tbuckley/cabot-search huggingface dataset:
Central nervous system morbidity following an initial isolated central nervous system relapse and its subsequent therapy in childhood acute lymphoblastic leukemia.
Authors: J J Ochs, G Rivera, R J Aur, H O Hustu, R Berg, J V Simone
Journal: Journal of Clinical Oncology (1985)

The frequency and types of major CNS toxicity and morbidity were analyzed in 107 children with acute lymphoblastic leukemia (ALL) following an isolated primary CNS relapse. Seventy-nine (73%) have had multiple subsequent marrow or CNS relapses requiring intensive and prolonged therapy to the CNS. Median survival time is two years. Of these 79 patients, two thirds have had one or more types of major CNS toxicity, including epileptiform seizures (35), moderate to severe structural abnormalities (24 of 27 evaluated), major motor disabilities (9), blindness (2), CNS infection (6), cranial nerve palsies (2), and intracranial lymphoma (2). The remaining 28 patients (26%) have had no or one additional CNS relapse and have received therapy for a median of eight years. One half of this surviving group of patients have had major CNS toxicity, including seizures (9), major motor disability (2), and intracranial calcifications (12/19). When neuropsychologic evaluations were compared between the 28 survivors and 50 of their contemporaries who had been in initial continuous complete remission, the CNS survivors had significantly lower Full Scale IQ scores (83 +/- 16 v 99 +/- 14, P = less than .001) with similarly lower measures of academic performance. The relative contributions of meningeal leukemia itself and intrathecal or radiation therapy to these effects cannot be determined. Since major CNS sequelae occurred in the majority of patients who had a primary isolated CNS relapse, and the frequency of CNS relapse is dependent on the efficacy of the method of CNS prophylaxis, the best method of avoiding major CNS sequelae is the most effective form of CNS prophylaxis.
Brief Report: Alternative Activation of Laser-Captured Murine Hemophagocytes
Authors: Scott W. Canna, Patrícia Costa‐Reis, William E. Bernal, Niansheng Chu, Kathleen E. Sullivan, Michele E. Paessler, Edward M. Behrens
Journal: Arthritis & Rheumatology (2014)

Hemophagocytes (HPCs) are activated macrophages that have engulfed other hematopoietic cells. Although HPCs are rarely identified in normal spleen tissue and bone marrow, an excess of these macrophages characterizes many cytokine storm syndromes, particularly macrophage activation syndrome and hemophagocytic lymphohistiocytosis. This study was undertaken to assess the functions of HPCs and their significance in acute inflammatory conditions.HPCs were generated in wild-type mice using repeated stimulation with Toll-like receptor 9 (TLR-9) and interleukin-10 receptor blockade. RNA was extracted from HPCs that had been isolated by lasercaptured microdissection. Transcriptional profiles of the HPCs were then compared to those of resting splenic macrophages. In addition, bone marrow samples were obtained from a diverse cohort of patients in whom excess hemophagocytosis was identified by clinical bone marrow biopsy or aspiration. The bone marrow samples were analyzed by immunohistochemistry for markers of classic (CD64) or alternative (CD163 and CD206) macrophage activation.Differential gene expression and gene set enrichment analyses of murine HPCs identified upregulation of genes and gene sets associated with alternative activation of HPCs. Immunohistochemical analyses of HPCs in human bone marrow samples showed universal staining of HPCs for CD163, but rarely for CD206 or CD64.Laser-captured murine TLR-9– induced HPCs had a transcriptional profile similar to that of alternatively activated macrophages. In addition, HPC expression of CD163 was confirmed in a uniquely diverse cohort of patients with hemophagocytic syndromes. Collectively, these data support the hypothesis that HPCs have both immunoregulatory and clean-up functions.
Community control of scabies: a model based on use of permethrin cream
Authors: D. Taplin, T.L. Meinking, S.L. Porcelain, R.L. Athey, D. Taplin, S.L. Porcelain, J.A. Chen, P.M. Castillero, R. Sanchez
Journal: The Lancet (1991)

