tbuckley/cabot-search huggingface dataset:
Higher Doses of Lenalidomide Are Associated With Unacceptable Toxicity Including Life-Threatening Tumor Flare in Patients With Chronic Lymphocytic Leukemia
Authors: Leslie A. Andritsos, Amy J. Johnson, Gerard Lozanski, William Blum, Cheryl Kefauver, Farrukh Awan, Lisa L. Smith, Rosa Lapalombella, Sarah E. May, Chelsey A. Raymond, Da-Sheng Wang, Robert D. Knight, Amy S. Ruppert, Amy Lehman, David Jarjoura, Ching-Shih Chen, John C. Byrd
Journal: Journal of Clinical Oncology (2008)

Purpose Lenalidomide is a novel therapeutic agent with uncertain mechanism of action that is clinically active in myelodysplastic syndrome (MDS) and multiple myeloma (MM). Application of high (MM) and low (MDS) doses of lenalidomide has been reported to have clinical activity in CLL. Herein, we highlight life-threatening tumor flare when higher doses of lenalidomide are administered to patients with CLL and provide a potential mechanism for its occurrence. Patients and Methods Four patients with relapsed CLL were treated with lenalidomide (25 mg/d for 21 days of a 28-day cycle). Serious adverse events including tumor flare and tumor lysis are summarized. In vitro studies examining drug-induced apoptosis and activation of CLL cells were also performed. Results Four consecutive patients were treated with lenalidomide; all had serious adverse events. Tumor flare was observed in three patients and was characterized by dramatic and painful lymph node enlargement resulting in hospitalization of two patients, with one fatal outcome. Another patient developed sepsis and renal failure. In vitro studies demonstrated lenalidomide-induced B-cell activation (upregulation of CD40 and CD86) corresponding to degree of tumor flare, possibly explaining the tumor flare observation. Conclusion Lenalidomide administered at 25 mg/d in relapsed CLL is associated with unacceptable toxicity; the rapid onset and adverse clinical effects of tumor flare represent a significant limitation of lenalidomide use in CLL at this dose. Drug-associated B-cell activation may contribute to this adverse event. Future studies with lenalidomide in CLL should focus on understanding this toxicity, investigating patients at risk, and investigating alternative safer dosing schedules.
Safety and Efficacy of an Injectable Extracellular Matrix Hydrogel for Treating Myocardial Infarction
Authors: Sonya B. Seif-Naraghi, Jennifer M. Singelyn, Michael A. Salvatore, Kent G. Osborn, Jean J. Wang, Unatti Sampat, Oi Ling Kwan, G. Monet Strachan, Jonathan Wong, Pamela J. Schup-Magoffin, Rebecca L. Braden, Kendra Bartels, Jessica A. DeQuach, Mark Preul, Adam M. Kinsey, Anthony N. DeMaria, Nabil Dib, Karen L. Christman
Journal: Science Translational Medicine (2013)

New therapies are needed to prevent heart failure after myocardial infarction (MI). As experimental treatment strategies for MI approach translation, safety and efficacy must be established in relevant animal models that mimic the clinical situation. We have developed an injectable hydrogel derived from porcine myocardial extracellular matrix as a scaffold for cardiac repair after MI. We establish the safety and efficacy of this injectable biomaterial in large- and small-animal studies that simulate the clinical setting. Infarcted pigs were treated with percutaneous transendocardial injections of the myocardial matrix hydrogel 2 weeks after MI and evaluated after 3 months. Echocardiography indicated improvement in cardiac function, ventricular volumes, and global wall motion scores. Furthermore, a significantly larger zone of cardiac muscle was found at the endocardium in matrix-injected pigs compared to controls. In rats, we establish the safety of this biomaterial and explore the host response via direct injection into the left ventricular lumen and in an inflammation study, both of which support the biocompatibility of this material. Hemocompatibility studies with human blood indicate that exposure to the material at relevant concentrations does not affect clotting times or platelet activation. This work therefore provides a strong platform to move forward in clinical studies with this cardiac-specific biomaterial that can be delivered by catheter.
Totally implantable central venous access ports for long-term chemotherapy A prospective study analyzing complications and costs of 333 devices with a minimum follow-up of 180 days
Authors: R. Biffi, F. de Braud, F. Orsi, S. Pozzi, S. Mauri, A. Goldhirsch, F. Nolè, B. Andreoni
Journal: Annals of Oncology (1998)
Weight reduction in a blood pressure clinic.
Authors: L E Ramsay, M H Ramsay, J Hettiarachchi, D L Davies, J Winchester
Journal: BMJ (1978)

