tbuckley/cabot-search huggingface dataset:
Gene Therapy for Adenosine Deaminase Deficiency
Authors: Robertson Parkman, Kenneth Weinberg, Gay Crooks, Jan Nolta, Neena Kapoor, Donald Kohn
Journal: Annual Review of Medicine (2000)

The clinical gene therapy trials for adenosine deaminase (ADA) deficiency have defined both the potential benefits and the present limitations of gene therapy with hematopoietic stem cells (HSC). Current clinical results indicate that (a) both umbilical cord blood and neonatal bone marrow HSC can be transduced with murine retroviral-based vectors, (b) the transduced HSC can engraft in nonmyeloablated patients, (c) the frequency of HSC transduction/engraftment is low (1/10,000), (d) an in vivo selective advantage can exist for transduced T lymphoid progeny, and (e) the transduced ADA gene is not expressed in nondividing T lymphocytes. Improving the clinical results of gene therapy for ADA deficiency and other genetic diseases involving HSC will require (a) developing new vectors that express the transduced gene in nondividing cells and (b) increasing the frequency of stable HSC transduction.
Dexamethasone inhibition of leucocyte adhesion to rat mesenteric postcapillary venules: role of intercellular adhesion molecule 1 and KC
Authors: A Tailor, A Tomlinson, A Salas, J Panes, D N Granger, R J Flower, M Perretti
Journal: Gut (1999)

<h3>BACKGROUND</h3> A previous study showed that the glucocorticoid dexamethasone, at doses of 100 μg/kg and above, inhibited leucocyte adhesion to rat mesenteric postcapillary venules activated with interleukin 1β (IL-1β), as assessed by videomicroscopy. <h3>AIMS</h3> To identify whether the adhesion molecule, intercellular adhesion molecule 1 (ICAM-1), or the chemokine KC could be targeted by the steroid to mediate its antiadhesive effect. <h3>METHODS</h3> Rat mesenteries were treated with IL-1β (20 ng intraperitoneally) and the extent of leucocyte adhesion measured at two and four hours using intravital microscopy. Rats were treated with dexamethasone, and passively immunised against ICAM-1 or KC. Endogenous expression of these two mediators was validated by immunohistochemistry, ELISA, and the injection of specific radiolabelled antibodies. <h3>RESULTS</h3> Dexamethasone greatly reduced IL-1β induced leucocyte adhesion, endothelial expression of ICAM-1 in the postcapillary venule, and release of the mast cell derived chemokine KC. Injection of specific antibodies to the latter mediators was also extremely effective in downregulating (&gt;80%) IL-1β induced leucocyte adhesion. <h3>CONCLUSIONS</h3> Induction by IL-1β of endogenous ICAM-1 and KC contributes to leucocyte adhesion to inflamed mesenteric vessels. Without excluding other possible mediators, these data clearly show that dexamethasone interferes with ICAM-1 expression and KC release from mast cells, resulting in suppression of leucocyte accumulation in the bowel wall, which is a prominent feature of several gastrointestinal pathologies.
Primary non‐Hodgkin lymphoma of the spleen
Authors: Alan Brox, Jonathan I. Bishinsky, Gerald Berry
Journal: American Journal of Hematology (1991)

Abstract Primary splenic lymphoma is a relatively infrequent cause of splenomegaly, its reported incidence being less than 1%. Nonetheless, various series have reported on its occurrence and its unfavorable prognosis, but these series have reported data on heterogenous populations, including many patients with nodal or hepatic disease. We report on a series of nine patients with primary splenic lymphoma. None of these patients had biopsy‐proven evidence of extrasplenic disease and were categorized as involving spleen only (stage 1) or spleen and splenic hilum (stage 2). In this series, classified by the recent N.C.I. working formulation, four patients had intermediate or high‐grade histology and five patients had low‐grade histology. There was no correlation between histological subtype and prognosis, nor could other factors be delineated to explain their favorable prognosis. The median survival in this group of patients was 7.48 years, and no evidence of relapse has been documented. The data suggest that primary splenic lymphoma, treated by splenectomy alone or combination therapy, may be potentially curative. Further studies should address the question of aggressive accurate staging in hopes of obtaining homogenous patient populations so that appropriate treatment in primary splenic lymphoma can be better defined.
Boosting Brain Uptake of a Therapeutic Antibody by Reducing Its Affinity for a Transcytosis Target
Authors: Y. Joy Yu, Yin Zhang, Margaret Kenrick, Kwame Hoyte, Wilman Luk, Yanmei Lu, Jasvinder Atwal, J. Michael Elliott, Saileta Prabhu, Ryan J. Watts, Mark S. Dennis
Journal: Science Translational Medicine (2011)

