tbuckley/cabot-search huggingface dataset:
Knockdown of FLOT1 Impairs Cell Proliferation and Tumorigenicity in Breast Cancer through Upregulation of FOXO3a
Authors: Chuyong Lin, Zhiqiang Wu, Xi Lin, Chunping Yu, Tingting Shi, Yong Zeng, Xi Wang, Jun Li, Libing Song
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Lipid rafts, specialized domains in cell membranes, function as physical platforms for various molecules to coordinate a variety of signal transduction processes. Flotinllin-1 (FLOT1), a marker of lipid rafts, is involved in the progression of cancer, but the precise mechanism remains unclear. The aim of the present study was to examine the role of FLOT1 on the tumorigenesis of breast cancer cells and its clinical significance in progression of the disease. Experimental Design: FLOT1 expression was analyzed in 212 paraffin-embedded, archived clinical breast cancer samples by using immunohistochemistry (IHC). The effect of FLOT1 on cell proliferation and tumorigenesis was examined in vitro and in vivo. Western blotting and luciferase reporter analyses were carried out to identify the effects of downregulating FLOT1 on expression of cell cycle regulators and transcriptional activity of FOXO3a. Results: IHC analysis revealed high expression of FLOT1 in 129 of the 212 (60.8%) paraffin-embedded archived breast cancer specimens. The overall expression level of FLOT1 significantly correlated with clinical staging and poor patient survival of breast cancer. Strikingly, we found that silencing FLOT1 inhibited proliferation and tumorigenicity of breast cancer cells both in vitro and in vivo, which was further shown to be mechanistically associated with suppression of Akt activity, enhanced transcriptional activity of FOXO3a, upregulation of cyclin-dependent kinase inhibitor p21Cip1 and p27Kip1, and downregulation of the CDK regulator cyclin D1. Conclusions: FLOT1 plays an important role in promoting proliferation and tumorigenesis of human breast cancer and may represent a novel prognostic biomarker and therapeutic target for the disease. Clin Cancer Res; 17(10); 3089–99. ©2011 AACR.
A novel role for CCL3 (MIP-1α) in myeloma-induced bone disease via osteocalcin downregulation and inhibition of osteoblast function
Authors: S Vallet, S Pozzi, K Patel, N Vaghela, M T Fulciniti, P Veiby, T Hideshima, L Santo, D Cirstea, D T Scadden, K C Anderson, N Raje
Journal: Leukemia (2011)
Morphological and functional changes in coronary vessel evoked by repeated endothelial injury in pigs
Authors: S Saitoh
Journal: Cardiovascular Research (1998)

We examined the morphological changes induced by repeated endothelial denudation in coronary artery (CA), as well as functional changes in the endothelium-dependent and smooth muscle responses to various vasoactive agents during the process of intimal thickening.We observed vascular responses in denuded and non-denuded portions of pig CA while being fed a normal diet (n = 11, N group) or 2% cholesterol diet (n = 25, C group) to intracoronary acetylcholine (ACh), 5-hydroxytryptamine (5-HT), substance P (SP), and isosorbide dinitrate (ISDN) with and without the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg i.v.) over a period of 8 weeks. Balloon endothelial denudation of the left anterior descending CA was carried out every 2 weeks.In N group, maximum vasoconstriction was obtained with ACh 2 weeks after the first denudation [26 +/- 5% vs. 1 +/- 1% pre-denudation, p < 0.05]. L-NAME did not affect ACh-induced CA diameter changes. Thereafter, the response to ACh was attenuated by repeated denudation in N groups. However, the degree of 5-HT-induced CA narrowing at the denuded portion increased from 7 +/- 4% (0 week) to 88 +/- 8% (8 weeks) (p < 0.05). The changes resulted in severe myocardial ischaemia, and suggested that endothelium-dependent vasodilation was progressively attenuated while hyperreactivity of vascular smooth muscle simultaneously increased. Vasodilation induced by SP was attenuated somewhat, but ISDN-induced vasodilation was preserved. Although mild hypercholesterolaemia was induced in C group, the vascular responses to these vasoactive agents did not differ from those of N group.Repeated CA endothelial injury and regeneration induce the change of morphology and vascular reactivity in the denuded portion regardless of atherogenic diet. This study strongly suggests that intimal thickening caused by repeated endothelial injury and regeneration induces specific vascular responses to vasoactive agents. Moreover, it is also suggested that during the progression of intimal thickening, increased vascular smooth muscle contraction and decreased endothelium-dependent dilation appear in a stimulus-dependent manner, often leading to severe coronary vasoconstriction accompanied with definitive ECG ST change.
Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial
Authors: Nancy Y Lee, Qiang Zhang, David G Pfister, John Kim, Adam S Garden, James Mechalakos, Kenneth Hu, Quynh T Le, A Dimitrios Colevas, Bonnie S Glisson, Anthony TC Chan, K Kian Ang
Journal: The Lancet Oncology (2011)
Establishing percent resection and residual volume thresholds affecting survival and recurrence for patients with newly diagnosed intracranial glioblastoma
Authors: Kaisorn L. Chaichana, Ignacio Jusue-Torres, Rodrigo Navarro-Ramirez, Shaan M. Raza, Maria Pascual-Gallego, Aly Ibrahim, Marta Hernandez-Hermann, Luis Gomez, Xiaobu Ye, Jon D. Weingart, Alessandro Olivi, Jaishri Blakeley, Gary L. Gallia, Michael Lim, Henry Brem, Alfredo Quinones-Hinojosa
Journal: Neuro-Oncology (2013)

