tbuckley/cabot-search huggingface dataset:
Dose Finding Study for the Use of Subcutaneous Recombinant Interleukin-2 to Augment Natural Killer Cell Numbers in an Outpatient Setting for Stage 4 Neuroblastoma After Megatherapy and Autologous Stem-Cell Reinfusion
Authors: Ruth Ladenstein, Ulrike Pötschger, Dimitris Siabalis, Alberto Garaventa, Christophe Bergeron, Ian J. Lewis, Jerry Stein, Janice Kohler, Peter J. Shaw, Wolfgang Holter, Vito Pistoia, Jean Michon
Journal: Journal of Clinical Oncology (2010)

To establish a safe dose of subcutaneous (SC) recombinant interleukin 2 (rIL-2) in an outpatient setting for children with stage 4 neuroblastoma after megatherapy (MGT) and autologous stem-cell reinfusion (ASCR) that is able to sustain an increase of natural-killer cells (NKCs) above the level previously reported for immunomodulatory potency.Between August 1997 and November 2000, 33 patients with stage 4 neuroblastoma entered the study from six countries after receiving MGT/ASCR according to national protocols. Dose levels of 3, 6, and 9 × 10(6) U rIL-2/m(2) were given SC in six 5-day cycles every 2 weeks.Median age at registration was 4.1 years (range, 1.8 to 7.4). Median observation time was 5 years (range, 4 to 9.8). Increase of NKCs was achieved in 89% of courses, with more than 100% increase over baseline and/or more than 1,000 NKCs/μL in 58%. On the basis of outpatient dose-limiting toxicity at dose level 3, dose level 2 was chosen for the confirmation stage. At dose level 2, the median increase in absolute NKCs was 1,180 cells/μL for all 83 cycles, corresponding to a median relative NKC increase over baseline of 711%. Fever was frequent but controllable with adequate supportive care; 6.5% of patients were hospitalized. Localized pain was moderate and acceptable. Event-free and overall survival rates at 5 years were 45% (± 9 standard deviation [SD]) and 48% (± 9 SD), respectively.The low toxicity profile and ability to sustain an increase in NKCs of IL-2 at 6 × 10(6) U/m(2) SC allows its integration in an outpatient setting.
An inherited mutation in <i>NLRC4</i> causes autoinflammation in human and mice
Authors: Akiko Kitamura, Yuki Sasaki, Takaya Abe, Hirotsugu Kano, Koji Yasutomo
Journal: The Journal of Experimental Medicine (2014)

Autoinflammatory syndromes cause sterile inflammation in the absence of any signs of autoimmune responses. Familial cold autoinflammatory syndrome (FCAS) is characterized by intermittent episodes of rash, arthralgia, and fever after exposure to cold stimuli. We have identified a missense mutation in the NLRC4 gene in patients with FCAS. NLRC4 has been known as a crucial sensor for several Gram-negative intracellular bacteria. The mutation in NLRC4 in FCAS patients promoted the formation of NLRC4-containing inflammasomes that cleave procaspase-1 and increase production of IL-1β. Transgenic mice that expressed mutant Nlrc4 under the invariant chain promoter developed dermatitis and arthritis. Inflammation within tissues depended on IL-1β–mediated production of IL-17A from neutrophils but not from T cells. Our findings reveal a previously unrecognized link between NLRC4 and a hereditary autoinflammatory disease and highlight the importance of NLRC4 not only in the innate immune response to bacterial infections but also in the genesis of inflammatory diseases.
Fluorouracil plus Levamisole as Effective Adjuvant Therapy after Resection of Stage III Colon Carcinoma: A Final Report
Authors: Charles G. Moertel
Journal: Annals of Internal Medicine (1995)

To determine the effectiveness of two adjuvant therapy regimens in improving surgical cure rates in stage III (Dukes stage C) colon cancer.Randomized, concurrently controlled clinical trial.Major cancer centers, universities, and community clinics affiliated with the North Cancer Treatment Group, the Southwest Oncology Group, and the Eastern Cooperative Oncology Group.Those who had had curative-intent resections of stage III colon cancer in the previous 1 to 5 weeks.Patients were assigned to observation only, to levamisole alone (50 mg orally three times/d for 3 days, repeated every 2 weeks for 1 year), or to this regimen of levamisole plus fluorouracil (450 mg/m2 body surface area intravenously daily for 5 days and then, beginning at 28 days, weekly for 48 weeks).Rates of cancer recurrence and death. Early- and late-treatment side effects.With all 929 eligible patients able to be followed for 5 years or more (median follow-up, 6.5 years), fluorouracil plus levamisole reduced the recurrence rate by 40% (P < 0.0001) and the death rate by 33% (P = 0.0007). Levamisole reduced the recurrence rate by only 2% and the death rate by only 6%. With few exceptions, toxicity was mild and patient compliance was excellent. No evidence of late side effects was seen.Fluorouracil plus levamisole is tolerable adjuvant therapy to surgery; it has been confirmed to substantially increase cure rates for patients with high-risk (stage III) colon cancer. It should be considered standard treatment for all such patients not entered into clinical trials.
Prescription Opioids, Overdose Deaths, and Physician Responsibility
Authors: A. Thomas McLellan
Journal: JAMA (2008)

