tbuckley/cabot-search huggingface dataset:
Lack of <i>p53</i> Augments Antitumor Functions in Cytolytic T Cells
Authors: Anirban Banerjee, Krishnamurthy Thyagarajan, Shilpak Chatterjee, Paramita Chakraborty, Pravin Kesarwani, Myroslawa Soloshchenko, Mazen Al-Hommrani, Kristina Andrijauskaite, Kelly Moxley, Harinarayanan Janakiraman, Matthew J. Scheffel, Kristi Helke, Kent Armenson, Viswanathan Palanisamy, Mark P. Rubinstein, Elizabeth-Garrett Mayer, David J. Cole, Chrystal M. Paulos, Christina Voelkel-Johnson, Michael I. Nishimura, Shikhar Mehrotra
Journal: Cancer Research (2016)

Abstract Repetitive stimulation of T-cell receptor (TCR) with cognate antigen results in robust proliferation and expansion of the T cells, and also imprints them with replicative senescence signatures. Our previous studies have shown that life-span and antitumor function of T cells can be enhanced by inhibiting reactive oxygen species (ROS) or intervening with ROS-dependent JNK activation that leads to its activation-induced cell death. Because tumor suppressor protein p53 is also a redox active transcription factor that regulates cellular ROS generation that triggers downstream factor–mediating apoptosis, we determined if p53 levels could influence persistence and function of tumor-reactive T cells. Using h3T TCR transgenic mice, with human tyrosinase epitope–reactive T cells developed on p53 knockout (KO) background, we determined its role in regulating antitumor T-cell function. Our data show that as compared with h3T cells, h3T-p53 KO T cells exhibited enhanced glycolytic commitment that correlated with increased proliferation, IFNγ secretion, cytolytic capacity, expression of stemness gene signature, and decreased TGF-β signaling. This increased effector function correlated to the improved control of subcutaneously established murine melanoma after adoptive transfer of p53-KO T cells. Pharmacological inhibition of human TCR-transduced T cells using a combination of p53 inhibitors also potentiated the T-cell effector function and improved persistence. Thus, our data highlight the key role of p53 in regulating the tumor-reactive T-cell response and that targeting this pathway could have potential translational significance in adoptive T-cell therapy. Cancer Res; 76(18); 5229–40. ©2016 AACR.
Factors associated with failure of emergency department management in children with acute moderate or severe asthma: a prospective, multicentre, cohort study
Authors: Francine M Ducharme, Roger Zemek, Bhupendrasinh F Chauhan, Jocelyn Gravel, Dominic Chalut, Naveen Poonai, Marie-Claude Guertin, Caroline Quach, Lucie Blondeau, Sophie Laberge
Journal: The Lancet Respiratory Medicine (2016)
Abstract 3294: Treponema denticola, a periodontal pathogen, promotes stemness and migration in oral squamous cell carcinoma
Authors: Pachiyappan Kamarajan, Islam Ateia, Jae M. Shin, J Christopher Fenno, Yvonne L. Kapila
Journal: Cancer Research (2016)

