tbuckley/cabot-search huggingface dataset:
Anti-A 42- and anti-A 40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model
Authors: Y. Levites
Journal: Journal of Clinical Investigation (2005)

Accumulation and aggregation of amyloid β peptide 1–42 (Aβ42) in the brain has been hypothesized as triggering a pathological cascade that causes Alzheimer disease (AD). To determine whether selective targeting of Aβ42 versus Aβ40 or total Aβ is an effective way to prevent or treat AD, we compared the effects of passive immunization with an anti-Aβ42 mAb, an anti-Aβ40 mAb, and multiple Aβ1–16 mAbs. We established in vivo binding selectivity of the anti-Aβ42 and anti-Aβ40 mAbs using novel TgBRI-Aβ mice. We then conducted a prevention study in which the anti-Aβ mAbs were administered to young Tg2576 mice, which have no significant Aβ deposition, and therapeutic studies in which mAbs were administered to Tg2576 or CRND8 mice with modest levels of preexisting Aβ deposits. Anti-Aβ42, anti-Aβ40, and anti-Aβ1–16 mAbs attenuated plaque deposition in the prevention study. In contrast, anti-Aβ42 and anti-Aβ40 mAbs were less effective in attenuating Aβ deposition in the therapeutic studies and were not effective in clearing diffuse plaques following direct injection into the cortex. These data suggest that selective targeting of Aβ42 or Aβ40 may be an effective strategy to prevent amyloid deposition, but may have limited benefit in a therapeutic setting.
Expression of a missense mutation in the messenger RNA for beta-myosin heavy chain in myocardial tissue in hypertrophic cardiomyopathy.
Authors: M B Perryman, Q T Yu, A J Marian, A Mares, G Czernuszewicz, J Ifegwu, R Hill, R Roberts
Journal: Journal of Clinical Investigation (1992)

We have determined that a missense mutation in exon 13 of the beta-myosin heavy chain (beta MHC) gene is expressed in the messenger RNA (mRNA) isolated from a right ventricular endomyocardial biopsy obtained from the proband of a family with hypertrophic cardiomyopathy. The mutation is the result of a substitution of an adenine for a guanine residue in one allele of the beta MHC gene and creates a second recognition site for the restriction endonuclease Ddel in exon 13. The mutation is inherited in a Mendelian fashion and co-segregates with hypertrophic cardiomyopathy in this family. Complementary DNAs synthesized from RNA isolated from the endomyocardial biopsy were cloned into a plasmid vector and sequenced to confirm the expression of both the normal and mutant allele in mRNA of myocardial tissue. This is the first report of the transcription of a mutant beta MHC gene allele into mRNA of the myocardium.
Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial
Authors: Tali Cukierman-Yaffe, Jackie Bosch, Rafael Diaz, Leanne Dyal, Nicolae Hancu, Pers Hildebrandt, Fernando Lanas, Basil S Lewis, Michel Marre, Jean-Francois Yale, Salim Yusuf, Hertzel C Gerstein
Journal: The Lancet Diabetes & Endocrinology (2014)
Comparative mitochondrial proteomics: perspective in human diseases
Authors: Yujie Jiang, Xin Wang
Journal: Journal of Hematology & Oncology (2012)

