tbuckley/cabot-search huggingface dataset:
Gene Transfer of Low Levels of β-Glucuronidase Corrects Hepatic Lysosomal Storage in a Large Animal Model of Mucopolysaccharidosis VII
Authors: John H. Wolfe, Mark S. Sands, Noam Harel, Margaret A. Weil, Micheal K. Parente, Aracelis C. Polesky, John J. Reilly, Christopher Hasson, Staci Weimelt, Mark E. Haskins
Journal: Molecular Therapy (2000)

Gene therapy has been at least partially effective in several mouse disease models, but treatment of large mammals has been more difficult to achieve. One major limitation is that only low levels of expression of the corrective gene are often maintained in vivo. In a mouse model of the lysosomal storage disease mucopolysaccharidosis (MPS) type VII (Sly disease) with a null mutation in β-glucuronidase, gene transfer experiments have shown that only 1-2% of normal β-glucuronidase can correct the storage in some major organs. In contrast, MPS VII dogs, cats, and humans that have residual β-glucuronidase activity levels in this range are affected. Thus, higher levels of transferred gene expression may be needed to achieve a therapeutic effect in large animals and humans. We tested this by examining liver pathology in MPS VII dogs after intraperitoneal transplantation of neo-organs containing retrovirus vector-corrected autologous fibroblasts that expressed low levels of β-glucuronidase. The enzyme secreted from the neo-organs was taken up by the liver and significantly reduced the substrate content compared with untreated dogs. This suggests that small amounts of normal enzyme, when delivered to target tissues, may be therapeutically effective in human MPS VII patients. Gene therapy has been at least partially effective in several mouse disease models, but treatment of large mammals has been more difficult to achieve. One major limitation is that only low levels of expression of the corrective gene are often maintained in vivo. In a mouse model of the lysosomal storage disease mucopolysaccharidosis (MPS) type VII (Sly disease) with a null mutation in β-glucuronidase, gene transfer experiments have shown that only 1-2% of normal β-glucuronidase can correct the storage in some major organs. In contrast, MPS VII dogs, cats, and humans that have residual β-glucuronidase activity levels in this range are affected. Thus, higher levels of transferred gene expression may be needed to achieve a therapeutic effect in large animals and humans. We tested this by examining liver pathology in MPS VII dogs after intraperitoneal transplantation of neo-organs containing retrovirus vector-corrected autologous fibroblasts that expressed low levels of β-glucuronidase. The enzyme secreted from the neo-organs was taken up by the liver and significantly reduced the substrate content compared with untreated dogs. This suggests that small amounts of normal enzyme, when delivered to target tissues, may be therapeutically effective in human MPS VII patients.
Toxic Effects of Marihuana
Authors: Doris H. Milman
Journal: JAMA (1973)

<h3>To the Editor.—</h3> Drs. Kolansky and Moore (222:35, 1972) are to be commended for their careful clinical studies of the toxic effects of longterm cannabis use. One would hope that this type of clinical assessment of adverse effects would receive at least as much public attention as uninformed laymen's enthusiastic endorsements. The authors make reference in six cases (7-11, 13) to a spontaneous recurrence of the "high" state or feelings of depersonalization in the absence of marihuana usage. These patients were all postulated to have structural biochemical changes. I wonder if the authors have given thought to the significance of this spontaneous recurrence phenomenon. It has also been noted, and, in fact, is considered to be a typical feature of usage of lysergic acid diethylamide (LSD). I have observed the recurrence phenomenon in several adolescent patients. Some of these are sporadic rather than heavy or long-term smokers. The experience is very
Proteins in Human Nutrition
Authors: Wayne Callaway
Journal: JAMA (1974)

Protein malnutrition is more an economic problem than a medical one, more a matter of food distribution than of production, more linked to the slowness of land reform than to the introduction of sophisticated technology. Present scientific knowledge is already capable of eliminating protein deficiency in most underdeveloped countries. The crucial problem is to overcome the formidable obstacles that impede the proper use of this knowledge... not to elaborate still more refined techniques. So begins this excellent international symposium. Ironically, the remaining 44 discussants devote most of their words to the problems of technique. Perhaps this is inevitable. After all, the biologist, the biochemist, the agricultural scientist, and the physician are neither economists nor politicians. The scientist can prepare the tools for solving some of society's problems, but, in the final analysis, political and economic forces determine if and how these tools will be used. The "tools" are amply demonstrated
Role of the Na+/H+ antiporter in rat proximal tubule bicarbonate absorption.
Authors: P A Preisig, H E Ives, E J Cragoe, R J Alpern, F C Rector
Journal: Journal of Clinical Investigation (1987)

