Mechanisms of Progranulin Action and Regulation in Genitourinary Cancers.

The growth factor progranulin has emerged in recent years as a critical regulator of transformation in several cancer models, including breast cancer, glioblastomas, leukemias, and hepatocellular carcinomas. Several laboratories, including ours, have also demonstrated an important role of progranulin in several genitourinary cancers, including ovarian, endometrial, cervical, prostate, and bladder tumors, where progranulin acts as an autocrine growth factor thereby modulating motility and invasion of transformed cells. In this review, we will focus on the mechanisms of action and regulation of progranulin signaling in genitourinary cancers with a special emphasis on prostate and bladder tumors

Neuroautonomic evaluation of patients with unexplained syncope: Incidence of complex neurally mediated diagnoses in the elderly

BACKGROUND: The incidence of syncope increases in individuals over the age of 70 years, but data about this condition in the elderly are limited. Little is known about tilt testing (TT), carotid sinus massage (CSM), or supine and upright blood pressure measurement related to age or about patients with complex diagnoses, for example, those with a double diagnosis, ie, positivity in two of these three tests. METHODS: A total of 873 consecutive patients of mean age 66.5±18 years underwent TT, CSM, and blood pressure measurement in the supine and upright positions according to the European Society of Cardiology guidelines on syncope.1 Neuroautonomic evaluation was performed if the first-line evaluation (clinical history, physical examination, electrocardiogram) was suggestive of neurally mediated syncope, or if the first-line evaluation was suggestive of cardiac syncope but this diagnosis was excluded after specific diagnostic tests according to European Society of Cardiology guidelines on syncope, or if certain or suspected diagnostic criteria were not present after the first-line evaluation. RESULTS: A diagnosis was reached in 64.3% of cases. TT was diagnostic in 50.4% of cases, CSM was diagnostic in 11.8% of cases, and orthostatic hypotension was present in 19.9% of cases. Predictors of a positive tilt test were prodromal symptoms and typical situational syncope. Increased age and a pathologic electrocardiogram were predictors of carotid sinus syndrome. Varicose veins and alpha-receptor blockers, nitrates, and benzodiazepines were associated with orthostatic hypotension. Twenty-three percent of the patients had a complex diagnosis. The most frequent association was between vasovagal syncope and orthostatic hypotension (15.8%); 42.9% of patients aged 80 years or older had a complex diagnosis, for which age was the strongest predictor. CONCLUSION: Neuroautonomic evaluation is useful in older patients with unexplained syncope after the initial evaluation. A complex neurally mediated diagnosis is frequent in older people. Our results suggest that complete neuroautonomic evaluation should be done particularly in older patients

Mitostatin Is Down-Regulated in Human Prostate Cancer and Suppresses the Invasive Phenotype of Prostate Cancer Cells

MITOSTATIN, a novel putative tumor suppressor gene induced by decorin overexpression, is expressed in most normal human tissues but is markedly down-regulated in advanced stages of mammary and bladder carcinomas. Mitostatin negatively affects cell growth, induces cell death and regulates the expression and activation levels of Hsp27. In this study, we demonstrated that ectopic expression of Mitostatin in PC3, DU145, and LNCaP prostate cancer cells not only induced a significant reduction in cell growth, but also inhibited migration and invasion. Moreover, Mitostatin inhibited colony formation in soft-agar of PC3 and LNCaP cells as well as tumorigenicity of LNCaP cells in nude mice. Conversely, targeting endogenous Mitostatin by siRNA and anti-sense strategies in PC3 and DU145 prostate cancer cells enhanced the malignant phenotype in both cell lines. In agreement of these anti-oncogenic roles, we discovered that Mitostatin was absent in ∼35% (n = 124) of prostate tumor samples and its overall reduction was associated with advanced cancer stages. Collectively, our findings indicate that MITOSTATIN may acts as a tumor suppressor gene in prostate cancer and provide a novel cellular and molecular mechanism to be further exploited and deciphered in our understanding of prostate cancer progression

IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway.

