tbuckley/cabot-search huggingface dataset:
P08.36 Radioresistance of glioblastoma stem-like cells is associated with DNA replication stress, which is a promising therapeutic target
Authors: S. U. Ahmed, R. Carruthers, D. Biasoli, N. Gomez-Roman, L. Gilmour, K. Strathdee, A. Hedley, G. Kalna, E. Hammond, A. J. Chalmers
Journal: Neuro-Oncology (2016)

Introduction:
The inevitability of tumour recurrence in glioblastoma (GBM) patients despite multi-modality treatment consisting of surgery, radiotherapy and chemotherapy, is reflected by a median survival of only 14 months. Tumour recurrence is thought to be driven by a small population of glioblastoma stem-like cells (GSCs) that are resistant to conventional therapies. DNA damage response (DDR) pathways have been shown to be up-regulated in GSCs and implicated in radioresistance and treatment failure. However the precise cause of enhanced DDR signalling in GSCs and the extent to which these signalling networks contribute to therapy resistance remains elusive. The objectives of this study were to investigate the underlying cause of DDR upregulation and treatment resistance in GSCs with a view to identifying novel and promising therapeutic targets.

Materials and Methods:
A panel of primary patient derived GBM cell lines cultured under conditions to enrich for or deplete the tumour stem cell population (GSC vs bulk respectively) were utilised in order to investigate enhanced GSC DDR under basal conditions and in response to ionising radiation. Confirmatory studies were also performed in cells sorted for the putative GSC marker CD133. The effects of a panel of small molecule DDR inhibitor agents on cell survival in GSC and bulk cells were quantified.

Results:
GSCs exhibited higher levels of total and activated DDR targets ATR, CHK1, ATM and PARP1 under basal conditions and were radioresistant compared to paired bulk populations. This was not due to increased levels of reactive oxygen species (ROS). Instead, we show that RPA is significantly higher in replicating GSCs and confirm by DNA fibre assays that GSCs and CD133+ cells have increased numbers of stalled replication forks, fewer new origins and slower DNA replication compared to bulk or CD133- populations, demonstrating for the first time that replication stress (RS) is a hallmark of GSCs. We identify increased expression of long neural genes as a likely mechanism for RS and DNA double strand breaks (DSBs) in GSCs and show that their radioresistance is reversed by dual inhibition of key RS and DDR proteins ATR and PARP.

Conclusions:
This study demonstrates the novel finding that replication stress is a hallmark of GSCs and resonates with recently published studies in neural progenitor cells showing that RS preferentially induces DNA DSB in long neural genes. Taken together, we implicate RS as a driver of enhanced DDR in GSCs and identify novel therapeutics with potential to improve clinical outcomes by overcoming the radioresistance of GBM
ANGI-09. microRNA INHIBITION OF ENDOTHELIAL DNA REPAIR CAPACITY AS A GLIOBLASTOMA THERAPEUTIC STRATEGY
Authors: Clark Chen, RaeAnna Wilson, Nathan Kanner, Cristina Espinosa-Diez, Sunil Advani, Jie Li, Omar Khan, Aleksandra Franovic, Sara Weis, Daniel Anderson, David Cheresh, Sudarshan Anand
Journal: Neuro-Oncology (2016)

Glioblastoma microenvironment can be modulated to induce tumor cell death. Here we report a microRNA based approach to achieve this end. We employed conducted a genetic screen to identify miRNAs that confer radiation sensitivity to endothelial cells. Targets of key miRNAs were identified. Efficacy of therapeutic delivery was tested in vitro and in vivo using patient derived glioblastoma xenograft models. We observed that silencing of the microRNA processing enzyme, Dicer, in Human Umbilical Vein Endothelial Cells (HUVEC) significantly increased DNA damage accumulation in these cells. To identify the specific miRs involved in this process, we identified miRs that were consistently up-regulated in HUVEC 6 hours after 20 Gy exposure to ionizing irradiation or hydrogen peroxide treatment. miR-103 emerged as the top candidate. Importantly, irradiation of a brain tumor xenograft resulted in rapid upregulation of miR-103 in the tumor vasculature but not in the tumor cells. Transfection of endothelial cells (EC) with miR-103 mimics increased accumulation of DNA strand breaks and apoptosis in ECs. Moreover, inhibition of radiation induced miR-103 expression suppressed EC apoptosis in vitro and in vivo, suggesting that induction miR-103 expression is a key mediator of the cytotoxic effects of radiation on EC. Using substractive expression and RISC-trap assay, we identified and confirmed that the radiation sensitizing effects of miR-103 on EC is mediated through 1) suppression of key DNA repair genes (TREX1 and FANCF) as well as 2) increased release of anti-angiogenic cytokines, including IP10. Local and systemic delivery of miR-103 in vivousing a patient derived, orthotopic glioblastoma xenograft model caused DNA damage accumulation in ECs, increased anti-angiogenic cytokine release form ECs, and suppressed glioblastoma growth. Our findings reveal miR-103 play critical roles in modulation endothelial DNA repair through regulation of EC DNA repair capacity and cytokine release. Disruption of the crosstalk between vasculature and tumor cells that can be exploited as a glioblastoma therapeutic strategy.
P10.01 Adolescent and Young Adults (AYAS) brain tumor national Web conference
Authors: D. Frappaz, M. Sunyach, E. Le Rhun, M. Blonski, V. Laurence, A. Bonneville Levard, H. Loiseau, D. Meyronnet, A. Callies, F. Laigle Donadey
Journal: Neuro-Oncology (2016)

