Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.

PurposeThe phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established.MethodsWe analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations.ResultsWe determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding.ConclusionThese findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196

LGR5 is associated with tumor aggressiveness in papillary thyroid cancer.

PurposeLeucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a cancer stem cell marker and a down-stream target in Wnt/β-catenin signaling. In human papillary thyroid cancer (PTC), over activation of Wnt/β-catenin has been associated with tumor aggressiveness.Patients and methodsUsing established human cell lines (TPC-1, KTC-1, Nthy-ori-3-1), we report LGR5 and R-spondin (RSPO1-3) overexpression in PTC and manipulate LGR5 and Wnt/β-catenin signaling via both pharmacologic and genetic interventions. We test the association of LGR5 tumor expression with markers of PTC aggressiveness using a Discovery Cohort (n = 26 patients) and a Validation Cohort (n = 157 patients). Lastly, we explore the association between LGR5 and the BRAFV600E mutation (n = 33 patients).ResultsOur results reveal that LGR5 and its ligand, RSPO, are overexpressed in human PTC, whereby Wnt/β-catenin signaling regulates LGR5 expression and promotes cellular migration. In two separate cohorts of patients, LGR5 and RSPO2 were associated with markers of tumor aggressiveness including: lymph node metastases, vascular invasion, increased tumor size, aggressive histology, advanced AJCC TNM stage, microscopic extra thyroidal extension, capsular invasion, and macroscopic invasion. As a biomarker, LGR5 positivity predicts lymph node metastasis with 95.5% sensitivity (95% CI 88.8%-98.7%) and 61% specificity (95% CI: 48.4%-72.4%) and has a negative predictive value (NPV) of 91.3% (95% CI 79.2%-97.5%) for lymph node metastatic disease. In human PTC, LGR5 is also strongly associated with the BRAFV600E mutation (p = 0.005).ConclusionWe conclude that overexpression of LGR5 is associated with markers of tumor aggressiveness in human PTC. LGR5 may serve as a future potential biomarker for patient risk stratification and loco regional metastases in PTC

Sexual reproduction in Phytophthora infestans

Potato late blight, caused by the oomycete Phytophthora infestans, is one of the most devastating plant diseases worldwide. It is becoming increasingly difficult to control the disease in Sweden, leading to an ever more intensified use of fungicides in the potato production. This unsustainable development could be caused by changes in the pathogen due to the introduction of sexual reproduction. These changes could result in an enhanced capability of the pathogen to adapt to different factors, e. g. weather, cultivar resistance, chemical control or other cultivation measures. This might manifest itself in earlier infections and a late blight that spreads faster in the potato fields requiring increasing efforts to control. Different approaches were taken to clarify the role of sexual reproduction in P. infestans in the epidemiology of potato late blight. The formation of sexually formed oospores and their ability to serve as primary inoculum was studied, both as field observations and by determining within-field genotypic diversity. To further estimate the importance of reproduction on a large spatial scale a population study based on molecular and phenotypic markers was performed on P. infestans isolates from the whole Nordic region. The variation in the aggressiveness of Nordic populations of P. infestans was studied by determining different components of aggressiveness, e.g. sporulation capacity, lesion growth and infection efficacy. The aggressiveness study was combined with an analysis of the phenotypic structure of the Nordic population of P. infestans. The results clearly indicate that the Swedish populations of P. infestans are influenced by sexual reproduction. The facts that both mating types are found all over the country in near 1:1 proportions and that oospores are commonly formed in field crops and serve as inoculum under field conditions support this. Studies of the genetic diversity also indicate that sexual reproduction has an effect on the population structure of P. infestans in Sweden and the Nordic region as a whole

Is there selection by quantitative resistances in the banana fungal pathogen Mycosphaerella fijiensis?

Plant pathogenic fungi are able to erode quantitative host resistance through changes in aggressiveness, thereby threatening the durability of host resistance. Such erosions are suspected in some areas in the fungus Mycosphaerella fijiensis, responsible for a recent and devastating banana pandemic, Black Leaf Streak Disease (BLSD). This study aims to test for the action of host-specific adaptation and to detect host-selected genes in M. fijiensis. We collected six samples in Cuba in three locations distributed throughout the banana production zones where resistant cultivars have been used for about 15 years. For each location, about 40 isolates were collected from two banana plots containing either a resistant variety or a susceptible variety located two to 10 km apart. We also included in the study three samples from Honduras where the disease was first introduced in the Latin America- Caribbean area. Some aggressiveness traits of a subsample of about 100 Cuban isolates coming from the three locations and the two cultivars were evaluated under controlled conditions on the same cultivars. A significant host effect was detected in some locations. A genome scan approach was conducted from whole-genome sequencing of pools of individuals (pool-seq). Differentiated genomic regions were detected between pathogen populations from the two cultivars in some locations. Further analyses have been undertaken to elucidate if these differentiated regions are due to either a host selective effect or demographic history

Elevated Tumor Lactate and Efflux in High-grade Prostate Cancer demonstrated by Hyperpolarized 13C Magnetic Resonance Spectroscopy of Prostate Tissue Slice Cultures.

