tbuckley/cabot-search huggingface dataset:
Discovery of siRNA Lipid Nanoparticles to Transfect Suspension Leukemia Cells and Provide In Vivo Delivery Capability
Authors: Wei He, Michael J Bennett, Leopoldo Luistro, Daisy Carvajal, Thomas Nevins, Melissa Smith, Gaurav Tyagi, James Cai, Xin Wei, Tai-An Lin, David C Heimbrook, Kathryn Packman, John F Boylan
Journal: Molecular Therapy (2013)

As a powerful research tool, siRNA's therapeutic and target validation utility with leukemia cells and long-term gene knockdown is severely restricted by the lack of omnipotent, safe, stable, and convenient delivery. Here, we detail our discovery of siRNA-containing lipid nanoparticles (LNPs) able to effectively transfect several leukemia and difficult-to-transfect adherent cell lines also providing in vivo delivery to mouse spleen and bone marrow tissues through tail-vein administration. We disclose a series of novel structurally related lipids accounting for the superior transfection ability, and reveal a correlation between expression of Caveolins and successful transfection. These LNPs, bearing low toxicity and long stability of >6 months, are ideal for continuous long-term dosing. Our discovery represents the first effective siRNA-containing LNPs for leukemia cells, which not only enables high-throughput siRNA screening with leukemia cells and difficult-to-transfect adherent cells but also paves the way for the development of therapeutic siRNA for leukemia treatment.
Long-Term Correction of Sandhoff Disease Following Intravenous Delivery of rAAV9 to Mouse Neonates
Authors: Jagdeep S Walia, Naderah Altaleb, Alexander Bello, Christa Kruck, Matthew C LaFave, Gaurav K Varshney, Shawn M Burgess, Biswajit Chowdhury, David Hurlbut, Richard Hemming, Gary P Kobinger, Barbara Triggs-Raine
Journal: Molecular Therapy (2014)

G(M2) gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in β-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb(-/-)) of the G(M2) gangliosidoses, we tested the potential of systemically delivered adeno-associated virus 9 (AAV9) expressing Hexb cDNA to correct the neurological phenotype. Neonatal or adult SD and normal mice were intravenously injected with AAV9-HexB or -LacZ and monitored for serum β-hexosaminidase activity, motor function, and survival. Brain G(M2) ganglioside, β-hexosaminidase activity, and inflammation were assessed at experimental week 43, or an earlier humane end point. SD mice injected with AAV9-LacZ died by 17 weeks of age, whereas all neonatal AAV9-HexB-treated SD mice survived until 43 weeks (P < 0.0001) with only three exhibiting neurological dysfunction. SD mice treated as adults with AAV9-HexB died between 17 and 35 weeks. Neonatal SD-HexB-treated mice had a significant increase in brain β-hexosaminidase activity, and a reduction in G(M2) ganglioside storage and neuroinflammation compared to adult SD-HexB- and SD-LacZ-treated groups. However, at 43 weeks, 8 of 10 neonatal-HexB injected control and SD mice exhibited liver or lung tumors. This study demonstrates the potential for long-term correction of SD and other G(M2) gangliosidoses through early rAAV9 based systemic gene therapy.
Importance of serum basal tryptase levels in children with insect venom allergy
Authors: S. T. Yavuz, C. Sackesen, U. M. Sahiner, B. Buyuktiryaki, E. Arik Yilmaz, B. E. Sekerel, O. U. Soyer, A. Tuncer
Journal: Allergy (2013)

Abstract Background The importance of serum basal tryptase ( sBT ) levels on patients with venom allergy is highlighted in recent adulthood studies. The aim of this study was to evaluate the sBT levels of venom‐allergic children with varying severity of clinical reactions. We also aimed to document the association between sBT levels and severe systemic reactions ( SR ). Methods Serum basal tryptase levels were estimated by U ni CAP ( P harmacia &amp; U pjohn, U ppsala, S weden). Children who suffered from large local reaction ( LLR ) or SR after insect stings were included along with healthy control subjects without a history of any local or SR after insect stings. Results A total of 128 children (55 with SR , 18 with LLR , and 55 age and sex‐matched control subjects) with a median age of 8.9 years (range 3.2–17.4) were enrolled. Severe SR was encountered in 24 (44%) patients with SR s. The median level of sBT in children with SR s (median, interquartile range) [4.2 μg/l (3.6–4.9)] was significantly higher than in children with LLR s [3.1 μg/l (2.5–4.0)] and healthy control subjects [2.9 μg/l (2.3–3.4)] ( P &lt; 0.001). Logistic regression analysis revealed s BT ≥ 4.8 μg/l as a significant risk factor for severe SR (5.7 [1.5–21.4]; P = 0.01) in children with venom allergy. Conclusions Our results indicate that sBT levels are associated with a higher risk of severe SR in children with insect venom hypersensitivity. Determination of sBT levels may help clinicians to identify patients under risk of severe SR s and optimal and timely use of therapeutic interventions in children with venom allergy.
Increased Metabolic Turnover Rate and Transcapillary Escape Rate of Albumin in Essential Hypertension
Authors: HANS-HENRIK PARVING, NIELS ROSSING, HENRIK AE. JENSEN
Journal: Circulation Research (1974)

