation of biocompatibility an important aspect to biomaterials development. Surface chemistry of titanium plays an important role in osseointegration. Different surface modification alters the surface chemistry and result in different biological response. In this study, three kinds of mixed acid solutions were used to treat Ti specimens to induce Ca-P formation. Following a strong mixed acid activation process, Ca-P coating successfully formed on the Ti surfaces in simulated body fluid. Strong mixed acid increased the roughness of the metal surface, because the porous and rough surface allows better adhesion between Ca-P coatings and substrates. After modification of titanium surface by mixed acidic solution and subsequently H2O2/HCL treatment evaluation of biocompatibility was conducted from hydroxyapatite formation by biomimetic process and cell viability on modified titanium surface. Nano-scale modification of titanium surfaces can alter cellular and tissue responses, which may benefit osseointegration and dental implant therapy. Results from this study indicated that surface treatment methods affect the surface morphology, type of TiO2 layer formed and subsequent apatite deposition and biological responses. The thermo scientific alamarblue cell viability assay reagent is used to quantitatively measure the viability of mammalian cell lines, bacteria and fungi by incorporating a rapid, sensitive and reliable fluorometric/colorimetric growth indicator, without any toxic and side effect to cell line. In addition, mixed acid treatment uses a lower temperature and shorter time period than widely used alkali treatment.

A New Practical Desensitization Protocol for Oxaliplatin-Induced Immediate Hypersensitivity Reactions: A Necessary and Useful Approach.

BACKGROUND AND OBJECTIVE: Desensitization protocols for patients with immediate hypersensitivity reactions (IHSRs) have proven to be effective, but they are not widely used in clinical practice because of impracticalities such as high cost, long procedure duration, and a lack of trained personnel. We aimed to determine the clinical characteristics of oxaliplatin-induced IHSRs and assess measures to protect against these reactions and to validate a new practical desensitization protocol. METHODS: We retrospectively reviewed 2640 cases of oxaliplatin IHSRs in 271 oxaliplatin users and prospectively used a newly designed desensitization protocol 32 times in 12 patients with hypersensitivity to platinum-based chemotherapy. The protocol consisted of increases in infusion rate every 15 minutes, regardless of the concentration of the chemotherapy agent in the infusion bags. RESULTS: Of the 271 patients administered oxaliplatin, 45 (16.6%) experienced IHSRs. Of 39 patients who experienced an IHSR but needed to continue oxaliplatin, 6 (15.4%) stopped treatment due to the reaction, and 33 (84.6%) continued despite the risk of further reactions. The new desensitization protocol was successfully completed in 12 patients (100%), but it was ineffective in 3 patients (all with a negative skin prick test), who experienced fever without urticaria. CONCLUSIONS: Many patients who experience oxaliplatin-induced IHSRs are required to stop first-line oxaliplatin-based chemotherapy or to continue without desensitization, with the associated risks. Our new desensitization protocol is practical and easy to use in clinical practice.

Effects of two calcium silicate cements on cell viability, angiogenic growth factor release and related gene expression in stem cells from the apical papilla.

AIM: To evaluate the effects of two types of calcium silicate cements on viability, angiogenic growth factor release, and angiogenic and inflammation-related gene expression in human stem cells from the apical papilla (SCAP). METHODOLOGY: SCAPs were grown for 7 days with either ProRoot mineral trioxide aggregate (MTA) or Biodentine (BD). Cell viability and media concentrations of vascular endothelial growth factor (VEGF/VEGFA) and angiopoietin 1 (ANGPT1) were measured. The expression of genes related to angiogenic potential and inflammatory response was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). One-way and two-way analyses of variance with multiple comparisons Tukey's test were performed (P < 0.05). RESULTS: Cells in contact with either cement were associated with increased cell viability compared with the no-treatment group at day 1 but there were no differences amongst groups at days 3 and 7. Exposure to either cement significantly increased VEGF concentrations at day 3; however, ANGPT-1 levels decreased significantly compared with the no-treatment group at day 3. Exposure to MTA and BD stimulated expression of VEGFA and FIGF/VEGFD. Furthermore, exposure to both cements significantly decreased the mRNA levels of ANGPT1 and FGF2 relative to the no-treatment group. CONCLUSIONS: Both MTA and BD stimulated the expression of angiogenic genes and release of VEGF, inducing similar expression patterns; however, they appeared to inhibit the expression of specific genes, including ANGPT1 and FGF2.

