tbuckley/cabot-search huggingface dataset:
A pooled analysis of concurrent chemoradiotherapy (CCRT) for patients with stage III non-small cell lung cancer (NSCLC) who participated in U.S. cooperative group trials: Comparing the outcomes of elderly to younger patients (pts).
Authors: Tom Stinchcombe, Ying J Zhang, Everett E. Vokes, Joan H. Schiller, Jeffrey D. Bradley, Walter John Curran, Benjamin Movsas, Steven E. Schild, Gerald H. Clamon, Ramaswamy Govindan, George R. Blumenschein, Mark A. Socinski, Neal Ready, Wallace L. Akerley, Harvey Jay Cohen, Herbert Pang, Xiaofei F. Wang
Journal: Journal of Clinical Oncology (2016)

8508 Background: CCRT is the standard treatment (TRT) for stage 3 NSCLC. Elderly pts are common and may have increased toxicity and poorer results from CCRT. Methods: We collected individual patient data (IPD) of pts who participated in cooperative group phase 2/3 trials of CCRT for stage 3A/3B pts from 1990-2012. We compared the overall survival (OS), progression-free survival (PFS), and adverse events (AE’s) for pts age ≥70 years (yrs) (elderly) vs. <70 yrs (younger). Unadjusted and adjusted Hazard Ratios (HRs) for survival time and their confidence intervals (CIs) were estimated by single-predictor and multivariable Cox models. Unadjusted and adjusted Odds Ratios (ORs) for AE’s and their CIs were obtained from single-predictor and multivariable logistic regression models. Results: IPD from 15 trials were analyzed; 2243 pts were younger and 702 were elderly. Median OS and PFS for elderly and younger pts are in the table. In the unadjusted and multivariable models elderly pts had worse OS (HR=1.19; 95%CI=1.08-1.31, and 1.18; 95% CI=1.06-1.32, respectively). In the unadjusted & multivariable models, elderly and younger pts had a similar PFS (HR=1.05; 95% CI=0.96-1.15 and 1.06, 95% CI=0.95-1.17, respectively). The rates of AE’s and TRT related deaths are presented in the table. Elderly pts had a higher rate of AE’s in the unadjusted & multivariable models (OR=1.27; 95% CI=0.99-1.63 and 1.33; 95% CI=1.04-1.72, respectively). A lower percentage of elderly pts completed TRT (50.9% and 61.2%, respectively; P < 0.0001) and higher percentage stopped due to AE’s (20.5% and 14.1%; P<0.0001). Conclusions: Elderly pts enrolled in cooperative group CCRT trials had worse OS, but similar PFS. The rates of severe AE’s was higher and a lower percentage of elderly pts completed TRT. Elderly Younger P-valuea Median OS (months) 15.3 17.7 0.0002 Median PFS (months) 8.6 9.1 0.2858 All toxicities grade ≥3 87% 84% 0.0575 Hematologic AE’s grade ≥3 65% 61% 0.0804 Non-hematologic AE’s ≥3 67% 59% 0.0002 Grade 5 AE’s 7.8% 3.9% <0.0001 TRT related deaths 3.2% 2.0% 0.1233 a Log-rank test for survival times, chi-square test for AE’s, and Fischer exact test for TRT related deaths.
Abstract 518: O-GlcNAcylation regulates breast cancer cell invasion via the NAD+-dependent deacetylase SIRT1
Authors: Christina M. Ferrer
Journal: Cancer Research (2015)

