tbuckley/cabot-search huggingface dataset:
Abstract P5-07-05: Insulin-like growth factor binding protein-3 is a key component of the breast cancer cell response to DNA-damaging therapy
Authors: RC Baxter, MZ Lin, KA Marzec, JL Martin
Journal: Cancer Research (2012)

Abstract Introduction. Breast cancer cells frequently develop resistance to DNA-damaging therapies, such as radiation and the cytotoxic drugs doxorubicin and etoposide, and activation of the epidermal growth factor receptor (EGFR) may play an important role in this process. However many estrogen receptor (ER)-negative breast tumors respond poorly to DNA-damaging drugs even when combined with an EGFR inhibitor. EGFR can modulate the repair of DNA double strand breaks (DSB) by non-homologous end-joining (NHEJ), by forming protein complexes that include the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). In previous studies we have shown that the growth-regulatory protein, insulin-like growth factor binding protein-3 (IGFBP-3), can translocate to the nucleus, is a substrate for DNA-PKcs, and can transactivate EGFR. The aim of this study was to delineate the role of IGFBP-3 in the response of breast cancer cells to DSB-inducing chemotherapeutic agents. Results. In the triple-negative breast cancer cell lines MDA-MB-468 and Hs578T, which express IGFBP-3 highly, nuclear localization of EGFR and IGFBP-3, and of their complex as measured by coimmunoprecipitation (coIP), was enhanced by exposure to etoposide or doxorubicin, peaking 2 h after etoposide treatment. This effect was blocked by the EGFR kinase inhibitor gefitinib. Concomitantly, the co-location of EGFR-IGFBP-3 complexes with lipid rafts, visualized by proximity ligation assay (PLA) and confocal microscopy, decreased in response to drug treatment, consistent with the loss of this complex from the plasma membrane. Similar to the nuclear DNA-PKcs-EGFR complex, the nuclear DNA-PKcs-IGFBP-3 complex (seen by both coIP and PLA) was greatest 4 h after treatment. DNA-PKcs activation at serine-2056, required for the repair of DNA DSB and stimulated by etoposide treatment, was decreased by IGFBP-3 downregulation using two separate siRNAs, and this treatment also attenuated the enhanced DNA-PKcs-EGFR complexes seen in response to etoposide. Collectively these data suggest that IGFBP-3 has an obligatory role in the DNA repair response to DNA-damaging therapy through its interactions with EGFR and DNA-PKcs. Conclusion. IGFBP-3 co-translocation to the nucleus of breast cancer cells and its complex formation with DNA-PKcs and EGFR in response to DNA damage demonstrate its previously unrecognized involvement in the regulation of DNA DSB repair by NHEJ. These novel findings suggests the possibility of a therapeutic approach for sensitizing ER-negative breast cancers to chemo- or radiotherapy by targeting the DNA repair function of IGFBP-3. Supported by the Australian Research Council. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-07-05.
Abstract LB-156: Improved T cell survival, tumor localization and tumor eradication by folate receptor-alpha redirected T cells is achieved by provision of CD137 costimulatory signaling
Authors: De-Gang Song, Silvana Canevari, Carl June, George Coukos, Daniel J. Powell
Journal: Cancer Research (2011)

Abstract Human T cells engineered to express a chimeric immune receptor (CIR) specific for folate receptor-alpha (FRα) have shown robust anti-tumor activity against epithelial cancers in vitro but not in the clinic due to their inability to persist and home to tumor in vivo. To address these issues, we constructed CIRs containing an FRα-specific scFv (MOv19) coupled to the T cell receptor CD3ζ chain signaling module alone or in combination with the CD137 (4–1BB) costimulatory motif in tandem. Primary human T cells transduced to express conventional MOv19-ζ or costimulated MOv19-BBζ CIRs secreted various proinflammatory cytokines and exerted cytotoxic function when cocultured with FRα+ tumor cells in vitro. However, only transfer of human T cells expressing the costimulated MOv19-BBζ CIR mediated tumor regression in immunodeficient mice bearing large, established FRα+ human cancer. MOv19-BBζ CIR T cell infusion mediated tumor regression in models of metastatic intraperitoneal, subcutaneous, and lung-involved human ovarian cancer. Importantly, tumor response was associated with the selective survival and tumor localization of human T cells in vivo and was only observed in mice receiving costimulated MOv19-BBζ CIR T cells. T cell persistence and anti-tumor activity were primarily antigen-driven, however, antigen-independent CD137 signaling by CIR did improve T cell persistence but not anti-tumor activity in vivo. Our results show that anti-FRα CIR outfitted with CD137 costimulatory signaling in tandem overcome issues of T cell persistence and tumor localization that limit the conventional FRα T cell targeting strategy to provide potent antitumor activity in vivo. Based upon these encouraging findings, we are preparing to open an anti-FRα CIR protocol for ovarian cancer in mid-2011, pending FDA approval. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-156. doi:10.1158/1538-7445.AM2011-LB-156
Successful Localization of Residual Culprit Tumor in a Case of Tumor-Induced Osteomalacia Using 68Ga-DOTANOC PET/CT
Authors: Niraj Naswa, Punit Sharma, Rakesh Kumar, Arun Malhotra, Chandrasekhar Bal
Journal: Clinical Nuclear Medicine (2013)

