Search

A male neutered Cavalier King Charles spaniel was presented initially because of pruritus, seborrhoea and otitis externa at about 15 months of age. The initial clinical diagnosis was allergic dermatitis. Treatment with antibiotic and antifungal ear preparations, prednisolone and cephalosporins over the following year did not fully resolve the problem and the dog also developed a mucopurulent conjunctivitis with keratoconjunctivitis sicca. The dermatological and ophthalmological conditions prompted investigation for the condition known as congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID), which has been previously reported overseas in Cavalier King Charles spaniels. Histopathology of skin biopsies confirmed the likelihood of the latter diagnosis. Genetic testing was undertaken and established that the dog was heterozygous for the disorder. The dermatosis and the keratoconjunctivitis are being managed by ongoing symptomatic therapy, with reasonable response to the former, however, the keratoconjunctivitis sicca is expected to result in eventual blindness. Clinical cases of CKCSID are generally thought to be homozygous for the genetic mutation, although this has been questioned in some publications. The heterozygosity of the present case adds support to another mode of expression. [ABSTRACT FROM AUTHOR]

This study evaluated the effect of yeast-derived products on growth performance, gut lesion score, intestinal population ofClostridium perfringens, and local innate immunity of broiler chickens challenged withC. perfringens. One-day-old broiler chickens were randomly assigned to eight dietary treatments providing six replicate pens of 55 birds each per treatment. Dietary treatments consisted of Control diets without and withC. perfringenschallenge, and diets containing bacitracin methylene disalicylate (BMD, 55 g/tonne), nucleotides (150 g/tonne), yeast cell wall (YCW, 300 g/tonne), and a commercial product Maxi-Gen Plus (1 kg/tonne) fed to chickens challenged withC. perfringens. Diets containing 10% distillers dried grains with solubles without and withC. perfringenschallenge were also used. Birds were orally challenged withC. perfringens(108 colony-forming units (cfu)/bird) on day 14. On day 21, intestinal samples were collected for gene expression analysis. Pathogen challenge significantly (P < 0.05) impaired feed intake, body weight gain, and feed conversion ratio (FCR) shortly after the challenge (14–21 days). IncreasedC. perfringenscounts and intestinal lesion scores were observed for challenged birds except the BMD-containing diet. Over the entire trial (1–35 days), no difference in growth performance was observed except the BMD diet which improved FCR over the Control, challenged group. Birds receiving nucleotides showed increased expression of toll-like receptors and cytokines interleukin (IL)-4 and IL-18 compared to the Control, challenged group. Expression of macrophage mannose receptor and IL-18 was upregulated in birds receiving YCW. Increased expression of cytokines and receptors involved in innate immunity in broilers receiving nucleotides and YCW suggests the immunomodulatory properties of these products under pathogen challenge conditions. [ABSTRACT FROM PUBLISHER]