The skills of adult versus pediatric neuro-oncologists are not completely similar though additive. Because the tumors are different (mostly glioma and meningiomas in adults, versus medulloblastomas, germ cell tumors and ependymomas). And because the tolerance and expected sequelae are specific. Multidisciplinary meetings including adult and pediatric neuro oncologists are warranted to share expertise. Method since 2008,a weekly national web based conference was held in France. Any patient with the following criteria could be discussed: Adolescent and Young Adults aged between 15 and 25 years, and any adult with a pediatric type pathology. Attendance during the year 2015 was as follows: 42 meetings were held; the median number of cases discussed at each meeting was 4 (1 to 8); the mean number of attendants was 7 (3 to 12) including adult neuro oncologists (2 from 1 to 7), pediatric neuro oncologists (2 from 1 to 3), radiotherapists (2 from 1 to 3), surgeons (1) and pathologist (1). 147 cases concerning 112 patients were discussed. Mean age was 30,72 years old (9 to 73). 82 were discussed at diagnosis, 65 at time of relapse; The patients had mostly medulloblastomas 38), germ cell tumors(14), ependymomas (10) gliomas (15), pineal tumors (11). The rate of inclusion in protocols was increased since the opening of this web conference, especially for germ cell tumor SIOP protocol that is opened without age restriction: half of the french patients were older than 19 Year. And the inclusion rate in RSMA standard risk adult medulloblastoma protocol was also increased. Multidisciplinary Web conference for AYAs is feasible and increases the inclusion rate in protocols. It should be developed further.
Receipt of guideline-concordant treatment in elderly African American and Caucasian patients with prostate cancer.
Authors: Ronald C. Chen, William Ruffin Carpenter, Laura H. Hendrix, Zhuang Andrew Wang, Matthew Edward Nielsen, Paul Alphonso Godley
Journal: Journal of Clinical Oncology (2012)

222 Background: Clinical management of cancer patients according to published guidelines is an important quality indicator. Prior studies have demonstrated less aggressive treatments of elderly patients with breast and colorectal cancers, raising concern about potential undertreatment of elderly patients overall. The rate of guideline concordant management in elderly prostate cancer patients is unknown, and we examined this using the Surveillance, Epidemiologic and End Results (SEER)-Medicare linked database. Given that prostate cancer is often slow growing, we were especially interested in guideline concordance in patients with "high risk" (aggressive) prostate cancer. Methods: 15,154 Caucasian (CA) and 2,924 African American (AA) men diagnosed in 2004 to 2007 with localized prostate cancer, age 66 to 79, were included. We characterized the proportions of men who received management concordant with the National Comprehensive Cancer Network guidelines within 12 months of diagnosis. Logistic regression was used to examine the odds of receiving guideline-concordant management while accounting for race, comorbidity (NCI combined index), SEER region, and sociodemographic factors. Results: Guideline concordance was more than 80% for both CA and AA patients with low- or intermediate-risk disease. Among high-risk patients, only 63% of CA and 48% AA patients received guideline-concordant management, mostly due to no treatment or hormonal therapy alone, which offer no curative potential. Findings were almost identical in the subgroup of patients with little or no comorbidity, who have more than 10 year life expectancy on average. On multivariable analysis, AA race (OR .62, p&lt;.001) and increasing age were associated with lower likelihood of guideline concordance for high-risk prostate cancer, but comorbidity was not. Conclusions: There is undertreatment of elderly but healthy patients with high-risk prostate cancer, the most aggressive form of this disease. Our results suggest a bias toward less aggressive treatment in elderly patients with less consideration for comorbidities or aggressiveness of cancer. Guideline concordance in elderly patients with aggressive prostate cancer is low.
Prospective Validation of Diagnostic Tumor Biomarkers in Men Treated With Radiotherapy for Prostate Cancer
Authors: Alan Pollack, Deukwoo Kwon, Gail Walker, Li Yan Khor, Eric M. Horwitz, Mark K. Buyyounouski, Radka Stoyanova
Journal: JNCI Journal of the National Cancer Institute (2016)

