tbuckley/cabot-search huggingface dataset:
Triiodothyronine-induced Thyrotoxicosis Increases Mononuclear Leukocyte β-Adrenergic Receptor Density in Man
Authors: Ann M. Ginsberg, William E. Clutter, Suresh D. Shah, Philip E. Cryer
Journal: Journal of Clinical Investigation (1981)

β-Adrenergic receptors are increased in some tissues of experimentally thyrotoxic animals but are reported to be unchanged in mononuclear leukocytes of spontaneously thyrotoxic humans. We examined the effects of triiodothyronine (100 μg/d for 7 d) and placebo on high-affinity mononuclear leukocyte β-adrenergic receptors in 24 normal human subjects, using a double-blind design. β-Adrenergic receptors were assessed by specific binding of the antagonist (-)[3H]dihydroalprenolol. Triiodothyronine administration resulted in objective evidence of moderate thyrotoxicosis and an increase in mean (-)[3H]dihydroalprenolol binding from 25±3 to 57±9 fmol/mg protein (P < 0.001). The latter was attributable, by Scatchard analysis, to an increase in β-adrenergic receptor density (967 ± 134 to 2250 ± 387 sites per cell, P < 0.01); apparent dissociation constants did not change. Placebo administration had no effects. Marked inter- and intraindividual variation in mononuclear leukocyte β-adrenergic receptor density was also noted. Because this was approximately threefold greater than analytical variation, it is largely attributable to biologic variation. Thus, we conclude: (a) The finding of a triiodothyronine-induced increase in mononuclear leukocyte β-adrenergic receptor density in human mononuclear leukocytes, coupled with similar findings in tissues of experimentally thyrotoxic animals, provides support for the use of mononuclear leukocytes to assess receptor status in man. (b) There is considerable biologic variation in β-adrenergic receptor density in man. (c) The findings of thyroid hormone-induced increments in β-adrenergic receptor density provide a plausible mechanism for the putative enhanced responsiveness to endogenous catecholamines of patients with thyrotoxicosis.
Reduced Production of Creatinine Limits Its Use as Marker of Kidney Injury in Sepsis
Authors: Kent Doi, Peter S.T. Yuen, Christoph Eisner, Xuzhen Hu, Asada Leelahavanichkul, Ju[Combining Diaeresis]rgen Schnermann, Robert A. Star
Journal: Journal of the American Society of Nephrology (2009)

Although diagnosis and staging of acute kidney injury uses serum creatinine, acute changes in creatinine lag behind both renal injury and recovery. The risk for mortality increases when acute kidney injury accompanies sepsis; therefore, we sought to explore the limitations of serum creatinine in this setting. In mice, induction of sepsis by cecal ligation and puncture in bilaterally nephrectomized mice increased markers of nonrenal organ injury and serum TNF-α. Serum creatinine, however, was significantly lower in septic animals than in animals subjected to bilateral nephrectomy and sham cecal ligation and puncture. Under these conditions treatment with chloroquine decreased nonrenal organ injury markers but paradoxically increased serum creatinine. Sepsis dramatically decreased production of creatinine in nephrectomized mice, without changes in body weight, hematocrit, or extracellular fluid volume. In conclusion, sepsis reduces production of creatinine, which blunts the increase in serum creatinine after sepsis, potentially limiting the early detection of acute kidney injury. This may partially explain why small absolute increases in serum creatinine levels are associated with poor clinical outcomes. These data support the need for new biomarkers that provide better measures of renal injury, especially in patients with sepsis.
Slippage of Mitotic Arrest and Enhanced Tumor Development in Mice with <b> <i>BubR1</i> </b> Haploinsufficiency
Authors: Wei Dai, Qi Wang, Tongyi Liu, Malisetty Swamy, Yuqiang Fang, Suqing Xie, Radma Mahmood, Yang-Ming Yang, Ming Xu, Chinthalapally V. Rao
Journal: Cancer Research (2004)