For 18 years treatment with lindane or crotamiton products has failed to stem the epidemic of scabies among the Kuna Indians in the San Blas islands of the Republic of Panama. Permethrin 5% cream was introduced as the only treatment in a programme to control scabies on an island of 756 inhabitants and involving workers recruited locally. Prevalence fell from 33% to less than 1% after every person was treated. As long as continued surveillance and treatment of newly introduced cases was maintained, prevalence of scabies remained below 1.5% for over 3 years. When supply of medication was interrupted for 3 weeks, prevalence rose to 3.6%. When control was lost after the US invasion of Panama, prevalence rose to 12% within 3 months. Bacterial skin infections decreased dramatically when scabies was controlled. Permethrin is safe and effective even in areas where this disease has become resistant to lindane.
Altered apoptosis in bronchoalveolar lavage lymphocytes after allergen exposure of atopic asthmatic subjects
Authors: M Müller, J Grunewald, C Olgart Höglund, B Dahlén, A Eklund, H Stridh
Journal: European Respiratory Journal (2006)

The increased number of lymphocytes in airways during an asthmatic response is believed to be the result of increased recruitment of these cells. However, it is possible that a decreased apoptotic rate could also contribute to the increased number. The aim of the present study was to investigate whether allergen airway provocation influences the apoptotic phenotype of lung and peripheral blood lymphocytes (PBL) in subjects with atopic asthma. Bronchoalveolar lavage (BAL) lymphocytes and PBL from 12 asthmatic subjects previously challenged with allergen (n = 7) or saline (n = 5) were exposed to the apoptotic stimulus tributyltin (TBT) in vitro and assayed for apoptosis. Airway allergen provocation resulted in decreased sensitivity of BAL lymphocytes to TBT-induced apoptosis, with 42.2% (range 33.9–62.5%) apoptotic cells before challenge versus 23.5% (range 15.3–42.4%) after challenge, while PBL were unaffected. The increased apoptosis resistance correlated with higher numbers of Bcl-2-expressing lymphocytes. Interestingly, baseline caspase-3-like activity was significantly elevated in viable BAL lymphocytes compared with viable PBL, and was unaltered by allergen exposure. In conclusion, allergen inhalation renders bronchoalveolar lavage lymphocytes more resistant to apoptosis while peripheral blood lymphocytes were not influenced at all, indicating that the apoptotic phenotype of airway lymphocytes may play a role in asthmatic inflammation.
Rapid Induction of Apoptosis by PI3K Inhibitors Is Dependent upon Their Transient Inhibition of RAS–ERK Signaling
Authors: Marie Will, Alice Can Ran Qin, Weiyi Toy, Zhan Yao, Vanessa Rodrik-Outmezguine, Claudia Schneider, Xiaodong Huang, Prashant Monian, Xuejun Jiang, Elisa de Stanchina, José Baselga, Ningshu Liu, Sarat Chandarlapaty, Neal Rosen
Journal: Cancer Discovery (2014)

The effects of selective phosphoinositide 3-kinase (PI3K) and AKT inhibitors were compared in human tumor cell lines in which the pathway is dysregulated. Both caused inhibition of AKT, relief of feedback inhibition of receptor tyrosine kinases, and growth arrest. However, only the PI3K inhibitors caused rapid induction of cell death. In seeking a mechanism for this phenomenon, we found that PI3K inhibition, but not AKT inhibition, causes rapid inhibition of wild-type RAS and of RAF-MEK-ERK signaling. Inhibition of RAS-ERK signaling is transient, rebounding a few hours after drug addition, and is required for rapid induction of apoptosis. Combined MEK and AKT inhibition also promotes cell death, and in murine models of HER2(+) cancer, either pulsatile PI3K inhibition or combined MEK and AKT inhibition causes tumor regression. We conclude that PI3K is upstream of RAS and AKT and that pulsatile inhibition of both pathways is sufficient for effective antitumor activity.
Vitamin D metabolites in synovial fluid.
Authors: A Fairney, A M Straffen, C May, M H Seifert
Journal: Annals of the Rheumatic Diseases (1987)

