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Objective: Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease.\ud \ud Design: Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of KrasG12D-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition.\ud \ud Results: We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours.\ud \ud Conclusions: KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future.

Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation. Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease. The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles. Here we show, in a humanized genetically-modified mouse model of pancreatic ductal adenocarcinoma (PDAC), that autophagy's role in tumour development is intrinsically connected to the status of the tumour suppressor p53. Mice with pancreases containing an activated oncogenic allele of Kras (also called Ki-Ras)--the most common mutational event in PDAC--develop a small number of pre-cancerous lesions that stochastically develop into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 or Atg7 accumulate low-grade, pre-malignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC is blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocks tumour progression, but actually accelerates tumour onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumour growth. These findings provide considerable insight into the role of autophagy in cancer and have important implications for autophagy inhibition in cancer therapy. In this regard, we also show that treatment of mice with the autophagy inhibitor hydroxychloroquine, which is currently being used in several clinical trials, significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53.

The ideal therapy for HIV infection requires a method to eliminate all HIV-harboring cells in the infected individual. The authors are developing an HIV-specific promoter to drive the expression of suicide genes that would induce cell death specifically in HIV-infected cells. The authors constructed a promoter that is 100-fold more responsive to the HIV transcriptional activator, Tat, than cellular transcription factors, using a plasmid expressing luciferase under the control of the mutated LTR promoter.

A short-cut review was carried out to establish the sensitivity and specificity of CRP as a tool for diagnosing bacteraemia. Three studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line suggests that CRP is not a useful tool in the initial diagnosis of severe bacterial infection.

A short cut review was carried out to determine whether measuring C Reactive Protein might help in the diagnosis of intracranial infection in a patient presenting to the Emergency department with an acute headache. 62 papers were found, but none answered the question. The clinical bottom line is that there doesn't appear to be any evidence for, or against, the use of C Reactive Protein in the diagnosis of intracranial infection in patients presenting to the Emergency department with an acute headache.

The phosphate-wasting condition, oncogenic osteomalacia, is problematic to diagnose and manage clinically due to difficulty in locating the causative tumor. Fibroblast growth factor 23 (FGF23) has recently been implicated in the pathogenesis of oncogenic osteomalacia. In this case the patient presented with clinical features typical of oncogenic osteomalacia. Removal of an angiolipoma from the thigh did not correct the clinical or biochemical abnormalities. Subsequent identification and removal of a benign giant cell tumor in the pubic ramus, however, did result in normalization of his symptoms and signs. Positive staining for FGF23 protein by immunohistochemistry was demonstrated in the giant cell tumor, but not in the angiolipoma. The serum concentration of FGF23 was elevated in preoperative serum, then normalized after removal of the giant cell tumor. Expression of both FGF23 mRNA and protein was demonstrated in the giant cell tumor tissue, and FGF23 mRNA expression and renal phosphate uptake inhibitory activity were also detected in cultured giant cell tumor cells. This case provides further evidence for the involvement of FGF23 in the pathogenesis of oncogenic osteomalacia and for the utility of serum FGF23 measurement and immunohistochemical detection of FGF23 in the diagnosis and clinical management of this condition.

A short-cut review was carried out to establish the sensitivity and specificity of CRP as a tool for diagnosing bacteraemia. Three studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line suggests that CRP is not a useful tool in the initial diagnosis of severe bacterial infection.

A short cut review was carried out to determine whether measuring C Reactive Protein might help in the diagnosis of intracranial infection in a patient presenting to the Emergency department with an acute headache. 62 papers were found, but none answered the question. The clinical bottom line is that there doesn’t appear to be any evidence for, or against, the use of C Reactive Protein in the diagnosis of intracranial infection in patients presenting to the Emergency department with an acute headache.