re-vealedthatopioidanalgesicscontributedto93%ofthose deaths and most of these potentially avoid-abledeathsoccurredinyoungerpersons(aged18-44years).Thesedisturbingfindingsarecertaintoraisequestionsaboutphysicianprescribingpractices,thesafetyandadverseeffectprofiles of opioid medications, and the appropriate man-agement of pain. These findings also raise several impor-tantquestionsforphysicianswhoaretryingtobalancetheirduty to relieve pain in individual patients and their obliga-tion to prevent the broader public health problems of ad-diction and overdose death.First, do these overdose deaths suggest excessive opioidprescribing practices? The 2006 death rate from uninten-tionaloverdosebyprescriptiondrugsinWestVirginiawas16.2/100000population,morethan2timeshigherthantheUS average of 5.6/100000 population during the same pe-riod.
ROLE OF THE THYMUS IN IMMUNE REACTIONS IN RATS
Authors: Barry G. Arnason, Branislav D. Janković, Byron H. Waksman, Christine Wennersten
Journal: The Journal of Experimental Medicine (1962)

In rats thymectomized at birth and tested in adult life, ability to develop autoallergic encephalomyelitis was completely suppressed, there was a marked diminution in the degree of tuberculin sensitization appearing after a single injection of mycobacteria in oil, rejection of skin homografts was markedly delayed, and adjuvant arthritis was not appreciably affected. At the same time there was a striking decrease in the circulating level of small lymphocytes.
Analysis of killer immunoglobulin-like receptor genes in ankylosing spondylitis
Authors: D Harvey, J J Pointon, C Sleator, A Meenagh, C Farrar, J Y Sun, D Senitzer, D Middleton, M A Brown, B P Wordsworth
Journal: Annals of the Rheumatic Diseases (2008)

To assess the possible association of killer immunoglobulin-like receptor (KIR) genes, specifically KIR3DL1, KIR3DS1 and KIR3DL2, with ankylosing spondylitis (AS).14 KIR genes were genotyped in 200 UK patients with AS and 405 healthy controls using multiplex polymerase chain reaction. Sequence-specific oligonucleotide probes were used to subtype 368 cases with AS and 366 controls for 12 KIR3DL2 alleles. Differences in KIR genotypes and KIR3DL2 allele frequencies were assessed using the chi(2) test.KIR3DL1 and KIR3DS1 gene frequencies were very similar in cases with AS and controls (odds ratio = 1.5, 95% confidence interval 0.8 to 3.0, and odds ratio = 1.02, 95% confidence interval 0.2 to 5.3, respectively). KIR3DL2 allele frequencies were not significantly different between cases with AS and controls.Neither the KIR gene content of particular KIR haplotypes nor KIR3DL2 polymorphisms contribute to AS.
Platelet-derived growth factor receptor-β promotes early endothelial cell differentiation
Authors: Charlotte Rolny, Ingrid Nilsson, Peetra Magnusson, Annika Armulik, Lars Jakobsson, Parri Wentzel, Per Lindblom, Jenny Norlin, Christer Betsholtz, Rainer Heuchel, Michael Welsh, Lena Claesson-Welsh
Journal: Blood (2006)
Timing and benefit of liver transplantation in acute liver failure
Authors: John O'Grady
Journal: Journal of Hepatology (2013)

