tbuckley/cabot-search huggingface dataset:
A sequence-based survey of the complex structural organization of tumor genomes
Authors: Benjamin J Raphael, Stanislav Volik, Peng Yu, Chunxiao Wu, Guiqing Huang, Elena V Linardopoulou, Barbara J Trask, Frederic Waldman, Joseph Costello, Kenneth J Pienta, Gordon B Mills, Krystyna Bajsarowicz, Yasuko Kobayashi, Shivaranjani Sridharan, Pamela L Paris, Quanzhou Tao, Sarah J Aerni, Raymond P Brown, Ali Bashir, Joe W Gray, Jan-Fang Cheng, Pieter de Jong, Mikhail Nefedov, Thomas Ried, Hesed M Padilla-Nash, Colin C Collins
Journal: Genome biology (2008)

The genomes of many epithelial tumors exhibit extensive chromosomal rearrangements. All classes of genome rearrangements can be identified using end sequencing profiling, which relies on paired-end sequencing of cloned tumor genomes. In the present study brain, breast, ovary, and prostate tumors, along with three breast cancer cell lines, were surveyed using end sequencing profiling, yielding the largest available collection of sequence-ready tumor genome breakpoints and providing evidence that some rearrangements may be recurrent. Sequencing and fluorescence in situ hybridization confirmed translocations and complex tumor genome structures that include co-amplification and packaging of disparate genomic loci with associated molecular heterogeneity. Comparison of the tumor genomes suggests recurrent rearrangements. Some are likely to be novel structural polymorphisms, whereas others may be bona fide somatic rearrangements. A recurrent fusion transcript in breast tumors and a constitutional fusion transcript resulting from a segmental duplication were identified. Analysis of end sequences for single nucleotide polymorphisms revealed candidate somatic mutations and an elevated rate of novel single nucleotide polymorphisms in an ovarian tumor. These results suggest that the genomes of many epithelial tumors may be far more dynamic and complex than was previously appreciated and that genomic fusions, including fusion transcripts and proteins, may be common, possibly yielding tumor-specific biomarkers and therapeutic targets.
Trastuzumab — Mechanism of Action and Use in Clinical Practice
Authors: Clifford A. Hudis
Journal: New England Journal of Medicine (2007)

Overexpression of human epidermal growth factor receptor type 2 (HER2) in breast cancer is associated with decreased overall survival. Trastuzumab, a humanized monoclonal antibody that targets HER2, is approved by the Food and Drug Administration for patients with invasive breast cancers that overexpress HER2. This review considers the mechanism of action and the use of this agent.
Therapeutic Potential of Adult Bone Marrow–Derived Mesenchymal Stem Cells in Prostate Cancer Bone Metastasis
Authors: Diptiman Chanda, Tatyana Isayeva, Sanjay Kumar, Jonathan A. Hensel, Anandi Sawant, Girish Ramaswamy, Gene P. Siegal, Matthew S. Beatty, Selvarangan Ponnazhagan
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Current evidence indicates that an osteoblast lesion in prostate cancer is preceded by osteolysis. Thus, prevention of osteolysis would reduce complications of bone metastasis. Bone marrow–derived mesenchymal stem cells have the ability to differentiate into osteoblast and produce osteoprotegerin, a decoy receptor for the receptor activator for nuclear factor κB ligand, naturally. The present study examined the potential of unmodified mesenchymal stem cells to prevent osteolytic bone lesions in a preclinical mouse model of prostate cancer. Experimental Design: The human prostate cancer cell line PC3 was implanted in tibiae of severe combined immunodeficient mice. After establishment of the tumor, either unmodified or genetically engineered mesenchymal stem cells overexpressing osteoprotegerin was injected at the site of tumor growth. The effects of therapy were monitored by bioluminescence imaging, micro–computed tomography, immunohistochemistry, and histomorphometry. Results: Data indicated significant (P &amp;lt; 0.001) inhibition of tumor growth and restoration of bone in mice treated with unmodified and modified mesenchymal stem cells. Detailed analysis suggested that the donor mesenchymal stem cell inhibited tumor progression by producing woven bone around the growing tumor cells in the tibiae and by preventing osteoclastogenesis. Conclusions: Overcoming the limitation of the number of mesenchymal stem cells available in the bone can provide significant amelioration for osteolytic damage without further modification. (Clin Cancer Res 2009;15(23):7175–85)
Phase II Study of Activated Charcoal to Prevent Irinotecan-Induced Diarrhea
Authors: Michael Michael, MaryAnne Brittain, Jane Nagai, Ronald Feld, David Hedley, Amit Oza, Lillian Siu, Malcolm J. Moore
Journal: Journal of Clinical Oncology (2004)

