Evaluating new therapies in gastrointestinal stromal tumor using in vivo molecular optical imaging

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the US. The majority (~85%) of GISTs possess gain-of-function mutations in KIT or PDGFRA, causing constitutive activation of the kinase receptor. GIST management has been transformed by the identification of tumor driver mutations leading to unprecedented disease control of advanced GIST with the introduction of imatinib mesylate (IM). Despite IM’s efficacy, most patients experience primary and/or secondary resistance within 2 y of treatment. Additional therapies and methods to optimize screening of novel approaches in preclinical studies are warranted. Clinically, treatment efficacy is typically assessed using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines or Choi criteria. Both require a period of time on therapy before changes indicative of response can be observed. In addition, neither informs directly about cell death. We evaluated the use of molecular imaging technology in an animal model using near-infrared (NIR) imaging probes together with three-dimensional fluorescence molecular tomography (FMT) for assessing therapeutic response and ultimately optimizing our understanding of the biologic effects of these agents. We determined the potential of NIR probes (PSVue(TM)794 and cell-penetrating KcapQ647) for detecting distinct markers of apoptosis and compare this to tumor size measured by MRI in response to IM treatment in GIST-T1 xenografts. Our studies revealed statistically significant increases in apoptosis due to IM treatment using both probes as early as 24 h post IM treatment which was confirmed by IHC. Molecular imaging will allow for faster and more effective screening of novel therapies in preclinical GIST models

Life's Joke: Bergson, Comedy, and the Meaning of Laughter

The present essay argues that Bergson’s account of the comic can only be fully appreciated when read in conjunction with his later metaphysical exposition of the élan vital in Creative Evolution and then by the account of fabulation that Bergson only elaborates fully three decades later in The Two Sources of Morality and Religion. The more substantive account of the élan vital ultimately shows that, in Laughter, Bergson misses his own point: laughter does not simply serve as a means for correcting human behavior but is rather the élan vital’s vital summons, the demand of life itself, that human beings challenge their obligations, question their societal forms, and thereby create new and, for Bergson, more ideal forms of life and community

Harmful algal blooms and climate change: exploring future distribution changes

Harmful algae can cause death in fish, shellfish, marine mammals, and humans, via their toxins or from effects associated with their sheer quantity. There are many species, which cause a variety of problems around north-west Europe, and the frequency and distribution of algal blooms have altered in the recent past. Species distribution modelling was used to understand how harmful algal species may respond in the future to climate change, by considering environmental preferences and how these may shift. Most distribution studies to date use low resolution global model outputs. In this study, high resolution, downscaled shelf seas climate projections for the north-west European shelf were nested within lower resolution global projections, to understand how the distribution of harmful algae may change by the mid to end of century. Projections suggest that the habitat of most species (defined by temperature, salinity, depth, and stratification) will shift north this century, with suitability increasing in the central and northern North Sea. An increase in occurrence here might lead to more frequent detrimental blooms if wind, irradiance and nutrient levels are also suitable. Prioritizing monitoring of species in these susceptible areas could help in establishing early-warning systems for aquaculture and health protection schemes

Synthetic Lethality of Chk1 Inhibition Combined with p53 and/or p21 Loss During a DNA Damage Response in Normal and Tumor Cells

Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53-deficient tumors in order to sensitize them to DNA-damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of p21 (p53 independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1 inhibition. As p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction

Effect of fulvic acids on lead-induced oxidative stress to metal sensitive Vicia faba L. plant

Lead (Pb) is a ubiquitous environmental pollutant capable to induce various morphological, physiological, and biochemical functions in plants. Only few publications focus on the influence of Pb speciation both on its phytoavailability and phytotoxicity. Therefore, Pb toxicity (in terms of lipid peroxidation, hydrogen peroxide induction, and photosynthetic pigments contents) was studied in Vicia faba plants in relation with Pb uptake and speciation. V. faba seedlings were exposed to Pb supplied as Pb(NO3)2 or complexed by two fulvic acids (FAs), i.e. Suwannee River fulvic acid (SRFA) and Elliott Soil fulvic acid (ESFA), for 1, 12, and 24 h under controlled hydroponic conditions. For both FAs, Pb uptake and translocation by Vicia faba increased at low level (5 mg l−1), whereas decreased at high level of application (25 mg l−1). Despite the increased Pb uptake with FAs at low concentrations, there was no influence on the Pb toxicity to the plants. However, at high concentrations, FAs reduced Pb toxicity by reducing its uptake. These results highlighted the role of the dilution factor for FAs reactivity in relation with structure; SRFA was more effective than ESFA in reducing Pb uptake and alleviating Pb toxicity to V. faba due to comparatively strong binding affinity for the heavy metal

Early Detection of Pancreatic Intraepithelial Neoplasias (PanINs) in Transgenic Mouse Model by Hyperpolarized 13C Metabolic Magnetic Resonance Spectroscopy