Predators are not perfect, as some of their prey capture attempts result in failure. Successful attempts may be partly due to predators modulating their capture kinematics in relation to variation in the visual cues of the prey to increase the probability of success. In praying mantises, which have been suggested to possess stereoscopic vision, variation in prey distance has been shown to elicit variation in the probability of an attempt. However, it remains to be examined whether variation in prey distance results in mantises modulating their attempt to successfully capture prey. The goals of this study were to examine these relationships using the praying mantis system. Using 11 adult female Sphodromantis lineola, we recorded 192 prey capture attempts at 1000 Hz with two cameras to examine the 3D kinematics of successful and unsuccessful prey capture attempts. Using a combination of principal component analysis (PCA) and logistic regression, our results show that as prey distance increases, mantises adjust through greater and faster expansion of the forelegs and body (PC1), which significantly predicts capture success. However, PC1 only explains 22% of the variation in all prey capture attempts, suggesting that the other components may be related to additional aspects of the prey. Our results suggest that the distances at which mantises prefer to attempt to capture prey may be the result of their greater probability of successfully capturing the prey. These results highlight the range of motions mantises use when attempting to capture prey, suggesting flexibility in their prey capture attempts in relation to prey position., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: There has been a precipitous decline in authorizations for medical cannabis since non-medical cannabis was legalized in Canada in 2018. This study examines the demographic and health- and medical cannabis-related factors associated with authorization as well as the differences in medical cannabis use, side effects, and sources of medical cannabis and information by authorization status., Methods: Individuals who were taking cannabis for therapeutic purposes completed an online survey in early 2022. Multivariable logistic regression was used to determine odds ratios (OR) and 95% confidence intervals (CI) of demographic and health- and medical cannabis-related variables associated with holding medical cannabis authorization. The differences in medical cannabis use, side effects, and sources of information by authorization status were determined via t-tests and chi-squared analysis., Results: A total of 5433 individuals who were currently taking cannabis for therapeutic purposes completed the study, of which 2941 (54.1%) currently held medical authorization. Individuals with authorization were more likely to be older (OR ≥ 70 years vs. < 30 years, 4.85 (95% CI, 3.49-6.76)), identify as a man (OR man vs. woman, 1.53 (1.34-1.74)), have a higher income (OR > $100,000/year vs. < $50,000 year, 1.55 (1.30-1.84)), and less likely to live in a small town (OR small town/rural vs. large city, 0.69 (0.59-0.81)). They were significantly more likely to report not experiencing any side effects (29.9% vs. 23.4%; p < 0.001), knowing the amount of cannabis they were taking (32.1% vs. 17.7%; p < 0.001), obtaining cannabis from regulated sources (74.1% vs. 47.5%; p < 0.001), and seeking information about medical cannabis from healthcare professionals (67.8% vs. 48.2%; p < 0.01) than individuals without authorization., Conclusions: These findings offer insight into the possible issues regarding equitable access to medical cannabis and how authorization may support and influence individuals in a jurisdiction where recreational cannabis is legalized, highlighting the value of a formal medical cannabis authorization process., (© 2024. The Author(s).)