Abstract Cancer cells increase nutrient consumption leading to the altered metabolic state known as the Warburg effect. One pathway dependent on glucose, glutamine and acetyl-CoA is the Hexosamine Biosynthetic Pathway (HBP). Increased flux through the HBP leads to elevated post-translation addition of O-linked-β-N-acetylglucosamine (O-GlcNAc) on a diverse population of nuclear and cytosolic proteins, many of which are implicated in cancer. Recently, our lab provided the first evidence that breast and prostate cancers increases total O-GlcNAcylation by increasing O-GlcNAc Transferase (OGT) levels. Importantly, reducing OGT activity inhibits cancer cell invasion in vitro and metastasis in vivo. OGT inhibition reduces breast and prostate cancer cell invasion through, in part, inhibition of the oncogenic transcription factor, FOXM1 and its transcriptional target matrix metalloproteinase 2 (MMP2). Here, we show that OGT regulation of FOXM1 and cancer cell invasion requires regulation of the NAD+-dependent deacetylase, SIRT1. SIRT1 is a NAD+-dependent deacetylase regulated by changes in energy metabolism and its levels have been found to be reduced during breast cancer progression. We demonstrate an inverse relationship between O-GlcNAcylation and SIRT1 protein level and activity in multiple breast cancer cells and show that SIRT1 regulation by O-GlcNAcylation occurs in an AMPK-dependent manner. Consistent with this idea that reducing O-GlcNAcylation increases SIRT1 activity, we found that reducing OGT levels results in increased NAD+ metabolite levels in breast cancer cells. Importantly, we demonstrate that SIRT1 is critical for OGT-mediated regulation of FOXM1 protein ubiquitination and proteosomal degradation as reducing SIRT1 levels or activity reverses OGT-mediated regulation of FOXM1 and invasion in aggressive triple negative breast cancer cells. Furthermore, we show that SIRT1 regulates FOXM1 to modulate its transcriptional target MMP2 to promote breast cancer cell invasion. Collectively, these data indicate that flux through HBP, via O-GlcNAcylation, connects this nutrient sensing pathways with SIRT deactylases to regulate cellular invasion signaling via regulation of FOXM1. Citation Format: Christina M. Ferrer. O-GlcNAcylation regulates breast cancer cell invasion via the NAD+-dependent deacetylase SIRT1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 518. doi:10.1158/1538-7445.AM2015-518
Fatal attractions? Correlations of CXCL12-CXCR4-CXCR7 expression with disease progression in melanoma and Kaposi sarcoma
Authors: L.C. Spender, G.J. Inman
Journal: British Journal of Dermatology (2016)

Linked Article:McConnell et al. Br J Dermatol 2016; 175:1210–1220. Linked Article:Desnoyer et al. Br J Dermatol 2016; 175: 1251–1262.
Erratum. George A. Bray, MD: Progress in Obesity—Multidisciplinary Research, Multidimensional Man. Diabetes Care 2016;39:1481–1485
Authors: Donna H. Ryan, Barbara C. Hansen, William T. Cefalu
Journal: Diabetes Care (2016)

In the second paragraph of the print version of the article listed above, it was stated that George Bray worked at G.D. Searle, located in New York, NY. The location was Skokie, IL, a suburb of Chicago.

In …
Clinical and Radiological Features of Pseudomyxoma Peritonei
Authors: J Hossain, T Malabarey, I Al-Mofleh, N E-D Hawass, A H Ismail
Journal: Journal of the Royal Society of Medicine (1989)

Pseudomyxoma peritonei is due to diffuse involvement of the peritoneal cavity with mucinous material. Four patients were found in two major general hospitals in Riyadh. All patients were male. Cardinal clinical features were abdominal distension, pain and weight loss. Computed tomography was helpful preoperatively. Laparoscopy or laparotomy were performed to arrive at a correct diagnosis.
Prognostic Factors and Life Expectancy in Myelodysplastic Syndromes Classified According to the WHO Criteria. A Basis for Clinical Decision-Making.
Authors: Luca Malcovati, Matteo G. Della Porta, Cristiana Pascutto, Lucia Malabarba, Erica Travaglino, Francesco Passamonti, Rosangela Invernizzi, Mario Lazzarino, Mario Cazzola
Journal: Blood (2004)
Abstract 3141: Restricting aerobic glycolysis provides functional improvement of chimeric antigen receptor (CAR)-modified T cells
Authors: Jillian P. Smith, Adrienne H. Long, Crystal L. Mackall
Journal: Cancer Research (2015)