Tumor-induced osteomalacia (TIO) is a rare disease entity characterized by clinical pictures of recurrent multiple fractures and biochemical features of phosphaturia, hypophosphatemia, and low vitamin D levels. Most often TIO is caused by benign soft tissue tumors. The main issue in management of such patients is proper tumor localization, as these tumors are small and often located at obscure sites. We describe a case of TIO where residual disease was clinically suspected after tumor resection and subsequently detected using Ga-DOTANOC PET/CT.
Testicular Germ-Cell Cancer
Authors: G J Bosl, R J Motzer
Journal: New England Journal of Medicine (1997)

Approximately 95 percent of malignant tumors arising in the testis are germ-cell tumors, a term that indicates their origin in primordial germ cells. Germ-cell tumors also occasionally arise in extragonadal primary sites, and their management follows that of testicular germ-cell tumors. More than 90 percent of patients with newly diagnosed germ-cell tumors are cured, and delay in diagnosis correlates with a higher stage at presentation for treatment.1,2 Management has changed substantially in the past 20 years, largely because of the ability of cisplatin-containing combination chemotherapy to cure advanced disease.3 In this review, we discuss recent developments in our understanding . . .
IMPACT OF THE SKIN AUTOFLUORESCENCE TO CORONARY ARTERY STENOSIS PROGRESSION
Authors: Yusuke Fujino, Satoko Tahara, Kensuke Takagi, Toru Naganuma, Guilherme F. Attizzani, Wei Wang, Hisaaki Ishiguro, Naoyuki Kurita, Shotarou Nakamura, Sunao Nakamura
Journal: Journal of the American College of Cardiology (2015)
NK-Cell and B-Cell Deficiency with a Thymic Mass
Authors: Samuel Ng, Christopher Fanta, Maureen Okam, Ami S. Bhatt
Journal: New England Journal of Medicine (2011)

To the Editor: We report a case of a combined immunodeficiency syndrome, thymic hyperplasia, and impaired lymphatic system function that strongly resembled the phenotype of the Ikaros-null knockout mouse. The patient was well until her early teenage years when she had bacteremia of unknown cause. At menarche, lymphedema developed in her legs. At 16 years of age, she had disseminated varicella–zoster infection, which culminated in a splenectomy for possible splenic rupture. In her 20s and 30s, she had frequent sinopulmonary infections, and severe IgA deficiency and a profound deficiency of natural killer (NK) and B cells were eventually diagnosed. She . . .
Abstract 4079: Pilot study of copper chaperon ATOX1 in oncogenesis of colon cancer
Authors: Huawei Cai, Fangyu Peng
Journal: Cancer Research (2011)

