Interstitial cell network volume is reduced in the terminal bowel of ageing mice

Ageing is associated with impaired neuromuscular function of the terminal gastrointestinal (GI) tract, which can result in chronic constipation, faecal impaction and incontinence. Interstitial cells of cajal (ICC) play an important role in regulation of intestinal smooth muscle contraction. However, changes in ICC volume with age in the terminal GI tract (the anal canal including the anal sphincter region and rectum)have not been studied. Here, the distribution, morphology and network volume of ICC in the terminal GI tract of 3‐to 4‐month‐old and 26‐to 28‐month‐old C57BL/6mice were investigated. ICC were identified by immunofluorescence labelling of wholemount preparations with an antibody against c‐Kit. ICC network volume was measured by software‐based 3D volume rendering of confocal Z stacks. A significant reduction in ICC network volume per unit volume of muscle was measured in aged animals. No age‐associated change in ICC morphology was detected. The thickness of the circular muscle layer of the anal sphincter region and rectum increased with age, while that in the distal colon decreased. These results suggest that ageing is associated with a reduction in the network volume of ICC in the terminal GI tract, which may influence the normal function of these regions

AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer

First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm(+)) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm(+) sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC is described as proof of principle. SIGNIFICANCE: We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented. (C) 2014 AACR.

The Impact of a Virtual Orthopaedic Surgery Symposium on Medical Students: Increasing Awareness and Knowledge of the Field

Background:. Orthopaedic surgery has become an increasingly popular field of residency training for medical students. Many institutions offer elective time to explore areas of interest through clinical rotations and research; however, most of these opportunities are reserved for senior medical students. The purpose of this study was to evaluate the impact of a dedicated medical student orthopaedic surgery symposium to increase awareness about the field and to assess students' interest and knowledge of orthopaedic surgery before and after the symposium. Methods:. Medical students were invited to submit orthopaedic surgery–related research to a free, 1-day virtual symposium held in April 2022. Abstracts were reviewed and selected from 9 different orthopaedic surgery subspecialty categories. Survey assessments were sent to medical students to complete before and after the symposium. The surveys included questions related to participant demographics as well as interest and knowledge about the field of orthopaedic surgery. Statistical analyses were completed to compare the participants' responses before and after the symposium. Results:. In total, 962 medical students registered for the 4-hour symposium. Of these, 58.5% completed the presymposium survey and 48.0% completed the postsymposium survey. 13.3% of the respondents reported being “very knowledgeable” about the various orthopaedic surgery subspecialties before the symposium, which increased to 18.4% after the symposium. 46.9% of the participants stated that they were “knowledgeable” about the daily life of an orthopaedic surgery resident before the symposium, which increased to 67.3% after the symposium. Similarly, the percentage of respondents who reported that they were “very knowledgeable” about the residency match process increased from 12.2% presymposium to 22.4% postsymposium. Conclusions:. As interest in pursuing a career in orthopaedic surgery increases, medical students will continue to seek information, mentorship, and opportunities to present their research in preparation for residency applications. Our study demonstrated that a large-scale, national, virtual orthopaedic surgery symposium provided a platform to augment medical students' knowledge of the field, present their research, and interact with faculty members. Level of Evidence:. Level V

Recipient BCL2 inhibition and NK cell ablation form part of a reduced intensity conditioning regime that improves allo-bone marrow transplantation outcomes

Allogeneic hematopoietic stem cell transplantation (alloSCT) is used to treat over 15,000 patients with acute myeloid leukemia (AML) per year. Donor graft-versus-leukemia (GVL) effect can prevent AML relapse; however, alloSCT is limited by significant toxicity related to conditioning intensity, immunosuppression, opportunistic infections, and graft-versus-host disease (GVHD). Reducing the intensity of conditioning regimens prior to alloSCT has improved their tolerability, but does not alter the pattern of GVHD and has been associated with increased rates of graft rejection and relapse. Here, using a murine pre-clinical model, we describe a novel recipient conditioning approach combining reduced intensity conditioning with either genetic or pharmacological inhibition of NK cell numbers that permits efficient donor engraftment and promotes GVL without inducing GVHD. We show that NK cell-specific deletion of Bcl2 or Mcl1 in mice, or pharmacological inhibition of BCL2 impairs radio-resistant NK cell-mediated rejection of allogeneic engraftment and allows reduction of conditioning intensity below that associated with GVHD priming. The combination of reduced intensity conditioning and NK cell targeting in mice allowed successful donor T cell engraftment and protective immunity against AML while avoiding GVHD. These findings suggest that reduced conditioning in combination with targeted therapies against recipient NK cells may allow the delivery of effective alloSCT against AML while reducing the toxicities associated with more intensive conditioning including GVHD.Yuhao Jiao, Joanne E. Davis, Jai Rautela, Emma M. Carrington, Mandy J. Ludford-Menting ... Benjamin T. Kile ... et al

Insights into social insects from the genome of the honeybee Apis mellifera

Here we report the genome sequence of the honeybee Apis mellifera, a key model for social behaviour and essential to global ecology through pollination. Compared with other sequenced insect genomes, the A. mellifera genome has high A+T and CpG contents, lacks major transposon families, evolves more slowly, and is more similar to vertebrates for circadian rhythm, RNA interference and DNA methylation genes, among others. Furthermore, A. mellifera has fewer genes for innate immunity, detoxification enzymes, cuticle-forming proteins and gustatory receptors, more genes for odorant receptors, and novel genes for nectar and pollen utilization, consistent with its ecology and social organization. Compared to Drosophila, genes in early developmental pathways differ in Apis, whereas similarities exist for functions that differ markedly, such as sex determination, brain function and behaviour. Population genetics suggests a novel African origin for the species A. mellifera and insights into whether Africanized bees spread throughout the New World via hybridization or displacement