Abstract Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has proven effective at treating hematologic malignancies, however similar success has not been observed using CARs targeting other antigens. We have observed that several CARs, including a GD2-targeted CAR, are limited in efficacy due to T cell exhaustion induced by tonic, antigen-independent signaling. This phenomenon is triggered by oligomerization of scFvs on the surface of transduced T cells, leading to chronic CAR zeta signaling and early exhaustion characterized by a diminished proliferative potential, poor cytokine production, and overexpression of inhibitory receptors including PD1, TIM3 and LAG3. Early CAR T cell exhaustion is also associated with an altered cellular metabolism that is more highly dependent on glycolysis compared to CD19 CAR T cells or untransduced, activated control cells. Using a Seahorse Extracellular Flux Analyzer, we found that the rate of glycolysis (ECAR) in GD2 CAR T cells was twice that of CD19 CAR T cells or untransduced controls, and no deficiencies in oxidative phosphorylation in GD2 CAR T cells were observed (normal OCR and spare respiratory capacity). To evaluate whether increased glycolytic metabolism contributes to the development of CAR T cell exhaustion, we sought to restrict glycolysis by culturing GD2 CAR T cells with the hexokinase inhibitor 2-deoxyglucose (2DG) or in media supplemented with galactose instead of glucose. Restricting CAR T cell glycolysis was associated with decreased TIM3 and LAG3 expression and enhanced cytokine production of GD2 CAR T cells but a modest decrease in cytokine production of CD19 CAR T cells. Given the previously reported role of mTOR on promoting glycolytic metabolism, we used rapamycin (sirolimus) in the cell culture during transduction and expansion. Culturing GD2 CAR T cells with rapamycin similarly resulted in slower acidification of cell culture medium and diminished expression of TIM3 and LAG3. Rapamycin treated GD2 CAR T cells retain specific lytic ability of GD2-positive tumor cells compared to non-treated GD2 CARs as measured by chromium release, and these cells persist longer than non-treated cells in a murine xenograft model of GD2-positive 143b osteosarcoma. These results suggest that modulation of T cell metabolism may provide functional benefit and enhance antitumor activity of adoptively transferred tumor antigen specific T cells by diminishing the susceptibility of highly activated T cells to exhaustion. Citation Format: Jillian P. Smith, Adrienne H. Long, Crystal L. Mackall. Restricting aerobic glycolysis provides functional improvement of chimeric antigen receptor (CAR)-modified T cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3141. doi:10.1158/1538-7445.AM2015-3141
Abstract 2645: Preclinical validation of Myc inhibition by a new generation of Omomyc-based inhibitors
Authors: Marie-Eve Beaulieu, Toni Jauset, Daniel Massó-Vallés, Jonathan Whitfield, Erika Serrano, Martin Montagne, Pierre Lavigne, Antonio Villaverde, Mireia Pesarrodona, Esther Vazquez, Laura Soucek
Journal: Cancer Research (2015)

