Reversibility of valve regurgitation due to cancer-related non-bacterial thrombotic endocarditis after switching direct oral anticoagulation for heparin.

Non-bacterial thrombotic endocarditis (NBTE) is a rare condition related to a state of hypercoagulability in advanced neoplastic disease. Most of the time, arterial thromboembolic event precedes the diagnosis of NBTE. We report here a case of NBTE responsible for multiple ischaemic strokes, which leads to the diagnosis of metastatic pancreatic adenocarcinoma. Aortic and mitral valvular regurgitations secondary to NBTE appeared within 6 weeks despite therapeutic anticoagulation with direct oral anticoagulant (DOAC) in stroke prevention of paroxysmal atrial fibrillation. Bivalvular regurgitations resolved 8 weeks after therapeutic switch to low-molecular-weight heparin (LMWH) and chemotherapy. DOACs are a possible alternative to LMWH for the prevention of venous thromboembolism in patients with active neoplasia. There is a lack of evidence for a clinical efficiency for the prevention of arterial thromboembolism in NBTE. We propose here a short review of the efficacy of anticoagulant therapy for the prevention of arterial thromboembolism in NBTE.

Sentinel lymph node (SLN) isolated tumor cells (ITCs) in otherwise stage I/II endometrioid endometrial cancer: To treat or not to treat?

OBJECTIVES: To assess associations between treatment and recurrence-free survival (RFS) among patients with isolated tumor cells (ITCs) in sentinel lymph nodes (SLN) and otherwise stage I/II endometrioid endometrial cancer (EC). METHODS: A multi-institutional retrospective study of patients with SLN ITCs (<200 cells and < 0.2 mm) was performed. Only patients with otherwise stage I/II EC, endometrioid histology, and no evidence of micro-or macrometastases were included. Univariate and multivariable Cox proportional hazard models were used to evaluate associations between treatment, tumor characteristics, and RFS. RESULTS: 175 patients were included. Median follow up time was 31 months. 39% stage IB and 12% stage II disease. 76 (43%) received no adjuvant therapy or vaginal brachytherapy only (NAT/VBT), 21 (12%) had external beam radiation (EBRT), and 78 (45%) received chemotherapy +/- radiation. Patients who received chemotherapy more often had tumors with deep myoinvasion, lymphovascular space invasion (LVSI), and higher grade. Nine (5.1%) patients recurred; 5 distant, 3 retroperitoneal, and 1 vaginal. Extra-vaginal recurrences were similar in patients with or without chemotherapy (5.2% vs 3.8%, p = 0.68). After controlling for stage, LVSI and grade, chemotherapy and EBRT were not associated with RFS (HR = 0.63, 95%CI 0.11-3.52, and HR = 0.90, 95%CI 0.22-3.61, respectively). Type of lymph node dissection and ITC detection method were not associated with RFS. CONCLUSIONS: Risk of retroperitoneal and/or distant recurrence is low (4.6%) for patients with stage I/II endometrioid EC and ITCs in SLNs regardless of treatment. Our preliminary data suggests that adjuvant therapy may not be significantly associated with RFS. However, longer follow-up time and a larger sample size are needed before definitive recommendations regarding adjuvant therapy for patients with EC and only ITCs in SLN can be made.

Angler Peptides: Macrocyclic Conjugates Inhibit p53:MDM2/X Interactions and Activate Apoptosis in Cancer Cells.

Peptides are being developed as targeted anticancer drugs to modulate cytosolic protein-protein interactions involved in cancer progression. However, their use as therapeutics is often limited by their low cell membrane permeation and/or inability to reach cytosolic targets. Conjugation to cell penetrating peptides has been successfully used to improve the cytosolic delivery of high affinity binder peptides, but cellular uptake does not always result in modulation of the targeted pathway. To overcome this limitation, we developed "angler peptides" by conjugating KD3, a noncell permeable but potent and specific peptide inhibitor of p53:MDM2 and p53:MDMX interactions, with a set of cyclic cell-penetrating peptides. We examined their binding affinity for MDM2 and MDMX, the cell entry mechanism, and role in reactivation of the p53 pathway. We identified two angler peptides, cTAT-KD3 and cR10-KD3, able to activate the p53 pathway in cancer cells. cTAT-KD3 entered cells via endocytic pathways, escaped endosomes, and activated the p53 pathway in breast (MCF7), lung (A549), and colon (HCT116) cancer cell lines at concentrations in the range of 1-12 µM. cR10-KD3 reached the cytosol via direct membrane translocation and activated the p53 pathway at 1 µM in all the tested cell lines. Our work demonstrates that nonpermeable anticancer peptides can be delivered into the cytosol and inhibit intracellular cancer pathways when they are conjugated with stable cell penetrating peptides. The mechanistic studies suggest that direct translocation leads to less toxicity, higher cytosol delivery at lower concentrations, and lower dependencies on the membrane of the tested cell line than occurs for an endocytic pathway with endosomal escape. The angler strategy can rescue high affinity peptide binders identified from high throughput screening and convert them into targeted anticancer therapeutics, but investigation of their cellular uptake and cell death mechanisms is essential to confirming modulation of the targeted cancer pathways.