The dose-limiting toxicity of irinotecan (CPT-11; Camptosar) is delayed-onset diarrhea, with an incidence at the grade 3 to 4 level of 20% to 35%. SN38, its active moiety, is responsible by a direct effect on mucosal topoisomerase-I. The aim of this study was to assess whether activated charcoal (AC), possibly by adsorbing free lumenal SN38, can reduce irinotecan-induced diarrhea (CID) and optimize its dose-intensity.Patients with advanced colorectal cancer receiving irinotecan 125 mg/m(2) intravenously once a week for 4 weeks every 6 weeks were studied. In cycle 1, patients received irinotecan plus AC (5 mL aqueous Charcodote [1,000 mg AC] plus 25 mL water) given the evening before the irinotecan dose and then tid for 48 hours after the dose. In cycle 2, no AC was given. National Cancer Institute Common Toxicity Criteria diarrhea grade, irinotecan dose-intensity, and loperamide consumption were recorded prospectively in both cycles.Twenty-eight patients had completed cycle 1 with AC; 24 subsequently completed cycle 2 without AC. Grade 3 to 4 diarrhea was 7.1% v 25%, and grade 0 diarrhea was 46.4% v 20.8% in cycles 1 and 2, respectively. Median percent planned dose delivered was 98% v 70% in cycles 1 and 2, respectively. In cycles 1 and 2, respectively, 25% v 54% patients took more than 10 loperamide tablets. AC was well tolerated with excellent compliance.The administration of AC with irinotecan reduced the incidence of grade 3 to 4 diarrhea and antidiarrheal medication consumption and increased irinotecan dose-intensity. Prophylactic AC may have a role in reducing dose-limiting CID and optimizing irinotecan therapy.
Molecular Pathways: Targeting ATR in Cancer Therapy
Authors: Larry M. Karnitz, Lee Zou
Journal: Clinical Cancer Research (2015)

The human ATR gene encodes a kinase that is activated by DNA damage and replication stress as a central transducer of a checkpoint signaling pathway. Once activated, ATR phosphorylates multiple substrates, including the kinase Chk1, to regulate cell-cycle progression, replication fork stability, and DNA repair. These events promote cell survival during replication stress and in cells with DNA damage. Accordingly, there has been the tantalizing possibility that ATR inhibitors would be therapeutically useful, especially if they were more effective in tumor versus normal cells. Indeed, multiple studies have demonstrated that alterations that promote tumorigenesis, such as defects in the ATM-p53 pathway, constitutive oncogene activation, and acquisition of the alternative lengthening of telomeres pathway, render tumor cells sensitive to ATR inhibitor monotherapy and/or increase the synergy between ATR inhibitors and genotoxic chemotherapies. Now, nearly two decades after the discovery of ATR, two highly selective and potent ATR inhibitors, AZD6738 and VX-970, are in early-phase clinical trials either as monotherapies or paired with a variety of genotoxic chemotherapies. These trials will generate important insights into the effects of ATR inhibition in humans and the potential role of inhibiting this kinase in the treatment of human malignancies.
Expression of CC Chemokine Receptor-7 and Regional Lymph Node Metastasis of B16 Murine Melanoma
Authors: H. E. Wiley, E. B. Gonzalez, W. Maki, M.-t. Wu, S. T. Hwang
Journal: JNCI Journal of the National Cancer Institute (2001)

