tbuckley/cabot-search huggingface dataset:
Adoptive Cell Therapy for Patients With Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative Regimens
Authors: Mark E. Dudley, James C. Yang, Richard Sherry, Marybeth S. Hughes, Richard Royal, Udai Kammula, Paul F. Robbins, JianPing Huang, Deborah E. Citrin, Susan F. Leitman, John Wunderlich, Nicholas P. Restifo, Armen Thomasian, Stephanie G. Downey, Franz O. Smith, Jacob Klapper, Kathleen Morton, Carolyn Laurencot, Donald E. White, Steven A. Rosenberg
Journal: Journal of Clinical Oncology (2008)

The two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens.We performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied.Although nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells.Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies.
Use of Statins and the Risk of Death in Patients With Prostate Cancer
Authors: Oriana Yu, Maria Eberg, Serge Benayoun, Armen Aprikian, Gerald Batist, Samy Suissa, Laurent Azoulay
Journal: Journal of Clinical Oncology (2013)

Purpose To determine whether the use of statins after prostate cancer diagnosis is associated with a decreased risk of cancer-related mortality and all-cause mortality and to assess whether this association is modified by prediagnostic use of statins. Patients and Methods A cohort of 11,772 men newly diagnosed with nonmetastatic prostate cancer between April 1, 1998, and December 31, 2009, followed until October 1, 2012, was identified using a large population-based electronic database from the United Kingdom. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% CIs of mortality outcomes associated with postdiagnostic use of statins, lagged by 1 year to account for latency considerations and to minimize reverse causality, and considering effect modification by prediagnostic use of statins. Results During a mean follow-up time of 4.4 years (standard deviation, 2.9 years), 3,499 deaths occurred, including 1,791 from prostate cancer. Postdiagnostic use of statins was associated with a decreased risk of prostate cancer mortality (HR, 0.76; 95% CI, 0.66 to 0.88) and all-cause mortality (HR, 0.86; 95% CI, 0.78 to 0.95). These decreased risks of prostate cancer mortality and all-cause mortality were more pronounced in patients who also used statins before diagnosis (HR, 0.55; 95% CI, 0.41 to 0.74; and HR, 0.66; 95% CI, 0.53 to 0.81, respectively), with weaker effects in patients who initiated the treatment only after diagnosis (HR, 0.82; 95% CI, 0.71 to 0.96; and HR, 0.91; 95% CI, 0.82 to 1.01, respectively). Conclusion Overall, the use of statins after diagnosis was associated with a decreased risk in prostate cancer mortality. However, this effect was stronger in patients who also used statins before diagnosis.
Oncolytic Treatment and Cure of Neuroblastoma by a Novel Attenuated Poliovirus in a Novel Poliovirus-Susceptible Animal Model
Authors: Hidemi Toyoda, Jiang Yin, Steffen Mueller, Eckard Wimmer, Jeronimo Cello
Journal: Cancer Research (2007)

Abstract Neuroblastoma is one of the most common solid tumors in children. Treatment is of limited utility for high-risk neuroblastoma and prognosis is poor. Resistance of neuroblastoma to conventional therapies has prompted us to search for a novel therapeutic approach based on genetically modified polioviruses. Poliovirus targets motor neurons leading to irreversible paralysis. Neurovirulence can be attenuated by point mutations or by exchange of genetic elements between different picornaviruses. We have developed a novel and stable attenuated poliovirus, replicating in neuroblastoma cells, by engineering an indigenous replication element (cre), copied from a genome-internal site, into the 5′-nontranslated genomic region (mono-crePV). An additional host range mutation (A133G) conferred replication in mouse neuroblastoma cells (Neuro-2aCD155) expressing CD155, the poliovirus receptor. Crossing immunocompetent transgenic mice susceptible to poliovirus (CD155 tg mice) with A/J mice generated CD155 tgA/J mice, which we immunized against poliovirus. Neuro-2aCD155 cells were then transplanted into these animals, leading to lethal tumors. Despite preexisting high titers of anti-poliovirus antibodies, established lethal s.c. Neuro-2aCD155 tumors in CD155 tgA/J mice were eliminated by intratumoral administrations of A133Gmono-crePV. No signs of paralysis were observed. Interestingly, no tumor growth was observed in mice cured of neuroblastoma that were reinoculated s.c. with Neuro-2aCD155. This result indicates that the destruction of neuroblastoma cells by A133Gmono-crePV may lead to a robust antitumor immune response. We suggest that our novel attenuated oncolytic poliovirus is a promising candidate for effective oncolytic treatment of human neuroblastoma or other cancer even in the presence of present or induced antipolio immunity. [Cancer Res 2007;67(6):2857–64]
Mesenteric blood flow is related to disease activity and risk of relapse in ulcerative colitis: a prospective follow up study
Authors: D Ludwig, S Wiener, A Bruning, K Schwarting, G Jantschek, K Fellermann, M Stahl, E F Stange
Journal: Gut (1999)