While pancreatic cancer (PC) survival rates have recently shown modest improvement, the disease remains largely incurable. Early detection of pancreatic cancer may result in improved outcomes and therefore, methods for early detection of cancer, even premalignant lesions, may provide more favorable outcomes. Pancreatic intraepithelial neoplasias (PanINs) have been identified as premalignant precursor lesions to pancreatic cancer. However, conventional imaging methods used for screening high-risk populations do not have the sensitivity to detect PanINs. Here, we have employed hyperpolarized metabolic imaging in vivo and nuclear magnetic resonance (1H-NMR) metabolomics ex vivo to identify and understand metabolic changes, towards enabling detection of early PanINs and progression to advanced PanINs lesions that precede pancreatic cancer formation. Progression of disease from tissue containing predominantly low-grade PanINs to tissue with high-grade PanINs showed a decreasing alanine/lactate ratio from high-resolution NMR metabolomics ex vivo. Hyperpolarized magnetic resonance spectroscopy (HP-MRS) allows over 10,000-fold sensitivity enhancement relative to conventional magnetic resonance. Real-time HP-MRS was employed to measure non-invasively changes of alanine and lactate metabolites with disease progression and in control mice in vivo, following injection of hyperpolarized [1-13C] pyruvate. The alanine-to-lactate signal intensity ratio was found to decrease as the disease progressed from low-grade PanINs to high-grade PanINs. The biochemical changes of alanine transaminase (ALT) and lactate dehydrogenase (LDH) enzyme activity were assessed. These results demonstrate that there are significant alterations of ALT and LDH activities during the transformation from early to advanced PanINs lesions. Furthermore, we demonstrate that real-time conversion kinetic rate constants (kPA and kPL) can be used as metabolic imaging biomarkers of pancreatic premalignant lesions. Findings from this emerging HP-MRS technique can be translated to the clinic for detection of pancreatic premalignant lesion in high-risk populations.Fil: Dutta, Prasanta. University of Texas; Estados UnidosFil: Castro Pando, Susana. University of Texas; Estados UnidosFil: Mascaró, Marilina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. University of Texas; Estados UnidosFil: Riquelme, Erick. University of Texas; Estados UnidosFil: Zoltan, Michelle. University of Texas; Estados UnidosFil: Zacharias, Niki M.. University of Texas; Estados UnidosFil: Gammon, Seth T.. University of Texas; Estados UnidosFil: Piwnica-Worms, David. University of Texas; Estados UnidosFil: Pagel, Mark D.. University of Texas; Estados UnidosFil: Sen, Subrata. University of Texas; Estados UnidosFil: Maitra, Anirban. University of Texas; Estados UnidosFil: Shams, Shayan. University of Texas; Estados UnidosFil: McAllister, Florencia. University of Texas; Estados UnidosFil: Bhattacharya, Pratip K.. University of Texas; Estados Unido

The ARF Tumor Suppressor Regulates Bone Remodeling and Osteosarcoma Development in Mice

The ARF tumor suppressor regulates p53 as well as basic developmental processes independent of p53, including osteoclast activation, by controlling ribosomal biogenesis. Here we provide evidence that ARF is a master regulator of bone remodeling and osteosarcoma (OS) development in mice. Arf-/- mice displayed increased osteoblast (OB) and osteoclast (OC) activity with a significant net increase in trabecular bone volume. The long bones of Arf-/- mice had increased expression of OB genes while Arf-/- OB showed enhanced differentiation in vitro. Mice transgenic for the Tax oncogene develop lymphocytic tumors with associated osteolytic lesions, while Tax+Arf-/- mice uniformly developed spontaneous OS by 7 months of age. Tax+Arf-/- tumors were well differentiated OS characterized by an abundance of new bone with OC recruitment, expressed OB markers and displayed intact levels of p53 mRNA and reduced Rb transcript levels. Cell lines established from OS recapitulated characteristics of the primary tumor, including the expression of mature OB markers and ability to form mineralized tumors when transplanted. Loss of heterozygosity in OS tumors arising in Tax+Arf+/- mice emphasized the necessity of ARF-loss in OS development. Hypothesizing that inhibition of ARF-regulated bone remodeling would repress development of OS, we demonstrated that treatment of Tax+Arf-/- mice with zoledronic acid, a bisphosphonate inhibitor of OC activity and repressor of bone turnover, prevented or delayed the onset of OS. These data describe a novel role for ARF as a regulator of bone remodeling through effects on both OB and OC. Finally, these data underscore the potential of targeting bone remodeling as adjuvant therapy or in patients with genetic predispositions to prevent the development of OS

TRE-dependent transcription activation by JDP2–CHOP10 association

The c-Jun dimerization protein 2, JDP2, is a member of the activating protein 1 (AP-1) family of transcription factors. Overexpression of JDP2 has been shown to result in repression of AP-1-dependent transcription and inhibition of cellular transformation. Other studies suggested that JDP2 may function as an oncogene. Here we describe the identification of CHOP10, a member of the CCAAT enhancer binding proteins, as a protein associating with JDP2. In contrast to the inhibition of transcription by JDP2, JDP2–CHOP complex strongly enhances transcription from promoters containing TPA response elements (TRE), but not from those containing cyclic AMP response elements (CRE). The association between JDP2 and CHOP10 involves the leucine zipper motifs of both proteins, whereas, the basic domain of CHOP10 contributes to the association of the JDP2–CHOP10 complex with the DNA. DNA binding of JDP2–CHOP complex is observed both in vitro and in vivo. Finally, overexpression of JDP2 results in increased cell viability following ER stress and counteracts CHOP10 pro-apoptotic activity. JDP2 expression may determine the threshold for cell sensitivity to ER stress. This is the first report describing TRE-dependent activation of transcription by JDP2 and thus may provide an explanation for the as yet unexplored oncogenic properties of JDP2

Anticancer Gene Transfer for Cancer Gene Therapy

Gene therapy vectors are among the treatments currently used to treat malignant tumors. Gene therapy vectors use a specific therapeutic transgene that causes death in cancer cells. In early attempts at gene therapy, therapeutic transgenes were driven by non-specific vectors which induced toxicity to normal cells in addition to the cancer cells. Recently, novel cancer specific viral vectors have been developed that target cancer cells leaving normal cells unharmed. Here we review such cancer specific gene therapy systems currently used in the treatment of cancer and discuss the major challenges and future directions in this field