The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is frequently mutated in human cancer. This pathway consists of a small GTP protein of the RAS family that is activated in response to extracellular signaling to recruit a member of the RAF kinase family to the cell membrane. Active RAF signals through MAP/ERK kinase to activate ERK and its downstream effectors to regulate a wide range of biological activities including cell differentiation, proliferation, senescence, and survival. Mutations in the v-raf murine sarcoma viral oncogenes homolog B1 (BRAF) isoform of the RAF kinase or KRAS isoform of the RAS protein are found as activating mutations in approximately 30% of all human cancers. The BRAF pathway has become a target of interest for molecular therapy, with promising results emerging from clinical trials. Here, the role of the most common BRAF mutation BRAF^V600E in human carcinogenesis is investigated through a review of the literature, with specific focus on its role in melanoma, colorectal, and thyroid cancers and its potential as a therapeutic target. Mol Cancer Ther; 10(3); 385–94. ©2011 AACR.

Involving patients in research broadens a researcher’s field of influence and may generate novel ideas. Preclinical research is integral to the progression of innovative healthcare. These are not patient-facing disciplines and implementing meaningful public and patient involvement (PPI) can be a challenge. A discussion forum and thematic analysis identified key challenges of implementing public and patient involvement for preclinical researchers. In response we developed a “PPI Ready” planning canvas. For contemporaneous evaluation of public and patient involvement, a psychometric questionnaire and an open source tool for its evaluation were developed. The questionnaire measures information, procedural and quality assessment. Combined with the open source evaluation tool, researchers are notified if public and patient involvement is unsatisfactory in any of these areas. The tool is easy to use and adapts a psychometric test into a format familiar to preclinical scientists. Designed to be used iteratively across a research project, it provides a simple reporting grade to document satisfaction trend over the research lifecycle.

Subglottic stenosis (SGS) is a narrowing of the airway just below the vocal cords. This narrowing typically consists of fibrotic scar tissue, which may be due to a variety of diseases. This review focuses on post-intubation (PI) SGS. SGS can result in partial or complete narrowing of the airway. This narrowing is caused by fibrosis and can cause serious breathing difficulties. It can occur in both adults and children. The pathogenesis of post-intubation SGS is not well understood; however, it is considered to be the product of an abnormal healing process. This review discusses how intubation can change the local micro-environment, leading to dysregulated tissue repair. We discuss how mucosal inflammation, local hypoxia and biomechanical stress associated with intubation can promote excess tissue deposition that occurs during the pathological process of SGS.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Emma R. Dorris1, Amanda O’Neill1, Ann Treacy2, Helmut Klocker3, Omri Teltsh1, Elaine Kay4 and R. William Watson1 1 UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland 2 Pathology Department, Mater Private Hospital, Dublin, Ireland 3 Department of Urology, Medical University of Innsbruck, Innsbruck, Austria 4 Department of Pathology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland Correspondence to: Emma R. Dorris, email: emma.dorris@ucd.ie Keywords: castration-resistant prostatic cancer; neoplasm invasiveness; androgen-independent prostatic cancer; recurrence Received: August 06, 2019 Accepted: January 29, 2020 Published: March 03, 2020 ABSTRACT Metastatic prostate cancer is treated with androgen ablation therapy but progress to castrate resistant prostate cancer (CRPC). This study aimed to investigate the role of CUX1 in CRPC using clinical samples and in vitro models. CUX1 expression was increased in androgen-independent cells compared to androgen-sensitive cells. The multi-isoform nature of CUX1 makes it difficult to assay in tissue microarrays as there is no epitope able to distinguish the many isoforms for immunohistochemistry. Using surrogate markers, we found no differential expression between castrate resistant and local hormone naïve tissue. However, differences have been demonstrated at the transcript level. In androgen-sensitive cells, migration, but not invasion, increased following CUX1 knockdown. Conversely, in androgen-independent cells, invasion was increased. This observed difference in invasion capacity is not E-cadherin mediated, as CUX1 knockdown increases the expression of E-cadherin in both cell lines with no inter-cell line difference. Cells expressed different ratios of p110/p200 isoforms depending on androgen status and cathepsin L was only detectable in androgen-sensitive cells. MMP3 is upregulated in the androgen-independent cells. Rather than a simple presence or absence of CUX1, the relative balance of CUX1 isoforms and their interplay may be a significant factor in the functional role of CUX1 in CRPC. <!--x2o[6fd3fa19]-->

Depletion of T cells following infection by Mycobacterium tuberculosis (Mtb) impairs disease resolution, and interferes with clinical test performance that relies on cell-mediated immunity. A number of mechanisms contribute to this T cell suppression, such as activation-induced death and trafficking of T cells out of the peripheral circulation and into the diseased lungs. The extent to which Mtb infection of human macrophages affects T cell viability however, is not well characterised. We found that lymphopenia (<1.5×10⁹ cells/l) was prevalent among culture-positive tuberculosis patients, and lymphocyte counts significantly improved post-therapy. We previously reported that Mtb-infected human macrophages resulted in death of infected and uninfected bystander macrophages. In the current study, we sought to examine the influence of infected human alveolar macrophages on T cells. We infected primary human alveolar macrophages (the primary host cell for Mtb) or PMA-differentiated THP-1 cells with Mtb H37Ra, then prepared cell-free supernatants. The supernatants of Mtb-infected macrophages caused dose-dependent, caspase-dependent, T cell apoptosis. This toxic effect of infected macrophage secreted factors did not require TNF-α or Fas. The supernatant cytotoxic signal(s) were heat-labile and greater than 50 kDa in molecular size. Although ESAT-6 was toxic to T cells, other Mtb-secreted factors tested did not influence T cell viability; nor did macrophage-free Mtb bacilli or broth from Mtb cultures. Furthermore, supernatants from Mycobacterium bovis Bacille de Calmette et Guerin (BCG)- infected macrophages also elicited T cell death suggesting that ESAT-6 itself, although cytotoxic, was not the principal mediator of T cell death in our system. Mtb-Infected macrophages secrete heat-labile factors that are toxic to T cells, and may contribute to the immunosuppression seen in tuberculosis as well as interfere with microbial eradication in the granuloma.