A Survey of the Barriers Associated with Academic-based Cancer Research Commercialization

Commercialization within the academic setting is associated with many challenges and barriers. Previous studies investigating these challenges/barriers have, in general, broadly focused on multiple disciplines and, oftentimes, several institutions simultaneously. The goal of the study presented here was to analyze a range of barriers that may be broadly associated with commercializing academic-based cancer research. This goal was addressed via a study of the barriers associated with cancer research commercialization at the University of Kentucky (UK). To this end, a research instrument in the form of an electronic survey was developed. General demographic information was collected on study participants and two research questions were addressed: 1) What are the general barriers inhibiting cancer research commercialization at UK? and 2) Would mitigation of the barriers potentially enhance faculty engagement in commercialization activities? Descriptive and statistical analysis of the data reveal that multiple barriers likely inhibit cancer research commercialization at UK with expense, time, infrastructure, and lack of industry partnerships being among the most commonly cited factors. The potential alleviation of these factors in addition to revised University policies/procedures, risk mitigation, more emphasis on commercialization by academia research field, and increased information on how to commercialize significantly correlated with the potential for increased commercialization activity. Furthermore, multivariate logistic regression modeling demonstrated that research commercialization would incrementally increase as barriers to the process are removed and that PhD-holding respondents and respondents in commercialization-supportive research fields would be more likely to commercialize their research upon barrier removal. Overall, as with other disciplines, these data suggest that for innovations derived from academic cancer-research to move more effectively and efficiently into the marketplace, university administrators and external agents, such as policymakers, need to address what are well-documented and defined issues

The Impact of General Strike on Government Healthcare Delivery in Kerala State in India

General strike (also known as hartal) is used as a mode of protest by organizations and political parties in India. It is generally thought that hartals negatively impact the healthcare delivery in a society. We used the Right to Information Act to obtain data from government health centers in Kerala state in India for four hartal days (H-day) and two control days (A-day and B-day) for each H-day, from sixteen health centers including 6 Community Health Center (CHC), 6 Secondary Health Center (SHC), and 4 Tertiary Health Center (THC). Data on emergency room visits was available for six HCs. 15 HCs had a statistically significant decrease in the number of outpatient visits on H-day. There was no difference in the number of outpatient visits between the two control days (A and B) in 15 HCs, suggesting the lack of a posthartal surge in visits. Median decrease in outpatient visits in CHCs, SHCs, and THCs was 50.4%, 59.5%, and 47.4%, respectively. Hartal did not impact the number of emergency room visits in 6 out of 7 health centers assessed. Our study identified a significant harmful impact on government healthcare delivery due to hartals in Kerala. These findings have major public health implications

Diverse Expression Patterns and Tumorigenic Role of Neurotensin Signaling Components in Colorectal Cancer Cells

Colorectal cancer (CRC), which is one of the most common malignancies worldwide, results from an accumulation of genetic and epigenetic modifications including DNA methylation. Neurotensin (NTS), a hormone localized to the gut and central nervous system, mediates its physiological and pathological effects, including growth stimulation for a variety of cancers, through three distinct NTS receptors (NTSRs). Most NTS functions are mediated through the high-affinity receptor NTSR1, and expression of NTSR1 is increased in many cancers including CRC. In this study, we investigated the expression profiles and cellular functions of the NTSRs, especially NTSR1, in CRC cells. We showed that expression levels for NTS and NTSR1 varied, that NTSR2 expression was not detectable and that NTSR3 was consistently expressed in all CRC cell lines examined. Treatment with the demethylating agent, 5-aza-2\u27-deoxycytidine, augmented levels of NTSR1/2 in Caco2 and DLD1 cells, which have little or no transcripts for NTSR1/2 suggesting that DNA methylation suppresses NTSR1/2 expression. In addition, we demonstrated that knockdown of NTSR1 decreased cell growth and migration in HCT116 and HT29 cells. Finally, we showed that treatment with SR48692, an antagonist of NTSR1, also inhibited cell proliferation and migration in the CRC cells. Our findings identify promoter methylation as an important process regulating the differential expression or silencing of NTSR1/2 in CRC cells. Moreover, inhibition of NTSR1 repressed tumorigenic effects in CRC cells, suggesting that NTSR1 may be used as a therapeutic target for CRC

Nuclear Factor of Activated T-Cells 5 Increases Intestinal Goblet Cell Differentiation Through an mTOR/Notch Signaling Pathway

The intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis that is regulated by multiple signaling pathways. Previously, we have shown that the nuclear factor of activated T-cells 5 (NFAT5) is involved in the regulation of intestinal enterocyte differentiation. Here we show that treatment with sodium chloride (NaCl), which activates NFAT5 signaling, increased mTORC1 repressor regulated in development and DNA damage response 1 (REDD1) protein expression and inhibited mTOR signaling; these alterations were attenuated by knockdown of NFAT5. Knockdown of NFAT5 activated mammalian target of rapamycin (mTOR) signaling and significantly inhibited REDD1 mRNA expression and protein expression. Consistently, overexpression of NFAT5 increased REDD1 expression. In addition, knockdown of REDD1 activated mTOR and Notch signaling, whereas treatment with mTOR inhibitor rapamycin repressed Notch signaling and increased the expression of the goblet cell differentiation marker mucin 2 (MUC2). Moreover, knockdown of NFAT5 activated Notch signaling and decreased MUC2 expression, while overexpression of NFAT5 inhibited Notch signaling and increased MUC2 expression. Our results demonstrate a role for NFAT5 in the regulation of mTOR signaling in intestinal cells. Importantly, these data suggest that NFAT5 participates in the regulation of intestinal homeostasis via the suppression of mTORC1/Notch signaling pathway

TSC2/mTORC1 Signaling Controls Paneth and Goblet Cell Differentiation in the Intestinal Epithelium

The intestinal mucosa undergoes a continual process of proliferation, differentiation and apoptosis, which is regulated by multiple signaling pathways. Notch signaling is critical for the control of intestinal stem cell maintenance and differentiation. However, the precise mechanisms involved in the regulation of differentiation are not fully understood. Previously, we have shown that tuberous sclerosis 2 (TSC2) positively regulates the expression of the goblet cell differentiation marker, MUC2, in intestinal cells. Using transgenic mice constitutively expressing a dominant negative TSC2 allele, we observed that TSC2 inactivation increased mTORC1 and Notch activities, and altered differentiation throughout the intestinal epithelium, with a marked decrease in the goblet and Paneth cell lineages. Conversely, treatment of mice with either Notch inhibitor dibenzazepine (DBZ) or mTORC1 inhibitor rapamycin significantly attenuated the reduction of goblet and Paneth cells. Accordingly, knockdown of TSC2 activated, whereas knockdown of mTOR or treatment with rapamycin decreased, the activity of Notch signaling in the intestinal cell line LS174T. Importantly, our findings demonstrate that TSC2/mTORC1 signaling contributes to the maintenance of intestinal epithelium homeostasis by regulating Notch activity

NFAT5 represses canonical Wnt signaling via inhibition of \u3cem\u3eβ\u3c/em\u3e-catenin acetylation and participates in regulating intestinal cell differentiation

The intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis, which is regulated by multiple signaling pathways. The Wnt/β-catenin pathway has a critical role in this process. Previously, we have shown that the calcineurin-dependent nuclear factor of activated T cell (NFAT) is involved in the regulation of intestinal cell differentiation, as noted by the alteration of brush-border enzyme intestinal alkaline phosphatase (IAP) activity. Here, we show that calcineurin-independent NFAT5 interacts with β-catenin to repress Wnt signaling. We found that overexpression of NFAT5 inhibits, whereas knockdown of NFAT5 increases, TOPflash reporter activity and the expression of Wnt/β-catenin target genes, suggesting that NFAT5 inhibits Wnt signaling. In addition, we demonstrated that NFAT5 directly interacts with the C-terminal transactivation domain (TAD) of β-catenin, inhibits CBP interaction with β-catenin, and inhibits CBP-mediated β-catenin acetylation. Moreover, NFAT5 is expressed in the mucosa of human intestine, with the most pronounced staining in the most differentiated region near the epithelial surface. Knockdown of NFAT5 attenuated sodium butyrate (NaBT)-mediated induction of IAP and sucrase activities; overexpression of NFAT5 induced IAP promoter activity. In summary, we provide evidence showing that NFAT5 is a regulator of Wnt signaling. Importantly, our results suggest that NFAT5 regulation of intestinal cell differentiation may be through inhibition of Wnt/β-catenin signaling

Neurotensin Receptor 3/Sortilin Contributes to Tumorigenesis of Neuroendocrine Tumors Through Augmentation of Cell Adhesion and Migration

Neurotensin (NTS), a 13–amino acid peptide which is distributed predominantly along gastrointestinal tract, has multiple physiologic and pathologic functions, and its effects are mediated by three distinct NTS receptors (NTSRs). Overexpression and activation of NTS signaling components, especially NTS and/or NTSR1, are closely linked with cancer progression and metastasis in various types of cancers including neuroendocrine tumors (NETs). Although deregulation of NTSR3/sortilin has been implicated in a variety of human diseases, the expression and role of NTSR3/sortilin in NETs have not been elucidated. In this study, we investigated the expression and oncogenic effect of NTSR3/sortilin in NETs. Increased protein levels of NTSR3/sortilin were noted in the majority of human clinical NETs (n = 21) by immunohistochemical analyses compared with normal tissues (n = 12). Expression of NTS and NTSR3/sortilin was also noted in all tested NET cell lines. In addition, small interfering RNA–mediated knockdown of NTSR3/sortilin decreased cell number without alteration of cell cycle progression and apoptosis induction in NET cell lines BON and QGP-1. Moreover, silencing of NTSR3/sortilin significantly suppressed cell adhesion and cell migration with inhibition of focal adhesion kinase and Src phosphorylation in the NET cells. Our results demonstrate increased expression of NTSR3/sortilin in NET patient tissues and a critical role of NTSR3/sortilin on NET cell adhesion and migration suggesting that NTSR3/sortilin contributes to NET tumorigenesis

