Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.=20

Background It is commonly believed that the presence of personality disorder influences the outcome of schizophrenia but no systematic examination of the literature has been published to examine this. Aims The aim of the current research was to review the literature in a standard systematic way in order to determine the influence of personality disorder on the outcome of schizophrenia in methodologically robust trials. The null hypothesis was that personality disorder had no influence on the outcome of schizophrenia. Method A systematic electronic search of the literature was carried out to identify papers. Relevant papers, written in English, were accessed and assessed for data. Suitable papers were identified to extract outcome data. Results A total of 3 972 papers were identified by the electronic search and two reviewers read all the abstracts. Of these, 97 were identified as potentially containing information about outcome in patients with schizophrenia and comorbid categorical personality disorders and were read in full. No papers satisfied the inclusion criteria of both recording the presence of personality status before treatment and outcome separated by personality pathology and change in schizophrenic symptoms (but several others reported on institutional treatment, reoffending and service usage). Five authors were contacted for further data and none provided usable information suitable for meta-analysis. Conclusions No research to date has examined the influence of personality disorder on the outcome of patients with schizophrenia in such a way as to indicate whether this form of comorbidity has a significant impact on the natural history or outcome of treatment on schizophrenia. The common belief that personality disorder worsens outcome in schizophrenia remains open to debate, and it is suggested that future research takes the opportunity of addressing this important issue directly. Copyright (C) 2007 John Wiley & Sons, Ltd.