tbuckley/cabot-search huggingface dataset:
Abstract 3686: ElephantTP53(ep53) retrogene protein expression enhances cellular apoptosis in response to DNA damage
Authors: Lisa M. Abegglen, Rosann Robinson, Lauren Donovan, Aleah F. Caulin, Mor Goldfeder, Avi Schroeder, Carlo C. Maley, Joshua D. Schiffman
Journal: Cancer Research (2016)

Abstract We previously reported that compared with other mammalian species, elephants have a lower than expected rate of cancer (Abegglen JAMA 2015). While exploring cancer resistance in elephants, we discovered that elephants have 20 copies of TP53 (1 ancestral gene with introns and 19 retrogenes) compared to humans with 1 copy. TP53 amplification was associated with increased p53-mediated apoptosis induced by DNA damage in elephant cells compared to human cells. As a follow up to this study, we further explored the function of these elephant TP53 retrogenes by expressing their protein (ep53) in cells with 2 functional TP53 alleles. NIH/3T3 cells were transfected with a mammalian expression construct encoding TP53 retrogene 9 fused to an epitope tag (myc). Western blot analysis probing for myc confirmed expression of retrogene 9. To measure the functional consequence of expression, we compared apoptosis of cells transfected with empty vector to cells transfected with myc-tagged retrogene 9 after doxorubicin treatment. Apoptosis was measured with a triplex assay that assesses viability, cytotoxicity and apoptosis (Apo Tox-Glo, Promega). We observed a significant increase in apoptosis of NIH/3T3 cells expressing retrogene 9 compared to empty vector transfected control cells (10μM doxorubicin, P&amp;lt;0.001). These results suggest that ep53 is a functional protein contributing to cancer resistance in elephants, and that elephant retrogenes can function in cells from other species to enhance their apoptotic response to DNA damage. These findings may hold significance for human cancer prevention and treatment. Citation Format: Lisa M. Abegglen, Rosann Robinson, Lauren Donovan, Aleah F. Caulin, Mor Goldfeder, Avi Schroeder, Carlo C. Maley, Joshua D. Schiffman. Elephant TP53 (ep53) retrogene protein expression enhances cellular apoptosis in response to DNA damage. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3686.
Abstract 1452: IL-15 overexpression protects cerulein-induced fibrosis in the mouse model of chronic pancreatitis
Authors: MURLI MANOHAR, SATHISHA UPPARAHALLI VENKATESHAIAH, CHANDRASHEKARA PUTANAPURA MAHADEVAPPA, ALOK KUMAR VERMA, ANIL MISHRA.
Journal: Cancer Research (2016)

Abstract Introduction: Earlier, interleukin (IL)-6, IL-8, IL-1β and IL-10 are implicated in the pathogenesis of pancreatitis. Recently, we observed reduced level of IL-15 in cerulein- induced acute and chronic mouse model of pancreatitis. IL-15 is a pleiotropic cytokine that has an important role in innate immunity. Therefore, we tested the hypothesis that IL-15 overexpression improves the pathogenesis of cerulein-induced pancreatitis. Experimental procedure: Accordingly, we tested our hypothesis by inducing chronic pancreatitis in rIL-15 pretreated Balb/c mice. Cerulein was given by repetitive intraperitoneal (i.p.) injections as reported earlier (50 μg/kg, 6 hourly injections/day, 3 days/week) along with the rIL-15 (5 μg in 100μl saline/ two-times/week/mice) for up to 4 weeks; the control mice received 100μl saline or saline with 5 μg IL-15. Mice were sacrificed 3 days after the last cerulein injection. Histopathological evaluation of H&amp;E stained tissue sections was performed including tissue remodeling and the accumulation of collagen by Masson's trichrome stain in the tissue sections. Additionally, pro-inflammatory and pro-fibrotic gene i.e. TGF-β1, IL-6, IL-8, Collagen 1 and α-SMA levels were measured by ELISA, immunofluorescence, qPCR and immunoblot analysis. Summary: We report acinar cells atrophy, induced inflammatiory cells and cytokines in the pancreas of cerulein treated mice along with perivascular collagen deposition compare to saline treated mice. Interestingly, rIL-15 treated and cerulein given mice showed significantly improved morphology of acinar cells and reduced perivascular collagen. Further, we also report that protein levels of TGF-β1 and α-SMA is also reduced in the pancreas of cerulein injected and IL-15 treated mice compare to cerulein treated mice by performing western blot and immunohistochemistry. Conclusion: Our data show that IL-15 overexpression protects mice from cerulein-induced pancreatic pathogenesis including fibrosis. Taken together, rIL-15 therapy may be a novel strategy to treat pancreatic fibrosis, and may also helpful to treat pancreatic cancer patients by down-regulating tissue fibrogenesis. Funding: NIH R01 DK067255 (AM), NIH R01 AI080581 (AM), Citation Format: MURLI MANOHAR, SATHISHA UPPARAHALLI VENKATESHAIAH, CHANDRASHEKARA PUTANAPURA MAHADEVAPPA, ALOK KUMAR VERMA, ANIL MISHRA. IL-15 overexpression protects cerulein-induced fibrosis in the mouse model of chronic pancreatitis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1452.
The effect of adjuvant radiotherapy on survival in locoregional urothelial malignancies of the upper urinary tract.
Authors: Andrew Hahn, Smith Giri, Ranjan Pathak, Vijaya Raj Bhatt, Michael Gary Martin
Journal: Journal of Clinical Oncology (2015)

