tbuckley/cabot-search huggingface dataset:
Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma: A phase I study
Authors: D. S. Siegel, D. M. Weber, C. S. Mitsiades, M. A. Dimopoulos, J. L. Harousseau, S. Rizvi, J. Howe, D. Reiser, K. C. Anderson, P. G. Richardson
Journal: Journal of Clinical Oncology (2009)

8586 Background: Novel drug combinations may improve patient outcome in relapsed/refractory multiple myeloma (MM), which remains especially challenging to treat. Preclinical studies suggest that the histone deacetylase inhibitor vorinostat may have synergistic potential when combined with lenalidomide and dexamethasone. This phase I, multicenter, open-label study evaluated vorinostat plus lenalidomide and dexamethasone in patients (pts) with relapsed or refractory MM. The primary objective was to determine the maximum tolerated dose (MTD); other endpoints included overall safety and tolerability, as well as activity of the combination. Methods: Pts aged ≥18 years with relapsed or refractory MM were enrolled sequentially into 1 of 5 dosing levels ( Table ) using a standard 3+3 design for ≤8 cycles. Barring dose-limiting toxicities (DLTs) in the first cycle, dose escalation continued until the MTD was established. Response was assessed, and adverse events (AEs) were recorded. Results: Of 12 pts accrued to date, 11 (92%) have experienced ≥1 AE, with drug-related AEs reported by 6 pts (96% ≤Grade 2). The most common drug-related AEs (each in 4 pts) were fatigue and thrombocytopenia. Serious AEs in 2 pts (17%) were not considered drug-related. No pts discontinued due to AEs, and no DLT has been observed to date. Dose escalation to dose level (DL) 4 was achieved as no DLTs were observed in DLs 1–3. The MTD has not yet been reached. Of 11 pts evaluable for efficacy, best responses include: complete response in 1 pt, partial response in 2 pts, minimal response in 2 pts, and stable disease in 3 pts; 3 pts had progressive disease (PD). Currently, 9 pts remain on treatment, with 3 pts discontinuing treatment due to PD. Conclusions: These preliminary data suggest that vorinostat with lenalidomide and dexamethasone represents a well tolerated and active novel oral combination therapy for the treatment of relapsed/refractory MM. [Table: see text] [Table: see text]
Radionuclide imaging. Use in diagnosis of osteomyelitis in children
Authors: M. J. Gelfand
Journal: JAMA (1977)

Forty-four children were studied for the presence of osteomyelitis by scintigraphy using Tc 99m etidronate tin complex. Evidence of osteomyelitis on radionuclide images was found in 16 of 19 patients considered to have osteomyelitis by their attending physicians. Bone scintigraphic changes were noted prior to or in the absence of roentgenographic abnormalities in 10 of 19 patients. Cases of acute hematogenous osteomyelitis, chronic osteomyelitis, and osteomyelitis caused by penetrating trauma and contiguous infection were identified. Three bone infarctions were correctly diagnosed.
Safety and efficacy of the HVTN 503/Phambili Study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study
Authors: Glenda E Gray, Mary Allen, Zoe Moodie, Gavin Churchyard, Linda-Gail Bekker, Maphoshane Nchabeleng, Koleka Mlisana, Barbara Metch, Guy de Bruyn, Mary H Latka, Surita Roux, Matsontso Mathebula, Nivashnee Naicker, Constance Ducar, Donald K Carter, Adrien Puren, Niles Eaton, M Julie McElrath, Michael Robertson, Lawrence Corey, James G Kublin
Journal: The Lancet Infectious Diseases (2011)
An unattended device for sleep-related breathing disorders: validation study in suspected obstructive sleep apnoea syndrome
Authors: M Zucconi, L Ferini-Strambi, V Castronovo, A Oldani, S Smirne
Journal: European Respiratory Journal (1996)

