A Renaissance on the Eastside: Motivating Inner-City Youth Through Art

Research tells us that children are more susceptible to temptations between the hours of 2:00 p.m. and 6:00 p.m.—the hours following the end of the school day when parents are not yet home from work. This study looks at the life histories of child participants in the Artists in the Making (AIM) program—a program that aims to motivate inner-city youth through the use of visual arts classes. Despite the diversity of the children who participated in the AIM program, several common themes emerged from the interview process: self-discovery, problem-solving skills, opportunities for positive risk taking, and the mastery of artistic skills. This article proposes that community-based visual arts programs can help children develop protective factors that will allow them to be resilient. When I draw, I feel like I am in another world. When I go home after class, I feel like I am walking back into hell. ( Rashie, a student in the Artists in the Making program, 1998)

Hexokinase 2 is important for tumor growth and metastasis in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths in the United States. The majority of PDAC patients are diagnosed with metastatic disease, where treatment options are limited to cytotoxic chemotherapies that provide modest improvements in overall survival. Over 95% of PDAC tumors contain activating mutations in the oncogene KRAS, causing constitutive activation of key pathways promoting cancer cell proliferation, metabolism, and survival. Direct targeting of KRAS and its canonical effector pathways has proven ineffective for the treatment of advanced PDAC, suggesting that additional processes required for KRAS-driven tumorigenesis may be therapeutically beneficial. Metabolic reprogramming and increased glucose uptake were required for tumor growth in a genetically engineered mouse model of PDAC, suggesting that this pathway is important for PDAC tumorigenesis. We found the glycolytic enzyme hexokinase 2 (HK2) to be significantly upregulated in primary PDAC tumors and PDAC metastases. Increased expression of HK2 was associated with poor overall survival after curative surgery, suggesting that HK2 promotes aggressive tumor biology. HK2 was shown to be both necessary and sufficient for regulating glycolysis, primary tumor growth and metastasis of PDAC cell lines. Pharmacologic inhibition of lactate production abrogated HK2-driven invasion in PDAC cell lines, while addition of extracellular lactate promoted invasion, suggesting that HK2 promotes metastasis by regulating glycolysis. Given this, direct inhibition of HK2 or lactate production may be a promising approach for the treatment of advanced PDAC. Because HK2 was a driver of PDAC tumor growth and metastasis, candidate microRNAs (miRNAs) were examined for their ability to function as tumor suppressors by inhibiting HK2 expression. miR-148a and miR-216b were negatively correlated with HK2 and down regulated in PDAC tumors. Both miR-148a and miR-216b interacted with the 3’UTR of HK2 and inhibited HK2 expression in PDAC cell lines, suggesting that these miRNAs directly regulate HK2 in PDAC. Restoration of miR-148a and miR-216b expression mimicked the effects of HK2 knockdown on anchorage independent growth and invasion of PDAC cell lines, suggesting a potential role for these miRNAs as inhibitors of PDAC tumor growth and metastasis via their regulation of HK2.Doctor of Philosoph

Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a KRAS-driven cancer with a high incidence of metastasis and an overall poor prognosis. Previous work in a genetically engineered mouse model of PDAC showed glucose metabolism to be important for maintaining tumor growth. Multiple glycolytic enzymes, including hexokinase 2 (HK2), were upregulated in primary PDAC patient tumors, supporting a role for glycolysis in promoting human disease. HK2 was most highly expressed in PDAC metastases, suggesting a link between HK2 and aggressive tumor biology. In support of this we found HK2 expression to be associated with shorter overall survival in PDAC patients undergoing curative surgery. Transient and stable knockdown of HK2 in primary PDAC cell lines decreased lactate production, anchorage independent growth (AIG) and invasion through a reconstituted matrix. Conversely, stable overexpression of HK2 increased lactate production, cell proliferation, AIG and invasion. Pharmacologic inhibition of lactate production reduced the HK2-driven increase in invasion while addition of extracellular lactate enhanced invasion, together providing a link between glycolytic activity and metastatic potential. Stable knockdown of HK2 decreased primary tumor growth in cell line xenografts and decreased incidence of lung metastasis after tail vein injection. Gene expression analysis of tumors with decreased HK2 expression showed alterations in VEGF-A signaling, a pathway important for angiogenesis and metastasis, consistent with a requirement of HK2 in promoting metastasis. Overall our data provides strong evidence for the role of HK2 in promoting PDAC disease progression, suggesting that direct inhibition of HK2 may be a promising approach in the clinic

The microtubule-based motor Kar3 and plus end–binding protein Bim1 provide structural support for the anaphase spindle

In budding yeast, the mitotic spindle is comprised of 32 kinetochore microtubules (kMTs) and ∼8 interpolar MTs (ipMTs). Upon anaphase onset, kMTs shorten to the pole, whereas ipMTs increase in length. Overlapping MTs are responsible for the maintenance of spindle integrity during anaphase. To dissect the requirements for anaphase spindle stability, we introduced a conditionally functional dicentric chromosome into yeast. When centromeres from the same sister chromatid attach to opposite poles, anaphase spindle elongation is delayed and a DNA breakage-fusion-bridge cycle ensues that is dependent on DNA repair proteins. We find that cell survival after dicentric chromosome activation requires the MT-binding proteins Kar3p, Bim1p, and Ase1p. In their absence, anaphase spindles are prone to collapse and buckle in the presence of a dicentric chromosome. Our analysis reveals the importance of Bim1p in maintaining a stable ipMT overlap zone by promoting polymerization of ipMTs during anaphase, whereas Kar3p contributes to spindle stability by cross-linking spindle MTs

Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial

Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes

G-Protein-Coupled Receptor 1, G-Protein Gα-Subunit 1, and Prephenate Dehydratase 1 Are Required for Blue Light-Induced Production of Phenylalanine in Etiolated Arabidopsis

Different classes of plant hormones and different wavelengths of light act through specific signal transduction mechanisms to coordinate higher plant development. A specific prephenate dehydratase protein (PD1) was discovered to have a strong interaction with the sole canonical G-protein Gα-subunit (GPA1) in Arabidopsis (Arabidopsis thaliana). PD1 is a protein located in the cytosol, present in etiolated seedlings, with a specific role in blue light-mediated synthesis of phenylpyruvate and subsequently of phenylalanine (Phe). Insertion mutagenesis confirms that GPA1 and the sole canonical G-protein-coupled receptor (GCR1) in Arabidopsis also have a role in this blue light-mediated event. In vitro analyses indicate that the increase in PD1 activity is the direct and specific consequence of its interaction with activated GPA1. Because of their shared role in the light-mediated synthesis of phenylpyruvate and Phe, because they are iteratively interactive, and because activated GPA1 is directly responsible for the activation of PD1; GCR1, GPA1, and PD1 form all of or part of a signal transduction mechanism responsible for the light-mediated synthesis of phenylpyruvate, Phe, and those metabolites that derive from that Phe. Data are also presented to confirm that abscisic acid can act through the same pathway. An additional outcome of the work is the confirmation that phenylpyruvate acts as the intermediate in the synthesis of Phe in etiolated plants, as it commonly does in bacteria and fungi