tbuckley/cabot-search huggingface dataset:
Lobaplatin arrests cell cycle progression in human hepatocellular carcinoma cells
Authors: Qiong Wu, Shu-Kui Qin, Feng-Meng Teng, Chang-Jie Chen, Rui Wang
Journal: Journal of Hematology & Oncology (2010)

Abstract Background Hepatocellular carcinoma (HCC) still is a big burden for China. In recent years, the third-generation platinum compounds have been proposed as potential active agents for HCC. However, more experimental and clinical data are warranted to support the proposal. In the present study, the effect of lobaplatin was assessed in five HCC cell lines and the underlying molecular mechanisms in terms of cell cycle kinetics were explored. Methods Cytotoxicity of lobaplatin to human HCC cell lines was examined using MTT cell proliferation assay. Cell cycle distribution was determined by flow cytometry. Expression of cell cycle-regulated genes was examined at both the mRNA (RT-PCR) and protein (Western blot) levels. The phosphorylation status of cyclin-dependent kinases (CDKs) and retinoblastoma (Rb) protein was also examined using Western blot analysis. Results Lobaplatin inhibited proliferation of human HCC cells in a dose-dependent manner. For the most sensitive SMMC-7721 cells, lobaplatin arrested cell cycle progression in G 1 and G 2 /M phases time-dependently which might be associated with the down-regulation of cyclin B, CDK1, CDC25C, phosphorylated CDK1 (pCDK1), pCDK4, Rb, E2F, and pRb, and the up-regulation of p53, p21, and p27. Conclusion Cytotoxicity of lobaplatin in human HCC cells might be due to its ability to arrest cell cycle progression which would contribute to the potential use of lobaplatin for the management of HCC.
Coordinated Control of Cell Ca <sup>2+</sup> Loading and Triggered Release From the Sarcoplasmic Reticulum Underlies the Rapid Inotropic Response to Increased L-Type Ca <sup>2+</sup> Current
Authors: A. W. Trafford, M. E. Díaz, D. A. Eisner
Journal: Circulation Research (2001)

Abstract —The aim of this study was to investigate how sarcoplasmic reticulum (SR) Ca 2+ content and systolic Ca 2+ are controlled when Ca 2+ entry into the cell is varied. Experiments were performed on voltage-clamped rat and ferret ventricular myocytes loaded with fluo-3 to measure intracellular Ca 2+ concentration ([Ca 2+ ] i ). Increasing external Ca 2+ concentration ([Ca 2+ ] o ) from 1 to 2 mmol/L increased the amplitude of the systolic Ca 2+ transient with no effect on SR Ca 2+ content. This constancy of SR content is shown to result because the larger Ca 2+ transient activates a larger Ca 2+ efflux from the cell that balances the increased influx. Decreasing [Ca 2+ ] o to 0.2 mmol/L decreased systolic Ca 2+ but produced a small increase of SR Ca 2+ content. This increase of SR Ca 2+ content is due to a decreased release of Ca 2+ from the SR resulting in decreased loss of Ca 2+ from the cell. An increase of [Ca 2+ ] o has two effects: (1) increasing the fraction of SR Ca 2+ content, which is released on depolarization and (2) increasing Ca 2+ entry into the cell. The results of this study show that the combination of these effects results in rapid changes in the amplitude of the systolic Ca 2+ transient. In support of this, the changes of amplitude of the transient occur more quickly following changes of [Ca 2+ ] o than following refilling of the SR after depletion with caffeine. We conclude that the coordinated control of increased Ca 2+ entry and greater fractional release of Ca 2+ is an important factor in regulating excitation-contraction coupling.
Prognostic Significance of RNA-Dependent Protein Kinase on Non–Small Cell Lung Cancer Patients
Authors: Abujiang Pataer, Maria Gabriela Raso, Arlene M. Correa, Carmen Behrens, Koji Tsuta, Luisa Solis, Bingliang Fang, Jack A. Roth, Ignacio I. Wistuba, Stephen G. Swisher
Journal: Clinical Cancer Research (2010)