Abstract Periodontitis is a chronic infectious disease characterized by inflammation and destruction of periodontal tissues including the periodontal ligament fibers and alveolar bone. Recent epidemiological studies have revealed a significant association between periodontitis and oral cancer. While the precise mechanisms that mediate these associations are not well understood, periodontal pathogens, including Treponema denticola (T. denticola), which are believed to initiate the destructive inflammatory responses and dysbiosis or dysregulation of tissue homeostasis that characterize periodontal disease may contribute to oral cancer. However, knowledge about T. denticola's contribution to oral cancer is limited. Previously, we showed that nisin ZP, a bacteriocin and commonly used food preservative, reduced tumorigenesis in vivo and long term treatment with nisin ZP extended survival. In a separate study, we further showed that nisin ZP exhibits antimicrobial and antibiofilm effects, limiting T. denticola viability. The antimicrobial doses of nisin ZP are two orders of magnitude lower than the antitumor doses. The present study investigated the impact of T. denticola on the stemness, migration, and tumorigenesis of oral squamous cell carcinoma (OSCC), and nisin's potential modulatory effects on these processes. To investigate the role of T. denticola on OSCC tumorigenesis, OSCC cells were treated with T. denticola and with or without nisin ZP then assayed for stemness (orasphere) and migration. Treatment with T. denticola enhanced OSCC orasphere formation and migration without affecting cell viability or inducing apoptosis. Addition of nisin ZP inhibited these T. denticola-mediated processes. These data indicate that the periodontal pathogen T. denticola promotes stemness and migration of OSCC cells, and thereby may contribute to oral cancer tumorigenesis. Citation Format: Pachiyappan Kamarajan, Islam Ateia, Jae M. Shin, J Christopher Fenno, Yvonne L. Kapila. Treponema denticola, a periodontal pathogen, promotes stemness and migration in oral squamous cell carcinoma. [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 3294.
P1167 : Shared disease-susceptibility genes between primary biliary cirrhosis and crohn's disease in the Japanese population
Authors: Y. Aiba, K. Yamazaki, N. Nishida, M. Kawashima, Y. Hitomi, A. Komori, M. Kubo, K. Tokunaga, M. Nakamura
Journal: Journal of Hepatology (2015)
Abstract 1259: MutT homolog 1 (MTH1) is upregulated in glioblastoma multiforme: its inhibition by siRNA or crizotinib results in impaired cell migration and tumor growth <i>in vivo</i>
Authors: Marco Timmer, Sara Gerdi Kannampuzha, Gabriele Röhn, Roland Goldbrunner
Journal: Cancer Research (2016)

Abstract Introduction: MutT homolog1 (MTH1) is required for the survival of cancer cells. These are characterized by irregular redox formation resulting in the production of reactive oxygen species which damage the deoxynucleoside triphosphate pool and subsequently the DNA. MTH1 inhibits the incorporation of oxidized bases into the DNA thus avoiding apoptosis of cancer cells. Our aim was to analyze the pathophysiological role of MTH1 in glioma. Materials and Methods: MTH1 expression was analyzed using quantitative PCR and Western Blot analysis in human glioma tissue (n = 80). We compared peritumoral tissue with grade II, III, and IV gliomas. Moreover, we compared primary to secondary GBM and initial tumors with recurrent tumors after temozolomide treatment. U87 cell migration was tested after siRNA knock-down of MTH1 and treatment with the MTH1 inhibitor crizotinib by scratch assays. After orthotopic implantation of MTH1-siRNA treated U87 into rats, tumor size was measured after 8 days. Results: In RT-PCR and Western blot we found a significantly higher expression of MTH1 in primary and secondary glioblastoma than in lower grade brain tumor. Immunofluorescence staining of histological sections of glioblastoma showed also a higher level of MTH1 than in lower grade tumors. By nucleofection, we transfected siRNA MTH1 into the U-87 glioblastoma cells and a slower migration was investigated applying migration assay. Furthermore, treatment with the drug crizotinib inhibited MTH1 and decreased U-87 cell migration. The xenograft study showed a slower tumor growth when U87 cells were transfected with MTH1 siRNA compared to normal U87. Conclusion: These results show that MTH1 plays an essential role in migration and proliferation of glioma cells resulting in clinically observed malignization of glioma and disease progression in recurrent glioblastoma. Moreover, MTH1 can be targeted by Crizotinib indicating a role for potential future therapies. Citation Format: Marco Timmer, Sara Gerdi Kannampuzha, Gabriele Röhn, Roland Goldbrunner. MutT homolog 1 (MTH1) is upregulated in glioblastoma multiforme: its inhibition by siRNA or crizotinib results in impaired cell migration and tumor growth in vivo. [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 1259.
US probes first apparent non-sexual person-to-person Zika transmission and first domestic outbreak
Authors: Owen Dyer
Journal: BMJ (2016)

A Utah man who cared for an elderly male relative infected with Zika virus has tested positive for the disease, despite not traveling to any known Zika zone. The case has raised new questions about how the disease may spread. It came in a week when the first apparent US case from local mosquito bite appeared in Florida, and a week after the first report of female-to-male sexual transmission in New York.

