Background: Conventional chemotherapeutics target bulk tumour cells and generally leave cancer stem cell (CSC) populations unaffected. Recent literature characterized the presence and the role of CSC in several types of solid tumors, including colorectal cancer. Colorectal CSCs (CCSCs) display enhanced WNT/β-catenin pathway activity, sustaining self-renewal and tumor-initiating capacity. Thus, CCSCs are crucial for tumour recurrence and metastasis. As one of the main contributors to sustained self-renewal activity in CCSCs, enhanced formation of β-catenin/CBP complex is fostering transactivation of canonical WNT target genes such as c-myc. However, maintenance of healthy intestinal stem cells also dependents on the canonical WNT pathway. Thus, selective targeting CCSCs while sparring normal intestinal cells is still a significant challenge. Interestingly, Sam68 is a key mediator of the interaction between β-catenin and CBP. It has been reported as a “druggable” target to selectively disrupt β-catenin/CBP in CSCs. Indeed, CWP232228 successfully targets CSCs in AML by facilitating Sam68/CBP complex formation, and consequently lowering the abundance of β-catenin/CBP complexes. CWP232228 was clinically tested on multiple human cancers. Unfortunately, such clinical trials were halted due to unknown causes, and limited information was released on clinical safety and benefits. Consequently, developing more potent pharmacological modulators of Sam68/CBP complex formation is still highly relevant to eradicate CCSCs. Here we describe the discovery and characterization of a new CWP analog, known as YB-0158, which displays enhanced potency and neoplastic selectivity against CCSC. Methods and Results: Following the confirmation that ICG/CWP class of compounds bind to Sam68 in CSCs, I used in silico docking methods to screen for CWP analogs having high predicted affinity for Sam68 Cterminal proline-rich domain. Using high content imaging techniques, I confirmed our top candidate (YB-0158) as more potent vs. CWP parent molecule to compromise cell growth, to induce loss of pluripotency, and to increase Sam68 nuclear localization in a surrogate model of human CSCs. YB-0158 also displayed enhanced selective toxicity in colorectal cancer models vs. normal intestinal epithelium progenitor cells. Moreover, I confirmed that YB-0158 exert negative impact on cancer cell growth by inducing apoptosis and reducing proliferation. Lentiviral-based knockdowns explicitly displayed decrease in drug effectivity in the absence of Sam68, reinforcing the essential role of Sam68 mediating ICG-001/CWP response in CSCs. I demonstrated that Sam68 expression is enriched in tumor-initiating cell fractions derived from primary colorectal tumor tissues vs. bulk heterogeneous tumor organoids. Therefore, YB-0158 showed striking efficacy at supressing tumor-initiation activity in a patient-based serial organoid formation assay. Finally, YB-0158 eradicated CSCs activity in vivo as demonstrated by a syngeneic mouse-to-mouse serial transplantation assay. Conclusion: Overall, YB-0158 is a novel analog of CWP232228 with superior potency to target CCSCs activity through facilitation of Sam68 nuclear localization, thus reducing the interaction frequency between CBP and β-catenin.

The purposes of this study were to compile demographic characteristics, educational backgrounds, coaching experiences, and duties of strength and conditioning (STC) coaches at NCAA Division II and III institutions, and compare the profile of Division II and III STC coaches to the Martinez (2004) study of Division I-A STC coaches. NCAA Division II and Division III athletic personnel (N=578) received an electronic survey for this study. The return rate from Division II and Division III STC coaches were as follows: Division II, 23 responses (n=175), Division III, 34 responses (n=403). Descriptive statistics were used to examine each item. STC coaches at NCAA Division II and III institutions are white, male, approximately 35 and 34 years of age respectively, earn an annual salary of $30,001-$40,000, hold the CSCS certification, and received a Master's degree. The results indicated differences between this study and Martinez's (2004) study of NCAA Division I-A STC coaches.

The purpose of this study was to assess and determine the current level of knowledge that National Collegiate Athletic Association (NCAA) Strength and Conditioning Coaches (SCCs) possess regarding exertional heat stroke (EHS) prevention and recognition and to determine if SCC certification type had any effect. Major findings of this study support the view that SCCs need more preparation, education and training to increase their competency in preventing and recognizing EHS. Research found that there was no significant difference in scores on the EHS scale based on SCC certification (CSCS vs. SCCC) after accounting for experience, education or division but the CSCS certified professionals scored higher on all the factors as compared to SCCs without the CSCS.. The major key finding was that SCCs lacked essential knowledge to prevent or recognize EHS. Furthermore, the study defines relevant EHS prevention and recognition competencies that an undergraduate curriculum, graduate curriculum and professional certification providers, should include and emphasize in their preparation programs.

Yes / Many developing countries across the world are allocating a significant share of their budgets for e-government initiatives. Common service centers (CSCs) are e-government initiatives that aim to increase access to public services and promote easy and direct interaction with the government. These e-government initiatives are largely underutilised, especially in rural areas in developing countries. This study attempts to identify the key challenges facing CSCs and determine their hierarchical relationships in the context of rural India. A set of 15 challenges was identified through a rigorous literature review and by surveying experts and CSC owners. Data were collected on the identified challenges and were analysed using interpretive structural modeling (ISM)-MICMAC-fuzzy MICMAC analysis. Subsequently, we developed a hierarchical model of challenges. The findings revealed that “longer travel time and transaction cost”, “low digital literacy”, and “low awareness” of e-government services are among the key challenges CSCs face in rural India. This study suggests several recommendations to all the stakeholders involved in the management of CSCs to improve the delivery of e-government services in rural India.