In prior retrospective studies, we assessed a number of prostate tumor tissue biomarkers that were associated independently with the clinical outcome of men treated with radiotherapy (RT) ± androgen deprivation therapy (ADT). In this report, the associations of selected biomarkers with biochemical or clinical disease failure (BCDF) were prospectively evaluated in men with T1-T3 prostate cancer on a randomized hypofractionation trial.Biomarkers were analyzed in 263 of 303 men randomly assigned to standard vs moderate hypofractionation. Median follow-up was 65.9 months. Archival tissue was analyzed for Ki-67 (n = 231), MDM2 (n = 209), p16 (n = 195), Cox-2 (n = 126), p53 (n = 206), bcl2 (n = 223), bax (n = 210), and PKA (n = 160). The base model for multivariable Fine-Gray regression analysis included treatment assignment and risk groups. All statistical tests were two-sided.Each biomarker was tested one at a time relative to the base model and selected for inclusion in multivariable analysis. Ki-67 (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.19 to 4.48, P = .01) and bcl2&bax (HR = 2.19, 95% CI = 1.08 to 4.46, P = .03) were statistically significantly related to higher BCDF and were independently statistically significant when considered jointly (Ki-67: HR = 2.26, 95% CI = 1.12 to 4.58, P = .02; bcl2&bax: HR = 2.14, 95% CI = 1.03 to 4.41, P = .04). At 2.5 years postradiotherapy, the C-index of Ki-67 was 73.2%, while for the base model was only 46.2%; Ki-67 was the most statistically significant when tested without bcl2&bax.In this prospective multiple biomarker analysis in men with prostate cancer treated with RT±ADT, both Ki-67 and bcl2&bax were independently related to early BCDF; however, Ki-67 alone is indicated to be the most clinically meaningful by C-index analysis and is universally available.
Statistical Concerns on Vismodegib for Basal Cell Carcinoma Meta-analysis
Authors: Joao Paulo da Silveira Nogueira Lima
Journal: JAMA Dermatology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
The Para-Isomer of Nitric Oxide-Donating Acetylic Salicylic Acid (p-NO-ASA) Effectively Induces Cell Death in B-Cell Chronic Lymphocytic Leukemia (CLL) Cells at Low Micromolar Concentrations.
Authors: Regina Razavi, Julian Paesler, Iris Gehrke, Felix Erdfelder, Magdalena Hertweck, Alexandra Filipovich, Rajesh Kumar Gandhirajan, Michael Hallek, Karl Anton Kreuzer
Journal: Blood (2008)
The effect of rikkunshito, a traditional Japanese herbal medicine, on food intake and plasma acylated ghrelin levels in lung cancer patients treated with platinum-based chemotherapy
Authors: T. Yoshiya, M. Ito, K. Misumi, H. Hanaki, Y. Tsutani, K. Satoh, Y. Miyata, M. Okada
Journal: Annals of Oncology (2016)
Anti-inflammatory Activity of Jurubeba (Solanum paniculatum L.) Through Reducing the T-bet and GATA3 Gene Expression, In Vitro
Authors: Raimon Rios, Hugo Bernardino Ferreira Silva, Norma Vilany Queiroz Carneiro, Ryan Santos Costa, Tamires Cana Brasil Carneiro, Cíntia Rodrigues Marques, Marta Santos Serafim Machado, Eudes Silva Velozo, Telma M.G. Silva, Tania Maria Sarmento Silva, Adilva Souza Conceição, Neuza Maria Alcântara-Neves, Camila Alexandrina Figueiredo
Journal: Journal of Allergy and Clinical Immunology (2017)
Long-Term Survivors after Stem Cell Transplantation in Multiple Myeloma: Bone Marrow Minimal Residual Disease, PET/CT and Immunological Status
Authors: Carlos Fernández de Larrea, Xavier Calvo, Natalia Tovar, Ester Lozano, Xavier Setoain, Manel Juan, Tania Díaz, Laura Rosiñol, Montserrat Elena, Mª Teresa Cibeira, Ignacio Isola, Maria Rozman, Juan I. Aróstegui, Jordi Yagüe, Joan Bladé
Journal: Blood (2015)
Establishment of esophagogastric xenografts: A model for characterizing disease heterogeneity.
Authors: Yelena Yuriy Janjigian, Christopher M. Gromisch, Gregory Carbonetti, Laura H. Tang, David Paul Kelsen, Daniel G. Coit, Efsevia Vakiani, Elisa de Stanchina, Vivian E. Strong
Journal: Journal of Clinical Oncology (2012)