Converting peptides into drugs targeting intracellular protein-protein interactions.

Peptides are gaining increasing attention as therapeutics to target intracellular protein-protein interactions that are involved in disease progression. In this review, we discuss how peptides that are able to bind and inhibit a therapeutic target can be translated into drug leads. We discuss the advantages of using peptides as therapeutics to target intracellular protein-protein interactions, chemical strategies to generate macrocyclic peptides that are resistant to proteolytic enzymes, high-throughput screening approaches to identify peptides that have high affinity for therapeutic targets, strategies that permit these peptides to cross cell membranes and so reach intracellular targets, and the importance of investigating their mode-of-action in guiding the development of novel therapeutics.

Cyclic peptide scaffold with ability to stabilize and deliver a helical cell-impermeable cargo across membranes of cultured cancer cells.

Cell penetrating peptides (CPPs) are valuable tools for developing anticancer therapies due to their ability to access intracellular targets, including protein-protein interactions. cPF4PD is a newly described CPP designed from a transduction domain of the human defense protein platelet factor 4 (PF4), that also has antimalarial activity. The cPF4PD peptide recapitulates the helical structure of the PF4 domain and maintains activity against intracellular malaria parasites via a selective membrane-active mechanism. We hypothesized that cPF4PD and PF4-derived peptide analogues would enter cancer cells and have utility as scaffolds for delivering a peptide dual inhibitor (pDI) sequence with ability to inhibit p53:MDM2/X interactions and reactivate the p53 pathway. Here we designed and produced PF4 peptide and PF4 peptide-pDI grafted analogues with low micromolar activity toward melanoma and leukemia. Two grafted analogues achieved a stable helical structure and inhibited interaction with MDM2 and MDMX. These peptides reached the cytoplasm of cells but were unable to reactivate the p53 pathway. Instead, the cytotoxic mechanism was attributed to peptide binding to mitochondrial membranes that perturbed function within two hours of treatment. These studies of PF4-derived CPPs suggest their potential as scaffolds for delivering cell-impermeable cargoes into the cytoplasm of cells and highlight the importance of characterizing the internalization and cell death mechanism of designer peptide-based drugs.

Cell Membrane Composition Drives Selectivity and Toxicity of Designed Cyclic Helix-Loop-Helix Peptides with Cell Penetrating and Tumor Suppressor Properties.

The tumor suppressor protein p53 is inactive in a large number of cancers, including some forms of sarcoma, breast cancer, and leukemia, due to overexpression of its intrinsic inhibitors MDM2 and MDMX. Reactivation of p53 tumor suppressor activity, via disruption of interactions between MDM2/X and p53 in the cytosol, is a promising strategy to treat cancer. Peptides able to bind MDM2 and/or MDMX were shown to prevent MDM2/X:p53 interactions, but most possess low cell penetrability, low stability, and/or high toxicity to healthy cells. Recently, the designed peptide cHLH-p53-R was reported to possess high affinity for MDM2, resistance toward proteases, cell-penetrating properties, and toxicity toward cancer cells. This peptide uses a stable cyclic helix-loop-helix (cHLH) scaffold, which includes two helices connected with a Gly loop and cyclized to improve stability. In the current study, we were interested in examining the cell selectivity of cHLH-p53-R, its cellular internalization, and ability to reactivate the p53 pathway. We designed analogues of cHLH-p53-R and employed biochemical and biophysical methodologies using in vitro model membranes and cell-based assays to compare their structure, activity, and mode-of-action. Our studies show that cHLH is an excellent scaffold to stabilize and constrain p53-mimetic peptides with helical conformation, and reveal that anticancer properties of cHLH-p53-R are mediated by its ability to selectively target, cross, and disrupt cancer cell membranes, and not by activation of the p53 pathway. These findings highlight the importance of examining the mode-of-action of designed peptides to fully exploit their potential to develop targeted therapies.