Disseminated mucormycosis with myocardial involvement in a renal transplant recipient.

We report the case of a renal transplant recipient with pulmonary and splenic mucormycosis whose demise was accelerated by a myocardial abscess. Once pulmonary and splenic mucormycosis was diagnosed, liposomal amphotericin B was started and immunosuppressant treatments were discontinued. The pulmonary cavities regressed during treatment, but new myocardial and peri-allograft abscesses developed. The myocardial abscess diffusely infiltrated the left ventricular wall and was associated with akinesia, which led to sudden cardiac arrest. This case demonstrates a rare manifestation of mucormycosis and highlights the fatality and invasiveness of this infection.

High normal albuminuria is associated with arterial stiffness and carotid atherosclerosis in Korean patients with type 2 diabetes.

BACKGROUND AND AIMS: Current evidence suggests that high normal albuminuria is significantly associated with increased cardiovascular risk. This study investigated the association between urine albumin-to-creatinine ratio (ACR) within the normal range and subclinical atherosclerosis in Korean patients with type 2 diabetes. METHODS AND RESULTS: This cross-sectional study involved 521 type 2 diabetic patients with normoalbuminuria. Brachial-ankle pulse wave velocity (baPWV) measurement and ultrasound assessment of carotid atherosclerosis was done. Subclinical atherosclerosis was assessed by the presence of high baPWV (>1682 cm/s), carotid atherosclerosis (intima-media thickness >0.8 mm or the presence of plaques), and carotid stenosis (≥50% of luminal narrowing). Across the tertiles of ACR, there was a trend for an increasing prevalence of high baPWV (16.8%, 20.0%, and 38.2%, P < 0.001), carotid atherosclerosis (46.9%, 55.4%, and 64.7%, P < 0.001), and carotid stenosis (12.7%, 16.0%, and 30.1%, P < 0.001). In multivariate analysis, patients in the highest ACR tertile had an odds ratio of 2.05 (95% confidence interval [CI], 1.13-3.72, P = 0.019) for high baPWV, 1.78 (95% CI, 1.08-2.93, P = 0.024) for carotid atherosclerosis, and 2.72 (95% CI, 1.44-5.11, P = 0.002) for carotid stenosis compared to those in the lowest tertile. The relation of ACR with carotid atherosclerosis and stenosis remained significant even in patients without diabetic retinopathy. CONCLUSION: High normal albuminuria was significantly associated with atherosclerotic vascular changes, independent of retinopathy and other cardiovascular risk factors. High normal albuminuria may be an early marker for subclinical atherosclerosis in type 2 diabetes.

Changes in serum immunomolecules during antibiotic therapy for Mycobacterium avium complex lung disease.

Little information is available regarding changes in immune status for patients with Mycobacterium avium complex (MAC) lung disease during antibiotic therapy. Serum immunomolecules from 42 patients with MAC lung disease were assayed comparatively using an array-based system according to (i) patients with MAC lung disease at the time of diagnosis versus healthy controls and (ii) alterations after 12 months of antibiotic therapy in the MAC lung disease group. In addition, cytokine analyses were performed to determine whether cytokine responses were associated specifically with the disease phenotype, treatment outcome and aetiological agent. Notably, the serum concentrations of type 1 cytokine-associated molecules, such as CD40L, interferon (IFN)-γ, interleukin (IL)-8 and IL-23, were decreased significantly in patients at the time of diagnosis, suggesting that these molecules may serve as indicators of host susceptibility to MAC disease. Although the overall serum level of T helper type 1 (Th1)-related molecules, such as CD40L and IFN-γ, was restored after treatment, Th17-related cytokines, such as IL-17 and IL-23, were down-regulated significantly at 12 months post-treatment compared to pretreatment. Furthermore, these cytokine patterns differed among patient subgroups. Decreased serum concentrations of IL-17 and/or IL-23 were associated with failure of sputum conversion, the fibrocavitary disease phenotype and M. intracellulare lung disease. Thus, the reciprocal balance between Th1 and Th17 immunity during antibiotic therapy for MAC lung disease is critical for dictating the treatment response. In conclusion, a low level of Th1-related immunomolecules may perpetuate MAC lung disease, and the serum concentrations of Th17-related cytokines can reflect the treatment outcome, disease phenotype and aetiological agent.