Role of AMPK and Akt in Triple Negative Breast Cancer Lung Colonization

Triple negative breast cancer (TNBC) is an aggressive disease with a 5-y relative survival rate of 11% after distant metastasis. To survive the metastatic cascade, tumor cells remodel their signaling pathways by regulating energy production and upregulating survival pathways. AMP-activated protein kinase (AMPK) and Akt regulate energy homeostasis and survival, however, the individual or synergistic role of AMPK and Akt isoforms during lung colonization by TNBC cells is unknown. The purpose of this study was to establish whether targeting Akt, AMPKα or both Akt and AMPKα isoforms in circulating cancer cells can suppress TNBC lung colonization. Transient silencing of Akt1 or Akt2 dramatically decreased metastatic colonization of lungs by inducing apoptosis or inhibiting invasion, respectively. Importantly, transient pharmacologic inhibition of Akt activity with MK-2206 or AZD5363 inhibitors did not prevent colonization of lung tissue by TNBC cells. Knockdown of AMPKα1, AMPKα2, or AMPKα1/2 also had no effect on metastatic colonization of lungs. Taken together, these findings demonstrate that transient decrease in AMPK isoforms expression alone or in combination with Akt1 in circulating tumor cells does not synergistically reduce TNBC metastatic lung colonization. Our results also provide evidence that Akt1 and Akt2 expression serve as a bottleneck that can challenge colonization of lungs by TNBC cells

Upregulation of CPT1A Is Essential for the Tumor-Promoting Effect of Adipocytes in Colon Cancer

Colon tumors grow in an adipose tissue-enriched microenvironment. Locally advanced colon cancers often invade into surrounding adipose tissue with a direct contact with adipocytes. We have previously shown that adipocytes promote tumor growth by modulating cellular metabolism. Here we demonstrate that carnitine palmitoyltransferase I (CPT1A), a key enzyme controlling fatty acid oxidation (FAO), was upregulated in colon cancer cells upon exposure to adipocytes or fatty acids. In addition, CPT1A expression was increased in invasive tumor cells within the adipose tissue compared to tumors without direct contact with adipocytes. Silencing CPT1A abolished the protective effect provided by fatty acids against nutrient deprivation and reduced tumor organoid formation in 3D culture and the expression of genes associated with cancer stem cells downstream of Wnt/β-catenin. Mechanistically, CPT1A-dependent FAO promoted the acetylation and nuclear translocation of β-catenin. Furthermore, knockdown of CPT1A blocked the tumor-promoting effect of adipocytes in vivo and inhibited xenograft tumor initiation. Taken together, our findings identify CPT1A-depedent FAO as an essential metabolic pathway that enables the interaction between adipocytes and colon cancer cells

Induction of AMPK Activation by \u3cem\u3eN,N\u27\u3c/em\u3e-Diarylurea FND-4b Decreases Growth and Increases Apoptosis in Triple Negative and Estrogen-Receptor Positive Breast Cancers

Purpose Triple negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer. AMP-activated protein kinase (AMPK) is a major energy regulator that suppresses tumor growth, and 1-(3-chloro-4-((trifluoromethyl)thio)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea (FND-4b) is a novel AMPK activator that inhibits growth and induces apoptosis in colon cancer. The purpose of this project was to test the effects of FND-4b on AMPK activation, proliferation, and apoptosis in breast cancer with a particular emphasis on TNBC. Materials and methods (i) Estrogen-receptor positive breast cancer (ER+BC; MCF-7, and T-47D), TNBC (MDA-MB-231 and HCC-1806), and breast cancer stem cells were treated with FND-4b for 24h. Immunoblot analysis assessed AMPK, acetyl-CoA carboxylase (ACC), ribosomal protein S6, cyclin D1, and cleaved PARP. (ii) Sulforhodamine B growth assays were performed after treating ER+BC and TNBC cells with FND-4b for 72h. Proliferation was also assessed by counting cells after 72h of FND-4b treatment. (iii) Cell death ELISA assays were performed after treating ER+BC and TNBC cells with FND-4b for 72h. Results (i) FND-4b increased AMPK activation with concomitant decreases in ACC activity, phosphorylated S6, and cyclin D1 in all subtypes. (ii) FND-4b decreased proliferation in all cells, while dose-dependent growth decreases were found in ER+BC and TNBC. (iii) Increases in apoptosis were observed in ER+BC and the MDA-MB-231 cell line with FND-4b treatment. Conclusions Our findings indicate that FND-4b decreases proliferation for a variety of breast cancers by activating AMPK and has notable effects on TNBC. The growth reductions were mediated through decreases in fatty acid synthesis (ACC), mTOR signaling (S6), and cell cycle flux (cyclin D1). ER+BC cells were more susceptible to FND-4b-induced apoptosis, but MDA-MB-231 cells still underwent apoptosis with higher dose treatment. Further development of FND compounds could result in a novel therapeutic for TNBC