tbuckley/cabot-search huggingface dataset:
Normalization and Improvement of CNS Deficits in Mice With Hurler Syndrome After Long-term Peripheral Delivery of BBB-targeted Iduronidase
Authors: Salim S El-Amouri, Mei Dai, Jing-Fen Han, Roscoe O Brady, Dao Pan
Journal: Molecular Therapy (2014)

Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disorder with systemic and central nervous system (CNS) involvement due to deficiency of α-l-iduronidase (IDUA). We previously identified a receptor-binding peptide from apolipoprotein E (e) that facilitated a widespread delivery of IDUAe fusion protein into CNS. In this study, we evaluated the long-term CNS biodistribution, dose-correlation, and therapeutic benefits of IDUAe after systemic, sustained delivery via hematopoietic stem cell (HSC)-mediated gene therapy with expression restricted to erythroid/megakaryocyte lineages. Compared to the highest dosage group treated by nontargeted control IDUAc (165 U/ml), physiological levels of IDUAe in the circulation (12 U/ml) led to better CNS benefits in MPS I mice as demonstrated in glycosaminoglycan accumulation, histopathology analysis, and neurological behavior. Long-term brain metabolic correction and normalization of exploratory behavior deficits in MPS I mice were observed by peripheral enzyme therapy with physiological levels of IDUAe derived from clinically attainable levels of HSC transduction efficiency (0.1). Importantly, these levels of IDUAe proved to be more beneficial on correction of cerebrum pathology and behavioral deficits in MPS I mice than wild-type HSCs fully engrafted in MPS I chimeras. These results provide compelling evidence for CNS efficacy of IDUAe and its prospective translation to clinical application. Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disorder with systemic and central nervous system (CNS) involvement due to deficiency of α-l-iduronidase (IDUA). We previously identified a receptor-binding peptide from apolipoprotein E (e) that facilitated a widespread delivery of IDUAe fusion protein into CNS. In this study, we evaluated the long-term CNS biodistribution, dose-correlation, and therapeutic benefits of IDUAe after systemic, sustained delivery via hematopoietic stem cell (HSC)-mediated gene therapy with expression restricted to erythroid/megakaryocyte lineages. Compared to the highest dosage group treated by nontargeted control IDUAc (165 U/ml), physiological levels of IDUAe in the circulation (12 U/ml) led to better CNS benefits in MPS I mice as demonstrated in glycosaminoglycan accumulation, histopathology analysis, and neurological behavior. Long-term brain metabolic correction and normalization of exploratory behavior deficits in MPS I mice were observed by peripheral enzyme therapy with physiological levels of IDUAe derived from clinically attainable levels of HSC transduction efficiency (0.1). Importantly, these levels of IDUAe proved to be more beneficial on correction of cerebrum pathology and behavioral deficits in MPS I mice than wild-type HSCs fully engrafted in MPS I chimeras. These results provide compelling evidence for CNS efficacy of IDUAe and its prospective translation to clinical application.
Cardiac Tamponade due to Hypertonic Contrast Medium in the Pericardial Sac Following Cineangiography
Authors: ROBERT W. POPPER, DAVID SCHUMACHER, CHARLES H. QUINN
Journal: Circulation (1967)

Relatively small amounts of contrast media reaching the pericardial sac can cause acute cardiac tamponade. The mechanism of this complication is on the basis of the hyperosmolarity of these angiographic media, resulting in the further accumulation of large amounts of fluid in the pericardial sac. Active bleeding due to possible perforation has probably not been a major factor in the cases reported. The appearance of contrast medium in the pericardial sac should alert the cardiac catheterization team to the possibility of impending severe cardiac tamponade, and pericardiocentesis should be prepared for immediately. Thoracotomy is probably not necessary in the majority of cases.
Reply to C.C. Earle
Authors: Jeffrey A. Meyerhardt, Al B. Benson, Pamela B. Mangu
Journal: Journal of Clinical Oncology (2014)

The American Society of Clinical Oncology's updated colorectal cancer surveillance guideline 1 provides, as always, rational, judicious guidance.However, I am concerned about the qualifying statement that "for patients at higher risk of recurrence, providers may want to consider more frequent interval testing." 1(p4468) Although on the surface it may seem reasonable, the evidence does not support this approach.3][4][5] Increased intensity of surveillance in high-risk disease will more often detect the tip of the iceberg of metastases and result in subjecting more patients to noncurative surgeries.The qualifying statement encourages or at least justifies the overuse of expensive, unnecessary tests that may result in harm to patients.
Papaveretum in women of childbearing potential
Authors: A W Asscher, L K Fowler
Journal: BMJ (1991)