Residual effect of reductions in red blood cell count and haematocrit and haemoglobin levels after 10-month withdrawal of pioglitazone in patients with Type 2 diabetes.

AIM: To investigate the recovery of thiazolidinedione-induced body weight gain and haematopoietic changes after stopping pioglitazone treatment in patients with Type 2 diabetes. METHODS: This retrospective cohort study included 214 patients divided into three groups according to pioglitazone treatment status. The first study arm included patients who received pioglitazone for 38 months then interrupted this for 10 months (pioglitazone-interruption group). The second arm consisted of patients who received pioglitazone throughout the 48 months (pioglitazone-continuous group); the third arm included patients who had never received pioglitazone therapy (control group). RESULTS: Red blood cell count and haematocrit and haemoglobin levels decreased significantly, while body weight increased in the two pioglitazone-treated groups as compared with the control group at 38 months. Multivariate regression analysis showed that the reductions in red blood cell count/haemoglobin levels were associated with pioglitazone use. In the pioglitazone-interruption group, no recoveries of red blood cells, or haematocrit or haemoglobin levels were observed after stopping pioglitazone for 10 months compared with the pioglitazone-continuous group, but body weight gain decreased to a level that was significantly lower than that in the pioglitazone-continuous group and did not differ significantly from the control group. CONCLUSION: In this study, we observed a reversal of body weight gain but no recoveries in red blood cells or haematocrit or haemoglobin levels after stopping pioglitazone for 10 months in patients treated with pioglitazone for 38 months. This finding should prompt a reconsideration of the sustained effect of thiazolidinediones on the haematopoietic system in patients with Type 2 diabetes.

Changes in high-density-lipoprotein cholesterol upon statin treatment in type 2 diabetic patients: a meta-analysis.

BACKGROUND AND AIM: To investigate the diversity of change in high-density-lipoprote in cholesterol (HDL-C) after statin treatment in patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: A systemic review searched for trials that reported a serum change in HDL-C in patients with T2DM after statin treatment, and extracted data for meta-analysis. Of 6709 articles surveyed, 160 articles were identified as eligible articles. In the analysis of simvastatin, serum HDL-C was increased in Non-Asian and Asian patients with T2DM by 2.17 mg/dl (95% CI 1.43 ∼ 2.90 mg/dl, p < 0.001) and 2.31 mg/dl (95% CI 1.37 ∼ 3.25 mg/dl, p < 0.001), respectively. In the analysis of atorvastatin, although significant, serum HDL-C was subtly increased in Non-Asian patients with T2DM by 1.14 mg/dl (95% CI 0.28 ∼ 2.01 mg/dl, p = 0.010) mg/dl; however, atorvastatin treatment did not significantly change the serum HDL-C by 0.12 mg/dl (95% CI -1.04 ∼ 1.27 mg/dl, p = 0.839) mg/dl in Asian patients with T2DM. According to meta-regression analysis, the baseline HDL-C did not affect the change in serum HDL-C in Asian patients with T2DM after either simvastatin or atorvastatin treatment. However, contrary to simvastatin, the coefficient of regression (r) showed a significant negative association (r = -0.18; 95% CI -0.32 to -0.04; p = 0.01) between baseline HDL-C and the change of HDL-C in non-Asian patients with T2DM after atorvastatin treatment. CONCLUSION: We have demonstrated for the first time that there may be a discrepancy in the change of serum HDL-C in Asian patients with T2DM after atorvastatin treatment.

Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1α axis in db/db mice.

AIMS/HYPOTHESIS: Many of the effects of resveratrol are consistent with the activation of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1) and peroxisome proliferator-activated receptor (PPAR)γ co-activator 1α (PGC-1α), which play key roles in the regulation of lipid and glucose homeostasis, and in the control of oxidative stress. We investigated whether resveratrol has protective effects on the kidney in type 2 diabetes. METHODS: Four groups of male C57BLKS/J db/m and db/db mice were used in this study. Resveratrol was administered via gavage to diabetic and non-diabetic mice, starting at 8 weeks of age, for 12 weeks. RESULTS: The db/db mice treated with resveratrol had decreased albuminuria. Resveratrol ameliorated glomerular matrix expansion and inflammation. Resveratrol also lowered the NEFA and triacylglycerol content of the kidney, and this action was related to increases in the phosphorylation of AMPK and the activation of SIRT1-PGC-1α signalling and of the key downstream effectors, the PPARα-oestrogen-related receptor (ERR)-1α-sterol regulatory element-binding protein 1 (SREBP1). Furthermore, resveratrol decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and class O forkhead box (FOXO)3a phosphorylation, which resulted in a decrease in B cell leukaemia/lymphoma 2 (BCL-2)-associated X protein (BAX) and increases in BCL-2, superoxide dismutase (SOD)1 and SOD2 production. Consequently, resveratrol reversed the increase in renal apoptotic cells and oxidative stress, as reflected by renal 8-hydroxy-deoxyguanosine (8-OH-dG), urinary 8-OH-dG and isoprostane concentrations. Resveratrol prevented high-glucose-induced oxidative stress and apoptosis in cultured mesangial cells through the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling and the downstream effectors, PPARα-ERR-1α-SREBP1. CONCLUSIONS/INTERPRETATION: The results suggest that resveratrol prevents diabetic nephropathy in db/db mice by the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling, which appear to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney.

Association between serum ferritin and microalbuminuria in Type 2 diabetes in Taiwan.

AIMS: Serum ferritin has been found closely related with diabetes and glucose metabolism, but its impact on diabetic nephropathy remains unknown. This study aimed to explore the association between serum ferritin and microalbuminuria in Type 2 diabetes. METHODS: Eight hundred and fifty-one subjects with Type 2 diabetes were selected from a cohort participating in a glycaemic control study in Taiwan in 2008. We used urine albumin:creatinine ratio to define microalbuminuria; serum ferritin was divided into quartiles for analysis. Logistic regression and trend tests were used to delineate the association between serum ferritin and microalbuminuria. RESULTS: Subjects with diabetes with higher ferritin tended to have more metabolic disorders, higher high-sensitivity C-reactive protein and higher prevalence of microalbuminuria. Compared with those in the lowest quartile, subjects with diabetes in the highest ferritin quartile were 55% (P = 0.029) more likely to have microalbuminuria. After controlling for demographics, metabolic profiles and other inflammatory markers, the association between serum ferritin levels and microalbuminuria remained significant (P for trend < 0.001). This independent relationship was not changed either for those who had better glycaemic control or those who had not used an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. CONCLUSIONS: The current study shows hyperferritinemia may be an independent risk factor of nephropathy in patients with Type 2 diabetes.

Incidence and clinical features of Clostridium difficile infection in Korea: a nationwide study.

The incidence and severity of Clostridium difficile infections (CDI) have increased in Western countries. However, there are limited data regarding the epidemiology of CDI in Eastern countries. This nationwide study was conducted in 17 hospitals to determine temporal trends in CDI incidence (from 2004 to 2008) in South Korea. The total incidence of CDI in Korea was 1·7 cases/1000 adult admissions in 2004, and 2·7/1000 cases in 2008 (P = 0·028). When analysing the clinical features of 1367 CDI patients diagnosed in 2008, oral metronidazole was effective as a first-line treatment for CDI (61·9%). Relapse rate was 8·9% and complicated CDI was only observed in 3·6%. The incidence of CDI increased significantly in Korea from 2004 to 2008. Although the clinical features were milder than in Western countries, the increasing burden of CDI needs ongoing surveillance systems.

