tbuckley/cabot-search huggingface dataset:
Abstract 4014: Combination of high-dose irradiation and local interleukin-12 treatment enhance tumor killing and have less toxicities than either treatment alone
Authors: Ji-Hong Hong, Ching-Fang Yu, Fang-Hsin Chen, Chi-Shiun Chiang
Journal: Cancer Research (2016)

Abstract Immunotherapy such as anti-PD-1/PD-L1 is effective in several types of tumors, but in general the response rate is less than 30%. Systemic administration of cytokine such as IL-12 could create anti-tumor immunity but has unacceptable side effects. This study is to test our hypothesis that combination of high-dose local radiotherapy (RT) and local production of IL-12 inside tumors within short period could have potent anti-tumor effects but low systemic toxicity. TRAMP-C1 tumors derived from a murine prostate cancer were either no treatment, or irradiated with 25 Gy, or intra-tumorally injected with Ad-sc-IL12 virus (1×10sup8 pfu), or treated with both modalities at the tumor size of 4mm. RT alone and Ad-sc-IL12 alone could not shrink tumors and only caused tumor growth delay around 7 and 12 days, respectively. The combination of RT with Ad-sc-IL12 virus could shrink the tumors to the sizes of &amp;lt; 2mm and further extended the tumor growth delay more than 20 days. The percentage of lymphocytes and IFN-γproduction were evaluated by flow cytometry and ELISA. The percentages of CD4 cells in tumors were too low to be reliably measured in all groups, but the percentages of CD8 cells were increased in Ad-sc-IL12 virus-treated groups and even much higher in those combined with RT. For mice treated with Ad-sc-IL12 virus injection, the serum IL-12 levels were around 4.5 times increase at day7, but those combined with with RT had significantly lower levels than those treated with virus alone. The serum IFN-γ(Th1 response) levels were around 12 times higher in Ad-sc-IL12 groups at day7 as compared to control or RT only group, but had no significant differences between those treated with combined modality and with Ad-sc-IL12 virus alone. Liver damage is an index for IL-12 toxicity and the levels of GOT and GTP were also lower in those treated IL-12 combined with RT than those treated with IL-12 alone. This study supported our hypothesis and showed that combination of local IL-12 production and local RT are effective in increasing CD8 cells, exerting Th1 response, and enhancing tumor growth delay. The most important is that this combination has less systemic toxicity than local IL-12 production alone. This study provides evidence to develop new strategy for producing a strong anti-tumor and low toxicity for radioresistant tumors by combining RT and IL-12 immunotherapy. Citation Format: Ji-Hong Hong, Ching-Fang Yu, Fang-Hsin Chen, Chi-Shiun Chiang. Combination of high-dose irradiation and local interleukin-12 treatment enhance tumor killing and have less toxicities than either treatment alone. [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 4014.
Abstract 2673: Inhibition of fatty-acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer
Authors: Roman Camarda, Alicia Y. Zhou, Rebecca A. Kohnz, Sanjeev Balakrishnan, Celine Mahieu, Brittany Anderton, Henok Eyob, Shingo Kajimura, Aaron Tward, Gregor Krings, Daniel K. Nomura, Andrei Goga
Journal: Cancer Research (2016)