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. The complex relationships between race and ethnicity and social determinants of health (SDOH) in influencing SLE and its course are increasingly appreciated. Multiple SDOH have been strongly associated with lupus incidence and outcomes and contribute to health disparities in lupus. Measures of socioeconomic status, including economic instability, poverty, unemployment, and food insecurity, as well as features of the neighborhood and built environment, including lack of safe and affordable housing, crime, stress, racial segregation, and discrimination, are associated with race and ethnicity in the US and are risk factors for poor outcomes in lupus. In this scientific statement, we aimed to summarize current evidence on the role of SDOH in relation to racial and ethnic disparities in SLE and SLE outcomes, primarily as experienced in the U.S. Lupus Foundation of America's Health Disparities Advisory Panel, comprising 10 health disparity experts, including academic researchers and patients, who met 12 times over the course of 18 months in assembling and reviewing the data for this study. Sources included articles published from 2011 to 2023 in PubMed, Centers for Disease Control and Prevention data, and bibliographies and recommendations. Search terms included lupus, race, ethnicity, and SDOH domains. Data were extracted and synthesized into this scientific statement. Poorer neighborhoods correlate with increased damage, reduced care, and stress-induced lupus flares. Large disparities in health care affordability, accessibility, and acceptability exist in the US, varying by region, insurance status, and racial and minority groups. Preliminary interventions targeted social support, depression, and shared-decision-making, but more research and intervention implementation and evaluation are needed. Disparities in lupus across racial and ethnic groups in the US are driven by SDOH, some of which are more easily remediable than others. A multidimensional and multidisciplinary approach involving various stakeholder groups is needed to address these complex challenges, address these diminish disparities, and improve outcomes., (© 2023 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments., Competing Interests: Declaration of interests E.M., E.C., M.J., C.B., C.-C.M., and D.M.B. are employees of Biosplice Therapeutics. O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder. O.A.-W. has received prior research funding from H3B Biomedicine, Nurix Therapeutics, and LOXO Oncology unrelated to the current manuscript. The remaining authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Clinical research in Canada is conducted primarily in "academic" hospitals, whereas most clinical care is provided in "community" hospitals. The objective of this nested observational study was to compare patient characteristics, outcomes, process-of-care variables, and trial metrics for patients enrolled in a large randomized controlled trial who were admitted to academic and community hospitals in Canada., Design: We conducted a preplanned observational study nested within the Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT, a randomized controlled trial comparing probiotics to placebo in mechanically ventilated patients) Research Program., Setting: ICUs., Patients: Mechanically ventilated patients., Measurements: We compared patient characteristics, interventions, outcomes, and trial metrics between patients enrolled in PROSPECT from academic and community hospitals., Main Results: Participating centers included 34 (82.9%) academic and seven (17.1%) community hospitals, which enrolled 2,203 (86.2%) and 352 (13.8%) patients, respectively. Compared with academic hospitals, patients enrolled in community hospitals were older (mean [sd] 62.7 yr [14.9 yr] vs 59.5 yr [16.4 yr]; p = 0.044), had longer ICU stays (median [interquartile range {IQR}], 13 d [8-23 d] vs 11 d [7-8 d]; p = 0.012) and higher mortality (percentage, [95% CI] in the ICU, 30.4% [25.8-35.4%]vs 20.5% [18.9-11.3%]; p = 0.002) and hospital (40.6% [35.6-45.8%] vs 26.1% [24.3-27.9%]; p < 0.001). Trial metrics, including informed consent rate (85.9% vs 76.3%; p = 0.149), mean (sd) monthly enrolment rate (2.1 [1.4] vs 1.1 [0.7]; p = 0.119), and protocol adherence (90.6% vs 91.6%; p = 0.207), were similar between community and academic ICUs., Conclusions: Community hospitals can conduct high-quality research, with similar trial metrics to academic hospitals. Patient characteristics differed between community and academic hospitals, highlighting the need for broader engagement of community hospitals in clinical research to ensure generalizability of study results., Competing Interests: The Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial Trial was funded by the Canadian Institutes of Health Research Research Grant. Dr. Tsang is supported by a Mid-Career Research Award of the McMaster University Department of Medicine. Dr. Cook is supported by a Canada Research Chair of the Canadian Institutes for Health Research. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR + /HER2 - breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G 1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression., Competing Interests: Declaration of interests All authors listed on this manuscript are/were paid employees and/or owned stock of Pfizer, Inc. during data collection, analysis, and interpretation of their contributions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Appendicitis is one of the most common surgically treated diseases in the world. CT scans are often over-utilized and ordered before a surgeon has evaluated the patient. Our aim was to develop a tool using machine learning (ML) algorithms that would help determine if there would be benefit in obtaining a CT scan prior to surgeon consultation., Methods: Retrospective chart review of 100 randomly selected cases who underwent appendectomy and 100 randomly selected controls was completed. Variables included components of the patient's history, laboratory values, CT readings, and pathology. Pathology was used as the gold standard for appendicitis diagnosis. All variables were then used to build the ML algorithms. Random Forest (RF), Support Vector Machine (SVM), and Bayesian Network Classifiers (BNC) models with and without CT scan results were trained and compared to CT scan results alone and the Alvarado score using area under the Receiver Operator Curve (ROC), sensitivity, and specificity measures as well as calibration indices from 500 bootstrapped samples., Results: Among the cases that underwent appendectomy, 88% had pathology-confirmed appendicitis. All the ML algorithms had better sensitivity, specificity, and ROC than the Alvarado score. SVM with and without CT had the best indices and could predict if imaging would aid in appendicitis diagnosis., Conclusion: This study demonstrated that SVM with and without CT results can be used for selective imaging in the diagnosis of appendicitis. This study serves as the initial step and proof-of-concept to externally validate these results with larger and more diverse patient population., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Using a mini-library of 1062 lentiviral shRNAs targeting 40 nuclear hormone receptors and 70 of their co-regulators, we searched for potential therapeutic targets that would be important during in vivo tumor growth using a parallel in vitro and in vivo shRNA screening strategy in the non-small cell lung cancer (NSCLC) line NCI-H1819. We identified 21 genes essential for in vitro growth, and nine genes specifically required for tumor survival in vivo, but not in vitro: NCOR2, FOXA1, HDAC1, RXRA, RORB, RARB, MTA2, ETV4, and NR1H2. We focused on FOXA1, since it lies within the most frequently amplified genomic region in lung adenocarcinomas. We found that 14q-amplification in NSCLC cell lines was a biomarker for FOXA1 dependency for both in vivo xenograft growth and colony formation, but not mass culture growth in vitro. FOXA1 knockdown identified genes involved in electron transport among the most differentially regulated, indicating FOXA1 loss may lead to a decrease in cellular respiration. In support of this, FOXA1 amplification was correlated with increased sensitivity to the complex I inhibitor phenformin. Integrative ChipSeq analyses reveal that FOXA1 functions in this genetic context may be at least partially independent of NKX2-1. Our findings are consistent with a neomorphic function for amplified FOXA1, driving an oncogenic transcriptional program. These data provide new insight into the functional consequences of FOXA1 amplification in lung adenocarcinomas, and identify new transcriptional networks for exploration of therapeutic vulnerabilities in this patient population., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