The diagnostic significance of increased splanchnic blood flow in ulcerative colitis is unclear. This prospective study was therefore undertaken to define the role of Doppler sonography in the assessment of disease activity and in the prediction of early relapse.Splanchnic flowmetry was performed in 76 patients with ulcerative colitis (47 with active disease and 29 in remission), six with infectious colitis, and 13 healthy controls during fasting and 30 minutes after ingestion of a standardised meal. Twenty seven of the patients with ulcerative colitis and all patients with infectious colitis were investigated during the active state as well as in clinical remission and followed up for six months. Flow velocity and pulsatility index (PI) of the superior (SMA) and inferior (IMA) mesenteric arteries and the portal vein were related to clinical (Truelove index), laboratory (C-reactive protein), and endoscopic (Sutherland index) parameters of disease activity.The mean flow velocity of the IMA correlated closest with clinical activity (Truelove, r = 0.41, p<0.005), the PI with C-reactive protein (r = 0.30, p<0.05), and endoscopic activity (r = 0.45, p<0.001). All patients in remission after six months (14/14) or with infectious colitis (6/6) showed an increase in PI of the IMA compared with the initial measurement during active disease (mean increase for ulcerative colitis +36% and for infectious colitis +77%). In contrast, most patients with later relapse or surgery (11/13) had decreased PI during initial remission (mean decrease -12%). The positive predictive value of this index for maintenance of remission was 0.77. Flow variables of the SMA and portal vein displayed weaker correlations.Flow measurements in the IMA are closely related to clinical and endoscopic disease activity in patients with ulcerative colitis. Repeated measurement of the PI allows estimation of the risk of recurrence.
Comprehensive Genomic Analysis of Rhabdomyosarcoma Reveals a Landscape of Alterations Affecting a Common Genetic Axis in Fusion-Positive and Fusion-Negative Tumors
Authors: Jack F. Shern, Li Chen, Juliann Chmielecki, Jun S. Wei, Rajesh Patidar, Mara Rosenberg, Lauren Ambrogio, Daniel Auclair, Jianjun Wang, Young K. Song, Catherine Tolman, Laura Hurd, Hongling Liao, Shile Zhang, Dominik Bogen, Andrew S. Brohl, Sivasish Sindiri, Daniel Catchpoole, Thomas Badgett, Gad Getz, Jaume Mora, James R. Anderson, Stephen X. Skapek, Frederic G. Barr, Matthew Meyerson, Douglas S. Hawkins, Javed Khan
Journal: Cancer Discovery (2014)

Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome, and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two genotypes are evident in rhabdomyosarcoma tumors: those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in rhabdomyosarcoma is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations in NRAS, KRAS, HRAS, FGFR4, PIK3CA, and CTNNB1, we found novel recurrent mutations in FBXW7 and BCOR, providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases, providing a framework for genomics-directed therapies that might improve outcomes for patients with rhabdomyosarcoma.This is the most comprehensive genomic analysis of rhabdomyosarcoma to date. Despite a relatively low mutation rate, multiple genes were recurrently altered, including NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR. In addition, a majority of rhabdomyosarcoma tumors alter the receptor tyrosine kinase/RAS/PIK3CA axis, providing an opportunity for genomics-guided intervention.
RESPONSE: Re: Modification of Clinical Presentation of Prostate Tumors by a Novel Genetic Variant in CYP3A4
Authors: B. Amirimani, A. H. Walker, B. L. Weber, T. R. Rebbeck
Journal: JNCI Journal of the National Cancer Institute (1999)