Abstract INTRODUCTION: Copper is an essential element for normal function of many cellular enzymes. Copper homeostasis is maintained by a delicate network of copper transporters, which include human copper transporter 1(hCtr1), ATP7A, ATP7B, and copper chaperons including ATOX1, CCS, and Cox17. It has been known that copper is required for cell proliferation and tumor angiogenesis. Human tumor xenografts in mice with increased uptake of radioactive copper could be localized with positron emission tomography. Copper hypermetabolism might play a role in oncogenesis of human cancers. Recently, it was reported that ATOX1 is a transcription factor involved in copper-stimulated cell proliferation. In this pilot study, we analyzed expression of ATOX in human colon cancer tissues compared with its expression in normal colon tissues. In addition, preliminary experiments were conducted to study potential role of ATOX1 in oncogenesis of colon cancer. METHODS: Immunohistochemistry analysis was conducted to compare expression of ATOX1 in colon cancer tissues and normal colon tissues. A lentiviral vector encoding short-hairpin RNA (shRNA) specific for ATOX1 (Lenti-ATOX-shRNA) was constructed and used to transduce HCT-116 human colon cancer cells. Suppression of ATOX1 in HCT-116 cells transduced with Lenti-ATOX-shRNA (ATOX1-shRNA-HCT116) was confirmed by Western blot. MTT assay was conducted to assess effect of ATOX1 silencing on proliferation and sensitivity of ATOX1-shRNA-HCT-116 cells to copper, cisplatin and copper 8-hydroxyquinoline-2-carboxaldehyde thiosemicarbazide complex (CuHQTS), a new anticancer copper complex. The HCT-116 cells transduced by a lentivirus encoding a scramble shRNA (Scramble-shRNA-HCT116) were used as control. RESULTS: Over-expression of ATOX1 is identified in all of human colon cancer tissue samples (N=10), compared with expression of ATOX1 in normal colon tissue samples (N=10). Suppression of ATOX1 with ATOX1-shRNA in HCT116 cells was confirmed by Western blot assay. However, the results of MTT assay revealed no significant effect of ATOX1 silencing on proliferation and sensitivity of ATOX1-shRNA HCT116 cells to copper chloride, cisplatin, and CuHQTS, compared with proliferation and sensitivity of Scramble-shRNA-HCT116 to these drugs. CONCLUSIONS: ATOX1 holds potential as a new biomarker of colon cancer. Additional studies are necessary to determine the role of ATOX1 and other copper transporters in oncogenesis of colon cancer. Key words: colon cancer, copper metabolism, copper chaperon, ATOX1 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4079. doi:10.1158/1538-7445.AM2011-4079
Informing 21st-Century Risk Assessments with 21st-Century Science
Authors: Linda S. Birnbaum, Thomas A. Burke, James J. Jones
Journal: Environmental Health Perspectives (2016)

SummaryUnderstanding and preventing adverse impacts from chemicals in the environment is fundamental to protecting public health, and chemical risk assessments are used to inform public health decisions in the United States and around the world. Traditional chemical risk assessments focus on health effects of environmental contaminants on a chemical-by-chemical basis, largely based on data from animal models using exposures that are typically higher than those experienced by humans. Results from environmental epidemiology studies sometimes show effects that are not observed in animal studies at human exposure levels that are lower than those used in animal studies. In addition, new approaches such as Toxicology in the 21st Century (Tox21) and exposure forecasting (ExpoCast) are generating mechanistic data that provide broad coverage of chemical space, chemical mixtures, and potential associated health outcomes, along with improved exposure estimates. It is becoming clear that risk assessments in the future will need to use the full range of available mechanistic, animal, and human data to integrate multiple types of data and to consider nontraditional health outcomes and end points. This perspective was developed at the "Strengthening the Scientific Basis of Chemical Safety Assessments" workshop, which was cosponsored by the U.S. Environmental Protection Agency and the National Institute of Environmental Health Sciences, where gaps between the emerging science and traditional chemical risk assessments were explored, and approaches for bridging the gaps were considered.
P5-19-08: Pooled Analysis of Individual Patient Data from Capecitabine Monotherapy Clinical Trials in Anthracycline-/Taxane-Pretreated Locally Advanced or Metastatic Breast Cancer (LA/MBC).
Authors: JL Blum, CH Barrios, N Feldman, S Verma, E McKenna, S Lee, N Scotto, J Gralow
Journal: Cancer Research (2011)