Multi-modal optimization of bismuth vanadate photoanodes via combinatorial alloying and hydrogen processing.

Alloying transition metals, such as Mo, into BiVO4 has emerged as the primary mechanism for improving carrier transport in this photoanode for solar fuels production. The present work establishes the generality of improving photoelectrochemical performance through co-alloying with a transition metal electron donor and a structure-modulating rare earth. Further improvement for all such alloys is obtained by annealing the oxide materials in H2, ultimately producing photoanodes with above 3 mA cm-2 photocurrent density under AM 1.5G illumination, in the top tier of compact BiVO4 films.

Adherence to the evidence-based heart failure drug treatment: Are there sex-specific differences among new users?

BACKGROUND: The evidence-based heart failure (HF) drug treatment is made of a ß-blocker and an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker, or hydralazine + isosorbide dinitrate. Little is known about sex-based difference in adherence to the evidence-based HF drug treatment. OBJECTIVES: To assess among new users of the evidence-based HF drug treatment, the association between sex and 1) persistence with the treatment 1 year after its initiation, 2) implementation of the treatment among those who persisted, and 3) overall adherence to treatment in the year following its initiation. METHODS: A cohort study was conducted among new users of this treatment using Quebec medico-administrative data. Patients still on the evidence-based HF drug treatment one year after initiation were considered persistent. Among persistent users, those with ≥88% of days covered by the treatment were deemed to have adequately implemented it. Persistent patients who have adequately implemented the treatment were considered adherent. To measure the association between, on one hand sex, and on the other persistence, implementation and adherence, adjusted proportion ratios (APR) with their 95% confidence intervals (CI) were calculated. RESULTS: Among 13,453 women, 72.1% were persistent, 72.2% adequately implemented the treatment, and 52.8% were adherent. Among the 14,614 men, these proportions were 73.6%, 67.9% and 50.1%, respectively. Men were less likely than women to be adherent to their treatment (APR: 0.96, 95% CI: 0.94-0.99). CONCLUSION: Among individuals initiating an evidence-based multi-drug treatment for HF, men are less likely than women to be adherent to this treatment.

The impact of incident depression on medication adherence in patients with type 2 diabetes.

BACKGROUND: Depression has been correlated with suboptimal adherence to antidiabetic drugs (ADs). Most studies on this topic were cross-sectional; thus, the directionality of this relationship could not be established. The objective of this study was to measure the association between incident depression and AD nonadherence among newly treated patients with diabetes. METHODS: We performed a population-based cohort study among new AD users using the Quebec public health insurance data. To avoid immortal time bias, we carried out depression diagnosis-time distribution matching by assigning a date of depression diagnosis to individuals without depression. Nonadherence (i.e.,<90% of days covered by≥1 AD) during the year following depression diagnosis (real or assigned date) was the outcome. Multivariate logistic regression analyses that adjusted for baseline adherence and other confounders were used to estimate the adjusted effect of depression on AD nonadherence. RESULTS: Between 2000 and 2006, we identified 3,106 new AD users with a subsequent diagnosis of depression and 70,633 without depression, of which 52% and 49% became non-adherent to AD treatment, respectively. Among patients with depression, 52.0% were considered AD non-adherent in the year after depression diagnosis compared with 49.0% of matched patients without depression. Depression was associated with AD nonadherence after accounting for baseline adherence and other confounders with an adjusted odds ratio of 1.24 (95% confidence interval: 1.13-1.37). CONCLUSIONS: The results suggest that depression is an independent risk factor for AD nonadherence. Patients with type 2 diabetes and depression might benefit from adherence-enhancing interventions.

New Composites LnBDC@AC and CB[6]@AC: From Design toward Selective Adsorption of Methylene Blue or Methyl Orange.

New porous composites LnBDC@AC (AC = Activated carbon, Ln = Eu and Gd and BDC = 1,4-benzenedicaboxylate) and CB[6]@AC (CB[6] = Cucurbit[6]uril) were obtained using hydrothermal route. The LnBDC and CB[B] are located inside the pore of the carbon materials as was observed in SEM-EDS, XRPD and FT-IR analysis. Porosimetry analysis showed values typically between AC and LnBDC material, with pore size and surface area, respectively, 29,56 Å and 353.98 m2g-1 for LnBDC@AC and 35,53 Å and 353.98 m2g-1 for CB[6]@AC. Both materials showed good absorptive capacity of metil orange (MO) and methylene blue (MB) with selectivity as a function of pH. For acid pH, both materials present selectivity by MB and alkaline pH for MO, with notable performance for CB[6]@AC. Additionally, europium luminescence was used as structural probe to investigate the coordination environment of Eu3+ ions in the EuBDC@AC composite after adsorption experiment.

