THE HDAC INHIBITOR ITF2357 (GIVINOSTAT) AS A KEY PLAYER IN EPIGENETIC TARGETING OF MELANOMA AND COLON CANCER CELLS

Histone deacetylase inhibitors (HDACIs) are epigenetic compounds that have been recently considered for their promising anti-tumor activity. The aim of this PhD thesis was to elucidate and characterize the anti-tumor effect of the HDAC inhibitor ITF2357 (Givinostat) in melanoma and colon cancer cells that are characterized by oncogenic BRAF mutations. Interestingly, data reported in this thesis demonstrate that ITF2357 exerts a remarkable anti-tumor effect in melanoma cells by inducing a switch from a pro-survival autophagy to caspase-dependent apoptosis. The thesis provides the first evidences that ITF2357 is able to target oncogenic BRAF and oncogenic p53. The ITF2357 decreasing effect on BRAF was due to both reduced expression and increased proteolysis, while the effect on p53 was mainly due to proteasome-mediated degradation. Moreover, the thesis demonstrates for the first time an interplay between oncogenic BRAF and oncogenic p53 in melanoma cells, which is reduced by ITF2357, thus supporting a possible use of this compound in melanoma targeted therapy. The anti-tumor effect of ITF2357 was also evaluated in colon cancer cells. In these models, the HDAC inhibitor was combined with other epigenetic drugs, including DNA methyltransferase (DNMT) inhibitors. The results indicated that ITF2357 potentiates the effects of both general and selective DNMT inhibitors in HCT116 cells. Furthermore, the compound was able to increase the immunogenic response induced by these other epi-drugs. Taken together, the results shown in this thesis pave the way for a possible use of ITF2357 for anti-tumor targeted therapy, either alone or in combination with other epigenetic compounds

Texas Education & Social Entrepreneurship: Falling Short of Impact

The United States has a significant issue with education equity– an issue that is especially pronounced in the state of Texas. With the racial wealth gap widening each year– and with it, the opportunity gap– the question remains as to how advocacy groups, policy changes, and social enterprises are addressing the growing racial and socioeconomic inequity. Although various studies seek to analyze the influence of policy and advocacy on education inequality exist, little research deep dives into the role that social enterprises play in closing the opportunity gap. This thesis 1) addresses the inequity issues that Texas specifically faces, 2) provide an overarching perspective on social entrepreneurship and the role of social enterprise, and 3) present three case studies on various types of social enterprises in Texas, each of which include a logic model and theory of change analysis to gauge the long-term, systemic impact each enterprise has on its beneficiary group. Using this theory of change and logic model framework, this thesis finds that most social enterprises fail to address the root-causes of inequity, choosing to use a reactionary as opposed to a preventative approach. Further, it asserts that stakeholders in the social sector must make an effort to shift their mindset to one of a systemic focus, as to address inequity issues at the root instead of at the surface. If this mindset shift does not occur, the opportunity gap will continue to persist.Plan II Honors Progra

Factors influencing career success of minority healthcare industry executives

Research has been conducted on the effects of a glass ceiling that still exists in US organizations for racial, ethnic, and female executives. A new barrier, defined as a concrete ceiling that is more difficult to penetrate, denser and less easily shattered than the glass ceiling has recently been identified as a barrier to progress namely for women of color (Catalyst, 1999,2000,2001; Moore & Jones, 2001). The primary purpose of this non-experimental, correlational, (explanatory), causal comparative (exploratory) study is to investigate the relationships among ethnicity, race, and gender on career success outcomes of healthcare executives and to examine those factors that influence their career success. Study findings showed that white females and white males had significantly more professional work experience than black or African American female and black or African American male healthcare industry executives. African American females had the least amount of professional work experience (M= 18.1 1 years, SD = 9.80) and white females had the greatest number of years of professional work experience (M= 28.02 years, SD = 9.02). Additionally, white females and white males had significantly more years of work experience (5 - 6.5 more years) in their current organizations than did African American females or males. Career success outcomes among minority and non-minority healthcare industry executives were analyzed using MANOVA. Significant disparities were observed relative to career promotions, compensation, psychological commitment, and career satisfaction. No significant differences were observed in perceived career success. Multiple stepwise regression analyses examined the influence of networking behaviors on career outcomes for minorities. For white female healthcare industry executives, maintaining contact and increasing internal visibility were significantly associated with promotions, perceived career success, psychological commitment, and career satisfaction. For African American female healthcare executives, participating in church and community activities as well as socializing were significantly related to compensation and psychological commitment. For African American male healthcare industry executives, socializing was significantly associated with promotions, compensation, and career satisfaction. For white males, engaging in professional activities, socializing and maintaining contact were significantly related to career outcomes. Regression analyses were not possible with the data gathered from the Hispanic/Latino population due to the small numbers of Hispanic/Latino participants. However, a MANOVA examined differences between Hispanics/Latinos and non- Hispanic/Latinos relative to their career promotions, compensation, perceived career success, psychological commitment, and career satisfaction. There were no significant differences between Hispanics or Latinos and non-Hispanics or Latinos relative to their number of promotions, perceived career success, psychological commitment, and career satisfaction. However, there was a significant difference between Hispanics/Latinos and non-Hispanics/Latinos relative to their compensation. Hispanic/Latino healthcare executives earned significantly more than non-Hispanics/Latinos

