Nuclear β-arrestin1 is a critical cofactor of hypoxia-inducible factor-1α signaling in endothelin-1-induced ovarian tumor progression

Hypoxia-inducible factor-1α (HIF-1α) mediates the response to hypoxia or other stimuli, such as growth factors, including endothelin-1 (ET-1), to promote malignant progression in numerous tumors. The importance of cofactors that regulate HIF-1α signalling within tumor is not well understood. Here we elucidate that ET-1/ET(A) receptor (ET(A)R)-induced pathway physically and functionally couples the scaffold protein β-arrestin1 (β-arr1) to HIF-1α signalling. In epithelial ovarian cancer (EOC) cells, ET-1/ET(A)R axis induced vascular-endothelial growth factor (VEGF) expression through HIF-1α nuclear accumulation. In these cells, activation of ET(A)R by ET-1, by mimicking hypoxia, promoted the nuclear interaction between β-arr1 and HIF-1α and the recruitment of p300 acetyltransferase to hypoxia response elements on the target gene promoters, resulting in enhanced histone acetylation, and HIF-1α target gene transcription. Indeed, β-arr1-HIF-1α interaction regulated the enhanced expression and release of downstream targets, such as ET-1 and VEGF, required for tumor cell invasion and pro-angiogenic effects in endothelial cells. These effects were abrogated by β-arr1 or HIF-1α silencing or by pharmacological treatment with the dual ET-1 receptor antagonist macitentan. Interestingly, ET(A)R/β-arr1 promoted the self-amplifying HIF-1α-mediated transcription of ET-1 that sustained a regulatory circuit involved in invasive and angiogenic behaviors. In a murine orthotopic model of metastatic human EOC, treatment with macitentan, or silencing of β-arr1, inhibits intravasation and metastasis formation. Collectively, these findings reveal the interplay of β-arr1 with HIF-1α in the complexity of ET-1/ET(A)R signalling, mediating epigenetic modifications directly involved in the metastatic process, and suggest that targeting ET-1-dependent β-arr1/HIF-1α pathway by using macitentan may impair EOC progression

RelA/NF-kappaB recruitment on the bax gene promoter antagonizes p73-dependent apoptosis in costimulated T cells

The balance between antiapoptotic and proapoptotic proteins of the Bcl-2 family is critical in determining the fate of T cells in response to death stimuli. Proapoptotic genes, such as bax, are generally regulated by the p53 family of transcription factors, whereas NF-kappaB subunits can activate the transcription of antiapoptotic Bcl-2 members. Here, we show that CD28 activation protects memory T cells from irradiation-induced apoptosis by both upregulating bcl-xL and inhibiting bax gene expression. We found that p73, but not p53, binds to and trans-activates the bax gene promoter in irradiated T cells. The activation of RelA/NF-kappaB subunit in CD28 costimulated T cells and its binding onto the bax gene promoter results in suppression of bax transcription and decrease in both p73 and RNA polymerase II recruitment in vivo. RelA recruitment on the bax gene promoter is also accompanied by the lost of p300 binding and the parallel appearance of histone deacetylase-1-containing complexes. These findings identify RelA/NF-kappaB as a critical regulator of T-cell survival by affecting the balance of Bcl-2 family members

Analyzing Transportation Amenities in the City of Shamokin: An Emphasis on the Lower Anthracite Transportation System

As the population gets older, and means of transportation get more expensive, the need for increased public transportation has increased exponentially. To develop recommendations for the Lower Anthracite Transportation System (LATS) in Northumberland County, this report compared various forms of multimodal transportation throughout the United States, and other foreign countries, and compared them with the current standards and practices set by LATS service. According to the United State Census Bureau, Shamokin is a small 3rd class city in Northumberland County Pennsylvania, with a population of 6,901, a poverty rate of 35.9%, and is in the LATS service area. Shamokin is vital for the LATS system, as it is the only city the system covers, and is the largest urban area. This report analyzes public transportation in rural communities and large-scale metropolitan areas to suggest changes to LATS. By speaking with the director of LATS and analyzing similar transportation systems, this report recommends that creating HVAC and solar capable bus shelters at popular bus stops in the greater Shamokin region will be a valuable amenity to add. This report was completed as part of requirements for an undergraduate integrated perspectives course at Bucknell University, “UNIV 200-13: Rural Climate Resilience” taught by Shaunna Barnhart and Taylor Lightman. The entry includes the final report as well as supplementary materials including a powerpoint presentation and a two page summary edited by Matt McMullen and Shaunna Barnhart