e15636 Background: While radical nephroureterectomy is the treatment of choice for localized or regional urothelial carcinoma of the upper urinary tract, the role of adjuvant radiotherapy is unknown with conflicting data from various small studies. We aimed to use a national database to study the impact of adjuvant radiotherapy on these malignancies. Methods: Using SEER 9 database, we identified patients with microscopically confirmed cases of urothelial malignancies of the upper urinary tract from 1998-2011 using appropriate ICD-O-3 codes. Cases were limited to those with locoregional stage, known radiation status, and who received partial, total or radical nephro-ureterectomy. Univariate, multivariate, and propensity score adjusted analyses were conducted to study the role of adjuvant radiation therapy among these patients. Statistical analysis was done using SEER*Stat 8.1.2 and STATA 13.0. Results: 113 patients (4.4%) received adjuvant radiotherapy out of 2572 identified cases; median age was 74 years (range 22-100 years), 57% male, and 90% white. Localized tumors comprised 30% (n = 780) of the cases, and the majority of patients had poorly differentiated (45%, n = 1172) or undifferentiated (40%, n = 1019) high-grade tumors. 42% of patients received radical nephroureterectomy (n = 1084). In univariate analysis, patients treated with adjuvant radiation therapy seemed to have a lower survival time than those without radiation therapy (19 months versus 31 months, 3 year survival 46% versus 31% and 5 year survival 44% versus 24.2%, log rank test < 0.01). After controlling for covariates including age, sex, race, type of surgery, tumor stage and grade, and year of diagnosis, radiation therapy did not have a survival benefit among surgically treated patients (HR 0.68; 95% CI 0.68-1.06, p value 0.85). This was further confirmed with propensity score adjusted multivariate regression analysis where adjuvant radiation therapy was not associated with a survival benefit (HR 0.88, 95% CI 0.71-1.11, p value 0.3). Conclusions: Adjuvant radiation therapy did not demonstrate a clear survival benefit in the management of patients with locoregional upper urothelial malignancies.
MiR-29a Assists in Preventing the Activation of Human Stellate Cells and Promotes Recovery From Liver Fibrosis in Mice
Authors: Yoshinari Matsumoto, Saori Itami, Masahiko Kuroda, Katsutoshi Yoshizato, Norifumi Kawada, Yoshiki Murakami
Journal: Molecular Therapy (2016)