Brain uptake of a therapeutic bispecific antibody by receptor-mediated transcytosis is enhanced by reducing the antibody’s affinity for the transferrin receptor.
Effect of Epidermal Growth Factor Receptor Expression Level on Survival in Patients with Epithelial Ovarian Cancer
Authors: Amanda Psyrri, Mohamad Kassar, Ziwei Yu, Aris Bamias, Paul M. Weinberger, Sonia Markakis, Diane Kowalski, Robert L. Camp, David L. Rimm, Meletios A. Dimopoulos
Journal: Clinical Cancer Research (2005)

Abstract Background: Several lines of laboratory evidence support the epidermal growth factor receptor (EGFR) as an adverse prognostic indicator in ovarian cancers. However, different methods of immunohistochemical assessment have yielded conflicting results. Here, we sought to determine the prognostic value of EGFR in ovarian cancer using a novel method of compartmentalized in situ protein analysis. Methods: A tissue array composed of 150 advanced-stage ovarian cancers uniformly treated, with surgical debulking followed by platinum-paclitaxel combination chemotherapy, was constructed. For evaluation of EGFR protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). Results: Mean follow-up time for the entire cohort was 34.4 months. Eighty-one of 150 cases had sufficient tissue for AQUA analysis. High tumor EGFR expression was associated with poor outcome for overall survival (P = 0.0001) and disease-free survival (P = 0.0005) at 3 years. In multivariable analysis, adjusting for well-characterized prognostic variables, EGFR expression status was the most significant prognostic factor for disease-free and overall survival. Conclusion: The conflicting results in the literature regarding the prognostic value of EGFR may be due to the technical difficulties inherent in assessing EGFR with immunocytochemistry. In the present study, we show that measurement of EGFR protein levels in ovarian cancer using AQUA is feasible and can give important prognostic information.
Legionella pneumophila-induced I B -dependent expression of interleukin-6 in lung epithelium
Authors: J. Lorenz, J. Zahlten, I. Pollok, J. Lippmann, S. Scharf, P.D. N'Guessan, B. Opitz, A. Flieger, N. Suttorp, S. Hippenstiel, B. Schmeck
Journal: European Respiratory Journal (2010)

Severe community- and hospital-acquired pneumonia is caused by Legionella pneumophila . Lung airway and alveolar epithelial cells comprise an important sentinel system in airborne infections. Although interleukin (IL)-6 is known as a central regulator of the immune response in pneumonia, its regulation in the lung is widely unknown. Herein, we demonstrate that different L. pneumophila strains induce delayed expression of IL-6 in comparison with IL-8 by human lung epithelial cells. IL-6 expression depended, at early time points, on flagellin recognition by Toll-like receptor (TLR)5, activity of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1 and p38 mitogen-activated protein (MAP) kinase, and, at later time points, on the type-IV secretion system. In the same manner, but more rapidly, the recently described transcription factor IκBζ was induced by Legionella infection and, binding to the nuclear factor (NF)-κB subunit p50 - recruited to the il6 promoter together with CCAAT-enhancer-binding protein β and phosphorylated activator protein-1 subunit cJun. Similarly, histone modifications and NF-κB subunit p65/RelA appeared at the iκbζ and subsequently at the il6 gene promoter, thereby initiating gene expression. Gene silencing of IκBζ reduced Legionella -related IL-6 expression by 41%. Overall, these data indicate a sequence of flagellin/TLR5- and type IV-dependent IκBζ expression, recruitment of IκBζ/p50 to the il6 promoter, chromatin remodelling and subsequent IL-6 transcription in L. pneumophila -infected lung epithelial cells.
Clinical and economic implications of the use of nanoparticle paclitaxel (Nanoxel) in India
Authors: A.A. Ranade, D.A. Joshi, G.K. Phadke, P.P. Patil, R.B. Kasbekar, T.G. Apte, R.R. Dasare, S.D. Mengde, P.M. Parikh, G.S. Bhattacharyya, G.L. Lopes
Journal: Annals of Oncology (2013)
EGFRvIII expression and PTEN loss synergistically induce chromosomal instability and glial tumors
Authors: Li Li, Amalia Dutra, Evgenia Pak, Joseph E. Labrie, Rachel M. Gerstein, Pier Paolo Pandolfi, Larry D. Recht, Alonzo H. Ross
Journal: Neuro-Oncology (2008)