The case for using emergency liver transplantation in acute liver failure was made two decades ago by a series of single centre experiences. The development of models identifying a poor prognosis assisted the selection of patients for liver transplantation but none of these delivers both high sensitivity and specificity for prediction of death. Enhanced sensitivity favours the individual patient while enhanced specificity targets the pool of organs available at those who will derive greatest benefit. The non-transplant survival rates have improved considerably for certain cohorts of patients and these prognostic models have not been adjusted to reflect these changes. The presumption of transplant benefit can no longer be taken as established in paracetamol-related acute liver failure and a policy review is appropriate. In other scenarios, such as seronegative hepatitis and the phenotype of sub-acute liver failure, spontaneous survival rates remain low and the basis for liver transplantation remains sound. Outcomes after liver transplantation are improving but are not yet comparable to elective transplantation. The understanding of factors associated with failure after liver transplantation is improving but accurate definition of futility has not yet been attained.
The Effects of Chemotherapy on Cognitive Function in a Mouse Model: A Prospective Study
Authors: Gordon Winocur, Mark Henkelman, J. Martin Wojtowicz, Haibo Zhang, Malcolm A. Binns, Ian F. Tannock
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Clinical studies indicate that up to 70% of patients with cancer who receive chemotherapy experience cognitive impairment. The present study used a prospective longitudinal design to assess short- and long-term effects of commonly used anticancer drugs on cognitive performance in a mouse model. Experimental Design: Normal mice received three weekly injections of a combination of methotrexate + 5-fluorouracil (CHEMO group) or an equal volume of saline (SAL group). Cognitive tests, measuring different aspects of learning and memory, were administered before treatment, immediately after treatment, and three months later. Structural MRI scanning was conducted at each stage of cognitive testing. Results: The CHEMO group exhibited deficits on cognitive tasks acquired pretreatment [spatial memory, nonmatching-to-sample (NMTS) learning, and delayed NMTS], as well as impaired new learning on two tasks (conditional associative learning, discrimination learning) introduced posttreatment. Consistent with clinical evidence, cognitive deficits were pronounced on tests that are sensitive to hippocampal and frontal lobe dysfunction, but the CHEMO group's poor performance on the discrimination learning problem suggests that impairment is more widespread than previously thought. Cognitive deficits persisted for at least three months after treatment but some recovery was noted, particularly on tests thought to be under frontal lobe control. The MRI tests did not detect brain changes that could be attributed to treatment. Conclusions: Chemotherapeutic agents can have adverse effects on information acquired pretreatment as well as new learning and memory and, despite some recovery, impairment is long lasting. Clin Cancer Res; 18(11); 3112–21. ©2012 AACR.
Corrigendum to: “Report from a Viral Hepatitis Policy Forum on implementing the WHO framework for global action on viral hepatitis in North Asia” [J Hepatol 2013;59:1073–1080]
Authors: Ding-Shinn Chen, Stephen Locarnini, Suzanne Wait, Si-Hyun Bae, Pei-Jer Chen, James Y.Y. Fung, Hong Soo Kim, Sheng-Nan Lu, Joseph Sung, Junko Tanaka, Takaji Wakita, John Ward, Jack Wallace
Journal: Journal of Hepatology (2014)
Beneficial Effects of Insulin on Glycemic Control and β-Cell Function in Newly Diagnosed Type 2 Diabetes With Severe Hyperglycemia After Short-Term Intensive Insulin Therapy
Authors: Harn-Shen Chen, Tzu-En Wu, Tjin-Shing Jap, Li-Chuan Hsiao, Shen-Hung Lee, Hong-Da Lin
Journal: Diabetes Care (2008)

To evaluate whether treatment with insulin is advantageous compared with oral antidiabetes agents in newly diagnosed type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy.Newly diagnosed type 2 diabetic patients with severe hyperglycemia were hospitalized and treated with intensive insulin injections for 10-14 days. The oral glucose tolerance test (OGTT) was performed after intensive insulin treatment. After discharge, the patients were randomized to receive either insulin injections or oral antidiabetes drugs (OADs) for further management. The OGTT was repeated 6 months later, and beta-cell function and insulin sensitivity were evaluated again. These subjects were continually followed up for another 6 months to evaluate their long-term glycemic control.At the 6th month of the study, the A1C level was significantly lower in the insulin group than in the OAD group (6.33 +/- 0.70% vs. 7.50 +/- 1.50%; P = 0.002). During the follow-up visit, the A1C level was still better in the insulin group (6.78 +/- 1.21% vs. 7.84 +/- 1.74%; P = 0.009). All parameters regarding beta-cell function measured in the OGTT were improved significantly in both groups after 6 months of treatment. Compared with the OAD group, the homeostasis model assessment of beta-cell function index, insulin area under the curve, and insulinogenic index were better in the insulin group.A 6-month course of insulin therapy, compared with OAD treatment, could more effectively achieve adequate glycemic control and significant improvement of beta-cell function in new-onset type 2 diabetic patients with severe hyperglycemia.
Aerosol recovery from large-volume reservoir delivery systems is highly dependent on the static properties of the reservoir
Authors: MJ van der Veen, JS van der Zee
Journal: European Respiratory Journal (1999)