The microRNA-29 (miR-29) family is known to suppress the activation of hepatic stellate cells (HSCs) and reversibly control liver fibrosis; however, the mechanism of how miR-29a controls liver fibrosis remains largely unknown. This study was conducted to clarify the mechanism of anti-fibrotic effect of miR-29a and to explore if miR-29a is a promising candidate for nucleic acid medicine against liver fibrosis. Two liver fibrosis murine models (carbon tetrachloride or thioacetamide) were used. MiR-29a mixed with atelocollagen was systemically administered. Hepatic fibrosis was evaluated by histological analysis and the expression levels of fibrosis-related genes. We observed that miR-29a treatment dramatically accelerated the reversion of liver fibrosis in vivo. Additionally, miR-29a regulated the mRNA expression of collagen type I alpha 1 (COL1A1) and platelet-derived growth factor C (PDGFC). We also noted that miR-29a significantly suppressed COL1A1 mRNA expression and cell viability and significantly increased caspase-9 activity (P < 0.05) in LX-2 cells. Pretreatment of miR-29a inhibited activation of LX-2 cell by transforming growth factor beta treatment. MiR-29a exhibited anti-fibrotic effect without cell toxicity in vivo and directly suppressed the expression of PDGF-related genes as well as COL1A1 and induced apoptosis of LX-2 cells. MiR-29a is a promising nucleic acid inhibitor to target liver fibrosis. The microRNA-29 (miR-29) family is known to suppress the activation of hepatic stellate cells (HSCs) and reversibly control liver fibrosis; however, the mechanism of how miR-29a controls liver fibrosis remains largely unknown. This study was conducted to clarify the mechanism of anti-fibrotic effect of miR-29a and to explore if miR-29a is a promising candidate for nucleic acid medicine against liver fibrosis. Two liver fibrosis murine models (carbon tetrachloride or thioacetamide) were used. MiR-29a mixed with atelocollagen was systemically administered. Hepatic fibrosis was evaluated by histological analysis and the expression levels of fibrosis-related genes. We observed that miR-29a treatment dramatically accelerated the reversion of liver fibrosis in vivo. Additionally, miR-29a regulated the mRNA expression of collagen type I alpha 1 (COL1A1) and platelet-derived growth factor C (PDGFC). We also noted that miR-29a significantly suppressed COL1A1 mRNA expression and cell viability and significantly increased caspase-9 activity (P < 0.05) in LX-2 cells. Pretreatment of miR-29a inhibited activation of LX-2 cell by transforming growth factor beta treatment. MiR-29a exhibited anti-fibrotic effect without cell toxicity in vivo and directly suppressed the expression of PDGF-related genes as well as COL1A1 and induced apoptosis of LX-2 cells. MiR-29a is a promising nucleic acid inhibitor to target liver fibrosis.
T/NK “Nasal Type” Lymphomas: An Italian Cooperative Retrospective Survey.
Authors: Livio Pagano, Andrea Gallamini, Giulio Trapè, Daniele Mattei, Eros Di Bona, Emilio Iannitto, Antonio Spadea, Elena Rossi, Raffaele Tartaglione, Maurizio Martelli, Anna Maria Nosari, Concetta Petti, Paolo Falcucci, Luigi Maria Larocca, Giuseppe Leone
Journal: Blood (2004)
Abstract 542: Assessing and augmenting the immune response to glioblastoma using repurposed pharmaceuticals
Authors: Breanna R. Brenneman, Desiree H. Floyd, Tajie Harris, Benjamin Purow
Journal: Cancer Research (2016)

Abstract In order to improve the therapeutic responses to immunotherapies in glioblastoma (GBM) patients, a known pharmaceutical, ritanserin, was repurposed to augment cytotoxic T cell responses and suppress tumor growth. To determine the kinetics of the immune response to GBM, the transplantable syngeneic glioma cell line GL261 was used in C57BL/6 mice to assess the tumor immune response in the brain, spleen, and cervical lymph node via flow cytometry weekly for one month. After identifying the optimal T cell response temporally, mice with established tumors were treated with 100mg/kg of Ritanserin for one week and harvested post treatment. Ritanserin is able to inhibit the activity of diacylglycerol kinase alpha (DGKA), an enzyme that converts diacylglycerol to phosphatidic acid, and can inhibit tumor growth in mice. In addition, DGKA is expressed in T cells, and is more highly expressed in those that have entered an unresponsive (anergic) state, characteristic of dysfunctional T cell responses to tumors. To determine if ritanserin can counteract T cell anergy, T cell responses were determined by assessment of T cell number by subset (CD8+, CD4+, CD4+FoxP3+), by activation (CD62L-CD44+), and by tumor-specific response to ovalbumin-expressing GL261 tumor cells in the brain, spleen, and cervical lymph nodes. In comparison to mock-injected mice, tumor-bearing mice showed a robust T cell response to tumors in the brain, peaking at days 21 and 28 post injection. Treatment with ritanserin resulted in a trend toward increased number and activation of T cells in the brain compared to vehicle-treated mice. In addition, there was a significant increase in OVA-specific T cells in the brain with treatment. In conclusion, T cells respond robustly to brain tumors in mice, and ritanserin treatment appears to increase this response by increased activation and priming of tumor-specific T cells. This indicates that ritanserin may have combinatorial effects on T cells when combined with checkpoint inhibitors such as ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). Future experiments will focus on combining ritanserin and other repurposed drugs with these checkpoint inhibitors and further characterizing the effect of ritanserin on T cells. Citation Format: Breanna R. Brenneman, Desiree H. Floyd, Tajie Harris, Benjamin Purow. Assessing and augmenting the immune response to glioblastoma using repurposed pharmaceuticals. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 542.
Prostate-Specific Membrane Antigen (PSMA) Avid Pancreatic Neuroendocrine Tumor
Authors: Shankar Vamadevan, Deepa Shetty, Ken Le, Chuong Bui, Robert Mansberg, Han Loh
Journal: Clinical Nuclear Medicine (2016)