Surgery is first-line therapy for glioblastoma, and there is evidence that gross total resection is associated with improved survival. Gross total resection, however, is not always possible, and relationships among extent (percent) of resection (EOR), residual volume (RV), and survival are unknown. The goals were to evaluate whether there is an association between EOR and RV with survival and recurrence and to establish minimum EOR and maximum RV thresholds. Adult patients who underwent primary glioblastoma surgery from 2007 to 2011 were retrospectively reviewed. Three-dimensional volumetric tumor measurements were made. Multivariate proportional hazards regression analysis was used to evaluate the relationship between EOR and RV with survival and recurrence. Of 259 patients, 203 (78%) died and 156 (60%) had tumor recurrence. The median survival and progression-free survival were 13.4 and 8.9 months, respectively. The median (interquartile range) pre- and postoperative tumor volumes were 32.2 (14.0–56.3) and 2.1 (0.0–7.9) cm3, respectively. EOR was independently associated with survival (hazard ratio [HR], 0.995; 95% confidence interval [CI]: 0.990–0.998; P = .008) and recurrence (HR [95% CI], 0.992 [0.983–0.998], P = .005). The minimum EOR threshold for survival (P = .0006) and recurrence (P = .005) was 70%. RV was also associated with survival (HR [95% CI], 1.019 [1.006–1.030], P = .004) and recurrence (HR [95% CI], 1.024 [1.001–1.044], P = .03). The maximum RV threshold for survival (P = .01) and recurrence (P = .01) was 5 cm3. This study shows for the first time that both EOR and RV are significantly associated with survival and recurrence, where the thresholds are 70% and 5 cm3, respectively. These findings may help guide surgical and adjuvant therapies aimed at optimizing outcomes for glioblastoma patients.
Genome-scale approaches for discovering novel nonconventional splicing substrates of the Ire1 nuclease.
Authors: Maho Niwa, Christopher K Patil, Joe DeRisi, Peter Walter
Journal: Genome biology (2004)

Abstract Background The unfolded protein response (UPR) allows intracellular feedback regulation that adjusts the protein-folding capacity of the endoplasmic reticulum (ER) according to need. The signal from the ER lumen is transmitted by the ER-transmembrane kinase Ire1, which upon activation displays a site-specific endoribonuclease activity. Endonucleolytic cleavage of the intron from the HAC1 mRNA (encoding a UPR-specific transcription factor) is the first step in a nonconventional mRNA splicing pathway; the released exons are then joined by tRNA ligase. Because only the spliced mRNA is translated, splicing is the key regulatory step of the UPR. Results We developed methods to search for additional mRNA substrates of Ire1p in three independent lines of genome-wide analysis. These methods exploited the well characterized enzymology and genetics of the UPR and the yeast genome sequence in conjunction with microarray-based detection. Each method successfully identified HAC1 mRNA as a substrate according to three criteria: HAC1 mRNA is selectively cleaved in vitro by Ire1; the HAC1 mRNA sequence contains two predicted Ire1 cleavage sites; and HAC1 mRNA is selectively degraded in tRNA ligase mutant cells. Conclusion Within the limits of detection, no other mRNA satisfies any of these criteria, suggesting that a unique nonconventional mRNA-processing mechanism has evolved solely for carrying out signal transduction between the ER and the nucleus. The approach described here, which combines biochemical and genetic 'fractionation' of mRNA with a novel application of cDNA microarrays, is generally applicable to the study of pathways in which RNA metabolism and alternative splicing have a regulatory role.
Blast Cell Crisis in Acute or Chronic Leukemia
Authors: H. Clark Hoagland
Journal: JAMA (1976)