Abstract A compromised spindle checkpoint is thought to play a key role in genetic instability that predisposes cells to malignant transformation. Loss of function mutations of BubR1, an important component of the spindle checkpoint, have been detected in human cancers. Here we show that BubR1+/− mouse embryonic fibroblasts are defective in spindle checkpoint activation, contain a significantly reduced amount of securin and Cdc20, and exhibit a greater level of micronuclei than do wild-type cells. RNA interference-mediated down-regulation of BubR1 also greatly reduced securin level. Moreover, compared with wild-type littermates, BubR1+/− mice rapidly develop lung as well as intestinal adenocarcinomas in response to challenge with carcinogen. BubR1 is thus essential for spindle checkpoint activation and tumor suppression.
Mucous membrane pemphigoid with autoantibodies to all the laminin 332 subunits and fatal outcome resulting from liver cirrhosis and hepatocellular carcinoma
Authors: Teruki Dainichi, Youichirou Hirakawa, Norito Ishii, Bungo Ohyama, Futoshi Kohda, Masakazu Takahara, Yoichi Moroi, Masutaka Furue, Shinichiro Yasumoto, Takashi Hashimoto
Journal: Journal of the American Academy of Dermatology (2011)
Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice
Authors: Marion Peyrou, Lucie Bourgoin, Anne-Laure Poher, Jordi Altirriba, Christine Maeder, Aurélie Caillon, Margot Fournier, Xavier Montet, Françoise Rohner-Jeanrenaud, Michelangelo Foti
Journal: Journal of Hepatology (2014)
Palifermin Induces Alveolar Maintenance Programs in Emphysematous Mice
Authors: Ali O Yildirim, Vandana Muyal, Gerrit John, Bernd Müller, Carola Seifart, Michael Kasper, Heinz Fehrenbach
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Emphysema is characterized by destruction of alveoli with ensuing airspace enlargement and loss of alveoli. Induction of alveolar regeneration is still a major challenge in emphysema therapy.Objectives: To investigate whether therapeutic application of palifermin (ΔN23-KGF) is able to induce a regenerative response in distal lung parenchyma after induction of pulmonary emphysema.Methods: Mice were therapeutically treated at three occasions by oropharyngeal aspiration of 10 mg ΔN23-KGF per kg body weight after induction of emphysema by porcine pancreatic elastase.Measurements and Main Results: Airflow limitation associated with emphysema was largely reversed as assessed by noninvasive head-out body plethysmography. Porcine pancreatic elastase–induced airspace enlargement and loss of alveoli were partially reversed as assessed by design-based stereology. ΔN23-KGF induced proliferation of epithelium, endothelium, and fibroblasts being associated with enhanced differentiation as well as increased expression of vascular endothelial growth factor, vascular endothelial growth factor receptors, transforming growth factor (TGF)-β1, TGF-β2, (phospho-) Smad2, plasminogen activator inhibitor–1, and elastin as assessed by quantitative reverse transcriptase–polymerase chain reaction, Western blotting, and immunohistochemistry. ΔN23-KGF induced the expression of TGF-β1 in and release of active TGF-β1 from primary mouse alveolar epithelial type 2 (AE2) cells, murine AE2-like cells LA-4, and cocultures of LA-4 and murine lung fibroblasts (MLF), but not in MLF cultured alone. Recombinant TGF-β1 but not ΔN23-KGF induced elastin gene expression in MLF. Blockade of TGF-signaling by neutralizing antibody abolished these effects of ΔN23-KGF in LA-4/MLF cocultures.Conclusions: Our data demonstrate that therapeutic application of ΔN23-KGF has the potential to induce alveolar maintenance programs in emphysematous lungs and suggest that the regenerative effect on interstitial tissue is linked to AE2 cell-derived TGF-β1.
Alcohol consumption enhances fatty acid ω-oxidation, with a greater increase in male than in female rats
Authors: Xiaoli Ma, Enrique Baraona, Charles S. Lieber
Journal: Hepatology (1993)

