tbuckley/cabot-search huggingface dataset:
Case 7-1979
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, John W. Braasch, James J. Galdabini
Journal: New England Journal of Medicine (1979)

Presentation of CaseAn 80-year-old woman was admitted to the hospital because of intestinal obstruction.She was well until one year previously, when she entered another hospital because of abdominal pain; gallstones were found, but she refused an operation and was discharged. Subsequently, she had several recurrences of mild abdominal pain. Five days before admission obstipation developed, accompanied by abdominal distention, intermittent crampy pain and mild nausea.There was a history of hemorrhoidectomy, performed many years earlier, followed by an anal stricture. She denied vomiting, diarrhea, melena, jaundice, fever, chills or previous abdominal operations.The temperature was 38.1°C, the pulse . . .
Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity
Authors: Dan A Erkes, Guangwu Xu, Constantine Daskalakis, Katherine A Zurbach, Nicole A Wilski, Toktam Moghbeli, Ann B Hill, Christopher M Snyder
Journal: Molecular Therapy (2016)

Cytomegalovirus is an attractive cancer vaccine platform because it induces strong, functional CD8(+) T-cell responses that accumulate over time and migrate into most tissues. To explore this, we used murine cytomegalovirus expressing a modified gp100 melanoma antigen. Therapeutic vaccination by the intraperitoneal and intradermal routes induced tumor infiltrating gp100-specific CD8(+) T-cells, but provided minimal benefit for subcutaneous lesions. In contrast, intratumoral infection of established tumor nodules greatly inhibited tumor growth and improved overall survival in a CD8(+) T-cell-dependent manner, even in mice previously infected with murine cytomegalovirus. Although murine cytomegalovirus could infect and kill B16F0s in vitro, infection was restricted to tumor-associated macrophages in vivo. Surprisingly, the presence of a tumor antigen in the virus only slightly increased the efficacy of intratumoral infection and tumor-specific CD8(+) T-cells in the tumor remained dysfunctional. Importantly, combining intratumoral murine cytomegalovirus infection with anti-PD-L1 therapy was synergistic, resulting in tumor clearance from over half of the mice and subsequent protection against tumor challenge. Thus, while a murine cytomegalovirus-based vaccine was poorly effective against established subcutaneous tumors, direct infection of tumor nodules unexpectedly delayed tumor growth and synergized with immune checkpoint blockade to promote tumor clearance and long-term protection.
Abstract 5148: Angiotensin II type I receptor drives cancer progression through the FLJ10540/S100A9 pathway in oral cancer
Authors: Chang-Han Chen.
Journal: Cancer Research (2016)

Abstract Oral cancer is the eighth most common cancers and a growing problem worldwide. Despite the easy approach for visual examination, oral cancer is often detected at advanced stages leading to severely decreased patient survival. Identifying reliable molecular markers for oral cancer provided in developing new therapeutic interventions is urgently needed. In this study, we explored that angiotensin II type I receptor (AT1R) was overexpression in tumor tissues of oral cancer patients, and its expression also significantly correlated with advanced TNM-stage, lymph node stage, and the poor 5-year survival rate. Functionally, gain-of function of AT1R in oral cancer cells promoted tumor cell growth in vitro and in xenograft model by MTT/colony formation/BrdU incorporation/time-lapse/IVIS, and 3D-Sonographic imaging appraoches. Furthermore, using the same cell panels, the migratory and invasive abilities were increased by wound healing and Transwell assays and the epithelial-mesenchymal transition (EMT) markers, such as N-cadherin, fibronectin and vimentin were also elevated. Conversely, loss-of function of AT1R in oral cancer cells by using siRNA and CRISPR/Cas9 systems demonstrated that the abilities of tumor proliferation, and motility were decreased in vitro and in vivo. By using syn-expression concept combinging with bioinformatic appraoch, we found that FLJ10540 was a novel dwonstream target of AT1R. FLJ10540 expression was not only regulated by AT1R, but also participated in AT1R-elicited cancer progression in vitro and in vivo. We established FLJ10540 knockout oral cancer cell lines by CRISPR/Casp9 to perform DNA microarray and found that S100A9 was a top ranking target among the differrentially expression in down-regulated candidate sets. By using biochemical approaches and xenograft model, the post-transcriptional level of S100A9 was modulated by FLJ10540. In addition, the AT1R-elicited cancer progression was required for FLJ10540/S100A9 expression. Finally, immunohistochemical analysis of human aggressive oral cancer specimens showed a significant positively correlation between AT1R/FLJ10540 and S100A9 expression. Taken together, these findings suggest that AT1R is not only an important prognostic factor but also a new therapeutic target in the FLJ10540/S100A9 pathway for human cancer. Citation Format: Chang-Han Chen. Angiotensin II type I receptor drives cancer progression through the FLJ10540/S100A9 pathway in oral 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 5148.
Evaluation of low-dose CT scans for surveillance in stage I testicular cancer.
Authors: P. W. M. Chung, M. O'Malley, M. A. S. Jewett, T. Panzarella, D. Hogg, M. J. Moore, P. Bedard, L. Anson-Cartwright, B. Tew-George, M. A. Haider, M. K. Gospodarowicz, P. R. Warde
Journal: Journal of Clinical Oncology (2011)