Abstract Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC) compared to estrogen, progesterone and/or human epidermal growth factor 2 receptor-positive (RP) breast tumors. We and others have shown that MYC alters metabolism during tumorigenesis. However, the role of MYC in TNBC metabolism remains largely unexplored. We hypothesized that pharmacologic inhibition of MYC-driven metabolic pathways may serve as a therapeutic strategy for this clinically challenging subtype of breast cancer. Using a targeted metabolomics approach, we identified fatty-acid oxidation (FAO) intermediates as dramatically upregulated in a MYC-driven model of TNBC. A lipid metabolism gene signature was identified in patients with TNBC in the TCGA and multiple other clinical datasets, implicating FAO as a dysregulated pathway critical for TNBC metabolism. We find that MYC-overexpressing TNBC, including a transgenic model and patient-derived xenograft (PDX), display increased bioenergetic reliance upon FAO. Pharmacologic inhibition of FAO catastrophically decreases energy metabolism of MYC-overexpressing breast cancer, blocks growth of a MYC-driven transgenic TNBC model and MYC-overexpressing PDX. Our results demonstrate that inhibition of FAO is a novel therapeutic strategy against TNBCs that overexpress MYC. Citation Format: Roman Camarda, Alicia Y. Zhou, Rebecca A. Kohnz, Sanjeev Balakrishnan, Celine Mahieu, Brittany Anderton, Henok Eyob, Shingo Kajimura, Aaron Tward, Gregor Krings, Daniel K. Nomura, Andrei Goga. Inhibition of fatty-acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. [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 2673.
Confirmation of the role of diabetes in the local recurrence of surgically resected non-small cell lung cancer.
Authors: A. Recht, J. M. Varlotto, L. N. Medford-Davis, E. Schaefer, J. C. Flickinger, M. M. DeCamp
Journal: Journal of Clinical Oncology (2010)

7069 Background: We recently demonstrated that DM was an independent risk factor for LR for patients undergoing resection of NSCLC. This investigation was performed to confirm or refute this finding in a different patient cohort. Methods: Patients were eligible if they did not have a second primary cancer within five years of original diagnosis, had at least three month follow-up, and did not receive radiotherapy. There were 373 and 168 patients in the original (P1) and confirmatory (P2) cohorts, respectively, with 66 and 30 patients with DM. Chi-squared (categorical) and Kruskal-Wallis (continuous) tests were used to compare characteristics of patient groups as well as failure patterns. Results: Median follow-up was 33 months (range, 3-98 months). Patients with DM were more likely to be older and have high grade tumors, squamous cell carcinoma, and CAD than non-diabetic patients, but did not differ in rates of surgical complications, tumor size, type of resection, number of nodes resected or positive, use of chemotherapy, T, N, or overall stage, or LVI using chi-square testing. DM was an independent risk factor for LR in a Cox model in P2 (p=0.05, HR =2.15) and in P1 (p=0.008, HR=1.90), separately from BMI, glucose control, and the presence of the metabolic syndrome. The rates of LR in the combined population with DM at 2,3, and 5 years were 23%, 33%, and 56%; respectively; these rates were 15%, 19%, and 26% in nondiabetics. There was no association of available mean pre- or post-surgical (n=25 and 27, respectively) HbA1c values on the risk of LR for patients with DM or between patients receiving insulin (n=13), those receiving oral medications (n=39), or those diagnosed with the metabolic syndrome (n=48). DM did not significantly affect patterns of LR. Conclusions: DM was confirmed to be an independent predictor of the risk of LR following resection of NSCLC. No significant financial relationships to disclose.
P1084 : Compound function of Jnk1 and Jnk2 in hepatocytes is protective in acetaminophen-induced liver injury
Authors: F.J. Cubero, W. Hu, G. Zhao, J. Peng, Y.A. Nevzorova, M. Al Masaoudi, L.P. Bechmann, M.V. Boekschoten, M. Muller, N. Gassler, A.E. Canbay, C. Liedtke, C. Trautwein
Journal: Journal of Hepatology (2015)
P1187 : CD4+ T cells from patients with PSC exhibit a reduced apoptotic sensitivity and downregulation of proapoptotic Bim in peripheral blood
Authors: T. Schoknecht, D. Schwinge, C. Weiler-Normann, N. Pannicke, M. Sebode, J. Herkel, A.W. Lohse, C. Schramm
Journal: Journal of Hepatology (2015)
Case 47-1982
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely
Journal: New England Journal of Medicine (1982)

Presentation of Case First admission. A 21-year-old woman was admitted to the hospital because of menorrhagia and a pelvic mass. She was well until 16 months earlier, when menorrhagia developed. Three months later dilatation and curettage revealed acute and chronic endometritis. An antibiotic was prescribed. The patient subsequently had normal menses until nine months before admission, when menorrhagia recurred. Another dilatation and curettage disclosed chronic endometritis, and an antibiotic was prescribed, with improvement. The patient was told that she had cervical lymphadenopathy and that an x-ray film of the chest was abnormal. A third bout of menorrhagia occurred four . . .
Abstract 3514: Inhibition of PI-3 kinase signaling potentiates the apoptotic response to mitotic arrest
Authors: Roaa M. Kassim, Charles B. Shuster
Journal: Cancer Research (2016)