After laying their eggs and refilling the egg chamber, sea turtles scatter sand extensively around the nest site. This is presumed to camouflage the nest, or optimize local conditions for egg development, but a consensus on its function is lacking. We quantified activity and mapped the movements of hawksbill ( Eretmochelys imbricata ) and leatherback ( Dermochelys coriacea ) turtles during sand-scattering. For leatherbacks, we also recorded activity at each sand-scattering position. For hawksbills, we recorded breathing rates during nesting as an indicator of metabolic investment and compared with published values for leatherbacks. Temporal and inferred metabolic investment in sand-scattering was substantial for both species. Neither species remained near the nest while sand-scattering, instead moving to several other positions to scatter sand, changing direction each time, progressively displacing themselves from the nest site. Movement patterns were highly diverse between individuals, but activity at each sand-scattering position changed little between completion of egg chamber refilling and return to the sea. Our findings are inconsistent with sand-scattering being to directly camouflage the nest, or primarily for modifying the nest-proximal environment. Instead, they are consistent with the construction of a series of dispersed decoy nests that may reduce the discovery of nests by predators., Competing Interests: The authors declare that they have no competing interests., (© 2020 The Authors.)

Aim: It is well-known that enterococci are abundant in the environment; however, the role of surface water as a reservoir of antimicrobial-resistant enterococci remains largely undefined. In this study, surface water samples were collected over a 2-year period from the Upper Oconee watershed, Athens, GA to examine enterococci and their antimicrobial resistance., Methods and Results: Approximately 97% (445/458) of the samples were positive for enterococci and a total of 637 enterococci were isolated. The predominant species were Enterococcus casseliflavus (33·6%) followed by Enterococcus faecalis (26·5%) and Enterococcus hirae (13·2%). Regardless of species, the highest levels of resistance were to lincomycin (88·5%) and tetracycline (13%); isolates also exhibited resistance to newer antimicrobials, daptomycin (8·9%) and tigecycline (6·4%). Multidrug resistance (resistance ≥3 antimicrobial classes) was observed to as many as five classes of antimicrobials. Resistant enterococci appeared to be randomly dispersed over the seasons rather than clustered by species or antimicrobial resistance., Conclusions: This study demonstrated that surface waters contain a large population of diverse species of antimicrobial-resistant enterococci, including resistance to new antimicrobials., Significance and Impact of the Study: These results may indicate the potential of human intestinal illness and/or colonization of the human gut with resistant enterococci as enterococci correlate with increased disease risk to humans during recreational exposure to water., (© 2019 The Society for Applied Microbiology.)

Compared to demographic data from other healthcare professions, genetic counselors (GCs) are more likely to be Caucasian females. Many current underrepresented in genetic counseling (URGC) professionals in the field found genetic counseling later in their careers due in part to their lack of awareness. A pilot study consisting of equal numbers of male and female sixth grade science club students was conducted to explore the impact that direct teaching might have on students' awareness of and interest in genetic counseling. The analysis used the non-parametric Wilcoxon signed rank test due to the ordinal, Likert-scale data. Results derived from a pre- and post-survey of lesson participants indicated a statistically significant increase in students' perceptions of having a role model in a science career. Efforts to reach local middle school students to highlight genetic counseling as a potential career choice, especially by role models, may add to the continued work being done to increase the diversity of future genetic counseling applicant pools.