Discoidin Domain Receptor 1 (DDR1) is a collagen receptor tyrosine-kinase that contributes to epithelial-to-mesenchymal transition and enhances cancer progression. Our previous data indicate that, in breast cancer cells, DDR1 interacts with IGF-1R and positively modulates IGF-1R expression and biological responses, suggesting that the DDR1-IGF-IR cross-talk may play an important role in cancer.In this study, we set out to evaluate whether IGF-I stimulation may affect DDR1 expression. Indeed, in breast cancer cells (MCF-7 and MDA-MB-231) IGF-I induced significant increase of DDR1 protein expression, in a time and dose dependent manner. However, we did not observe parallel changes in DDR1 mRNA. DDR1 upregulation required the activation of the PI3K/AKT pathway while the ERK1/2, the p70/mTOR and the PKC pathways were not involved. Moreover, we observed that DDR1 protein upregulation was induced by translational mechanisms involving miR-199a-5p suppression through PI3K/AKT activation. This effect was confirmed by both IGF-II produced by cancer-associated fibroblasts from human breast cancer and by stable transfection of breast cancer cells with a human IGF-II expression construct. Transfection with a constitutively active form of AKT was sufficient to decrease miR-199a-5p and upregulate DDR1. Accordingly, IGF-I-induced DDR1 upregulation was inhibited by transfection with pre-miR-199a-5p, which also impaired AKT activation and cell migration and proliferation in response to IGF-I.These results demonstrate that, in breast cancer cells, a novel pathway involving AKT/miR-199a-5p/DDR1 plays a role in modulating IGFs biological responses. Therefore, this signaling pathway may represent an important target for breast cancers with over-activation of the IGF-IR axis

Complexity of Progranulin Mechanisms of Action in Mesothelioma

Background: Mesothelioma is an aggressive disease with limited therapeutic options. The growth factor progranulin plays a critical role in several cancer models, where it regulates tumor initiation and progression. Recent data from our laboratories have demonstrated that progranulin and its receptor, EphA2, constitute an oncogenic pathway in bladder cancer by promoting motility, invasion and in vivo tumor formation. Progranulin and EphA2 are expressed in mesothelioma cells but their mechanisms of action are not well defined. In addition, there are no data establishing whether the progranulin/EphA2 axis is tumorigenic for mesothelioma cells. Methods: The expression of progranulin in various mesothelioma cell lines derived from all major mesothelioma subtypes was examined by western blots on cell lysates, conditioned media and ELISA assays. The biological roles of progranulin, EphA2, EGFR, RYK and FAK were assessed in vitro by immunoblots, human phospho-RTK antibody arrays, pharmacological (specific inhibitors) and genetic (siRNAs, shRNAs, CRISPR/Cas9) approaches, motility, invasion and adhesion assays. In vivo tumorigenesis was determined by xenograft models. Focal adhesion turnover was evaluated biochemically using focal adhesion assembly/disassembly assays and immunofluorescence analysis with focal adhesion-specific markers. Results: In the present study we show that progranulin is upregulated in various mesothelioma cell lines covering all mesothelioma subtypes and is an important regulator of motility, invasion, adhesion and in vivo tumor formation. However, our results indicate that EphA2 is not the major functional receptor for progranulin in mesothelioma cells, where progranulin activates a complex signaling network including EGFR and RYK. We further characterized progranulin mechanisms of action and demonstrated that progranulin, by modulating FAK activity, regulates the kinetic of focal adhesion disassembly, a critical step for cell motility. Conclusion: Collectively, our results highlight the complexity of progranulin oncogenic signaling in mesothelioma, where progranulin modulate functional cross-talks between multiple RTKs, thereby suggesting the need for combinatorial therapeutic approaches to improve treatments of this aggressive disease

Unexplained falls are frequent in patients with fall-related injury admitted to Orthopaedic wards: the UFO Study (Unexplained Falls in Older patients)

To evaluate the incidence of unexplained falls in elderly patients affected by fall-related fractures admitted to orthopaedic wards, we recruited 246 consecutive patients older than 65 (mean age 82 \ub1 7 years, range 65-101). Falls were defined "accidental" (fall explained by a definite accidental cause), "medical" (fall caused directly by a specific medical disease), "dementia-related" (fall in patients affected by moderate-severe dementia), and "unexplained" (nonaccidental falls, not related to a clear medical or drug-induced cause or with no apparent cause). According to the anamnestic features of the event, older patients had a lower tendency to remember the fall. Patients with accidental fall remember more often the event. Unexplained falls were frequent in both groups of age. Accidental falls were more frequent in younger patients, while dementia-related falls were more common in the older ones. Patients with unexplained falls showed a higher number of depressive symptoms. In a multivariate analysis a higher GDS and syncopal spells were independent predictors of unexplained falls. In conclusion, more than one third of all falls in patients hospitalized in orthopaedic wards were unexplained, particularly in patients with depressive symptoms and syncopal spells. The identification of fall causes must be evaluated in older patients with a fall-related injury