Portable devices for the diagnosis of obstructive sleep apnoea (OSA) are considered to be an acceptable alternative to polysomnography (PSG), but their validation is essential. The aim of our study was to validate a device specifically designed for OSA diagnosis. Twenty nine suspected OSA patients were studied with simultaneous nocturnal PSG and an unattended recording device (MicroDigitrapper-S) (M-S). The device measured body position, snoring sound, oronasal flow, thoracic and abdominal effort, heart rate and percentage arterial oxygen saturation (Sa,O2%). We compared the apnoea plus hypopnoea index (AHI) and Sa,O2% results of PSG with that of the system's automatic analysis (M-SA). We also performed a semiautomatic analysis (M-SS) with visual editing of the raw data. Results at different AHI cut-off levels were analysed to obtain an indication of accuracy in diagnosis and severity. Both M-SA and M-SS showed a sensitivity and specificity of 100% at the cut-off level of AHI > 10. When increasing the cut-off levels, M-SA sensitivity decreased (55% for AHI > 40), while specificity remained high (95%). This was improved to a clinically acceptable level of agreement by M-SS analysis (sensitivity 91% and specificity 94%). In conclusion, the MicroDigitrapper-S device showed a good sensitivity and specificity for the diagnosis of OSA. However, the device could not predict the severity of OSA precisely enough. In severe cases (apnoea plus hypopnoea index > 40), semi-automatic scoring was necessary to obtain a more accurate detection of the severity of the disease.
Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response
Authors: Zoë Weaver, Simone Difilippantonio, Julian Carretero, Philip L. Martin, Rajaa El Meskini, Anthony J. Iacovelli, Michelle Gumprecht, Alan Kulaga, Theresa Guerin, Jerome Schlomer, Maureen Baran, Serguei Kozlov, Thomas McCann, Salvador Mena, Fatima Al-Shahrour, Danny Alexander, Kwok-Kin Wong, Terry Van Dyke
Journal: Cancer Research (2012)

Patients with lung cancer with activating mutations in the EGF receptor (EGFR) kinase, who are treated long-term with tyrosine kinase inhibitors (TKI), often develop secondary mutations in EGFR associated with resistance. Mice engineered to develop lung adenocarcinomas driven by the human EGFR T790M resistance mutation are similarly resistant to the EGFR TKI erlotinib. By tumor volume endpoint analysis, these mouse tumors respond to BIBW 2992 (an irreversible EGFR/HER2 TKI) and rapamycin combination therapy. To correlate EGFR-driven changes in the lung with response to drug treatment, we conducted an integrative analysis of global transcriptome and metabolite profiling compared with quantitative imaging and histopathology at several time points during tumor progression and treatment. Responses to single-drug treatments were temporary, whereas combination therapy elicited a sustained response. During tumor development, metabolomic signatures indicated a shift to high anabolic activity and suppression of antitumor programs with 11 metabolites consistently present in both lung tissue and blood. Combination drug treatment reversed many of the molecular changes found in tumored lung. Data integration linking cancer signaling networks with metabolic activity identified key pathways such as glutamine and glutathione metabolism that signified response to single or dual treatments. Results from combination drug treatment suggest that metabolic transcriptional control through C-MYC and SREBP, as well as ELK1, NRF1, and NRF2, depends on both EGFR and mTORC1 signaling. Our findings establish the importance of kinetic therapeutic studies in preclinical assessment and provide in vivo evidence that TKI-mediated antiproliferative effects also manifest in specific metabolic regulation.
Radioactive Iron Metabolism and Erythrocyte Survival Studies of the Mechanism of the Anemia Associated with Rheumatoid Arthritis1
Authors: Emil J. Freireich, Joseph F. Ross, Theodore B. Bayles, Charles P. Emerson, Stuart C. Finch
Journal: Journal of Clinical Investigation (1957)

Anemia of moderate severity occurs frequently in rheumatoid arthritis patients (1).These patients show abnormalities of iron metabolism such as low serum iron concentration and rapid loss of injected iron from the plasma (1-4).Abnormali- ties of red cell survival have been described (5-7), while studies of heme pigment excretion products have not shown evidence of increased hemoglobin catabolism (8).The role of these disturbances in the genesis of the anemia in arthritic patients is not clearly understood.The present study was undertaken to define the role of changes in rates of red cell production and destruction in the pathogenesis of the anemia oc- curring in rheumatoid arthritis patients, and to clarify the effect of disturbances of iron metabolism on red cell production in these patients.An ab- stract of this work has been published previously (9). MATERIALS AND METHODSA. Clinical material 1. Patients.The patients studied had active rheuma- toid arthritis and were hospitalized for at least the first three weeks of the study.Cases were selected without regard for the presence or degree of anemia.Those with evidence of active bleeding or past history of significant blood loss were excluded from the study.Study cases
Doxorubicin-DNA Adducts Induce a Non-Topoisomerase II–Mediated Form of Cell Death
Authors: Lonnie P. Swift, Ada Rephaeli, Abraham Nudelman, Don R. Phillips, Suzanne M. Cutts
Journal: Cancer Research (2006)