Childbearing women’s experiences of early pushing urge

AIM: To explore childbearing women’s experiences of early pushing urge (EPU). STUDY DESIGN: A qualitative phenomenological study was undertaken in an Italian maternity hospital. The sample included 8 women that experienced EPU during labor. Data were collected through semi-structured interviews. FINDINGS: The findings are presented as three main themes: (a) women’s perceptions of EPU, (b) bodily sensations versus midwives’ advice: struggling between conflicting messages, and (c) the “a posteriori” feeling of women about midwives’ guidance during EPU. The perception of EPU was characterized by sense of obstruction, bone pain, and different intensity of pushing efforts when compared with those of the expulsive phase. Women found it difficult to follow the midwife’s suggestion to stop pushing because this contradicted their bodily sensations. However, the women recognized a posteriori the importance of the midwife’s support while experiencing EPU. Women appreciated the midwives’ presence and emotional support most of all because they seemed to be more concerned with the personal relationship they formed in labor rather than the usefulness or appropriateness of their advice. CONCLUSION: Midwives should consider women’s physical perceptions to help them cope with EPU, acknowledging that women may struggle when caregivers’ suggestions are in contrast to their physical perceptions. The women’s overall positive experiences of birth suggest that EPU might be considered as a physiological event during labor, reinforcing the hypotheses of previous research. The optimal response to the EPU phenomenon remains unclear and should be studied, considering EPU at different dilatation ranges and related clinical outcomes

Tributyltin(Iv) butyrate: A novel epigenetic modifier with er stress-and apoptosis-inducing properties in colon cancer cells

Organotin(IV) compounds are a class of non-platinum metallo-conjugates exhibiting antitumor activity. The effects of different organotin types has been related to several mechanisms, including their ability to modify acetylation protein status and to promote apoptosis. Here, we focus on triorganotin(IV) complexes of butyric acid, a well-known HDAC inhibitor with antitumor properties. The conjugated compounds were synthesized and characterised by FTIR spectroscopy, multi-nuclear (1H,13C and119Sn) NMR, and mass spectrometry (ESI-MS). In the triorganotin(IV) complexes, an anionic monodentate butyrate ligand was observed, which coordinated the tin atom on a tetra-coordinated, monomeric environment similar to ester. FTIR and NMR findings confirm this structure both in solid state and solution. The antitumor efficacy of the triorganotin(IV) butyrates was tested in colon cancer cells and, among them, tributyltin(IV) butyrate (BT2) was selected as the most efficacious. BT2 induced G2/M cell cycle arrest, ER stress, and apoptotic cell death. These effects were obtained using low concentrations of BT2 up to 1 µM, whereas butyric acid alone was completely inefficacious, and the parent compound TBT was poorly effective at the same treatment conditions. To assess whether butyrate in the coordinated form maintains its epigenetic effects, histone acetylation was evaluated and a dramatic decrease in acetyl-H3 and-H4 histones was found. In contrast, butyrate alone stimulated histone acetylation at a higher concentration (5 mM). BT2 was also capable of preventing histone acetylation induced by SAHA, another potent HDAC inhibitor, thus suggesting that it may activate HDACs. These results support a potential use of BT2, a novel epigenetic modulator, in colon cancer treatment

The undesired fellow traveller

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Lion-porcupine interactions in Africa, including impacts on lion predatory behavior

Although African crested porcupines Hystrix spp. represent 0.5–34% of lion Panthera leo kills, interactions between the two species are poorly documented. Here we review porcupine-lion interactions and their impact on lion behaviour, including: 1) lion predation on porcupines; 2) lions injured or killed by porcupine quills; and 3) a case of a lion severely injured by a porcupine  quill. Porcupine quills can be effective weapons and sometimes seriously wound lions, resulting in death. Death from quills can be a slow process and under these circumstances, death may be the result of starvation or infection (septicaemia).Keywords: predator-prey relations, quill, behaviour modification, Hayward-Kerley’ threat index, septicaemi

Microbial translocation in chronic liver diseases.

The intestinal microflora is not only involved in the digestion of nutrients, but also in local immunity, forming a barrier against pathogenic microorganisms. The derangement of the gut microflora may lead to microbial translocation, defined as the passage of viable microorganisms or bacterial products (i.e., LPS, lipopeptides) from the intestinal lumen to the mesenteric lymph nodes and other extraintestinal sites. The most recent evidence suggests that microbial translocation (MT) may occur not only in cirrhosis, but also in the early stage of several liver diseases, including alcoholic hepatopathy and nonalcoholic fatty liver disease. Different mechanisms, such as small intestinal bacterial overgrowth, increased permeability of intestinal mucosa, and impaired immunity, may favor MT. Furthermore, MT has been implicated in the pathogenesis of the complications of cirrhosis, which are a significant cause of morbidity and mortality in cirrhotic subjects. Therapeutic strategies aiming at modulating the gut microflora and reducing MT have focused on antibiotic-based options, such as selective intestinal decontamination, and nonantibiotic-based options, such as prokinetics and probiotics. In particular, probiotics may represent an attractive strategy, even though the promising results of experimental models and limited clinical studies need to be confirmed in larger randomized trials