tbuckley/cabot-search huggingface dataset:
A Phase I Dose-Escalation Study of Antibody BI-505 in Relapsed/Refractory Multiple Myeloma
Authors: Markus Hansson, Peter Gimsing, Ashraf Badros, Titti Martinsson Niskanen, Hareth Nahi, Fritz Offner, Morten Salomo, Elisabeth Sonesson, Morten Mau-Sorensen, Yvonne Stenberg, Annika Sundberg, Ingrid Teige, Jan Van Droogenbroeck, Stina Wichert, Maurizio Zangari, Björn Frendeus, Magnus Korsgren, Martine Poelman, Guido Tricot
Journal: Clinical Cancer Research (2015)

Abstract Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients. Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses. Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505′s half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months. Conclusions: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206). Clin Cancer Res; 21(12); 2730–6. ©2015 AACR.
At home management of aplastic phase following high-dose chemotherapy with stem-cell rescue for hematological and non-hematological malignancies
Authors: A M Westermann, M M Holtkamp, G A Linthorst, L van Leeuwen, E J Willemse, W C van Dijk, W J Nooijen, J W Baars, J H Schornagel, S Rodenhuis
Journal: Annals of Oncology (1999)
Training history, deliberate practice and elite sports performance: an analysis in response to Tucker and Collins review—what makes champions?
Authors: K Anders Ericsson
Journal: British Journal of Sports Medicine (2012)

Locus coeruleus (LC) neurons, the source of hippocampal norepinephrine (NE), are activated by novelty and changes in environmental contingencies. Based on the role of monoamines in reconfiguring invertebrate networks, and data from mammalian systems, a network reset hypothesis for the effects of LC activation has been proposed. We used the cellular compartmental analysis of temporal FISH technique based on the cellular distribution of immediate early genes to examine the effect of LC activation and inactivation, on regional hippocampal maps in male rats, when LC activity was manipulated just before placement in a second familiar (A/A) and/or novel environment (A/B). We found that bilateral phasic, but not tonic, activation of LC reset hippocampal maps in the A/A condition, whereas silencing the LC with clonidine before placement in the A/B condition blocked map reset and a familiar map emerged in the dentate gyrus, proximal and distal CA1, and CA3c. However, CA3a and CA3b encoded the novel environment. These results support a role for phasic LC responses in generating novel hippocampal sequences during memory encoding and, potentially, memory updating. The silencing experiments suggest that novel environments may not be recognized as different by dentate gyrus and CA1 without LC input. The functional distinction between phasic and tonic LC activity argues that these parameters are critical for determining network changes. These data are consistent with the hippocampus activating internal network representations to encode novel experiential episodes and suggest LC input is critical for this role. <b>SIGNIFICANCE STATEMENT</b> Burst activation of the broadly projecting novelty signaling system of the locus coeruleus initiates new network representations throughout the hippocampus despite unchanged external environments. Tonic activation does not alter network representations in the same condition. This suggests differences in the temporal parameters of neuromodulator network activation are critical for neuromodulator function. Silencing this novelty signaling system prevented the appearance of new network representations in a novel environment. Instead, familiar representations were expressed in a subset of hippocampal areas, with another subset encoding the novel environment. This "being in two places at once" argues for independent functional regions within the hippocampus. These experiments strengthen the view that internal states are major determinants of the brain9s construction of environmental representations.
The Skeletal Proteome of the Coral Acropora millepora: The Evolution of Calcification by Co-Option and Domain Shuffling
Authors: Paula Ramos-Silva, Jaap Kaandorp, Lotte Huisman, Benjamin Marie, Isabelle Zanella-Cléon, Nathalie Guichard, David J. Miller, Frédéric Marin
Journal: Molecular Biology and Evolution (2013)

