tbuckley/cabot-search huggingface dataset:
INFLUENCE OF DOSE AND ROUTE OF ANTIGEN INJECTION ON THE IMMUNOLOGICAL INDUCTION OF T CELLS
Authors: P. H. Lagrange, G. B. Mackaness, T. E. Miller
Journal: The Journal of Experimental Medicine (1974)

Delayed-type hypersensitivity (DTH) develops in the absence of an adjuvant when mice are injected intravenously or subcutaneously with an appropriate dose of sheep red blood cells (SRBC). The optimal intravenous dose of 105 SRBC (in CD-1 mice) produces maximum DTH which decays exponentially from its peak on day 4. Increasing the dose of SRBC reduces and eventually abolishes all evidence of DTH. DTH fails to reappear in respose to secondary stimulation except in splenectomized mice in whom the development of DTH is not suppressed, even by massive doses of SRBC. Hence the suppression cannot be due to antigen as such. The optimal dose of SRBC for sensitization by footpad inoculation is 100-fold higher (107 SRBC in CD-1 mice), but even 109 SRBC do not block the induction of DTH by this route of immunization. A blocking dose of SRBC, given intravenously 1 day before footpad inoculation, completely suppresses cell proliferation in the draining lymph node, prevents PFC production there, and blocks the induction of DTH by a sensitizing dose of SRBC. If given 1 day after footpad sensitization, intravenous antigen has little effect on the cellular response in the regional node but DTH is still completely suppressed. Blocking of induction and expression may depend, therefore, on different mechanisms.
Matrix Metalloproteinase-14 Deficiency in Bone Marrow–Derived Cells Promotes Collagen Accumulation in Mouse Atherosclerotic Plaques
Authors: Fabrice Schneider, Galina K. Sukhova, Masanori Aikawa, James Canner, Norbert Gerdes, Sai-Man Timothy Tang, Guo-Ping Shi, Suneel S. Apte, Peter Libby
Journal: Circulation (2008)

Interstitial collagen plays a crucial structural role in arteries. Although in vitro results suggest collagenase activity for membrane-bound matrix metalloproteinase type 1 (MMP-14), in vivo evidence for such a function in atherosclerosis remains scant.Because Mmp14-/- mice die by 3 weeks of age, this study used lethally irradiated low-density lipoprotein receptor-deficient mice reconstituted with syngeneic bone marrow cells of Mmp14-/- or Mmp14+/+ mice. In both groups, histological analyses of the aortic root revealed similar plaque size and macrophage and smooth muscle cell content after 8 or 16 weeks of atherogenic diet. By 16 weeks, however, the plaques of low-density lipoprotein receptor-deficient mice engrafted with Mmp14-/- bone marrow (n=12) contained significantly more interstitial collagen than those receiving Mmp14+/+ bone marrow (n=14; P<0.05). In vitro, bone marrow-derived macrophages from Mmp14-/- mice had significantly less interstitial collagenase activity than those from Mmp14+/+ mice both basally (P<0.01) and on tumor necrosis factor-alpha stimulation (P<0.05). Western blot analysis and gelatin zymography of aortic extracts revealed that MMP-14 deficiency yielded decreased activation of pro-MMP-13 but not of pro-MMP-2 or pro-MMP-8.MMP-14 from bone marrow-derived cells can influence the collagen content of mouse atheroma, a critical component of plaque stability.
Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome
Authors: J R Brown, H T Kim, P Armand, C Cutler, D C Fisher, V Ho, J Koreth, J Ritz, C Wu, J H Antin, R J Soiffer, J G Gribben, E P Alyea
Journal: Leukemia (2012)
MEK-Dependent Negative Feedback Underlies BCR–ABL-Mediated Oncogene Addiction
Authors: Jennifer Asmussen, Elisabeth A. Lasater, Cheryl Tajon, Juan Oses-Prieto, Young-wook Jun, Barry S. Taylor, Alma Burlingame, Charles S. Craik, Neil P. Shah
Journal: Cancer Discovery (2013)

The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKI) for the treatment of chronic myelogenous leukemia (CML) provides compelling evidence for oncogene addiction. Yet, the molecular basis of oncogene addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAF(V600E) in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated oncogene addiction is facilitated by persistent high levels of MAP-ERK kinase (MEK)-dependent negative feedback.We found that BCR–ABL can confer addiction in vitro by rewiring myeloid GF-R signaling through establishment of MEK-dependent negative feedback. Our findings predict that deeper, more durable responses to targeted agents across a range of malignancies may be facilitated by maintaining negative feedback concurrently with oncoprotein inhibition.
129-derived Strains of Mice Are Deficient in DNA Polymerase ι and Have Normal Immunoglobulin Hypermutation
Authors: John P. McDonald, Ekaterina G. Frank, Brian S. Plosky, Igor B. Rogozin, Chikahide Masutani, Fumio Hanaoka, Roger Woodgate, Patricia J. Gearhart
Journal: The Journal of Experimental Medicine (2003)

