A stochastic view on surface inhomogeneity of nanoparticles

The interactions between and with nanostructures can only be fully understood when the functional group distribution on their surfaces can be quantified accurately. Here we apply a combination of direct stochastic optical reconstruction microscopy (dSTORM) imaging and probabilistic modelling to analyse molecular distributions on spherical nanoparticles. The properties of individual fluorophores are assessed and incorporated into a model for the dSTORM imaging process. Using this tailored model, overcounting artefacts are greatly reduced and the locations of dye labels can be accurately estimated, revealing their spatial distribution. We show that standard chemical protocols for dye attachment lead to inhomogeneous functionalization in the case of ubiquitous polystyrene nanoparticles. Moreover, we demonstrate that stochastic fluctuations result in large variability of the local group density between particles. These results cast doubt on the uniform surface coverage commonly assumed in the creation of amorphous functional nanoparticles and expose a striking difference between the average population and individual nanoparticle coverage

Local Orientation and the Evolution of Foraging: Changes in Decision Making Can Eliminate Evolutionary Trade-offs

Information processing is a major aspect of the evolution of animal behavior. In foraging, responsiveness to local feeding opportunities can generate patterns of behavior which reflect or “recognize patterns” in the environment beyond the perception of individuals. Theory on the evolution of behavior generally neglects such opportunity-based adaptation. Using a spatial individual-based model we study the role of opportunity-based adaptation in the evolution of foraging, and how it depends on local decision making. We compare two model variants which differ in the individual decision making that can evolve (restricted and extended model), and study the evolution of simple foraging behavior in environments where food is distributed either uniformly or in patches. We find that opportunity-based adaptation and the pattern recognition it generates, plays an important role in foraging success, particularly in patchy environments where one of the main challenges is “staying in patches”. In the restricted model this is achieved by genetic adaptation of move and search behavior, in light of a trade-off on within- and between-patch behavior. In the extended model this trade-off does not arise because decision making capabilities allow for differentiated behavioral patterns. As a consequence, it becomes possible for properties of movement to be specialized for detection of patches with more food, a larger scale information processing not present in the restricted model. Our results show that changes in decision making abilities can alter what kinds of pattern recognition are possible, eliminate an evolutionary trade-off and change the adaptive landscape

Muscle mass, muscle strength and mortality in kidney transplant recipients:results of the TransplantLines Biobank and Cohort Study

Background: Survival of kidney transplant recipients (KTR) is low compared with the general population. Low muscle mass and muscle strength may contribute to lower survival, but practical measures of muscle status suitable for routine care have not been evaluated for their association with long-term survival and their relation with each other in a large cohort of KTR. Methods: Data of outpatient KTR ≥ 1 year post-transplantation, included in the TransplantLines Biobank and Cohort Study (ClinicalTrials.gov Identifier: NCT03272841), were used. Muscle mass was determined as appendicular skeletal muscle mass indexed for height2 (ASMI) through bio-electrical impedance analysis (BIA), and by 24-h urinary creatinine excretion rate indexed for height2 (CERI). Muscle strength was determined by hand grip strength indexed for height2 (HGSI). Secondary analyses were performed using parameters not indexed for height2. Cox proportional hazards models were used to investigate the associations between muscle mass and muscle strength and all-cause mortality, both in univariable and multivariable models with adjustment for potential confounders, including age, sex, body mass index (BMI), estimated glomerular filtration rate (eGFR) and proteinuria. Results: We included 741 KTR (62% male, age 55 ± 13 years, BMI 27.3 ± 4.6 kg/m2), of which 62 (8%) died during a median [interquartile range] follow-up of 3.0 [2.3–5.7] years. Compared with patients who survived, patients who died had similar ASMI (7.0 ± 1.0 vs. 7.0 ± 1.0 kg/m2; P = 0.57), lower CERI (4.2 ± 1.1 vs. 3.5 ± 0.9 mmol/24 h/m2; P &lt; 0.001) and lower HGSI (12.6 ± 3.3 vs. 10.4 ± 2.8 kg/m2; P &lt; 0.001). We observed no association between ASMI and all-cause mortality (HR 0.93 per SD increase; 95% confidence interval [CI] [0.72, 1.19]; P = 0.54), whereas CERI and HGSI were significantly associated with mortality, independent of potential confounders (HR 0.57 per SD increase; 95% CI [0.44, 0.81]; P = 0.002 and HR 0.47 per SD increase; 95% CI [0.33, 0.68]; P &lt; 0.001, respectively), and associations of CERI and HGSI with mortality remained independent of each other (HR 0.68 per SD increase; 95% CI [0.47, 0.98]; P = 0.04 and HR 0.53 per SD increase; 95% CI [0.36, 0.76]; P = 0.001, respectively). Similar associations were found for unindexed parameters. Conclusions: Higher muscle mass assessed by creatinine excretion rate and higher muscle strength assessed by hand grip strength are complementary in their association with lower risk of all-cause mortality in KTR. Muscle mass assessed by BIA is not associated with mortality. Routine assessment using both 24-h urine samples and hand grip strength is recommended, to potentially target interdisciplinary interventions for KTR at risk for poor survival to improve muscle status.</p