4565 Background: Surveillance is a standard management option for clinical stage I testicular cancer. Serial CT imaging of the abdomen and pelvis (CTA/P) is a key component of all surveillance protocols. Standard dose CTA/P may result in a radiation exposure of up to 20 mSv and the cumulative exposure to ionizing radiation may have a carcinogenic effect over the lifespan of these young patients who are all cured of their disease. This study evaluated the safety of using low dose CT scans in this setting. Methods: Between 2005 and 2010, 239 patients (193 seminoma, 46 nonseminoma) with stage I testicular cancer were enrolled into a prospective phase II study and initially underwent standard dose CTA/P and low dose CTA/P (40-60% dose reduction). Patients continued with low dose CT alone if image quality was adequate (only 1 patient had poor quality images that could not be used for surveillance). Relapse in the retroperitoneum detected on low dose CT was confirmed with standard dose CT. These CT images were prospectively evaluated by a single radiologist to compare nodal size/number between the 2 imaging techniques. Results: Median age of patients was 36 years (range 18-83) and median follow up was 26 months (range 1-80). There were 32 relapses: 30 in retroperitoneal lymph nodes, 1 with raised serum tumour markers, and 1 in lung alone. Of the 30 nodal relapses, 28 pairs of CTs were assessed for nodal size. Mean size of retroperitoneal nodal relapse (short axis) was 16.9 mm and 16.6 mm for standard and low dose CT, respectively (p=0.28; 95% CI 0.61-0.82). In all cases there was ≤2 mm difference in the nodal size between the imaging techniques. Conclusions: Low dose CT scans may safely reduce radiation exposure due to retroperitoneal imaging during surveillance of stage I testicular cancer with minimal loss of diagnostic quality. The use of this imaging technique should be considered in all surveillance protocols.
Abstract 1011: Endostatin regulates androgen receptor-mediated metabolic and oxido-reductive pathways in prostate cancer cells
Authors: Joo Hyoung Lee, Minsung Kang, James A. Mobley, Guru Sonpavde, W. Timothy Garvey, Victor M. Darley-Usmar, Selvarangan Ponnazhagan
Journal: Cancer Research (2016)

Abstract Endostatin (ES) has been recognized for decades as an endogenous protein with antiangiogenic function. Recent findings, however, indicate the pleiotropic effects of ES in different tissue and cell types, ensuing further investigation on unidentified molecular mechanisms of action. Previously, we have shown that ES exerts a direct role in suppressing prostate cancer cell proliferation by inhibiting androgen receptor (AR) activity, signifying therapeutic potential of ES for targeting both tumor epithelia and endothelia. Subsequent to this finding, we identified robust glucose influx and significant reduction of intracellular ROS levels in LNCaP cells upon ES treatment. The ES mutants with low AR binding did not promote glucose uptake through GLUT1 augmentation, suggesting that AR-targeted effects of ES include modulation of downstream metabolic pathways. Surprisingly, global proteome analysis showed that the levels of major metabolic enzymes either in glycolytic pathway or TCA cycle were not changed upon ES treatment. Instead, ES markedly increased the levels of G6PD (5-fold), NAMPT (2.5-fold), and NAPRT (5-fold), indicating upregulation of the late-limiting steps in NAD biosynthesis and pentose phosphate pathway (PPP). Further proteome analysis of ES-treated LNCaP cells strongly indicated upregulation of ROS scavenging machinery, including SOD2 (3- fold), CAT (2-folds), GSS (2-fold), GSR (1.8-fold), and POR (4.6-fold). Overall, these data suggest that ES can modulate intracellular ROS levels by augmenting glucose uptake, NAD biosynthesis, and the NADPH levels by shunting metabolic pathways to PPP. Given that basal ROS levels are known to increase upon disease progression to higher grade prostate tumors, ES effect of promoting ROS scavenging machinery can be employed as an adjuvant to re-sensitize prostate cancer cells to ROS-inducing chemo- and radiation therapies. Abbreviations: CAT: catalase, GLUT1: glucose transporter isoform 1, G6PD: glucose-6-phosphate dehydrogenase, GSS: glutathione synthase, GSR: glutathione reductase, NAMPT: nicotinamide phosphoribosyltransferase, NAPRT: nicotinate phosphoribosyltransferase, POR: NADPH-cytochrome P450 reductase, ROS: reactive oxygen species, SOD2: manganese superoxide dismutase, TCA: tricarboxylic acid Citation Format: Joo Hyoung Lee, Minsung Kang, James A. Mobley, Guru Sonpavde, W. Timothy Garvey, Victor M. Darley-Usmar, Selvarangan Ponnazhagan. Endostatin regulates androgen receptor-mediated metabolic and oxido-reductive pathways in prostate cancer 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 1011.
A novel small molecule liver X receptor transcriptional regulator, nagilactone B, suppresses atherosclerosis in apoE-deficient mice
Authors: Yuzhou Gui, Sheng Yao, Hong Yan, Liang Hu, Chengyin Yu, Fei Gao, Cong Xi, Huihui Li, Yang Ye, Yiping Wang
Journal: Cardiovascular Research (2016)