In this study, the role of electrostatic fields on aerosol recovery from a system with a large collapsible reservoir (30 L) was investigated. In addition, the efficacy of the reservoir method for bronchial challenge procedures was assessed in vivo. Aerosol recovery was determined by measuring the fraction of aerosol (0.05% 99mTc-tagged human albumin solution) retrieved from the reservoir. Before aerosol recovery experiments, electrostatic fields in the reservoir were measured. Aerosol recovery varied significantly with wall thickness of the reservoir and presence of an antistatic coating (range 6.0-70.3%). A close inverse relationship was found between the mean electrostatic field in the reservoir and aerosol recovery. The nebulized provocative concentration of histamine causing a 20% fall in forced expiratory volume in one second in asthmatics was found to be approximately half that of a standard method when compared with the reservoir system (mean ratio 2.24 (95% confidence interval, 1.60-3.12)). Recovery from an aerosol delivery system with a relatively large collapsible aerosol reservoir was highly dependent on the electrostatic field in the reservoir. In these systems the use of electrostatic field dissipative material for the reservoir is therefore recommended.
Heparin‐induced thrombocytopenia and thrombosis: Reversal with streptokinase a case report and review of literature
Authors: Daksha P. Mehta, Ernest L. Yoder, Joel Appel, Kenneth L. Bergsman
Journal: American Journal of Hematology (1991)

Abstract Heparin‐induced thrombocytopenia and thrombosis is associated with a significant incidence of morbidity and mortality. Prompt recognition of this complication and immediate withdrawal of heparin therapy are imperative. This report describes a case of heparin‐induced thrombosis and thrombocytopenia with major vascular insufficiency of the extremities. This is the first reported instance of the use of intravenous streptokinase for the treatment of heparin‐induced venous thrombosis.
Idiopathic Pulmonary Fibrosis
Authors: Kevin R. Flaherty, Adin-Cristian Andrei, Susan Murray, Chris Fraley, Thomas V. Colby, William D. Travis, Vibha Lama, Ella A. Kazerooni, Barry H. Gross, Galen B. Toews, Fernando J. Martinez
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Idiopathic pulmonary fibrosis is a fatal disease with a variable rate of progression. We hypothesized that changes in distance walked and quantity of desaturation during a six-minute-walk test (6MWT) would add prognostic information to changes in FVC or diffusing capacity for carbon monoxide.One hundred ninety-seven patients with idiopathic pulmonary fibrosis were evaluated. Desaturation during the 6MWT was associated with increased mortality even if a threshold of 88% was not reached. Baseline walk distance predicted subsequent walk distance but was not a reliable predictor of subsequent mortality in multivariate survival models. The predictive ability of serial changes in physiology varied when patients were stratified by the presence/absence of desaturation < or = 88% during a baseline 6MWT. For patients with a baseline saturation < or = 88% during a 6MWT, the strongest observed predictor of mortality was serial change in diffusing capacity for carbon monoxide. For patients with saturation > 88% during their baseline walk test, serial decreases in FVC and increases in desaturation area significantly predicted subsequent mortality, whereas decreases in walk distance and in diffusing capacity for carbon monoxide displayed less consistent statistical evidence of increasing mortality in our patients.These data highlight the importance of stratifying patients by degree of desaturation during a 6MWT before attributing prognostic value to serial changes in other physiologic variables.
Choking Hypoxia-Inducible Factor 1α: A Novel Mechanism for Connective Tissue Growth Factor Inhibition of Angiogenesis
Authors: Francesca Tosetti, Douglas M. Noonan, Adriana Albini
Journal: JNCI Journal of the National Cancer Institute (2006)