Recent studies suggest that DNA polymerase η (polη) and DNA polymerase ι (polι) are involved in somatic hypermutation of immunoglobulin variable genes. To test the role of polι in generating mutations in an animal model, we first characterized the biochemical properties of murine polι. Like its human counterpart, murine polι is extremely error-prone when catalyzing synthesis on a variety of DNA templates in vitro. Interestingly, when filling in a 1 base-pair gap, DNA synthesis and subsequent strand displacement was greatest in the presence of both pols ι and η. Genomic sequence analysis of Poli led to the serendipitous discovery that 129-derived strains of mice have a nonsense codon mutation in exon 2 that abrogates production of polι. Analysis of hypermutation in variable genes from 129/SvJ (Poli−/−) and C57BL/6J (Poli+/+) mice revealed that the overall frequency and spectrum of mutation were normal in polι-deficient mice. Thus, either polι does not participate in hypermutation, or its role is nonessential and can be readily assumed by another low-fidelity polymerase.
Thyroid Cancer in Olmsted County 1935–1965&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: John E. Verby, M.D., Lewis B. Woolner, M.D., Fred T. Nobrega, M.D., Leonard T. Kurland, M.D., William M. McConahey, M.D.
Journal: JNCI Journal of the National Cancer Institute (1969)

To evaluate the trend of thyroid cancer from 1935–65, inclusive, reports of all diagnosed cases occurring in bona fide residents of Olmsted County, Minnesota, were identified and reviewed. There were 46 acceptable cases of thyroid cancer (group 1). The average annual incidence rates (age-adjusted to the 1950 U.S. white population) increased from 1.7 to 3.1 to 3.6/100,000 population in 1935–44, 1945–54, and 1955–65. The increase, most marked between the first and second decades, is not statistically significant. There has probably been an upward trend, but it is believed to reflect an increasing awareness of the problem and improved diagnostic capabilities for thyroid cancer in the community. The age range was 11–91 years and the median age was 50 years. The female-to-male ratio was 3:1. In addition, 21 patients (18 females and 3 males) had “occult,” grade 1, papillary carcinoma of less than 1.5 cm in diameter without evidence of regional metastasis (group 2). These lesions are considered innocuous and relatively benign in the absence of clinical evidence of metastasis to cervical nodes. In 16 of the 21 cases, the diagnosis was made between 1955 and 1965. If these occult lesions were included, the age-adjusted incidence rates/100,000 population increased significantly from 2.2 to 3.7 to 6.1, respectively, in the 3 periods. The increased recognition of these occult lesions, particularly since 1955, is believed to account for this upward trend. If the increased exposure to diagnostic irradiation, radioactive fallout, and other environmental radiation has significantly affected the incidence of the thyroid cancer in adults, our survey procedure is not sufficiently sensitive to detect the effect. If the Olmsted County data were extrapolated to the population of the United States, based on the group-1 cases during 1955–65, we would expect about 7,000 persons in the country to develop clinically identifiable thyroid cancer each year.
A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome
Authors: Maximilian Muenke, Ute Schell, Andreas Hehr, Nathaniel H. Robin, H. Wolfgang Losken, Albert Schinzel, Louise J. Pulleyn, Paul Rutland, William Reardon, Sue Malcolm, Robin M. Winter
Journal: Nature Genetics (1994)
Room temperature influences output from the Wright jet nebulizer
Authors: J Kongerud, V Soyseth, B Johansen
Journal: European Respiratory Journal (1989)

Standardization of the solute output from the Wright nebulizer is necessary in nonspecific bronchial challenge to obtain reproducible results. Airflow and driving pressure are known determinants of the output. In an epidemiological study, in which day-to-day variations in room temperature occurred, we found the reproducibility of the output from a Wright nebulizer to be outside the range of acceptance. We have, therefore, examined to what extent ambient temperature and humidity might influence the output from three Wright nebulizers. The solute output was linearly correlated not only to flow (r = 0.98) and driving pressure (r = 0.90) but also to room temperature (r = 0.96). The mean output increased approximately 23% when room temperature was increased from 19 to 24 degrees C. This is equivalent to an increase in airflow of more than one litre. Ambient humidity did not influence the nebulizer output. When temperature was included in the calibration procedure, the coefficient of variation of the output decreased from 5 to 2%. This emphasizes the need for calibration of the Wright nebulizer with regard to ambient temperature as well as to airflow and pressure, especially in epidemiological field studies in which large variations of temperature are likely to occur.
Peripheral Vascular Adaptation and Orthostatic Tolerance in Fontan Physiology
Authors: Usha S. Krishnan, Indu Taneja, Michael Gewitz, Richard Young, Julian Stewart
Journal: Circulation (2009)