CC chemokine receptor-7 (CCR7), which plays a critical role in the migration of activated dendritic cells to regional lymph nodes via afferent lymphatic vessels, is also expressed by human breast and melanoma cell lines. Because neoplastic cells also enter lymphatic vessels before metastasis to the lymph nodes, we investigated whether CCR7 expression enhances metastasis of B16 murine melanoma cells to regional lymph nodes.B16 cells were transduced with a retroviral vector containing CCR7 complementary DNA (CCR7-B16 cells) or with vector alone (pLNCX2-B16 control cells). The functional assay for CCR7 protein was Ca(2+) flux stimulated by the chemokine CCL21, a CCR7-specific ligand produced by lymphatic endothelial cells. B16 tumor cells were injected into the footpad of mice. Tumor cell metastasis to draining lymph nodes was assessed by measuring messenger RNA (mRNA) for tyrosinase-related protein-1 (TRP), a melanocyte-specific enzyme, with real-time, quantitative reverse transcription-coupled polymerase chain reaction. All statistical tests were two-sided.One week after injection into the footpad, 701-fold (95% confidence interval [CI] = 64- to 1336-fold) more TRP mRNA was detected in draining lymph nodes from CCR7-B16 cell-injected mice than in those from control cell-injected mice. Three weeks after footpad injection, 58% (11 of 19) of the draining lymph nodes from CCR7-B16 cell-injected mice and 5% (one of 19) of those from control mice showed gross metastases (P<.001). CCR7-B16 cells isolated from lymph node metastases retained functional CCR7 expression. Lymph node metastasis of CCR7-B16 cells was blocked by neutralizing anti-CCL21 antibodies (metastasis in none of five lymph nodes) but not by control immunoglobulin G (three of five). Enhanced metastasis of CCR7-B16 cells was specific for a lymphatic route because both CCR7-B16 and control cells co-injected intravenously metastasized to the lung at the same frequency.Expression of a single chemokine receptor gene, CCR7, increased B16 cell metastasis to draining lymph nodes, suggesting that cancer cells may co-opt normal mechanisms of lymph node homing during metastasis.
Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats
Authors: B A Vogels, M A Maas, J Daalhuisen, G Quack, R A Chamuleau
Journal: Hepatology (1997)

The aim of this study was to investigate the possible role of N -methyl-D-aspartate (NMDA)-receptor overactivity in two different experimental rat models of encephalopathy: subacute encephalopathy caused by severe hyperammonemia in portacaval-shunted rats (AI-PCS rats) and acute hepatic encephalopathy caused by complete liver ischemia (LIS rats). The effect of the noncompetitive NMDA-receptor antagonist memantine (intraperitoneal [i.p.] 10-20 mg/kg bw or intravenous [i.v.] 5 mg/kg bw) was studied on the severity of encephalopathy by assessment of clinical grading and electroencephalogram (EEG) spectral analysis, on plasma ammonia concentrations, amino acid concentrations in cerebrospinal fluid (CSF), intracranial pressure (ICP), and brain water content. Both rat models developed encephalopathy within 3 to 6 hours, associated with increased CSF glutamate and aspartate concentrations and increased ICP and brain water content. Memantine administration in AI-PCS and LIS rats resulted in a significant improvement in clinical grading and less slowing of EEG activity ( P &lt; .05), and smaller increases in CSF glutamate ( P &lt; .05) concentrations. Moreover, ICP and brain water content were significantly lower in memantine-treated AI-PCS rats than in untreated AI-PCS rats ( P &lt; .05). Memantine had no significant effect on ICP and brain water content in LIS rats, and on ammonia concentrations in both models. These results indicate that NMDA- receptor activation might be involved in the pathogenesis of hyperammonemia-induced encephalopathy and of acute hepatic encephalopathy caused by LIS.
The Relationship Between Impaired Retinal Vascular Reactivity and Renal Function in Patients with Degenerative Vascular Disease
Authors: H. O. SIEKER, J. B. HICKAM, J. F. GIBSON
Journal: Circulation (1955)