68Ga-PSMA PET/CT is increasingly used to evaluate recurrent prostatic malignancy due to its high specificity. A 75-year-old man with a previous history of treated prostate cancer 3 years earlier presented with rising prostate-specific antigen (PSA) level and underwent 68Ga-PSMA PET/CT which demonstrated a PSMA-avid focus in the neck of the pancreas. Triple-phase abdominal CT demonstrated enhancement in the arterial phase and to a lesser extent the venous phase of a soft tissue mass in the neck of the pancreas. Cytological and histopathological examination of the soft tissue mass confirmed a low-grade pancreatic neuroendocrine tumor.
IL-10+ regulatory B cells are enriched in cord blood and may protect against cGVHD after cord blood transplantation
Authors: Anushruti Sarvaria, Rafet Basar, Rohtesh S. Mehta, Hila Shaim, Muharrem Muftuoglu, Ahmad Khoder, Takuye Sekine, Elif Gokdemir, Kayo Kondo, David Marin, May Daher, Amin M. Alousi, Abdullah Alsuliman, Enli Liu, Betul Oran, Amanda Olson, Roy B. Jones, Uday Popat, Chitra Hosing, Richard Champlin, Elizabeth J. Shpall, Katayoun Rezvani
Journal: Blood (2016)
The effectiveness of therapy with octreotide LAR in combination treatment with zoledronic acid versus zoledronic acid alone.
Authors: Massimo Vincenzo Martino
Journal: Journal of Clinical Oncology (2014)

e16107 Background: We evaluate the effectiveness of therapy with octreotide LAR versus zoledronic acid in combination treatment with zoledronic acid in a unique population of patients with metastatic prostate cancer with hormone-refractory disease, having already received second-line antiandrogen with BAT, and Chromogranin a values above normal levels Methods: The study included 35 patients affected by bone metastases from prostate cancer, in hormone refractory state, already treated with LHRH-A. It was necessary to suspend the non-steroidal anti-androgen, bicalutamide, for biochemical progression of disease. All patients had the following: Aged between seventy and eighty years old. Bone pain. An increase of PSA values. A high values of Chromogranin (> 5 U / L). Elevated prostatic acid phosphatase The population was randomly put into two arms, namely: Eighteen patients who underwent combined treatment with octreotide LAR 30 mg (deep intramuscular injection in the buttock every 28 days) and zoledronic acid 4 mg (administered intravenously every 28 days), versus 17 patients who received 4 mg zoledronic acid alone (intravenous every 28 days). The clinical study included a follow up of 18 months. The efficacy was evaluated in terms of reduction of pain, laboratory values altered and control ofdisease progression as well. Results: Both the median progression-free survival (6 months vs. 1 month) that the median overall survival (11 months vs. 8 months) was better in the group of patients who had received a combined octreotide LAR and zoledronic acid group in comparison to the patients treated with zoledronic acid. Conclusions: The results that had been achieved, in part, they did confirm that the rationale therapeutic assumed, they d revealed a scenario absolutely new and they also got impact points of special offers a reflection. Obviously that only a treatment with zoledronic acid is not able to guarantee an arrest of disease progression for such a treatment. In fact it has the purpose of restoring, within certain limits, the bone homeostasis altered by the presence of metastases adenocarcinomatose.
bmjlearning.com: M-learning
Authors: Kieran Walsh
Journal: BMJ (2005)