Underexposure of Seniors to Heart Failure Drug Therapy.

BACKGROUND: Little is known about exposure to heart failure (HF) treatment among seniors with ischemic heart disease. OBJECTIVES: In a population of seniors, we: 1) estimated the association between age and exposure to HF drug therapy at 6, 12, 36 and 60 month intervals after HF diagnosis, and 2) determined the influence of the passage of time on exposure to drug therapy. METHODS: Using the Quebec provincial administrative databases, we conducted a population-based inception cohort study that included all individuals aged ≥ 65 with a first HF diagnosis between 2000 and 2009 and an ischemic heart disease diagnosis in the year before HF diagnosis. We assessed exposure to HF drug therapy and to drug therapy at target doses at 6, 12, 36 and 60 month intervals after HF diagnosis. Adjusted prevalence ratios (aPR) between age at diagnosis and exposure to drug therapy and the influence of time (6-month periods) were assessed using multivariate modified Poisson regressions. RESULTS: Among the 86,428 seniors, those who were older were less likely to be exposed to both HF drug therapy and drug therapy at target doses at each time point, than were the younger ones (aged 65-69). The aPRs for exposure to drug therapy for the 90+ age group were 0.64, 0.64, 0.56 and 0.53 at the 6, 12, 36 and 60 month intervals, respectively. After HF diagnosis, exposure increased by a maximum of 8% per 6-month period. CONCLUSION: Increasing age is associated with a decrease in exposure to drug therapy, with only slight improvement in exposure after HF diagnosis.

Comparative effectiveness of cardioprotective drugs in elderly individuals with type 2 diabetes.

AIMS: Although many elderly individuals suffer from type 2 diabetes, the effectiveness of cardioprotective drugs in primary prevention of cardiovascular events in clinical practice in this population has rarely been evaluated. We aimed to assess the effectiveness of, (i) angiotensin converting enzyme inhibitors or angiotensin receptor blockers, (ii) statins, (iii) antiplatelet drugs and (iv) the combination of these three drugs, in the prevention of myocardial infarction (MI) and stroke in elderly individuals with type 2 diabetes. METHODS: Using Quebec administrative databases, we conducted nested case-control analyses among a cohort of 17,384 individuals without a history of cardiovascular disease. Individuals were aged ≥ 66 years, newly treated with oral antidiabetes drugs and had not used any of the three above classes of cardioprotective drugs in the year before cohort entry. For each case (MI/stroke during follow-up), five controls were matched for age, year of cohort entry and sex. Use of each drug and of their combination was defined as current, past or no use. We calculated adjusted odds ratios (AOR) of MI/stroke. RESULTS: We observed no reduction in the MI/stroke risk for users of ACEI/ARB nor for users of the three drugs combination. Longer exposure to statins was associated with a lower risk (AOR for every 30 days of therapy: 0.97; 95% CI: 0.96-0.99). By contrast, current use of antiplatelet drugs was associated with an increased risk of MI/stroke (1.40; 1.12-1.75). CONCLUSION: The benefit of cardioprotective drugs in primary prevention was not clear in this cohort of elderly individuals with type 2 diabetes. A short duration of exposure to these drugs might explain the lack of benefit.

High-throughput synchrotron X-ray diffraction for combinatorial phase mapping.

Discovery of new materials drives the deployment of new technologies. Complex technological requirements demand precisely tailored material functionalities, and materials scientists are driven to search for these new materials in compositionally complex and often non-equilibrium spaces containing three, four or more elements. The phase behavior of these high-order composition spaces is mostly unknown and unexplored. High-throughput methods can offer strategies for efficiently searching complex and multi-dimensional material genomes for these much needed new materials and can also suggest a processing pathway for synthesizing them. However, high-throughput structural characterization is still relatively under-developed for rapid material discovery. Here, a synchrotron X-ray diffraction and fluorescence experiment for rapid measurement of both X-ray powder patterns and compositions for an array of samples in a material library is presented. The experiment is capable of measuring more than 5000 samples per day, as demonstrated by the acquisition of high-quality powder patterns in a bismuth-vanadium-iron oxide composition library. A detailed discussion of the scattering geometry and its ability to be tailored for different material systems is provided, with specific attention given to the characterization of fiber textured thin films. The described prototype facility is capable of meeting the structural characterization needs for the first generation of high-throughput material genomic searches.

On-farm evaluation of methods to assess welfare of gestating sows.