Abstract Doxorubicin (Adriamycin) is one of the most commonly used chemotherapeutic drugs and exhibits a wide spectrum of activity against solid tumors, lymphomas, and leukemias. Doxorubicin is classified as a topoisomerase II poison, although other mechanisms of action have been characterized. Here, we show that doxorubicin-DNA adducts (formed by the coadministration of doxorubicin with non-toxic doses of formaldehyde-releasing prodrugs) induce a more cytotoxic response in HL-60 cells than doxorubicin as a single agent. Doxorubicin-DNA adducts seem to be independent of classic topoisomerase II–mediated cellular responses (as observed by employing topoisomerase II catalytic inhibitors and HL-60/MX2 cells). Apoptosis induced by doxorubicin-DNA adducts initiates a caspase cascade that can be blocked by overexpressed Bcl-2, suggesting that adducts induce a classic mode of apoptosis. A reduction in the level of topoisomerase II–mediated double-strand-breaks was also observed with increasing levels of doxorubicin-DNA adducts and increased levels of apoptosis, further confirming that adducts exhibit a separate mechanism of action compared with the classic topoisomerase II poison mode of cell death by doxorubicin alone. Collectively, these results indicate that the presence of formaldehyde transfers doxorubicin from topoisomerase II–mediated cellular damage to the formation of doxorubicin-DNA adducts, and that these adducts are more cytotoxic than topoisomerase II–mediated lesions. These results also show that doxorubicin can induce apoptosis by a non-topoisomerase II–dependent mechanism, and this provides exciting new prospects for enhancing the clinical use of this agent and for the development of new derivatives and new tumor-targeted therapies. (Cancer Res 2006; 66(9): 4863-71)
Lymphocytes transformed by Epstein-Barr virus. Induction of nuclear antigen reactive with antibody in rheumatoid arthritis.
Authors: M A Alspaugh, F C Jensen, H Rabin, E M Tan
Journal: The Journal of Experimental Medicine (1978)

Sera from approximately two-thirds of patients with rheumatoid arthritis contain an antibody which is reactive with a nuclear antigen present in human B-lymphocyte tissue culture cells. The immunological reaction can be demonstrated by precipitation and immunofluorescence. Evidence is present that the reactive nuclear antigen is associated with Epstein-Barr (EB) virus-transformed lymphocytes. Normal human peripheral blood lymphocytes did not contain the nuclear antigen reactive with rheumatoid arthritis sera, but after infection with EB virus, they showed increasing amounts of reactive nuclear antigen as the cells were transformed into continuous lines. Several established human and simian lymphocyte cell lines known to carry EB viral genomes were shown to contain rheumatoid arthritis-associated nuclear antigen. Evidence is presented which suggests that the rheumatoid arthritis-associated nuclear antigen is different from the previously described EB nuclear antigen.
Current evidence on diagnostic accuracy of commercially based nucleic acid amplification tests for the diagnosis of pulmonary tuberculosis
Authors: S Greco, E Girardi, A Navarra, C Saltini
Journal: Thorax (2006)

<b>Background:</b> Even though commercial nucleic acid amplification tests (NAATs) have become the most frequently used molecular tests for laboratory diagnosis of pulmonary tuberculosis (TB), published studies report variable estimates of their diagnostic accuracy. We analysed the accuracy of commercial NAATs for the diagnosis of pulmonary TB in smear positive and smear negative respiratory samples using culture as a reference standard. <b>Methods:</b> English language studies reporting data sufficient for calculating sensitivity and specificity of commercial NAATs on smear positive and/or smear negative respiratory samples were included. Meta-regression was used to analyse associations with reference test quality, the prevalence of TB, sample and test type. Predictive values for different levels of pre-test probability were quantified using Bayes' approach. <b>Results:</b> Sixty three journal articles published between 1995 and 2004 met the inclusion criteria. Pooled sensitivity and specificity were 0.96 and 0.85 among smear positive samples and 0.66 and 0.98 among smear negative samples. The number of culture media used as reference test, the inclusion of bronchial samples, and the TB prevalence were found to influence the reported accuracy. The test type had no effect on the diagnostic odds ratio but seemed to be correlated with sensitivity or specificity, probably via a threshold effect. <b>Conclusions:</b> Commercial NAATs can be confidently used to exclude TB in patients with smear positive samples in which environmental mycobacteria infection is suspected and to confirm TB in a proportion of smear negative cases. The methodological characteristics of primary studies have a considerable effect on the reported diagnostic accuracy.
The comparative effects of elastase-induced emphysema on costal and crural diaphragm and parasternal intercostal muscle contractility.
Authors: S G Kelsen, W P Sexauer, I A Mardini, G J Criner
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