Abstract Background Capecitabine (C) has shown efficacy as monotherapy in anthracycline (A)-/taxane (T)-pretreated LA/MBC in phase II/III trials. Since its approval, the treatment landscape in MBC has evolved, and C has served as the combination partner and/or active comparator in trials of novel agents in pretreated MBC. This pooled analysis of clinical trial data, spanning a 12-yr period, assessed the efficacy and safety of C across treatment lines and the impact of disease characteristics on clinical outcomes with C. Methods: Individual patient (pt) data were pooled from 7 clinical trials conducted by Roche/GNE from Feb 1996-Jun 2008 where C monotherapy was the test/control regimen for pts with LA/MBC with/without prior A/T therapy. Analyses were performed on an ITT basis. Univariate and multivariate regression analyses assessed the impact of pt/disease characteristics and prior therapy on outcomes. Results: Data from 805 pts enrolled to intermittent C monotherapy were analyzed: 268 in the 1st-line metastatic setting; 537 in the ≥2nd-line metastatic setting (table). Median age: 55 yrs (range 23–90). Most pts were Caucasian (81%) with ECOG PS of 0 (55%). Baseline demographics were balanced across treatment lines. Data on A/T treatment history were available for 719 pts; 557 pts received prior A/T therapy, 176 were A-refractory, 234 T-refractory and 154 A- and T-refractory. Pooled overall response rate (ORR) was 21.0% (1.7% complete; 19.3% partial). ORR was 25.0% and 19.0% for pts treated in the 1st- and ≥2nd-line settings (OR 0.70, 95% CI: 0.5−1.0; p=0.0486). Median PFS was 126.9 days (95% CI: 119–132) in the pooled analysis, and significantly longer in pts receiving 1st- vs ≥2nd-line C: 150.0 vs 112.0 days (HR 1.45, 95% CI: 1.23−1.71; p&amp;lt;0.0001). Pooled median OS was 482.1 days (95% CI: 438–516). Significantly longer median OS was seen in pts receiving 1st- vs ≥2nd-line C: 666.0 vs 396.0 days (HR 1.98, 95% CI: 1.62−2.41; p&amp;lt;0.0001). 62 pts (8%) withdrew due to C-related AEs, which were severe in 4% of pts and life threatening in 2%. AEs of special interest occurred in 489 pts (63%); these were severe in 24% of pts and life threatening in 2%. Gastrointestinal disorders were most frequent (417 pts [53%]), and were severe or life threatening in 13% and 1% of pts. Conclusions: This pooled analysis of pt data (n=805) revealed significantly longer ORR/survival in pts receiving 1st- vs ≥2nd-line C for A-/T-pretreated MBC. Univariate and multivariate analyses are ongoing; results will be presented. Safety data were in-line with findings from phase III trials of C in MBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-08.
Antecubital Phlebotomy Complicated by Lateral Antebrachial Cutaneous Neuropathy
Authors: Howard W. Sander, Matthew F. Conigliari, Joseph C. Masdeu
Journal: New England Journal of Medicine (1998)

Beta-Blockers after Myocardial InfarctionTo the Editor: In their report on an observational study of beta-blockade after myocardial infarction, Gottlieb et al. (Aug.20 issue) 1 firmly conclude that beta-blockers should be used for high-risk patients after acute myocardial infarction, including patients with congestive heart failure.This conclusion is not supported by the data presented.The randomized studies of beta-blockers excluded patients with severe heart failure -and all physicians are trained in such contraindications.Therefore, we know that physicians will be reluctant to use beta-blockers in high-risk patients, and we can readily anticipate that the willingness to use a beta-blocker is a marker of low risk, both overall and in subgroups of patients.The authors' demonstration that beta-blockers are associated with a dramatic reduction in risk confirms a self-evident truth, regardless of the huge sample.The authors could have confirmed this explanation by demonstrating that beta-blockers are a marker of good exercise performance, a short hospital stay, and higher social status -other unspecific indicators of low risk.The value of beta-blockers in high-risk patients must be considered uncertain until proper randomized trials have proved otherwise.Such studies are under way in our country and elsewhere, and their completion must be awaited before firm conclusions are drawn.
Lack of Association between Genital Mycoplasmas and Infertility
Authors: Dieter W. Gump, Mark Gibson, Taka Ashikaga
Journal: New England Journal of Medicine (1984)