Mitochondria are the most complex and the most important organelles of eukaryotic cells, which are involved in many cellular processes, including energy metabolism, apoptosis, and aging. And mitochondria have been identified as the "hot spot" by researchers for exploring relevant associated dysfunctions in many fields. The emergence of comparative proteomics enables us to have a close look at the mitochondrial proteome in a comprehensive and effective manner under various conditions and cellular circumstances. Two-dimensional electrophoresis combined with mass spectrometry is still the most popular techniques to study comparative mitochondrial proteomics. Furthermore, many new techniques, such as ICAT, MudPIT, and SILAC, equip researchers with more flexibilities inselecting proper methods. This article also reviews the recent development of comparative mitochondrial proteomics on diverse human diseases. And the results of mitochondrial proteomics enhance a better understanding of the pathogenesis associated with mitochondria and provide promising therapeutic targets.
A Limited Sampling Schedule to Estimate Individual Pharmacokinetic Parameters of Fludarabine in Hematopoietic Cell Transplant Patients
Authors: David H. Salinger, David K. Blough, Paolo Vicini, Claudio Anasetti, Paul V. O'Donnell, Brenda M. Sandmaier, Jeannine S. McCune
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Fludarabine monophosphate (fludarabine) is frequently administered to patients receiving a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplant (HCT) in an ambulatory care setting. These patients experience significant interpatient variability in clinical outcomes, potentially due to pharmacokinetic variability in 2-fluoroadenine (F-ara-A) plasma concentrations. To test such hypotheses, patient compliance with the blood sampling should be optimized by the development of a minimally intrusive limited sampling schedule (LSS) to characterize F-ara-A pharmacokinetics. To this end, we sought to create the first F-ara-A population pharmacokinetic model and subsequently a LSS. Experimental Design: A retrospective evaluation of F-ara-A pharmacokinetics was conducted after one or more doses of daily i.v. fludarabine in 42 adult HCT recipients. NONMEM software was used to estimate the population pharmacokinetic parameters and compute the area under the concentration-time curve. Results: A two-compartment model best fits the data. A LSS was constructed using a simulation approach, seeking to minimize the scaled mean squared error for the area under the concentration-time curve for each simulated individual. The LSS times chosen were 0.583, 1.5, 6.5, and 24 hours after the start of the 30-minute fludarabine infusion. Discussion: The pharmacokinetics of F-ara-A in an individual HCT patient can be accurately estimated by obtaining four blood samples (using the LSS) and maximum a posteriori Bayesian estimation. Conclusion: These are essential tools for prospective pharmacodynamic studies seeking to determine if clinical outcomes are related to F-ara-A pharmacokinetics in patients receiving i.v. fludarabine in the ambulatory clinic. (Clin Cancer Res 2009;15(16):5280–7)
Safety of measles, mumps and rubella vaccination in juvenile idiopathic arthritis
Authors: M. W Heijstek, G. C S Pileggi, E. Zonneveld-Huijssoon, W. Armbrust, E. P A H Hoppenreijs, C. S P M Uiterwaal, W. Kuis, N. M Wulffraat
Journal: Annals of the Rheumatic Diseases (2007)

To assess the effect of measles, mumps and rubella (MMR) vaccination on disease activity in children with juvenile idiopathic arthritis (JIA).
Studies on gastrin: Part I A method of biological assay of gastrin
Authors: K. S. Lai
Journal: Gut (1964)

These three papers present studies on gastrin. The first paper describes a method of biological assay using the rat. The second paper demonstrates that the highest concentration of gastrin-like activity occurs in the antral mucosa, with a clear gradient of concentration of activity down the gut. However, it is to be noted that the total amount of extractable activity is greatest in the duodenum, although the concentration there is less than in the antrum. No activity was detected in the pancreas. The third paper studies the contents of gastrin-like activity in patients with duodenal ulcer and demonstrates higher figures when stenosis is present. Patients with benign gastric ulcer and carcinomata showed results equal to or greater than in those with the average uncomplicated duodenal ulcer. It was noted that two patients with dilated antra both had very low total gastrin-like activity. There was no correlation between total activity and maximal histamine-stimulated output of acid. There was, however, a positive correlation between the insulin-stimulated acid secretion and the total gastrin-like activity in the cases of uncomplicated duodenal ulcers. The clinical studies are still tentative in view of the several variables present, but it seems likely that they will in due course clarify the role of gastrin in the ulcer problem.
Michael T. McManus: Interrupting biology
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2008)

The human genome encodes snippets of RNAs ranging from 21–23 nucleotides in length, called microRNAs (miRNAs). Rather than code for proteins, miRNAs instead sabotage the translation of mRNAs. miRNAs are first generated as longer, hairpin-like precursors in the nucleus. In the cytoplasm, a collection of enzymes strips down the hairpins into their tiny and unwound final structure. miRNA-bound mRNAs are either sequestered from translation or destroyed outright—processes known as RNA interference (RNAi).




Figure 1





Michael McManus




Michael McManus has been a fan of small RNAs and their manipulative power his entire career. As a graduate student, he studied how small RNAs in trypanosomes guide RNA editing, whereby incomplete mitochondrial mRNAs are filled in with uridine residues (1, 2).