Glioblastomas often show activation of epidermal growth factor receptor (EGFR) and loss of PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor, but it is not known if these two genetic lesions act together to transform cells. To answer this question, we infected PTEN-/- neural precursor cells with a retrovirus encoding EGFRvIII, which is a constitutively activated receptor. EGFRvIII PTEN-/- cells formed highly mitotic tumors with nuclear pleomorphism, necrotic areas, and glioblastoma markers. The transformed cells showed increased cell proliferation, centrosome amplification, colony formation in soft agar, self-renewal, expression of the stem cell marker CD133, and resistance to oxidative stress and ionizing radiation. The RAS/mitogen-activated protein kinase (ERK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways were activated, and checkpoint kinase 1 (Chk1), the DNA damage regulator, was phosphorylated at S280 by Akt, suppressing Chk1 phosphorylation at S345 in response to ionizing irradiation. The PTEN-/- cells showed low levels of DNA damage in the absence of irradiation, which was increased by EGFRvIII expression. Finally, secondary changes occurred during tumor growth in mice. Cells from these tumors showed decreased tumor latencies and additional chromosomal aberrations. Most of these tumor lines showed translocations of mouse chromosome 15. Intracranial injections of one of these lines led to invasive, glial fibrillary acidic protein-positive, nestin-positive tumors. These results provide a molecular basis for the occurrence of these two genetic lesions in brain tumors and point to a role in induction of genomic instability.
Risk-Stratified Therapy and the Intensive Use of Cytarabine Improves the Outcome in Childhood Acute Myeloid Leukemia: The AML99 Trial From the Japanese Childhood AML Cooperative Study Group
Authors: Ichiro Tsukimoto, Akio Tawa, Keizo Horibe, Ken Tabuchi, Hisato Kigasawa, Masahiro Tsuchida, Hiromasa Yabe, Hideki Nakayama, Kazuko Kudo, Ryoji Kobayashi, Kazuko Hamamoto, Masue Imaizumi, Akira Morimoto, Shigeru Tsuchiya, Ryoji Hanada
Journal: Journal of Clinical Oncology (2009)

Purpose To improve the prognosis in children with newly diagnosed acute myeloid leukemia (AML) by introducing a dose-dense intensive chemotherapy regimen and an appropriate risk stratification system. Patients and Methods Two hundred forty children with de novo AML were treated with continuous cytarabine-based induction therapy and stratified to three risk groups based on the initial treatment response, age, and WBC at diagnosis and cytogenetics. All of the patients were treated with intensive consolidation chemotherapy including three or four courses of high-dose cytarabine. Allogeneic hematopoietic stem-cell transplantation (HSCT) was indicated for only the intermediate-risk patients with matched related donors and for all the high-risk subsets. Results Two hundred twenty-seven children (94.6%) achieved a complete remission (CR). Four children demonstrated induction death. The median follow-up of the live patients was 55 months (range, 37 to 73 months). The 5-year overall survival of all 240 children was 75.6% (95% CI, 70.3% to 81.4%) and event-free survival was 61.6% (95% CI, 55.8% to 68.1%). The 5-year disease-free survival in each risk group were 71.3% (95% CI, 63.4% to 80.2%) in the low-risk group (n = 112), 59.8% (95% CI, 50.6% to 70.7%) in the intermediate-risk group (n = 92), and 56.5% (95% CI, 39.5% to 80.9%) in the high-risk group (n = 23). Eight children died during the first CR, including four after HSCT. Conclusion A high survival rate, 75.6% at 5 years, was achieved for childhood with de novo AML in the AML99 trial. The treatment strategy was well tolerated with only 1.7% induction death rate and 3.5% remission death rate. Low-risk children were successfully treated with chemotherapy alone.
Previous experience influences pacing during 20 km time trial cycling
Authors: D Micklewright, E Papadopoulou, J Swart, T Noakes
Journal: British Journal of Sports Medicine (2009)