Because ethanol inhibits mitochondrial fatty acid oxidation, with substantial accumulation of fatty acids in the livers of female (but not male) rats, and induces microsomal activities, we assessed possible changes in omega-oxidation. To study this, we pair-fed 24 male and 24 female littermate rats of the same age liquid diets containing 36% of energy either as ethanol or as additional carbohydrate for 4 wk. In controls, the microsomal omega-hydroxylation of lauric acid was 28% greater in female than in male rats (p < 0.05). Ethanol feeding significantly increased this activity in both genders (p < 0.01), but the rise in male rats (89%) was significantly higher than that in female rats (24%). This activity was unaffected by the presence of ethanol in the assay. The effects of ethanol were associated with increases in the content of cytochrome P-450 4A1 (as assessed in Western blots by the reactivity against a sheep antibody against P-450 4A1), and more so in male than in female rats. Despite possible competition by ethanol with the hydroxy fatty acid oxidation to dicarboxylic acids through alcohol dehydrogenase, suberic and sebacic acids accumulated significantly in the livers of alcohol-fed male rats. These effects of ethanol and gender on omega-oxidation paralleled those on the hepatic cytosolic fatty acid-binding protein and fatty acid esterification previously reported in similarly treated rats. Dicarboxylic acid products of omega-oxidation have been incriminated as mediators of similar effects by other drugs.(ABSTRACT TRUNCATED AT 250 WORDS)
Control of T Cell Viability
Authors: Philippa Marrack, John Kappler
Journal: Annual Review of Immunology (2004)

The factors affecting T cell viability vary depending on the type and status of the T cell involved. Naive T cells die via a Bcl-2/Bim dependent route. Their deaths are prevented in animals by IL-7 and contact with MHC. Activated T cells die in many different ways. Among these is a pathway involving signals that come from outside the T cell and affect it via surface receptors such as Fas. Activated T cells also die through a pathway driven by signals generated within the T cell itself, a cell autonomous route. This pathway involves members of the Bcl-2 family, in particular Bcl-2, Bcl-xl, Bim, and probably Bak. The viability of CD8+ and CD4+ memory T cells is controlled in different ways. CD8+ memory T cells are maintained by IL-15 and IL-7. The control of CD4+ memory T cells is more mysterious, with roles reported for IL-7 and/or contact via the TCR.
Antitumor Activity of Rapamycin in a Transgenic Mouse Model of ErbB2-Dependent Human Breast Cancer
Authors: Mei Liu, Amy Howes, Jacqueline Lesperance, William B. Stallcup, Craig A. Hauser, Kuniko Kadoya, Robert G. Oshima, Robert T. Abraham
Journal: Cancer Research (2005)

Abstract The ErbB2 (Neu) receptor tyrosine kinase is frequently overexpressed in human breast cancers, and this phenotype correlates with a poor clinical prognosis. We examined the effects of the mammalian target of rapamycin inhibitor, rapamycin, on mammary tumorigenesis in transgenic mice bearing an activated ErbB2 (NeuYD) transgene in the absence or presence of a second transgene encoding vascular endothelial growth factor (VEGF). Treatment of NeuYD or NeuYD × VEGF mice with rapamycin dramatically inhibited tumor growth accompanied by a marked decrease in tumor vascularization. Two key events that may underlie the antitumor activity of rapamycin were decreased expression of ErbB3 and inhibition of hypoxia-inducible factor-1–dependent responses to hypoxic stress. Rapamycin exposure caused only a modest inhibition of the proliferation of tumor-derived cell lines in standard monolayer cultures, but dramatically inhibited the growth of the same cells in three-dimensional cultures, due in part to the induction of apoptotic cell death. These studies underscore the therapeutic potential of mammalian target of rapamycin inhibitors in ErbB2-positive breast cancers and indicate that, relative to monolayer cultures, three-dimensional cell cultures are more predictive in vitro models for studies of the antitumor mechanisms of rapamycin and related compounds.
Assessment of cutaneous sensory and autonomic axon reflexes in rheumatoid arthritis.
Authors: V.A. Jolliffe, P Anand, B.L. Kidd
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVE--To assess sensory function in skin overlying the joints of patients with rheumatoid arthritis, in relation to the pain and tenderness which commonly arises in structures not directly involved in the inflammatory process. METHODS--An intradermal injection of capsaicin 0.05 microgram in 10 microliters was made over the wrists and forearms of 40 patients with rheumatoid arthritis and 46 control subjects. Axon reflex vasodilatation was measured using laser Doppler flowmetry. Cholinergic sympathetic function was assessed by measuring axon reflex sweating induced by a single intradermal injection of nicotine 0.5 microgram in 0.1 ml. RESULTS--Capsaicin induced axon reflex vasodilation over the wrists was found to decrease with age in normal subjects (r = -0.62, p &lt; 0.001). In patients with rheumatoid arthritis, capsaicin induced axon reflex vasodilatation was significantly greater over the wrists, but not the forearms, when compared with age matched normal controls (p &lt; 0.01). A minimal correlation between axon reflex vasodilatation and visual analogue pain score was apparent in the rheumatoid group (r = -0.37, p &lt; 0.05). Nicotine induced sweating responses were similar in the rheumatoid and normal groups, and both showed a linear age related decline. CONCLUSIONS--The results show a selective increase of capsaicin induced vasodilatation in skin overlying joints in patients with rheumatoid arthritis. This suggests that the activity of a sub-population of periarticular small sensory fibres is altered, which may explain, at least in part, some of the clinical findings in this disorder.
Improvement in volitional tests of muscle function alone may not be adequate evidence that inspiratory muscle training is effective
Authors: M.I. Polkey, J. Moxham
Journal: European Respiratory Journal (2003)