Abstract Deregulated Myc is associated with most human cancers suggesting that its inhibition would be a useful therapeutic strategy. Indeed, we have shown that Myc inhibition displays extraordinary therapeutic benefit in various transgenic mouse models of cancer (i.e. skin, lung, pancreatic cancer and glioma) and causes only mild, well-tolerated and reversible side effects in normal tissues. Furthermore, we demonstrated that Myc has a non-degenerate function in cancer that cannot be replaced by other pathways, even in the most aggressive p53-null tumors. Therefore, Myc could be targeted safely and successfully without eliciting resistance to therapy. For these studies we employed a dominant negative inhibitor of Myc, called Omomyc, which is an effective inhibitor of Myc transactivation function both in vitro and in vivo. Omomyc has so far been utilized exclusively as a transgene and served as a successful proof of principle. Here we discuss our current research with Omomyc and our efforts to develop a clinically viable approach to Myc inhibition. One is based on the direct use of Omomyc itself as a peptide since we have discovered that it natively possesses cell-penetrating activity and it rapidly biodistributes to the lung and brain after intranasal administration. We are finding that the Omomyc peptide - like its transgenic counterpart before - has a therapeutic impact and we are continuing with the preclinical validation of this innovative therapeutic approach to pharmacological Myc inhibition. The second approach takes advantage of state-of-the-art nanocarrier technology to deliver Omomyc systemically, that can be combined with tumour-targeting ligands. These two novel Myc inhibition strategies have the potential to be translated rapidly to the clinic. Citation Format: Marie-Eve Beaulieu, Toni Jauset, Daniel Massó-Vallés, Jonathan Whitfield, Erika Serrano, Martin Montagne, Pierre Lavigne, Antonio Villaverde, Mireia Pesarrodona, Esther Vazquez, Laura Soucek. Preclinical validation of Myc inhibition by a new generation of Omomyc-based inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2645. doi:10.1158/1538-7445.AM2015-2645
Conditional Loss of Dnmt3a Results in Myeloproliferation and Liver-Specific Myeloid Expansion
Authors: Olga A Guryanova, Yen Lieu, Kaitlyn R Shank, Sharon Rivera, Francine E Garrett-Bakelman, Jacob Glass, Matthew D Keller, Suveg Pandey, Daniel Tovbin, Abby R Weinstein, Julie Teruya-Feldstein, Omar Abdel-Wahab, Christopher E Mason, Ari M Melnick, Siddhartha Mukherjee, Ross L. Levine
Journal: Blood (2014)
Genome Wide Single Nucleotide Polymorphism Typing for Identification of Putative Minor Histocompatibility Antigens in Graft Versus Host Disease.
Authors: Ann Mullally, Cheng Li, Haesook Kim, Mehrdad Mohseni, Edwin P. Alyea, Joseph H. Antin, Robert J. Soiffer, Jerome Ritz
Journal: Blood (2006)
Abstract 1270: Ribosome biogenesis is reduced by oncogenic stress in normal cells and is sufficient to trigger cellular senescence
Authors: Frédéric Lessard, Véronique Bourdeau, Sebastian Igelmann, Xavier Deschênes-Simard, Marinieve Montero, Gerardo Ferbeyre
Journal: Cancer Research (2015)

Abstract Senescence is a stable arrest of cell proliferation in which the cells remain viable and metabolically active but display a constitutive activation of the DNA damage response and of the tumor suppressors p53 and RB. The senescent phenotype can be induced by multiple stresses including short telomeres and oncogenes. We have shown that senescence involves the ERK-dependent degradation of selective proteins involved in cell cycle progression and tumorigenesis. We called this process senescence associated protein degradation (SAPD) and it involves many nucleolar proteins that play a role in ribosome biogenesis. Using tritium pulse labelling we found a strong decrease of rRNA synthesis in senescent cells. In addition, qPCR with primers flanking known rRNA processing sites demonstrated defects in the processing of rRNA in senescent cells. Knocking down some of the nucleolar proteins degraded in senescence was sufficient to trigger the process indicating that a decrease in ribosome biogenesis is causal to cellular senescence. Senescence induced by depletion of ribosome biogenesis factors was characterized by accumulation of p53 and in some cases rescued by inhibition of p53 using shRNAs or the viral oncoprotein E6. We will discuss how reduced ribosome biogenesis impact protein biosynthesis in senescent cells. Citation Format: Frédéric Lessard, Véronique Bourdeau, Sebastian Igelmann, Xavier Deschênes-Simard, Marinieve Montero, Gerardo Ferbeyre. Ribosome biogenesis is reduced by oncogenic stress in normal cells and is sufficient to trigger cellular senescence. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1270. doi:10.1158/1538-7445.AM2015-1270
Hemophagocytic Lymphohistiocytosis Is Not Only a Childhood Disease: A Multi-Center Study of 613 Cases from Chinese HLH Workgroup
Authors: Zhao Wang, Yini Wang, Wenqiu Huang, Liangding Hu, Xinan Cen, Lihong Li, Jijun Wang, Na Wei, Xiangzong Zeng, Jia Zhang, Jingshi Wang, Lin Wu
Journal: Blood (2014)
Activity of Selumetinib in Neurofibromatosis Type 1–Related Plexiform Neurofibromas
Authors: Eva Dombi, Andrea Baldwin, Leigh J. Marcus, Michael J. Fisher, Brian Weiss, AeRang Kim, Patricia Whitcomb, Staci Martin, Lindsey E. Aschbacher-Smith, Tilat A. Rizvi, Jianqiang Wu, Rachel Ershler, Pamela Wolters, Janet Therrien, John Glod, Jean B. Belasco, Elizabeth Schorry, Alessandra Brofferio, Amy J. Starosta, Andrea Gillespie, Austin L. Doyle, Nancy Ratner, Brigitte C. Widemann
Journal: New England Journal of Medicine (2016)