Journal of the National Cancer Institute, Vol. 98, No. 14, July 19, 2006 Among the driving forces that orchestrate oncogenic transformation, aberrant tumor angiogenesis has evolved as a process assured by the conscription of various signaling pathways with redundant functions. These pathways converge on the same task: to produce more vessels, without ensuring correct structural constraints and proper function. Different cellular components in tissues are equipped with proangiogenic molecular machinery, as demonstrated by studies on the role of infl ammatory cells in tumor promotion that have driven the development of new therapies for cancer prevention and treatment ( 1 , 2 ) . Transcriptional reprogramming controlled by dysregulated signaling pathways is one of the mechanisms that are the basis for the cellular adaptations necessary for cancer establishment. In particular, one master regulator, the hypoxia-inducible transcription factor 1 (HIF-1) complex, which controls tissue homeostasis, seems to take center stage as a pervasive instigator of transformation for almost all cellular compartments in tissues. HIF-1, primarily recognized as a mediator of adaptive responses to tissue oxygenation, integrates diverse information related to energy status, glucose, and iron metabolism, as well as growth factor signaling in normoxia and hypoxia ( 3 , 4 ) . Furthermore, recent evidence indicates that HIF-1 – activated metabolic responses are essential for the recruitment and infi ltration of myeloid cells at early stages of infl ammation ( 5 ) . The decision to constitutively activate HIF-1 α as a means for coping with stressful or threatening local conditions in the microenvironment carries the high cost of increased risk of neoplastic transformation. HIF-1 also contributes to defi ne an invasive, lethal cancer phenotype by elevating the metabolic resources of cells through increased glucose uptake, glycolysis, and angiogenesis ( 6 ) . The HIF-1 α subunit of the heterodimeric transcriptional complex HIF-1 is the labile regulatory element destined to ubiquitination and default destruction in the absence of alerting signals from the microenvironment. Proteins of the von Hippel-Lindau (pVHL) – ubiquitin – proteasome pathway, isoforms of prolyl hydroxylases (PHDs), and the acetyltransferase ARD1 eliminate necessary HIF-1 α under normoxia in normal cells. Hydroxylation of HIF-1 α at proline residues 402 and 564 in the oxygendependent degradation (ODD) domain by PHDs targets HIF-1 α Affi liations of authors: Molecular Oncology Laboratory, National Cancer Research Institute, Genoa, Italy (FT, AA); University of Insubria, Varese, Italy (DMN). Correspondence to: Adriana Albini, PhD, Ist. Nazionale per la Ricerca sul Cancro, Molecular Oncology, Largo Rosanna Benzi, 10, Genova 16132, Italy (e-mail: adriana.albini@istge.it ).
T cells get energized
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

Many cell types use AMPK (AMP-activated protein kinase) to signal that energy reserves are low so more energy generation is needed. But, say Tamas et al. on page 1665, T cells also use AMPK to signal that energy will be needed in the near future, for attacking target cells, proliferating or churning out cytokines.






Figure 1

AMPK gets phosphorylated (and thus activated) after TCR ligation (α-CD3) in primary T cells.




When cellular energy is in short supply—due, for example, to nutrient deficiency or metabolic stress—rising levels of AMP and falling levels of ATP trigger the activation of AMPK. AMPK then activates ATP-generating pathways, such as fatty acid oxidation. Tamas and colleagues now show that this pathway is also activated in T cells when their energy reserves dwindle. This is the first demonstration of physiological AMPK regulation in T cells.

But T cells turned on AMPK not only in response to falling energy levels but also in anticipation of upcoming energy needs. “If a T cell fluxes calcium,” says senior author Doreen Cantrell, “it is indicating that it is about to activate and will need ATP.” And this Ca2+ flux, they found, triggered the activation of AMPK.

Ca2+-induced AMPK activation required upstream Ca2+/calmodulin-dependent protein kinase kinases, which were not needed for AMPK activation in response to rising AMP/ATP ratios. PI3 kinase (PI3K)—an enzyme required for cytokine- and costimulation-induced energy generation in T cells—was also dispensable for AMPK activation. Determining the importance of the AMPK pathway, relative to these other energy-boosting pathways, awaits the development of conditional AMPK-deficient mice.
Limited T Cell Receptor Diversity of HCV-specific T Cell Responses Is Associated with CTL Escape
Authors: Dirk Meyer-Olson, Naglaa H. Shoukry, Kristen W. Brady, Helen Kim, Douglas P. Olson, Kelly Hartman, Ayumi K. Shintani, Christopher M. Walker, Spyros A. Kalams
Journal: The Journal of Experimental Medicine (2004)

Escape mutations are believed to be important contributors to immune evasion by rapidly evolving viruses such as hepatitis C virus (HCV). We show that the majority of HCV-specific cytotoxic T lymphocyte (CTL) responses directed against viral epitopes that escaped immune recognition in HCV-infected chimpanzees displayed a reduced CDR3 amino acid diversity when compared with responses in which no CTL epitope variation was detected during chronic infection or with those associated with protective immunity. Decreased T cell receptor (TCR) CDR3 amino acid diversity in chronic infection could be detected long before the appearance of viral escape mutations in the plasma. In both chronic and resolved infection, identical T cell receptor clonotypes were present in liver and peripheral blood. These findings provide a deeper understanding of the evolution of CTL epitope variations in chronic viral infections and highlight the importance of the generation and maintenance of a diverse TCR repertoire directed against individual epitopes.