Background— The Fontan circulation is critically dependent on elevated venous pressures to sustain effective venous return. We hypothesized that chronically increased systemic venous pressures lead to adaptive changes in regional and peripheral vessels to maintain cardiac output, especially when patients are upright. Methods and Results— Nine post–Fontan procedure patients (aged 13 to 24 years) and 6 age- and sex-matched controls were compared with techniques to measure circulatory responses (peripheral and compartmental blood flow, venous capacity, and microvascular filtration). Parameters studied included strain-gauge plethysmography measures of peripheral circulatory function, regional blood volume distribution by impedance plethysmography, and head-up tilt testing. Important differences between Fontan patients and controls were seen in several vascular compartments: (1) Calf capacitance was lower (median, 3.5 versus 5.5 mL/100 mL tissue; P =0.005), and resting venous pressure was higher (13.0 versus 10.5 mm Hg; P =0.004); (2) higher leg arterial resistance was observed (32.1 versus 22.2; P =0.03); (3) microvascular filtration pressures and threshold for edema were elevated; and (4) with head-up tilt testing, splanchnic flow was not reduced in Fontan patients versus controls (fractional change, +4% versus −32%; P =0.004), and splanchnic arterial resistance did not increase as expected (fractional change, +8% versus +79%; P =0.003). Conclusions— Reduced venous compliance and increased filtration thresholds may act as adaptive mechanisms in maintaining venous return in Fontan circulation. Well-compensated Fontan subjects demonstrate superior orthostatic tolerance resulting from decreased compartmental fluid shifts in response to head-up tilt and higher vascular resistance. This results from increased venous stiffness and decreased splanchnic capacitance and may also be an adaptive mechanism to maintain venous return in these patients while standing.
1096 EFFECT OF IGF-I AND MECHANISMS OF ITS ACTION ON PROLIFERATION AND PROTEIN PRODUCTION BY RAT HEPATOCYTES
Authors: Y. Tanoue, T. Tomiya, N. Ohtomo, Y. Inoue, T. Nishikawa, H. Ikeda, H. Shiratak, K. Koike, K. Fujiwara
Journal: Journal of Hepatology (2011)
Hepassocin as a treatment for fulminant hepatic failure: will it translate from rats to human?
Authors: V. Calvaruso
Journal: Gut (2010)

Acute liver failure (ALF) is defined as the abrupt loss of hepatic cellular function in a patient without pre-existing liver disease, with the subsequent development of coagulopathy, jaundice and encephalopathy. It remains one of the most challenging medical emergencies, due to the multiorgan nature of the disease, the rapid evolution of the clinical condition and the need for multidisciplinary supportive interventions in order to assess the necessity for liver transplantation (LT) correctly.1

Despite different causes of ALF, the mode of cell death typically follows one of two patterns: necrosis or apoptosis; apoptosis is manifest by nuclear and cytoplasmic shrinkage without disturbance of cell membrane integrity or liberation of intracellular content. Consequently, secondary inflammation is not a feature. Necrosis involves depletion of ATP with resultant cell swelling and lysis, leading to release of cellular content and secondary inflammation. However, there is increasing evidence that they are alternative outcomes of the same initiating factors and signalling pathways, a process known as necroapoptosis.2 The main mechanism of liver cell death in ALF is the activation of cell membrane receptors. The cytokine, tumour necrosis factor α (TNFα), and the Fas ligand mediate hepatocellular death through interaction with structurally related cell membrane receptors. In addition to TNFα, other proinflammatory and anti-inflammatory cytokines may have a role in the pathogenesis of acute liver injury of various aetiologies, both experimentally and clinically. Although all the factors responsible for regeneration in the setting of such severe liver cell loss remain incompletely understood, it has been shown …
Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors
Authors: Timothy J. Hobday, Rui Qin, Diane Reidy-Lagunes, Malcolm J. Moore, Jonathan Strosberg, Andreas Kaubisch, Manisha Shah, Hedy Lee Kindler, Heinz-Josef Lenz, Helen Chen, Charles Erlichman
Journal: Journal of Clinical Oncology (2014)

Purpose There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway–targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. Patients and Methods We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. Results A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). Conclusion The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.
Susceptibility to lymphocytic choriomeningitis virus isolates correlates directly with early and high cytotoxic T cell activity, as well as with footpad swelling reaction, and all three are regulated by H-2D.
Authors: R M Zinkernagel, T Leist, H Hengartner, A Althage
Journal: The Journal of Experimental Medicine (1985)