Forty-nine hypertensive patients who were overweight were randomly allocated to one of three strategies for attaining weight reduction and were followed for one year. Those referred to a dietitian lost more weight (mean 5.1 kg) than those given a diet sheet (mean 2.64 kg) or simply advised by the doctor to reduce weight (mean 2.15 kg). One-third of all the patients lost 6 kg or more. Successful weight loss was associated with a highly significant and substantial improvement in blood pressure control and with less frequent increases in antihypertensive treatment.
Pathogenesis of "Electrolyte-Steroid-Cardiopathy"
Authors: MARK NICKERSON, GERALD W. KARR, PETER E. DRESEL
Journal: Circulation Research (1961)

The production of acute necrotic lesions of the myocardium and concomitant changes in myocardial and skeletal muscle potassium concentrations were investigated in rats. Lesions were induced by the administration of 2α inethyl-9α-chlorocortisol plus oral Na 2 SO 4 (which caused a profuse catharsis), steroid plus an irritant cathartic (croton oil), steroid plus low-potassium diet, and low-potassium diet alone. Lesions in the various groups were grossly and microscopically indistinguishable. Their incidence and severity were well correlated with the degree of myocardial potassium depletion below a threshold value of approximately 72 mEq./Kg. wet weight. Skeletal muscle potassium was decreased roughly parallel to that of the myocardium, but some what more variably. Other treatments, including steroid or oral Na 2 SO 4 alone and steroid plus subcutaneous Na 2 SO 4 which failed to produce comparable reductions in myocardial potassium, failed to induce morphological lesions. Any specific interaction between steroid and electrolyte in the production of the myocardial lesions appears to be ruled out by the ineffectiveness of Na 2 SO 4 administered sub cutaneously. It is concluded that the "electro lyte-steroid-cardiopathy" results from a simple intracellular potassium deficiency and its sequelae, and that the roles of the steroid-cathartic electrolyte, and other agents and procedures are to induce potassium depletion by various mechanisms.
Exposure to prescription opioid analgesics in utero and risk of neonatal abstinence syndrome: population based cohort study
Authors: R. J. Desai, K. F. Huybrechts, S. Hernandez-Diaz, H. Mogun, E. Patorno, K. Kaltenbach, L. S. Kerzner, B. T. Bateman
Journal: BMJ (2015)

To provide absolute and relative risk estimates of neonatal abstinence syndrome (NAS) based on duration and timing of prescription opioid use during pregnancy in the presence or absence of additional NAS risk factors of history of opioid misuse or dependence, misuse of other substances, non-opioid psychotropic drug use, and smoking.
Role of Different T Cell Receptors in the Development of Pre–T Cells
Authors: Jan Buer, Iannis Aifantis, James P. DiSanto, Hans Joerg Fehling, Harald von Boehmer
Journal: The Journal of Experimental Medicine (1997)

The development of pre–T cells with productive TCR-β rearrangements can be mediated by each the pre–T cell receptor (pre-TCR), the TCR-αβ as well as the TCR-γδ, albeit by distinct mechanisms. Although the TCR-γδ affects CD4−8− precursor cells irrespective of their rearrangement status by TCR-β mechanisms not involving TCR-β selection, both the preTCR and the TCR-αβ select only cells with productive TCR-β genes for expansion and maturation. The TCR-αβ appears to be much less effective than the pre-TCR because of the paucity of TCR-α proteins in TCR-β–positive precursors since an early expressed transgenic TCR-αβ can largely substitute for the pre-TCR. Thus, the TCR-αβ can assume a role not only in the rescue from programmed cell death of CD4+8+ but also of CD4−8− thymocytes. In evolution this double function of the TCR-αβ may have been responsible for the maturation of αβ T cells before the advent of the pre–TCR-α chain.
Characterization of the interleukin 2 receptors (IL-2R) expressed on human natural killer cells activated in vivo by IL-2: association of the p64 IL-2R gamma chain with the IL-2R beta chain in functional intermediate-affinity IL-2R.
Authors: S D Voss, P M Sondel, R J Robb
Journal: The Journal of Experimental Medicine (1992)