The metabolic turnover rate and the transcapillary escape rate of albumin were studied using 131 I-labeled human albumin in nine untreated subjects suffering from essential hypertension. The average mean arterial blood pressure of these subjects was 162/109 mm Hg; seven subjects had grade I-II funduscopic changes. Plasma albumin concentration was normal, but plasma volume was reduced ( P &lt; 0.05) in these subjects. Thus, the previously reported moderate decrease in the intravascular albumin mass of hypertensive subjects was confirmed; the average value for intravascular albumin mass in the present study was 62.8 g/m2 surface area compared with a normal value of 70.6 g/m 2 (-11%, P &lt; 0.05). A surprising finding was a marked enhancement of albumin metabolic rate in essential hypertension. The fraction of intravascular albumin mass metabolized per 24-hour period was on the average 14.4% compared with a normal value of 8.4% (+72%, P &lt; 0.001). The rate of synthesis was 9.1 g/24 hours m -2 compared with a normal value of 5.9 g/24 hours m -2 (+54%, P &lt; 0.001). Total body albumin mass was decreased proportionally to intravascular albumin mass. Confirming a previous observation, we found an increase in the transcapillary escape rate of albumin (fraction of intravascular mass passing to the extravascular space per unit time) from a normal average of 5.6%/hour to 7.5%/hour (+34%, P &lt; 0.001). There was a statistically significant positive correlation between the transcapillary escape rate of albumin and blood pressure ( P &lt; 0.05). These findings can best be explained by increased filtration due to the high arterial blood pressure. There was also a positive correlation between the transcapillary escape rate and the fractional catabolic rate of albumin ( P &lt; 0.05). This finding supports the concept that albumin is catabolized in connection with its permeation through the capillary endothelium.
Serum bilirubin levels and mortality after myeloablative allogeneic hematopoietic cell transplantation†
Authors: Ted A. Gooley, Pankaj Rajvanshi, H. Gary Schoch, George B. McDonald
Journal: Hepatology (2005)

Many patients who undergo hematopoietic cell transplantation experience liver injury. We examined the association of serum bilirubin levels with nonrelapse mortality by day +200, testing the hypothesis that the duration of jaundice up to a given point in time provides more prognostic information than either the maximum bilirubin value or the value at that point in time. We studied 1,419 consecutive patients transplanted from allogeneic donors. Total serum bilirubin values up to day +100, death, or relapse were retrieved-along with nonrelapse mortality by day +200 as an outcome measure--using Cox regression models with each bilirubin measure modeled as a time-dependent covariate. The bilirubin value at a particular point in time provided the best fit to the model for mortality. With bilirubin at a point in time modeled as an 8th-degree polynomial, an increase in bilirubin from 1 to 3 mg/dL is associated with a mortality hazard ratio of 6.42. An increase from 4 to 6 mg/dL yields a hazard ratio of 2.05, and an increase from 10 to 12 mg/dL yields a hazard ratio of 1.17. Among patients who were deeply jaundiced, survival was related to the absence of multiorgan failure and to higher platelet counts. In conclusion, the value of total serum bilirubin at a particular point in time after transplant carries more informative prognostic information than does the maximum or average value up to that point in time. The increase in mortality for a given increase in bilirubin value is larger when the starting value is lower.
AIDS and Progressive Disseminated Histoplasmosis
Authors: Philip C. Johnson
Journal: JAMA (1987)