Muscle mass, muscle strength and mortality in kidney transplant recipients:results of the TransplantLines Biobank and Cohort Study

Background: Survival of kidney transplant recipients (KTR) is low compared with the general population. Low muscle mass and muscle strength may contribute to lower survival, but practical measures of muscle status suitable for routine care have not been evaluated for their association with long-term survival and their relation with each other in a large cohort of KTR. Methods: Data of outpatient KTR ≥ 1 year post-transplantation, included in the TransplantLines Biobank and Cohort Study (ClinicalTrials.gov Identifier: NCT03272841), were used. Muscle mass was determined as appendicular skeletal muscle mass indexed for height2 (ASMI) through bio-electrical impedance analysis (BIA), and by 24-h urinary creatinine excretion rate indexed for height2 (CERI). Muscle strength was determined by hand grip strength indexed for height2 (HGSI). Secondary analyses were performed using parameters not indexed for height2. Cox proportional hazards models were used to investigate the associations between muscle mass and muscle strength and all-cause mortality, both in univariable and multivariable models with adjustment for potential confounders, including age, sex, body mass index (BMI), estimated glomerular filtration rate (eGFR) and proteinuria. Results: We included 741 KTR (62% male, age 55 ± 13 years, BMI 27.3 ± 4.6 kg/m2), of which 62 (8%) died during a median [interquartile range] follow-up of 3.0 [2.3–5.7] years. Compared with patients who survived, patients who died had similar ASMI (7.0 ± 1.0 vs. 7.0 ± 1.0 kg/m2; P = 0.57), lower CERI (4.2 ± 1.1 vs. 3.5 ± 0.9 mmol/24 h/m2; P &lt; 0.001) and lower HGSI (12.6 ± 3.3 vs. 10.4 ± 2.8 kg/m2; P &lt; 0.001). We observed no association between ASMI and all-cause mortality (HR 0.93 per SD increase; 95% confidence interval [CI] [0.72, 1.19]; P = 0.54), whereas CERI and HGSI were significantly associated with mortality, independent of potential confounders (HR 0.57 per SD increase; 95% CI [0.44, 0.81]; P = 0.002 and HR 0.47 per SD increase; 95% CI [0.33, 0.68]; P &lt; 0.001, respectively), and associations of CERI and HGSI with mortality remained independent of each other (HR 0.68 per SD increase; 95% CI [0.47, 0.98]; P = 0.04 and HR 0.53 per SD increase; 95% CI [0.36, 0.76]; P = 0.001, respectively). Similar associations were found for unindexed parameters. Conclusions: Higher muscle mass assessed by creatinine excretion rate and higher muscle strength assessed by hand grip strength are complementary in their association with lower risk of all-cause mortality in KTR. Muscle mass assessed by BIA is not associated with mortality. Routine assessment using both 24-h urine samples and hand grip strength is recommended, to potentially target interdisciplinary interventions for KTR at risk for poor survival to improve muscle status.</p