The impact of dermatological toxicities of anti-cancer therapy on the dermatological quality of life of cancer patients.

BACKGROUND: One of the most common side effects of anti-cancer therapies is treatment-induced skin changes, referred to as dermatological toxicities. These dermatological toxicities are noteworthy since they have a negative association with quality of life (QoL). OBJECTIVES: To evaluate the impact of dermatological toxicities on QoL of cancer patients and to identify the relationship between disease-related characteristics and QoL and changes in skin protective behaviours following anti-cancer therapy. METHODS: Cancer patients (n = 80: stage II-IV) in a longitudinal prospective study completed a battery of questionnaires at the time of enrolment and after 3 months of anti-cancer therapy. QoL, skin toxicities, smoking and drinking behaviour, sun-protective and skin care behaviour assessments were performed before and at 3 months after anti-cancer therapy. QoL was measured with the Dermatology Life Quality Index (DLQI). RESULTS: A total of 73 patients completed the study. Among them, 48 patients (65.8%) experienced at least grade 1 skin toxicity at 3 months after anti-cancer therapy. Hair loss, hyperpigmentation and dry skin were the most common dermatological toxicities. The mean baseline DLQI score changed from 1.38 to 3.49 at 3 months after anti-cancer therapy. Domain 1 (symptoms and feelings, 1.38 points) was the most greatly impacted among patients by anti-cancer treatment. Patients who experienced at least grade 1 skin toxicity (P = 0.001, 95% CI: 1.939-4.899), employed (P = 0.042, 95% CI: 0.030-1.476), more highly educated (P = 0.030, 95% CI: 0.161-3.132), and diagnosed with gastric cancer (P = 0.001, 95% CI: 2.141-8.250) or renal cell cancer (P = 0.002, 95% CI: 2.731-11.364) showed significantly higher DLQI scores. Patients showed significant change in skin protective behaviour such as use of body moisturizer (P = 0.021) and change in drinking behaviour (P = 0.006) at 3 months following anti-cancer therapy. CONCLUSION: Dermatological toxicities due to anti-cancer therapy affect the QoL of cancer patients. Therefore, health care professionals should pay attention to the psychological effects of skin problems and educate cancer patients to adapt proactive skin protective behaviours to minimize dermatological toxicities of anti-cancer therapy and maximize QoL.

Phase II study of a trastuzumab biosimilar in combination with paclitaxel for HER2-positive recurrent or metastatic urothelial carcinoma: KCSG GU18-18.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is a widely explored therapeutic target in solid tumors. We evaluated the efficacy and safety of trastuzumab-pkrb, a biosimilar of trastuzumab, in combination with paclitaxel, in HER2-positive recurrent or metastatic urothelial carcinoma (UC). PATIENTS AND METHODS: We enrolled 27 patients; they were administered a loading dose of 8 mg/kg trastuzumab-pkrb on day 1, followed by 6 mg/kg and 175 mg/m2 paclitaxel on day 1 every 3 weeks, intravenously. All patients received six cycles of the combination treatment and continued to receive trastuzumab-pkrb maintenance until disease progression, unacceptable toxicity, or for up to 2 years. HER2 positivity (based on immunohistochemistry analysis) was determined according to the 2013 American Society of Clinical Oncology /College of American Pathologists HER2 testing guidelines. The primary endpoint was objective response rate (ORR); the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. RESULTS: Twenty-six patients were evaluated via primary endpoint analysis. The ORR was 48.1% (1 complete and 12 partial responses) and the duration of response was 6.9 months [95% confidence interval (CI) 4.4-9.3 months]. With a median follow-up of 10.5 months, the median PFS and OS were 8.4 months (95% CI 6.2-8.8 months) and 13.5 months (95% CI 9.8 months-not reached), respectively. The most common treatment-related adverse event (TRAE) of any grade was peripheral neuropathy (88.9%). The most common grade 3/4 TRAEs were neutropenia (25.9%), thrombocytopenia (7.4%), and anemia (7.4%). CONCLUSIONS: Trastuzumab-pkrb plus paclitaxel demonstrates promising efficacy with manageable toxicity profiles in patients with HER2-positive recurrent or metastatic UC.