To the Editor.—  The timely review in the March 13, 1987, issue of JAMA entitled Treatment of Patients With Acquired Immunodeficiency Syndrome and Associated Manifestations by Kaplan and coworkers 1 from San Francisco fails to mention progressive disseminated histoplasmosis (PDH), an important early opportunistic infection of acquired immunodeficiency syndrome (AIDS) found in patients in the endemic area for histoplasmosis. This disease, which is rare in patients with intact cellular immunity, was added to the Centers for Disease Control definition of AIDS in 1985. 2   We encountered ten (2.7%) cases of PDH among 370 confirmed cases of AIDS in the Houston Standard Metropolitan Statistical Area as of October 1985. 3 This figure was lower than in the previous reports by Bonner et al 4 from Birmingham, Ala, and Wheat et al 5 from Indianapolis, which together described PDH in ten of 19 patients with AIDS. 6 This represented the most common
CHRONIC POISONING BY ACETANILID.
Authors: D. D. STEWART
Journal: JAMA (1905)

That chronic poisoning characterized by degenerative changes in the blood, and by physical disability, may result from the continued ingestion of anilin derivatives is well known, as it is also well recognized that acetanilid, one of these products, because of its small cost and its toxicity in excess of others of this group in common use, renders it particularly liable to be the offending agent. Acetanilid is the chief ingredient in headache powders so generally dispensed by pharmacists without prescription, as it is in certain secret nostrums both in use by the rank and file of the profession, and, unfortunately, thus introduced by them to the laity. The toxicity of acetanilid in common with related coal-tar products of the antipyretic group, has long been known, and the serious, if not fatal, results which may follow its incautious use in fevers and debilitating conditions should have in past years been brought
Thyroglobulin Flare Response After Radioiodine Ablation in 2 Patients With Differentiated Thyroid Cancer
Authors: James F. Tsang, Daniel P. Levin, William D. Leslie
Journal: Clinical Nuclear Medicine (2014)

Serum thyroglobulin (Tg) measurement facilitates monitoring differentiated thyroid cancer. We describe 2 patients with papillary thyroid cancer who developed dramatic transient serum Tg level elevations within 1 week of 131I radioiodine (RAI) ablation without cancer recurrence on follow-up. The first patient received recombinant human thyroid-stimulating hormone injections. The pre–injection Tg level was 3.8 μg/L and increased to 3060 μg/L 3 days post-RAI. In the second patient, the serum Tg level increased from 1.3 μg/L to 209.9 μg/L 7 days after RAI. This transient early serum Tg “flare response” could be misleading if interpreted as suggesting more extensive high-risk thyroid cancer.
Local Radiotherapy Rescues Responsiveness to Anti-CD137 Immunotherapy in a Mouse Model of Advanced Breast Cancer.
Authors: K. Pilones, N. Kawashima, S. Formenti, S. Demaria
Journal: Cancer Research (2009)

Abstract BACKGROUND: The benefits of immunotherapy are often hampered by immunosuppressive networks in the tumor microenvironment. Accumulating evidence indicates that local ionizing radiation (IR) can synergize with immunotherapy and improve tumor response.CD137/4-1BB is a co-stimulatory molecule expressed on activated T-cells that provides a survival signal to promote the expansion and differentiation of antigen-specific T-cells. Pre-clinical studies have shown the ability of agonistic anti-CD137 antibodies to enhance anti-tumor immunity. 4T1 is a poorly immunogenic experimental mouse model of metastatic breast cancer. 4T1 cells injected s.c. form a tumor and rapidly spread systemically giving rise to lung metastases that kill the animals. We have previously shown that IR as single modality can delay growth of the irradiated 4T1 s.c. tumors but not extend mice survival.METHODS: BALB/c mice were inoculated s.c. with 4T1 cells on day 0. Treatment with anti-CD137 mAb (200 mg, BMS-469492 from Bristol Myers Squibb) was started on day 7 or 15 and repeated every 3 days for two or three times. For radiotherapy mice were randomized into 4 groups receiving (1) no treatment, (2) IR alone, (3) anti-CD137 mAb and (4) IR+ anti-CD137 mAb. IR was delivered exclusively to the tumor in 2 fractions of 12 Gy at 24 hours interval starting on day 13. Mice were followed for tumor growth and survival.RESULTS: Administration of anti-CD137 mAb to 4T1 tumor-bearing mice starting at day 7 resulted in significant tumor growth delay which correlated with an 8-fold increase in the ratio of intratumural effector CD8 T cells (Teff) to regulatory T cells (Treg) at day 15. In contrast, when administration of anti-CD137 mAb was delayed until day 15 no anti-tumor effect was observed.The median survival of mice (39 days) was not increased by treatment with anti-CD137 mAb or IR used as single modalities (39 days). On the other hand, the combination of IR and anti-CD137 mAb increased survival to 49 days, although no complete tumor remission was observed.CONCLUSIONS:Overall, our studies indicate that with tumor progression mice became resistant to immunotherapy with single modality anti-CD137 mAb. However, a therapeutic effect was seen when anti-CD137 mAb was combined with local radiotherapy. We are currently investigating the mechanisms of resistance to anti-CD137 mAb treatment that develop with 4T1 tumor progression. Accumulation of Treg and myeloid-derived suppressor cells (MDSC) within the tumors likely contribute to resistance to immunotherapy by creating a highly immunosuppressive microenvironment. Identification of these mechanisms will provide new therapeutic targets to improve the response to treatment. Importantly, data support the combination of local radiotherapy with immunotherapy in advanced breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4134.
Historically black US medical schools perform best on "social mission"
Authors: R. Wilkins
Journal: BMJ (2010)