95 Background: Gastric cancer is a heterogeneous disease that may be subdivided into distinct subtypes—proximal/gastroesophageal (GE) junction, diffuse/signet ring type, and distal gastric cancer/intestinal type—based on histopathologic and anatomic criteria. Each subtype is associated with unique epidemiology and gene expression. Human epidermal growth factor receptor (HER2) is a validated treatment target in gastric cancer. For patients with metastatic disease, the available cytotoxic agents are applied indiscriminately to all disease subtypes, and with only modest success. The purpose of this study is to establish xenograft models from gastric cancer subtypes to improve our understanding of disease heterogeneity and develop therapies geared for each subtype of gastric cancer. Methods: Fresh specimens obtained from resected primary or metastatic tumors under aseptic conditions. 1 g tumor samples injected SQ into flanks of NSG mice. Xenografts established after 5 passages and maintained by serial transplantation into new mice. Cell cultures established after 5 in vitro passages; cell lines after 15 passages Results: To date, 66 tumor samples have been implanted from which 16 xenografts have been established. The table below summarizes the results. Single-agent afatinib (pan-ErbB inhibitor) demonstrated antitumor activity in an HER2-positive xenograft established from MSKCC patient’s tumor harvested from a skin metastasis. Conclusions: We have established xenograft models of gastric cancer. In vivo testing of afatinib showed a reduction of tumor growth of HER2-positive gastric cancer. These models provide a platform to study potential therapeutics for esophagogastric cancer to further validate difference in their biology and guide rational design of clinical trials. [Table: see text]
PDTB-27. PRECISION MEDICINE IN PEDIATRIC NEURO-ONCOLOGY
Authors: Prajwal Rajappa, David Pisapia
Journal: Neuro-Oncology (2016)

Current paradigms utilized in pediatric neuro-oncology as either primary or adjunctive modalities of therapy have failed in enhancing overall survival. Recent studies have shed light on the many facets of genetic instability that drive tumor heterogeneity and evolutionary change within an individual’s tumor that often leads to therapeutic resistance. Chemotherapeutic regimens largely focused on cell cycle inhibition are ineffective and outdated. Faced with dismal outcomes for high grade tumors, the implications for personalized medicine that targets the unique molecular landscape and genetic vulnerabilities of each person’s specific disease becomes paramount. We provide an overview of our institution’s preliminary experience with a patient-specific precision medicine algorithm offered to patients with central nervous system (CNS) tumors. We reviewed the logistics and coordination required for tissue procurement in the operating room to subsequent DNA extraction and whole exome sequencing (WES) culminating with a precision medicine report being generated for each patient. Germline analyses were also performed. Patient WES data is then analyzed for functional relevance using big data portals such as CBIOPORTAL. We report the successful coordination of our precision medicine algorithm for n=30 patients with reports being disseminated to treating neuro-oncology teams. WES data is ultimately presented at the multi-disciplinary precision medicine tumor board on a bi-weekly basis. The reporting mechanism time interval from initial receipt of all materials necessary for WES is roughly 6-8 weeks. Roughly 20% of somatic alterations detected from WES sequencing have yielded molecular targets that may have specificity for FDA approved compounds. We strongly encourage patients to enroll in our precision medicine pathway. The WES platform capture reads for over 20,000 genes and offers a unique data set that may shed light on both known cancer relevant somatic alterations but also functional relevance for less known mutations on a case-specific basis.
Sex Differences Impact the Lung-Bone Inflammatory Response to Repetitive Inhalant Lipopolysaccharide Exposures in Mice
Authors: Jill A. Poole, Amy Nelson, Kristi J. Warren, Debra Romberger, Michael Duryee, Lynell Klassen, Ted Mikuls, Dong Wang, Geoffrey Thiele
Journal: Journal of Allergy and Clinical Immunology (2017)
A phase II study of lapatinib and capecitabine in second line treatment of locally advanced/metastatic pancreatic cancer.
Authors: A. R. He, J. J. Hwang, J. Marshall, M. Pishvaian, R. Slack, L. M. Weiner, A. Wellstein
Journal: Journal of Clinical Oncology (2011)