In the Utah case the original patient, who contracted the disease abroad, has now died, the first death in a person with Zika virus in continental United States. The exact cause of death has not been attributed, as he had comorbid conditions. His death was preceded by severe thrombocytopenia. Thrombocytopenia was also present in a man with Zika virus who died in Puerto Rico last week.

The younger Utah patient recovered after a brief fever with rash. Health officials were …
Abstract 3592: BaP induces chromosome missegregation through mitotic spindle defects in normal lung epithelial cells
Authors: Jose T. Thaiparambil, Randa El-Zein
Journal: Cancer Research (2016)

Abstract Lung cancer remains the leading cause of cancer related deaths in the United States. Cancer results from an accumulation of multiple genetic events leading to genomic instability that is a crucial early event in carcinogenesis. Aneuploidy is the most frequently identified genomic abnormality in cancer. We have previously reported a significantly higher level of aneuploidy in smokers who developed lung cancer as compared to smoker controls. Benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon, is a pulmonary carcinogen and one of 60 different carcinogens found in tobacco smoke. In this study, we hypothesize that B(a)P disrupts mitotic spindle assembly that impairs the fidelity of mitosis leading to chromosome missegregation and aneuploidy. To test our hypothesis, we use confocal imaging in combination with traditional molecular biology techniques to dissect the precise mechanism by which B[a]P induces chromosome missegregation and aneuploidy. Mitotic spindle defects in the form of chromosome lags and bridges, monopolar and multipolar spindles, were assessed in normal lung epithelial cells after treatment with 10μM B[a]P for 6 hrs. Spindle defects were assessed at 24, 48, 72 and 96 hours after treatment. Immunofluorescence revealed abnormal mitosis in the prometaphase through the telophase stage of mitosis. Our result show that B[a]P exposure induced abnormal spindles in the form of monopolar (14%) and multipolar (4%) spindles. High resolution confocal images further revealed that B[a]P exposure led to misoriented mitotic spindles with an abnormal spindle angle [-380] relative to normal plane [180]. Chromosome lagging at both metaphase (17%) and anaphase (9%) has also been recorded in response to B[a]P exposure, observations that result from defects in the mitotic apparatus and kinetochores. Furthermore, we assessed the extent of B[a]P induced genetic instability [in the form of double strand DNA breaks] using gama-H2AX in order to elucidate the underlying mechanism associated with accumulated genetic damage and chromosome missegregation. Our data indicate that B[a]P results in accumulation of mitotic abnormalities and gama-H2AX foci (22%) peaks at 48 hr compared to other time points. Taken together, our data show that B[a]P potently induces mitotic abnormalities by disrupting kinetochore microtubules. The induction of mitotic abnormalities by B[a]P leading to chromosome missegregation and aneuploidy, would unravel a novel targetable molecular mechanism of cigarette smoke induced lung tumorigenesis. Citation Format: Jose T. Thaiparambil, Randa El-Zein. BaP induces chromosome missegregation through mitotic spindle defects in normal lung epithelial cells. [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 3592.
Appropriate Apixaban Dosing
Authors: Jeffrey I. Weitz, John W. Eikelboom
Journal: JAMA Cardiology (2016)

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Leucopenia during Treatment Is a Good Prognostic Risk Factor for Patients Undergoing Chemotherapy for Hodgkin’s Lymphoma: An Analysis of the German Hodgkin Study Group (GHSG).
Authors: Beate Klimm, Thorsten Reineke, Heinz Haverkamp, Hans T. Eich, Karolin Behringer, Andreas Josting, Beate Pfistner, Volker Diehl, Andreas Engert
Journal: Blood (2005)
Abstract 4881: CD300f-regulated efferocytosis by dendritic cells and macrophages controls the initiation and resolution of experimental colitis
Authors: Ha-Na Lee, Linjie Tian, Jacquice Davis, Mariam Quinones, Yasmine Belkaid, Konrad Krzewski, John E. Coligan
Journal: Cancer Research (2016)