Abstract Purpose: The role of RNA-dependent protein kinase (PKR) in antiviral defense mechanisms and in cellular differentiation, growth, and apoptosis is well known, but the role of PKR in human lung cancer remains poorly understood. To explore the role of PKR in human lung cancer, we evaluated the expression of PKR in tissue microarray (TMA) specimens from both non–small cell lung cancer (NSCLC) and normal human bronchial epithelium tissue. Experimental Design: TMA samples (TMA-1) from 231 lung cancers were stained with PKR antibody and validated on TMA-2 from 224 lung cancers. Immunohistochemical expression score was quantified by three pathologists independently. Survival probability was computed by the Kaplan-Meier method. Results: The NSCLC cells showed lower levels of PKR expression than normal bronchial epithelium cells did. We also found a significant association between lower levels of PKR expression and lymph node metastasis. We found that loss of PKR expression is correlated with a more aggressive behavior, and that a high PKR expression predicts a subgroup of patients with a favorable outcome. Univariate and multivariate Cox proportional hazards regression models showed that a lower level of PKR expression was significantly associated with shorter survival in NSCLC patients. We further validated and confirmed PKR to be a powerful prognostic factor in TMA-2 lung cancer (hazard ratio, 0.22; P &amp;lt; 0.0001). Conclusions: Our findings first indicate that PKR expression is an independent prognostic variable in NSCLC patients. Clin Cancer Res; 16(22); 5522–8. ©2010 AACR.
Endocrine-disrupting effects of cattle feedlot effluent on an aquatic sentinel species, the fathead minnow.
Authors: Edward F Orlando, Alan S Kolok, Gerry A Binzcik, Jennifer L Gates, Megan K Horton, Christy S Lambright, L Earl Gray, Ana M Soto, Louis J Guillette
Journal: Environmental Health Perspectives (2003)

Over the last decade, research has examined the endocrine-disrupting action of various environmental pollutants, including hormones, pharmaceuticals, and surfactants, in sewage treatment plant effluent. Responding to the growth of concentrated animal feeding operations (CAFOs) and the pollutants present in their wastewater (e.g., nutrients, pharmaceuticals, and hormones), the U.S. Environmental Protection Agency developed a new rule that tightens the regulation of CAFOs. In this study, we collected wild fathead minnows (Pimephales promelas) exposed to feedlot effluent (FLE) and observed significant alterations in their reproductive biology. Male fish were demasculinized (having lower testicular testosterone synthesis, altered head morphometrics, and smaller testis size). Defeminization of females, as evidenced by a decreased estrogen:androgen ratio of in vitro steroid hormone synthesis, was also documented. We did not observe characteristics in either male or female fish indicative of exposure to environmental estrogens. Using cells transfected with the human androgen receptor, we detected potent androgenic responses from the FLE. Taken together, our morphologic, endocrinologic, and in vitro gene activation assay data suggest two hypotheses: a) there are potent androgenic substance(s) in the FLE, and/or b) there is a complex mixture of androgenic and estrogenic substances that alter the hypothalamic-pituitary-gonadal axis, inhibiting the release of gonadotropin-releasing hormone or gonadotropins. This is the first study demonstrating that the endocrine and reproductive systems of wild fish can be adversely affected by FLE. Future studies are needed to further investigate the effects of agricultural runoff and to identify the biologically active agents, whether natural or pharmaceutical in origin.
The Diagnosis of Stupor and Coma.
Authors: F Plum, J B Posner
Journal: Annals of Internal Medicine (1967)

Advances in the knowledge and understanding of stupor and coma, aided by the considerable impact of CT scanning on neurological diagnosis, are reflected in this substantially revised edition. The authors have included new references and illustrations, but the third edition retains its approach to that art of diagnosis based on the understanding of pathophysiology and pathobiochemistry.
Pivotal Role of CXCR3 in Melanoma Cell Metastasis to Lymph Nodes
Authors: Kenji Kawada, Masahiro Sonoshita, Hiromi Sakashita, Arimichi Takabayashi, Yoshio Yamaoka, Toshiaki Manabe, Kayo Inaba, Nagahiro Minato, Masanobu Oshima, Makoto Mark Taketo
Journal: Cancer Research (2004)