Effective medical therapies are lacking for the treatment of neurofibromatosis type 1–related plexiform neurofibromas, which are characterized by elevated RAS–mitogen-activated protein kinase (MAPK) signaling.
551. Enhancement of Gene Therapy Treatment for Sandhoff Disease Through Complimentary Drug Therapy
Authors: Evan J.R. Woodley, Karlaina Osmon, Patrick Thompson, Subha Karumuthil-Melethil, Steven Gray, Jagdeep Walia
Journal: Molecular Therapy (2016)

GM2 gangliosidoses is a group of neurodegenerative lysosomal storage disorders caused by deficiency in the β-hexosaminidase A (HexA) enzyme. HexA is a heterodimer composed of 2 subunits; α- (encoded by the HEXA gene) and β-hexosaminidase β (Encoded by the HEXB gene). Mutations in either gene may cause inactivity of HexA leading to either Tay-Sachs disease (TSD, HEXA mutation) or Sandhoff disease (SD, HEXB mutation) respectively. TSD and SD are clinically indistinguishable phenotypes principally affecting infants and young children that are fatal before the age of 4 years; there is currently no effective available treatment. A mouse model for SD has been developed and these mice reach a humane end point at 14-17 weeks of age. Gene therapy can be an important primary therapeutic strategy, but may fall short of a complete rescue. Neuroinflammation and neurodegeneration have been identified as hallmark pathological mechanisms in GM2 gangliosidosis and can be adjunctive therapeutic targets. Neuroanti-inflammatory/neuroprotective agents like non-steroidal anti-inflammatory drugs (NSAIDs), Histone deacetylase inhibitors and pharmacological chaperones have shown ameliorating effects in SD and similar disease models when used alone. Adeno associated virus (AAV) based expression of Hexosaminidase isoenzymes has been shown to increase survival of Sandhoff mice for long term. We tested the combined role of gene therapy and neuroanti-inflammatory/neuroprotective agents in SD mice. Our methods include injecting neonatal SD mice with a relatively low dose (2×1013 vg/kg) of a novel AAV9 vector expressing Hex A using both α and β subunits. A pilot study established the survival of these mice to be approximately 24 weeks, a 55% increase in life span over vehicle-injected controls. We observed a 47% increase in Hex A activity in the midbrain of treated mice as compared to the vehicle injected controls. Cohorts received treatment with neonatal gene therapy alone or in combination with indomethacin (a NSAID), pyrimethamine (a proven pharmacological chaperone for Hex A) and ITF2357 (a histone deactylase inhibitor) to elicit their combinational therapeutic potential. Each drug is administered daily via oral gavage starting the age of 6 weeks. All treatments have been completed and mice are being monitored for survival benefit and locomotor behaviour. Further analyses of enzyme activity, GM2 ganglioside levels and copy numbers will be done. The results of this study will establish a proof-of-concept for a novel combination gene therapy approach for treatment of GM2 gangliosidoses and similar disorders.
Changes in renal .ALPHA.2-adrenoceptor in experimental hypertension in rats.
Authors: Kazuya Fukuda, Masato Kuchii, Takuzo Hano, Osamu Mohara, Yasumasa Miyamoto, Ichiro Nishio, Yoshiaki Masuyama
Journal: Circulation (1983)