This study has shown that it is possible to measure vitamin D metabolites and vitamin D binding protein (DBP) in synovial fluid as well as serum. Significant amounts of 25-OHD, 24,25-(OH)2D, and DBP are present in synovial fluid. The 25-OHD and DBP maintain a serum:synovial fluid ratio of approximately 2:1 irrespective of the type of joint disease, whereas no such relationship was detected for 24,25-(OH)2D. The possible reasons for these findings are diffusion of the metabolites into synovial fluid or local production from suitable precursors, or both.
Hypoxia-Inducible Factor-1α and Hypoxia-Inducible Factor-2α Are Expressed in Kaposi Sarcoma and Modulated by Insulin-like Growth Factor-I
Authors: Sergiu-Bogdan Catrina, Ileana Ruxandra Botusan, Anja Rantanen, Anca Irinel Catrina, Pawan Pyakurel, Octavian Savu, Magnus Axelson, Peter Biberfeld, Lorenz Poellinger, Kerstin Brismar
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Neoangiogenesis is essential for tumor development. Hypoxia-inducible factor (HIF), a transcriptional factor composed of two subunits (α and β), plays a key role in this process, activating proangiogenic factors such as vascular endothelial growth factor (VEGF). The HIF α subunits are critically regulated by oxygen and are also modulated by growth factors. Kaposi sarcoma (KS) is a highly vascular tumor that releases large amounts of VEGF and for which we have recently described an essential role for the insulin-like growth factor (IGF) system. We therefore investigated the expression of HIF α subunits in biopsies from KS tumors and their modulation by IGF-I in KSIMM, a KS cell line. Results: Both HIF-1α and HIF-2α were expressed in KS biopsies in all tumoral stages. HIF-1α immunopositivity increased through the tumor development with highest expression in the late nodular stages. In KSIMM cells, IGF-I induced accumulation of both HIF α subunits. The induction suggests a translation mechanism as documented by cycloheximide chase experiment coupled with constant RNA levels as evaluated by quantitative real-time PCR. IGF-I–induced HIF α accumulation was followed by an increase in HIF function as assessed both by reporter gene assay and by induction of endogenous target gene expression (VEGF-A). Specific blockade of IGF-I receptor with αIR3 antibody or with picropodophyllin, a specific IGF-IR tyrosine kinase inhibitor, diminishes the basal and IGF-I–dependent induction of both HIF α congeners. Conclusion: These novel findings show the coupling between the IGF and HIF signaling in KS and suggest a coordinated contribution by these pathways to the characteristic vascular phenotype of this tumor.
High-Efficiency Postdilution Online Hemodiafiltration Reduces All-Cause Mortality in Hemodialysis Patients
Authors: Francisco Maduell, Francesc Moreso, Mercedes Pons, Rosa Ramos, Josep Mora-Macià, Jordi Carreras, Jordi Soler, Ferran Torres, Josep M. Campistol, Alberto Martinez-Castelao
Journal: Journal of the American Society of Nephrology (2013)

Retrospective studies suggest that online hemodiafiltration (OL-HDF) may reduce the risk of mortality compared with standard hemodialysis in patients with ESRD. We conducted a multicenter, open-label, randomized controlled trial in which we assigned 906 chronic hemodialysis patients either to continue hemodialysis (n=450) or to switch to high-efficiency postdilution OL-HDF (n=456). The primary outcome was all-cause mortality, and secondary outcomes included cardiovascular mortality, all-cause hospitalization, treatment tolerability, and laboratory data. Compared with patients who continued on hemodialysis, those assigned to OL-HDF had a 30% lower risk of all-cause mortality (hazard ratio [HR], 0.70; 95% confidence interval [95% CI], 0.53-0.92; P=0.01), a 33% lower risk of cardiovascular mortality (HR, 0.67; 95% CI, 0.44-1.02; P=0.06), and a 55% lower risk of infection-related mortality (HR, 0.45; 95% CI, 0.21-0.96; P=0.03). The estimated number needed to treat suggested that switching eight patients from hemodialysis to OL-HDF may prevent one annual death. The incidence rates of dialysis sessions complicated by hypotension and of all-cause hospitalization were lower in patients assigned to OL-HDF. In conclusion, high-efficiency postdilution OL-HDF reduces all-cause mortality compared with conventional hemodialysis.
4-Ipomeanol: A Novel Investigational New Drug for Lung Cancer
Authors: M. C. Christian, R. E. Wittes, B. Leyland-Jones, T. L. McLemore, A. C. Smith, C. K. Grieshaber, B. A. Chabner, M. R. Boyd
Journal: JNCI Journal of the National Cancer Institute (1989)