Abstract Anti-mitotic drugs represent a common strategy for cancer chemotherapy by inducing a prolonged prometaphase delay and eventual cell death by apoptosis. Kinesin Spindle Protein (KSP) inhibitors arrest cells in mitosis by blocking bipolar spindle assembly, and these drugs have demonstrated limited side effects in clinical trials. However, they are not as effective as Taxol, whose efficacy is limited by the frequent development of resistance as well as the deleterious effects on non-dividing cells. Recent studies suggest that the ability of cells to maintain energy levels during mitosis could account for the differential responses of cancer cells to mitotic arrest. To determine if manipulating cellular metabolism could potentiate the efficacy of KSP inhibitors, we arrested cells in mitosis in the absence or presence of the PI3-kinase LY294002, and probed for the induction of apoptosis. Because tumor cells respond differently to mitotic arrest, we employed two cell lines that either survive mitotic arrest (MCF7) or undergo apoptosis shortly following mitotic slippage (HeLa). In both cases, simultaneous inhibition of KSP and PI3-kinase induced apoptosis more effectively than mitotic arrest or PI3-K inhibition alone. In the case of HeLa cells, there also appeared to be an acceleration of cell death such that arrested cells underwent apoptosis prior to mitotic slippage. Similar effects were observed using Akt inhibitors, providing additional evidence that PI3-kinase signaling was critical for surviving mitotic arrest. Lastly, we found that increased glucose had a protective effect, further supporting the notion that the ability to survive mitotic arrest depended on the ability to maintain energy levels. If confirmed, this may represent a novel approach for potentiating the anti-tumor activity of KSP inhibitors in the clinic. Citation Format: Roaa M. Kassim, Charles B. Shuster. Inhibition of PI-3 kinase signaling potentiates the apoptotic response to mitotic arrest. [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 3514.
Personalized Therapy by Phenotype and Genotype
Authors: Valeriya Lyssenko, Cristina Bianchi, Stefano Del Prato
Journal: Diabetes Care (2016)

Upon the publication of the results of the 20-year-long UK Prospective Diabetes Study (UKPDS) (1), the general recommendation was to achieve, in as many as possible of individuals with type 2 diabetes (T2DM), a target HbA1c value ≤7%, i.e., the average value associated with significant reduction in the risk of micro- and macrovascular complications. This “universal” glycemic target, however, has been challenged by the results of subsequent intervention trials (2–4). Given the critical analysis of the results of these trials, the American Diabetes Association (ADA) and the American Heart Association suggested that an individualized HbA1c target should be identified based on the duration of diabetes, life expectancy, presence and severity of diabetes complications, and propensity for hypoglycemia (5). This suggestion has been endorsed by several international guidelines. They also suggest a selection of glucose-lowering strategies to be individualized in order to ensure the most appropriate risk-to-benefit ratio for all patients. According to the ADA/European Association for the Study of Diabetes position statement for T2DM management (6), this can be achieved through balanced assessment of efficacy, risk of hypoglycemia, effect on body weight, and costs of available glucose-lowering agents and their combination.

Although the concept of treatment individualization is appealing, how to pursue it in the clinical setting remains highly debated. To this purpose, careful phenotypic description of the person with T2DM may be appropriate. A few years ago, the ABCD approach was proposed to help physicians in individualizing glycemic target and treatment selection (7). “ABCD” stands for four phenotypic traits that are easy to collect and to factor in: age, body weight, complications and comorbidities, and duration of diabetes.

