tbuckley/cabot-search huggingface dataset:
Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory B-Cell Neoplasms
Authors: Beata Holkova, E. Brent Perkins, Viswanathan Ramakrishnan, Mary Beth Tombes, Ellen Shrader, Neha Talreja, Martha D. Wellons, Kevin T. Hogan, G. David Roodman, Domenico Coppola, Loveleen Kang, Jana Dawson, Robert K. Stuart, Cody Peer, William D. Figg, Sarah Kolla, Austin Doyle, John Wright, Daniel M. Sullivan, John D. Roberts, Steven Grant
Journal: Clinical Cancer Research (2011)

Abstract Purpose: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, and mantle cell lymphoma). Experimental Design: Patients received bortezomib by intravenous push on days 1, 4, 8, and 11. Patients also received alvocidib on days 1 and 8 by 30-minute bolus infusion followed by a 4-hour continuous infusion. Treatment was on a 21-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose escalation employed a standard 3 + 3 design until the MTD was identified on the basis of DLTs. Pharmacokinetic studies and pharmacodynamic studies were conducted. Results: Sixteen patients were treated. The MTD was established as 1.3 mg/m2 for bortezomib and 30 mg/m2 for alvocidib (both the 30-minute bolus and 4-hour infusions). Common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common nonhematologic toxicities included fatigue and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate = 44%). Pharmacokinetic results were typical for alvocidib and pharmacodynamic studies yielded variable results. Conclusions: The combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen appears active in patients with relapsed and/or refractory multiple myeloma or non–Hodgkin's lymphoma, justifying phase II studies to determine the activity of this regimen more definitively. Clin Cancer Res; 17(10); 3388–97. ©2011 AACR.
Trastuzamab (Herceptin<sup>®</sup>)-related cardiotoxicity in pregnancy
Authors: Nicole J Roberts, Barry J Auld
Journal: Journal of the Royal Society of Medicine (2010)

Trastuzamab (Herceptin®) is a humanized monoclonal antibody that binds to the extracellular juxtamembrane domain of Human Epidermal Growth Factor Receptor type 2 (HER2) and prevents the activation of its intracellular tyrosine kinase.1 HER2 occurs in 20–30% of invasive breast cancers and Trastuzamab inhibits the proliferation and survival of HER2 dependent tumours thereby improving disease-free survival when used in combination with chemotherapy.1 An increasing number of women diagnosed with HER2 positive breast cancer are becoming pregnant while receiving treatment with Trastuzamab. The fetal effects such as anhydramnios2 have been reported in the literature but as yet no maternal side-effects from the drug have been published. Although in general Trastuzamab is well-tolerated by patients, there is a 5% risk of cardiotoxicity.3 We report such a case in pregnancy.
Gallstone disease in Peruvian coastal natives and highland migrants
Authors: P L Moro
Journal: Gut (2000)

<h3>BACKGROUND</h3> In a previous study, we found that gallstones were a common occurrence in the high altitude villages of the Peruvian Andes. <h3>AIMS</h3> To determine if high altitude (⩾ 1500 m) is a contributing risk factor for gallstone disease. <h3>METHODS</h3> We conducted a cross sectional study in a periurban community in Lima, Peru, and compared the prevalence of gallstone disease between coastal natives, highland (Sierra) natives and Sierra natives who had migrated to the coast. We also compared the prevalence rates from this study with those from a previous study conducted at high altitude. We examined 1534 subjects &gt;15 years of age for gallstone disease. Subjects were interviewed for the presence or absence of risk factors. <h3>RESULTS</h3> Gallstone disease was more common in females (16.1 cases per 100, 95% CI 13.8–18.2) than in males (10.7 per 100, 95% CI 8.0–13.4). Females had a greater risk of gallstone disease, especially if they had used oral contraception and/or had four or more children. The age adjusted prevalence was not significantly different between coastal natives, Sierra migrants, and Andean villagers. The prevalence of gallstone disease was not associated with time since migration or with having native Sierra parents. After adjusting for other risk factors, Sierra natives who migrated to the coast had a lower prevalence of gallstone disease than coastal natives (odds ratio 0.74, 95% CI 0.58–0.94). <h3>CONCLUSIONS</h3> This study indicates that high altitude is not a positive risk factor for gallstone disease and confirms that this disease is common in Peruvians, which may be attributable to Peruvian-Indian ethnicity.
Combined Deficiency of Dystrophin and β1 Integrin in the Cardiac Myocyte Causes Myocardial Dysfunction, Fibrosis and Calcification
Authors: Laila Elsherif, Michael S. Huang, Shaw-Yung Shai, Yuan Yang, Rita Y. Li, June Chun, Majid A. Mekany, Andrew L. Chu, Stephen J. Kaufman, Robert S. Ross
Journal: Circulation Research (2008)