Abstract Chemokines and their receptors play key roles in leukocyte trafficking and are also implicated in cancer metastasis to specific organs. Here we show that mouse B16F10 melanoma cells constitutively express chemokine receptor CXCR3, and that its ligands CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC induce cellular responses in vitro, such as actin polymerization, migration, invasion, and cell survival. To determine whether CXCR3 could play a role in metastasis to lymph nodes (LNs), we constructed B16F10 cells with reduced CXCR3 expression by antisense RNA and investigated their metastatic activities after s.c. inoculations to syngeneic hosts, C57BL/6 mice. The metastatic frequency of these cells to LNs was markedly reduced to ∼15% (P &amp;lt; 0.05) compared with the parental or empty vector-transduced cells. On the other hand, pretreatment of mice with complete Freund’s adjuvant increased the levels of CXCL9 and CXCL10 in the draining LNs, which caused 2.5–3.0-fold increase (P &amp;lt; 0.05) in the metastatic frequency of B16F10 cells to the nodes with much larger foci. Importantly, such a stimulation of metastasis was largely suppressed when CXCR3 expression in B16F10 cells was reduced by antisense RNA or when mice were treated with specific antibodies against CXCL9 and CXCL10. We also demonstrate that CXCR3 is expressed on several human melanoma cell lines as well as primary human melanoma tissues (5 of 9 samples tested). These results suggest that CXCR3 inhibitors may be promising therapeutic agents for treatment of LN metastasis, including that of melanoma.
Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ
Authors: Andrew C. Li, Christoph J. Binder, Alejandra Gutierrez, Kathleen K. Brown, Christine R. Plotkin, Jennifer W. Pattison, Annabel F. Valledor, Roger A. Davis, Timothy M. Willson, Joseph L. Witztum, Wulf Palinski, Christopher K. Glass
Journal: Journal of Clinical Investigation (2004)

PPARα, β/δ, and γ regulate genes involved in the control of lipid metabolism and inflammation and are expressed in all major cell types of atherosclerotic lesions. In vitro studies have suggested that PPARs exert antiatherogenic effects by inhibiting the expression of proinflammatory genes and enhancing cholesterol efflux via activation of the liver X receptor–ABCA1 (LXR-ABCA1) pathway. To investigate the potential importance of these activities in vivo, we performed a systematic analysis of the effects of PPARα, β, and γ agonists on foam-cell formation and atherosclerosis in male LDL receptor–deficient (LDLR–/–) mice. Like the PPARγ agonist, a PPARα-specific agonist strongly inhibited atherosclerosis, whereas a PPARβ-specific agonist failed to inhibit lesion formation. In concert with their effects on atherosclerosis, PPARα and PPARγ agonists, but not the PPARβ agonist, inhibited the formation of macrophage foam cells in the peritoneal cavity. Unexpectedly, PPARα and PPARγ agonists inhibited foam-cell formation in vivo through distinct ABCA1-independent pathways. While inhibition of foam-cell formation by PPARα required LXRs, activation of PPARγ reduced cholesterol esterification, induced expression of ABCG1, and stimulated HDL-dependent cholesterol efflux in an LXR-independent manner. In concert, these findings reveal receptor-specific mechanisms by which PPARs influence macrophage cholesterol homeostasis. In the future, these mechanisms may be exploited pharmacologically to inhibit the development of atherosclerosis.
The Psychiatric Emergency Service: Mirror of Change
Authors: AARON SATLOFF, CYRIL M. WORBY
Journal: American Journal of Psychiatry (1970)

The authors compared the population contacting a psychiatric emergency service in 1958 with that contacting it in 1968. Among the most striking findings were the shift to a younger age group being treated, the lower rate of referral to inpatient care, and an increase in patient load that greatly exceeded the area population increase. The implications of the findings for the planning of an adequate network of community mental health facilities are discussed.
Human in vivo fluorescence microimaging of the alveolar ducts and sacs during bronchoscopy
Authors: L Thiberville, M Salaün, S Lachkar, S Dominique, S Moreno-Swirc, C Vever-Bizet, G Bourg-Heckly
Journal: European Respiratory Journal (2009)

The aim of the present study was to assess fibred confocal fluorescence microscopy (FCFM) as a tool for imaging the alveolar respiratory system in vivo during bronchoscopy. A 488-nm excitation wavelength FCFM device was used in 41 healthy subjects including 17 active smokers. After topical anaesthesia, the 1.4-mm miniprobe was introduced into the bronchoscope working channel and advanced distally to the alveoli. Morphometric and cellular analyses were performed on selected frames harbouring a minimal compression effect. In vivo acinar microimaging was obtained from each lung segment except for the apical and posterior segments of both upper lobes. Reproducible patterns, corresponding to the elastic framework of the axial and peripheral interstitial systems, were recorded from 192 separate acini. The mean± sd thickness of the acinar elastic fibres was 10±2.7 μm. Alveolar mouth diameters (mean± sd 278±53 μm) were normally distributed but appeared smaller in the right upper lobe and right medial basal segment. Lobular microvessels (median diameter 90 μm) were equally distributed throughout the lungs. Alveolar macrophages were not detectable in nonsmokers, whereas a specific tobacco-tar-induced fluorescence was observed in smoking subjects, providing fine details of the alveolar walls and macrophages. A strong correlation was found between the number of cigarettes smoked per day and the amount of large and mobile macrophages observed in vivo , as well as with the intensity of the macrophage alveolitis. Fibred confocal fluorescence microscopy enables accurate exploration of the peripheral lung in vivo in both smokers and nonsmokers.
Prospective analysis of quality of life in elderly patients treated with adjuvant chemotherapy for non-small-cell lung cancer
Authors: S. Park, I.R. Kim, K.K. Baek, S.J. Lee, W.J. Chang, C.H. Maeng, J.Y. Hong, M.K. Choi, Y.S. Kim, J.M. Sun, J.S. Ahn, K. Park, J. Jo, S.H. Jung, M.J. Ahn
Journal: Annals of Oncology (2013)
Invertebrate recognition protein cross-reacts with an immunoglobulin idiotype.
Authors: G R Vasta, J J Marchalonis, H Kohler
Journal: The Journal of Experimental Medicine (1984)