In hypertension and diabetes retinal vascular changes which are evident on fundiscopic examination are usually accompanied by renal vascular changes which are evident on microscopic examination. It has been found that the retinal vessels of most patients with hypertension or diabetes fail to constrict normally when the blood oxygen tension is elevated. This investigation evaluates the clinical significance of decreased retinal vascular reactivity in patients with degenerative vascular disease by relating it to kidney function as measured by common clinical tests. The results of the study show that impairment of retinal arterial reactivity usually occurs in the course of degenerative vascular disease, particularly in hypertension, in advance of clinical evidence of altered kidney function. When clinical tests of renal function demonstrate renal damage, loss of retinal arterial and venous reactivity is marked.
Allergen-specific Th2 responses in young children precede sensitization later in life
Authors: L. L. Reubsaet, J. Meerding, R. Scholman, B. Arets, B. J. Prakken, F. van Wijk, E. F. Knol
Journal: Allergy (2014)

Allergic sensitization is initiated by allergen-specific Th2-cell responses. Data on early allergen-specific T-cell responses in allergic children are scarce. We hypothesized that allergen-specific Th2-cell responses can be detected preceding sensitization. Therefore, peripheral blood mononuclear cells (PBMC) of nonsensitized, 'not-yet' sensitized or sensitized children were cultured with highly purified allergens. Cytokine levels in supernatant were determined using multiplex assay and GATA3 expression by flow cytometry. PBMC of sensitized children aged 3 and 5 years showed higher production of IL4, IL5 and IL13 and higher expression of GATA3 in response to purified allergens compared to nonsensitized children. PBMC of children that were 'not-yet' sensitized already showed higher levels of IL5 and IL13 and higher GATA3 expression at age 3 years. This shows that allergen-specific in vitro Th2 responses precede the detection of allergen-specific IgE, which can provide a window of opportunity for novel therapeutic interventions.
Correlates of Quality of Life in Older Adults With Diabetes
Authors: Neda Laiteerapong, Andrew J. Karter, Jennifer Y. Liu, Howard H. Moffet, Rebecca Sudore, Dean Schillinger, Priya M. John, Elbert S. Huang
Journal: Diabetes Care (2011)

To evaluate associations between health-related quality of life (HRQL) and geriatric syndromes, diabetes complications, and hypoglycemia in older adults with diabetes.A race-stratified random sample of 6,317 adults with type 2 or type 1 diabetes, aged 60 to 75 years, enrolled in Kaiser Permanente Northern California, who completed a survey that included a HRQL instrument based on the Short Form 8-item health survey. Administrative records were used to ascertain diagnoses of geriatric syndromes, diabetes complications, and hypoglycemia. Associations were estimated between HRQL and exposures in exposure-specific and combined exposure models (any syndrome, any complication, or hypoglycemia). Conservatively, differences of ≥3 points were considered the minimally important difference in HRQL scores.HRQL was lower with nearly all exposures of interest. The lowest physical HRQL was associated with amputation. In combined exposure models, geriatric syndromes (-5.3 [95% CI -5.8 to -4.8], P < 0.001) and diabetes complications (-3.5 [-4.0 to -2.9], P < 0.001) were associated with lower physical HRQL. The lowest mental HRQL was associated with depression, underweight (BMI <18 kg/m(2)), amputation, and hypoglycemia. In combined exposure models, only hypoglycemia was associated with lower mental HRQL (-4.0 [-7.0 to -1.1], P = 0.008).Geriatric syndromes and hypoglycemia are associated with lower HRQL to a comparable degree as diabetes complications. Addressing geriatric syndromes and avoiding hypoglycemia should be given as high a priority as preventing diabetes complications in older adults with diabetes.
Hypertrophy causes delayed conduction in human and guinea pig myocardium: accentuation during ischaemic perfusion
Authors: S J Winterton, M A Turner, D J O'Gorman, N A Flores, D J Sheridan
Journal: Cardiovascular Research (1994)

