tbuckley/cabot-search huggingface dataset:
The Genetic Engineering of Hematopoietic Stem Cells: the Rise of Lentiviral Vectors, the Conundrum of the LTR, and the Promise of Lineage-restricted Vectors
Authors: Alex H Chang, Michel Sadelain
Journal: Molecular Therapy (2007)

Recent studies on the integration patterns of different categories of retroviral vectors, the genotoxicity of long-terminal repeats (LTRs) and other genetic elements, the rise of lentiviral technology and the emergence of regulated vector systems providing tissue-restricted transgene expression and RNA interference, are profoundly changing the landscape of stem cell-based therapies. New developments in vector design and an increasing understanding of the mechanisms underlying insertional oncogenesis are ushering in a new phase in hematopoietic stem cell (HSC) engineering, thus bringing the hitherto exclusive reliance on LTR-driven, γ-retroviral vectors to an end. Based on their ability to transduce non-dividing cells and their genomic stability, lentiviral vectors offer new prospects for the manipulation of HSCs. Tissue-specific vectors, as exemplified by globin vectors, not only provide therapeutic efficacy, but may also enhance safety, insofar that they restrict transgene expression in stem cells, progenitor cells and blood cells in all but the transcriptionally targeted lineage. This review provides a survey of these advances as well as several remaining challenges, focusing in particular on the importance of achieving adequate levels of protein expression from a limited number of vector copies per cell—ideally one to two. Recent studies on the integration patterns of different categories of retroviral vectors, the genotoxicity of long-terminal repeats (LTRs) and other genetic elements, the rise of lentiviral technology and the emergence of regulated vector systems providing tissue-restricted transgene expression and RNA interference, are profoundly changing the landscape of stem cell-based therapies. New developments in vector design and an increasing understanding of the mechanisms underlying insertional oncogenesis are ushering in a new phase in hematopoietic stem cell (HSC) engineering, thus bringing the hitherto exclusive reliance on LTR-driven, γ-retroviral vectors to an end. Based on their ability to transduce non-dividing cells and their genomic stability, lentiviral vectors offer new prospects for the manipulation of HSCs. Tissue-specific vectors, as exemplified by globin vectors, not only provide therapeutic efficacy, but may also enhance safety, insofar that they restrict transgene expression in stem cells, progenitor cells and blood cells in all but the transcriptionally targeted lineage. This review provides a survey of these advances as well as several remaining challenges, focusing in particular on the importance of achieving adequate levels of protein expression from a limited number of vector copies per cell—ideally one to two.
Asymptomatic Glomerulonephritis After Nonstreptococcal Upper Respiratory Infections
Authors: MICHAEL C. SMITH
Journal: Annals of Internal Medicine (1979)

Two hundred forty previously healthy military personnel with nonstreptococcal upper respiratory infections were prospectively studied to define the incidence and clinicopathologic characteristics of possible virus-associated glomerulonephritis. Nine patients without preceding streptococcal infection had erythrocyte casts on urinalysis and glomerulonephritis on biopsy. Of these nine, four had a reduction in total hemolytic complement and five had serologic evidence of infection with adenovirus, influenza A, or influenza B. Initial renal biopsy showed either focal or diffuse mesangial proliferation in all nine, with mesangial C3 deposits in six specimens. Repeat biopsy in three showed histologic improvement or loss of immunofluorescent staining, or both. Sequential creatinine clearances were reduced to 74 to 90 mL/min.1.73 m2 in five patients for the duration of follow-up. We conclude that nonstreptococcal upper respiratory infection is frequently associated with glomerulonephritis and that abnormal glomerular structure and decreased creatinine clearances may persist for at least 2 to 8 months.
The Treatment of Hyperthyroidism
Authors: Edward Rose
Journal: JAMA (1967)

