tbuckley/cabot-search huggingface dataset:
Gene expression and tissue microarray analysis of interleukin-2 complete responders in patients with metastatic renal cell carcinoma
Authors: A. J. Pantuck, Z. Fang, X. Liu, D. B. Seligson, S. Horvath, J. T. Leppert, A. S. Belldegrun, R. A. Figlin
Journal: Journal of Clinical Oncology (2005)

4535 Background: Although some aspects of the molecular genetics of RCC are beginning to be understood, little is known about the genes that dictate treatment response. We hoped to characterize IL-2 Complete Responders by gene expression profile and tissue array analysis. Methods: Total RNA was extracted from fresh frozen tissue, purified, reverse transcribed to cDNA, and hybridized to Affymetrix UI33a gene chips. To reveal global gene differences, we used unsupervised and supervised learning analyses. Tumors were clustered based on a combination of fold change and absolute difference in gene expression. A p value of 0.05 was considered significant. Genes of interest identified by gene arrays having available antibodies suitable for immunohistochemistry (IHC) were evaluated in a RCC tissue array containing 109 patients treated by nephrectomy and immunotherapy. Results: Statistically significant global gene differences between CR and NR groups included genes involved in apoptosis, G protein signaling, the ubiquitin-proteasome proteolytic system, chemokines, intermediate filaments and actin associated proteins heat shock proteins, MHC antigens, and the MAP kinase pathway. A set of 73 genes was able to distinguish Complete from Non Responders. Genes of particular interest included the PTEN tumor suppressor and Carbonic Anhydrase IX (CAIX), both expressed greater in the CR group. Antibodies for CAIX, CAXII, PTEN, Vimentin, Gelsolin, EpCAM, p53, and Ki67 were analyzed by IHC. Univariate predictors of immunotherapy response included CAIX>85% (p=0.027), PTEN (p=0.012), EpCAM (p=0.05), and Vimentin (p=0.02). CAIX and PTEN were the only two markers retained as independent predictors in multivariate models. Conclusions: IL-2 Complete Responders have a signature gene expression pattern that can be differentiated from Non-Responders, and these differences translate into corresponding differences in protein expression. CAIX, PTEN, CXCR4, and other genes may play important roles in dictating IL-2 treatment response in RCC or as possible therapeutic targets. If prospectively validated, gene expression analysis may aid clinicians in selecting appropriate treatment options. No significant financial relationships to disclose.
Tragedy's Legacy
Authors: Garen J Wintemute
Journal: New England Journal of Medicine (2013)

The events in Newtown, Connecticut, described in the Perspective article by Wintemute (Jan. 31 issue)1 were not only national tragedies for the United States but human tragedies for the world. Many sovereign nations have experienced the pain of mass shootings. In April 1996, a man armed with two semiautomatic weapons killed 35 people in Australia. Despite considerable opposition, the government at the time swiftly legislated against ownership of automatic and semiautomatic weapons. State-based laws were repealed for national laws, and large-scale buyback schemes were instituted.2 One fifth of the stock of firearms in Australia was removed. After these actions, the rate of firearm-related deaths in Australia was cut in half.3 In the 18 years before 1996, there were 13 mass shootings.4 There have been none since. Given the potential to reduce by half the 8000 homicides by firearms that occur annually in the United States,5 we remind doctors that this is not just an issue of law but also of public health. We urge clinicians in the United States to take the lead in supporting the reforms described in Wintemute's article. 1 Wintemute, GJTragedy's legacy. N Engl J Med 2013;368:397-399 2 Howard JW. Lazarus rising: a personal and political autobiography. Sydney: HarperCollins, 2011:247-54. 3 Alpers P, Wilson M. Guns in Australia: facts, figures and firearm law. Sydney: Sydney School of Public Health, University of Sydney, 2013 (http://www.gunpolicy.org/firearms/compareyears/10/total_number_of_gun_deaths). 4 Chapman, S, Alpers, P, Agho, K, Jones, MAustralia's 1996 gun law reforms: faster falls in firearm deaths, firearm suicides, and a decade without mass shootings. Inj Prev 2006;12:365-372 5 Federal Bureau of Investigation. Crime in the United States 2011 (http://www.fbi.gov/about-us/cjis/ucr/crime-in-the-u.s/2011/crime-in-the-u.s.-2011/tables/expanded-homicide-data-table-8). Language: en
Phase II study of docetaxel-prednisone (DP) in combination with metronomic cyclophosphamide (CTX) and celecoxib (C) as first-line treatment in castration resistant prostate cancer (CRPC) patients (Pts)
Authors: A. Fontana, G. Bocci, L. Galli, L. Derosa, G. Minuti, M. D'Arcangelo, D. Santini, L. Landi, S. Bursi, A. Falcone
Journal: Journal of Clinical Oncology (2009)