Aim: This study aimed to determine the prevalence of high-risk sexual behaviours, sequelae and associated factors in young people attending a youth mental health service., Methods: The study design was a cross-sectional survey of 103 young people aged between 15-25 years carried out across four specialist mental health clinics. A questionnaire on the sexual health of secondary level students was adapted for this study. Mental health symptomatology was assessed through the Brief Psychiatric Rating Scale (BPRS)., Results: The mean age was 20.9 (SD ±2.8) years, with 50.5% being female, 41.7% male and 7.7% transgender. A total of 52.4% (N = 54) attended the psychosis [EPPIC] clinic; 15.6% (N = 16) attended the ultra-high risk for psychosis [PACE] clinic; 19.4% (N = 20) attended the personality disorders [HYPE] clinic; and 12.6% (N = 13) attended the mood clinic [YMC]. The mean BPRS score was 47.7 (SD ±12.2). A total of 77.7% of young people had previously been sexually active and of these, 37.5% did not use consistent contraception; 26.3% had been pregnant, of which 95.2% were unplanned. A total of 68.8% reported having been tested for sexually transmitted infections and 25.5% tested positive. The severity of symptoms or clinical characteristics were not associated with engagement in high-risk sexual behaviours., Conclusions: These results indicate that young people with mental health disorders have high needs in regard to their sexual health, which could be addressed by incorporating sexual health referral pathways into early intervention services., (© 2018 John Wiley & Sons Australia, Ltd.)

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein crucial for iron-sulfur cluster biogenesis and adenosine triphosphate (ATP) production. Currently, there is no therapy to slow down the progression of FRDA. Recent evidence indicates that posttranslational regulation of residual frataxin levels can rescue some of the functional deficit of FRDA, raising the possibility of enhancing levels of residual frataxin as a treatment for FRDA. Here, we present evidence that mitochondrial molecular chaperone GRP75, also known as mortalin/mthsp70/PBP74, directly interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Overexpressing GRP75 increases the levels of both wild-type frataxin and clinically relevant missense frataxin variants in human embryonic kidney 293 cells, while clinical GRP75 variants such as R126W, A476T and P509S impair the binding of GRP75 with frataxin and the effect of GRP75 on frataxin levels. In addition, GRP75 overexpression rescues frataxin deficiency and abnormal cellular phenotypes such as the abnormal mitochondrial network and decreased ATP levels in FRDA patient-derived cells. The effect of GRP75 on frataxin might be in part mediated by the physical interaction between GRP75 and mitochondrial processing peptidase (MPP), which makes frataxin more accessible to MPP. As GRP75 levels are decreased in multiple cell types of FRDA patients, restoring GRP75 might be effective in treating both typical FRDA patients with two guanine-adenine-adenine repeat expansions and compound heterozygous patients with point mutations., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease with developmental features caused by a genetic deficiency of frataxin, a small, nuclear-encoded mitochondrial protein. Frataxin deficiency leads to impairment of iron-sulphur cluster synthesis, and consequently, ATP production abnormalities. Based on the involvement of such processes in FRDA, initial pathophysiological hypotheses focused on reactive oxygen species (ROS) production as a key component of the mechanism. With further study, a variety of other events appear to be involved, including abnormalities of mitochondrially related metabolism and dysfunction in mitochondrial biogenesis. Consequently, present therapies focus not only on free radical damage, but also on control of metabolic abnormalities and correction of mitochondrial biogenesis. Understanding the multitude of abnormalities in FRDA thus offers possibilities for treatment of this disorder., Competing Interests: The authors declare that there are no competing interests associated with the manuscript., (© 2018 The Author(s).)

The majority of mental disorders have their onset in late adolescence and early adulthood and this coincides with important stages of sexual development. Although sexual dysfunction is highly prevalent among people with mental health disorders, little is known about this topic among youth. This study aimed to evaluate the sexual functioning and subjective experience of sex in young people aged between 15 and 26 years attending a youth mental health service. One hundred and three participants were assessed with the Sexual Health Questionnaire, Sexual Functioning Questionnaire, Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms and the Medication Adherence Rating Scale. There were 43 males, 52 females, and 8 transgender and gender diverse participants with a range of mental health disorders. Eighty (77.7%) had experienced consensual sexual intercourse. Ninety-nine (95.8%) endorsed at least one item of sexual dysfunction and clinical sexual dysfunction was present in 37 (38.9%) cases. Sexual dysfunction was associated with greater severity of general psychopathology, negative symptoms, antipsychotic use, lower antipsychotic medication adherence, and negative subjective experiences around sex. Addressing this sexual dysfunction in young people could lead to both an improvement in subjective experiences of sexual relationships and potentially improvement in adherence to treatment., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