Amiloride and the more potent amiloride analog, 5-(N-t-butyl) amiloride (t-butylamiloride), were used to examine the role of the Na+/H+ antiporter in bicarbonate absorption in the in vivo microperfused rat proximal convoluted tubule. Bicarbonate absorption was inhibited 29, 46, and 47% by 0.9 mM or 4.3 mM amiloride, or 1 mM t-butylamiloride, respectively. Sensitivity of the Na+/H+ antiporter to these compounds in vivo was examined using fluorescent measurements of intracellular pH with (2', 7')-bis(carboxyethyl)-(5,6)-carboxyfluorescein (BCECF). Amiloride and t-butylamiloride were shown to be as potent against the antiporter in vivo as in brush border membrane vesicles. A model of proximal tubule bicarbonate absorption was used to correct for changes in the luminal profiles for pH and inhibitor concentration, and for changes in luminal flow rate in the various series. We conclude that the majority of apical membrane proton secretion involved in transepithelial bicarbonate absorption is mediated by the Na+-dependent, amiloride-sensitive Na+H+ antiporter. However, a second mechanism of proton secretion contributes significantly to bicarbonate absorption. This mechanism is Na+-independent and amiloride-insensitive.
Pneumonia and Pulmonary Infarction in Sickle Cell Anemia
Authors: Elizabeth Barrett-Connor
Journal: JAMA (1973)

Patients with sickle anemia are clearly at increased risk to both pneumococcal pneumonia and pulmonary infarction. Certain data suggest that pneumonia is the more common condition, but in some patients differential diagnosis may be impossible. It is suggested that because the pneumococcal infection may be fulminant in patients with sickle cell anemia, all acute pulmonary episodes be treated with antibiotics. Anticoagulant therapy for infarction is theoretically desirable, but there is no evidence that it alters the course of the illness.
ERK Plays a Regulatory Role in Induction of LTP by Theta Frequency Stimulation and Its Modulation by β-Adrenergic Receptors
Authors: Danny G Winder, Kelsey C Martin, Isabel A Muzzio, Daniel Rohrer, Andrzej Chruscinski, Brian Kobilka, Eric R Kandel
Journal: Neuron (1999)

MAP kinase (ERK) translates cell surface signals into alterations in transcription. We have found that ERK also regulates hippocampal neuronal excitability during 5 Hz stimulation and thereby regulates forms of long-term potentiation (LTP) that do not require macromolecular synthesis. Moreover, ERK-mediated changes in excitability are selectively required for some forms of LTP but not others. ERK is required for the early phase of LTP elicited by brief 5 Hz stimulation, as well as for LTP elicited by more prolonged 5 Hz stimulation when paired with beta1-adrenergic receptor activation. By contrast, ERK plays no role in LTP elicited by a single 1 s 100 Hz train. Consistent with these results, we find that ERK is activated by beta-adrenergic receptors in CA1 pyramidal cell somas and dendrites.
Molecular cloning of hamster brain and atrial natriuretic peptide cDNAs. Cardiomyopathic hamsters are useful models for brain and atrial natriuretic peptides.
Authors: N Tamura, Y Ogawa, H Itoh, H Arai, S Suga, O Nakagawa, Y Komatsu, I Kishimoto, K Takaya, T Yoshimasa
Journal: Journal of Clinical Investigation (1994)