In 1976 Leith and Bradley 1 generated the hypothesis that the inspiratory muscles, like other muscles, could be trained. In the now classic study 12 healthy adults were divided into three groups of four. One group underwent strength testing, consisting of maximal voluntary efforts against a closed airway over a range of lung volumes for 30 min per day for 5 days a week for 5 weeks. The second group performed voluntary hyperventilation for a similar period and the third group served as controls. They found that subjects undergoing strength training increased strength by 55% while endurance trainers experienced a 15–19% increase in the time that they could sustain maximal and submaximal ventilation. Only minor improvements were seen in control subjects. Since the seminal observations of Leith and Bradley 1 numerous investigators (a PubMed search with the term respiratory muscle training yielded over 1500 citations in September 2003) have explored the field, yet theclinical role of inspiratory muscle training remains controversial.

In high income countries chronic obstructive pulmonary disease (COPD) is the most …
Novel Delivery Systems for Improving the Clinical Use of Peptides
Authors: Miia Kovalainen, Juha Mönkäre, Joakim Riikonen, Ullamari Pesonen, Maria Vlasova, Jarno Salonen, Vesa-Pekka Lehto, Kristiina Järvinen, Karl-Heinz Herzig
Journal: Pharmacological Reviews (2015)

Peptides have long been recognized as a promising group of therapeutic substances to treat various diseases. Delivery systems for peptides have been under development since the discovery of insulin for the treatment of diabetes. The challenge of using peptides as drugs arises from their poor bioavailability resulting from the low permeability of biological membranes and their instability. Currently, subcutaneous injection is clinically the most common administration route for peptides. This route is cost-effective and suitable for self-administration, and the development of appropriate dosing equipment has made performing the repeated injections relatively easy; however, only few clinical subcutaneous peptide delivery systems provide sustained peptide release. As a result, frequent injections are needed, which may cause discomfort and additional risks resulting from a poor administration technique. Controlled peptide delivery systems, able to provide required therapeutic plasma concentrations over an extended period, are needed to increase peptide safety and patient compliancy. In this review, we summarize the current peptidergic drugs, future developments, and parenteral peptide delivery systems. Special emphasis is given to porous silicon, a novel material in peptide delivery. Biodegradable and biocompatible porous silicon possesses some unique properties, such as the ability to carry exceptional high peptide payloads and to modify peptide release extensively. We have successfully developed porous silicon as a carrier material for improved parenteral peptide delivery. Nanotechnology, with its different delivery systems, will enable better use of peptides in several therapeutic applications in the near future.
Midkine Regulates BP through Cytochrome P450–Derived Eicosanoids
Authors: Yuka Sato, Waichi Sato, Shoichi Maruyama, Christopher S. Wilcox, John R. Falck, Tomohiro Masuda, Tomoki Kosugi, Hiroshi Kojima, Kayaho Maeda, Kazuhiro Furuhashi, Masahiko Ando, Enyu Imai, Seiichi Matsuo, Kenji Kadomatsu
Journal: Journal of the American Society of Nephrology (2014)