The questionnaire showed that a wide range of alternative opioids had been used to replace papaveretum, of which morphine sulphate was the most common.A second postal questionnaire to 15 district hospital pharmacies in the Wessex region confirmed this.The recommendations have received almost uniform acceptance, as befits guidelines from a national body regulating drug safety.As the guidelines have necessitated a change in clinical practice, however, many anaesthetists considered that wider dissemination of the evidence that had been valuated was needed.
Evidence for multiple mechanisms of polyclonal T cell activation in murine lupus.
Authors: R R Singh, B H Hahn, B P Tsao, F M Ebling
Journal: Journal of Clinical Investigation (1998)

Individuals with systemic autoantibody-mediated diseases such as lupus have polyclonal T and B cell activation. Yet, autoantibody production is restricted to certain autoantigens. The mechanisms underlying this phenomenon remain unclear. We propose three potential mechanisms by which autoreactive helper T cell responses diversify to become polyclonal, yet are restricted to certain antigens. First, using a model where self-Ig peptides spontaneously activate T cells and modulate disease in lupus mice, we demonstrate that the numbers of autoantibody-augmenting T helper peptides increased across the Ig molecule as mice aged ("intramolecular determinant spreading"). Secondly, a single T cell hybridoma established from a (NZB x NZW)F1 mouse immunized with one self-Ig peptide recognized several Ig-derived determinants, which had little sequence homology with the immunizing peptide. Such determinant degeneracy can lead to polyclonality. To explore a mechanism for restriction to certain autoantigens, a protein database search was done for homologies with sequences of selected stimulatory Ig peptides. Identical sequences of such determinants were not found in murine proteins other than Ig. These occurred infrequently in nonautoantibody Ig, but quite commonly in lupus-related autoantibodies such as antibodies to DNA, cardiolipin, and erythrocytes. Thus, determinant spreading and degenerate recognition in T cells coupled with recurring use of T cell determinant sequences among autoantibodies result in polyclonality that is restricted to certain autoantigens.
Abstract 4484: The dual PI3K/mTOR inhibitor, PI-103, demonstrates therapeutic efficacy in undifferentiated pleomorphic sarcoma
Authors: Quansheng Zhu, Xianbiao Xie, Theresa Nguyen, Svetlana Bolshakov, Raphael E. Pollock, Dina Chelouche Lev
Journal: Cancer Research (2011)

Abstract The lack of effective systemic therapy is the major unresolved clinical problem in undifferentiated pleomorphic sarcoma (UPS)/malignant fibrohistocytoma (MFH). Novel effective therapeutic approaches are crucially needed. Given the heterogeneity of UPS/MFH, identifying common molecular deregulations amenable to therapeutic targeting would be of major importance. PI3K/AKT/mTOR pathway has been implicated in cancer progression and metastasis, and is highly activated in soft tissue sarcoma (STS). However, not much is known about this pathway in UPS/MFH specifically. We sought to assess AKT/mTOR pathway expression and activation in human UPS/MFH specimens and to evaluate whether combined inhibition of this pathway affects the proliferation and survival of UPS/MFH cells. Materials and methods: A UPS/MFH tissue microarray (TMA) consisting of 180 primary UPS/MFH samples from patients who underwent complete surgical resection has been used to detect the expression of phospho-AKT. Human UPS/MFH primary cell strains/cell lines and murine undifferentiated pleomorphic sarcoma cell lines have been established to determine the pro-tumorigenic effects of PI3K/AKT/mTOR intracellular signaling and to evaluate the efficacy of dual PI3K/mTOR inhibitor PI-103 on cell growth and survival. Results: Phospho-AKT was found to be commonly expressed in UPS/MFH. Enhanced pAKT expression levels inversely correlated with shorter 5-yr disease specific survival (DSS). Phosphorylation of AKT, p70S6K and 4E-BP1 were observed in a panel of human UPS/MFH primary cell strains/cell lines and murine UPS cell lines. PI-103 inhibited PI3/AKT/mTOR pathway signaling in UPS/MFH as observed by WB analysis resulting in marked decrease in tumor cell proliferation, enhanced G1 phase cell cycle arrest, and abrogated migration and invasion. Interestingly, PI103 treatment resulted in decreased expression and activation of the tyrosine kinase receptors EGFR and c-MET. This novel finding suggests that a feedback loop may exist between AKT/mTOR and tyrosine kinase receptor expression. Conclusions: PI3K/AKT/mTOR pathway is a common molecular deregulation in the heterogeneous group of UPS/MFH. The Dual PI3K/mTOR inhibitor, PI-103, should be further be investigated for its anti-UPS/MFH effects. 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 4484. doi:10.1158/1538-7445.AM2011-4484
Inaccurate assumptions about oropharyngeal cancer
Authors: E. M Sturgis, K. R Dahlstrom
Journal: BMJ (2009)