In corals, biocalcification is a major function that may be drastically affected by ocean acidification (OA). Scleractinian corals grow by building up aragonitic exoskeletons that provide support and protection for soft tissues. Although this process has been extensively studied, the molecular basis of biocalcification is poorly understood. Notably lacking is a comprehensive catalog of the skeleton-occluded proteins—the skeletal organic matrix proteins (SOMPs) that are thought to regulate the mineral deposition. Using a combination of proteomics and transcriptomics, we report the first survey of such proteins in the staghorn coral Acropora millepora. The organic matrix (OM) extracted from the coral skeleton was analyzed by mass spectrometry and bioinformatics, enabling the identification of 36 SOMPs. These results provide novel insights into the molecular basis of coral calcification and the macroevolution of metazoan calcifying systems, whereas establishing a platform for studying the impact of OA at molecular level. Besides secreted proteins, extracellular regions of transmembrane proteins are also present, suggesting a close control of aragonite deposition by the calicoblastic epithelium. In addition to the expected SOMPs (Asp/Glu-rich, galaxins), the skeletal repertoire included several proteins containing known extracellular matrix domains. From an evolutionary perspective, the number of coral-specific proteins is low, many SOMPs having counterparts in the noncalcifying cnidarians. Extending the comparison with the skeletal OM proteomes of other metazoans allowed the identification of a pool of functional domains shared between phyla. These data suggest that co-option and domain shuffling may be general mechanisms by which the trait of calcification has evolved.
Autoantibodies specific for different isoforms of CD45 in systemic lupus erythematosus.
Authors: T Mimura, P Fernsten, W Jarjour, J B Winfield
Journal: The Journal of Experimental Medicine (1990)

Nearly one-third of IgM antilymphocyte autoantibody-positive sera from patients with systemic lupus erythematosus (SLE) contain IgM antibodies to one or more 180-220-kD molecules (p180, p190, p205, and p220) in blots of glycoproteins purified from T cells by wheat germ agglutinin affinity chromatography. Identity of these IgM targets with multiple isoforms of CD45 was established by their specific depletion from T cell glycoproteins by immunoprecipitation with T191, a monoclonal antibody (mAb) that reacts with an epitope common to all CD45 isoforms. Although the anti-CD45 autoantibodies recognize higher molecular weight isoforms primarily, antigenic specificity in this system is quite heterogeneous and includes multiple distinct CD45 isoforms on different types of T cells that are, at least in part, different from those reactive with mAbs 2H4 and UCHL-1. Because CD45 is a major membrane protein tyrosine phosphatase that plays a critical role in antigen-induced T cell activation, the present data may be relevant to some of the antilymphocyte antibody-mediated immunologic abnormalities that characterize SLE and related autoimmune diseases.
Comparison of epidermal growth factor receptor mutations between primary and corresponding metastatic tumors in tyrosine kinase inhibitor-naive non-small-cell lung cancer
Authors: C.-H. Gow, Y.-L. Chang, Y.-C. Hsu, M.-F. Tsai, C.-T. Wu, C.-J. Yu, C.-H. Yang, Y.-C. Lee, P.-C. Yang, J.-Y. Shih
Journal: Annals of Oncology (2008)
Choline deficiency: A cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation
Authors: Alan L. Buchman, Mark D. Dubin, Adib A. Moukarzel, Donald J. Jenden, Margareth Roch, Kathleen M. Rice, Jeff Gornbein, Marvin E. Ament
Journal: Hepatology (1995)

Patients receiving long-term total parenteral nutrition (TPN) develop hepatic steatosis as a complication. Our previous studies have shown this to be caused, at least in part, by choline deficiency. We studied four patients (1 man, 3 women) aged 50 +/- 13 years who had low plasma-free choline concentrations 4.8 +/- 1.7 (normal, 11.4 +/- 3.7 nmol/mL). The patients had received TPN for 9.7 +/- 4.7 years. They received parenteral nutrition solutions containing choline chloride (1 to 4 g/d) for 6 weeks. Abdominal computed tomography (CT) was performed at baseline, biweekly during the choline supplementation, and 4 weeks after discontinuation of choline. During choline administration, the plasma-free choline concentration increased into the normal range within 1 week in all four patients and remained at or above the normal range for all 6 weeks, but decreased back to baseline when choline supplementation was discontinued. Hepatic steatosis resolved completely, as estimated by CT. Liver density increased from -14.2 +/- 22.3 Hounsfield units (HU) to 8.4 +/- 10.3 HU at week 2 (P = .002); 9.6 +/- 10.7 HU at week 4 and 13.1 +/- 7.3 HU at week 6, as determined by the liver-spleen CT number difference obtained by the subtraction of the average spleen CT number (in HU) from the average liver CT number. This improvement continued up to 4 weeks after choline supplementation (13.8 +/- 2.8 HU). Hepatic steatosis was shown to have recurred in one patient after 10 weeks of return to choline-free parenteral nutrition. The hepatic steatosis associated with parenteral nutrition can be ameliorated, and possibly prevented, with choline supplementation. Therefore, choline may be an essential nutrient for patients who require long-term parenteral nutrition.
Response to Letter Regarding Article, “Cardiovascular Risk of High- Versus Moderate-Intensity Aerobic Exercise in Coronary Heart Disease Patients”
Authors: Øivind Rognmo, Trine Moholdt, Hilde Bakken, Torstein Hole, Per Mølstad, Nils Erling Myhr, Jostein Grimsmo, Ulrik Wisløff
Journal: Circulation (2013)