Medical schools in the northeast of the United States are least likely to produce graduates who end up working in primary care, a new analysis shows. Graduates from these schools are also least likely to end up in areas that are underserved by doctors and to come from an ethnic minority, it found.

The study, which aimed to score all US medical schools on their ability to meet a “social mission,” found that “historically black” schools performed the best and that public schools performed better than private ones ( Annals of Internal Medicine 2010;152:804-11). “Historically black” institutions are those that were established before 1964 with the intention of serving …
SURGERY OF THE APPENDIX
Authors: WILLIAM E. LOWER
Journal: JAMA (1923)

It is gratifying to note that the establishment of appendicitis as a distinct disease entity was an American achievement. We do not intend to review the enormous literature pertaining to diagnosis and treatment which has developed since the primary publications of Reginald Fitz of Boston, in 1886, and such other earlier writers on this subject as Stimson, McBurney and Bull, but rather to point attention to certain problems that still remain. There has been great progress in the treatment of appendicitis and peritonitis. The increasing readiness of the public to submit to the operation which they have been taught to believe is attended with little danger, and the simplicity of the operation itself, have perhaps lulled the medical profession into a kind of false security. That this is the case is indicated by the fact that while, for a number of years, at every session of this Association the subject
NO mediates mural cell recruitment and vessel morphogenesis in murine melanomas and tissue-engineered blood vessels
Authors: Satoshi Kashiwagi, Yotaro Izumi, Takeshi Gohongi, Zoe N. Demou, Lei Xu, Paul L. Huang, Donald G. Buerk, Lance L. Munn, Rakesh K. Jain, Dai Fukumura
Journal: Journal of Clinical Investigation (2005)

NO has been shown to mediate angiogenesis; however, its role in vessel morphogenesis and maturation is not known. Using intravital microscopy, histological analysis, α–smooth muscle actin and chondroitin sulfate proteoglycan 4 staining, microsensor NO measurements, and an NO synthase (NOS) inhibitor, we found that NO mediates mural cell coverage as well as vessel branching and longitudinal extension but not the circumferential growth of blood vessels in B16 murine melanomas. NO-sensitive fluorescent probe 4,5-diaminofluorescein imaging, NOS immunostaining, and the use of NOS-deficient mice revealed that eNOS in vascular endothelial cells is the predominant source of NO and induces these effects. To further dissect the role of NO in mural cell recruitment and vascular morphogenesis, we performed a series of independent analyses. Transwell and under-agarose migration assays demonstrated that endothelial cell–derived NO induces directional migration of mural cell precursors toward endothelial cells. An in vivo tissue-engineered blood vessel model revealed that NO mediates endothelial–mural cell interaction prior to vessel perfusion and also induces recruitment of mural cells to angiogenic vessels, vessel branching, and longitudinal extension and subsequent stabilization of the vessels. These data indicate that endothelial cell–derived NO induces mural cell recruitment as well as subsequent morphogenesis and stabilization of angiogenic vessels.
A New Method of Blood Pressure Recording That May Enhance Patient Compliance
Authors: Martin L. Gelman
Journal: JAMA (1981)