α2-Adrenoceptors were studied in renal membrane fractions from spontaneously hypertensive (SHR), two-kidney, one clip hypertensive (2K, 1C HT) and DOCA-salt hypertensive (DOCA-salt HT) rats, using radioligand binding method. α2-Adrenoceptor concentration in the kidney measured by [3H] yohimbine binding was significantly increased in SHR at 4 weeks old (41.5±2.8 fmol/mg protein, mean ±SEM, p<0.01), 12 weeks old (54.9±2.5 fmol/mg protein, p<0.01) and 35 weeks old (59.8±3.4 fmol/mg protein, p<0.01) as compared with age-matched Wistar-Kyoto rats (WKY, 31.5±2.5, 40.9±1.8, 47.8±2.0 fmol/mg protein, respectively). There were no significant differences in binding affinity and 5'-nucleotidase activity (plasma membrane marker enzyme) between SHR and WKY at any age. In 2K, 1C HT rats, α2-Adrenoceptor concentration in the clipped kidney was higher than that of control rats, but α2-Adrenoceptor concentration in the unclipped kidney was unchanged. binding affinity and 5'-nucleotidase activity showed no significant changes in renal hypertensive rats. In DOCA-salt HT rats, no significant change was found in concentration and affinity of renal α2-Adrenoceptor. The observed increase in renal α2-Adrenoceptor concentration in SHR may contribute to the pathogenesis and maintenance of hypertension through increased sodium and water reabsorption in the kidney.
Abstract 2069: Stromal-epithelial crosstalk of <i>Mig-6</i> has an important role for tumor suppression via progesterone in endometrial cancer
Authors: Tae Hoon Kim, Byung Gak Kim, Jung-Yoon Yoo, Jae Hee Lee, Diego H. Castrillon, Jae-Wook Jeong
Journal: Cancer Research (2015)

Abstract Endometrial cancer is the most common malignancy of the female genital tract. This disease is commonly caused by an imbalance of progesterone (P4) and estrogen (E2) action that E2 stimulates proliferation of uterine epithelial cells while P4 is inhibitory to estrogen-mediated proliferation of the epithelium. Endometrial hyperplasia is also associated with endometrial cancer, which is a proliferative process in epithelium by E2. Responsiveness of progesterone is required to treat endometrial cancer and preserve the fertility of patients. Furthermore, PR expression in the uteri of patients with endometrial cancer has been used as an indicator for a first-rate prognosis. However, more than 30% of patients do not respond to progesterone treatment as a result of progesterone resistance and the mechanism of progesterone resistance is still unknown. Thus, identifying the mechanism of progesterone in endometrial cancer is essential to improve the therapy of this disease. Mitogen-inducible gene 6 (Mig-6) is an important mediator of progesterone receptor (PR) action in the murine uterus. As P4 achieves the inhibition of proliferation by coordinating stromal-epithelial cross-talk, we generated a mouse model in which we specifically ablate epithelial endometrial Mig-6 using Sprr2f-cre mice (Sprr2fcre+ Mig-6f/f) to understand the role of epithelial Mig-6 in the uterus. Sprr2fcre+ Mig-6f/f mice displayed endometrial hyperplasia upon 10 weeks of age and develop endometrial cancer by E2 treatment for 3 months. Interestingly, the hyperplasia exhibited by Sprr2fcre+ Mig-6f/f mice was prevented by P4 treatment for 1 week in morphological and histological analysis. Proliferation decreased in the glandular epithelium of Sprr2fcre+ Mig-6f/f mice by P4, and apoptotic signal was also reduced. The expressions of stromal PR and its target genes were induced in Sprr2fcre+ Mig-6f/f mice after P4 treatment, indicating that P4-induced stromal Mig-6 can prevent the hyperplasia via regulating steroid hormonal signaling. This study suggested that stromal-epithelial communication of Mig-6 is critical in tumor suppressor function via regulating steroid hormonal signaling by progesterone. (This work was supported by American Cancer Society Research Grant, RSG-12-084-01-TBG to J.W.J.) Citation Format: Tae Hoon Kim, Byung Gak Kim, Jung-Yoon Yoo, Jae Hee Lee, Diego H. Castrillon, Jae-Wook Jeong. Stromal-epithelial crosstalk of Mig-6 has an important role for tumor suppression via progesterone in endometrial cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2069. doi:10.1158/1538-7445.AM2015-2069