The lymphocytic choriomeningitis virus (LCMV) isolates Docile (D) and Aggressive (A) of Pfau et al. were studied in various strains of mice. Disease susceptibility, assessed as mortality and time to death to LCMV-D or -A varied greatly amongst mouse strains, and all four possible susceptibility patterns were observed: susceptibility to both (e.g. SWR/J), resistance to both (e.g. DBA/2), susceptibility to A but resistance to D (C57BL/6), or vice versa (CBA/J). Irrespective of the virus isolate or the mouse strain tested, susceptibility correlated with both early and high cytotoxic T cell activity found in spleens or leptomeningeal infiltrates, and with early and high primary footpad swelling reaction after local infection. C57BL/6 mice infected with A or SWR/J infected with A or with D showed, in both test systems, early and high activities; in contrast, DBA/2 mice infected with either D or A, and C57BL/6 infected with D showed no or only slow and low responses in both tests. Early and high LCMV-specific cytotoxic T cell activity, and the rapidity and extent of the primary footpad reaction directly correlated with susceptibility to LCM and all were dominantly regulated by H-2D.
Growth factor-based therapies provide additional benefit beyond physical therapy in resistant elbow tendinopathy: a prospective, single-blind, randomised trial of autologous blood injections versus platelet-rich plasma injections
Authors: Leon Creaney, Andrew Wallace, Mark Curtis, David Connell
Journal: British Journal of Sports Medicine (2011)

Background Growth factor technologies are increasingly used to enhance healing in musculoskeletal injuries, particularly in sports medicine. Two such products; platelet-rich plasma (PRP) and autologous blood, have a growing body of supporting evidence. No previous trial has directly compared the efficacy of these two methods. Hypothesis Growth factor administration improves tissue regeneration in patients who have failed to respond to conservative therapy. Study design A prospective, double-blind, randomised trial. Methods Elbow tendinopathy patients who had failed conservative physical therapy were divided into two patient groups: PRP injection (N=80) and autologous blood injection (ABI) (N=70). Each patient received two injections at 0 and 1 month. Patient-related tennis elbow evaluation (PRTEE) was recorded by a blinded investigator at 0, 1, 3 and 6 months. The main outcome measure was PRTEE, a validated composite outcome for pain, activities of daily living and physical function, utilising a 0–100 scale. Results At 6 months the authors observed a 66% success rate in the PRP group versus 72% in the ABI group, p=NS. There was a higher rate of conversion to surgery in the ABI group (20%) versus the PRP group (10%). Conclusion In patients who are resistant to first-line physical therapy such as eccentric loading, ABI or PRP injections are useful second-line therapies to improve clinical outcomes. In this study, up to seven out of 10 additional patients in this difficult to treat cohort benefit from a surgery-sparing intervention.
Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial
Authors: J Roger Owen, Anita Ashton, Judith M Bliss, Janis Homewood, Caroline Harper, Jane Hanson, Joanne Haviland, Soren M Bentzen, John R Yarnold
Journal: The Lancet Oncology (2006)
The Metabolic Syndrome: The Emperor Needs Some Consistent Clothes
Authors: Charles M. Alexander
Journal: Diabetes Care (2004)

Drs. Vinicor and Bowman (1) point to a number of challenges associated with formalizing medical syndromes for clinical and public health purposes in this issue of Diabetes Care . I agree with the issues they raise; it is not yet clear whether the metabolic syndrome is a separate syndrome or simply a collection of commonly recognized cardiovascular risk factors. The current working definitions …
Time-course of functional and pathological changes after a single high acute inhalation of chlorine in rats
Authors: R Demnati, R Fraser, H Ghezzo, JG Martin, G Plaa, JL Malo
Journal: European Respiratory Journal (1998)

Reactive airways dysfunction syndrome (RADS) is an asthma-like condition that follows exposure to very high concentrations of an irritant material. We assessed the time-course of pathophysiological alterations in a model of RADS. Sprague-Dawley rats were exposed to 1,500 parts per million (ppm) of chlorine for 5 min. Lung resistance (RL), responsiveness to inhaled methacholine (MCh), the airway epithelium and bronchoalveolar lavage (BAL) were assessed over a 3 month period after exposure. RL increased significantly up to 3 days after exposure, reaching a maximal change of 110+/-16% from baseline. There was a significant decrease in the concentration of MCh required to increase RL by 0.20 cmH2O x mL(-1) x s from days 1-7 after exposure. In some rats, MCh hyperresponsiveness and RL changes persisted after exposure for as long as 1 and 3 months, respectively. Histological evaluation with morphometric evaluation revealed epithelial flattening, necrosis, increase in smooth muscle mass and evidence of epithelial regeneration. BAL showed an increased number of neutrophils. The timing of maximal abnormality in the appearance of the epithelium (days 1-3) corresponded to that of the maximal functional changes. Acute high chlorine exposure results in functional and pathological abnormalities that resolve in the majority of animals after a variable period; however, these changes can persist in some animals. Functional abnormalities in the initial stages may be related to airway epithelial damage.