We describe a new method of self-recording of blood pressure (BP) that requires only a BP cuff. The method is easy and fast but cannot be used by all subjects. We describe 21 normal subjects, 14 hypertensive patients, and 20 patients studied at cardiac catheterization. In all three groups the new technique, the sensory detection method (SDM), showed no significant differences from the routine indirect BP and from the direct arterial BP in patients undergoing catheterization. Some 15% of patients who were unable to use this method were easily identified during the testing and instructing of the technique. The simplicity of the SDM may increase patient vigilance and compliance to antihypertensive regimens.
Correlation between blood ethylenethiourea and thyroid gland disorders among banana plantation workers in the Philippines.
Authors: Lynn Panganiban, Nelia Cortes-Maramba, Carissa Dioquino, Maria Lurenda Suplido, Herbert Ho, Ana Francisco-Rivera, Ailyn Manglicmot-Yabes
Journal: Environmental Health Perspectives (2003)

Ethylenebisdithiocarbamates (EBDCs) are metabolized into ethylenethiourea (ETU), a possible human carcinogen and an antithyroid compound. In this study our goal was to correlate ETU levels with the incidence of thyroid gland disorders among banana plantation workers exposed to EBDC. We randomly selected 57 directly exposed workers and 31 indirectly exposed workers from four banana plantations and 43 workers from an organic farm; all subjects underwent complete medical examinations and laboratory tests. Results showed a higher mean thyroid-stimulating hormone measurement among exposed workers compared with the control group, although the levels were well within normal range. Nine of the exposed farmers had abnormal thyroid ultrasound findings, consisting mostly of solitary nodules, compared with three among the control group. Analysis of variance showed significantly different blood ETU levels among the directly exposed, indirectly exposed, and control groups (p < 0.001), but ETU levels in urine were not significantly different (p = 0.10). Environmental ETU levels were below the U.S. Environmental Protection Agency remediation levels. Among farmers with solitary thyroid nodules, we found a very good direct correlation between the size of the nodule and blood ETU level. In this study we showed that blood ETU is a more reliable biomarker for EBDC exposure than urinary ETU; therefore, the determination of blood ETU should be part of medical surveillance efforts among workers exposed to EBDC to detect occurrences of thyroid gland disorders.
A Little VEGF Goes a Long Way
Authors: Mark W. Majesky
Journal: Circulation (1996)

Nevertheless, the simplicity of using injections of naked plasmid DNA into skeletal muscle tissue as an effective means to deliver a potent, secreted angiogenesis factor into ischemic peripheral vascular beds is both an exciting and encouraging finding. It is estimated that 150,000 patients per year require lower-limb amputations for ischemic peripheral vascular disease in the United States. The impressive progress being made toward the use of VEGF gene therapy for effective therapeutic angiogenesis in ischemic peripheral vascular disease is truly welcome news for clinicians faced with the task of providing care for those patients suffering from lower-limb vascular insufficiency.
749-3 Time Evolutive (Recursive) Heart Rate Variability Analysis Provides New Insights into the Mechanisms of Vasovagal Syncope During Head-up Tilt Test
Authors: Etienne Pruvot, Karin Vibe, Jean M. Vesin, Jürg Schläpfer, Martin Fromer, Lukas Kappenberger
Journal: Journal of the American College of Cardiology (1995)
Cathepsin S contributes to macrophage migration via degradation of elastic fibre integrity to facilitate vein graft neointimal hyperplasia
Authors: Hong-Tao Shi, Ying Wang, Li-Xin Jia, Yan-Wen Qin, Yan Liu, Hui-Hua Li, Yong-Fen Qi, Jie Du
Journal: Cardiovascular Research (2013)

Cathepsin S (Cat S) is a potent lysosomal protease that is secreted into the extracellular space and has been implicated in elastin and collagen degradation in diseases such as atherosclerosis. Elastin degradation plays an important role in vascular remodelling. However, the mechanism by which Cat regulates this process and its contribution to vein graft remodelling remains unclear.Using a murine vein graft model, we examined the expression pattern of Cat family members. Expression of cathepsin genes was induced in vein grafts, with that of Cat S being the highest. Elevated Cat S expression was confirmed in both mouse and human vein grafts. To explore the role of Cat S, vein grafts were created between wild-type (WT) littermates and Cat S knockout (Cat S KO) mice. Knockout of Cat S in the recipients (vein(CatS-KO)-artery(CatS-KO) or vein(WT)-artery(CatS-KO)) significantly inhibited neointima formation and reduced the accumulation of macrophages and proliferation of smooth muscle cells in vein grafts. Knockout of Cat S preserved the elastic fibre integrity of vein grafts and inhibited the migration of macrophages across the elastin fibres.These results demonstrated that Cat S contributes to macrophage migration via degradation of elastic fibre integrity to facilitate neointima formation of vein grafts, which might provide a novel therapeutic target for preserving vein graft patency.