<h3>To the Editor:—</h3> The editorial inThe Journal(<b>200</b>:162, 1967) entitled "Treatment of Hyperthyroidism" displays a regrettable lack of objectivity. All present methods of treatment for hyperthyroidism possess certain disadvantages, and the cumulative long-term incidence of hypothyroidism after treatment with radioactive iodine is certainly among them. However, the magnitude of this disadvantage is moot. Total thyroid ablation by radiation or surgery has long been employed in the treatment of certain cardiac disorders, rarely in severe diabetes and blood dyscrasias, and more recently in progressive ophthalmopathy complicating Graves' disease. Accidental post-therapeutic myxedema is amenable to complete control by adequate doses of thyroid hormone, the principal risks appearing consequent to the patient's lapse from supervision and treatment. While emphasizing the 70% estimated cumulative incidence of hypothyroidism ten years after radioactive iodine treatment, cited by Nofal et al, the editorial fails to mention other data in the same article. These include the
Enteroscopy and capsule endoscopy
Authors: M. Pennazio
Journal: Endoscopy (2006)

Research interest in small-bowel endoscopy continues to be strong, even though 5 years have now passed since the advent of capsule endoscopy (CE), followed by that of double-balloon endoscopy (DBE), causing a revolution in this sector of endoscopy. Fully 120 scientific contributions on the subject were presented at Digestive Disease Week (DDW) this year, 83 of which concerned CE, 27 DBE, with 10 being comparisons between the two techniques (Figure [1]). This review discusses in detail the 20 most significant of these. Numerous studies have analyzed technical aspects of CE and the wide therapeutic applications of DBE, often in series that were insufficiently large, heterogeneous, and mainly with retrospective analysis. Gastrointestinal bleeding is still the field in which the two methods are most often clinically applied, and that in which the scientific evidence is most solid. For some indications for CE, such as inflammatory bowel diseases and esophageal disorders, there is still controversy regarding its real clinical usefulness. Most comparative studies hold that CE is a valuable screening test, while DBE should serve as the confirmatory/therapeutic modality (Figure [2]).
Abstract 4901: Impact of the TGF-β1 isoform on p53 signalling in ovarian cancer cell lines in response to cisplatin
Authors: Sébastien Baribeau, Parvesh Chaudhry, Éric Asselin
Journal: Cancer Research (2012)

Abstract Transforming growth factor β is a pleiotropic cytokine which inhibits cell growth, induces cellular differentiation, and can lead to cellular apoptosis under certain conditions. TGF-β is also involved in epithelial-mesenchymal transition (EMT), a phenomenon by which cells acquire a dedifferentiated phenotype and gain motility and invasive properties. In the present study, we investigated the impact of TGF-β1 on p53 mediated cellular signalling in ovarian cancer cell lines in response to cisplatin. Four cell lines with different p53 status: A2780 (wild-type p53), A2780CP (derived from A2780, resistant to cisplatin, one p53 allele mutated V172F and one p53 allele wild-type), OVCAR-3 (p53 mutated R248Q) and SKOV-3 (p53 negative) were used in the present study. Cells were co-treated with TGF-β1 (10ng/mL) and cisplatin (10μM) for 24 hours and protein levels were analysed by western blotting. Our results show that TGF-β1 inhibits cisplatin-induced apoptosis in SKOV-3 cells as demonstrated by reduced PARP cleavage and caspase-3 activation. However, the inhibition of cisplatin-induced apoptosis was not observed in cells with wild type or mutated p53. Co-treatment of TGF-β1 and cisplatin decreased the levels of phosphorylated/active Akt compared to cisplatin alone, suggesting that TGF-β1 promotes cisplatin-induced apoptosis in A2780 cells in part through p53. In addition, Mdm2 was cleaved in response to cisplatin treatment only in p53 wild-type expressing A2780 cells. The levels of the caspase inhibitor XIAP were also decreased in A2780 cells when treated with cisplatin. Together, these results suggest that TGF-β1 promotes apoptosis when used in combination with cisplatin in p53 wild-type ovarian cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4901. doi:1538-7445.AM2012-4901
Evidence of Structural Remodeling in the Dyssynchronous Failing Heart
Authors: Patrick A. Helm, Laurent Younes, Mirza F. Beg, Daniel B. Ennis, Christophe Leclercq, Owen P. Faris, Elliot McVeigh, David Kass, Michael I. Miller, Raimond L. Winslow
Journal: Circulation Research (2005)