Interleukin 2 (IL-2) receptors expressed on the surface of activated T cells and natural killer (NK) cells exhibit a variety of affinity states depending on their subunit composition. Low-affinity binding is associated with a 55-kDa alpha chain, intermediate-affinity binding with a 70-75-kD beta chain, and high-affinity binding with a bimolecular complex of the alpha and beta subunits. In a previous study of the IL-2 receptors expressed on NK cells obtained from cancer patients after in vivo IL-2 therapy, we documented a discrepancy between the level of beta chain and the level of intermediate-affinity IL-2 binding sites expressed on the cell surface. Based on this result, we postulated that formation of intermediate-affinity receptor sites required a component in addition to the beta chain, and that this component was present at limiting levels in the patient NK cells. In the present study we have examined the structure of the intermediate-affinity receptor complex using monoclonal antibodies that recognize the beta chain, but that do not interfere with its ability to bind IL-2. Evidence is presented establishing the physical association of a novel protein of 64 kD with the beta chain in intermediate-affinity IL-2 binding sites. This molecule, termed IL-2R gamma chain, coprecipitated with beta chains prepared from cells that had been incubated with IL-2, but was undetectable in immunoprecipitates prepared in the absence of IL-2. Examination of gamma chain expression in post-IL-2 therapy NK cells, where only low levels of intermediate-affinity IL-2 binding were detectable, revealed that the gamma chain was associated with, on average, only 10-12% of the beta chains expressed on such cells. This contrasted with approximately equal levels of beta and gamma chain expression on YT cells, a cell line that has both high levels of cell surface beta chain expression and high levels of IL-2 binding. Thus, the ratio of gamma chain to beta chain present in the immunoprecipitates roughly correlated with the proportion of beta chain involved in intermediate-affinity receptor sites. This result suggests that the 64-kD gamma chain is the component responsible for regulating the affinity of IL-2 association with the beta subunit. By further defining the structural components necessary for IL-2 receptor formation, these studies provide additional insight into mechanisms whereby lymphocytes might regulate their responsiveness to IL-2.
PGC-1α regulates the mitochondrial antioxidant defense system in vascular endothelial cells
Authors: I VALLE, A ALVAREZBARRIENTOS, E ARZA, S LAMAS, M MONSALVE
Journal: Cardiovascular Research (2005)

Mitochondrial production of oxidants contributes to a variety of pathological conditions including the vascular complications of diabetes, neurodegenerative diseases, and cellular senescence. We postulated that a transcriptional coactivator, peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha), a major regulator of oxidative metabolism and mitochondrial biogenesis, could be involved in the transcriptional regulation of the mitochondrial antioxidant defense system in vascular endothelial cells.We show that PGC-1alpha is present in human, bovine, and mouse endothelial cells and positively modulates the expression of the mitochondrial detoxification system. Endothelial cells that overexpress PGC-1alpha show reduced accumulation of reactive oxygen species (ROS), increased mitochondrial membrane potential, and reduced apoptotic cell death both in basal and oxidative stress conditions. Downregulation of PGC-1alpha levels by siRNA reduces the expression of mitochondrial detoxification proteins.These results unveil a novel regulatory pathway that links mitochondrial activity and mitochondrial oxidative stress protective systems. In addition, they suggest that PGC-1alpha could play a crucial protective role in vascular complications of diabetes, where the mitochondrial metabolism of glucose has been shown to result in oxidative stress and vascular endothelial cell dysfunction.
Suppression of food intake by apolipoprotein A-IV is mediated through the central nervous system in rats.
Authors: K Fujimoto, K Fukagawa, T Sakata, P Tso
Journal: Journal of Clinical Investigation (1993)

The aim of this experiment was to investigate whether the anorectic effect of apolipoprotein A-IV (apo A-IV) after lipid feeding is mediated via the central nervous system. Infusion of 0.5 micrograms of apo A-IV into the third ventricle failed to suppress food intake. Higher doses (1 micrograms or higher) of apo A-IV infused into the third ventricle inhibited food intake in a dose-dependent manner. In contrast, when apo A-I was infused into the third ventricle it had no effect on food intake. To further test the hypothesis that apo A-IV is an important factor controlling food intake, we administered goat anti-rat apo A-IV serum into the third ventricle of rats that were allowed food and water and lib. In all rats tested, this treatment resulted in enhanced food intake. In contrast, infusion of goat anti-rat apo A-IV serum failed to elicit such a response. Lastly, we determined the apo A-IV concentration in plasma and cerebrospinal fluid before and during active lipid absorption. Apo A-IV concentration in cerebrospinal fluid was about 1/20 that of plasma. Both serum and cerebrospinal fluid apo A-IV increased markedly as a result of feeding of lipid. In conclusion, we propose that apo A-IV may act centrally to control food intake.
A multicenter study of primary brain tumor incidence in Australia (2000–2008)
Authors: Martin Dobes, Bruce Shadbolt, Vini G. Khurana, Sanjiv Jain, Sarah F. Smith, Robert Smee, Mark Dexter, Raymond Cook
Journal: Neuro-Oncology (2011)