Overview of neuropathy associated with taxanes for the treatment of metastatic breast cancer

Taxanes are an established option in the standard treatment paradigm for patients with metastatic breast cancer (MBC). Neuropathy is a common, dose-limiting side effect of taxane therapy that is often managed by dose reductions and delays. The severity, time to onset, and improvement in neuropathy are important considerations for patient management and vary among currently approved taxanes. The rate of grade ≥3 neuropathy with taxanes has been shown to be dose and schedule dependent; however, time to improvement to grade ≤1 is typically shorter for nab-paclitaxel than for other taxanes in patients with MBC. Many tools for assessing patient-reported neuropathy exist. Because MBC is incurable and patient quality of life must be critically considered when making treatment decisions, there is a need for more prospective trials to assess patient-reported neuropathy. Validated predictors of taxane-related neuropathy may play an important role in treatment decisions in the future. This review will focus on the toxicity profile (i.e., neuropathy) of each of the taxanes used in the treatment of MBC, will provide updates on tools used for the assessment of neuropathy, and will highlight newly discovered predictors of taxane-related neuropathy

Integrins as therapeutic targets: lessons and opportunities.

The integrins are a large family of cell adhesion molecules that are essential for the regulation of cell growth and function. The identification of key roles for integrins in a diverse range of diseases, including cancer, infection, thrombosis and autoimmune disorders, has revealed their substantial potential as therapeutic targets. However, so far, pharmacological inhibitors for only three integrins have received marketing approval. This article discusses the structure and function of integrins, their roles in disease and the chequered history of the approved integrin antagonists. Recent advances in the understanding of integrin function, ligand interaction and signalling pathways suggest novel strategies for inhibiting integrin function that could help harness their full potential as therapeutic targets

Use of HER2-Directed Therapy in Metastatic Breast Cancer and How Community Physicians Collaborate to Improve Care.

The development of new HER2-directed therapies has resulted in a significant prolongation of survival for women with metastatic HER2-positive breast cancer. Discoveries in the laboratory inform clinical trials which are the basis for improving the standard of care and are also the backbone for quality improvement. Clinical trials can be completed more rapidly by expanding trial enrollment to community sites. In this article we review some of the challenges in treating metastatic breast cancer with HER2-directed therapies and our strategies for incorporating our community partners into the research network

The opinions and feelings about their educational needs and role of familial caregivers of parkinson’s disease patients: A qualitative study

Background and aim of the work. In the advanced stages of Parkinson’s Disease, patients need com-plex care and support, especially at home, where they often receive assistance by familial caregivers. However, caregivers may be or feel unable to cope with their role and, despite the needs of caregivers are often assessed in the literature, their opinions and feelings about these needs are not widely explored yet. This study aimed at exploring the opinions and feelings about their educational needs and role of familial caregivers of Parkinson’s Disease patients. Methods. A qualitative study was conducted from October to December 2017 in a polyclinic of central Italy. Fourteen caregivers voluntarily participated in the study; semi-structured face-to-face interviews were conducted, and audio recorded until data saturation. Two investigators reviewed the transcribed notes, created Meaning Units, Sub-categories and finally the Categories with emerged themes. Results. The analysis of the 14 interviews generated three categories: supportiveness of healthcare educational programs; sense of inability to manage caregiver tasks; need for interaction with other familial caregivers. Conclusions. The caregivers declared their belief that healthcare educational courses can be useful in helping them live and understand the caregiving tasks and expressed their need to share their experiences with other caregivers. In fact, they often they felt abandoned and poorly trained for the patient’s management at the home. The clinical practice should allow healthcare professionals to meet the training and emotional needs of caregivers and create a trust relationship with them to make caregivers skilled in caring for patients. (www.actabiomedica.it)