Pathways involved in androgen metabolism have been implicated in the etiology of prostate cancer. The goal of this study was to evaluate the effect of CYP3A4, a gene associated with the oxidative deactivation of testosterone, on the clinical presentation of prostate cancers.A polymerase chain reaction-based approach was used to identify sequence variants of the human CYP3A4 gene. To ascertain whether allelic variants of the CYP3A4 gene were associated with tumor stage and grade and age of the patient at diagnosis, we determined CYP3A4 genotypes in 230 Caucasian men with incident prostate cancer.We identified a novel genetic variant (CYP3A4-V) that has an altered 5' regulatory element, containing an A to G mutation, upstream of the CYP3A4 gene. We then compared clinical characteristics of prostate cancers in men who did and did not carry this variant. The presence of the CYP3A4-V allele was associated with a higher tumor-lymph node-metastasis (TNM) stage and Gleason grade. The association between CYP3A4 genotype and tumor stage was most pronounced in men diagnosed at a relatively old age who reported no family history of prostate cancer. In this group, 46% of men with stage T3/T4 tumors carried CYP3A4-V, whereas only 5% of individuals with stage T1 tumors carried CYP3A4-V (adjusted odds ratio = 9.45; 95% confidence interval = 2.54-35.17; chi2(1) = 12.28; two-sided P<.001).We determined that a single base change in the 5' flanking region of the CYP3A4 gene was associated with higher clinical stage and grade in men with prostate tumors. Our results suggest that mutations in the CYP3A4 gene may influence prostate carcinogenesis.
Meta-Analysis of Soy Intake and Breast Cancer Risk
Authors: Bruce J. Trock, Leena Hilakivi-Clarke, Robert Clarke
Journal: JNCI Journal of the National Cancer Institute (2006)

Background: High intake of soy foods has been proposed to contribute to the low breast cancer risk in Asian countries. However, results of epidemiologic studies of this association are highly variable, and experimental data suggest that soy constituents can be estrogenic and potentially risk enhancing. Thus, rigorous evaluation of available epidemiologic data is necessary before appropriate recommendations can be made, especially for women at high risk of breast cancer or those who have survived the disease. Methods: We performed a meta-analysis of 18 epidemiologic studies (12 case–control and six cohort or nested case–control) published from 1978 through 2004 that examined soy exposure and breast cancer risk. Pooled relative risk estimates were based on either the original soy exposure measure defined in each study or on an estimate of daily soy protein intake. Results: Risk estimates, levels and measures of soy exposure, and control for confounding factors varied considerably across studies. In a pooled analysis, among all women, high soy intake was modestly associated with reduced breast cancer risk (odds ratio [OR] = 0.86, 95% confidence interval [CI] = 0.75 to 0.99); the association was not statistically significant among women in Asian countries (OR = 0.89, 95% CI = 0.71 to 1.12). Among the 10 studies that stratified by menopausal status the inverse association between soy exposure and breast cancer risk was somewhat stronger in premenopausal women (OR = 0.70, 95% CI = 0.58 to 0.85) than in postmenopausal women (OR = 0.77, 95% CI = 0.60 to 0.98); however, eight studies did not provide menopause-specific results, six of which did not support an association. When exposure was analyzed by soy protein intake in grams per day, a statistically significant association with breast cancer risk was seen only among premenopausal women (OR = 0.94, 95% CI = 0.92 to 0.97). Conclusions: Soy intake may be associated with a small reduction in breast cancer risk. However, this result should be interpreted with caution due to potential exposure misclassification, confounding, and lack of a dose response. Given these caveats and results of some experimental studies that suggest adverse effects from soy constituents, recommendations for high-dose isoflavone supplementation to prevent breast cancer or prevent its recurrence are premature.
<i>IDH1</i> and <i>IDH2</i> Gene Mutations Identify Novel Molecular Subsets Within De Novo Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study
Authors: Guido Marcucci, Kati Maharry, Yue-Zhong Wu, Michael D. Radmacher, Krzysztof Mrózek, Dean Margeson, Kelsi B. Holland, Susan P. Whitman, Heiko Becker, Sebastian Schwind, Klaus H. Metzeler, Bayard L. Powell, Thomas H. Carter, Jonathan E. Kolitz, Meir Wetzler, Andrew J. Carroll, Maria R. Baer, Michael A. Caligiuri, Richard A. Larson, Clara D. Bloomfield
Journal: Journal of Clinical Oncology (2010)

