Disruption of the pro-oncogenic c-RAF-PDE8A complex represents a differentiated approach to treating KRAS-c-RAF dependent PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is considered the third leading cause of cancer mortality in the western world, offering advanced stage patients with few viable treatment options. Consequently, there remains an urgent unmet need to develop novel therapeutic strategies that can effectively inhibit pro-oncogenic molecular targets underpinning PDACs pathogenesis and progression. One such target is c-RAF, a downstream effector of RAS that is considered essential for the oncogenic growth and survival of mutant RAS-driven cancers (including KRAS PDAC).

Establishment of a fluorescent reporter of RNA-polymerase II activity to identify dormant cells.

Dormancy, a reversible quiescent cellular state characterized by greatly reduced metabolic activity, protects from genetic damage, prolongs survival and is crucial for tissue homeostasis and cellular response to injury or transplantation. Dormant cells have been characterized in many tissues, but their identification, isolation and characterization irrespective of tissue of origin remains elusive. Here, we develop a live cell ratiometric fluorescent Optical Stem Cell Activity Reporter (OSCAR) based on the observation that phosphorylation of RNA Polymerase II (RNApII), a hallmark of active mRNA transcription elongation, is largely absent in dormant stem cells from multiple lineages.

Targeting TOPK sensitises tumour cells to radiation-induced damage by enhancing replication stress.

T-LAK-originated protein kinase (TOPK) overexpression is a feature of multiple cancers, yet is absent from most phenotypically normal tissues. As such, TOPK expression profiling and the development of TOPK-targeting pharmaceutical agents have raised hopes for its future potential in the development of targeted therapeutics. Results presented in this paper confirm the value of TOPK as a potential target for the treatment of solid tumours, and demonstrate the efficacy of a TOPK inhibitor (OTS964) when used in combination with radiation treatment.

External Beam Radiation Therapy and Enadenotucirev: Inhibition of the DDR and Mechanisms of Radiation-Mediated Virus Increase.

Ionising radiation causes cell death through the induction of DNA damage, particularly double-stranded DNA (dsDNA) breaks. Evidence suggests that adenoviruses inhibit proteins involved in the DNA damage response (DDR) to prevent recognition of double-stranded viral DNA genomes as cellular dsDNA breaks. We hypothesise that combining adenovirus treatment with radiotherapy has the potential for enhancing tumour-specific cytotoxicity through inhibition of the DDR and augmentation of virus production.

BRN2 suppresses apoptosis, reprograms DNA damage repair, and is associated with a high somatic mutation burden in melanoma.

Whether cell types exposed to a high level of environmental insults possess cell type-specific prosurvival mechanisms or enhanced DNA damage repair capacity is not well understood. BRN2 is a tissue-restricted POU domain transcription factor implicated in neural development and several cancers. In melanoma, BRN2 plays a key role in promoting invasion and regulating proliferation.

T-LAK cell-originated protein kinase (TOPK): an emerging target for cancer-specific therapeutics.

'Targeted' or 'biological' cancer treatments rely on differential gene expression between normal tissue and cancer, and genetic changes that render tumour cells especially sensitive to the agent being applied. Problems exist with the application of many agents as a result of damage to local tissues, tumour evolution and treatment resistance, or through systemic toxicity. Hence, there is a therapeutic need to uncover specific clinical targets which enhance the efficacy of cancer treatment whilst minimising the risk to healthy tissues.

CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner.

Cyclin-dependent kinase 1 (CDK1) orchestrates the transition from the G2 phase into mitosis and as cancer cells often display enhanced CDK1 activity, it has been proposed as a tumor specific anti-cancer target. Here we show that the effects of CDK1 inhibition are not restricted to tumor cells but can also reduce viability in non-cancer cells and sensitize them to radiation in a cell cycle dependent manner. Radiosensitization by the specific CDK1 inhibitor, RO-3306, was determined by colony formation assays in three tumor lines (HeLa, T24, SQ20B) and three non-cancer lines (HFL1, MRC-5, RPE).

TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy.

Background: Tumour-specific radiosensitising treatments may enhance the efficacy of radiotherapy without exacerbating side effects. In this study we determined the radiation response following depletion or inhibition of TOPK, a mitogen-activated protein kinase kinase family Ser/Thr protein kinase that is upregulated in many cancers.

Methods: Radiation response was studied in a wide range of cancer cell lines and normal cells using colony formation assays.

Vaccination of chemotherapy patients--effect of guideline implementation.

Purpose: Despite substantial morbidity and mortality of influenza and pneumococcal infections in cancer patients treated with chemotherapy, vaccination against both illnesses is infrequent. We evaluated the impact of implementation of clinical guidelines on vaccination of chemotherapy patients treated in our institute.

Methods: We performed a prospective audit before (2012) and after (2013-2014) the introduction of immunisation guidelines for chemotherapy patients in a UK tertiary cancer centre.

Arsenic exposure disrupts epigenetic regulation of SIRT1 in human keratinocytes.

Arsenic is an environmental toxin which increases skin cancer risk for exposed populations worldwide; however the underlying biomolecular mechanism for arsenic-induced carcinogenesis is complex and poorly defined. Recent investigations show that histone deacetylase and DNA methyltransferase activity is impaired, and epigenetic patterns of gene regulation are consistently altered in cancers associated with arsenic exposure. Expression of the histone deacetylase SIRT1 is altered in solid tumours and haematological malignancies; however its role in arsenic-induced pathology is unknown.

SIRT1 inhibition restores apoptotic sensitivity in p53-mutated human keratinocytes.

Mutations to the p53 gene are common in UV-exposed keratinocytes and contribute to apoptotic resistance in skin cancer. P53-dependent activity is modulated, in part, by a complex, self-limiting feedback loop imposed by miR-34a-mediated regulation of the lysine deacetylase, SIRT1. Expression of numerous microRNAs is dysregulated in squamous and basal cell carcinomas; however the contribution of specific microRNAs to the pathogenesis of skin cancer remains untested.

SIRT1 modulates miRNA processing defects in p53-mutated human keratinocytes.

Background: Together with p53, the NAD-dependent lysine deacetylase SIRT1 and the microRNA miR-34a form a feedback loop which self-regulates SIRT1 expression and modulates p53-dependent responses. In addition to its well-described role in mediating transcriptional responses to genotoxic stress, p53 may also regulate microRNA processing and maturation.

Objective: This study explored the functional relationship among p53, SIRT1 and miR-34a, and the influence of p53 and SIRT1 on microRNA biogenesis and maturation in primary (NHEK) and p53-mutated (HaCaT) keratinocyte cell lines.

Modulation of arsenic-induced epidermal growth factor receptor pathway signalling by resveratrol.

Arsenic (As) is both a human carcinogen and an effective anticancer drug. These aspects of arsenic toxicity develop as a consequence of arsenic-induced oxidative stress and modifications to signal pathway activity which alter gene expression. Resveratrol (RVL) a food antioxidant found in grapes and other fruits, exhibits anti-carcinogenic properties by reducing oxidative stress and restoring signal pathway control.

Prevalence of risk factors for non-communicable diseases in prison populations worldwide: a systematic review.

Background: The burden of non-communicable diseases (NCDs) is disproportionately carried by low-income and middle-income countries and disadvantaged sectors of society such as prisoners. No systematic analysis has been done to assess the prevalence of poor diet, inadequate physical activity, and overweight and obesity in prisoners. We aim to synthesise current evidence and to highlight areas for action and further research.