e16032 Background: Metronomic oral CTX and C has demonstrated activity and a favourable toxicity profile in CRCP. Combination of such strategy with the standard DP could be of interest. Methods: Pts with CRPC received D 60 mg/sqm iv day 1 every 3 weeks up to 12 cycles and from day 2 continuously: P 5 mg po BID, CTX 50 mg po daily, and C 200 mg po BID. Primary objective is the percentage of pts free of progression at 6 months; secondary are: PSA levels decrease ≥ 50%, objective responses (RECIST), toxicities (NCI-CTC criteria) survival and pharmacodynamic evaluations. Results: To date 29 pts have been enrolled. Main pts characteristics are: median age 72 years (52–78 years), median PS 0 (0–2), median baseline PSA level 38,8 ng/mL (2.5–1309 ng/mL); main sites of disease: bone 23 pts (79%), lymphnodes 6 pts (21%), liver 1 pt (3,5%). Twenty-nine pts are evaluable for toxicity whereas 28 for PSA response (1 pt abandoned the study due to allergic reaction after first D administration). Median number of D cycles delivered is 10 (1–12) and median duration of metronomic CTX plus P and C is 224 days (35–874 days). Main grade 3 side-effects are: neutropenia (2 pt; 7%), thrombocytopenia, diarrhoea, stomatitis and onycholysis (1 pt; 3.5%). No grade 4 toxicities have been observed.The rate of pts free of progression at 6 months is 80%. Overall 18 pts (64%) showed a PSA decrease ≥ 50% and 23 pts (82%) showed any PSA decrease from baseline (range: 4%-99%of decrease). Four pts are evaluable according to RECIST criteria: we observed 1 CR, 2 SD and 1 PD. At a median follow up of 12,4 months median time to PSA progression is 11.6 months (95% CI 8,3–15). Conclusions: Metronomic CTX plus C in combination with DP is a feasible and tolerable regimen with a promising preliminary activity. The evaluation of plasma levels of thrombospondin-1 (TSP-1), VEGF, sVEGFR-2, VE-cadherin mRNA, and the expression of TSP-1 and VEGF in peripheral blood mononuclear cells, as potential surrogated markers of antiangiogenic activity of the combination, is ongoing. No significant financial relationships to disclose.
PlGF/VEGFR-1 Signaling Promotes Macrophage Polarization and Accelerated Tumor Progression in Obesity
Authors: Joao Incio, Josh Tam, Nuh N. Rahbari, Priya Suboj, Dan T. McManus, Shan M. Chin, Trupti D. Vardam, Ana Batista, Suboj Babykutty, Keehoon Jung, Anna Khachatryan, Tai Hato, Jennifer A. Ligibel, Ian E. Krop, Stefan B. Puchner, Christopher L. Schlett, Udo Hoffmman, Marek Ancukiewicz, Masabumi Shibuya, Peter Carmeliet, Raquel Soares, Dan G. Duda, Rakesh K. Jain, Dai Fukumura
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor VEGFR-1 have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity. Experimental Design: We established diet-induced obese mouse models of wild-type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null, or PlGF-null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples. Results: We found that obesity increased TAM infiltration, tumor growth, and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment toward an antitumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced antitumor immunity. Conclusions: Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993–3004. ©2016 AACR.
Pazopanib (Paz) monotherapy in Asian women who have not progressed after first-line chemotherapy for advanced ovarian, Fallopian tube, or primary peritoneal carcinoma.
Authors: Rongyu Zang, Lingying Wu, Jianqing Zhu, Beihua Kong, Byoung-Gie Kim, Yuanquing Yao, Rutie Yin, Jihong Liu, Qiang Wu, Hextan Yuen Sheung Ngan, Xing Xie, Kung-Liahng Wang, Xiuqin Li, Ming-Shyen Yen, Lihui Wei, Qiong Wang, Ionel Mitrica, Christopher Carpenter, Pingkuan Zhang
Journal: Journal of Clinical Oncology (2013)