The article by Kim and Goldie on the cost effectiveness of including boys in a human papillomavirus (HPV) vaccination programme made assumptions about oropharyngeal cancers that are inaccurate.1 The prevalence of HPV in oropharyngeal …
Brain Metastases in Small Cell Carcinoma
Authors: Nicholas J. DiBella
Journal: JAMA (1980)

<h3>To the Editor.—</h3> We appreciated the comments by Okin and Brandstetter (243:2154, 1980) in respect to our study on small cell carcinoma of the lung (242:2084, 1979). They reviewed their data and obtained different results. We agree with their comment that the observed differences could be secondary to a different patient population. Only 24% of their patients had brain metastases develop. This is much lower than that which is reported in the literature, with some authors reporting an incidence as high as 65% in patients on whom autopsies were performed.<sup>1</sup>If the incidence were truly 24%, then prophylactic cranial irradiation (PCI) would be difficult to justify in this tumor. In their letter they state that their longer mean survival of 5.75 months for those patients with brain metastases vs 3.5 months for those without brain metastases was not statistically significant. They commented that this was similar to our mean
Suppression of Peutz-Jeghers Polyposis by Targeting Mammalian Target of Rapamycin Signaling
Authors: Chongjuan Wei, Christopher I. Amos, Nianxiang Zhang, Xiaopei Wang, Asif Rashid, Cheryl L. Walker, Richard R. Behringer, Marsha L. Frazier
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Peutz-Jeghers syndrome (PJS) is a unique disorder characterized by the development of hamartomas in the gastrointestinal tract as well as increased risks for variety of malignancies. Germ-line mutations of LKB1 cause PJS. We have generated Lkb1+/− mice, which model human PJS. Rapamycin and its analogues are promising preventive and therapeutic agents that specifically inhibit signaling from mammalian target of rapamycin (mTOR). Hyperactivation of mTOR signaling has been associated with PJS. The objective of the study is to investigate the efficacy of mTOR inhibition in suppressing Peutz-Jeghers polyposis in Lkb1+/− mice. Experimental Design: We initiated a trial of rapamycin in Lkb1+/− mice at 9 months of age (after the onset of polyposis) at the dose of 2 mg/kg/d for a 2-month period. We assessed the efficacy of rapamycin by measuring polyp sizes and tumor burden. To examine the effect of rapamycin on mTOR signaling, phosphorylation levels of S6 were evaluated by immunostaining. Results: We observed a significant decrease in mean tumor burden (Student's t test, P = 0.023) as well as total tumor burden in rapamycin-treated group compared with control group. Comparison of the polyp size observed in both rapamycin-treated and control groups showed that rapamycin efficiently decreased the tumor burden of large polyps (&amp;gt;8 mm). This inhibition of rapamycin was associated with a decrease in phosphorylated S6 levels in the polyps. Conclusions: Rapamycin effectively suppresses Peutz-Jeghers polyposis in a mouse model, suggesting that rapamycin or its analogues may represent a new targeted therapy for the treatment of PJS.
Cancers Exhibit a Mutator Phenotype: Clinical Implications
Authors: Lawrence A. Loeb, Jason H. Bielas, Robert A. Beckman
Journal: Cancer Research (2008)