PATIENTS with acute leukemia often have a modest elevation in the leukocyte count and many blast cells in the peripheral blood smear. This is true of both patients with acute lymphocytic leukemia and those with acute nonlymphocytic leukemia. Similarly, in the terminal stage of chronic granulocytic leukemia, patients commonly have an increase in white blood cells (WBCs), a percentage of which are blast forms in the peripheral blood. This situation does not occur in chronic lymphocytic leukemia. However, occasional patients with these diseases will have exceedingly high WBC counts, in excess of 100,000/ cu mm, and the blast cell level in the peripheral blood smear will likewise be in excess of 100,000/cu mm. Such a situation would then justifiably be called a "blast crisis." Patients with this finding deserve urgent medical therapy to forestall the development of leukocyte sludging in the vessels of the cerebral cortex. Subsequent diapedesis of leukemic
Amplitude of Ventricular Fibrillation Waveform and Outcome After Cardiac Arrest
Authors: W. DOUGLAS WEAVER
Journal: Annals of Internal Medicine (1985)

The amplitude of ventricular fibrillation found initially in 394 patients was compared to clinical and logistical findings at the time of cardiac arrest. Peak-to-peak amplitude averaged 0.55±0.25 mV; a very low amplitude (0.2 mV or less) or "fine" fibrillation was present in 66 patients (17%). The amplitude was not found to be related to clinical histories, but depended on the length of the period from collapse until start of basic life support (p=0.004) and the delay until assessment by paramedics (p=0.001). Survival rates were strongly associated with amplitude: only 4 patients (6%) with fine ventricular fibrillation survived, compared to 117 or 328 patients (36%) in whom the initial amplitude was higher (p < 0. 001). Patient outcome related to amplitude even after adjusting for clinical history and logistical delays (p < 0.005). We conclude that fine ventricular fibrillation is in part the result of delay in initiation of treatment, and that fibrillation amplitude is a powerful indicator of outcome after cardiac arrest.
Longitudinal course of extrinsic allergic alveolitis in pigeon breeders.
Authors: S J Bourke, S W Banham, R Carter, P Lynch, G Boyd
Journal: Thorax (1989)

The purpose of this study was to assess the longitudinal course of pigeon breeders' disease by evaluating 24 patients with the acute form of the disease 10 years after their original diagnosis. Twenty one patients attended for clinical assessment, pulmonary function studies, chest radiography, and antibody measurement. Eighteen had continued to keep pigeons, emphasising their commitment to the hobby. Despite continued antigen exposure pigeon related symptoms had improved in most patients and only five still had troublesome symptoms. Four patients had residual abnormalities of pulmonary function or chest radiographs and three had chronic bronchitis. Fanciers had attempted to regulate their exposure to the birds by use of masks and by spending less time in their lofts but this is an unlikely explanation for the benign course of their disease, as levels of antibody to pigeon gammaglobulin remained high, suggesting that appreciable antigen exposure was still occurring. In most cases a state of equilibrium between host and antigen appeared to have developed. This observation has implications for the clinical management and understanding of the nature of the disease.
Acute weight loss followed by an aggressive nutritional recovery strategy has little impact on on-water rowing performance
Authors: G Slater, A J Rice, R Tanner, K Sharpe, C J Gore, D G Jenkins, A G Hahn
Journal: British Journal of Sports Medicine (2005)