We thank Dr Halle for his comments on our study. 1Smaller studies in cardiac rehabilitation have concluded that high-intensity interval training gives superior clinical effects compared with moderateintensity training, 2 and the key questions that arise are whether highintensity interval training is transferable to larger trials and whether it is safe.Dr Halle claims that, until larger trials have been performed showing similar or even superior clinical effects and prognosis and fewer serious adverse events during high-intensity interval training, this exercise regimen should be limited to controlled settings.We agree with Dr Halle that more work is needed to clarify the optimal exercise training program in patients with coronary heart disease.The strength of our study lies in its novelty, but as we state in the article, it is underpowered to give any definite answers on safety.However, the results provide the first glimpse of the number of adverse events that could be expected by high-intensity interval training.It also highlights that more work remains relative to a better understanding of optimal exercise training in patients with coronary heart disease. 3We would emphasize that the high relative intensities (percent of peak heart rate) used in our studies of patients with coronary heart disease often are very low in absolute terms and correspond to intensities attainable by daily living, such as walking up stairs and rushing to the bus.Finally, we cite Keteyian, as he states in the editorial to the study "It is now a good time for clinical investigators, interested in the study of exercise, to increase the 'intensity' of our scientific efforts to explore whether high-intensity interval training constitutes best practice or not."
Prediction of Broad Spectrum Resistance of Tumors towards Anticancer Drugs
Authors: Thomas Efferth, V. Badireenath Konkimalla, Yi-Fen Wang, Axel Sauerbrey, Silke Meinhardt, Felix Zintl, Jürgen Mattern, Manfred Volm
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Drug resistance is a major obstacle in cancer chemotherapy. Although the statistical probability of therapeutic success is known for larger patient groups from clinical therapy trials, it is difficult to predict the individual response of tumors. The concept of individualized therapy aims to determine in vitro the drug response of tumors beforehand to choose effective treatment options for each individual patient. Experimental Design: We analyzed the cross-resistance profiles of different tumor types (cancers of lung, breast, and colon, and leukemia) towards drugs from different classes (anthracyclines, antibiotics, Vinca alkaloids, epipodophyllotoxins, antimetabolites, and alkylating agents) by nucleotide incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Hierarchical cluster analysis and COMPARE analyses were applied. Results: Tumors exert broad resistance profiles, e.g., tumors resistant to one drug tend to also be resistant to other drugs, whereas sensitive tumors reveal sensitivity towards many drugs. Interestingly, the broad spectrum resistance phenotype could reliably be predicted by doxorubicin alone. Expression of the ATP-binding cassette transporter P-glycoprotein (ABCB1, MDR1) and the proliferative activity of tumors were identified as underlying mechanisms of broad spectrum resistance. To find novel compounds with activity against drug-resistant tumors, a database with 2,420 natural products was screened for compounds acting independent of P-glycoprotein and the proliferative state of tumor cells. Conclusions: Tumors exert cross-resistance profiles much broader than the classical multidrug resistance phenotype. Broad spectrum resistance can be predicted by doxorubicin due to the multifactorial mode of action of this drug. Novel cytotoxic compounds from natural resources might be valuable tools for strategies to bypass broad spectrum resistance.
Selection and Slippage Creating Serine Homopolymers
Authors: Melanie A Huntley, G Brian Golding
Journal: Molecular Biology and Evolution (2006)