To investigate how experience and feedback influence pacing and performance during time trial cycling.Twenty-nine cyclists performed three 20 km cycling time trials using a Computrainer. The first two time trials (TT1 and TT2) were performed (1) without any performance feedback (n = 10), (2) with accurate performance feedback (n = 10) or (3) with false feedback showing the speed to be 5% greater than the actual speed (n = 9). All participants received full feedback during the third time trial (TT3), and their performance and pacing data were compared against TT2.Completion time, average power and average speed did not change among the false feedback group, but their pacing strategy did change as indicated by a lower average cadence, 89.2 (SD 5.2) vs 96.4 (6.8) rpm, p<0.05, and higher power during the first 5 km (SMD = 39, 36, 36, 27 and 27 W for 1-5 km respectively). Pacing changed among the blind feedback group indicated by a faster completion time, 35.9 (3.1) vs 36.8 (4.4) min, p<0.05, and power increases during the final 5 km (SMD = 14, 13, 18, 23 and 53 W for 16-20 km respectively). No performance or pacing changes were observed among the accurate feedback group.Pacing is influenced by an interaction between feedback and previous experience. Conscious cognitive processes that lead to ratings of perceived exertion and pacing appear to be influenced by previous experience.
Bone mineral density in patients with rheumatoid arthritis treated with infliximab
Authors: M Vis
Journal: Annals of the Rheumatic Diseases (2005)

Osteoporosis is a well known feature of rheumatoid arthritis (RA).1 Cross sectional studies have shown that patients with RA have a lower bone mineral density (BMD) than healthy controls.2 Disease activity, steroid use, and immobility are associated with loss of BMD in RA.3–7 It has been suggested that active treatment of patients with RA may prevent loss of BMD.8 The current most effective drugs in the treatment of RA are the tumour necrosis factor α blocking agents. The beneficial effects of short term treatment with infliximab on markers of bone metabolism in patients with active RA have recently been shown.9 From this we proposed the hypothesis that bone loss might be arrested in patients with RA during treatment with infliximab.

This open cohort study consisted of consecutive patients …
Positive End-Expiratory Pressure Setting in Adults With Acute Lung Injury and Acute Respiratory Distress Syndrome
Authors: Alain Mercat, Jean-Christophe M. Richard, Bruno Vielle, Samir Jaber, David Osman, Jean-Luc Diehl, Jean-Yves Lefrant, Gwenaël Prat, Jack Richecoeur, Ania Nieszkowska, Claude Gervais, Jérôme Baudot, Lila Bouadma, Laurent Brochard, for the Expiratory Pressure (Express) Study Group
Journal: JAMA (2008)

OSITIVE END-EXPIRATORY PRESsure (PEEP) is an essential component of the management of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). 1 PEEP improves hypoxemia and decreases intrapulmonary shunting, and these effects have been the basis for titrating PEEP in clinical practice. 24][5][6] Although the mechanisms of this protective effect are not fully elucidated, they may be mediated by PEEP-induced alveolar recruitment, which avoids cyclic air-See also pp 637, 691, and 693.
Vascular Mineralocorticoid Receptors Regulate Blood Pressure Effects on Myogenic Tone and Role in Aging
Authors: Ernesto L. Schiffrin
Journal: Circulation Research (2013)

E ffects of aldosterone on blood pressure control have classically been attributed to sodium retention through its action on the kidney.However, increasingly it has been appreciated that aldosterone exerts effects directly on the vasculature.Here, we comment on novel data published recently that sheds light on new mechanisms, whereby aldosterone acting through the mineralocorticoid receptor on blood vessels, in interaction with angiotensin II and via oxidative stress and calcium channels, may affect age-associated changes in myogenic tone and exert effects on blood pressure regulation.Aldosterone is produced by the adrenal glomerulosa in response to angiotensin (Ang) II, elevated serum potassium, and corticotropin.It acts on the kidney to increase sodium reabsorption in the distal nephron interacting with the mineralocorticoid receptor (MR) and by activation of the apical epithelial sodium channel. 1 In humans, primary hyperaldosteronism clearly establishes the role that aldosterone has on blood pressure (BP) and hypertension. 2However, in both normotensive subjects and in essential hypertension, contribution of aldosterone to BP has been more difficult to establish.In the Framingham study, quartiles of plasma levels of aldosterone were directly associated with BP. 3 A fraction of patients with essential hypertension shows mild elevation of aldosterone plasma concentrations. 4On the contrary, treatment with MR antagonists lowers BP in human patients with essential hypertension, 5 and particularly drug-resistant hypertension. 6ecause aldosterone synthase inhibitors have similar effects as MR blockade in humans with hypertension, 7 it is likely that the effects reported for MR antagonism are mediated by blockade of the action of aldosterone. Vascular Mineralocorticoid Receptors Regulate Blood PressureEffects on Myogenic Tone and Role in Aging
Periodontal Disease and Atherosclerotic Vascular Disease: Does the Evidence Support an Independent Association?
Authors: Peter B. Lockhart, Ann F. Bolger, Panos N. Papapanou, Olusegun Osinbowale, Maurizio Trevisan, Matthew E. Levison, Kathryn A. Taubert, Jane W. Newburger, Heather L. Gornik, Michael H. Gewitz, Walter R. Wilson, Sidney C. Smith, Larry M. Baddour
Journal: Circulation (2012)