Abstract Malignancies are characterized by mutations. We have hypothesized that the thousands of mutations in most human cancers do not result from the low mutation rates exhibited by normal human cells. Instead, cancer cells express a mutator phenotype (i.e., the mutation rate in the cancer cells is much greater than that in normal cells). We consider the following points: (a) Mutations in genes that govern genetic stability could be the cause of a mutator phenotype exhibited by human cancers. (b) A mutator phenotype increases the efficiency of acquiring mutations including those associated with cancer. (c) Recent experimental evidence indicates that human tumors contain a vast array of both clonal mutations and nonexpanded (random) mutations. (d) The presence of nonexpanded mutations in tumors has fundamental clinical implications for cancer risk assessment, grading, and prognosis including the rapid emergence of resistance to chemotherapeutic agents. Lastly, (e) if a mutator phenotype drives carcinogenesis, drugs that target mutator pathways might prevent cancer by delay. [Cancer Res 2008;68(10):3551–7]
P3-067: Clinical and molecular characteristics of advanced non-small cell lung cancer (NSCLC) patients (pts) with rapid progressive disease (RPD) on gefitinib therapy (G)
Authors: Mary J. Fidler, Lela Buckingham, Meryl Gale, John Coon Iv, Ann Mauer, Victoria Villaflor, Kelly Kaiser, Shannon McCormack, Phillip Bonomi
Journal: Journal of Thoracic Oncology (2007)
Chronic one-kidney hypertension in rabbits. I. Treatment with kidney extracts.
Authors: L T Skeggs, J R Kahn, M Levine, F E Dorer, K E Lentz
Journal: Circulation Research (1975)

An investigation into the mechanism that sustains the blood pressure in chronic one-kidney hypertension in rabbits was made using passive and active immunization with hog kidney extracts containing renin and with angiotensin antagonists. Seven hypertensive rabbits were passively immunized for extended periods with antiserum prepared in other rabbits. Antirenin levels were in the range of 1-3 units/ml. Control experiments demonstrated that antirenin concentrations of 1.0 unit/ml or more eliminated more than 99% of the pressor response to renin. There was no lowering of blood pressure that could be attributed to the antibodies. No decrease in blood pressure was observed in 13 experiments in 7 rabbits given the angiotensin II antagonist 1-Sar-8-Ile-angiotensin II; infusion rates of 0.09-87 mug/min kg-1 were used for periods of a few hours up to 3 days. A reduction in blood pressure occurred in 16 of 19 rabbits immunized directly with extracts containing renin with specific activities of 9.6-757 GU/mg. Plasma antirenin titers correlated poorly with reductions in blood pressure. The blood pressure of 22 rabbits given equal amounts of protein without renin was unaffected. It is concluded that the elevation of blood pressure in rabbits with chronic one-kidney hypertension is not dependent on ciculating renin or angiotensin; rather, it results from the presence of renin in an extravascular location or from an unknown pressor substance.
INTERPRETATION OF CHEST ROENTGENOGRAMS
Authors: KENNON DUNHAM
Journal: JAMA (1933)

For more than twenty years the laboratory with which I am associated (as many other laboratories) has studied necropsy material to determine the relation between x-ray densities and pathologic observations. It is my opinion that the relative degrees of scar tissue and pulmonary exudate can be determined from a study of x-ray films with sufficient accuracy to be of great practical value in the diagnosis, prognosis and treatment of pulmonary tuberculosis. Pulmonary tuberculosis can be understood more easily if the various lesions are regarded as the products of inflammation and if it is remembered that tuberculous infection varies from marked chronicity to severe activity. Thus, the densities as shown on the x-ray film reveal lesions that vary from dense scar tissue (proliferative type) to extensive pulmonary exudate (exudative type). The study of a case of pulmonary tuberculosis necessitates determining not only the extent and location of the lesions but also
Trans-splicing Into Highly Abundant Albumin Transcripts for Production of Therapeutic Proteins In Vivo
Authors: Jun Wang, S Gary Mansfield, Colette A Cote, Ping Du Jiang, Ke Weng, Marcelo JA Amar, Bryan H Brewer, Alan T Remaley, Gerard J McGarrity, Mariano A Garcia-Blanco, M Puttaraju
Journal: Molecular Therapy (2008)