Highly repetitive sequence within proteins is an abundant feature yet is considered by some to be the protein equivalent of "junk DNA." Homopolymer sequences, the most highly repetitive of this group, are typically encoded by trinucleotide repeats at the DNA level. It is thought that many of these sequences are produced by a replicative slippage mechanism. Recent studies suggest that these highly mutable regions within proteins may allow for rapid morphological evolution emerging from the increased variability afforded by such coding structures. However, in a homopolymer, it is difficult to determine if the repeated amino acid is due to slippage at the DNA level or due to selection at the protein level. Here we develop and test a model to detect cases for which the homopolymer tract has clearly been selected for, with no evidence of slippage at the DNA level. The polyserine tract within the phosphatidylserine receptor protein is used as an excellent example of one such case.
B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice
Authors: Daniel P. Ankeny, Zhen Guan, Phillip G. Popovich
Journal: Journal of Clinical Investigation (2009)

Traumatic injury to the mammalian spinal cord activates B cells, which culminates in the synthesis of autoantibodies. The functional significance of this immune response is unclear. Here, we show that locomotor recovery was improved and lesion pathology was reduced after spinal cord injury (SCI) in mice lacking B cells. After SCI, antibody-secreting B cells and Igs were present in the cerebrospinal fluid and/or injured spinal cord of WT mice but not mice lacking B cells. In mice with normal B cell function, large deposits of antibody and complement component 1q (C1q) accumulated at sites of axon pathology and demyelination. Antibodies produced after SCI caused pathology, in part by activating intraspinal complement and cells bearing Fc receptors. These data indicate that B cells, through the production of antibodies, affect pathology in SCI. One or more components of this pathologic immune response could be considered as novel therapeutic targets for minimizing tissue injury and/or promoting repair after SCI.
Human Leukocyte Antigen and Antigen Processing Machinery Component Defects in Astrocytic Tumors
Authors: Angelica Facoetti, Rosanna Nano, Paola Zelini, Patrizia Morbini, Eugenio Benericetti, Mauro Ceroni, Michael Campoli, Soldano Ferrone
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To determine the frequency of abnormalities in human leukocyte antigen (HLA) and antigen processing machinery (APM) component expression in malignant brain tumors. This information may contribute to our understanding of the immune escape mechanisms used by malignant brain tumors because HLA antigens mediate interactions of tumor cells with the host's immune system. Experimental Design: Eighty-eight surgically removed malignant astrocytic tumors, classified according to the WHO criteria, were stained in immunoperoxidase reactions with monoclonal antibody recognizing monomorphic, locus-specific, and allospecific determinants of HLA class I antigens, β2-microglobulin, APM components (LMP2, LMP7, TAP1, TAP2, calnexin, calreticulin, and tapasin), and HLA class II antigens. Results: HLA class I antigens were lost in ∼50% of the 47 glioblastoma multiforme (GBM) lesions and in ∼20% of the 18 grade 2 astrocytoma lesions stained. Selective HLA-A2 antigen loss was observed in ∼80% of the 24 GBM lesions and in ∼50% of the 12 grade 2 astrocytoma lesions stained. HLA class I antigen loss was significantly (P &amp;lt; 0.025) correlated with tumor grade. Among the APM components investigated, tapasin expression was down-regulated in ∼20% of the GBM lesions analyzed; it was associated, although not significantly, with HLA class I antigen down-regulation and tumor grade. HLA class II antigen expression was detected in ∼30% of the 44 lesions analyzed. Conclusion: The presence of HLA antigen defects in malignant brain tumors may provide an explanation for the relatively poor clinical response rates observed in the majority of the T cell–based immunotherapy clinical trials conducted to date in patients with malignant brain tumors.
Satisfaction With Work-Life Balance and the Career and Retirement Plans of US Oncologists
Authors: Tait D. Shanafelt, Marilyn Raymond, Michael Kosty, Daniel Satele, Leora Horn, John Pippen, Quyen Chu, Helen Chew, William Benton Clark, Amy E. Hanley, Jeff Sloan, William J. Gradishar
Journal: Journal of Clinical Oncology (2014)