The dystrophin-glycoprotein complex is a large complex of membrane-associated proteins linking the cytoskeleton to the extracellular matrix in muscle. Transmembrane heterodimeric (alphabeta) integrins serve also as cellular adhesion molecules and mechanotransducers. In the animal model for Duchenne muscular dystrophy, the mdx mouse, loss of dystrophin causes more severe abnormalities in skeletal than in cardiac muscle. We hypothesized that ablation of cardiac myocyte integrins in the mdx background would lead to a severe cardiomyopathic phenotype. Mdx mice were crossed to ones with cardiac myocyte-specific deletion of beta1 integrin (beta1KO) to generate beta1KOmdx. Unstressed beta1KOmdx mice were viable and had normal cardiac function; however, high mortality was seen in peri- and postpartum females by 6 months of age, when severe myocardial necrosis and fibrosis and extensive dystrophic calcification was seen. Decreased ventricular function and blunted adrenergic responsiveness was found in the beta1KOmdx mice compared with control (Lox/Lox, no Cre), beta1KO, and mdx. Similarly, adult beta1KOmdx males were more prone to isoproterenol-induced heart failure and death compared with control groups. Given the extensive calcification, we analyzed transcript levels of genes linked to fibrosis and calcification and found matrix gamma-carboxyglutamic acid protein, decorin, periostin, and the osteoblast transcription factor Runx2/Cbfa1 significantly increased in beta1KOmdx cardiac muscle. Our data show that combined deficiency of dystrophin and integrins in murine cardiac myocytes results in more severe cardiomyopathic changes in the stressed myocardium than reduction of either dystrophin or integrins alone and predisposes to myocardial calcification.
Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma
Authors: S. Vincent Rajkumar, Suzanne R. Hayman, Martha Q. Lacy, Angela Dispenzieri, Susan M. Geyer, Brian Kabat, Steven R. Zeldenrust, Shaji Kumar, Philip R. Greipp, Rafael Fonseca, John A. Lust, Stephen J. Russell, Robert A. Kyle, Thomas E. Witzig, Morie A. Gertz
Journal: Blood (2005)
CELLULAR IMMUNITY TO HERPES SIMPLEX VIRUS MEDIATED BY INTERFERON
Authors: Donald L. Lodmell, Abner Louis Notkins
Journal: The Journal of Experimental Medicine (1974)

Rabbit kidney cell monolayers infected with herpes simplex virus (HSV) were incubated with leukocytes from rabbits immunized with complete Freund's adjuvant. When the leukocytes were exposed to tuberculin purified protein derivative (PPD), viral replication and plaque formation were markedly inhibited. Similarly, when leukocytes from animals immunized with HSV were exposed to UV-inactivated HSV, viral replication was markedly inhibited. Exposure of leukocytes from unimmunized animals or animals immunized with incomplete Freund's adjuvant to UV-inactivated virus or PPD produced relatively little inhibition of viral replication. Examination of supernatant fluids from stimulated cultures revealed a soluble mediator that had the properties of interferon. Interferon production was detected within several hours after exposure of sensitized leukocytes to antigen. Supernatant fluids from as few as one sensitized leukocyte per 200 rabbit kidney cells inhibited HSV replication by over 90%. These findings support the concept that the cellular immune response to HSV consists of two phases: an immunologically specific antigen recognition phase, and a nonspecific effector phase that stops HSV spread by generating interferon.
CRB-65 for the assessment of pneumonia severity: who could ask for more?
Authors: S. Ewig, T. Welte
Journal: Thorax (2008)

According to a widespread consensus reflected in all authoritative guidelines, assessment of severity is the key step in the management of patients with community acquired pneumonia (CAP). It is a major criterion in the decision where to treat a patient and it widely determines the amount of diagnostic workup as well as the selection of initial empiric antimicrobial treatment. Overall, it has major implications in terms of outcomes and costs. Two lines of investigation have resulted in two competing tools of severity assessment: the pneumonia severity index (PSI)1 and the CURB score and its modifications (CURB-65, CRB-65).2–5 In the meantime, it has become evident that the PSI and the CRB-65 score, as the most simple modification of the original CURB score, perform equivalent in terms of prediction of inhospital death. Both predict death in a class 3 pattern, with mortality rates of approximately 1–3% (PSI class I–III, CRB-65 class 1), 8–10% (PSI class IV and CRB-class 2) and 20–30% (PSI class V and CRB-65 class 3).5 6 Both scores also work reasonably well in ambulatory patients.5 However, as the CRB-65 score is far easier to remember and to compute, being based exclusively on variables which can be immediately determined without any technical expense other than blood pressure measurement, this score is the one which will gain general acceptance.7

