S146L in MYC is a context-dependent activating substitution in cancer development.

MYC is one of the most dysregulated oncogenes and is thought to be fundamental to tumor formation and/or maintenance in many cancer types. This dominant pro-tumor activity makes MYC an attractive target for cancer therapy. However, MYC is a transcription factor lacking enzymatic activity, and the structure of one of its two domains is unknown e.

Luminescence complementation technology for the identification of MYC:TRRAP inhibitors.

Mechanism-based targeted therapies have exhibited remarkable success in treating otherwise untreatable or unresectable cancers. Novel targeted therapies that correct dysregulated transcriptional programs in cancer are an unmet medical need. The transcription factor MYC is the most frequently amplified gene in human cancer and is overexpressed because of mutations in an array of oncogenic signaling pathways.

Inhibition of Protein Synthesis Induced by CHK1 Inhibitors Discriminates Sensitive from Resistant Cancer Cells.

The DNA-damage-activated checkpoint protein CHK1 is required to prevent replication or mitosis in the presence of unrepaired DNA damage. Inhibitors of CHK1 (CHK1i) circumvent this checkpoint and enhance cell killing by DNA-damaging drugs. CHK1i also elicit single-agent cytotoxicity in a small subset of cell lines.

Identification of Let-7f-5p as a novel biomarker of recurrence in non-muscle invasive bladder cancer.

Background: Among patients diagnosed with non-muscle invasive bladder cancer (NMIBC), 30% to 70% experience recurrences within 6 to 12 years of diagnosis. The need to screen for these events every 3 to 6 months and ultimately annually by cystoscopy makes bladder cancer one of the most expensive malignancies to manage.

Objective: The purpose of this study was to identify reproducible prognostic microRNAs in resected non-muscle invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype as potential biomarkers and molecular therapeutic targets.

Selective Induction of Cellular Toxicity and Anti-tumor Efficacy by N-Methylpiperazinyl Diarylidenylpiperidone and its Pro-nitroxide Conjugate through ROS-mediated Mitochondrial Dysfunction and G2/M Cell-cycle Arrest in Human Pancreatic Cancer.

Pancreatic adenocarcinoma is an aggressive cancer with poor clinical prognosis and limited therapeutic options. There is a significant lack of effective, safe, and targeted therapies for successful treatment of pancreatic cancer. In this report, we describe the anticancer efficacy of two novel compounds, N-methylpiperazinyl diarylidenylpiperidone (L-2663) and its pro-nitroxide conjugate (HO-4589) evaluated on human pancreatic adenocarcinoma (AsPC-1) cell line and xenograft tumor in mice.

Formation of a structurally-stable conformation by the intrinsically disordered MYC:TRRAP complex.

Our primary goal is to therapeutically target the oncogenic transcription factor MYC to stop tumor growth and cancer progression. Here, we report aspects of the biophysical states of the MYC protein and its interaction with one of the best-characterized MYC cofactors, TRansactivation/tRansformation-domain Associated Protein (TRRAP). The MYC:TRRAP interaction is critical for MYC function in promoting cancer.

Therapeutically targeting tumor microenvironment-mediated drug resistance in estrogen receptor-positive breast cancer.

Drug resistance to approved systemic therapies in estrogen receptor-positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer.

London Trauma Conference 2015 : London, UK, 8-11 December 2015.

I1: Trauma, Pre-hospital and Cardiac Arrest Care 2015 Pascale Avery, Leopold Salm, Flora Bird A1: Retrospective evaluation of HEMS ‘Direct to CT’ protocol Anja Hutchinson, Ashley Matthies, Anthony Hudson, Heather Jarman A2 Rush hour – Crush hour: temporal relationship of cyclist vs. HGV trauma admissions. A single site observational study Maria Bergman Nilsson, Tom Konig, Nigel Tai A3 Semiprone position endotracheal intubation during continuous cardiopulmonary resuscitation in drowned children with regurgitation: a case report and experimental manikin study Espen Fevang, Børge Hognestad, Håkon B.

Impact brain apnoea - A forgotten cause of cardiovascular collapse in trauma.

Objective: Early death following cranial trauma is often considered unsurvivable traumatic brain injury (TBI). However, Impact Brain Apnoea (IBA), the phenomenon of apnoea following TBI, may be a significant and preventable contributor to death attributed to primary injury. This paper reviews the history of IBA, cites case examples and reports a survey of emergency responder experience.

Oxygenation, ventilation, and airway management in out-of-hospital cardiac arrest: a review.

Recently published evidence has challenged some protocols related to oxygenation, ventilation, and airway management for out-of-hospital cardiac arrest. Interrupting chest compressions to attempt airway intervention in the early stages of OHCA in adults may worsen patient outcomes. The change of BLS algorithms from ABC to CAB was recommended by the AHA in 2010.

C3'/C4'-Stereochemical Effects of Digitoxigenin α-L-/α-D-Glycoside in Cancer Cytotoxicity.

Sweet'n low in stereo: A Wharton reaction was employed along with a diastereoselective palladium-catalyzed glycosylation and other post-glycosylation transformations to synthesize digitoxin analogues. Cytotoxic evaluation against a panel of cancer cell lines uncovered the stereochemical and substitutional limits of the C3'/C4'-hydroxy functionality in digitoxin monosaccharide.

Functional heterogeneity of breast fibroblasts is defined by a prostaglandin secretory phenotype that promotes expansion of cancer-stem like cells.

Fibroblasts are important in orchestrating various functions necessary for maintaining normal tissue homeostasis as well as promoting malignant tumor growth. Significant evidence indicates that fibroblasts are functionally heterogeneous with respect to their ability to promote tumor growth, but markers that can be used to distinguish growth promoting from growth suppressing fibroblasts remain ill-defined. Here we show that human breast fibroblasts are functionally heterogeneous with respect to tumor-promoting activity regardless of whether they were isolated from normal or cancerous breast tissues.

Trauma and motorcyclists: born to be wild, bound to be injured?

Background: Regrettably motorcyclists frequently suffer related significant injuries. Doctors who manage trauma will encounter victims of motorcycle accidents and many aspects of care are unique to these patients due to the protective and performance enhancing equipment used by motorcyclists. This review examines the patterns of major injuries suffered by motorcyclists, the unique aspects of airway, circulatory and spine management, and suggests some interventions, which may allow primary injury prevention for the future.