Atherosclerosis is the most common cause of cardiovascular diseases, such as myocardial infarction and stroke. We hypothesized that nagilactone B (NLB), a small molecule extracted from the root bark of Podocarpus nagi (Podocarpaceae), suppresses atherosclerosis in an atherosclerotic mouse model.Male apoE-deficient mice on C57BL/6J background received NLB (10 and 30 mg/kg) for 12 weeks. Compared with the model group, NLB treatment (10 and 30 mg/kg) significantly reduced en face lesions of total aorta areas. In RAW264.7 cells, NLB significantly ameliorated cholesterol accumulation in macrophages via enhancing apolipoprotein A-I and HDL-mediated cholesterol efflux. Mechanistically, NLB induced messenger RNA and protein expression of the ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) in RAW264.7 and THP-1 cells. Liver X receptor (LXR) site mutations in the mouse ABCA1 promoter abrogated NLB-mediated luciferase reporter activity. LXRα and LXRβ small interfering RNA suppressed NLB-mediated induction of ABCA1 expression. Consistent with in vitro results, NLB induced ABCA1 expression and suppressed macrophage areas in the aortic sinus. Moreover, NLB treatment did not induce the protein expression of LXR in liver. Hepatic and intestinal cholesterol accumulation was significantly alleviated on NLB treatment. Besides, NLB significantly improved plasma lipid profiles in apoE-deficient mice.Selective LXR activation in macrophages with NLB induces ABCA1- and ABCG1-mediated cholesterol efflux while exerting minimal effects on lipogenesis and lipid accumulation in liver, resulting in regression of atherosclerosis, and therefore might be a promising strategy for therapeutics.
Progress towards 2030 UN goal to end HIV epidemic falters
Authors: Sophie Cousins
Journal: BMJ (2016)

UN leaders have expressed doubt that the goal to end the HIV and AIDS epidemic by 2030 will be met, amid concerns over declining funds and the failure to reduce numbers of new infections in adults.

Speaking in Durban at the International AIDS Conference, the executive director of UNAIDS (the joint UN programme on HIV and AIDS), Michel Sidibe, said that there was a risk the epidemic might slip out of control if investment was lost.

“I’m seeing for the first time a decline in financing from donor countries. If we continue this trend . . . we will not be able to end AIDS by 2030,” he said. “I don’t want to lie to …
Abstract 3552: Regulation of immune homeostasis by direct activator BH3-only proteins
Authors: Lindsey M. Ludwig, Lauren E. Roach, Jill K. Fisher, Loren D. Walensky, James L. LaBelle
Journal: Cancer Research (2016)