Objectives: To assess the influence of moderate, acute weight loss on on-water rowing performance when aggressive nutritional recovery strategies were used in the two hours between weigh in and racing. Methods: Competitive rowers (n = 17) undertook three on-water 1800 m time trials under cool conditions (mean (SD) temperature 8.4 (2.0)°C), each separated by 48 hours. No weight limit was imposed for the first time trial—that is, unrestricted body mass (UNR 1 ). However, one of the remaining two trials followed a 4% loss in body mass in the previous 24 hours (WT −4% ). No weight limit was imposed for the other trial (UNR 2 ). Aggressive nutritional recovery strategies (WT −4% , 2.3 g/kg carbohydrate, 34 mg/kg Na + , and 28.4 ml/kg fluid; UNR, ad libitum) were used in the first 90 minutes of the two hours between weigh in and performance trials. Results: WT −4% had only a small and statistically non-significant effect on the on-water time trial performance (mean 1.0 second, 95% confidence interval (CI) −0.9 to 2.8; p = 0.29) compared with UNR. This was despite a significant decrease in plasma volume at the time of weigh in for WT −4% compared with UNR (−9.2%, 95% CI −12.8% to −5.6%; p&lt;0.001). Conclusions: Acute weight loss of up to 4% over 24 hours, when combined with aggressive nutritional recovery strategies, can be undertaken with minimal impact on on-water rowing performance, at least in cool conditions.
Mesenchymal Stem Cells Use IDO to Regulate Immunity in Tumor Microenvironment
Authors: Weifang Ling, Jimin Zhang, Zengrong Yuan, Guangwen Ren, Liying Zhang, Xiaodong Chen, Arnold B. Rabson, Arthur I. Roberts, Ying Wang, Yufang Shi
Journal: Cancer Research (2014)

Mesenchymal stem cells (MSC) are present in most, if not all, tissues and are believed to contribute to tissue regeneration and the tissue immune microenvironment. Murine MSCs exert immunosuppressive effects through production of inducible nitric oxide synthase (iNOS), whereas human MSCs use indoleamine 2,3-dioxygenase (IDO). Thus, studies of MSC-mediated immunomodulation in mice may not be informative in the setting of human disease, although this critical difference has been mainly ignored. To address this issue, we established a novel humanized system to model human MSCs, using murine iNOS(-/-) MSCs that constitutively or inducibly express an ectopic human IDO gene. In this system, inducible IDO expression is driven by a mouse iNOS promoter that can be activated by inflammatory cytokine stimulation in a similar fashion as the human IDO promoter. These IDO-expressing humanized MSCs (MSC-IDO) were capable of suppressing T-lymphocyte proliferation in vitro. In melanoma and lymphoma tumor models, MSC-IDO promoted tumor growth in vivo, an effect that was reversed by the IDO inhibitor 1-methyl-tryptophan. We found that MSC-IDO dramatically reduced both tumor-infiltrating CD8(+) T cells and B cells. Our findings offer an important new line of evidence that interventional targeting of IDO activity could be used to restore tumor immunity in humans, by relieving IDO-mediated immune suppression of MSCs in the tumor microenvironment as well as in tumor cells themselves.
The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison
Authors: David G Sherman, Gregory W Albers, Christopher Bladin, Cesare Fieschi, Alberto A Gabbai, Carlos S Kase, William O'Riordan, Graham F Pineo
Journal: The Lancet (2007)
A new chromosome abnormality in idiopathic sideroblastic anemia: 46, XY, del11q23
Authors: Dan M. Hyder, Sylvia S. Bottomley, Richard H. Bottomley
Journal: American Journal of Hematology (1978)

