Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging

Dysregulated signaling through the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways is often the result of genetic alterations in critical components in these pathways or upstream activators. Unrestricted cellular proliferation and decreased sensitivity to apoptotic-inducing agents are typically associated with activation of these pro-survival pathways. This review discusses the functions these pathways have in normal and neoplastic tissue growth and how they contribute to resistance to apoptotic stimuli. Crosstalk and commonly identified mutations that occur within these pathways that contribute to abnormal activation and cancer growth will also be addressed. Finally the recently described roles of these pathways in cancer stem cells, cellular senescence and aging will be evaluated. Controlling the expression of these pathways could ameliorate human health

Advances in Targeting Signal Transduction Pathways

Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies

Emerging targeted therapies for melanoma treatment (Review)

Cutaneous melanoma is an aggressive cancer with a poor prognosis for patients with advanced disease. The identification of several key molecular pathways implicated in the pathogenesis of melanoma has led to the development of novel therapies for this devastating disease. In melanoma, both the Ras/Raf/MEK/ERK (MAPK) and the PI3K/AKT (AKT) signalling pathways are constitutively activated through multiple mechanisms. Targeting various effectors of these pathways with pharmacologic inhibitors may inhibit melanoma cell growth and angiogenesis. Ongoing clinical trials provide hope to improve progression-free survival of patients with advanced melanoma. This review summarizes the most relevant studies focused on the specific action of these new molecular targeted agents. Mechanisms of resistance to therapy are also discussed

GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function

Peer reviewe

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation

Impact of renal impairment on atrial fibrillation: ESC-EHRA EORP-AF Long-Term General Registry

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p <.001. Over 24 months, impaired renal function was associated with significantly greater incidence of the primary composite outcome and all secondary outcomes. Multivariable Cox regression analysis demonstrated an inverse relationship between eGFR and the primary outcome (HR 1.07 [95% CI, 1.01–1.14] per 10 ml/min/1.73 m2 decrease), that was most notable in patients with eGFR <30 ml/min/1.73 m2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90 ml/min/1.73 m2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Stakeholder influence on brand identity co-creation in startups

The purpose of this thesis was exploring stakeholder influence on brand identity co-creation in startups, by answering the research question: "How do stakeholders influence brand identity co-creation in startups?". To answer this question, a multiple case study was conducted, consisting of interviews with six B2C (business-to-customer) startups. Furthermore, the startups studied are all tenants of incubators. This context is of interest, since incubators have been suggested to provide extensive resources and knowledge for startups struggling with their businesses' establishment. To analyze the data from the case studies, mainly the Corporate Brand Identity Matrix (Urde, 2013) was used, which helps to provide an overview of how different elements of brand identity are co-created with stakeholders in startups. In addition, to study this subject requires an overview and discussion of brand management research, stakeholder theory and co-creation litertature.  The findings show that several of the brand identity elements are co-created with stakeholders in startups. The stakeholders identified in co-creation are several, mainly cusomers, financiers, producers, designers and programmers. Furthermore, an interesting correlation between startups' orientations and co-creation, was discovered. The startups with a mainly market-oriented approach to branding are co-creating the brand identity elements to a much further extent, than brand-oriented startups. Finally, incubators are revealed as co-creators of several of the brand identity elements in startups, but the study also provides further insightsd into their important role in supporting the startups and facilitating networking opportunities.

Evaluating Fallopian Tube Patency: What the Radiologist Needs to Know

Impaired tubal patency accounts for up to 35% of cases of subfer-tility and infertility. Hysterosalpingography (HSG) or hysterosal-pingo-contrast sonography (HyCoSy) represents a first-line test in evaluating fallopian tube patency. Despite the association of HSG with ionizing radiation, HSG is a reference standard in assessing fallopian tube patency and tubal conditions such as tubal occlusion, salpingitis isthmica nodosa, and hydrosalpinx. HSG is widely available and utilizes either a water-soluble contrast medium (WSCM) or an oil-soluble contrast medium (OSCM). Compared with WSCM, HSG with OSCM results in a higher incidence of non–in vitro fertilization pregnancies and, therefore, may be pre-ferred in women younger than 38 years with unexplained subfer-tility. HSG may also be helpful in assessment after sterilization or before fallopian tube recanalization. US-based tubal tests are free of ionizing radiation and include HyCoSy, with either air-saline or microbubble US contrast material, and hysterosalpingo-foam sonography (HyFoSy), a tubal patency test that utilizes a gel foam. A comprehensive US infertility evaluation of the pelvis and fallopian tubes can be achieved in one setting by adding coronal three-dimensional imaging of the uterus, saline infusion sonohysterogra-phy, and HyCoSy or HyFoSy to routine pelvic US. MR HSG and virtual CT HSG also depict tubal patency and uterine and adnexal pathologic conditions and may be considered in select patients. While laparoscopic chromopertubation remains the standard for tubal patency evaluation, its disadvantages are its invasiveness and cost. Knowledge of the different fallopian tube tests and radiologic appearance of normal and abnormal fallopian tubes results in fewer pitfalls, accurate interpretation, and optimal patient care

Anticancer and Differentiation Properties of the Nitric Oxide Derivative of Lopinavir in Human Glioblastoma Cells

Glioblastoma (GBM) is the most frequent and deadly form of primary malignant brain tumor among adults. A promising emerging approach for GBM treatment may be offered from HIV protease inhibitors (HIV-PIs). In fact, in addition to their primary pharmacological activity in the treatment of HIV infection, they possess important anti-neoplastic effects. According to previous studies, the addition of a nitric oxide (NO) donating group to parental compounds can reduce their toxicity and enhance the anticancer action of various compounds, including HIV-PIs. In this study we compared the effects of the HIV-PI Lopinavir (Lopi) and of its NO-derivative Lopinavir-NO (Lopi-NO) on the in vitro growth of LN-229 and U-251 human GBM cell lines. Lopi-NO reduced the viability of LN-229 and U-251 cells at significantly lower concentrations than the parental drug. In particular, Lopi-NO inhibited tumor cell proliferation and induced the differentiation of U-251 cells toward an astrocyte-like phenotype without triggering significant cell death in both cell types. The anticancer effect of Lopi-NO was persistent even upon drug removal. Furthermore, Lopi-NO induced strong autophagy that did not appear to be related to its chemotherapeutic action. Overall, our results suggest that Lopi-NO could be a potential effective anticancer drug for GBM treatment