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.

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.

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.

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.

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.

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.

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.

Glycaemic status influences the nature and severity of coronary artery disease.

AIMS/HYPOTHESIS: We sought to understand the relationships between glycaemic status and both severity and progression of coronary artery disease (CAD), the leading cause of death in diabetes. METHODS: Baseline fasting blood glucose (FBG) and HbA1c (%)were measured in 426 patients with known or suspected stable CAD, who underwent coronary artery intravascular ultrasound(IVUS) at baseline and after a mean follow-up period of 664 days (range 257 to 961). The patients were categorised as normoglycaemic (n=226, 53%), or as having impaired fasting glucose (n=118, 28%) or diabetes (n=82, 19%). RESULTS: The maximum percentage coronary atheroma area at baseline was greater in diabetic patients (73.33+/-8.86%) than in those with normoglycaemia (69.08+/-10.43%; p=0.001) and impaired fasting glucose (69.32+/-9.59%; p=0.0031). In averaged IVUS measurements of the 30-mm target segment(n=332 participants), change in percentage atheroma area during follow-up was also greater in the diabetes (1.86+/-3.90%) than in other groups (0.28+/-3.32% and 0.56+/-2.96%,p=0.0047 global). FBG correlated with maximum percentage atheroma area at baseline (r=0.17; p=0.0003). HbA1c also correlated with maximum percentage atheroma area at baseline (r=0.26; p=0.0001) and with change in maximum plaque area (r=0.16; p=0.016). A similar pattern of results occurred with plaque volume. The relationships between diabetes or HbA1c and both IVUS measurements of plaque burden and remodelling persisted after adjustment. CONCLUSIONS/INTERPRETATION: Fasting blood glucose, HbA1c and the presence of diabetes are associated with the severity and progression of coronary atherosclerosis. These observations support the hypothesis that better glycaemic control may favourably influence CAD in patients with abnormal glucose tolerance or diabetes.

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.

Regulation of lymphoid-specific immunoglobulin mu heavy chain gene enhancer by ETS-domain proteins.

The enhancer for the immunoglobulin mu heavy chain gene (IgH) activates a heterologous gene at the pre-B cell stage of B lymphocyte differentiation. A lymphoid-specific element, microB, is necessary for enhancer function in pre-B cells. A microB binding protein is encoded by the PU.1/Spi-1 proto-oncogene. Another sequence element, microA, was identified in the mu enhancer that binds the product of the ets-1 proto-oncogene. The microA motif was required for microB-dependent enhancer activity, which suggests that a minimal B cell-specific enhancer is composed of both the PU.1 and Ets-1 binding sites. Co-expression of both PU.1 and Ets-1 in nonlymphoid cells trans-activated reporter plasmids that contained the minimal mu enhancer. These results implicate two members of the Ets family in the activation of IgH gene expression.

Aeolanthus biformifolius De Wild.: A Hyperaccumulator of Copper from Zaire.

Aeolanthus biformifolius (Labiatae) from Shaba Province, Zaïre, has been shown to be a hyperaccumulator of copper. The copper content of the total plant during the rest period after the rainy season was 1.3 percent (dry weight basis) and is easily the highest copper concentration ever found in living material. This species should be classified as a "copper flower" because of its exclusive occurrence over mineralized ground.

Insomnia and its relationship to health-care utilization, work absenteeism, productivity and accidents.