The objectives were to evaluate quantitative animal-based measures of sow welfare (lameness, oral stereotypies and reactivity to humans) under commercial farm conditions, and to estimate the influence of housing, sow parity and stage of gestation on the outcome of these measures. Across 10 farms, 311 sows were used. Farms differed in terms of housing design (pen v. stall), space allowance, floor type in stalls (partially v. fully slatted), and feeding system in pens (floor v. trough). Lameness was assessed in terms of gait score, walking speed, stride length, stepping behaviour, response to a stand-up test and latency to lie down after feeding. The presence of oral stereotypies and saliva foam were recorded. Reactivity to humans was assessed by approach (attempt to touch the sow between the ears) and handling tests (exit of the stall for stall-housed sows, or isolation of the animal for pen-housed sows). Only stride length and walking speed were associated with lameness in stall-housed sows (P<0.05 and P<0.01). In stalls, the probability that a sow was lame when it presented a short stride length (<83 cm) or a low speed (<1 m/s) was high (69% and 72%, respectively), suggesting that these variables were good indicators of lameness, but were not sufficient to detect every lame sow in a herd (sensitivity of 0.39 and 0.71, respectively). The stage of gestation and parity also influenced measures of stride length and walking speed (P<0.05). Saliva foam around the mouth was associated with the presence of sham chewing and fixture biting (P<0.05). The probability that a sow presents sham chewing behaviour when saliva foam around her mouth was observed was moderate (63%) but was not sufficient to detect all sows with stereotypies (41%). A high discrimination index was obtained for behavioural measures (aggressions, escapes) and vocalisations during the approach test (stalls: 78.0 and 64.0; pens: 71.9 and 75.0, respectively), the number of interventions needed to make the sow exit the stall during the handling test for stall-housed sows (74.9), and attempts to escape during the handling test for pen-housed sows (96.9). These results suggest that these measures have a good power to discriminate between sows with low and high reactivity to humans. Finally, the outcome of several measures of lameness, stereotypies and reactivity to humans were influenced by the housing characteristics, sow parity and stage of gestation. Therefore, these factors should be considered to avoid misinterpretations of these measures in terms of welfare.

Flying the nest: male dispersal and multiple paternity enables extrafamilial matings for the invasive bark beetle Dendroctonus micans.

There is an evolutionary trade-off between the resources that a species invests in dispersal versus those invested in reproduction. For many insects, reproductive success in patchily-distributed species can be improved by sibling-mating. In many cases, such strategies correspond to sexual dimorphism, with males-whose reproductive activities can take place without dispersal-investing less energy in development of dispersive resources such as large body size and wings. This dimorphism is particularly likely when males have little or no chance of mating outside their place of birth, such as when sperm competition precludes successful fertilisation in females that have already mated. The economically important bark beetle pest species Dendroctonus micans (Coleoptera: Curculionidae, Scolytinae) has been considered to be exclusively sibling-mating, with 90% of females having already mated with their brothers by emergence. The species does not, however, show strong sexual dimorphism; males closely resemble females, and have been observed flying through forests. We hypothesised that this lack of sexual dimorphism indicates that male D. micans are able to mate with unrelated females, and to sire some or all of their offspring, permitting extrafamilial reproduction. Using novel microsatellite markers, we carried out cross-breeding laboratory experiments and conducted paternity analyses of resulting offspring. Our results demonstrate that a second mating with a less-related male can indeed lead to some offspring being sired by the latecomer, but that most are sired by the first, sibling male. We discuss these findings in the context of sperm competition versus possible outbreeding depression.

Rapid increase in dispersal during range expansion in the invasive ladybird Harmonia axyridis.

The evolutionary trajectories associated with demographic, genetic and spatial disequilibrium have become an issue of growing interest in population biology. Invasive species provide unique opportunities to explore the impact of recent range expansion on life-history traits, making it possible to test for a spatial arrangement of dispersal abilities along the expanding range, in particular. We carried out controlled experiments in laboratory conditions to test the hypothesis of an increase in dispersal capacity with range expansion in Harmonia axyridis, a ladybird that has been invading Europe since 2001. We found a marked increase in the flight speed of the insects from the core to the front of the invasion range in two independent sampling transects. By contrast, we found that two other traits associated with dispersal (endurance and motivation to fly off) did not follow the same spatial gradient. Our results provide a striking illustration of the way in which predictable directional genetic changes may occur rapidly for some traits associated with dispersal during biological invasions. We discuss the consequences of our results for invasion dynamics and the evolutionary outcomes of spatially expanding populations.