To evaluate satisfaction with work-life balance (WLB) and career plans of US oncologists.
Glycogen synthase activity is reduced in cultured skeletal muscle cells of non-insulin-dependent diabetes mellitus subjects. Biochemical and molecular mechanisms.
Authors: R R Henry, T P Ciaraldi, L Abrams-Carter, S Mudaliar, K S Park, S E Nikoulina
Journal: Journal of Clinical Investigation (1996)

To determine whether glycogen synthase (GS) activity remains impaired in skeletal muscle of non-insulin-dependent diabetes mellitus (NIDDM) patients or can be normalized after prolonged culture, needle biopsies of vastus lateralis were obtained from 8 healthy nondiabetic control (ND) and 11 NIDDM subjects. After 4-6 wk growth and 4 d fusion in media containing normal physiologic concentrations of insulin (22 pM) and glucose (5.5 mM), both basal (5.21 +/- 0.79 vs 9.01 +/- 1.25%, P < 0.05) and acute insulin-stimulated (9.35 +/- 1.81 vs 16.31 +/- 2.39, P < 0.05) GS fractional velocity were reduced in NIDDM compared to ND cells. Determination of GS kinetic constants from muscle cells of NIDDM revealed an increased basal and insulin-stimulated Km(0.1) for UDP-glucose, a decreased insulin-stimulated Vmax(0.1) and an increased insulin-stimulated activation constant (A(0.5)) for glucose-6-phosphate. GS protein expression, determined by Western blotting, was decreased in NIDDM compared to ND cells (1.57 +/- 0.29 vs 3.30 +/- 0.41 arbitrary U/mg protein, P < 0.05). GS mRNA abundance also tended to be lower, but not significantly so (0.168 +/- 0.017 vs 0.243 +/- 0.035 arbitrary U, P = 0.08), in myotubes of NIDDM subjects. These results indicate that skeletal muscle cells of NIDDM subjects grown and fused in normal culture conditions retain defects of basal and insulin-stimulated GS activity that involve altered kinetic behavior and possibly reduced GS protein expression. We conclude that impaired regulation of skeletal muscle GS in NIDDM patients is not completely reversible in normal culture conditions and involves mechanisms that may be genetic in origin.
Phase 1b Study of Dulanermin (recombinant human Apo2L/TRAIL) in Combination With Paclitaxel, Carboplatin, and Bevacizumab in Patients With Advanced Non-Squamous Non–Small-Cell Lung Cancer
Authors: Jean-Charles Soria, Egbert Smit, David Khayat, Benjamin Besse, Xinqun Yang, Cheng-Pang Hsu, David Reese, Jeffrey Wiezorek, Fiona Blackhall
Journal: Journal of Clinical Oncology (2010)

To determine the safety, pharmacokinetics (PK), and maximum-tolerated dose (MTD) up to a prespecified target dose of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab (PCB) in patients with previously untreated, nonsquamous, stage IIIb (with pleural effusion)/IV or recurrent non-small-cell lung cancer (NSCLC).In this phase 1b study, patients (n = 24) received PCB on day 1 of each 21-day cycle then dulanermin at 4 or 8 mg/kg/d for 5 consecutive days or 15 or 20 mg/kg/d for 2 consecutive days per assigned treatment cohort. Incidence of dose-limiting toxicities (DLTs), adverse events, and antidulanermin antibodies were assessed. PK parameters were recorded for each agent. Tumor response was measured by modified Response Evaluation Criteria in Solid Tumors.Twenty-four patients received at least one dose of dulanermin plus PCB, six in each treatment cohort. There were no DLTs. An MTD was not reached, and the drug combination was well tolerated. Treatment-emergent adverse events were generally as expected for the PCB regimen. Adverse events attributed to dulanermin were grade 1/2; no significant hepatotoxicity occurred. There was minimal impact of PCB on the PK of dulanermin. There was one confirmed complete response and 13 confirmed partial responses. The overall response rate was 58% (95% CI, 37 to 78). Median progression-free survival was 7.2 months (95% CI, 4.7 to 10.3).Dulanermin plus PCB was well tolerated with no occurrence of DLTs and demonstrated antitumor activity in this patient population. Dulanermin at 8 mg/kg/d for 5 days and 20 mg/kg/d for 2 days every 3 weeks in combination with PCB is being studied in a phase II trial.