Safety and efficacy of cobimetinib plus atezolizumab in patients with solid tumors: a phase II, open-label, multicenter, multicohort study.

BACKGROUND: Although introduction of immune checkpoint inhibitors has revolutionized the treatment of cancer, their response rates are generally low. Preclinical and early phase clinical data suggest that MEK inhibition may sensitize tumors to immune checkpoint inhibitors by upregulating tumor antigen expression, programmed death-ligand 1 (PD-L1) expression, and tumor T-cell infiltration. We evaluated the efficacy and safety of cobimetinib plus atezolizumab in patients with advanced solid tumors in the open-label, multicohort phase II COTEST study. PATIENTS AND METHODS: This analysis of the COTEST trial included patients from cohorts 1-4 [1-3: anti-programmed cell death protein 1 (PD-1)/PD-L1 treatment-naive patients; 4: patients with disease progression on anti-PD-1/anti-PD-L1 treatment] who received cobimetinib 60 mg once daily for the first 21 days and intravenous infusions of atezolizumab 840 mg on days 1 and 15 of each 28-day cycle. Efficacy endpoints included objective response rate, overall survival, progression-free survival (PFS), and disease control rate. RESULTS: Overall, 77 patients were enrolled in cohorts 1-4 (78% male; median age 62.8 years). Objective response rate was 20% in cohort 1 [squamous cell carcinoma of the head and neck (SCCHN)], 30% in cohort 2 (urothelial carcinoma), and 18% in cohort 3 (renal cell carcinoma); there were no responders among 20 patients in cohort 4 (SCCHN). The disease control rates in cohorts 1-4 were 50%, 40%, 24%, and 25%, respectively. The median PFS was 5.5, 3.4, 3.4, and 3.6 months in cohorts 1-4, respectively, and the median overall survival was 16.8, 18.7, 21.7, and 7.7 months, respectively. Most adverse events were of grade 1/2 and were manageable. CONCLUSIONS: Cobimetinib plus atezolizumab had moderate activity in patients with anti-PD-1/PD-L1 treatment-naive SCCHN and urothelial carcinoma, and weak activity in anti-PD-1/PD-L1 treatment-naive renal cell carcinoma, and no activity in checkpoint inhibitor-treated patients.

HbA1c variability is associated with microalbuminuria development in type 2 diabetes: a 7-year prospective cohort study.

AIMS/HYPOTHESIS: HbA(1c) variability has been shown to be an independent risk factor for nephropathy in patients with type 1 diabetes. In this study, we aimed to explore the association between HbA(1c) variability and microalbuminuria development in patients with type 2 diabetes. We also intended to test the applicability of serially measured HbA(1c) over 2 years for this risk assessment. METHODS: Between 2003 and 2005, we recruited 821 middle-aged normoalbuminuric individuals with type 2 diabetes and followed them through to the end of 2010. The average follow-up time was 6.2 years. We defined microalbuminuria as a urine albumin to creatinine ratio of 30 mg/g (3.4 mg/mmol) or higher. HbA(1c) variability was calculated by the SD of serially measured HbA(1c). The Cox proportional hazards model was used to evaluate the association between HbA(1c) SD quartile and development of microalbuminuria. RESULTS: The incidence of microalbuminuria for the overall population was 58.4, 58.6, 60.8 and 91.9 per 1,000 person-years for Q1- to Q4-adjusted HbA(1c) SD, respectively (p for trend = 0.042). Compared with patients in Q1, those in Q4 were about 37% more likely to develop microalbuminuria. The HR derived from a series of 2 year HbA(1c) measurements was similar to that from data collection for longer than 4 years. CONCLUSIONS/INTERPRETATION: In addition to mean HbA(1c) values, HbA(1c) variability, even measured as early as 2 years, is independently associated with the development of microalbuminuria in patients with type 2 diabetes.