### Age

Age is the strongest risk factor for life expectancy and mortality. The number of elderly people with diabetes is growing, and >70% of the elderly with T2DM …
Abstract 725: HMGB1-mediated RAGE activation mechanism in M2 macrophages
Authors: Armando Rojas, Paulina Araya, Jacqueline Romero, Fernando Delgado-López, Ramón Pérez-Castro, Ileana González, Carolina Añazco, Erik Morales, Jorge Llanos, Fernando Vidal-Vanaclocha
Journal: Cancer Research (2016)

Abstract Tumor-associated macrophages display M2 phenotype and promote immunosuppression, tumor growth, angiogenesis and metastasis. We have previously reported that M2 macrophages express the receptor of advanced glycation end-products (RAGE) and their protumoral activities enhanced by HMGB1, a RAGE ligand highly abundant at the cancer microenvironment. However, RAGE is highly expressed by M1 macrophages and it is unknown if proinflammatory and antitumor cytotoxicity of M1 macrophages become skewed from classical antitumor activities to a tumor permissive profile when M2 macrophages are induced by HMGB1. In order to clarify whether RAGE contributes to inflammatory response inhibition in M2 macrophages, we look at some microRNAs, a tolerance-like state as well as to some epigenetic changes. Polarized M1 and M2 macrophages were derived from wild-type and RAGE-targeted knock-down THP-1 cells and treated with HMGB1 at different times. NFkB activation was assessed by p65, IKBalpha western blots, and p50 and p65 Transcription Factor Assay. Additionally, we analyzed changes of chromatin activity related to HMGB1 treatment by quantitative chromatin immunoprecipitation (ChIP) with antibodies against acetylated or methylated histone H3 at the IL-10 promoter. We showed that RAGE activation by HMGB1 did not produce NFkB activation, as assessed by either IKB alpha and phospho p65 western blots or by p65 and p50 trascription factor assays. In addition, HMGB1 did not modify M2 macrophage expression profile of relevant microRNAs for macrophage polarization such as miR-155, miR-21 and miR-125b. However, ChIP analysis showed that HMGB1 induced a transcription-prone histone modification at the IL-10 promoter in M2 macrophages and this epigenetic imprinting correlated with HMGB1-induced IL-10 production, leading to immunosupression. These results demonstrate that RAGE activation on M2 macrophages did not induce NFkB activation and suggest that epigenetic changes are a major mechanism by which activities described for M1 macrophages upon RAGE activation have become skewed during macrophage polarization. Citation Format: Armando Rojas, Paulina Araya, Jacqueline Romero, Fernando Delgado-López, Ramón Pérez-Castro, Ileana González, Carolina Añazco, Erik Morales, Jorge Llanos, Fernando Vidal-Vanaclocha. HMGB1-mediated RAGE activation mechanism in M2 macrophages. [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 725.
Abstract 3801: Pro-chemotherapeutic effects of antibody against extracellular domain of claudin-4 in bladder cancer
Authors: Masaomi Kuwada, Yoshitomo Chihara, Yi Luo, Takamitsu Sasaki, Kiyohide Fujimoto, Masuo Kondou, Hiroki Kuniyasu
Journal: Cancer Research (2016)

Abstract Bladder cancer displays an aggressive phenotype in the muscle-invasive phase, and is associated with a high mortality rate. Therefore, novel molecular therapeutic targets are needed to improve patient survival. A monoclonal antibody against the extracellular domain of the claudin-4 (CLDN4) tight junction protein was established by immunizing rats with a plasmid vector encoding human CLDN4. A hybridoma clone, producing a rat monoclonal antibody recognizing CLDN4 (clone 4D3), was obtained. Immunohistochemistry by using the 4D3 antibody showed that CLDN4 expression was associated with local invasion, nodal metastasis, distant metastasis, and advanced stage in 86 cases of bladder cancer. The 4D3 antibody inhibited growth, invasion, and survival, associated with abrogation of the intratumoral microenvironment; lowered concentrations of epidermal growth factor and vascular endothelial growth factor were found in 3-dimentional cultures of T24 and RT4 cells. In combination with cisplatin therapy, 4D3 enhanced cisplatin cytotoxicity by increasing cellular permeability, leading to increased intracellular cisplatin concentrations. In mouse models of subcutaneous tumors and lung metastasis, 4D3 enhanced tumor growth inhibition, alone and with concurrent cisplatin treatment. The anti-tumor activity of the newly established 4D3 antibody suggests that it may be a powerful tool in CLDN4-targeting therapy, and in combination with chemotherapy. Citation Format: Masaomi Kuwada, Yoshitomo Chihara, Yi Luo, Takamitsu Sasaki, Kiyohide Fujimoto, Masuo Kondou, Hiroki Kuniyasu. Pro-chemotherapeutic effects of antibody against extracellular domain of claudin-4 in bladder cancer. [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 3801.
Abstract 5214: Stage IV colorectal cancer sub-site and patterns of distant metastases
Authors: Jamaica R. Robinson, Polly A. Newcomb, Sheetal Hardikar, Stacey A. Cohen, Amanda I. Phipps
Journal: Cancer Research (2016)