Spliceosome-mediated RNA trans-splicing has emerged as an exciting mode of RNA therapy. Here we describe a novel trans-splicing strategy, which targets highly abundant pre-mRNAs, to produce therapeutic proteins in vivo. First, we used a pre-trans-splicing molecule (PTM) that mediated trans-splicing of human apolipoprotein A-I (hapoA-I) into the highly abundant mouse albumin exon 1. Hydrodynamic tail vein injection of the hapoA-I PTM plasmid in mice followed by analysis of the chimeric transcripts and protein, confirmed accurate and efficient trans-splicing into albumin pre-mRNA and production of hapoA-I protein. The versatility of this approach was demonstrated by producing functional human papillomavirus type-16 E7 (HPV16-E7) single-chain antibody in C57BL/6 mice and functional factor VIII (FVIII) and phenotypic correction in hemophilia A mice. Altogether, these studies demonstrate that trans-splicing to highly abundant albumin transcripts can be used as a general platform to produce therapeutic proteins in vivo. Spliceosome-mediated RNA trans-splicing has emerged as an exciting mode of RNA therapy. Here we describe a novel trans-splicing strategy, which targets highly abundant pre-mRNAs, to produce therapeutic proteins in vivo. First, we used a pre-trans-splicing molecule (PTM) that mediated trans-splicing of human apolipoprotein A-I (hapoA-I) into the highly abundant mouse albumin exon 1. Hydrodynamic tail vein injection of the hapoA-I PTM plasmid in mice followed by analysis of the chimeric transcripts and protein, confirmed accurate and efficient trans-splicing into albumin pre-mRNA and production of hapoA-I protein. The versatility of this approach was demonstrated by producing functional human papillomavirus type-16 E7 (HPV16-E7) single-chain antibody in C57BL/6 mice and functional factor VIII (FVIII) and phenotypic correction in hemophilia A mice. Altogether, these studies demonstrate that trans-splicing to highly abundant albumin transcripts can be used as a general platform to produce therapeutic proteins in vivo.
MELANIFEROUS LEUKOCYTES IN THE DIAGNOSIS OF MALARIA
Authors: James Ross Clemens
Journal: JAMA (1923)

To the Editor:  —In and about St. Louis, a district in which the manifestations of malaria are protean in character and of endless variety, it seems strange that a means of diagnosis in malaria is ignored that is used by the American government in the Philippines, employed in the malarial zones of the British Empire, and warmly advocated and championed by no less an authority than Sir Patrick Manson. Since the discovery by Laveran, we have been in a position to explain the observation of Loomis, who forty years ago drew attention to the relationship that existed between pigmented leukocytes and malaria. That plasmodial pigment is engulfed by the phagocytes no one will deny, but in scientific proselytizing I have found that to gain assent in reasoning back from effect to cause, from plasmodial pigment to the plasmodium itself, is quite another matter.  In G. A. Gibson's Text Book of
Gene "Volatility" Is Most Unlikely to Reveal Adaptation
Authors: P. M. Sharp
Journal: Molecular Biology and Evolution (2004)

It has recently been claimed that adaptive molecular evolution can be detected within single genome sequences by use of gene "volatility" scores. However, the approach used was entirely based on the assumption that synonymous codon usage is normally shaped by selection for low volatility; this is most unlikely to be true. Furthermore, even if that assumption could be justified, the method would clearly lack power, detecting only genes where a very large number of nonsynonymous substitutions had occurred. Volatility scores are susceptible to other influences. The unusually high volatilities of the Mycobacterium tuberculosis and Plasmodium falciparum genes that were identified as putatively having undergone adaptive changes were largely the result of internally repetitive structures, in which unusual codon usage was caused by the mechanisms that generated this repetition rather than by adaptive changes.
A CASE OF PNEUMOCOCCIC ARTHRITIS
Authors: S. Raw
Journal: BMJ (1906)

on large doses of ipecacuanha from April 26th to 30th on the supposition that there might be some latent amoebic dysentery in the upper part of the large bowel.On examining him again with the x rays, the right arch of the diaphragm was rather high, and moving less freely than the right, so on May 7th exploratory puncture was again performed but no pus was found.Except for occasional slight dragging pain on deep respiration, he remains quite well five weeks after the opera- tion and is about to return tO his work.The high leucocyte counts during convalescence were probably caused by absorption of the remaining pus in the abscess.
Boycott publisher because of holdings in arms trade, readers told
Authors: Owen Dyer
Journal: BMJ (2007)

The former editor of the BMJ Richard Smith has called on researchers and authors to boycott the world's largest publisher of scientific and medical journals, Reed Elsevier, to pressure the company to divest itself of holdings in the arms trade.

Writing in the Journal of the Royal Society of Medicine , Dr Smith argues that it is hypocritical for a company that publishes health journals to promote arms sales. His editorial will appear in the March issue (2007;100:114-6) but is currently available online (www.jrsm.org).

Dr Smith notes that Reed Elsevier's flagship journal, the Lancet , has been outspoken in its criticism of the arms trade and …