To estimate the minimal structural requirements for cross-reaction of idiotypic determinants, we determined the capacity of monoclonal antibodies specific for the idiotype of the phosphorylcholine (PC)-binding myeloma protein TEPC-15 for cross-reactivities with the PC-binding, acute-phase protein C-reactive protein (CRP) and the hemagglutinin from the horseshoe crab Limulus polyphemus (limulin), which binds sialic acid and PC. Certain monoclonal antibodies (MAb) to the TEPC-15 idiotype showed strong cross-reactions with CRP and limulin when tested by enzyme-linked immunoadsorbent assays. The specificity of the cross-reactivities was confirmed by testing the binding of the reactive anti-TEPC-15 MAb to both CRP and limulin in the presence of p-nitrophenylphosphorylcholine (pNPPC), N-acetylneuraminic acid, and bovine submaxillary mucin. The binding of the MAb to both CRP and limulin was strongly decreased by pNPPC, partially decreased by free PC, and not affected by N-acetylneuraminic acid or bovine submaxillary mucin. Neither CRP nor limulin showed significant overall sequence homology to vertebrate immunoglobulins. However, CRP, limulin, and TEPC-15 variable region heavy chain (VH) shared short stretches of homology (8-10 amino acids) that mapped to a stretch comprised of the second complementarity determining region and third framework region of the TEPC-15 VH. These results might reflect either evolutionary convergence forced upon molecules of diverse evolutionary histories because of steric requirements of binding the same ligand, or a conservation of primitive combining site gene segments in evolution.
Anion transport processes in the mammalian superficial proximal straight tubule.
Authors: J A Schafer, T E Andreoli
Journal: Journal of Clinical Investigation (1976)

The experiments reported in this paper were designed to evaluate some of the characteristics of anion transport processes during fluid absorption from superficial proximal straight tubules isolated from rabbit kidney. We measured net chemical C1- flux during fluid absorption from tubules perfused and bathed with Krebs-Ringer buffers containing 113.6 mM C1-, 10 mM acetate, and 25 mM HCO-/3 at pH 7.4; assessed the effects of carbonic anhydrase inhibitors on net fluid absorption in the presence and absence of CO2; and evaluated the influx and efflux coefficients for [14C]-acetate transport at 37degreesC, at 21degreesC, and in the presence of carbonic anhydrase inhibitors. The experimental data shown that, for this nephron segment, net C1- flux accompanies approximately 27.5% of net Na+ absorption; and net C1- absorption may be accounted for by a passive transport process, primarily diffusional in nature. Fluid absorption in this nephron segment is reduced 40-60% by carbonic anhydrase inhibitors, but only when the tubules are exposed to 95% O2-5% CO2 rather than 100% O2. Thus, it seems probably that approximately half of Na+ absorption in these tubules may be rationalized in terms of a carbonic anhydrase-dependent CO2 hydration process. In addition, there may occur in these isolated proximal tubules an acetazolamide-insensitive moiety of HCO-/3 absorption comparable to that observed for proximal tubules in vivo. Finally, we provide evidence that net efflux of luminal acetate is due to metabolic energy-dependent processes other than CO2 hydration and may, under appropriate conditions, account for approximately one-fourth of net Na+ absorption.
Reduced Nitric Oxide Causes Age-Associated Impairment of Circadian Rhythmicity
Authors: Takeshige Kunieda, Tohru Minamino, Kentaro Miura, Taro Katsuno, Kaoru Tateno, Hideyuki Miyauchi, Shuichi Kaneko, Christopher A. Bradfield, Garret A. FitzGerald, Issei Komuro
Journal: Circulation Research (2008)