BACKGROUND AND PURPOSE: To document and provide a micro analysis of the relationship between insomnia and health problems, health-care use, absenteeism, productivity and accidents. PARTICIPANTS AND METHODS: A population-based sample of 953 French-speaking adults from Québec, Canada. Participants were categorized as having insomnia syndrome (SYND) or insomnia symptoms (SYMPT) or as good sleepers (GS). They completed questionnaires on sleep, health, use of health-care services and products, accidents, work absences and reduced work productivity. Data were also obtained from the Québec-government-administered health insurance board on selected variables (e.g., consultations with health-care professionals, diagnoses). RESULTS: There were significantly more individuals in the SYND group relative to the GS group reporting at least one chronic health problem (83% vs. 53%; OR: 2.78) and who had consulted a health-care professional in the past year (81% vs. 60%; OR: 2.8). There were also higher proportions of individuals in the SYND group than in the GS group who had used prescription medications (57% vs. 30.7%; OR: 2.8), most notably to treat insomnia, mood and anxiety disorders, or who had used over-the-counter products (75.6% vs. 62.0%; OR: 1.8) and alcohol as a sleep aid (17.8% vs. 3.9%; OR: 4.6). In terms of daytime function, 25.0% of the SYND had been absent from work relative to 17.1% of GS (OR: 1.7), 40.6% reported having experienced reduced productivity compared to 12.3% of GS (OR: 4.8) and non-motor-vehicle accidents occurred at higher rates in the SYND group (12.5% vs. 6.4% for GS; OR: 2.4). No differences were found for hospitalisations or motor-vehicle accidents. Most of the associations remained significant even after controlling for psychiatric comorbidity. Rates for the SYMPT group were situated between SYND and GS on all major dependent variables. Furthermore, insomnia and fatigue were perceived as contributing significantly to accidents, absences and decreased work productivity, regardless of insomnia status. CONCLUSIONS: This study indicates that insomnia is associated with significant morbidity in terms of health problems and health-care utilization, work absenteeism and reduced productivity, and risk of non-motor-vehicle accidents. Future studies should evaluate whether treating insomnia can reverse this morbidity.

Cytology and outcome of LSIL: cannot exclude HSIL compared to ASC-H.

OBJECTIVE: The cytological features associated with clinical outcome of 'LSIL cannot exclude HSIL (LSIL-H)' in comparison with 'atypical squamous cells cannot exclude HSIL (ASC-H)' are incompletely described. METHODS: LSIL-H and ASC-H Pap tests reported in a regional laboratory during a 13-month period were reviewed by two pathologists. Cytological features suspicious for HSIL were evaluated against a check list of 52 atypical features. All histology over 2 years of follow up for tests reclassified as LSIL-H and ASC-H was retrieved to determine clinical outcome. Atypical cytological features were correlated with outcome. RESULTS: The review yielded 89 LSIL-H and 86 ASC-H. The highest ranked atypical cytological feature in each group was increased nuclear cytoplasmic ratio. Clinical outcome was positive (CIN II/III or AIS) in 44 (49%) LSIL-H and 33 (38%) ASC-H. Round (P = 0.02) and naked nuclei (P = 0.009) were significant correlates of outcome amongst LSIL-H tests, but no feature correlated with outcome in the ASC-H group. CONCLUSIONS: LSIL-H is different to ASC-H because of the 11% higher frequency of a positive outcome and the cytological features associated with outcome.

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.

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.

Underuse of cardioprotective treatment by the elderly with type 2 diabetes.

AIMS: To assess whether elderly patients with type 2 diabetes use a comprehensive cardioprotective regimen (CCR) of antihypertensive, lipid-lowering and antiplatelet drugs in the year following oral antidiabetic drug initiation and, if so, to identify the determinants of such use. METHODS: Using the Quebec Diabetes Surveillance System administrative database, we carried out an inception cohort study of individuals aged 66 years and over who began oral antidiabetic therapy between 1998 and 2002. Those individuals with at least one claim in the year after starting antidiabetic treatment for an antihypertensive, a lipid-lowering and an antiplatelet drugs were deemed to be using a CCR. A multivariate logistic regression model was built to identify the characteristics associated with CCR use. RESULTS: Of the 48,505 individuals included in the study, 9912 (20.4%) used a CCR during the year following the first antidiabetic claim. Those more likely to use a CCR were men (odds ratio [OR]: 1.2; 99% confidence intervals [CI]: 1.1-1.3), those who had used an antihypertensive (1.6; 1.4-1.7), lipid-lowering (7.4; 6.8-8.0) or antiplatelet (7.3; 6.7-7.9) drug in the year before the first antidiabetic claim and those with a preexisting diagnosis of cardiovascular disease (1.9; 1.8-2.1). The odds of using a CCR increased every year. CONCLUSIONS: CCR use by the elderly with type 2 diabetes in the year following antidiabetic initiation is low, and prior use of individual cardioprotective drugs is a strong predictor of its use. These findings suggest that the treatment of important modifiable risk factors for cardiovascular disease is suboptimal.