Purpose To analyze the frequency and associations with prognostic markers and outcome of mutations in IDH genes encoding isocitrate dehydrogenases in adult de novo cytogenetically normal acute myeloid leukemia (CN-AML). Patients and Methods Diagnostic bone marrow or blood samples from 358 patients were analyzed for IDH1 and IDH2 mutations by DNA polymerase chain reaction amplification/sequencing. FLT3, NPM1, CEBPA, WT1, and MLL mutational analyses and gene- and microRNA-expression profiling were performed centrally. Results IDH mutations were found in 33% of the patients. IDH1 mutations were detected in 49 patients (14%; 47 with R132). IDH2 mutations, previously unreported in AML, were detected in 69 patients (19%; 13 with R172 and 56 with R140). R172 IDH2 mutations were mutually exclusive with all other prognostic mutations analyzed. Younger age (&lt; 60 years), molecular low-risk (NPM1-mutated/FLT3-internal tandem duplication–negative) IDH1-mutated patients had shorter disease-free survival than molecular low-risk IDH1/IDH2-wild-type (wt) patients (P = .046). R172 IDH2-mutated patients had lower complete remission rates than IDH1/IDH2wt patients (P = .007). Distinctive microarray gene- and microRNA-expression profiles accurately predicted R172 IDH2 mutations. The highest expressed gene and microRNAs in R172 IDH2-mutated patients compared with the IDH1/IDH2wt patients were APP (previously associated with complex karyotype AML) and miR-1 and miR-133 (involved in embryonal stem-cell differentiation), respectively. Conclusion IDH1 and IDH2 mutations are recurrent in CN-AML and have an unfavorable impact on outcome. The R172 IDH2 mutations, previously unreported in AML, characterize a novel subset of CN-AML patients lacking other prognostic mutations and associate with unique gene- and microRNA-expression profiles that may lead to the discovery of novel, therapeutically targetable leukemogenic mechanisms.
Loss of expression of the Hoxa-9 homeobox gene impairs the proliferation and repopulating ability of hematopoietic stem cells
Authors: H. Jeffrey Lawrence, Julie Christensen, Stephen Fong, Yu-Long Hu, Irving Weissman, Guy Sauvageau, R. Keith Humphries, Corey Largman
Journal: Blood (2005)

The homeobox gene Hoxa-9 is normally expressed in primitive bone marrow cells, and overexpression of Hoxa-9 markedly expands hematopoietic stem cells, suggesting a function in early hematopoiesis. We present evidence for major functional defects in Hoxa-9-/- hematopoietic stem cells. Hoxa-9-/- marrow cells have normal numbers of immunophenotypic stem cells (Lin(-)c-kit(+)flk-2(-)Sca-1+ [KLFS] cells). However, sublethally irradiated Hoxa-9-/- mice develop persistent pancytopenia, indicating unusual sensitivity to ionizing irradiation. In competitive transplantation assays, Hoxa-9-/- cells showed an 8-fold reduction in multilineage long-term repopulating ability, a defect not seen in marrow cells deficient for the adjacent Hoxa-10 gene. Single-cell cultures of KLFS cells showed a 4-fold reduction in large high-proliferation potential colonies. In liquid cultures, Hoxa-9-deficient Lin(-)Sca-1(+) cells showed slowed proliferation (a 5-fold reduction in cell numbers at day 8) and delayed emergence of committed progenitors (a 5-fold decrease in colony-forming cells). Slowing of proliferation was accompanied by a delay in myeloid maturation, with a decrease in Gr-1hiMac-1hi cells at the end of the culture. Retroviral transduction with a Hoxa-9 expression vector dramatically enhanced the cytokine-driven proliferation and in vivo engraftment of Hoxa-9-/- marrow cells. Hoxa-9 appears to be specifically required for normal hematopoietic stem cell function both in vitro and in vivo.
Effect of gastro-oesophageal reflux on upper oesophageal sphincter motility in children.
Authors: J Willing, G P Davidson, J Dent, I Cook
Journal: Gut (1993)