5512 Background: Paz, an oral multikinase inhibitor of VEGF, PDGF and c-Kit has showed activity in advanced ovarian cancer. This study evaluated paz as maintenance therapy in Asian women with advanced ovarian cancer. Methods: Subjects with FIGO stage II, III, or IV ovarian, fallopian tube, or primary peritoneal cancer whose disease had not progressed after debulking surgery and followed by chemotherapy were randomized 1:1 to paz 800 mg once daily or placebo for up to 24 months. Primary endpoint was PFS by RECIST v1.0 based on visit date. If a progression occurred between the 2 scheduled visits (6 mos apart), progression was considered to have occurred at the next scheduled scan date. This minimized potential bias due to any imbalance of visit frequency between the arms. Results: 145 Asian subjects were randomized; 144 were treated. Mean age was 52.9 years. At diagnosis 17% were FIGO stage II, 73% stage III and 10% stage IV. After debulking surgery, 30% (n = 44) had no residual disease and 41% (n = 59) had. 47% (28/59) had residual disease ≤1cm. Prior to randomization, all subjects received median 8 cycles of chemotherapy; all subjects received platinum and taxane. At randomization 81% had ECOG status 0, 97% were disease free and all had normal CA-125. At clinical data cut-off median PFS was 18.1 months in both arms. Because of the small sample size a HR was not calculated but the KM curves indicated a trend in favor of paz from 6 to 18 mos; the curves crossed after 18 mos. The adverse event (AE) profile for paz was similar to previous reports except rates of hypertension and neutropenia were higher. The most frequent AEs (≥ 20%) on the paz arm were hypertension (76%), neutropenia (64%), leucopenia (53%), diarrhea (47%), hair color changes (40%), palm-plantar erythrodysaethesia syndrome (29%), ALT increase (28%), thrombocytopenia (24%), AST increase (22%) and TSH increase (21%). Most of these AEs were Grade 1-2. Conclusions: The results of this study alone cannot confirm the efficacy of paz maintenance treatment in Asian women with ovarian cancer, but should be interpreted in conjunction of AGO-OVAR16 study. Clinical trial information: NCT01227928.
Indirect Allorecognition of Donor Class I and II Major Histocompatibility Complex Peptides Promotes the Development of Transplant Vasculopathy
Authors: KARL L. WOMER, JAMES R. STONE, BARBARA MURPHY, ANIL CHANDRAKER, MOHAMED H. SAYEGH
Journal: Journal of the American Society of Nephrology (2001)

Recent clinical and experimental evidence suggests that indirect allorecognition may promote the development of chronic rejection, but definitive experimental studies are lacking. To study the contribution of indirect allorecognition to chronic rejection, naïve Lewis (RT11) rats were immunized with synthetic Wistar Furth (WF) class II-RT1u.D (HLA-DR—like) or -RT1u.B (HLA-DQ—like) or class I-RT1u.A (HLA-A—like) peptides emulsified in complete Freund's adjuvant 7 d before transplantation (n = 5 to 7/group). Experimental and control animals then acted as recipients of fully mismatched WF vascularized cardiac allografts. Recipients received immunosuppression in the form of cyclosporine at a tapering dose that allows for long-term allograft survival. Animals were sacrificed at either 3 or 6 mo, with allograft arterial luminal occlusion scored on elastin stains by a blinded observer. At 3 mo, mean vessel scores were significantly higher in the RT1u.A-immunized versus class II—immunized and control groups (P < 0.05). By 6 mo, there was progression of chronic allograft vasculopathy and a significantly higher mean vessel score in the RT1u.A- and RT1u.D-immunized versus RT1u.B and control groups (P < 0.05). In vitro studies show evidence of shifting MHC allopeptide immunogenicity. It was concluded that T cells primed by specific donor class I and II MHC allopeptides promote the development of chronic vascularized allograft rejection. These novel observations provide definitive evidence of a link between indirect allorecognition and the development and progression of chronic rejection.
Contralateral prophylactic mastectomy in affected carriers of deleterious <i>BRCA1</i> or <i>BRCA2</i> mutations: Does timing of genetic testing matter?
Authors: J. Tchou, S. Sonnad, M. Sargen, B. Weber, K. Nathanson, S. Domchek
Journal: Journal of Clinical Oncology (2006)