It is intriguing that such a simple rule is able to predict the risk of death so accurately. Nevertheless, in this issue of Thorax , Chalmers and colleagues8 provide convincing data from a large population showing that the CRB-65 score can be simplified …
Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1.
Authors: P Tan, C Anasetti, J A Hansen, J Melrose, M Brunvand, J Bradshaw, J A Ledbetter, P S Linsley
Journal: The Journal of Experimental Medicine (1993)

The specificity of T lymphocyte activation is determined by engagement of the T cell receptor (TCR) by peptide/major histocompatibility complexes expressed on the antigen-presenting cell (APC). Lacking costimulation by accessory molecules on the APC, T cell proliferation does not occur and unresponsiveness to subsequent antigenic stimulus is induced. The B7/BB1 receptor on APCs binds CD28 and CTLA-4 on T cells, and provides a costimulus for T cell proliferation. Here, we show that prolonged, specific T cell hyporesponsiveness to antigenic restimulation is achieved by blocking the interaction between CD28 and B7/BB1 in human mixed leukocyte culture (MLC). Secondary T cell proliferative responses to specific alloantigen were inhibited by addition to the primary culture of monovalent Fab fragments of anti-CD28 monoclonal antibody (mAb) 9.3, which block interaction of CD28 with B7/BB1 without activating T cells. Hypo-responsiveness was also induced in MLC by CTLA4Ig, a chimeric immunoglobulin fusion protein incorporating the extracellular domain of CTLA-4 with high binding avidity for B7/BB1. Cells previously primed could also be made hyporesponsive, if exposed to alloantigen in the presence of CTLA4Ig. Maximal hyporesponsiveness was achieved in MLC after 2 d of incubation with CTLA4Ig, and was maintained for at least 27 d after removal of CTLA4Ig. Accumulation of interleukin 2 (IL-2) and interferon gamma but not IL-4 mRNA was blocked by CTLA4Ig in T cells stimulated by alloantigen. Antigen-specific responses could be restored by addition of exogenous IL-2 at the time of the secondary stimulation. Addition to primary cultures of the intact bivalent anti-CD28 mAb 9.3, or B7/BB1+ transfected CHO cells or exogenous IL-2, abrogated induction of hyporesponsiveness by CTLA4Ig. These data indicate that interaction of CD28 with B7/BB1 during TCR engagement with antigen is required to maintain T cell competence and that blocking such interaction can result in a state of T cell hyporesponsiveness.
Sarcoplasmic Reticulum Ca <sup>2+</sup> /Calmodulin-Dependent Protein Kinase Is Altered in Heart Failure
Authors: Thomas Netticadan, Rana M. Temsah, Kenichi Kawabata, Naranjan S. Dhalla
Journal: Circulation Research (2000)

Abstract —Although Ca 2+ /calmodulin-dependent protein kinase-II (CaMK) is known to phosphorylate different Ca 2+ cycling proteins in the cardiac sarcoplasmic reticulum (SR) and regulate its function, the status of CaMK in heart failure has not been investigated previously. In this study, we examined the hypothesis that changes in the CaMK-mediated phosphorylation of the SR Ca 2+ cycling proteins are associated with heart failure. For this purpose, heart failure in rats was induced by occluding the coronary artery for 8 weeks, and animals with &gt;30% infarct of the left ventricle wall plus septum mass were used. Noninfarcted left ventricle was used for biochemical assessment; sham-operated animals served as control. A significant depression in SR Ca 2+ uptake and release activities was associated with a decrease in SR CaMK phosphorylation of the SR proteins, ryanodine receptor (RyR), Ca 2+ pump ATPase (SR/endoplasmic reticulum Ca 2+ ATPase [SERCA2a]), and phospholamban (PLB) in the failing heart. The SR protein contents for RyR, SERCA2a, and PLB were decreased in the failing hearts. Although the SR Ca 2+ /calmodulin-dependent CaMK activity, CaMK content, and CaMK autophosphorylation were depressed, the SR phosphatase activity was enhanced in the failing heart. On the other hand, the cAMP-dependent protein kinase–mediated phosphorylation of RyR and PLB was not affected in the failing heart. On the basis of these results, we conclude that alterations in SR CaMK-mediated phosphorylation may be partly responsible for impaired SR function in heart failure.
Oligoclonal Expansions of CD8+ T Cells in Chronic HIV Infection Are Antigen Specific
Authors: Jamie D.K. Wilson, Graham S. Ogg, Rachel L. Allen, Philip J.R. Goulder, Anthony Kelleher, Andy K. Sewell, Christopher A. O'Callaghan, Sarah L. Rowland-Jones, Margaret F.C. Callan, Andrew J. McMichael
Journal: The Journal of Experimental Medicine (1998)