Abstract A new marker chromosome, deletion 11q23, was observed with the Giemsa banding technique in the bone marrow of a patient with idiopathic sideroblastic anemia. The abnormality was not detectable in the peripheral blood or with nonbanded chromosome studies. Nineteen of 40 cases of this disorder studied and reported to date had chromosomal aberrations, although the majority had only nonbanded karyotypes performed. This apparently high incidence of chromosomal defects and the finding in the present case indicate that more banded‐karyotype analyses are needed to assess the presence of possible nonrandom cytogenetic changes in idiopathic sideroblastic anemia.
Anti-CD22 Immunotoxin RFB4(dsFv)-PE38 (BL22) for CD22-Positive Hematologic Malignancies of Childhood: Preclinical Studies and Phase I Clinical Trial
Authors: Alan S. Wayne, Robert J. Kreitman, Harry W. Findley, Glen Lew, Cynthia Delbrook, Seth M. Steinberg, Maryalice Stetler-Stevenson, David J. FitzGerald, Ira Pastan
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Although most children with B-lineage acute lymphoblastic leukemia (ALL) and non–Hodgkin lymphoma are cured, new agents are needed to overcome drug resistance and reduce toxicities of chemotherapy. We hypothesized that the novel anti-CD22 immunotoxin, RFB4(dsFv)-PE38 (BL22, CAT-3888), would be active and have limited nonspecific side effects in children with CD22-expressing hematologic malignancies. We conducted the first preclinical and phase I clinical studies of BL22 in that setting. Experimental Design: Lymphoblasts from children with B-lineage ALL were assessed for CD22 expression by flow cytometry and for BL22 sensitivity by in vitro cytotoxicity assay. BL22 was evaluated in a human ALL murine xenograft model. A phase I clinical trial was conducted for pediatric subjects with CD22+ ALL and non–Hodgkin lymphoma. Results: All samples screened were CD22+. BL22 was cytotoxic to blasts in vitro (median IC50, 9.8 ng/mL) and prolonged the leukemia-free survival of murine xenografts. Phase I trial cohorts were treated at escalating doses and schedules ranging from 10 to 40 μg/kg every other day for three or six doses repeated every 21 or 28 days. Treatment was associated with an acceptable safety profile, adverse events were rapidly reversible, and no maximum tolerated dose was defined. Pharmacokinetics were influenced by disease burden consistent with rapid drug binding by CD22+ blasts. Although no responses were observed, transient clinical activity was seen in most subjects. Conclusions: CD22 represents an excellent target and anti-CD22 immunotoxins offer therapeutic promise in B-lineage hematologic malignancies of childhood. Clin Cancer Res; 16(6); 1894–903
Glial Cell Loss in the Anterior Cingulate Cortex, a Subregion of the Prefrontal Cortex, in Subjects With Schizophrenia
Authors: Anette K. Stark, Harry B.M. Uylings, Ernesto Sanz-Arigita, Bente Pakkenberg
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Structural deficits in the anterior cingulate cortex such as changes in glial cell and neuron numbers may be part of the anatomical substrate for schizophrenia and need to be investigated. The total number of neurons and glial cells in brains of 12 schizophrenia subjects and 14 comparison subjects were determined in two subdivisions of the prefrontal cortex: Brodmann's area 24, a part of the anterior cingulate cortex, and Brodmann's area 32 in the paracingulate cortex. METHOD: The estimate of the total cell number was obtained by multiplying the volume of the region (estimated by using Cavalieri's point counting method) by the numerical density obtained from optical disectors in the cytoarchitectonically defined areas from the prefrontal cortex. RESULTS: The average total of bilateral glial cells in Brodmann's area 24 was 201×106 in subjects with schizophrenia and 302×106 in comparison subjects, a statistically significant difference of 33%, whereas there was a nonsignificant difference between the schizophrenia subjects and the comparison subjects in total number of glial cells in Brodmann's area 32. The bilateral average total number of neurons in areas 24 and 32 did not differ significantly between the schizophrenia and comparison subjects. CONCLUSIONS: A selective reduction in glial cells in Brodmann's area 24 (but not in area 32) is seen in brains of subjects with schizophrenia relative to those of comparison subjects. Further investigations of the glial cells, their mutual relationship, and their relationship with neurons are needed to understand the role of specific glial components in this mental disorder.
Investigative use of fibreoptic bronchoscopy for local airway challenge in asthma
Authors: HK Makker, S Montefort, S Holgate
Journal: European Respiratory Journal (1993)

Local airway challenge has advantages over inhalation bronchial challenge as the response of the airway can be restricted and directly observed. It has been safely performed in subjects with mild or moderate asthma, either by the direct instillation of challenge solution to the selected segmental airways via a bronchoscope, or delivered to an airway segment isolated with a double-balloon catheter. However, these techniques carry potential complications, such as generalized wheeze, and due care is required in selection of subjects. Most investigators have used the method for studying the airway events following allergen challenge. Others have studied the airway changes following challenge with non-allergen provocation agents, such as hypertonic saline, adenosine 5'-monophosphate and cold dry air. The method has helped to define changes in the inflammatory cells and mediators in relation to early and late airway responses to allergen. Similarly, study of airway events following local challenge with hypertonic solution has provided useful knowledge in understanding the mechanisms of exercise-induced asthma. With more experience and an improved margin of safety, it will be possible to study local changes in airway physiology following local airway challenge. Finally, the techniques also have potential use for studying the airway events following provocation with a wide range of agents of potential relevance to the pathogenesis of asthma.