Motor events of the upper oesophageal sphincter associated with gastro-oesophageal reflux were evaluated in 53 symptomatic children (median age 13 months) who were studied recumbent and unsedated. Children were divided into four groups according to symptoms, and then into two groups according to the presence or absence of neurological deficit. No grouping had basal upper oesophageal sphincter pressure that differed significantly from any other. Oesophageal distention due to gastro-oesophageal reflux, which was recognisable as oesophageal common cavity episodes, was associated with augmentation of mean basal upper oesophageal sphincter pressure from 36.5 (SD 18) mm Hg to 48.5 (18) mm Hg (p &lt; 0.0001), irrespective of whether gastro-oesophageal reflux caused oesophageal acidification. Abrupt relaxations of the upper oesophageal sphincter independent of swallowing and lasting up to three seconds occurred during 54% of common cavity episodes. Forty nine per cent of these relaxations occurred within four seconds after the onset of distention. The oesophageal distention caused by gastro-oesophageal reflux is a potent stimulus of transient upper oesophageal sphincter relaxations in children. These relaxations are a more likely explanation for oesophagopharyngeal reflux than defective basal upper oesophageal sphincter tone.
Intestinal barriers to water-soluble macromolecules
Authors: James G. Lecce
Journal: Environmental Health Perspectives (1979)

Neonates of some species of mammals absorb water-soluble macromolecules from the lumen of the gut to the circulation. This is a means for providing the neonate with passive immunological protection. The accepted model for absorption of macromolecules, particularly immunoglobulin G (IgG), has at least three phases: adherence of the macromolecule to the brush border on enterocytes; internalization of the macromolecule within the enterocytes; and egress of the macromolecule into the lamina propria. With regard to the absorption of IgG, adherence is thought to be a specific reaction of ligand (IgG) with a plasmalemma binding site. Pinocytosis is activated and internalization follows. Egress into the lamina propria occurs at the basal-lateral membrane by a process of reverse pinocytosis. Unbound (unprotected) macromolecules that are internalized in the pinocytosic fluid are shunted off to lysosomes and either digested or stored therein. Neonatal rodents fit this model for macromolecular absorption. However, in another group of neonates (e.g., pig, cow, horse), nonselected absorption takes place, in that IgG and other macromolecules are transported from the gut lumen to the blood. In a third group of neonates, (e.g., human, guinea pig) absorption of IgG is either of low order or nonexistent. Since neonatal mammals possess a mechanism for absorbing macromolecules, there is the potential for internalizing toxic macromolecules if the toxin is presented to the neonate's enterocytes in competitive amounts. Adults retain remnants of the neonatal absorptive mechanism.
Clonality of multifocal nonsmall cell lung cancer: implications for staging and therapy
Authors: Arne Warth, Stephan Macher-Goeppinger, Thomas Muley, Michael Thomas, Hans Hoffmann, Philipp A. Schnabel, Roland Penzel, Peter Schirmacher, Sebastian Aulmann
Journal: European Respiratory Journal (2011)

Nonsmall cell lung cancers (NSCLCs) display a variety of morphological and molecular features. Accurate subtyping of NSCLC has been shown to predict patient survival as well as response rates and toxicities of specific drugs. Assessment of multifocal lung tumours and the distinction of synchronous primary tumours from intrapulmonary metastases represent an important problem as this decision significantly influences tumour staging and subsequent treatment strategies. In order to provide a basis for evidence-based treatment decisions in these patients, we analysed the clonal relationship of multifocal NSCLC with indistinguishable histomorphology in a series of 78 patients by allelotyping (using polymorphic short tandem repeat markers) as well as KRAS and epidermal growth factor receptor (EGFR) mutation testing. Our data demonstrate a common clonal origin indicative of intrapulmonary metastases in almost two-thirds (~62%) of the cases, while ~36% of multifocal NSCLC displayed unique molecular profiles suggesting separate primary tumours. Divergent KRAS and/or EGFR mutations were observed in ~8% of all cases. With the increased availability of EGFR-targeted therapy options, nonresectable, multifocal NSCLC with diverging KRAS and/or EGFR mutations are likely to show different treatment responses, underlining the need to separately analyse multifocal tumours. Obviously, this also holds true for further, novel molecular predictors of targeted therapies.