Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities

Kras-driven non–small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes residing in PRC2-regulated chromatin. During this process, tumor cells overcome GSK126 antiproliferative effects. We identified oncogenes that may mediate progression through an in vivo RNAi screen aimed at targets of PRC2/NF-κB. An in vitro compound screening linked GSK126-driven inflammation and therapeutic vulnerability in human cells to regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated NSCLCs in vivo also showed an enhanced response to a combination of nimesulide and bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote defined adaptive responses. Targeting these responses potentially improves outcomes in Kras-driven NSCLCs

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Effect of clinical signs, endocrinopathies, timing of surgery, hyperlipidemia, and hyperbilirubinemia on outcome in dogs with gallbladder mucocele

Gallbladder mucocele (GBM) is a common extra-hepatic biliary syndrome in dogs with death rates ranging from 7 to 45%. Therefore, the aim of this study was to identify the association of survival with variables that could be utilized to improve clinical decisions. A total of 1194 dogs with a gross and histopathological diagnosis of GBM were included from 41 veterinary referral hospitals in this retrospective study. Dogs with GBM that demonstrated abnormal clinical signs had significantly greater odds of death than subclinical dogs in a univariable analysis (OR, 4.2; 95% CI, 2.14–8.23; P < 0.001). The multivariable model indicated that categorical variables including owner recognition of jaundice (OR, 2.12; 95% CI, 1.19–3.77; P = 0.011), concurrent hyperadrenocorticism (OR 1.94; 95% CI, 1.08–3.47; P = 0.026), and Pomeranian breed (OR, 2.46; 95% CI 1.10–5.50; P = 0.029) were associated with increased odds of death, and vomiting was associated with decreased odds of death (OR, 0.48; 95% CI, 0.30–0.72; P = 0.001). Continuous variables in the multivariable model, total serum/plasma bilirubin concentration (OR, 1.03; 95% CI, 1.01–1.04; P < 0.001) and age (OR, 1.17; 95% CI, 1.08–1.26; P < 0.001), were associated with increased odds of death. The clinical utility of total serum/plasma bilirubin concentration as a biomarker to predict death was poor with a sensitivity of 0.61 (95% CI, 0.54–0.69) and a specificity of 0.63 (95% CI, 0.59–0.66). This study identified several prognostic variables in dogs with GBM including total serum/plasma bilirubin concentration, age, clinical signs, concurrent hyperadrenocorticism, and the Pomeranian breed. The presence of hypothyroidism or diabetes mellitus did not impact outcome in this study.Supplemental Table S1. Number of dogs included from each institution and years reviewed.Supplemental Table S2. Included breeds.Supplemental Table S3. Distribution of various reasons given for performing cholecystectomy in the 179 subclinical dogs with gallbladder mucocele (GBM).Supplemental Table S4. Distribution of clinical signs associated with systemic illness in 982 dogs with gallbladder mucocele.Supplemental Table S5. Distribution of reasons for death in-hospital (i.e. euthanized and died) in 179 dogs with gallbladder mucocele that underwent cholecystectomy.http://www.elsevier.com/locate/tvjlhj2020Companion Animal Clinical Studie

The effectiveness of a computer-assisted instruction programme on communication skills of medical specialists in oncology.

Although doctor-patient communication is important in health care, medical specialists are generally not well trained in communication skills. Conventional training programmes are generally time consuming and hard to fit into busy working schedules of medical specialists. A computer-assisted instruction (CAI) programme was developed -'Interact-Cancer' - which is a time-efficient learning method and easily accessible at the workplace. To investigate the effect of the CAI training, 'Interact-Cancer', on the communication behaviour of medical specialists, and on satisfaction of patients about their physician interaction. Consultation of medical specialists with cancer outpatients were videotaped at 4 specific stages, 2 before and 2 after Interact-Cancer, with intervals of 4 weeks . Participants were 21 medical specialists, mainly internists, working in 7 hospitals, and 385 cancer outpatients. Communication behaviour was assessed on 23 observation categories derived from the course content. Frequencies were rated as well as judgments about the quality of the performance of each target skill. Satisfaction was measured by the Medical interview Satisfaction scale. Data were analyzed by means of multilevel statistical methods. The behavioural assessment showed course effects on ratings of the physicians' quality of performance. No course effects were found on the frequencies of physicians' behaviours and on the patient satisfaction ratings. CAI is a promising method to supply medical specialists with postgraduate training of communication skills. The application of judgement ratings of communication behaviour proved to be valuable to evaluate course effects in real-life patient encounters. (aut.ref.

Teaching clinically experienced physicians communication skills: a review of evaluation studies.

Interest in the teaching of communication skills in medical schools has increased since the early seventies but, despite this growing interest, relatively limited curricular time is spent on the teaching of communication skills. The limited attention to the teaching of these skills applies even more to the physicians' clinical years, when attention becomes highly focused on biomedical and technical competence. Continuing training after medical school is necessary to refresh knowledge and skills, to prohibit decline of performance and to establish further improvements. Objective: this review provides an overview of evaluation studies of communication skills training programmes for clinically experienced physicians who have finished their undergraduate medical education. The review focuses on the training objectives, the applied educational methods, the evaluation methodology and instruments, and training results. Methods: CD-ROM searches were performed on Medline and Psychlit, with a focus on effect-studies dating from 1985. Results: fifteen papers on 14 evaluation studies were located. There appears to be some consistency in the aims and methods of the training programmes. Course effect measurements include physician self-ratings, independent behavioural observations and patient outcomes. Most of the studies used inadequate research designs. Overall, positive training effects on the physicians' communication behaviour are found on half or less of the observed behaviours. Studies with the most adequate designs report the fewest positive training effects. Conclusion: several reasons are discussed to explain the limited findings. Future research may benefit from research methods which focus on factors that inhibit and facilitate the physicians' implementation of skills into actual behaviours in daily practice. (aut.ref.

The effect of the computer-assisted interactive video training interact-cancer on the communication skills of medical specialists in oncology.

Introduction. INTERACT-CANCER is an interactive course for training communication skills of medical specialists in oncology. The course aims at teaching patient-centred behaviour. It includes four main topics in doctor-patient communication: basic skills, communicating bad news, informing patients, and dealing with emotional reactions of the patient. The course program was developed to facilitate the access to learning of post-graduate physicians. Methods. The course is tested in and evaluated by 21 medical specialists in oncology, working in 7 hospitals. An assessment of their communication behaviour in real life consultations with cancer patients was made at 4 measurement moments; 2 pre-course measurements, and 2 post-course measurements. The physicians did the course between T2 and T3 at their workplace on an individual basis. Each measurement moment three sources of information were used to assess the communication behaviour of the participating physicians: 1) independent ratings of videotaped consultations, 2) satisfaction of the patients about the interaction, 3) satisfaction of the physician about the interaction. Results. Interact-Cancer was positively evaluated by the participating physicians. The computer-assisted training method was evaluated as attractive and pleasant. The course content was evaluated as being worthwhile, relevant, appropriate, and well-structured. Furthermore, the participants stated they are attended on inadequate behaviour, stimulated to think about own behaviour and stimulated to change behaviour. The measurements show an improvement in the quality of communication skills from pre to post training in a subgroup of physicians who state themselves that they put aspects of the training into practice. No training effects were found on the satisfaction ratings of the patients and the physicians. Conclusion. INTERACT-CANCER shows to be a very promising course. Especially among well motivated physicians an improvement in the quality of communication is achievable by means of a computer assisted course. (aut. ref.