10512 Introduction: Prophylactic mastectomy (PM) reduces breast cancer risk by &gt;90% in women who are carriers of deleterious BRCA1 or BRCA2 mutations. Genetic testing prior to breast cancer surgery has been reported to affect PM decision in high-risk patients. The ideal timing of genetic testing as well as the clinical characteristics of affected mutation carriers electing PM remain unclear. This is a pilot study to identify significant clinical characteristics associated with affected carriers who had undergone PM. Methods: Retrospective chart review was performed on 103 breast cancer affected BRCA1 or BRCA2 mutation carriers that were seen at our high risk clinic who had undergone genetic testing between 1995 and 2005. Clinical characteristic, initial surgery treatment modalities, and dates of genetic testing and prophylactic mastectomy were collected and analyzed using the chi-square or Fisher exact tests. Results: Of the 103 affected mutation carriers, 30 (29%) underwent prophylactic mastectomy (PM) where as 73 (71%) did not (no PM). Ethnicity, age of diagnosis, tumor size, nodal status, family history and initial breast cancer surgery types (BCT vs. mastectomy) were not significantly different between the two groups. Of the 30 women who underwent PM, 19 (63%) vs. 9 (30%) underwent PM before and after their genetic testing respectively. Of the 19 women who had PM before their genetic testing, 4 (21%) had BCT as initial treatment whereas 15 (78.9%) had mastectomy as initial treatment and 9 of 15 (60%) had synchronous contralateral prophylactic mastectomy. For the 9 women who had PM after their genetic testing, 5 (56%) had BCT vs. 4 (44%) had mastectomy as their initial surgical treatment (p &lt; 0.001). Conclusion: In this study, we found a significant correlation between the initial breast cancer surgical modality of mastectomy with women undergoing prophylactic mastectomy. The impact of family history of breast cancer does not appear to be significant. Physician recommendations or patient preference are unknown. Our data suggest that high risk women who elect mastectomy as their initial surgical management to treat their breast cancer are more likely to undergo prophylactic mastectomy regardless of knowledge of their mutation status. No significant financial relationships to disclose.
Effect of CD34+ Selection and Various Schedules of Stem Cell Reinfusion and Granulocyte Colony-Stimulating Factor Priming on Hematopoietic Recovery After High-Dose Chemotherapy for Breast Cancer
Authors: G. Somlo, I. Sniecinski, T. Odom-Maryon, B. Nowicki, W. Chow, V. Hamasaki, L. Leong, K. Margolin, R. Morgan, J. Raschko, S. Shibata, M. Tetef, A. Molina, R.J. Berenson, S.J. Forman, J.H. Doroshow
Journal: Blood (1997)
Drugging "Undruggable" Targets in Cancer
Authors: Gregory Verdine
Journal: Clinical Cancer Research (2007)