There are conflicting reports from Europe and North America regarding trends in the incidence of primary brain tumor, whereas the incidence of primary brain tumors in Australia is currently unknown. We aimed to determine the incidence in Australia with age-, sex-, and benign-versus-malignant histology-specific analyses. A multicenter study was performed in the state of New South Wales (NSW) and the Australian Capital Territory (ACT), which has a combined population of >7 million with >97% rate of population retention for medical care. We retrospectively mined pathology databases servicing neurosurgical centers in NSW and ACT for histologically confirmed primary brain tumors diagnosed from January 2000 through December 2008. Data were weighted for patient outflow and data completeness. Incidence rates were age standardized and trends analyzed using joinpoint analysis. A weighted total of 7651 primary brain tumors were analyzed. The overall US-standardized incidence of primary brain tumors was 11.3 cases 100 000 person-years (±0.13; 95% confidence interval, 9.8–12.3) during the study period with no significant linear increase. A significant increase in primary malignant brain tumors from 2000 to 2008 was observed; this appears to be largely due to an increase in malignant tumor incidence in the ≥65-year age group. This collection represents the most contemporary data on primary brain tumor incidence in Australia. Whether the observed increase in malignant primary brain tumors, particularly in persons aged ≥65 years, is due to improved detection, diagnosis, and care delivery or a true change in incidence remains undetermined. We recommend a direct, uniform, and centralized approach to monitoring primary brain tumor incidence that can be independent of multiple interstate cancer registries.
Expression of Heparanase by Primary Breast Tumors Promotes Bone Resorption in the Absence of Detectable Bone Metastases
Authors: Thomas Kelly, Larry J. Suva, Yan Huang, Veronica MacLeod, Hua-Quan Miao, Ronald C. Walker, Ralph D. Sanderson
Journal: Cancer Research (2005)

Abstract Heparanase is an enzyme that cleaves heparan sulfate and through this activity promotes tumor growth, angiogenesis, invasion, and metastasis in several tumor types. In human breast cancer patients, heparanase expression is associated with sentinel lymph node metastases. However, the precise role of heparanase in the malignant progression of breast cancer is unknown. To examine this, a variant of MDA-MB-231 cells was transfected with the cDNA for human heparanase (HPSE cells) or with vector alone as a control (NEO cells). Transfection produced a 6-fold increase in heparanase activity in HPSE cells relative to NEO cells. When injected into the mammary fat pads of severe combined immunodeficient mice, the tumors formed by HPSE cells initially grow significantly faster than the tumors formed by NEO cells. The rapid growth is due in part to increased angiogenesis, as microvessel densities are substantially elevated in primary HPSE tumors compared with NEO tumors. Although metastases to bones are not detected, surprisingly vigorous bone resorption is stimulated in animals bearing tumors formed by the HPSE cells. These animals have high serum levels of the C-telopeptide derived from type I collagen as well as significant elevation of the active form of tartrate-resistant acid phosphatase (TRAP)-5b. In contrast, in animals having a high tumor burden of Neo cells, the serum levels of C-telopeptide and TRAP-5b never increase above the levels found before tumor injection. Consistent with these findings, histologic analysis for TRAP-expressing cells reveals extensive osteoclastogenesis in animals harboring HPSE tumors. In vitro osteoclastogenesis assays show that the osteoclastogenic activity of HPSE cell conditioned medium is significantly enhanced beyond that of NEO conditioned medium. This confirms that a soluble factor or factors that stimulate osteoclastogenesis are specifically produced when heparanase expression is elevated. These factors exert a distal effect resulting in resorption of bone and the accompanying enrichment of the bone microenvironment with growth-promoting factors that may nurture the growth of metastatic tumor cells. This novel role for heparanase as a promoter of osteolysis before tumor metastasis suggests that therapies designed to block heparanase function may disrupt the early progression of bone-homing tumors.
Role of vascular channels as a novel mechanism for subchondral bone damage at cruciate ligament entheses in osteoarthritis and inflammatory arthritis
Authors: D A Binks, E M Gravallese, D Bergin, R J Hodgson, A L Tan, M M Matzelle, D McGonagle, A Radjenovic
Journal: Annals of the Rheumatic Diseases (2013)