Abstract The BH3-only proteins BIM, BID, and PUMA have emerged as both inhibitors of anti-apoptotic BCL-2 family proteins and direct activators of the pro-apoptotic executioner proteins BAX and BAK, and have been implicated in regulating immune cell homeostasis. For example, BIM is a master regulator of B and T cells and its deletion in mice causes splenomegaly and lymphocytosis. Although deletion of Bid or Puma do not grossly impact murine hematopoietic organs, loss of each can protect lymphocytes from certain forms of cell death. Combined deletion of Puma and Bim causes increased lymphocytosis and spontaneous development of B-cell lymphoma, while loss of BID and BIM leads to delayed T cell contraction following antigen-mediated proliferation. To investigate the role of direct activator BH3-only proteins in regulating the adaptive immune response over time, we performed peripheral lymphocyte analyses on single and combinatorial knock-outs of Bim, Puma, and Bid. Select genotypes, such as Bim−/−, Bim−/−Puma−/−, and Bim−/−Puma−/−Bid−/− mice, show lymphocytosis early in life but, unexpectedly, counts were observed to gradually normalize by 40 weeks of age. Given the dominant role of BIM in immune cell homeostasis, we investigated whether this phenotype was dictated by global deletion of Bim or intrinsic to T or B cell-specific Bim deletion. In generating and analyzing Lck-cre and CD19-cre Bim floxed animals, we found that T cell-specific Bim deletion recapitulated early lymphocyte expansion followed by contraction, whereas the lymphocytosis of mice with B cell-specific Bim deletion showed no age-related changes. Further characterization of aged Lck-cre Bim floxed mice revealed spleen weights similar to wild type mice, and thymocytes with increased sensitivity to a range of apoptotic stimuli; these mice also have an increased percentage of regulatory T cells compared to similarly aged wild-type mice, as has been reported for globally-deleted Bim−/− animals. To determine the mechanism underlying the observed lymphocyte contraction, we performed qRT-PCR analysis for a panel of BCL-2 family proteins. We find that aged Lck-cre Bim floxed mice manifest upregulation of a series of BH3-only transcripts, including Puma and Bid, reflective of an intriguing compensatory mechanism to remedy, over time, the lymphocytosis that derives from Bim deletion in T cells. These studies provide new insight into the complexity and dynamism underlying BH3-only regulation of immune cell homeostasis during health, disease, and aging. Citation Format: Lindsey M. Ludwig, Lauren E. Roach, Jill K. Fisher, Loren D. Walensky, James L. LaBelle. Regulation of immune homeostasis by direct activator BH3-only proteins. [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 3552.
Randomized Comparison of Melphalan 200 Mg/m2 v. 280 Mg/m2 As a Preparative Regimen for Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation
Authors: William I. Bensinger, Pamela S Becker, Ted A. Gooley, Thomas Chauncey, David G. Maloney, Robert Vescio, Ajay K. Gopal, Damian J. Green, Oliver W. Press, Michael Lill, Leona Holmberg, Jainulabdeen J Ifthikharuddin, Gordon L. Phillips
Journal: Blood (2012)
Abstract 903: IFN-ã induced PD-L1 on tumor and host cells co-operatively prevents tumor immune elimination after cancer immunoediting
Authors: Takuro Noguchi, Jeffrey P. Ward, Matthew M. Gubin, Cora Arthur, Robert D. Schreiber
Journal: Cancer Research (2016)

Abstract Tumor cells can escape immune destruction via engaging the PD-1/PD-L1 inhibitory pathway. However since PD-L1 is induced on many different cell types by IFN-ã, the importance of PD-L1 on tumor versus host cells in mediating immune escape remains unclear. In this study, we assessed the role of PD-L1 expression on two closely-related but distinct clones derived from the same d42m1 methylcholanthrene (MCA)-induced sarcoma line. Edited d42m1-T3 sarcoma cells grow progressively in wild type (WT) mice but are rejected in mice treated with anti-PD-L1. Upregulation of PD-L1 was observed on both immune and tumor cells in vivo. To assess the role of PD-L1 specifically on tumor cells, we generated d42m1-T3 cells lacking PD-L1 (T3ÄPDL1) using CRISPR-Cas9. T3ÄPDL1 cells were spontaneously rejected in naïve syngeneic WT mice but formed progressively growing tumors in Rag2-/- mice. To explore the role of host-cell expressed PD-L1, we challenged WT mice with 3-fold higher numbers of T3ÄPDL1 cells and found that the tumor cells formed progressively growing tumors in WT mice. However, when tumor bearing mice injected with the high dose of T3ÄPDL1 cells were treated with blocking PD-L1 mAb, they all rejected their tumors. Thus, PD-L1 expression on both tumor and host cells plays a critical role in preventing immune elimination of edited MCA sarcoma cells. Alternatively highly immunogenic, unedited d42m1-T9 sarcoma cells were spontaneously rejected in WT mice due to the presence of the strong rejection antigen, mutant Spectrin-â2. Enforced expression of PD-L1 on unedited d42m1-T9 cells to levels similar to those induced under physiologic in vivo conditions did not alter the regressor phenotype of these cells. In contrast, enforced overexpression of PD-L1 on d42m-T9 cells to levels that were 20 fold higher than physiologic led to formation of progressively growing tumors in WT mice. Thus, physiologic levels of PD-L1 expression on highly immunogenic unedited tumor cells are not sufficient to counteract immune effector mechanisms driven by “strong” tumor antigens. This result shows that adaptive immune resistance occurs only on tumor cells that have undergone immunoediting. Citation Format: Takuro Noguchi, Jeffrey P. Ward, Matthew M. Gubin, Cora Arthur, Robert D. Schreiber. IFN-ã induced PD-L1 on tumor and host cells co-operatively prevents tumor immune elimination after cancer immunoediting. [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 903.
Abstract 775: Combinatorial compound stratification based on integration of LINCS, TCGA and PubChem data
Authors: Vasileios Stathias, Bryce Allen, Jennifer Clarke, Nagi G. Ayad, Stephan Schürer
Journal: Cancer Research (2016)