Acute HIV infection is associated with a vigorous immune response characterized by the proliferation of selected T cell receptor V beta (BV)-expressing CD8+ T cells. These ‘expansions', which are commonly detected in the peripheral blood, can persist during chronic HIV infection and may result in the dominance of particular clones. Such clonal populations are most consistent with antigen-driven expansions of CD8+ T cells. However, due to the difficulties in studying antigen-specific T cells in vivo, it has been hard to prove that oligoclonal BV expansions are actually HIV specific. The use of tetrameric major histocompatibility complex–peptide complexes has recently enabled direct visualization of antigen-specific T cells ex vivo but has not provided information on their clonal composition. We have now made use of these tetrameric complexes in conjunction with anti-BV chain–specific monoclonal antibodies and analysis of cytotoxic T lymphocyte lines/clones to show that chronically clonally expanded CD8+ T cells are HIV specific in vivo.
Immunological Insulin Resistance Due to Insulin Antibodies Developed After Cessation of Insulin Therapy in a Patient With Type 2 Diabetes
Authors: Miho Hirano, Hiroshi Arima, Yutaka Oiso
Journal: Diabetes Care (2008)

While insulin antibodies reportedly exist in about half of patients with type 2 diabetes who inject insulin, these antibodies do not often severely affect blood glucose levels (1). Here, we report a patient who had insulin antibodies against human insulin and developed insulin resistance after episodes of frequent hypoglycemic attacks, even though insulin therapy had been discontinued. A 68-year-old Japanese male was referred to our hospital because of hyperglycemia in October 2003. He weighed 89 kg, and his height was 171 cm. His levels of fasting plasma glucose, A1C, and urine C-peptide immunoreactivity were 313 mg/dl, 10.6%, and 38.7 μg/day, respectively. Anti-GAD antibody …
DRIED MILK AS A FOOD FOR INFANTS
Authors: C. K. Millard
Journal: BMJ (1910)

<h3>Abstract</h3> In his theoretical work of the 70’s, Robert May introduced a Random Matrix Theory (RMT) approach for studying the stability of large complex biological systems. Unlike the established paradigm, May demonstrated that complexity leads to instability in generic models of biological networks. The RMT approach has since similarly been applied in many disciplines. Central to the approach is the famous “circular law” that describes the eigenvalue distribution of an important class of random matrices. However the “circular law” generally does not apply for ecological and biological systems in which density-dependence (DD) operates. Here we directly determine the far more complicated eigenvalue distributions of complex DD systems. A simple mathematical solution falls out, that allows us to explore the connection between feasible systems (i.e., having all equilibrium populations positive) and stability. In particular, for these RMT systems, almost all feasible systems are stable. The degree of stability, or resilience, is shown to depend on the minimum equilibrium population, and not directly on factors such as network topology.
THE RELATIONSHIP OF TOXIN AND ANTITOXIN INJECTION SITE TO TETANUS DEVELOPMENT IN THE RAT
Authors: Alexander A. Fedinec, Howard A. Matzke
Journal: The Journal of Experimental Medicine (1959)