A link between oral health and cardiovascular disease has been proposed for more than a century. Recently, concern about possible links between periodontal disease (PD) and atherosclerotic vascular disease (ASVD) has intensified and is driving an active field of investigation into possible association and causality. The 2 disorders share several common risk factors, including cigarette smoking, age, and diabetes mellitus. Patients and providers are increasingly presented with claims that PD treatment strategies offer ASVD protection; these claims are often endorsed by professional and industrial stakeholders. The focus of this review is to assess whether available data support an independent association between ASVD and PD and whether PD treatment might modify ASVD risks or outcomes. It also presents mechanistic details of both PD and ASVD relevant to this topic. The correlation of PD with ASVD outcomes and surrogate markers is discussed, as well as the correlation of response to PD therapy with ASVD event rates. Methodological issues that complicate studies of this association are outlined, with an emphasis on the terms and metrics that would be applicable in future studies. Observational studies to date support an association between PD and ASVD independent of known confounders. They do not, however, support a causative relationship. Although periodontal interventions result in a reduction in systemic inflammation and endothelial dysfunction in short-term studies, there is no evidence that they prevent ASVD or modify its outcomes.
Gay Men and Lesbians in Medicine: Has Discrimination Left the Room?
Authors: Sue Sun Yom
Journal: JAMA (1999)

S brutal murder of Wyoming college student Matthew Shepard brought forth recognition that despite much greater acceptance of gay and lesbian people than in recent history, antihomosexual discrimination marked by occasional violence remains a divisive fixture in the American social landscape. 1 Certainly conditions for gay and lesbian people have improved, especially within the medical profession.A moderate number of gay and lesbian medical students and physicians are now formally protected by antidiscrimination clauses in their academic and working lives.Many gay and lesbian physicians achieve high degrees of professional success, even after having disclosed their orientation to select colleagues and employers.In this issue, Jason Schneider and Saul Levin, MD, trace the American Medical Association's growing acceptance of gay and lesbian visibility within its own ranks over the past 2 decades.Kate O'Hanlan, MD, follows with a discussion of her experiences over the past 10 years in successfully advocating for domestic partner benefits at Albert Einstein College of Medicine and Stanford University.Yet despite successes in professional representation and employment status, surveys have documented that many admissions officers and residency directors are less enthusiastic about gay and lesbian candidates than heterosexual candidates, and that physicians who disclose a nonheterosexual orientation to colleagues face the potential loss of referrals and privileges. 2,3A nationwide survey of women physicians by researchers at Emory University provides new evidence that lesbian physicians do in fact experience harassment at a greater prevalence than their heterosexual counterparts.From the patient's perspective, sexual orientation may expose one to specific health risks.Gary Remafedi, MD, provides a sobering view of the most catastrophic result of antihomosexual discrimination in his review of studies linking adolescent suicide to gay or lesbian sexual orientation.Suicide is among the most dangerous health risks of all to gay and lesbian teenagers and the most unrelentingly tragic.Finally, this month's MSJAMA online features an interview with and new poetry by Rafael Campo, MD, who has made a point of addressing gay issues and the patient-physician relationship in his writing.Campo inspires readers with his injunctions to remain human as a first priority-and thereby to experience empathy with others.One may hope, as Campo's writing and these articles suggest, that these special insights of the medical profession have the potential to better a society still struggling with its prejudices.