PL02-02   One of the most vexing problems in life science is that of “undruggability,” the difficulty of targeting certain biological macromolecules in vivo using existing drug or ligand discovery technologies. It has been estimated that as many as 80-90% of all potential targets, including many that have been extensively validated in humans and in animal models, are undruggable. The Verdine laboratory is developing powerful new chemistry-based platform technologies to address these undruggable targets. Specifically, the lab is developing “synthetic biologics,” molecules that, like biologics, possess the ability to target large flat surfaces, but that, like small molecules, are fully synthetic and hence can be modified at will. Progress on the development of synthetic biologics will be reviewed in this talk.  Walensky, L. D.; Kung, A. L.; Escher, I.; Malia, T. J.; Barbuto, S.; Wright, R.; Wagner, G.; Verdine, G. L.; Korsmeyer, S. J. “Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix,” Science 2004, 305, 1466-1470.  Walensky, L. D.; Pitter, K.; Morash, J.; Oh, K. J.; Barbuto, S.; Fisher, J.; Smith, E.; Verdine, G. L.; Korsmeyer, S. J. “A Stapled BID BH3 Helix Directly Binds and Activates BAX,”  Mol. Cell  2006,  24 , 199-210.  Bernal, F.; Tyler, A. F.; Korsmeyer, S. J.; Walensky, L. D.; Verdine, G. L. “Reactivation of the p53 Tumor Suppressor Pathway by a Stapled p53 Peptide,”  J. Am. Chem. Soc.  2007, 2456-2457.
Evaluation of chromosome 17 (Chr-17) polysomy in HER2 FISH-negative metastatic breast cancer (MBC) patients enrolled in a randomized phase III study of paclitaxel and lapatinib
Authors: R. B. Livingston, L. Downey, A. Di Leo, M. Koehler, M. Arbushites, L. Williams, M. F. Press
Journal: Journal of Clinical Oncology (2008)

1006 Background: Patients with polysomy of Chr-17 have been suggested as a FISH-negative subpopulation that might benefit from HER2-directed therapy, due to an increase in HER2 gene expression without HER2 specific amplification. A recent phase III clinical trial studied lapatinib (L) in combination with paclitaxel (P) as 1st-line therapy for HER2-negative or HER2-untested MBC. We examined the hypothesis that HER2 FISH-negative patients with Chr-17 polysomy may be sensitive to HER2 inhibitors using data from this trial. Methods: Patients (n=579) with newly diagnosed MBC were randomized to P with placebo or L (P+L). Response rate (RR) using RECIST and progression-free survival (PFS), were evaluated. HER2 expression level by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and mean HER2 ratio of Chr-17 values were determined in a central laboratory using archival tissue. Tumors with a HER2:Chr-17 ratio < 2.0 were considered HER2-negative by FISH. Chr-17 centromere averages of 2.0 and 2.2 were used as thresholds for Chr-17 polysomy. Associations with PFS and RR in the HER2-negative groups were evaluated across treatment arms. There were insufficient numbers of patients in higher categories of polysomy for meaningful comparisons. Results: In this study, 406 pts were HER2 FISH-negative. Data are available for PFS in 405, of whom 44 (11%) met the definition of polysomy (Chr-17 >2.2, HER2 FISH-negative). Median PFS in the polysomy group was 20.9 vs. 24.4 wks for L+P and P respectively, while in the non-polysomy group, the median PFS times were 24.6 and 23.1 wks for L+P and P. Log-rank testing showed no treatment advantage for either polysomy group. Similar results were found for the PFS comparisons using 2.0 as the specified cutoff for Chr-17 polysomy. RR in the polysomy group were 17.4% for P+L vs. 9.5% for P, while in the non-polysomy group RR was 32.0% for P+L vs. 25.1% for P; neither comparison was statistically significant. Conclusions: We could not confirm the hypothesis that Chr-17 polysomy in HER2 FISH-negative pts is associated with improved outcome when lapatinib is added to chemotherapy as a HER2-targeted treatment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Roche GlaxoSmithKline Genentech, GlaxoSmithKline, Roche Genentech, GlaxoSmithKline
Metabolic rate and directional nucleotide substitution in animal mitochondrial DNA.
Authors: A P Martin
Journal: Molecular Biology and Evolution (1995)

There is marked heterogeneity of nucleotide composition in mitochondrial DNA across divergent animals. Differences in nucleotide composition presumably reflect differences in directional nucleotide substitution for A+T or G+C nucleotides. In mitochondrial DNA, there is A+T directional nucleotide substitution in most (if not all) animals surveyed, and the magnitude of directional A+T nucleotide substitution differs greatly within and among groups. Differences in directional nucleotide substitution among lineages of mammals can be explained by changes in metabolic physiology. This relationship is thought to be mediated by the effect of oxygen radicals because these toxic compounds are by-products of aerobic metabolism and are known mutagens. Association between metabolism and nucleotide composition provides additional evidence in favor of the hypothesis that rates and patterns of nucleotide substitution in mitochondrial DNA can be influenced by factors that impinge on rates of endogenous DNA damage.