The pattern of development of symptoms was studied following injection of 3 MLD (minimum lethal dose) of tetanus toxin in each of the following sites in the rat: vein, muscle, endoneurium, epineurium, spinal cord, subarachnoid space, and subdural space. Similar observations were made when 3 MPD (minimum protective dose) of antitoxin were injected into each of the above sites a few minutes after the intramuscular injection of toxin. Local tetanus followed intramuscular, endoneurial, and epineurial injection of the toxin; blood-borne tetanus also appeared in the latter instance. Tetanus dolorosus followed intraspinal injection of toxin. Both dorsal tetanus and blood-borne tetanus developed after subdural administration of toxin. Blood-borne tetanus, alone, appeared following intravenous and subarachnoid injection of toxin. In no case did injection of antitoxin at the various sites listed above prevent local tetanus from developing after intramuscular injection of toxin. Of the various sites injected with antitoxin, the intramuscular, intraspinal, and intravenous were the most effective. It is suggested that the endoneurial tissue spaces serve as a conduit for tetanus toxin from the muscle to the CNS. The perilemma of the peripheral nerve trunk may act as a selectively permeable membrane which permits tetanus toxin to pass from the epineurium to the endoneurium. Outward diffusion of toxin from the endoneurial spaces is apparently markedly reduced. The antitoxin probably is prevented from permeating this barrier in either direction. The importance of absorption of tetanus toxin by the lymphatic and blood circulation is discussed.
Detection of movement intention from single-trial movement-related cortical potentials using random and non-random paradigms
Authors: Susan Aliakbaryhosseinabadi, Ning Jiang, Aleksandra Vuckovic, Kim Dremstrup, Dario Farina, Natalie Mrachacz-Kersting
Journal: Brain-Computer Interfaces (2015)

Detection of motor intention with short latency from scalp electroencephalography (EEG) is essential for the development of brain-computer interface (BCI) systems for neuromodulation. This latency determines the temporal association between motor intention and the triggered afferent neurofeedback. In this study, we compared two typical experimental paradigms for the detection of movement intention from EEG. A template-matching algorithm was used to detect movement-related cortical potentials (MRCPs) in eight healthy subjects for two types of cued motor imageries using either a random or non-random cue. For the random cue, the true positive rates of detection of movement intention were 63.5 ± 5.9% (foot movement) and 61 ± 6.5% (right hand movement). Detection occurred 102.8 ± 119.3 ms and 112.2 ± 104 ms prior to onset of execution cue. On the other hand, foot and hand movement intentions were detected significantly earlier (p < 0.05) (198 ± 147.3 ms and 206 ± 134.2 ms prior to onset, respectively) and with a greater true positive rate (p < 0.05) (75.3 ± 5.5% and 70.2 ± 6.1%) when non-random cues were used. These results suggest that a non-random cue paradigm is preferable to a typical random cue in BCI systems designed for neuromodulation. However, the important consideration of variable practice afforded by the random cue, which is known to facilitate learning, requires further study.
Adenosine deaminase, an useful tool for the diagnosis of tuberculous pleuritis in France
Authors: Hervé Le Floch, Sandrine Duron, Hervé Delacour, Frédéric Rivière, Inès Ngampolo, Fabien Vaylet, Jacques Margery, Christophe Rapp
Journal: European Respiratory Journal (2011)

Pleural tuberculosis is a diagnosis challenge for usual mycobacterial analysis given that the bacillary concentration is low in the pleural effusion. Adenosine deaminase is a pleural inflammatory marker recommanded for the diagnosis of pleural tuberculosis in the high-prevalence countries. There is not enough data to support its use in a low-prevalence country.

Objective: To know the utility of ADA for the diagnosis of pleural tuberclosis in France, a low prevalence country.

Material an method: Retrospective study of the exsudative pleural effusion with the ADA dosage (Giusti's method) done in two military hospital near Paris. We compared tuberculous and non-tuberculous pleural effusion. The best cut-off value of ADA for the diagnosis of pleural tuberculosis was found using ROC curves.

Results: 183 patients were studied, including 29 tuberculosis, 65 cancers, 5 malignant hemopathies, 32 parapneumonic pleural effusions, 24 purulent pleuritis, 12 old transudative effusions, 14 effusions from others aetiologies. Sixty-eight effusions were rich of lymphocytes including 23 tuberculosis. The young age (≤35 years-old), the foreign origin and the presence of general manifestations were independanltly associated with tuberculosis. The best cut-off value for ADA was 47 UI/l, with Se: 95,7%, Spe: 91,1%, PPV: 84,6%, NPV: 97,6%. When ADA ≥ 70 UI/l, the PPV was 90,5%.

Discussion: ADA dosage is usefull in France. Lowers than 47 UI/l, it may exclude tuberculosis. When ADA ≥ 47 UI/l, the result should be interpretated considering the context and the pre-test probability of tuberculosis. When this pre-test probability of tuberculosis is important, ADA ≥ 70 UI/l is very likely for tuberculosis.