Ventricular remodeling of both geometry and fiber structure is a prominent feature of several cardiac pathologies. Advances in MRI and analytical methods now make it possible to measure changes of cardiac geometry, fiber, and sheet orientation at high spatial resolution. In this report, we use diffusion tensor imaging to measure the geometry, fiber, and sheet architecture of eight normal and five dyssynchronous failing canine hearts, which were explanted and fixed in an unloaded state. We apply novel computational methods to identify statistically significant changes of cardiac anatomic structure in the failing and control heart populations. The results demonstrate significant regional differences in geometric remodeling in the dyssynchronous failing heart versus control. Ventricular chamber dilatation and reduction in wall thickness in septal and some posterior and anterior regions are observed. Primary fiber orientation showed no significant change. However, this result coupled with the local wall thinning in the septum implies an altered transmural fiber gradient. Further, we observe that orientation of laminar sheets become more vertical in the early-activated septum, with no significant change of sheet orientation in the late-activated lateral wall. Measured changes in both fiber gradient and sheet structure will affect both the heterogeneity of passive myocardial properties as well as electrical activation of the ventricles.
Australian find suggests worldwide reach for metapneumovirus
Authors: Megan Howe
Journal: The Lancet Infectious Diseases (2002)

A respiratory virus discovered last year in the Netherlands has been isolated for the first time in Australian children, with researchers now suggesting it is likely to be relatively common worldwide. The human metapneumovirus (hMPV), a paramyxovirus most closely related to avian pneumovirus, was first reported by Dutch researchers in 28 children with symptoms ranging from upper respiratory tract infection to severe bronchiolitis and pneumonia (Nat Med 2001; 7: 719–24). Albert Osterhaus, from the Erasmus Medical Centre in Rotterdam, reported that serological studies showed that virtually all children in the Netherlands had been exposed to hMPV by the age of 5, and that it had been circulating in human beings for at least 50 years. The virus was not identified earlier because of its poor replication in standard culture assays and because it appears to take up to 10 days after inoculation to cause cytopathic changes, he suggested. At the time the Dutch results were published, Michael Nissen, Theo Sloots, and their team at the Royal Children's Hospital in Brisbane, Australia, were seeking a molecular diagnosis in the 25–33% of children with unexplained illness consistent with viral pneumonia or bronchiolitis. Using a random sample of nasopharyngeal aspirate specimens, they screened for hMPV by PCR based on the known sequence of the virus after excluding nine common viruses (respiratory syncytial virus [RSV], influenza A and B, parainfluenza 1, 2, and 3, rhinovirus, coronavirus, and adenovirus) and atypical bacteria. Of the 200 samples screened, three were identified as homologous with hMPV, and viral growth was subsequently confirmed in cultures from two samples (Med J Aust 2002; 176: 188). The findings of this preliminary study led Nissen to predict that “hMPV is also relatively common in the Australian community”, a view reinforced by extension of the screening study to 525 samples, of which 40 tested positive for hMPV in 38 children with an average age of 2·4 years. Studies of antibody responses in selected, positive samples showed antibody titres at 3 to 6 months after infection, “but we are not entirely sure how long lasting the immunity is”, reports Nissen. The virus has been identified in several European countries and North America as well as Australia. “Given some additional preliminary data from other countries as well, we think indeed that the virus occurs worldwide”, says Osterhaus. The Australian and Dutch teams agree that the findings could have implications for infection control. Nissen warns that: “It may be important to isolate children with the virus, as occurs with RSV”.
Ethnic Disparities in Cardiovascular Risk Factors and Coronary Disease Prevalence among Individuals with Chronic Kidney Disease
Authors: Hoang Thanh Nguyen, Austin G. Stack
Journal: Journal of the American Society of Nephrology (2006)