Objective: The aim was to investigate why cardiac hypertrophy causes increased vulnerability to arrhythmias during myocardial ischaemia. Methods: The electrophysiological basis for this increased vulnerability was studied in isolated perfused guinea pig hearts obtained 50 and 150 d after aortic constriction, and in sham operated controls. Cellular electrophysiology, conduction, and refractory periods were examined during control perfusion and during low flow (coronary flow reduced to 10% of control) and zero flow ischaemia. ECGs in patients with left ventricular hypertrophy and in controls matched for age and heart rate were also studied. Results: Aortic constriction increased heart weight:body weight ratio by 33% at 50 d and by 69% at 150 d. Action potentials were unchanged in hypertrophied hearts. Significant conduction delay occurred in 150 d hypertrophied hearts [conduction time index 23(SEM 4) ms v 18(3) ms, p<0.001; QRS width 40(1) ms v 35(1) ms, p<0.01], but not in 50 d hypertrophied hearts. Conduction delay was also present in humans with left ventricular hypertrophy [QRS width 96(13) ms v 87(8) ms, p<0.01]. Although the QTc interval was increased in humans, at 422(23) ms v 411(17) ms in controls, p<0.05, this could be explained by the increased QRS duration. During ischaemia, ventricular arrhythmias tended to occur earlier in hypertrophied hearts. Hypertrophy was also associated with a greater increase in conduction delay. Ischaemia reduced action potential duration and refractory periods; the reduction in action potential duration was attenuated by hypertrophy (p<0.01), although the reverse was apparent during low flow ischaemia at 50 d. Conclusions: Delayed conduction is an important feature of severe cardiac hypertrophy in guinea pigs and man. Hypertrophy is associated with accentuated conduction delay and altered repolarisation during ischaemia. Cardiovascular Research 1994;28:47-54
Heparin modulates intracellular cyclic AMP in human trabecular bone cells and adherent rheumatoid synovial cells.
Authors: A.J Crisp, M.S Roelke, S.R Goldring, S.M Krane
Journal: Annals of the Rheumatic Diseases (1984)

Cells were cultured from explants of human trabecular bone excised from eight patients and incubated usually for 20 minutes with bovine parathyroid hormone, salmon calcitonin, prostaglandin E2, or heparin. The intracellular content of cyclic AMP was measured by radioimmunoassay and was significantly increased by parathyroid hormone in four, by calcitonin in two, by prostaglandin E2 in eight, and by heparin in seven out of eight cultures. In the two cultures containing calcitonin-responsive cells heparin inhibited the cyclic AMP response induced by calcitonin. Heparin did not affect the cyclic AMP response to parathyroid hormone or prostaglandin E2. Heparin also increased the cyclic AMP content of cultured adherent rheumatoid synovial cells. It is proposed that, in certain situations of focal pathological bone resorption, although concentrations of circulating hormones may be normal, the local release of products such as heparin may modify the effect of hormones which regulate connective tissue homoeostasis. local changes in hormone responses could contribute to the enhanced bone resorption associated with inflammatory processes such as rheumatoid arthritis.
Participation of the major histocompatibility complex in antibody recognition of viral antigens expressed on infected cells.
Authors: D E Wylie, L A Sherman, N R Klinman
Journal: The Journal of Experimental Medicine (1982)

The capacity of the antibody repertoire to recognize complex antigens on viral-infected cells was investigated at the level of monoclonal B cell responses. A majority of primary B cells responsive to PR8(H1N1)-infected H-2 syngeneic cells produced antibody that bound viral determinants only in the context of infected cells and not the isolated virion. An examination of the fine specificity of such antibodies revealed that most could be distinguished by a panel of cells infected with closely related heterologous H1 influenza strains. Indeed, most antibodies bound hemagglutinin determinants of PR8 exclusively, and few were broadly cross-reactive. An examination of the same antibodies for their recognition of cell surface antigens revealed that the majority recognized MHC-encoded antigenic determinants. Thus, most BALB.K (H-2k) primary B cells responsive to PR8-L919 (H-2k) cells produced monoclonal antibodies that bound PR8-antigens only in the context of H-2Dk-infected cells. Most C57BL/10 (H-2b) B cells responsive to PR8-EL4 (H-2b) cells produced monoclonal antibodies that bound PR8 antigens only in the context of H-2Kb-infected cells. These latter antibodies were further shown to recognize that H-2Kb molecule by virtue of their capacity to be discriminated by a panel of PR8-infected H-2Kb mutant cells. These findings demonstrate that much of the antibody repertoire is capable of highly specific complex recognition of viral antigenic determinants in the context of the appropriate MHC alloantigen.