Abstract Approximately 20% of individuals diagnosed with colorectal cancer (CRC) in the United States are found to have distant metastases at the time of their diagnosis, indicating an extremely poor prognosis. Although it is well known that primary CRC typically metastasizes to the liver and/or lungs, little is known regarding which factors might explain the anatomic pattern of CRC metastatic spread. Using population-based registry data from the Surveillance, Epidemiology and End Results (SEER) cancer registry of the Seattle-Puget Sound region, we assessed the relationship between primary CRC sub-site and the presence of synchronous metastases in the liver, lungs, and both the liver and lungs. All individuals with stage IV CRC who were diagnosed between 2010-2014 in the 13-county catchment area and who also had complete data on site of metastasis at diagnosis were included in analyses (N = 1287). In total, 703 (55%) patients had distant metastases confined to the liver at the time of diagnosis, 78 (6%) had lung-only metastases, 190 (15%) had metastases in both the liver and lungs but not at other sites, and 316 (25%) exhibited different patterns of metastatic spread, including to the bone, brain, and other anatomic sites. Using multiple logistic regression models, we compared individuals with different patterns of metastatic spread at diagnosis with respect to primary CRC site and with separate models comparing cases with liver-only metastases to all other metastatic cases, comparing cases with lung-only metastases to all other metastatic cases, and comparing cases with metastases to both the liver and lungs to all other metastatic CRC cases. All models were adjusted for age at diagnosis and sex, as well as for depth of primary tumor growth within the colorectum (T-stage) and extent of cancer spread to lymph nodes (N-stage). The odds of having a primary CRC tumor in the rectum, versus proximal colon, were significantly lower among patients with liver-only synchronous metastases relative to those with other patterns of metastatic spread at diagnosis [odds ratio (OR): 0.62, 95% confidence interval (CI): 0.46 - 0.82]. Conversely, the odds of having a primary CRC located in the rectum were significantly higher among those with metastatic disease confined to the lungs (OR: 2.48, 95% CI: 1.38 - 4.47) and those with metastases to the liver and lungs (OR: 1.97, 95% CI: 1.29 - 3.01). Our findings suggest that a patient's site of primary CRC may be informative with respect to possible pattern of metastatic spread. Citation Format: Jamaica R. Robinson, Polly A. Newcomb, Sheetal Hardikar, Stacey A. Cohen, Amanda I. Phipps. Stage IV colorectal cancer sub-site and patterns of distant metastases. [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 5214.
Subjective or Objective Measures of Cognitive Functioning—What’s More Important?
Authors: Josée Savard, Patricia A. Ganz
Journal: JAMA Oncology (2016)

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A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-AT3) Targeting Antithrombin for Treatment of Hemophilia: Interim Weekly and Monthly Dosing Results in Patients with Hemophilia A or B
Authors: K John Pasi, Pencho Georgiev, Tim Mant, Michael Desmond Creagh, Toshko Lissitchkov, David Bevan, Steve Austin, Charles R Hay, Brigit Brand, Rashid Kazmi, Pratima Chowdary, Margaret V Ragni, Jihong Chen, Akin Akinc, Benny Sorensen, Savita Rangarajan
Journal: Blood (2015)