As genomics advances reveal the cancer gene landscape, a daunting task is to understand how these genes contribute to dysregulated oncogenic pathways. Integration of cancer genes into networks offers opportunities to reveal protein-protein interactions (PPIs) with functional and therapeutic significance. Here, we report the generation of a cancer-focused PPI network, termed OncoPPi, and identification of >260 cancer-associated PPIs not in other large-scale interactomes. PPI hubs reveal new regulatory mechanisms for cancer genes like MYC, STK11, RASSF1 and CDK4. As example, the NSD3 (WHSC1L1)-MYC interaction suggests a new mechanism for NSD3/BRD4 chromatin complex regulation of MYC-driven tumours. Association of undruggable tumour suppressors with drug targets informs therapeutic options. Based on OncoPPi-derived STK11-CDK4 connectivity, we observe enhanced sensitivity of STK11-silenced lung cancer cells to the FDA-approved CDK4 inhibitor palbociclib. OncoPPi is a focused PPI resource that links cancer genes into a signalling network for discovery of PPI targets and network-implicated tumour vulnerabilities for therapeutic interrogation.

The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies. Here we demonstrate the acute and specific cell-autonomous addiction of KRAS-mutant non-small-cell lung cancer cells to receptor-dependent nuclear export. A multi-genomic, data-driven approach, utilizing 106 human non-small-cell lung cancer cell lines, was used to interrogate 4,725 biological processes with 39,760 short interfering RNA pools for those selectively required for the survival of KRAS-mutant cells that harbour a broad spectrum of phenotypic variation. Nuclear transport machinery was the sole process-level discriminator of statistical significance. Chemical perturbation of the nuclear export receptor XPO1 (also known as CRM1), with a clinically available drug, revealed a robust synthetic-lethal interaction with native or engineered oncogenic KRAS both in vitro and in vivo. The primary mechanism underpinning XPO1 inhibitor sensitivity was intolerance to the accumulation of nuclear IκBα (also known as NFKBIA), with consequent inhibition of NFκB transcription factor activity. Intrinsic resistance associated with concurrent FSTL5 mutations was detected and determined to be a consequence of YAP1 activation via a previously unappreciated FSTL5-Hippo pathway regulatory axis. This occurs in approximately 17% of KRAS-mutant lung cancers, and can be overcome with the co-administration of a YAP1-TEAD inhibitor. These findings indicate that clinically available XPO1 inhibitors are a promising therapeutic strategy for a considerable cohort of patients with lung cancer when coupled to genomics-guided patient selection and observation., Competing Interests: The authors declare no competing financial interests. Readers are welcome to comment on the online version of the paper.

Pancreatic ductal adenocarcinoma (PDAC) harbors the worst prognosis of any common solid tumor, and multiple failed clinical trials indicate therapeutic recalcitrance. Here, we use exome sequencing of patient tumors and find multiple conserved genetic alterations. However, the majority of tumors exhibit no clearly defined therapeutic target. High-throughput drug screens using patient-derived cell lines found rare examples of sensitivity to monotherapy, with most models requiring combination therapy. Using PDX models, we confirmed the effectiveness and selectivity of the identified treatment responses. Out of more than 500 single and combination drug regimens tested, no single treatment was effective for the majority of PDAC tumors, and each case had unique sensitivity profiles that could not be predicted using genetic analyses. These data indicate a shortcoming of reliance on genetic analysis to predict efficacy of currently available agents against PDAC and suggest that sensitivity profiling of patient-derived models could inform personalized therapy design for PDAC., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

The efficacy of avilamycin for the prevention of necrotic enteritis (NE) was investigated in a 35-day floor pen study of 2200 broiler cockerels using a Clostridium perfringens (Cp) feed inoculum challenge model. Treatments consisted of (1) nonmedicated, nonchallenged; (2) nonmedicated, challenged; (3) avilamycin at 15 ppm, challenged; (4) avilamycin at 30 ppm, challenged. Avilamycin was administered in the feed from day 7 to day 30 of the study. Challenge inoculum was administered on day 14 and delivered approximately 10(9) CFU Cp/bird. NE mortality rates from day 14-35 were significantly (P < 0.0001) lower in birds treated with avilamycin at 15 and 30 ppm when compared to nonmedicated, challenged birds. Treatment with avilamycin also resulted in a significant reduction in ileal Cp count on day 21 (P < 0.0001) and NE lesion scores on day 17 (P < 0.006) when compared to nonmedicated, challenged birds. The performance of birds treated with avilamycin was also improved when compared to nonmedicated, challenged birds. Cockerels that received either 15 or 30 ppm avilamycin had a significantly (P < 0.0001) increased body weight on day 35 and average daily gain from days 0-35 than nonmedicated, challenged birds. Furthermore, birds treated with avilamycin had an improved feed conversion rate from days 0-35 compared to both nonmedicated, nonchallenged birds and nonmedicated, challenged birds. This study confirms that avilamycin is effective at controlling mortality related to NE in growing broiler chickens.