Do you commute to work or spend a lot of time travelling to meetings and conferences? If you do then you are likely to spend a sizeable amount of your time in railway stations, airports, and hotels. Most of us find these places deathly boring. Retailers have realised this, and some of the busiest shops in these transitory places are bookshops. But if you get bored reading blockbusters about the “Da Vinci Code” you could do something more constructive with your time. Let's first look at some of the advantages of what Auge calls non-places.1

When you are travelling you generally have privacy and solitude: you can read or work for a substantial period without being interrupted.1 And perhaps most importantly you are a captive audience—you have to be there. These are all prime conditions for learning. E-learning has been one of the buzz words of recent years, but educationalists are already talking about a new idea, m-learning or mobile learning. In this type of learning you can take out your laptop on the train and start learning. You can learn at any time and in any place. You can also communicate with fellow learners at work via email and discussion forums. Soon most of us will be able to use mobile phones to learn online.

At BMJ Learning, we have tried to publish material that is concise enough to use on the journey home or on a trip to a meeting. Most of the pages on the modules are quick to download, even with narrow band access to the internet. One of our most recent modules for junior hospital doctors is on the treatment of patients with status epilepticus. It outlines the basics and dispels some myths about this condition. For example, it shows why prolactin is an unreliable marker of seizures: prolactin can return to normal during prolonged status, so you are better off relying on clinical features to distinguish status epilepticus from non-epileptic seizures. If your patient is thrashing about in a poorly coordinated way, is arching his back, or squeezing his eyes shut then you should suspect non-epileptic seizures.

The module also outlines the advantages and disadvantages of new treatments. One of the few advantages of fosphenytoin over phenytoin is that it causes fewer injection site reactions. However, it can cause severe cardiac dysrhythmias, including cardiac arrest, so you should always start electrocardiographic monitoring when giving it.

To find out more have a look on www.bmjlearning.com. At the end of your journey you can test your knowledge with a short quiz.
Abstract 2363: Combinational therapy with specific immunization plus checkpoint inhibition results in enhanced tumor regression and survival benefit
Authors: Elizabeth Gabitzsch, Adrian Rice, Yvette Latchman, Joseph P. Balint, Frank Jones
Journal: Cancer Research (2016)

Abstract Effective immunotherapeutic treatment of various cancers may require combinational approaches to induce specific immunity to the tumor as well as inhibition of immune check-points. We have developed a viral gene delivery platform to immunize against numerous tumor associated antigens (TAA) such as carcinoembryonic antigen (CEA), HER2/neu and HPV 16. We investigated the therapeutic benefit of the immunotherapeutics alone and in combination with check-point inhibitors such as programmed death-ligand 1 (PD-1) blockade and LAG3 blockade in murine tumor models. As single agents, immunization with the viral delivery platform encoding the TAA induced target-specific cell-mediated immunity and anti-tumor responses in the respective model. When the immunotherapies were combined with immune checkpoint blockade, an increased level of anti-tumor activity against was observed in addition to an improvement in survival. Tumor microenvironment analysis immunized mice revealed an increase in CD8+ tumor-infiltrating lymphocytes (TILs). In addition, we observed induction of suppressive mechanisms such as programmed death-ligand 1 (PD-L1) expression on tumor cells and an increase in PD-1+ TILs. When immunotherapy was combined with anti-PD-1 antibody, we observed CD8+ TILs at the same increased level but found that a smaller fraction of these were PD-1+. Furthermore, we observed a reduction in PD-L1 expression on tumor cells, providing a mechanism by which combination therapy favors tumor clearance and a rationale for pairing antigen-specific vaccines with checkpoint inhibitors in future clinical trials. Citation Format: Elizabeth Gabitzsch, Adrian Rice, Yvette Latchman, Joseph P. Balint, Frank Jones. Combinational therapy with specific immunization plus checkpoint inhibition results in enhanced tumor regression and survival benefit. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2363.