e14542 Background: Anti-EGFR therapy erlotinib was FDA approved for the treatment of patients with advanced pancreas cancer. Human epidermal growth factor receptor 2 (HER-2) is another member of the ErbB family of growth factor receptor tyrosine kinases, is found overexpressed in 20% of pancreatic cancers . Target EGFR and HER-2 with separate specific monoclonal antibodies showed synergistic inhibition of pancreas cancer tumor progression compared with single mAb injection (P = 0.006) or no treatment (P = 0.0004) and even induced some complete remissions in xenograft mice. Lapatinib is a tyrosine kinase inhibitor which binds to both EGFR and HER-2. We propose a single arm phase II study to evaluate the combination of lapatinib and capecitabine in the second-line treatment of metastatic pancreatic cancer. Methods: We have initiated an open label phase II study. Patients with metastatic, unresectable pancreatic cancer who have failed first line Gemcitabine-based therapy, who have an adequate performance status (ECOG 0-2) and normal hepatic and renal function will be eligible. Patients will receive lapatinib 1,250 mg PO daily one hour before or after meals, and capecitabine 1,000 mg/m2 PO twice daily on days 1-14 of 21 day cycle.The primary endpoint is median overall survival (OS). A total of 51 patients will be enrolled over a total of 2 years, with 6 additional months of follow-up time for the final patient. Calculation using Stplan shows that this would provide 90% power to detect 6 months as significantly greater than four months at a one-sided 10% significance level. If eight of the first fourteen patients die within four months of enrolling on the trial, then the trial will stop to protect patients from receiving ineffective therapy. In addition to the clinical study endpoints, circulating microRNA is analyzed during the treatment course in each patient to correlates patient’s outcome. Results: The trial opened in September, 2009 and has accrued seventeen patients, beyond the early stopping rule. Conclusions: The combination is well tolerated and shows promising clinical activity.
The Illness Experience of Undocumented Immigrants With End-stage Renal Disease
Authors: Lilia Cervantes, Stacy Fischer, Nancy Berlinger, Maria Zabalaga, Claudia Camacho, Stuart Linas, Debora Ortega
Journal: JAMA Internal Medicine (2017)

The exclusion of undocumented immigrants from Medicare coverage for hemodialysis based on a diagnosis of end-stage renal disease (ESRD) requires physicians in some states to manage chronic illness in this population using emergent-only hemodialysis. Emergent-only dialysis is expensive and burdensome for patients.To understand the illness experience of undocumented immigrants with ESRD who lack access to scheduled hemodialysis.A qualitative, semistructured, interview study was conducted in a Colorado safety-net hospital from July 1 to December 31, 2015, with 20 undocumented immigrants (hereinafter referred to as undocumented patients) with ESRD and no access to scheduled hemodialysis. Demographic information was collected from the participants' medical records. The interviews were audiorecorded, translated, and then transcribed verbatim. The interviews were analyzed using inductive qualitative theme analysis by 4 research team members from March 1 to June 30, 2016.Themes and subthemes from semistructured interviews.All 20 undocumented patients included in the study (10 men and 10 women; mean [SD] age, 51.4 [13.8] years) had been in the United States for at least 5 years preceding their diagnosis with ESRD. They described the following 4 main themes: (1) a distressing symptom burden and unpredictable access to emergent-only hemodialysis, (2) death anxiety associated with weekly episodes of life-threatening illness, (3) family and social consequences of accommodating emergent-only hemodialysis, and (4) perceptions of the health care system.Undocumented patients with ESRD experience debilitating, potentially life-threatening physical symptoms and psychosocial distress resulting from emergent-only hemodialysis. States excluding undocumented immigrants with ESRD from scheduled dialysis should reconsider their policies.
A Cross-Sectional Study of Asthma Exacerbations in the Emergency Department: Viral Infections and the Microbiome
Authors: Joshua Kennedy, Olga Hardin, Jesse Denson, Kurt Schwalm, Suzanne Godbold, Lee Crawley, Thomas Abramo, Ashley N. Stoner, John C. Kincaid, Darrell L. Dinwiddie
Journal: Journal of Allergy and Clinical Immunology (2017)