Motivation: Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets., Results: Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding. In particular, many NSCLC cell lines were especially sensitive to the loss of components of the LSm2-8 protein complex or the CCT/TRiC chaperonin. Different vulnerabilities were also found for different cell line subgroups. Furthermore, the predicted vulnerability of a single adenocarcinoma cell line to loss of the Wnt pathway was experimentally validated with screening of small-molecule Wnt inhibitors against an extensive cell line panel., Availability and Implementation: The clustering algorithm is implemented in Python and is freely available at https://bitbucket.org/youngjh/nsclc&#95;paper, Contact: marcotte@icmb.utexas.edu or jon.young@utexas.edu, Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2016. Published by Oxford University Press.)

Non-small cell lung cancer (NSCLC) is heterogeneous in the genetic and environmental parameters that influence cell metabolism in culture. Here, we assessed the impact of these factors on human NSCLC metabolism in vivo using intraoperative (13)C-glucose infusions in nine NSCLC patients to compare metabolism between tumors and benign lung. While enhanced glycolysis and glucose oxidation were common among these tumors, we observed evidence for oxidation of multiple nutrients in each of them, including lactate as a potential carbon source. Moreover, metabolically heterogeneous regions were identified within and between tumors, and surprisingly, our data suggested potential contributions of non-glucose nutrients in well-perfused tumor areas. Our findings not only demonstrate the heterogeneity in tumor metabolism in vivo but also highlight the strong influence of the microenvironment on this feature., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Large-scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease. Thus, restoration of miRNA activity may represent a common vulnerability among diverse EOC oncogenotypes. To test this, we employed genome-scale, gain-of-function, miRNA mimic toxicity screens in a large, diverse spectrum of EOC cell lines. We found that all cell lines responded to at least some miRNA mimics, but that the nature of the miRNA mimics provoking a response was highly selective within the panel. These selective toxicity profiles were leveraged to define modes of action and molecular response indicators for miRNA mimics with tumor-suppressive characteristics in vivo. A mechanistic principle emerging from this analysis was sensitivity of EOC to miRNA-mediated release of cell fate specification programs, loss of which may be a prerequisite for development of this disease., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)

The Nicotine Dependence in Teens (NDIT) study is a prospective cohort investigation of 1294 students recruited in 1999-2000 from all grade 7 classes in a convenience sample of 10 high schools in Montreal, Canada. Its primary objectives were to study the natural course and determinants of cigarette smoking and nicotine dependence in novice smokers. The main source of data was self-report questionnaires administered in class at school every 3 months from grade 7 to grade 11 (1999-2005), for a total of 20 survey cycles during high school education. Questionnaires were also completed after graduation from high school in 2007-08 and 2011-12 (survey cycles 21 and 22, respectively) when participants were aged 20 and 24 years on average, respectively. In addition to its primary objectives, NDIT has embedded studies on obesity, blood pressure, physical activity, team sports, sedentary behaviour, diet, genetics, alcohol use, use of illicit drugs, second-hand smoke, gambling, sleep and mental health. Results to date are described in 58 publications, 20 manuscripts in preparation, 13 MSc and PhD theses and 111 conference presentations. Access to NDIT data is open to university-appointed or affiliated investigators and to masters, doctoral and postdoctoral students, through their primary supervisor (www.nditstudy.ca)., (© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Centronuclear myopathy (CNM) is a congenital myopathy that is histopathologically characterized by centrally located nuclei, central aggregation of oxidative activity, and type I fiber predominance and hypotrophy. Here, we obtained commercially available mice overexpressing phospholamban (Pln(OE)), a well-known inhibitor of sarco(endo)plasmic reticulum Ca(2+)-ATPases (SERCAs), in their slow-twitch type I skeletal muscle fibers to determine the effects on SERCA function. As expected with a 6- to 7-fold overexpression of phospholamban, SERCA dysfunction was evident in Pln(OE) muscles, with marked reductions in rates of Ca(2+) uptake, maximal ATPase activity and the apparent affinity of SERCA for Ca(2+). However, our most significant discovery was that the soleus and gluteus minimus muscles from the Pln(OE) mice displayed overt signs of myopathy: they histopathologically resembled human CNM, with centrally located nuclei, central aggregation of oxidative activity, type I fiber predominance and hypotrophy, progressive fibrosis and muscle weakness. This phenotype is associated with significant upregulation of muscle sarcolipin and dynamin 2, increased Ca(2+)-activated proteolysis, oxidative stress and protein nitrosylation. Moreover, in our assessment of muscle biopsies from three human CNM patients, we found a significant 53% reduction in SERCA activity and increases in both total and monomeric PLN content compared with five healthy subjects, thereby justifying future studies with more CNM patients. Altogether, our results suggest that the commercially available Pln(OE) mouse phenotypically resembles human CNM and could be used as a model to test potential mechanisms and therapeutic strategies. To date, there is no cure for CNM and our results suggest that targeting SERCA function, which has already been shown to be an effective therapeutic target for murine muscular dystrophy and human cardiomyopathy, might represent a novel therapeutic strategy to combat CNM., (© 2015. Published by The Company of Biologists Ltd.)