Non-invasive assessment of the biological aggressiveness of prostate cancer (PCa) is needed for men with localized disease. Hyperpolarized (HP) 13C magnetic resonance (MR) spectroscopy is a powerful approach to image metabolism, specifically the conversion of HP [1-13C]pyruvate to [1-13C]lactate, catalyzed by lactate dehydrogenase (LDH). Significant increase in tumor lactate was measured in high-grade PCa relative to benign and low-grade cancer, suggesting that HP 13C MR could distinguish low-risk (Gleason score ≤3 + 4) from high-risk (Gleason score ≥4 + 3) PCa. To test this and the ability of HP 13C MR to detect these metabolic changes, we cultured prostate tissues in an MR-compatible bioreactor under continuous perfusion. 31P spectra demonstrated good viability and dynamic HP 13C-pyruvate MR demonstrated that high-grade PCa had significantly increased lactate efflux compared to low-grade PCa and benign prostate tissue. These metabolic differences are attributed to significantly increased LDHA expression and LDH activity, as well as significantly increased monocarboxylate transporter 4 (MCT4) expression in high- versus low- grade PCa. Moreover, lactate efflux, LDH activity, and MCT4 expression were not different between low-grade PCa and benign prostate tissues, indicating that these metabolic alterations are specific for high-grade disease. These distinctive metabolic alterations can be used to differentiate high-grade PCa from low-grade PCa and benign prostate tissues using clinically translatable HP [1-13C]pyruvate MR

Psychological, emotional and social impairments are associated with adherence and healthcare spending in type 2 diabetic patients: an observational study

OBJECTIVE: The aim of the present study was to assess the association among anxiety, depression, stress, social support and emotional abilities with adherence and healthcare spending in type 2 diabetic patients. PATIENTS AND METHODS: Sixty-four patients were enrolled and completed: Interpersonal Processes of Care (IPC), 20-item Toronto Alexithymia Scale (TAS-20), Rapid Stress Assessment Scale (RSAS), Morisky Medication Adherence Scale (MMAS-4), International Physical Activity Questionnaire (IPAQ)-Short Form and a socio-anamnestic questionnaire regarding also the healthcare spending. RESULTS: Mathematical linear regressions models were performed showing the predictive effects of: anxiety and social support scores (RSAS) on adherence levels (respectively p =. 019; p =. 016); adherence levels on anxiolytic use (p =.04); aggressiveness scores (RSAS) on the number of general check-ups (p =.031); TAS-20 and physician-patient communication (IPC) on the number of hospitalization days (respectively p=.001; p=.008); physician patient decision making (IPC) scores on physical activity (IPAQ) levels (p=.025); physical activity (IPAQ) on the number of medical examinations (p=.039). CONCLUSIONS: An association among psychosocial impairment, adherence and health- care spending was found. Future studies should investigate the effect of a brief psychological intervention in increasing adherence levels and reducing the healthcare spending in this clinical population

A Family History of Lethal Prostate Cancer and Risk of Aggressive Prostate Cancer in Patients Undergoing Radical Prostatectomy.

We investigated whether a family history of lethal prostate cancer (PCa) was associated with high-risk disease or biochemical recurrence in patients undergoing radical prostatectomy. A cohort of radical prostatectomy patients was stratified into men with no family history of PCa (NFH); a first-degree relative with PCa (FH); and those with a first-degree relative who had died of PCa (FHD). Demographic, operative and pathologic outcomes were analyzed. Freedom from biochemical recurrence was examined using Kaplan-Meier log rank. A multivariate Cox logistic regression analysis was also performed. We analyzed 471 men who underwent radical prostatectomy at our institution with known family history. The three groups had: 355 patients (75%) in NFH; 97 patients (21%) in FH; and 19 patients (4%) in FHD. The prevalence of a Gleason score ≥8, higher pathologic T stage, and biochemical recurrence (BCR) rates did not significantly differ between groups. On Kaplan-Meier analysis there were no differences in short-term BCR rates (p = 0.212). In this cohort of patients undergoing radical prostatectomy, those with first-degree relatives who died of PCa did not have an increased likelihood of high-risk or aggressive PCa or shorter-term risk of BCR than those who did not

Differential expression of miR-34b and androgen receptor pathway regulate prostate cancer aggressiveness between African-Americans and Caucasians.

African-Americans are diagnosed with more aggressive prostate cancers and have worse survival than Caucasians, however a comprehensive understanding of this health disparity remains unclear. To clarify the mechanisms leading to this disparity, we analyzed the potential involvement of miR-34b expression in African-Americans and Caucasians. miR-34b functions as a tumor suppressor and has a multi-functional role, through regulation of cell proliferation, cell cycle and apoptosis. We found that miR-34b expression is lower in human prostate cancer tissues from African-Americans compared to Caucasians. DNA hypermethylation of the miR-34b-3p promoter region showed significantly higher methylation in prostate cancer compared to normal samples. We then sequenced the promoter region of miR-34b-3p and found a chromosomal deletion in miR-34b in African-American prostate cancer cell line (MDA-PCA-2b) and not in Caucasian cell line (DU-145). We found that AR and ETV1 genes are differentially expressed in MDA-PCa-2b and DU-145 cells after overexpression of miR-34b. Direct interaction of miR-34b with the 3' untranslated region of AR and ETV1 was validated by luciferase reporter assay. We found that miR-34b downregulation in African-Americans is inversely correlated with high AR levels that lead to increased cell proliferation. Overexpression of miR-34b in cell lines showed higher inhibition of cell proliferation, apoptosis and G1 arrest in the African-American cells (MDA-PCa-2b) compared to Caucasian cell line (DU-145). Taken together, our results show that differential expression of miR-34b and AR are associated with prostate cancer aggressiveness in African-Americans