Chronically, hyperinflated human subjects with chronic obstructive pulmonary disease and animals with experimentally induced emphysema generate greater than expected levels of transdiaphragmatic pressure at high lung volume because of adaptive changes in the length-tension relationship of the costal diaphragm. The ability to lower intrathoracic pressure during inspiration depends on the mechanical action of all the inspiratory muscles acting in concert. However, the effect of chronic hyperinflation on the mechanical action of inspiratory muscles other than the costal diaphragm remains unknown. This study compares the effect of chronic hyperinflation in the form of elastase-induced emphysema on the contractile properties of the three major inspiratory muscles of the hamster (i.e., the costal and crural diaphragm and parasternal intercostals). Muscles were studied in vitro 6 months after emphysema was induced by intratracheal injection of elastase. Saline-injected animals served as controls. TLC in the elastase-injected hamsters was significantly greater than in controls (12.5 +/- 0.8 ml versus 9.0 +/- 0.3 ml, p < 0.002). Maximal tetanic tension, time to peak tension, maximal velocity of shortening, and the force-velocity relationship differed among the three muscles but for any given muscle were similar in control and emphysematous animals. In contrast, the fiber length optimal for tension generation (Lo) not only differed across muscles but was significantly shorter in the costal diaphragm of emphysematous animals compared with control animals. However, Lo of the parasternal intercostal and crural diaphragm was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Tubular Epithelial Cell Dedifferentiation Is Driven by the Helix-Loop-Helix Transcriptional Inhibitor Id1
Authors: Yingjian Li, Junwei Yang, Jian-Hua Luo, Shoukat Dedhar, Youhua Liu
Journal: Journal of the American Society of Nephrology (2007)

In the fibrotic kidney, tubular cells undergo epithelial-to-mesenchymal transition (EMT), a phenotypic conversion that is characterized by sequential loss of epithelial markers and gain of mesenchymal features. For understanding of the molecular mechanism that governs this process, a high-throughput gene expression microarray analysis was used to identify the critical genes in the initial phase of the TGF-beta1-mediated EMT. Inhibitor of differentiation-1 (Id1), a dominant negative antagonist of the basic helix-loop-helix transcription factors, was found to be induced rapidly in human proximal tubular epithelial cells after TGF-beta1 treatment. This induction of Id1 depended on intracellular Smad signaling. Ectopic expression of Id1 suppressed epithelial E-cadherin and zonula occludens-1 expression. Id1 physically formed complex with basic helix-loop-helix transcription factor HEB (Hela E-box binding factor), sequestered its ability to bind to E-box, and repressed the trans-activation of E-cadherin promoter. However, overexpression of Id1 failed to induce alpha-smooth muscle actin, matrix metalloproteinase-2, fibronectin, and integrin-linked kinase (ILK), indicating its inability to confer a complete EMT. Overexpression of ILK or inhibition of ILK activity had no effect on Id1 induction by TGF-beta1, suggesting that Id1 and ILK have independent roles in epithelial dedifferentiation and EMT. In vivo, Id1 was induced exclusively in the degenerated, dilated renal tubular epithelium after unilateral ureteral obstruction. These studies identify Id1 transcriptional inhibitor as a crucial player in mediating cell dedifferentiation of renal tubular epithelium and suggest that EMT is a multistep process in which loss of epithelial adhesion does not necessarily lead to an autonomous mesenchymal transition.
Pax5 Activates Immunoglobulin Heavy Chain V to DJ Rearrangement in Transgenic Thymocytes
Authors: Lih-Yun Hsu, Hong-Erh Liang, Kristen Johnson, Chulho Kang, Mark S. Schlissel
Journal: The Journal of Experimental Medicine (2004)

Mice deficient for the B cell–restricted transcription factor Pax5 show a defect in the VH to DJH rearrangement step of immunoglobulin heavy chain gene assembly even though the expression of the V(D)J recombinase is not diminished in Pax5−/− pro–B cells. To investigate whether Pax5 is limiting for VH to DJH rearrangement, we generated transgenic mice which express Pax5 in developing thymocytes. We show that enforced expression of Pax5 in thymocytes results in a partial block in T cell development due to defective pre-TCR signaling in β-selection. Moreover, our results demonstrate that expression of Pax5 in early thymocytes is sufficient to induce VH to DJH rearrangements in CD4+CD8+ T cells and lead us to suggest that Pax5 may play a direct role in the lineage-specific regulation of immunoglobulin heavy chain gene rearrangement.
PROBLEMS OF INSTITUTIONAL CARE OF THE AGED
Authors: DAVID A. BOYD
Journal: American Journal of Psychiatry (1950)