Abstract Phagocytic clearance of apoptotic cells (efferocytosis) is critical for resolution of inflammation and prevention of chronic inflammatory disorders, including inflammatory bowel diseases, and inflammation-associated cancer. CD300f (CLM-1), a cell surface receptor that recognizes phosphatidylserine exposed on apoptotic cells, has been shown to promote efferocytosis by macrophages. In the present study, we found that CD300f plays a critical role in controlling the severity and duration of dextran sulfate sodium (DSS)-induced colitis, and CD300f-expressing macrophages and dendritic cells (DC) were identified as key players controlling disease pathogenesis. Compared to Cd300f+/+ mice, Cd300f-/- mice showed increased susceptibility to DSS-induced colitis and impaired resolution of inflammation. In Cd300f-/- mice, macrophage-mediated efferocytosis was reduced, resulting in apoptotic cell accumulation in the gut mucosa. In contrast, Cd300f-/- DC engulfed apoptotic cells more efficiently than Cd300f+/+ DC. CD300f-deficient DC transfer exacerbated DSS-induced inflammation and delayed its resolution, whereas CD300f-expressing macrophage transfer attenuated DSS-induced inflammation. Hyperactive efferocytosis by CD300f-deficient gut DC resulted in excessive tumor necrosis factor-á (TNF-á) secretion, which induced secondary interferon-ã (IFN-ã) over-production, both of which impaired the resolution of colitis. TNF-á neutralization resulted in decreased levels of gut pro-inflammatory cytokines and significant disease amelioration. Collectively, these results suggest that CD300f is important for preventing chronic inflammation by enhancing macrophage efferocytosis and inhibiting TNF-á production induced by DC efferocytosis. From these findings, it is conceivable that increasing macrophage-mediated efferocytosis and suppressing DC-mediated efferocytosis through upregulation of CD300f expression would provide a new therapeutic strategy for inflammatory bowel disease patients. Citation Format: Ha-Na Lee, Linjie Tian, Jacquice Davis, Mariam Quinones, Yasmine Belkaid, Konrad Krzewski, John E. Coligan. CD300f-regulated efferocytosis by dendritic cells and macrophages controls the initiation and resolution of experimental colitis. [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 4881.
A new perspective in cancer treatment: Low dose metronomic chemotherapy with old known drugs in advanced breast cancer patients—Phase II clinical trial.
Authors: Herman Andres Perroud, Carlos Maria Alasino, Maria Jose Rico, Mauricio Ariel Menacho, Leandro Ernesto Mainetti, Stella Maris Pezzotto, Francisco Nestor Queralt, Viviana Rosa Rozados, Olga Graciela Scharovsky
Journal: Journal of Clinical Oncology (2015)

