Therapeutic opportunities within the DNA damage response

The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets

Why and how does shared language affect subsidiary knowledge inflows? A social identity perspective

We draw on social identity theory to conceptualize a moderated mediation model that examines the relationship between shared language among subsidiary and HQ managers, and subsidiaries’ knowledge inflows from HQ. Specifically, we study (1) whether this relationship is mediated by the extent to which subsidiary managers share HQ goals and vision, and the extent to which HR decisions are centralized; and (2) whether subsidiary type moderates these mediated relationships. Building on a sample of 817 subsidiaries in nine countries/regions, we find support for our model. Implications for research on HQ-subsidiary knowledge flows, social identity theory and international HRM are discussed

Cytologic studies of the fallopian tube in patients undergoing salpingo-oophorectomy

Background: Mounting evidence suggests the fallopian tube as the origin for ovarian high grade serous carcinoma (HGSC). We attempted to identify the tubal cytological features that allow us to distinguish malignant from benign conditions. Methods: Tubal specimens (n = 56) were collected from patients who underwent bilateral salpingo-oophorectomy (BSO) due to various clinical indications. A standard procedure to collect fallopian tube brushings from freshly received surgical specimens was developed. Cytological diagnoses were classified into three categories: benign, atypical, and suspicious for malignancy/malignant. Cytological variables of individual cells and epithelia were subjected to statistical analysis. The fallopian tube histology was used as diagnostic reference for confirmation of cytology diagnosis. Results: Among the 56 fallopian tube specimens, 2 (3.7 %) showed inadequate cellularity preventing further evaluation, 11 (20.4 %) were diagnosed as malignant or suspicious of malignancy, 7 were atypical, and 36 were benign. The presence of three dimensional clusters (p < 0.0001, Fisher's Exact Test), or prominent nucleoli (p = 0.0252, Fisher Exact test) was highly correlated with the diagnosis of malignancy. The suspicious malignant/malignant cytological diagnosis was also highly correlated with presence of HGSC with or without serous tubal intraepithelial carcinoma (STIC). Conclusions: Tubal cytology may be useful for ovarian cancer screening and early detection.Depart of Pathology, University of Arizona; Mark and Jane Gibson endowment fundThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

Epidemiological studies support a strong association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. Experimental evidence from different angles supports the view that low HDL is unlikely an innocent bystander in the development of heart failure. HDL exerts direct cardioprotective effects, which are mediated via its interactions with the myocardium and more specifically with cardiomyocytes. HDL may improve cardiac function in several ways. Firstly, HDL may protect the heart against ischaemia/reperfusion injury resulting in a reduction of infarct size and thus in myocardial salvage. Secondly, HDL can improve cardiac function in the absence of ischaemic heart disease as illustrated by beneficial effects conferred by these lipoproteins in diabetic cardiomyopathy. Thirdly, HDL may improve cardiac function by reducing infarct expansion and by attenuating ventricular remodelling post-myocardial infarction. These different mechanisms are substantiated by in vitro, ex vivo, and in vivo intervention studies that applied treatment with native HDL, treatment with reconstituted HDL, or human apo A-I gene transfer. The effect of human apo A-I gene transfer on infarct expansion and ventricular remodelling post-myocardial infarction illustrates the beneficial effects of HDL on tissue repair. The role of HDL in tissue repair is further underpinned by the potent effects of these lipoproteins on endothelial progenitor cell number, function, and incorporation, which may in particular be relevant under conditions of high endothelial cell turnover. Furthermore, topical HDL therapy enhances cutaneous wound healing in different models. In conclusion, the development of HDL-targeted interventions in these strategically chosen therapeutic areas is supported by a strong clinical rationale and significant preclinical data.status: publishe