Differences in coronary disease have been reported among ethnic minorities in the US population. Whether these persist in patients with chronic kidney disease is unknown. The prevalence of myocardial infarction (MI) and angina was compared by race and GFR in the Third National Health and Nutrition Examination Survey using the Modification of Diet in Renal Disease Study equation. Age-gender standardized estimates were computed for each GFR category (>or=90, 60 to 89, and <60 ml/min per 1.73 m2), and odds ratios were compared using weighted multivariable logistic regression for each race. The age-gender standardized prevalence of MI was 3.0, 3.1, and 4.9% in white individuals; 2.8, 3.8, and 9.9% in black individuals; and 1.9, 2.9, and 3.8% in Mexican-American individuals in each category: >or=90, 60 to 89, and <60 ml/min, respectively. Compared with the referent (Mexican-American; GFR>or=90 ml/min; odds ratio 1.00), Mexican-American individuals with GFR of 60 to 89 and <60 ml/min had more than four and nine times the odds for MI; black individuals at successively lower GFR levels had 1.6, 6.1, and 16.3 times the odds for MI, whereas white individuals had 1.9, 4.7, and 20.2 times that of the referent, respectively. After adjustment for traditional risk factors, the inverse association of GFR with MI was substantially attenuated in black and white individuals and completely abolished in Mexican-American individuals. The burden of coronary disease is lower in Mexican-American than in white or black individuals with reduced kidney function even accounting for differences in traditional risk factors.
Abstract 3362: IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway
Authors: Arti Yadav, Bhavna Kumar, Jharna Datta, Theodoros N. Teknos, Pawan Kumar
Journal: Cancer Research (2011)

Abstract Distant metastases in head and neck cancer patients almost invariably herald a poor prognosis. Five year survival rates for early stage localized head and neck cancers are over 80% but this drop to 40% where disease has spread to neck nodes, and to below 20% for patients with distant metastatic disease. Uncontrolled cell proliferation and angiogenesis are key characteristics of initiation and early growth of epithelial origin cancers. However, it is the subsequent acquisition of motility and invasiveness that leads to metastatic dissemination of these tumor cells. A key process in this metastatic cascade that converts an adherent epithelial cell into a migratory cell which can invade through the extracellular matrix is known as epithelial-mesenchymal transition (EMT). EMT plays a critical role in epithelial tumor cell metastasis and is commonly observed in tumor samples from head and neck cancer patients. However, the precise molecular events that initiate this complex process of EMT in head and neck cancers are poorly understood. There is increasing evidence that suggest an important role of tumor microenvironment in promoting EMT changes in tumor cells. We have previously shown that head and neck tumors exhibit significantly higher levels of Bcl-2 expression in tumor associated endothelial cells and overexpression of Bcl-2 alone in tumor-associated endothelial cells was sufficient to enhance tumor metastasis of oral squamous cell carcinoma in a SCID mouse model. In this study, we show that endothelial cells expressing Bcl-2 (EC-Bcl-2) when co-cultured with head and neck tumor cells significantly enhance EMT-related changes in tumor cells and this EC-Bcl-2-induced EMT in tumor cells is mediated predominantly by IL-6 secretion. Treatment with recombinant IL-6 or stable IL-6 overexpression in CAL27 cells or normal oral epithelial cells (NOE) significantly induced the expression of vimentin while repressing E-cadherin expression via the JAK/STAT3/Snail signaling pathway. This phenotype was further associated with enhanced tumor and NOE cell scattering and motility. STAT3 knock-down significantly reversed IL-6-mediated tumor and NOE cell motility by inhibiting FAK activation. Furthermore, tumor cells overexpressing IL-6 showed marked increase in lymph node and lung metastasis, in vivo. These results suggest a novel function for IL-6 in mediating head and neck tumor EMT and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3362. doi:10.1158/1538-7445.AM2011-3362
POLYNEURITIS FOLLOWING ADMINISTRATION OF SOLUTION OF POTASSIUM ARSENITE IN A CASE OF CHOREA
Authors: Junius W. Stephenson
Journal: JAMA (1924)