4-Ipomeanol (IPO) is the first agent to undergo preclinical development at the National Cancer Institute (NCI) based principally on a specific biochemical-biological rationale for clinical investigation as an antineoplastic agent targeted against lung cancer. This disease-specific development of IPO was initially stimulated by observations that the compound was activated by metabolism, preferentially within the mammalian lung, specifically within bronchiolar Clara cells, and that its predominant toxicity was to the lung in most species. IPO is inactive or only minimally active against most conventional antitumor test systems. However, some human lung cancer cell lines, as well as a variety of fresh human lung tumor biopsy specimens, have been shown to be capable of mediating the in situ biotransformation of IPO to a potentially cytotoxic intermediate. In this report, the biochemistry, metabolism, preclinical pharmacology, and toxicology of IPO are reviewed and the clinical development plans for this unique and challenging new agent are presented. [J Natl Cancer Inst 81:1133–1143, 1989]
Enhanced acetaminophen toxicity in rats with bilirubin glucuronyl transferase deficiency
Authors: Sonia M. F. de Morais, Peter G. Wells
Journal: Hepatology (1989)

Glucuronidation is the major pathway for elimination of acetaminophen, diverting it from the toxifying pathway catalyzed by cytochromes P-450. A genetic deficiency in bilirubin UDP-glucuronyl transferase may predispose humans and animals to the toxicity of drugs that are extensively glucuronidated, if other glucuronyl transferase isoenzymes are concurrently deficient. Homozygous and heterozygous Gunn rats are, respectively, severely and moderately deficient in glucuronyl transferase. Acetaminophen (500 mg per kg) was administered intraperitoneally to homozygous and heterozygous Gunn rats and to Wistar controls. Hepatic and renal cellular damage was assessed by peak plasma concentrations of ALT and blood urea nitrogen, respectively. Homozygous and heterozygous Gunn rats showed, respectively, 115-fold and 9-fold higher ALT concentrations compared to Wistar controls. Blood urea nitrogen was elevated only in the homozygous Gunn rats (3-fold). Biotransformation of acetaminophen was measured by high-performance liquid chromatography. Acetaminophen glucuronidation was decreased by 72 and 35% (p &lt; 0.05), respectively, in the homozygous and heterozygous Gunn rats compared with Wistar controls. Production of acetaminophen glucuronide correlated negatively with ALT concentration (r = −0.89, p &lt; 0.001). Production of glutathione-derived metabolites, reflecting acetaminophen bioactivation, was 2 to 3-fold higher in the Gunn rats (p &lt; 0.05) and correlated with ALT concentrations (r = 0.90, p &lt; 0.001). The results indicate that heterozygous and homozygous deficiencies in glucuronyl transferase are, respectively, intermediate and major determinants of acetaminophen bioactivation and toxicity. Also, a genetic deficiency in bilirubin glucuronyl transferase in Gunn rats is associated with a deficiency in the glucuronidation of drug substrates.
Biomonitoring for assessment of organic dust-induced lung inflammation
Authors: L. J. Mueller-Anneling, M. E. O'Neill, P. S. Thorne
Journal: European Respiratory Journal (2006)

Inhalation exposure to particulate matter containing endotoxin (or lipopolysaccharide (LPS)) occurs in a variety of occupations. Nasal lavage and induced sputum have been used to evaluate lung inflammation resulting from such exposures. Whole blood assay (WBA) measures cytokine production of leukocytes after ex vivo stimulation with LPS. The present study examined the effectiveness of WBA for evaluating inflammatory responses and susceptibility. C3HeB/FEJ mice were tolerised by LPS injection or sham tolerised with saline. Animals then inhaled either swine barn dust extract containing endotoxin or saline. Bronchoalveolar lavage (BAL) fluid was assayed for leukocyte counts and pro-inflammatory cytokines (interleukin-6, tumour necrosis factor-α). Whole blood was stimulated with 10 or 100 ng·mL -1 of LPS, incubated for 5 or 18 h and assayed for cytokines. Barn dust-exposed groups revealed significantly higher total cells, neutrophils and cytokines in BAL compared with saline-exposed groups. Animals tolerised to LPS and exposed to barn dust demonstrated lower cellular and cytokine BAL responses. Similarly, WBA yielded significantly elevated cytokines with barn dust exposure and reduced responses with tolerisation. This study demonstrates the efficacy of whole blood assay as a biomarker of inhalation exposure to inflammatory agents and its use for assessing susceptibility to organic dust-induced lung inflammation.
Atenolol versus propranolol for the treatment of infantile hemangiomas: A randomized controlled study
Authors: Álvaro Abarzúa-Araya, Cristián P. Navarrete-Dechent, Felipe Heusser, Javiera Retamal, María Soledad Zegpi-Trueba
Journal: Journal of the American Academy of Dermatology (2014)
The mechanisms of sulfonylurea-induced immune hemolysis: Case report and review of the literature
Authors: Joyce A. Kopicky, Charles H. Packman
Journal: American Journal of Hematology (1986)