We studied the relation between colonization with Mycoplasma hominis and Ureaplasma urealyticum, and the results of infertility studies in 205 women with involuntary infertility of at least one year's duration. Isolation of M. hominis (but not of U. urealyticum) was significantly (P = 0.002) more common in patients with a history of pelvic inflammatory disease. However, no relation could be shown between these genital mycoplasmas and any of the following: evidence of prior pelvic inflammatory disease as determined by hysterosalpingography and laparoscopy; cervical inflammation; numbers and motility of spermatozoa on postcoital test; pyosemia; quality of cervical mucus; whether the cause of infertility was related to male or female factors, both, or neither; and occurrence and outcome of subsequent pregnancy. Mycoplasmas were cultured from only 10 of 203 endometrial biopsy specimens (4.9 per cent), and in no instance was inflammation associated with this finding. Our studies do not support a role for genital mycoplasmas in the cause of infertility. (N Engl J Med 1984; 310:937–41.)
Abstract 1605: α-cryptoxanthin supplementation inhibits the carcinogen-initiated and nicotine-promoted lung carcinogenesis in AJ mice by suppression of AKT activation
Authors: Anita R. Iskandar, Chun Liu, Hansgeorg Ernst, Sang-Woon Choi, Lynne Ausman, Xiang-Dong Wang
Journal: Cancer Research (2012)

Abstract A pooled analysis from well-implemented cohort studies reported that increased dietary α-cryptoxanthin (BCX) intake, rather than α-carotene used in earlier human trials, is associated with reduced risk of lung cancer. Nonetheless, BCX efficacy on lung carcinogenesis has not been reported. In these studies, we examined the protective effects of BCX at different doses against lung carcinogenesis at the initiation and the promotion stages of the cancer development in male AJ mice. In the tobacco carcinogen 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone [NNK]-initiated lung carcinogenesis model, we found a 52-63% reduction of lung tumor multiplicity in mice pre-treated with BCX at 0.2 and 2 mg kg BW-1 d-1, as compared to the NNK group (P&amp;lt;0.01). In contrast, BCX did not significantly alter the spontaneous lung tumor multiplcitiy in mice without the NNK treatment. Furthermore, in the NNK-initiated and nicotine-promoted lung cancer model, we found that nicotine treatment by intraperitoneal injections not only significantly induced emphysema, a risk for lung cancer, but also greatly increased lung tumor multiplicity of the NNK-treated mice. Remarkably, BCX at 2 and 4 mg kg BW-1 d-1 prevented the nicotine-induced pulmonary emphysema and decreased tumor multiplicity by 86-91% (P&amp;lt;0.01). BCX protective effect on carcinogenesis was associated with significant suppression of lung AKT activation measured by immunoblotting. BCX also reduced the emphysema-related IL-6 and early growth response-1 induction of mRNA levels measured by real-time PCR. Contrary to α-carotene reported in prior animal studies, BCX also induced the retinoic acid receptor-α mRNA. As measured by HPLC analysis, the concentrations of liver BCX were higher in the BCX supplemented mice, without alteration of the retinol concentrations. Our data suggest that BCX is a unique chemopreventive agent for lung cancer prevention, which is likely to be independent of its provitamin A activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1605. doi:1538-7445.AM2012-1605
Abstract 2183: Tumor suppressor LZAP regulates cell cycle progression and doming during zebrafish epiboly
Authors: Dan Liu, Wendell G. Yarbrough, Ela W. Kanpik, Wen-Der Wang
Journal: Cancer Research (2011)

Abstract Initial stages of embryonic development rely on rapid, synchronized cell divisions of the fertilized egg followed by a set of morphogenetic movements collectively called epiboly and gastrulation. Lzap is a putative tumor suppressor whose expression is lost in 30% of head and neck squamous cell carcinomas. Lzap activities include regulation of cell cycle progression and response to therapeutic agents. Here we explore developmental roles of the lzap gene during zebrafish morphogenesis. Lzap is highly conserved among vertebrates and is maternally deposited. Expression is initially ubiquitous during gastrulation, and later becomes more prominent in the pharyngeal arches, digestive tract and brain. Antisense morpholino-mediated depletion of Lzap resulted in delayed cell divisions during blastomere formation, resulting in fewer, larger cells. Furthermore, the Lzap-deficient embryos failed to initiate epiboly – the earliest morphogenetic movement in animal development – which has been shown to be dependent on cell adhesion and migration of epithelial sheets. Our results strongly implicate Lzap in regulation of cell cycle progression, adhesion and migratory activity of epithelial cell sheets during early development. These functions provide further insight into Lzap activity that may contribute not only to development, but also to tumor formation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2183. doi:10.1158/1538-7445.AM2011-2183