Impairment of circadian rhythmicity in the elderly has been suggested to cause age-associated diseases such as atherosclerosis and hypertension. Endothelium-derived nitric oxide (NO) is a critical regulator of cardiovascular homeostasis, but its production declines with aging, thereby inducing vascular dysfunction. We show here that impaired circadian rhythmicity is related to a decrease of NO production with aging. Treatment with an NO donor significantly upregulated the promoter activity of the clock gene Period via the cAMP response element–dependent and the E-box enhancer element–dependent pathways. Both phosphorylation and S -nitrosylation by NO are involved in this upregulation. In aged animals, endothelial NO synthase activity was markedly decreased during the daytime, along with impairment of clock gene expression and the circadian variation in blood pressure. Treatment of aged animals with an NO donor significantly improved the impairments. Inhibition of NO synthase activity also led to impairment of clock gene expression and blood pressure rhythm. These results suggest that NO is a key regulator of the circadian clock in the cardiovascular system and may be a novel target for the treatment of age-associated alteration of circadian rhythms.
What happens to patients with respiratory disease when they fly?
Authors: R K Coker
Journal: Thorax (2004)

Updated guidelines now available but more research is needed into the safety of air travel for those with respiratory disease

Despite current concerns about terrorism, commercial air travel remains a common mode of travel for millions. It has been estimated that a single major UK airline carries over 30 million passengers each year. There are no data available to indicate how many passengers flying on commercial aircraft have respiratory disease, but as far back as 1974 it was estimated that around 5% of passengers were ambulatory patients. As the average age of western populations continues to rise, so does the propensity for passengers to have some form of medical condition. In addition, flights are getting longer and aircraft bigger. The new Airbus 380, for example, will carry around 600 passengers for up to and in some cases exceeding 20 hours.

Air travel is in general safe, even for those with medical conditions, and there are no established methods for determining morbidity associated with air travel. Nevertheless, available airline data consistently record around 10% of in-flight medical emergencies as being respiratory in nature, with approximately one third attributed to asthma. Medaire, a North American company offering radio link emergency medical assistance to commercial aircraft, has published figures for 2002 which show that respiratory problems are the third most common cause of in-flight medical emergency (A Hawkins, Medaire, personal communication). Respiratory problems are also the third most common cause of medical diversion after cardiac and neurological events (including syncope), accounting for 9% of diversions. In 2002 Medaire recorded 414 diversions, 206 advised by Medaire and 208 …
Phase I Trial of Intrathecal Spartaject Busulfan in Children with Neoplastic Meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004)
Authors: Sridharan Gururangan, William P. Petros, Tina Young Poussaint, Michael L. Hancock, Peter C. Phillips, Henry S. Friedman, Lisa Bomgaars, Susan M. Blaney, Larry E. Kun, James M. Boyett
Journal: Clinical Cancer Research (2006)

Abstract Purpose: A phase I trial of intrathecal Spartaject Busulfan (SuperGen, Inc., San Ramon, CA) was conducted in children with neoplastic meningitis following recurrent primary brain tumors to describe toxicities, estimate the maximum tolerated dose (MTD), and document evidence of responses to this agent. Experimental Design: The continuous reassessment method was used to assign cohorts of patients to doses of intrathecal Spartaject Busulfan via an Ommaya reservoir and/or lumbar puncture twice weekly for 2 weeks followed by an assessment of toxicity and response. Patients with stable disease or an objective response continued to receive intrathecal Spartaject Busulfan plus systemic chemotherapy at regular intervals. Cerebrospinal fluid and blood were obtained for pharmacokinetic studies in patients with Ommaya reservoirs after the first dose of intrathecal Spartaject Busulfan. Seven evaluable patients were assigned to the starting dose of 5 mg, two patients to 7.5 mg, three patients to 10 mg, seven patients to 13 mg, and four patients to 17 mg. Results: Between September 2000 and May 2003, 28 patients were enrolled in this study. Twenty-three patients (median age, 8.8 years; range, 2.5-19.5 years) were evaluable for estimating the MTD, and dose-limiting toxicities were observed in three and included grade 3 vomiting (n = 1 at 5 mg), grade 3 headache (n = 1 at 17 mg), and grade 3 arachnoiditis (n = 1 at 17 mg). Pharmacokinetic data showed that post-infusion concentrations of busulfan ranged from 50 to 150 μg/mL and declined to &amp;lt;1 μg/mL within 5 hours. Conclusions: Intrathecal Spartaject Busulfan was well tolerated in children with neoplastic meningitis from brain tumors, and the recommended dose for future phase II studies is 13 mg.