Abstract Chlorpropamide, a sulfonylurea antidiabetic drug, was found to be the etiologic agent in a patient with immune hemolytic anemia. Hemolysis was severe, and ceased promptly when the drug was discontinued. The direct antiglobulin test was positive for complement, and the indirect antiglobulin test was also positive when the drug, patient serum, and fresh serum complement were all present. In this patient, and in four other patients described in the literature, hemolysis was mediated by the immune complex mechanism. In reports of two other patients taking a sulfonylurea drug, a milder form of hemolysis was mediated by the hapten mechanism. Sulfonylurea drugs are widely used. Since immune complex‐mediated hemolysis in these patients is dramatic, it is not likely to be missed. However, the slower, milder hemolysis mediated by the hapten mechanism may be more common than is realized. Such patients may have only mild anemia and a near‐normal reticulocyte count, making the diagnosis difficult. It is thus important to consider drug‐immune hemolysis in patients who become anemic while taking sulfonylurea drugs.
Cis3/Socs3/Ssi3 Plays a Negative Regulatory Role in Stat3 Activation and Intestinal Inflammation
Authors: Asuka Suzuki, Toshikatsu Hanada, Keiichi Mitsuyama, Takafumi Yoshida, Shintaro Kamizono, Tomoaki Hoshino, Masato Kubo, Atsuko Yamashita, Masaru Okabe, Kiyoshi Takeda, Shizuo Akira, Satoshi Matsumoto, Atsushi Toyonaga, Michio Sata, Akihiko Yoshimura
Journal: The Journal of Experimental Medicine (2001)

Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription (STAT) transcription factors. We recently identified two intrinsic Janus kinase (JAK) inhibitors, JAK binding protein (JAB; also referred to as suppressor of cytokine signaling [SOCS1]/STAT-induced STAT inhibitor [SSI1]) and cytokine-inducible SH2 protein (CIS)3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, STAT3 was most strongly tyrosine phosphorylated in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of colitis as well as STAT3 activation was significantly reduced in IL-6–deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice as well as several T cell–dependent colitis models. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.
Renin‐Angiotensin System: An Old Player with Novel Functions in Skeletal Muscle
Authors: Claudio Cabello‐Verrugio, María Gabriela Morales, Juan Carlos Rivera, Daniel Cabrera, Felipe Simon
Journal: Medicinal Research Reviews (2015)

Skeletal muscle is a tissue that shows the most plasticity in the body; it can change in response to physiological and pathological stimuli. Among the diseases that affect skeletal muscle are myopathy-associated fibrosis, insulin resistance, and muscle atrophy. A common factor in these pathologies is the participation of the renin-angiotensin system (RAS). This system can be functionally separated into the classical and nonclassical RAS axis. The main components of the classical RAS pathway are angiotensin-converting enzyme (ACE), angiotensin II (Ang-II), and Ang-II receptors (AT receptors), whereas the nonclassical axis is composed of ACE2, angiotensin 1-7 [Ang (1-7)], and the Mas receptor. Hyperactivity of the classical axis in skeletal muscle has been associated with insulin resistance, atrophy, and fibrosis. In contrast, current evidence supports the action of the nonclassical RAS as a counter-regulator axis of the classical RAS pathway in skeletal muscle. In this review, we describe the mechanisms involved in the pathological effects of the classical RAS, advances in the use of pharmacological molecules to inhibit this axis, and the beneficial effects of stimulation of the nonclassical RAS pathway on insulin resistance, atrophy, and fibrosis in skeletal muscle.
Incidence of decompression-induced pulmonary haemorrhage in young and old rats.
Authors: H S Fang, B F Guo
Journal: Thorax (1977)

Seventeen young rats (40-52 days of age) and 17 old rats (545-702 days of age) were decompressed from one atmospheric pressure to an ambient pressure of 30 mmHg in 0.25 second. It was found that 11 of 34 young lungs (32%) and 23 of 34 old lungs (68%) showed decompression-induced pulmonary haemorrhage. The difference was statistically significant. The pulmonary haemorrhage of the old rats was markedly more severe than that of the young rats.