Brain and atrial natriuretic peptides (BNP and ANP) are cardiac hormones with diuretic, natriuretic, and vasodilatory activities. Cardiomyopathic hamsters are widely used animal models of heart failure. Due to the structural divergence of BNP among species, examination on pathophysiological roles of BNP using cardiomyopathic hamsters is so far impossible. We therefore isolated hamster BNP and ANP cDNAs, and investigated synthesis and secretion of these peptides in normal and cardiomyopathic hamsters. The COOH-terminal 32-residue peptide of cloned hamster preproBNP with 122 amino acids, preceded by a single arginine residue, supposedly represents hamster BNP showing < 50% homology to rat BNP. Alpha-hamster ANP, 28-residue peptide, is identical to alpha-rat ANP. In hamsters, BNP and ANP occur mainly in the ventricle and the atrium, respectively. The 32-wk-old hypertrophic cardiomyopathic BIO14.6 strain exhibited ventricular hypertrophy. The 32-wk-old dilated cardiomyopathic BIO53.58 strain remained at the stage without apparent heart failure. In BIO14.6 and BIO53.58 strains at this age, ventricular BNP and ANP gene expressions are augmented, and the plasma BNP concentration is elevated to 136 and 108 fmol/ml, respectively, three times greater than the elevated plasma ANP concentration, which well mimics changes of the plasma BNP and ANP concentrations in human heart failure. Cardiomyopathic hamsters, therefore, are useful models to investigate the implication of BNP in human cardiovascular diseases.
Spacing between doses on a thrice-daily regimen.
Authors: L S Alfredsson, S E Norell
Journal: BMJ (1981)

Cancer invasion and metastasis occur in a complex three-dimensional (3D) environment, with reciprocal feedback from the surrounding host tissue and vasculature-governing behavior. In this study, we used a novel intravital method that revealed spatiotemporal regulation of Src activity in response to the anti-invasive Src inhibitor dasatinib. A fluorescence lifetime imaging microscopy–fluorescence resonance energy transfer (FLIM-FRET) Src biosensor was used to monitor drug-targeting efficacy in a transgenic p53-mutant mouse model of pancreatic cancer. In contrast to conventional techniques, FLIM-FRET analysis allowed for accurate, time-dependent, live monitoring of drug efficacy and clearance in live tumors. In 3D organotypic cultures, we showed that a spatially distinct gradient of Src activity exists within invading tumor cells, governed by the depth of penetration into complex matrices. In parallel, this gradient was also found to exist within live tumors, where Src activity is enhanced at the invasive border relative to the tumor cortex. Upon treatment with dasatinib, we observed a switch in activity at the invasive borders, correlating with impaired metastatic capacity in vivo. Src regulation was governed by the proximity of cells to the host vasculature, as cells distal to the vasculature were regulated differentially in response to drug treatment compared with cells proximal to the vasculature. Overall, our results in live tumors revealed that a threshold of drug penetrance exists in vivo and that this can be used to map areas of poor drug-targeting efficiency within specific tumor microenvironments. We propose that using FLIM-FRET in this capacity could provide a useful preclinical tool in animal models before clinical translation. Cancer Res; 73(15); 4674–86. ©2013 AACR.
A Large, Symptomatic, Left Adrenal Mass
Authors: Kevin Almerico, Osama Hadid, Lauren Ghee
Journal: JAMA Surgery (2015)

A man in his 40s presented with sudden left-sided abdominal pain that was sharp, severe, and associated with emesis. He denied fevers, dizziness, or recent trauma. He had no notable medical or surgical history. He was afebrile with normal vital signs. He was well nourished, alert, and in no acute distress. Results of an abdominal examination revealed normoactive bowel sounds, no distention, but tenderness on the left side. Computed tomography (CT) of the abdomen and pelvis with intravenous contrast revealed a 12 × 13 × 11-cm left-sided adrenal mass (Figure 1). Results of laboratory examination revealed plasma levels of metanephrines, normetanephrines, cortisol, renin, and aldosterone within reference limits. Quiz at jamasurgery.com Lossy 120 mm
Introduction--the methyl parathion story: a chronicle of misuse and preventable human exposure.
Authors: Carol Rubin, Emilio Esteban, Robert H Hill, Ken Pearce
Journal: Environmental Health Perspectives (2002)