Abstract The purpose of this study is to leverage the large number of perturbation signatures from the NIH Library of Integrative Network-based Cellular Signatures (LINCS) and integrate them with patient data from The Cancer Genome Atlas (TCGA) and PubChem bioactivity data in an effort to prioritize compounds based on their synergistic effect in cancer treatment. From the large number of LINCS L1000 transcriptional data capturing cellular responses after chemical or genetic perturbations, we extracted gene expression signatures that were indicative of specific LINCS compounds. Moreover, we compared the L1000 transcriptional profiles with ones from TCGA in order to identify characteristic signatures of major cancer types and prioritized small molecule compounds with discordant expression profiles to those cancer types. We then linked the above compounds to protein target annotations and therefore produced a compound-specific protein target profile. For this, we utilized biochemical data produced by the LINCS KinomeScan and KiNative assays and also biochemical data obtained through PubChem. Using the above information, we obtained pairs of compounds that would inhibit unlinked gene sub-networks that were produced through processing of the TCGA transcriptional data. The above process can be used as a means to suggest compound combinations towards specific cancer types and to prioritize the development of compounds with targeted polypharmacology. Citation Format: Vasileios Stathias, Bryce Allen, Jennifer Clarke, Nagi G. Ayad, Stephan Schürer. Combinatorial compound stratification based on integration of LINCS, TCGA and PubChem data. [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 775.
Sunitinib (SU) in patients with advanced, progressive pancreatic neuroendocrine tumors (pNET): Final overall survival (OS) results from a phase III randomized study including adjustment for crossover.
Authors: Eric Raymond, Patricia Niccoli, Daniel Castellano, Juan W. Valle, Pascal Hammel, Jean-Luc Raoul, Aaron Vinik, Yung-Jue Bang, Se-Hoon Lee, Ivan Borbath, Catherine Lombard Bohas, Peter Metrakos, Denis Michel Smith, Jen-Shi Chen, Jean Francois Seitz, Shem Patyna, Xin Huang, Jack Ishak, Sandrine J. Faivre, Philippe B. Ruszniewski
Journal: Journal of Clinical Oncology (2016)

309 Background: In 2010, the pivotal double blind Phase III study met its primary endpoint with a median progression-free survival (PFS) of 11.4 months (mo) for sunitinib vs. 5.5 mo for placebo (PBO) (HR=0.42; 95% CI 0.26-0.66; P &lt;0.001) in patients (pts) with advanced, progressive pNET. This trial showed an OS difference favouring sunitinib (HR=0.41; 95% CI 0.19-0.89; P = 0.02). At 2 years since study closure, median OS was 33.0 mo for SU and 26.7 mo for PBO (HR=0.71; 95% CI 0.47-1.09; P = 0.115). Methods: A total of 171 pts were randomly assigned 1:1 to SU 37.5 mg continuous daily dose (n = 86) or PBO (n = 85). The primary end-point was investigator assessed PFS. Pts receiving PBO could crossover to SU at disease progression. Final OS at 5 years follow-up since study closure was analyzed using the Kaplan-Meier method and Cox proportional hazards model in the intent-to-treat (ITT) population. In addition, a series of methods were used to adjust for cross-over including rank-preserving structural failure time (RPSFT). Clinical trial information: NCT00428597 . Results: At 5 years follow-up since study closure, the median OS was 38.6 mo for those randomized to SU and 29.1 mo for those randomized to PBO (HR=0.73, 95% CI 0.50-1.06; P = 0.094). In total, 59 pts randomized to PBO (69%) crossed over to SU. OS results obtained applying methods to adjust for cross-over are shown in Table 1. Conclusions: The 5-year OS difference (9.5 mo) between SU and PBO is confirmed. Correction for crossover yielded a stronger OS advantage with SU, confirming that crossover likely confounded the OS results. Clinical trial information: NCT00428597. [Table: see text]