Precision oncology for patients with advanced cancer: the challenges of malignant snowflakes.

Precision oncology implies customizing treatment to the unique molecular and biologic characteristics of each individual and their cancer. Its implementation is being facilitated by remarkable technological advances in genomic sequencing, as well as the increasing availability of targeted and immunotherapeutic drugs. Yet, next generation sequencing may be a disruptive technology in that its results suggest that classic paradigms for clinical research and practice are a poor fit with the complex reality encountered in metastatic malignancies. Indeed, it is evident that advanced tumors have heterogeneous molecular landscapes that mostly differ between patients. Traditional modes of clinical research/practice are drug centered, with a strategy of finding commonalities between patients so that they can be grouped together and treated similarly. However, if each patient with metastatic cancer has a unique molecular portfolio, a new patient-centered, N-of-one approach that utilizes individually tailored treatment is needed

Application of the Interactional Model of Cultural Diversity to Identify Diversity Climate Factors Associated with Organizational Effectiveness in Accredited U.S. Physical Therapist Education Programs

Accredited U.S. physical therapist education programs are responsible for the preparation of its graduates to provide culturally sensitive care to meet the physical therapy needs of an increasingly diverse population. While the importance of workforce diversity has been articulated, the effect of diversity climate on organizational effectiveness within accredited U.S. physical therapist education programs has not been described. The purpose of this study was to evaluate the effectiveness of the Interactional Model of Cultural Diversity (IMCD, Cox, 1993) as a theoretical framework to identify diversity climate factors associated with organizational effectiveness in accredited U.S. physical therapist education programs. A descriptive, cross-sectional design was used to examine two constructs of the theoretical framework. A total of 151 programs (RR=83.9%) participated in the study. Key informants were academic coordinators/directors of clinical education (N=151). Cronbach\u27s alpha coefficients were .82 for the IAPCC-R (Campinha-Bacote, 2002) and .78 for the perception of diversity climate survey adapted from The Ethnicity Subscale of The Diversity Survey (Brinkman et al, 1992). Some diversity climate factors were associated with organizational effectiveness in accredited U.S. physical therapist education programs in this analysis. Identity structures significantly predicted graduation rate, number of graduates, number of minority graduates and percent minority graduates. Culture and acculturation process significantly predicted licensure rate. Structural integration significantly predicted graduation rate, number of minority graduates and percent minority graduates. Institutional bias in human resource systems significantly predicted number of minority graduates and percent minority graduates. Favorable perceptions of diversity climate were associated with a higher number of minority graduates and higher percent minority graduates. The current diversity climate in accredited U.S. physical therapist education programs is sub-optimal. Unfavorable perceptions of diversity climate were identified in all institutional bias in human resource systems subscales. Future policy directions should explore evidence-based strategies and the effectiveness of studies related to diversity climate to foster the profession\u27s contributions to eliminating health disparities and improving workforce diversity

An Inventory and Assessment of Data Requirements for the development of a Coes Pond Watershed Management Plan

Once a site of great public appeal, Coes Pond in Worcester, Massachusetts has become a forgotten glory. In 2014, the Coes Zone Task Force began planning, and working, to revitalize the pond. Utilizing local and state resources, we built and analyzed an inventory of physical documents from shareholders, and data layers from MassGIS archives, focusing on what data are available, and what remain to be collected, in order to support the task force. The results from this project can be used to assist the Coes Zone Task Force, and other organizations and individuals, in their goal to revitalize Coes Pond, and its encompassing watershed

Multi-Use Academic, Athletic, and Parking Structure, Considering Vibration Performance

Using vibrations as the primary design consideration, this project produced three designs of varying vibration performance for a 170,000 square foot, multi-use structure with rooftop athletic fields on the WPI campus. All three designs adhere to AISC, ASCE, ACI, LEED, NIBS, and NFPA specifications and the Massachusetts State Building Code. A cost analysis using RSMeans was performed to select the design that best optimized performance and economy. Final design details include: structural framing and foundation plans; geometrics for two levels of parking; architectural, egress, lighting, and HVAC considerations for a multipurpose academic, athletic, and recreational space; and site grading and drainage plans

Targeting autophagy: a novel anticancer strategy with therapeutic implications for imatinib resistance

Autophagy is an ancient, intracellular degradative system which plays important roles in regulating protein homeostasis and which is essential for survival when cells are faced with metabolic stress. Increasing evidence suggests that autophagy also functions as a tumor suppressor mechanism that harnesses the growth and/or survival of cells as they transition towards a rapidly dividing malignant state. However, the impact of autophagy on cancer progression and on the efficacy of cancer therapeutics is controversial. In particular, although the induction of autophagy has been reported after treatment with a number of therapeutic agents, including imatinib, this response has variously been suggested to either impair or contribute to the effects of anticancer agents. More recent studies support the notion that autophagy compromises the efficacy of anticancer agents, where agents such as chloroquine (CQ) that impair autophagy augment the anticancer activity of histone deacetylase (HDAC) inhibitors and alkylating agents. Inhibition of autophagy is a particularly attractive strategy for the treatment of imatinib-refractory chronic myelogenous leukemia (CML) since a combination of CQ with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) compromises the survival of even BCR-ABL-T315I+ imatinib-resistant CML. Additional studies are clearly needed to establish the clinical utility of autophagy inhibitors and to identify patients most likely to benefit from this novel therapeutic approach

Repurposing metformin for cancer treatment: current clinical studies.

In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment

Evolving Therapeutic Strategies for the Classic Philadelphia-Negative Myeloproliferative Neoplasms

AbstractDespite the emergence of JAK inhibitors, there is a need for disease-modifying treatments for Philadelphia-negative myeloproliferative neoplasms (MPNs). JAK inhibitors ameliorate symptoms and address splenomegaly, but because of the heterogeneous contributors to the disease process, JAK inhibitor monotherapy incompletely addresses the burden of disease. The ever-growing understanding of MPN pathogenesis has provided the rationale for testing novel and targeted therapeutic agents, as monotherapies or in combination, in preclinical and clinical settings. A number of intriguing options have emerged, and it is hoped that further progress will lead to significant changes in the natural history of MPNs

Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma.

Mutations in DNA repair genes lead to increased genomic instability and mutation frequency. These mutations represent potential biomarkers for cancer immunotherapy efficacy, as high tumor mutational burden has been associated with increased neo-antigens and tumor infiltrating lymphocytes. While mismatch repair mutations have successfully predicted response to anti-PD-1 therapy in colorectal and other cancers, they have not yet been tested for lung cancer, and few have investigated genes from other DNA repair pathways. We utilized TCGA samples to comprehensively immunophenotype lung tumors and analyze the links between DNA repair mutations, neo-antigen and total mutational burden, and tumor immune infiltration. Overall, 73% of lung tumors contained infiltration by at least one T cell subset, with high mutational burden tumors containing significantly increased infiltration by activated CD4 and CD8 T cells. Further, mutations in mismatch repair genes, homologous recombination genes, or POLE accurately predicted increased tumor mutational burden, neo-antigen load, and T cell infiltration. Finally, neo-antigen load correlated with expression of M1-polarized macrophage genes, PD-1, PD-L1, IFNγ, GZMB, and FASLG, among other immune-related genes. Overall, after defining the immune infiltrate in lung tumors, we demonstrate the potential value of utilizing gene mutations from multiple DNA repair pathways as biomarkers for lung cancer immunotherapy. Oncotarget 2018; 9(8):7949-796