In the fall of 1994, Lorain County, Ohio, became the site of the first investigation of several large-scale incidences in which the organophosphate pesticide methyl parathion was illegally applied to private residences. The extent of potential human exposure to this pesticide led the Ohio Department of Health to formally request technical assistance from the Centers for Disease Control and Prevention (CDC). This article describes the initial investigation of 64 homes in Ohio and introduces the method of using both biological markers of exposure (p-nitrophenol levels in human urine samples) and environmental markers of contamination in dust and air samples when making public health decisions about the cleanup of homes sprayed with methyl parathion. The results of the CDC rapid investigation led the U.S. Environmental Protection Agency to declare the contaminated homes in Lorain County a Superfund cleanup site. Seven years after the Lorain incident, and after subsequent Superfund actions had been implemented in Illinois and Mississippi, researchers participated in an expanded session devoted to methyl parathion at the 11th Annual Meeting of the International Society of Exposure Analysis held in Charleston, South Carolina, in the fall of 2001. The articles included in this monograph are based on presentations at that meeting. They report previously unpublished data that tell the methyl parathion story from different perspectives, each providing in-depth information about separate aspects of this multistate, multiagency, and multimillion dollar chemical exposure. This monograph is the methyl parathion story.
Abstract 3526: The mTORC2 component RICTOR plays a key role in lung cancer cell growth
Authors: Haiying Cheng, Yiyu Zou, Alain Borczuk, Wanglong Qiu, Bilal Piperdi, Mimi Kim, Balazs Halmos, Roman Perez-Soler‎
Journal: Cancer Research (2014)

Abstract RICTOR (Rapamycin-insensitive companion of mTOR protein) is a key component of mTORC2 (the mammalian target of rapamycin complex 2). One of the most-recognized targets for RICTOR-mTORC2 is AKT (Ser473). RICTOR also carries functions independent of mTORC2. RICTOR signaling has been suggested to play key roles in regulating cancer cell migration, invasion and metastasis in breast, ovarian, colorectal cancers and gliomas. The potential roles of RICTOR in lung cancer remain to be elucidated. We first examined the expression profile of RICTOR in primary lung tumor specimens and in lung cancer cell lines by immunohistochemistry. Among 125 FFPE patients' specimen, ninety nine were stained positive for RICTOR (intensity 1+ to 3+). More interestingly, the RICTOR IHC expression is stronger in squamous cell lung cancer in comparison to adenocarcinoma. Furthermore, twenty four out of 36 lung cancer cell lines showed positive RICTOR IHC staining. Thus, RICTOR is expressed in most lung tumors. To investigate the role of RICTOR in lung cancer cell growth, we found that RICTOR knockdown by siRNA reduced colony formation in A549, HCC827 and Calu3 cells, regardless of KRAS or EGFR mutational status (A549 is KRAS mutated whereas HCC827 is EGFR mutated). Western blot confirmed RICTOR knockdown and also decreased level of its downstream pAKT S473. We further blocked RICTOR signaling by utilizing inducible shRNAs of RICTOR. Similar inhibition of lung cancer cell growth was observed. Moreover, to test the in vivo role of RICTOR, we preformed xenograft mouse experiments. When RICTOR was inducibly knockdown by the presence of doxycycline, the growth of A549 lung tumor xenografts was markedly reduced by 60% (P&amp;lt;0.05). Taken together, our study provides the rational basis for a potential RICTOR-targeted therapy in lung cancer. Citation Format: Haiying Cheng, Yiyu Zou, Alain Borczuk, Wanglong Qiu, Bilal Piperdi, Mimi Kim, Balazs Halmos, Roman Perez-Soler‎. The mTORC2 component RICTOR plays a key role in lung cancer cell growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3526. doi:10.1158/1538-7445.AM2014-3526
Two Cases of Cryptococcal Meningitis, one Treated with 5-Fluorocytosine
Authors: J. S. Watkins, M. J. Campbell, D. Gardner-Medwin, H. R. Ingham, I. G. Murray
Journal: BMJ (1969)

Cryptococcal meningitis occurred in two patients in the North of England. One, an elderly woman who was ill for 12 months with an obscure indolent meningitis until use of steroid drugs resulted in an acute exacerbation during which cryptococci were isolated, was treated successfully with amphotericin B. The other, a student from New Guinea with subacute meningitis, could not tolerate amphotericin B but responded to two courses of oral treatment with 5-fluorocytosine 100-200 mg./kg./ day without any appreciable side-effects. Further trials of this drug in the treatment of cryptococcosis are recommended.
Evidence for a protective role of pulmonary surfactant protein D (SP-D) against influenza A viruses.
Authors: K L Hartshorn, E C Crouch, M R White, P Eggleton, A I Tauber, D Chang, K Sastry
Journal: Journal of Clinical Investigation (1994)