Adenosine triphosphate-based chemotherapy response assay-guided chemotherapy in unresectable colorectal liver metastasis.

BACKGROUND: This study aims to evaluate the effectiveness of adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided neoadjuvant chemotherapy for increasing resectability in patients with unresectable colorectal liver metastasis. PATIENTS AND METHODS: Patients were randomised into two groups: Group A was treated by conventional chemotherapy regimen and Group B was treated by chemotherapy regimen according to the ATP-CRA. Three chemotherapeutic agents (5-fluorouracil, oxaliplatin and irinotecan) were tested by ATP-CRA and more sensitive agents were selected. Either FOLFOX or FOLFIRI was administered. Between Group A and B, treatment response and resectability were compared. RESULTS: Between November 2008 and October 2010, a total 63 patients were randomised to Group A (N=32) or Group B (N=31). FOLFOX was more preferred in Group A than in Group B (26 out of 32 (81.3%) vs 20 out of 31 (64.5%)). Group B showed better treatment response than Group A (48.4% vs 21.9%, P=0.027). The resectability of hepatic lesion was higher in Group B (35.5% vs 12.5%, P=0.032). Mean duration from chemotherapy onset to the time of liver resection was 11 cycles (range 4-12) in Group A and 8 cycles (range 8-16) in Group B. CONCLUSION: This study showed that tailored-chemotherapy based on ATP-CRA could improve the treatment response and resectability in initially unresectable colorectal liver metastasis.

Room-temperature charge stability modulated by quantum effects in a nanoscale silicon island.

We report on transport measurement performed on a room-temperature-operating ultrasmall Coulomb blockade devices with a silicon island of sub5 nm. The charge stability at 300K exhibits a substantial change in slopes and diagonal size of each successive Coulomb diamond, but remarkably its main feature persists even at low temperature down to 5.3K except for additional Coulomb peak splitting. This key feature of charge stability with additional fine structures of Coulomb peaks are successfully modeled by including the interplay between Coulomb interaction, valley splitting, and strong quantum confinement, which leads to several low-energy many-body excited states for each dot occupancy. These excited states become enhanced in the sub5 nm ultrasmall scale and persist even at 300K in the form of cluster, leading to the substantial modulation of charge stability.

The efficacy of immune checkpoint inhibitors in elderly patients: a meta-analysis and meta-regression.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has improved patient survival in advanced cancers; however, the efficacy of ICIs in elderly patients is still elusive. This study assessed the efficacy of ICIs in elderly patients with advanced cancer in terms of overall survival (OS) and progression-free survival (PFS). MATERIALS AND METHODS: We carried out a systematic review and identified 30 head-to-head phase II/III randomized controlled trials that compared immunotherapy with the standard of care in advanced solid tumor patients. The data on patients younger or over 65 years of age were indexed from PubMed-Medline, Embase, and Scopus and obtained for meta-analysis. The subgroup analyses were stratified by primary tumor type, line of treatment, or type of immunotherapy, and a meta-regression analysis was carried out after adjusting for all other variables. RESULTS: The study included 17 476 patients, comprising 58% (10 119) younger (<65 years old) and 42% (7357) elderly (≥65 years old) patients. The hazard ratio (HR) for OS was 0.77 [95% confidence interval (CI) 0.70-0.85] and 0.77 (95% CI 0.70-0.85) in the younger and elderly groups, respectively, suggesting similar efficacies of ICIs in these two age groups. The subgroup analyses revealed no significant relationship between age and treatment outcomes, except for the PFS benefit in younger patients with melanoma than in elderly patients (HR 0.44 in younger patients versus 0.65 in elderly patients, P = 0.04). These results were further supported by meta-regression analysis, which showed no statistically significant difference in OS (P = 0.954) and PFS (P = 0.555) between the two age groups. CONCLUSIONS: The findings suggest that age-associated impairments of the immune system did not affect the efficacy of ICIs in elderly patients compared to younger patients. Therefore, the choice of ICIs for elderly patients can be considered, regardless of chronological age.