Gallbladder Cancer:Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

SIMPLE SUMMARY: Knowledge of genetic alterations in gallbladder cancer (GBC) continues to increase. This systematic review provides an overview of frequently occurring genetic alterations in GBC and describes their possible therapeutic implications. We detected three frequently (>5%) altered genes (ATM, ERBB2 and PIK3CA) for which targeted therapies are available in other cancer types. For solid cancers with microsatellite instability or a high tumor mutational burden pembrolizumab is FDA-approved. Altogether, these five biomarkers might be used in future molecular panels to enable precision medicine for patients with GBC. We found only nine clinical trials evaluating targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials. ABSTRACT: Due to the fast progression in molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) increases. This systematic review provides an overview of frequently occurring genetic alterations occurring in GBC and their possible therapeutic implications. A literature search was performed utilizing PubMed, EMBASE, Cochrane Library, and Web of Science. Only studies reporting genetic alterations in human GBC were included. In total, data were extracted from 62 articles, describing a total of 3893 GBC samples. Frequently detected genetic alterations (>5% in >5 samples across all studies) in GBC for which targeted therapies are available in other cancer types included mutations in ATM, ERBB2, and PIK3CA, and ERBB2 amplifications. High tumor mutational burden (TMB-H) and microsatellite instability (MSI-H) were infrequently observed in GBC (1.7% and 3.5%, respectively). For solid cancers with TMB-H or MSI-H pembrolizumab is FDA-approved and shows an objective response rates of 50% for TMB-H GBC and 41% for MSI-H biliary tract cancer. Only nine clinical trials evaluated targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM, and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials

Identifying Biomarkers in Lymph Node Metastases of Esophageal Adenocarcinoma for Tumor-Targeted Imaging

INTRODUCTION: Tumor-targeted imaging is a promising technique for the detection of lymph node metastases (LNM) and primary tumors. It remains unclear which biomarker is the most suitable target to distinguish malignant from healthy tissue in esophageal adenocarcinoma (EAC). OBJECTIVE: We performed an immunohistochemistry study to identify viable tumor markers for tumor-targeted imaging of EAC. METHODS: We used samples from 72 patients with EAC to determine the immunohistochemical expression of ten potential tumor biomarkers for EAC (carbonic anhydrase IX [CA-IX], carcinoembryonic antigen [CEA], hepatic growth factor receptor, epidermal growth factor receptor, epithelial membrane antigen [EMA], epithelial cell adhesion molecule [EpCAM], human epidermal growth factor receptor 2 [HER-2], urokinase plasminogen activator receptor, vascular endothelial growth factor-A [VEGF-A], and VEGF receptor 2). Immunohistochemistry was performed on tissue microarrays of LNM (n = 48), primary EACs (n = 62), fibrotic tissues (n = 11), nonmalignant lymph nodes (n = 24), and normal esophageal and gastric tissues (n = 40). Tumor marker staining was scored on intensity and percentage of positive cells. RESULTS: EMA and EpCAM showed strong expression in LNM (> 95%) and primary EACs (> 95%). Significant expression was also observed for LNM and EAC using VEGF-A (85 and 92%), CEA (68 and 54%), and CA-IX (4 and 34%). The other tumor biomarkers showed expression of 0-15% for LNM and primary EAC. Except for VEGF-A, nonmalignant lymph node staining was scored as slight or absent. CONCLUSIONS: High expression rates and correlation between LNM in EAC combined with low expression rates in healthy lymph nodes and esophagus tissues were observed for EpCAM and CEA, meaning these are promising targets for tumor-targeted imaging approaches for lymph nodes in patients with EAC

Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers

Contains fulltext : 89346.pdf (publisher's version ) (Open Access)BACKGROUND: Colorectal, endometrial and upper urinary tract tumours are characteristic for Lynch syndrome (hereditary non-polyposis colon carcinoma, HNPCC). The aim of the present study was to establish whether carriers of mutations in mismatch repair genes MLH1, MSH2 or MSH6 are at increased risk of urinary bladder cancer. METHODS: Carriers and first degree relatives of 95 families with a germline mutation in the MLH1 (n=26), MSH2 (n=43), or MSH6 (n=26) gene were systematically questioned about the occurrence of carcinoma. The cumulative risk of cancer occurring before the age of 70 years (CR70) was compared to the CR70 of the general Dutch population. Microsatellite instability (MSI) testing and/or immunohistochemistry (IHC) for mismatch repair proteins was performed on bladder tumour tissue. RESULTS: Bladder cancer was diagnosed in 21 patients (90% men) from 19 Lynch syndrome families (2 MLH1, 15 MSH2, and 4 MSH6). CR70 for bladder cancer was 7.5% (95% CI 3.1% to 11.9%) for men and 1.0% (95% CI 0% to 2.4%) for women, resulting in relative risks for mutation carriers and first degree relatives of 4.2 (95% CI 2.2 to 7.2) for men and 2.2 (95% CI 0.3 to 8.0) for women. Men carrying an MSH2 mutation and their first degree relatives were at highest risks: CR70 for bladder and upper urinary tract cancer being 12.3% (95% CI 4.3% to 20.3%) and 5.9% (95% CI 0.7% to 11.1%). Bladder cancer tissue was MSI positive in 6/7 tumours and loss of IHC staining was found in 14/17 tumours, indicating Lynch syndrome aetiology. CONCLUSION: Patients with Lynch syndrome carrying an MSH2 mutation are at increased risk of urinary tract cancer including bladder cancer. In these cases surveillance should be considered.01 juli 201

Resonant multiple Andreev reflections in mesoscopic superconducting junctions

We investigate the properties of subharmonic gap structure (SGS) in superconducting quantum contacts with normal-electron resonances. We find two distinct new features of the SGS in resonant junctions which distinguish them from non-resonant point contacts: (i) The odd-order structures on the current-voltage characteristics of resonant junctions are strongly enhanced and have pronounced peaks, while the even-order structures are suppressed, in the case of a normal electron resonance being close to the Fermi level. (ii) Tremendous current peaks develop at $eV=\pm 2E_0$ where $E_0$ indicates a distance of the resonance to the Fermi level. These properties are determined by the effect of narrowing of the resonance during multiple Andreev reflections and by overlap of electron and hole resonances.Comment: 13 pages, 10 figure

Behavioral determinants as predictors of return to work after long-term sickness absence: an application of the theory of planned behavior

Background The aim of this prospective, longitudinal cohort study was to analyze the association between the three behavioral determinants of the theory of planned behavior (TPB) model-attitude, subjective norm and self-efficacy-and the time to return-to-work (RTW) in employees on long-term sick leave. Methods The study was based on a sample of 926 employees on sickness absence (maximum duration of 12 weeks). The employees filled out a baseline questionnaire and were subsequently followed until the tenth month after listing sick. The TPB-determinants were measured at baseline. Work attitude was measured with a Dutch language version of the Work Involvement Scale. Subjective norm was measured with a self-structured scale reflecting a person's perception of social support and social pressure. Self-efficacy was measured with the three subscales of a standardised Dutch version of the general self-efficacy scale (ALCOS): willingness to expend effort in completing the behavior, persistence in the face of adversity, and willingness to initiate behavior. Cox proportional hazards regression analyses were used to identify behavioral determinants of the time to RTW. Results Median time to RTW was 160 days. In the univariate analysis, all potential prognostic factors were significantly associated (P < 0.15) with time to RTW: work attitude, social support, and the three subscales of self-efficacy. The final multivariate model with time to RTW as the predicted outcome included work attitude, social support and willingness to expend effort in completing the behavior as significant predictive factors. Conclusions This prospective, longitudinal cohort-study showed that work attitude, social support and willingness to expend effort in completing the behavior are significantly associated with a shorter time to RTW in employees on long-term sickness absence. This provides suggestive evidence for the relevance of behavioral characteristics in the prediction of duration of sickness absence. It may be a promising approach to address the behavioral determinants in the development of interventions focusing on RTW in employees on long-term sick leave

Full Counting Statistics of Multiple Andreev Reflections in incoherent diffusive superconducting junctions

We present a theory for the full distribution of current fluctuations in incoherent diffusive superconducting junctions, subjected to a voltage bias. This theory of full counting statistics of incoherent multiple Andreev reflections is valid for arbitrary applied voltage. We present a detailed discussion of the properties of the first four cumulants as well as the low and high voltage regimes of the full counting statistics. The work is an extension of the results of Pilgram and the author, Phys. Rev. Lett. 94, 086806 (2005).Comment: Included in special issue Spin Physics of Superconducting heterostructures of Applied Physics A: Materials Science & Processin