We tested the hypothesis that pulmonary surfactant-associated lectins--surfactant proteins A and D (SP-A, and -D)--contribute to initial protective mechanisms against influenza A viruses (IAVs). SP-D potently inhibited hemagglutination activity of several strains of IAV as well as causing viral aggregation. SP-D enhanced neutrophil binding of IAV and neutrophil respiratory burst responses to the virus. Neutrophil dysfunction resulting from IAV exposure was diminished when the virus was pre-incubated with SP-D. Each of these effects was mediated by the calcium-dependent carbohydrate-binding property of SP-D. Native SP-D preparations of both human and rat origin, as well as recombinant rat SP-D, had similar activity. SP-A also inhibited IAV hemagglutination activity. We have previously reported that related mammalian serum lectins (mannose-binding lectin [MBL] and conglutinin) have similar effects. SP-D was at least 10-fold more potent at causing hemagglutination inhibition than were SP-A or MBL. SP-D was shown to contribute to potent anti-IAV activity of human bronchoalveolar lavage fluid. These results suggest that SP-D--alone, and in conjunction with SP-A and phagocytic cells--constitutes an important component of the natural immune response to IAV infection within the respiratory tract.
Prevention of Heart Failure
Authors: Douglas D. Schocken, Emelia J. Benjamin, Gregg C. Fonarow, Harlan M. Krumholz, Daniel Levy, George A. Mensah, Jagat Narula, Eileen Stuart Shor, James B. Young, Yuling Hong
Journal: Circulation (2008)

The increase in heart failure (HF) rates throughout the developed and developing regions of the world poses enormous challenges for caregivers, researchers, and policymakers. Therefore, prevention of this global scourge deserves high priority. Identifying and preventing the well-recognized illnesses that lead to HF, including hypertension and coronary heart disease, should be paramount among the approaches to prevent HF. Aggressive implementation of evidence-based management of risk factors for coronary heart disease should be at the core of HF prevention strategies. Questions currently in need of attention include how to identify and treat patients with asymptomatic left ventricular systolic dysfunction (Stage B HF) and how to prevent its development. The relationship of chronic kidney disease to HF and control of chronic kidney disease in prevention of HF need further investigation. Currently, we have limited understanding of the pathophysiological basis of HF in patients with preserved left ventricular systolic function and management techniques to prevent it. New developments in the field of biomarker identification have opened possibilities for the early detection of individuals at risk for developing HF (Stage A HF). Patient groups meriting special interest include the elderly, women, and ethnic/racial minorities. Future research ought to focus on obtaining a much better knowledge of genetics and HF, especially both genetic risk factors for development of HF and genetic markers as tools to guide prevention. Lastly, a national awareness campaign should be created and implemented to increase public awareness of HF and the importance of its prevention. Heightened public awareness will provide a platform for advocacy to create national research programs and healthcare policies dedicated to the prevention of HF.
A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic.
Authors: S Jobling, T Reynolds, R White, M G Parker, J P Sumpter
Journal: Environmental Health Perspectives (1995)

Sewage, a complex mixture of organic and inorganic chemicals, is considered to be a major source of environmental pollution. A random screen of 20 organic man-made chemicals present in liquid effluents revealed that half appeared able to interact with the estradiol receptor. This was demonstrated by their ability to inhibit binding of 17 beta-estradiol to the fish estrogen receptor. Further studies, using mammalian estrogen screens in vitro, revealed that the two phthalate esters butylbenzyl phthalate (BBP) and di-n-butylphthalate (DBP) and a food antioxidant, butylated hydroxyanisole (BHA) were estrogenic; however, they were all less estrogenic than the environmental estrogen octylphenol. Phthalate esters, used in the production of various plastics (including PVC), are among the most common industrial chemicals. Their ubiquity in the environment and tendency to bioconcentrate in animal fat are well known. Neither BBP nor DBP were able to act as antagonists, indicating that, in the presence of endogenous estrogens, their overall effect would be cumulative. Recently, it has been suggested that environmental estrogens may be etiological agents in several human diseases, including disorders of the male reproductive tract and breast and testicular cancers. The current finding that some phthalate compounds and some food additives are weakly estrogenic in vitro, needs to be supported by further studies on their effects in vivo before any conclusions can be made regarding their possible role in the development of these conditions.