The effects of endothelium-derived hyperpolarizing factors have been attributed to cytochrome P450–derived epoxyeicosatrienoic acids (EETs), but the regulation and role of EETs in endothelial dysfunction remain largely unexplored. Hypertension is a primary risk factor for renal dysfunction, which is frequently accompanied by various systemic diseases induced by endothelial dysfunction in the microcirculation. We previously reported that the endothelial growth factor midkine (MK) enhances hypertension in a model of CKD. Here, we investigated the hypothesis that MK regulates EET activity and thereby BP. MK gene-deleted mice were resistant to hypertension and developed less glomerulosclerosis and proteinuria after administration of a nitric oxide synthase (NOS) inhibitor in the setting of uninephrectomy. The hypertension observed in uninephrectomized wild-type mice after NOS inhibition was ameliorated by anti-MK antibody. MK-deficient mice produced higher amounts of EETs, and EETs dominantly regulated BP in these mice. Furthermore, MK administration to MK-deficient mice recapitulated the BP control observed in wild-type mice. EETs also dominantly regulated renal blood flow, which may influence renal function, in MK-deficient mice. Taken together, these results suggest that the MK/EET pathway is physiologically engaged in BP control and could be a target for the treatment of hypertension complicated by endothelial dysfunction.
New Technologies for Human Cancer Imaging
Authors: John V. Frangioni
Journal: Journal of Clinical Oncology (2008)

Despite technical advances in many areas of diagnostic radiology, the detection and imaging of human cancer remains poor. A meaningful impact on cancer screening, staging, and treatment is unlikely to occur until the tumor-to-background ratio improves by three to four orders of magnitude (ie, 10(3)- to 10(4)-fold), which in turn will require proportional improvements in sensitivity and contrast agent targeting. This review analyzes the physics and chemistry of cancer imaging and highlights the fundamental principles underlying the detection of malignant cells within a background of normal cells. The use of various contrast agents and radiotracers for cancer imaging is reviewed, as are the current limitations of ultrasound, x-ray imaging, magnetic resonance imaging (MRI), single-photon emission computed tomography, positron emission tomography (PET), and optical imaging. Innovative technologies are emerging that hold great promise for patients, such as positron emission mammography of the breast and spectroscopy-enhanced colonoscopy for cancer screening, hyperpolarization MRI and time-of-flight PET for staging, and ion beam-induced PET scanning and near-infrared fluorescence-guided surgery for cancer treatment. This review explores these emerging technologies and considers their potential impact on clinical care. Finally, those cancers that are currently difficult to image and quantify, such as ovarian cancer and acute leukemia, are discussed.
Clones and Subclones in the Lung Cancer Field
Authors: W. N. Hittelman
Journal: JNCI Journal of the National Cancer Institute (1999)

Based on a variety of clinical (1,2), histologic (3,4), cytogenetic (5–7), and molecular (8–10) data, lung cancer, like many other epithelial cancers, is suggested to develop as a multistep tumorigenesis process in a field of cancerization (11,12). Carcinogen exposure (e.g., tobacco) is believed to induce genetic damage in target cells that accumulates over years of exposure. Moreover, chronic tissue injury leads to chronic wound healing, whereby cells carrying genetic alterations that are important for survival and preferential regrowth expand at the expense of their neighbors. These surviving colonies continue to accumulate new tissue-relevant genetic alterations and eventually evolve into an invasive lesion. Since the whole aerodigestive tract is similarly exposed to carcinogen, one might predict that such clonal outgrowths develop throughout the exposed tissue. Until recently, characterization of the fine structure of such a multifocal and multistep tumorigenesis process in lung tissue was technically hampered by the need for tissue dissociation either for cell culture or for bulk molecular genetic or cytogenetic analyses. The advent of molecular techniques that could be used on smaller amounts of tissue, including polymerase chain reaction on microdissected epithelium (13,14) and in situ hybridization techniques (15–17), increased the spatial resolution of the analyses. Moreover, the identification of molecular changes that occurred at relatively high frequencies in lung tumors provided informative markers that could be used on small tissue samples to query the nature of the lung cancerization field (18,19). As a result, several groups have now demonstrated the presence of clonal outgrowths in the epithelial field of lung tumors, with higher frequencies of genetic changes detectable in dysplastic lesions than in normal-appearing and metaplastic le-
HORIZONTAL TRANSMISSION OF ADULT T-CELL LEUKAEMIA VIRUS FROM MALE TO FEMALE JAPANESE MONKEY
Authors: Isao Miyoshi, Masatoshi Fujishita, Hirokuni Taguchi, Kenji Niiya, Makoto Kobayashi, KiyoakiMatsuba Yashi, Norikatsu Miwa
Journal: The Lancet (1983)