e13500 Background: The oral administration of Cyclophosphamide (Cy) and Celecoxib (Cel) encourage the use of low-dose metronomic chemotherapy (MC) to treat heavily pretreated, multidrug resistant, advanced breast cancer patients (ABCP). Methods: Study design: Single arm, mono-institutional, nonrandomized, phase II, two steps clinical trial (Approved by Bioethics Committee #5732/2007 and ANMAT-Argentine Regulatory Authority- #4596/09). 15 patients were enrolled in the first stage, and 5 additional patients in the second one (β error = 0.10-0.20; α error = 0.05). Treatment plan: Cy 50 mg po.d+Cel 200 mg p.o bid. Patient eligibility criteria: 21-80 years old, ≥ than 3 month of life expectancy, ABCP progressed to anthracyclines, taxanes and capecitabine, ≤ 4 chemotherapy schemes, at least 1 measurable lesion (RESIST 1.1), ECOG scale ≤ 2, appropriate bone marrow and renal function. Informed consent signed. Primary endpoint: Progression free survival (PFS) and clinical benefit (CB). Results: The main clinical outcomes were prolonged disease stabilization (SD > 24 weeks) in 10/20 patients (50%) and partial remission (PR) in 1/20 (5%). No complete remissions (CR) were observed. Response rate was 5% (CR+PR: 1/20). CB was 55% (PR+SD ≥ 24 weeks: 11/20). TTP was 21.1 weeks (median: 15.5, range: 3-81). Median TTP in patients who achieved CB was 35.6 weeks (median: 27, range: 24-81). PFS at 24 weeks was 50%. Overall survival (OS) rate 1 year after enrollment was 25%. Mean OS was 44.20 weeks (median: 36 range: 5.14-232.14 weeks). There were no grade 3/4 toxicities associated to treatment. Quality of life did not change or improved transiently in a high proportion of patients. Conclusions: Treatment was effective to control advanced disease in this group of patients, with a low toxicity profile and excellent tolerability. These results encourage the use of this MC scheme in heavily pretreated ABCP, as well as the development of new oral MC schemes that do not affect the quality of life. Although the main objective was not the evaluation of effectiveness in elderly patients, due to the lack of toxicity and clinical benefit, this kind of treatment could be a valid option for this group of patients. Clinical trial information: 4596/09.
Abstract 3713: Targeting alternative DNA repair pathways for cancer cell killing with heavy ion particles
Authors: Huichen Wang, Premkuma Saganti
Journal: Cancer Research (2016)

Abstract Heavy ion therapy is a promising approach for cancer treatment, particularly for locally advanced solid tumors. High linear energy transfer (LET) radiation induces greater lesions density in close proximity (clusters) compared that in low-LET radiation. Such clustered DNA damage is thought to be more difficult to repair than isolated DNA damage produced by equivalent doses of low-LET radiation and persist longer in irradiated cells. It has been known that homologous combination contributes to the repair of clustered DNA damage other than classic non-homologous end-joining (NHEJ). DNA double-strand breaks are also repaired by an alternative NHEJ pathway with PARP1, DNA ligase III and Mre11. This alternative pathway is error prone and contributes to genomic instability, such as chromosomal translocation and telomere fusion. Genetic analysis of tumors in TCGA database revealed that these genes are amplified in human tumors and their overexpression is correlated with poor overall survival of cancer patients. However, influence of alternative NHEJ pathways on the relative biological effectiveness (RBE) of heavy ions remains unclear. Here we investigated the effect of PARP-1 and DNA ligase III on RBE of heavy ion particles on cell survival and chromosomal aberration in breast cancer cells and pancreatic cancer cells. Cells were irradiated with X-ray, Carbon (290 MeV/n, 13 KeV/μM) and Iron (1 GeV/n, 150 KeV/μM). We found that overexpression of PARP-1 and DNA ligase III increased RBE of carbon and iron. PARP inhibitor reduced chromosomal aberration induced by heavy ions. This study may provide predictor of radiation responsive of tumor cells from cancer patients that would lead to patient stratification for heavy ion therapy selection Citation Format: Huichen Wang, Premkuma Saganti. Targeting alternative DNA repair pathways for cancer cell killing with heavy ion particles. [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 3713.
Endoscopic gastroesophageal mucosal flap valvuloplasty with anti-reflux potential
Authors: Jiaoyang Lu, Yanmei Li, Taotao Jiao, Ying Liu, Yanan Wang, Yatian Wang, Minhua Zheng, Xuefeng Lu
Journal: Endoscopy (2016)

The lower esophageal sphincter (LES), the crural diaphragm, and the gastroesophageal flap valve (GEFV) are key components of the esophagogastric junction (EGJ) and the anti-reflux barrier. Currently available endoscopic techniques to treat gastroesophageal reflux disease (GERD) include suturing devices, transmural staplers, prosthetic implantation, and radiofrequency ablation; all aimed at reinforcing the LES [1]. Although reflux can occur when increases in intra-abdominal pressure surpass the hypotensive LES pressure, most reflux takes place during spontaneous relaxations of the EGJ, which are known as "the transient LES relaxations" (TLESRs) [2].