The purpose of this work was to test whether normal peri-entheseal vascular anatomy at anterior and posterior cruciate ligaments (ACL and PCL) was associated with distribution of peri-entheseal bone erosion/bone marrow lesions (BMLs) in inflammatory arthritis (IA) and osteoarthritis (OA).
1H-NMR based metabonomic profiling of human esophageal cancer tissue
Authors: Liang Wang, Jie Chen, Longqi Chen, Pengchi Deng, Qian bu, Pu Xiang, Manli Li, Wenjie Lu, Youzhi Xu, Hongjun Lin, Tianming Wu, Huijuan Wang, Jing Hu, Xiaoni Shao, Xiaobo Cen, Ying-Lan Zhao
Journal: Molecular Cancer (2013)

Abstract Background The biomarker identification of human esophageal cancer is critical for its early diagnosis and therapeutic approaches that will significantly improve patient survival. Specially, those that involves in progression of disease would be helpful to mechanism research. Methods In the present study, we investigated the distinguishing metabolites in human esophageal cancer tissues (n = 89) and normal esophageal mucosae (n = 26) using a 1 H nuclear magnetic resonance ( 1 H-NMR) based assay, which is a highly sensitive and non-destructive method for biomarker identification in biological systems. Principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and orthogonal partial least-squares-discriminant anlaysis (OPLS-DA) were applied to analyse 1 H-NMR profiling data to identify potential biomarkers. Results The constructed OPLS-DA model achieved an excellent separation of the esophageal cancer tissues and normal mucosae. Excellent separation was obtained between the different stages of esophageal cancer tissues (stage II = 28; stage III = 45 and stage IV = 16) and normal mucosae. A total of 45 metabolites were identified, and 12 of them were closely correlated with the stage of esophageal cancer. The downregulation of glucose, AMP and NAD, upregulation of formate indicated the large energy requirement due to accelerated cell proliferation in esophageal cancer. The increases in acetate, short-chain fatty acid and GABA in esophageal cancer tissue revealed the activation of fatty acids metabolism, which could satisfy the need for cellular membrane formation. Other modified metabolites were involved in choline metabolic pathway, including creatinine, creatine, DMG, DMA and TMA. These 12 metabolites, which are involved in energy, fatty acids and choline metabolism, may be associated with the progression of human esophageal cancer. Conclusion Our findings firstly identify the distinguishing metabolites in different stages of esophageal cancer tissues, indicating the attribution of metabolites disturbance to the progression of esophageal cancer. The potential biomarkers provide a promising molecular diagnostic approach for clinical diagnosis of human esophageal cancer and a new direction for the mechanism study.
THE PLASMA PROTEINS IN RELATION TO BLOOD HYDRATION
Authors: F. S. Bruckman, L. M. D'Esopo, J. P. Peters
Journal: Journal of Clinical Investigation (1930)

Peters and associates (12, 13) in previous articles of this series pointed out that in severely undernourished patients with diabetes .andother pathological conditions, the concentration of proteins in the serum was usually low.The purpose of the present paper is to show that malnutrition or protein starvation, is the direct cause of the protein deficiency and that it affects only the albumin fraction of the serum proteins.REVIEW OF THE LITERATURE Lusk (9) and Kohman (8) have reviewed the literature on the relation of edema to protein deficiency.Gaspard (5) described a dropsical condition in individuals in France in 1817.During this period the inhabitants lived for three months on potatoes, oat bread and other poor foods.As conditions became progressively worse, the inhabitants had only plants and herbs to eat.On such a diet these people developed edema of the extremities which disappeared after they had received normal food.Budzynski and Chelchowski (3) report a similar condition in Poland in 1915 during a famine period.Park (11) who made a study of prisoners on war rations, thought the condition was due to underfeeding of fats and proteins and to the large amounts of fluid ingested, together with increased amounts of salt.Schiff (16) in his study on war edema, found that edema occurred after chronic inanition extending over months and years and upon a diet containing predominantly carbohydrate and little protein.Its occurrence was widespread in Germany in the early part of 1917.Older men, 40 to 56 years old were es- pecially affected.There was swelling of legs, arms and sometimes other parts of 1 Some of the data in this paper are from the thesis of Dr. L.