The present methods of managing the problems of the aged have proved unsatisfactory and inadequate. Common humanity demands the formulation of some program of care that permits the elderly to maintain dignity, self-respect, and a sense of worth as well as providing physical necessities. This can be accomplished by state institutions designed to provide a program of activities and care suited to the needs and abilities of an aged resident population. In the long run, the total cost of such care will be no greater than the present wasteful and haphazard types of custodial management. In addition, it will permit this ever larger group to spend their declining years in a setting that encourages a sense of personal dignity and utilizes their skills. It has been said, "Three score and ten years make the upshot of man's pleasurable existence." This does not have to be so if the problem is met by careful planning and new approaches. Not only will the lives of the aged be enriched, but the public mental hospitals will be enabled to return to their primary function of treating the mentally ill.
Characterization and Enrichment of Cardiomyocytes Derived From Human Embryonic Stem Cells
Authors: Chunhui Xu, Shailaja Police, Namitha Rao, Melissa K. Carpenter
Journal: Circulation Research (2002)

Cell replacement therapy is a promising approach for the treatment of cardiac diseases, but is challenged by a limited supply of appropriate cells. We have investigated whether functional cardiomyocytes can be efficiently generated from human embryonic stem (hES) cells. Cardiomyocyte differentiation was evaluated using 3 parent (H1, H7, and H9) hES cell lines and 2 clonal (H9.1 and H9.2) hES cell lines. All cell lines examined differentiated into cardiomyocytes, even after long-term culture (50 passages or approximately 260 population doublings). Upon differentiation, beating cells were observed after one week in differentiation conditions, increased in numbers with time, and could retain contractility for over 70 days. The beating cells expressed markers characteristic of cardiomyocytes, such as cardiac alpha-myosin heavy chain, cardiac troponin I and T, atrial natriuretic factor, and cardiac transcription factors GATA-4, Nkx2.5, and MEF-2. In addition, cardiomyocyte differentiation could be enhanced by treatment of cells with 5-aza-2'-deoxycytidine but not DMSO or retinoic acid. Furthermore, the differentiated cultures could be dissociated and enriched by Percoll density centrifugation to give a population containing 70% cardiomyocytes. The enriched population was proliferative and showed appropriate expression of cardiomyocyte markers. The extended replicative capacity of hES cells and the ability to differentiate and enrich for functional human cardiomyocytes warrant further development of these cells for clinical application in heart diseases.
Platelet 12-Lipoxygenase Activation via Glycoprotein VI
Authors: Marcus J. Coffey, Gavin E. Jarvis, Jonathan M. Gibbins, Barbara Coles, Natasha E. Barrett, Oliver R.E. Wylie, Valerie B. O’Donnell
Journal: Circulation Research (2004)

Lipoxygenases (LOX) contribute to vascular disease and inflammation through generation of bioactive lipids, including 12-hydro(pero)xyeicosatetraenoic acid (12-H(P)ETE). The physiological mechanisms that acutely control LOX product generation in mammalian cells are uncharacterized. Human platelets that contain a 12-LOX isoform (p12-LOX) were used to define pathways that activate H(P)ETE synthesis in the vasculature. Collagen and collagen-related peptide (CRP) (1 to 10 μg/mL) acutely induced platelet 12-H(P)ETE synthesis. This implicated the collagen receptor glycoprotein VI (GPVI), which signals via the immunoreceptor-based activatory motif (ITAM)-containing FcRγ chain. Conversely, thrombin only activated at high concentrations (&gt; 0.2 U/mL), whereas U46619 and ADP alone were ineffective. Collagen or CRP-stimulated 12-H(P)ETE generation was inhibited by staurosporine, PP2, wortmannin, BAPTA/AM, EGTA, and L-655238, implicating src -tyrosine kinases, PI3-kinase, Ca 2+ mobilization, and p12-LOX translocation. In contrast, protein kinase C (PKC) inhibition potentiated 12-H(P)ETE generation. Finally, activation of the immunoreceptor tyrosine-based inhibitory motif (ITIM)–containing platelet endothelial cell adhesion molecule (PECAM-1) inhibited p12-LOX product generation. This study characterizes a receptor-dependent pathway for 12-H(P)ETE synthesis via the collagen receptor GPVI, which is negatively regulated by PECAM-1 and PKC, and demonstrates a novel link between immune receptor signaling and lipid mediator generation in the vasculature.