Quantitative Biophysical Metrics for Rapid Evaluation of Ovarian Cancer Metastatic Potential

Ovarian cancer is routinely diagnosed long after the disease has metastasized through the fibrous sub-mesothelium. Despite extensive research in the field linking ovarian cancer progression to increasingly poor prognosis, there are currently no validated cellular markers or hallmarks of ovarian cancer that can predict metastatic potential. To discern disease progression across a syngeneic mouse ovarian cancer progression model, here, we fabricated extracellular-matrix mimicking suspended fiber networks: crosshatches of mismatch diameters for studying protrusion dynamics, aligned same diameter networks of varying inter-fiber spacing for studying migration, and aligned nanonets for measuring cell forces. We found that migration correlated with disease, while force-disease biphasic relationship exhibited f-actin stress-fiber network dependence. However, unique to suspended fibers, coiling occurring at tips of protrusions and not the length or breadth of protrusions displayed strongest correlation with metastatic potential. To confirm that our findings were more broadly applicable beyond the mouse model, we repeated our studies in human ovarian cancer cell lines and found that the biophysical trends were consistent with our mouse model results. Altogether, we report complementary high throughput and high content biophysical metrics capable of identifying ovarian cancer metastatic potential on time scale of hours. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer

Small cell lung cancer (SCLC) has a 5-year survival rate of <7%. Rapid emergence of acquired resistance to standard platinum-etoposide chemotherapy is common and improved therapies are required for this recalcitrant tumour. We exploit six paired pre-treatment and post-chemotherapy circulating tumour cell patient-derived explant (CDX) models from donors with extensive stage SCLC to investigate changes at disease progression after chemotherapy. Soluble guanylate cyclase (sGC) is recurrently upregulated in post-chemotherapy progression CDX models, which correlates with acquired chemoresistance. Expression and activation of sGC is regulated by Notch and nitric oxide (NO) signalling with downstream activation of protein kinase G. Genetic targeting of sGC or pharmacological inhibition of NO synthase re-sensitizes a chemoresistant CDX progression model in vivo, revealing this pathway as a mediator of chemoresistance and potential vulnerability of relapsed SCLC.

Exploring The Power Clean

The power clean and its variations are prescribed by strength and conditioning coaches as part of the ‘big three’ to develop “total body strength”. This article explores the application of the power clean and its variations to athletic performance and introduces strength and conditioning coaches to teaching progressions, with specific emphasis on developing the correct body positioning required for the power clean. Teaching components are addressed with special reference to taller athletes. It is recommended that strength and conditioning coaches teach the hang clean follow a progression model to decrease movement complexity when advancing athletes to the power clean.

3-D vascularized breast cancer model to study the role of osteoblast in formation of a pre-metastatic niche

Breast cancer cells (BCCs) preferentially metastasize to bone. It is known that BCCs remotely primes the distant bone site prior to metastasis. However, the reciprocal influence of bone cells on the primary tumor is relatively overlooked. Here, to study the bone-tumor paracrine influence, a tri-cellular 3-D vascularized breast cancer tissue (VBCTs) model is engineered which comprised MDA-MB231, a triple-negative breast cancer cells (TNBC), fibroblasts, and endothelial cells. This is indirectly co-cultured with osteoblasts (OBs), thereby constituting a complex quad-cellular tumor progression model. VBCTs alone and in conjunction with OBs led to abnormal vasculature and reduced vessel density but enhanced VEGF production. A total of 1476 significantly upregulated and 775 downregulated genes are identified in the VBCTs exposed to OBs. HSP90N, CYCS, RPS27A, and EGFR are recognized as upregulated hub-genes. Kaplan Meier plot shows HSP90N to have a significant outcome in TNBC patient survivability. Furthermore, compared to cancer tissues without vessels, gene analysis recognized 1278 significantly upregulated and 566 downregulated genes in VBCTs. DKK1, CXCL13, C3 protein and BMP4 are identified to be downregulated hub genes in VBCTs. Together, a multi-cellular breast cancer model and culture protocols are established to study pre-metastatic events in the presence of OBs.

Blood–Brain Barrier Disruption Is Not Associated With Disease Aggressiveness in Amyotrophic Lateral Sclerosis

The pathogenesis of the fatal neurodegenerative condition amyotrophic lateral sclerosis (ALS) remains to be fully understood. Blood–brain barrier damage (BBBD) has been implicated as an exacerbating factor in several neurodegenerative conditions, including ALS. Therefore, this cross-sectional study used the novel D50 progression model to assess the clinical relevance of BBBD within a cohort of individuals with either ALS (n = 160) or ALS mimicking conditions (n = 31). Routine laboratory parameters in cerebrospinal fluid (CSF) and blood were measured, and the ratio of CSF to serum albumin levels (Qalb) was used as a proxy measure of BBBD. In the univariate analyses, Qalb levels correlated weakly with disease aggressiveness (as indicated by individual D50 values) and physical function (as measured by ALS Functional Rating Scale). However, after adjustment for cofactors in the elastic net regularization, only having limb-onset disease was associated with BBBD. The results reported here emphasize the clinical heterogeneity of ALS and the need for additional longitudinal and multi-modal studies to fully clarify the extent and effect of BBBD in ALS.

The New Progression Model of Entrepreneurial Education—Guideline for the Development of an Entrepreneurial University with a Sustainability Approach

Entrepreneurship is becoming understood as a set of competencies needed for many professions and, as a result, requires to be integrated into higher education even in such seemingly distant areas as, e.g., public administration, sport, agriculture, tourism, etc. Therefore, there is a need for research-based guidance on how to introduce and develop entrepreneurial education as an enabling approach to the transition in higher education that could serve as an integral part of a paradigm shift towards an entrepreneurial university. This paper aims to support that transition and to address related challenges by the presentation of a new progression model, which provides guidelines for the development of courses at the tertiary level with an entrepreneurial university approach. The construction of the new applicable model is central to the purpose of this study and based on a systematized literature review. Additionally, the input–process–output–outcome framework, originally constructed for the evaluation of educational programs, was adapted to the incorporation of an overall framework into the new model. In the results, the paper redefines some of the relevant core terms, such as “entrepreneurial education” and its “progression model”. The research outcomes offer broad practical and theoretical applicability to a range of stakeholders—educators, students/learners, industry/business, policy makers, and researchers.