A girl, aged 8 years, was admitted to the second division of the Neurological Institute, July 26, 1924, unable to walk and also unable to raise her wrists all the way. The duration of the illness was given as two months, and the mother stated that there had been slight improvement in the left arm. The child had had the usual diseases of childhood, but there was nothing of significance except the chorea antedating the condition for which she sought relief. <h3>History.</h3> —About May 15, the patient had become fidgety, irritable and cross; nothing seemed to suit her, and she was always finding fault. The right side of the mouth twitched. The tongue also twitched and turned so that one could hardly understand what she said. Her physician diagnosed the case as chorea. He put her on a yellowish liquid fluid, beginning 2 drops a day and increasing by 1
DISSENT ON OXYGEN THERAPY
Authors: THOMAS L. PETTY
Journal: Annals of Internal Medicine (1969)

Letters and Comments1 March 1969DISSENT ON OXYGEN THERAPYTHOMAS L. PETTY, M.D.THOMAS L. PETTY, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-70-3-647_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the Editor:I believe Question 248 on p. 1154 of the December ANNALSrequires reevaluation and comment. One hundred percent oxygen is not indicated in any of the clinical situations depicted by the five arterial blood gas patterns. One hundred percent oxygen has certain toxicity if given for prolonged periods, and it is therefore possible that 100% oxygen administration might harm any or all of the patients represented in the question. At the same time, Patient D (the so-called correct answer) is in greatest need of oxygen because of his degree of hypoxemia butprobablynot 100% oxygen. I... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 March 1969Volume 70, Issue 3Page: 647-647KeywordsArterial blood gasHypoxiaOxygenToxicity Issue Published: 1 March 1969 PDF DownloadLoading ...
Sites of in vivo extraction and interconversion of testosterone and androstenedione in dogs
Authors: Alcide Chapdelaine
Journal: Journal of Clinical Investigation (1969)

The interconversion and extraction of testosterone and androstenedione across and within different tissues or areas have been studied by the constant infusion technique. The results were calculated using the (3)H/(14)C ratios and radioactive concentrations of testosterone and androstenedione obtained from afferent and efferent blood and tissues at equilibrium. In each tissue studied, the interconversion between testosterone and androstenedione inside the tissue was significantly higher than the corresponding interconversion across the tissue. The pulmonary contribution to the total interconversion between testosterone and androstenedione was far more important than that of any of the other tissues studied. The hepatic metabolic clearance rates of testosterone and androstenedione were not different from their metabolic clearance rates in the mesenteric area. The extraction of each of these compounds, although not negligible, was lower in the kidney and the femoral bed compared with the extraction in the liver and the mesenteric area. Finally, with the possible exception of the liver, testosterone and androstenedione were more completely metabolized when they originated from the cells than from afferent blood. The evaluation of these different tissue transfer constants provides more precise information concerning the relative importance of different sites in the metabolism of these interconverting hormones.
Role of mTOR in podocyte function and diabetic nephropathy in humans and mice
Authors: Markus Gödel, Björn Hartleben, Nadja Herbach, Shuya Liu, Stefan Zschiedrich, Shun Lu, Andrea Debreczeni-Mór, Maja T. Lindenmeyer, Maria-Pia Rastaldi, Götz Hartleben, Thorsten Wiech, Alessia Fornoni, Robert G. Nelson, Matthias Kretzler, Rüdiger Wanke, Hermann Pavenstädt, Dontscho Kerjaschki, Clemens D. Cohen, Michael N. Hall, Markus A. Rüegg, Ken Inoki, Gerd Walz, Tobias B. Huber
Journal: Journal of Clinical Investigation (2011)

Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse podocytes induced proteinuria and progressive glomerulosclerosis. Furthermore, simultaneous deletion of both mTORC1 and mTORC2 from mouse podocytes aggravated the glomerular lesions, revealing the importance of both mTOR complexes for podocyte homeostasis. In contrast, increased mTOR activity accompanied human diabetic nephropathy, characterized by early glomerular hypertrophy and hyperfiltration. Curtailing mTORC1 signaling in mice by genetically reducing mTORC1 copy number in podocytes prevented glomerulosclerosis and significantly ameliorated the progression of glomerular disease in diabetic nephropathy. These results demonstrate the requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhibition can protect podocytes and prevent progressive diabetic nephropathy.