A 75-year-old man with severe aortic stenosis, severe chronic obstructive pulmonary disease, NYHA class III heart failure and a large abdominal aortic aneurysm underwent concurrent transfemoral transcatheter aortic valve replacement (TF-TAVR) and endovascular aneurysm repair (EVAR). An Edwards Sapien device was implanted with resolution of hemodynamics. EVAR was performed using an Endurant bifurcated stent graft system. We describe the procedure technique, periprocedural management and one year outcome. To the authors' best knowledge, this is the first case of simultaneous TF-TAVR and EVAR published in North America., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The primary cause of death for men under the age of 30 is unintentional injury and, despite health-promotion efforts and programme interventions, male injury and death rates have not decreased in recent years. Drawing on 22 interviews from a study of men, risk and grief, we describe how a risk-related tragedy shaped the participants' understandings of and practices of risk-taking. The findings indicate that most participants did not alter their perceptions and engagement in risky practices, which reflected their alignment to masculine ideals within specific communities of practice where risk-taking was normalised and valorised. Continued reliance on risky practices following the death of a friend was predominantly expressed as 'living for the moment,' where caution and safety were framed as conservative practices that undermined and diluted the robustness ideally embodied by this subgroup of young men. Two main themes: living life, accepting death and upping the ante illustrate how risk-taking can persist following a death. A smaller group of participants articulated a different viewpoint; reining in risk practices, to describe their risk management approaches after the death of a male friend. This novel study confirms the ongoing challenge of reducing men's risk-taking practices, even after the death of a friend., (© 2015 Foundation for the Sociology of Health & Illness.)

Lung cancer is the leading cause of cancer-related fatalities. Recent success developing genotypically targeted therapies, with potency only in well-defined subpopulations of tumors, suggests a path to improving patient survival. We used a library of oligonucleotide inhibitors of microRNAs, a class of posttranscriptional gene regulators, to identify novel synthetic lethal interactions between miRNA inhibition and molecular mechanisms in non-small cell lung cancer (NSCLC). Two inhibitors, those for miR-92a and miR-1226*, produced a toxicity distribution across a panel of 27 cell lines that correlated with loss of p53 protein expression. Notably, depletion of p53 was sufficient to confer sensitivity to otherwise resistant telomerase-immortalized bronchial epithelial cells. We found that both miR inhibitors cause sequence-specific downregulation of the miR-17∼92 polycistron, and this downregulation was toxic only in the context of p53 loss. Mechanistic studies indicated that the selective toxicity of miR-17∼92 polycistron inactivation was the consequence of derepression of vitamin D signaling via suppression of CYP24A1, a rate-limiting enzyme in the 1α,25-dihydroxyvitamin D3 metabolic pathway. Of note, high CYP24A1 expression significantly correlated with poor patient outcome in multiple lung cancer cohorts. Our results indicate that the screening approach used in this study can identify clinically relevant synthetic lethal interactions and that vitamin D receptor agonists may show enhanced efficacy in p53-negative lung cancer patients., (©2014 American Association for Cancer Research.)