During his postdoctoral stay in Nobel Laureate Phillip Sharp's laboratory at MIT, McManus's work led to one of the first reports of RNAi activity in mammalian cells (3). He showed that T cell genes could be suppressed by a class of small double-stranded RNA called short interfering RNAs (siRNA). His next discovery—that synthetic miRNA hairpin structures could be stably introduced into cells via DNA vectors—gave the field a reliable tool for studying RNAi (4).

Now heading his own lab at the University of California, San Francisco, McManus is exploring the role of miRNAs during development and disease. His team has developed a mouse model in which the gene for the miRNA-processing enzyme Dicer can be selectively switched off (5) and a technique to visualize miRNA expression patterns in situ (6). They are now creating RNAi libraries that can be used to analyze gene function in cells and in animal models. McManus is also involved in collaborations to understand how miRNA failures lead to diseases such as diabetes. He recently began a project funded by the Keck Foundation to create 100 different miRNA mouse knockouts.
The Prognostic Biomarkers <i>HOXB13, IL17BR</i>, and <i>CHDH</i> Are Regulated by Estrogen in Breast Cancer
Authors: Zuncai Wang, Sonika Dahiya, Heather Provencher, Beth Muir, Erin Carney, Kathryn Coser, Toshi Shioda, Xiao-Jun Ma, Dennis C. Sgroi
Journal: Clinical Cancer Research (2007)

Abstract Purpose: We previously identified three genes, HOXB13, IL17BR, and CHDH, that strongly predict clinical outcome in estrogen receptor (ER)–positive breast cancer patients receiving tamoxifen monotherapy. The biological mechanisms linking these genes to estrogen signaling and tamoxifen response in breast cancer remain to be determined. Experimental Design: In a consecutive series of 148 ER-positive and ER-negative breast cancers, HOXB13, IL17BR, and CHDH gene expression was measured by quantitative real-time PCR and correlated with ER, PR, and HER2 expression. The role of estrogen and ER in the regulation of these three genes was assessed in several ER-positive and ER-negative breast cancer cell lines. Results: In primary breast tumors, HOXB13 expression correlated negatively, and IL17BR and CHDH expression correlated positively, with ER status, and all three genes exhibited an ER-dependent correlation pattern with HER2 status that differs from PR and PS2, two canonical estrogen-regulated genes. Results using breast cancer cell lines show that these genes are regulated by estradiol in an ER-dependent manner, and that this regulation is abrogated by tamoxifen. Conclusions: HOXB13, IL17BR, and CHDH are estrogen-regulated genes, but their pattern of correlation with known positive (ER, PR) and negative (HER2) predictors of tamoxifen response differs from canonical ER signature genes. These results provide a biological rationale for the prognostic utility of these three genes in early-stage ER-positive breast cancer and for their potential to predict anti-estrogen resistance.
Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression
Authors: Kristina E. Hoot, Jessyka Lighthall, Gangwen Han, Shi-Long Lu, Allen Li, Wenjun Ju, Molly Kulesz-Martin, Erwin Bottinger, Xiao-Jing Wang
Journal: Journal of Clinical Investigation (2008)

TGF-β and its signaling mediators, Smad2, -3, and -4, are involved with tumor suppression and promotion functions. Smad4–/– mouse epidermis develops spontaneous skin squamous cell carcinomas (SCCs), and Smad3–/– mice are resistant to carcinogen-induced skin cancer; however, the role of Smad2 in skin carcinogenesis has not been explored. In the present study, we found that Smad2 and Smad4, but not Smad3, were frequently lost in human SCCs. Mice with keratinocyte-specific Smad2 deletion exhibited accelerated formation and malignant progression of chemically induced skin tumors compared with WT mice. Consistent with the loss of Smad2 in poorly differentiated human SCCs, Smad2–/– tumors were poorly differentiated and underwent epithelial-mesenchymal transition (EMT) prior to spontaneous Smad4 loss. Reduced E-cadherin and activation of its transcriptional repressor Snail were also found in Smad2–/– mouse epidermis and occurred more frequently in Smad2-negative human SCCs than in Smad2-positive SCCs. Knocking down Snail abrogated Smad2 loss–associated EMT, suggesting that Snail upregulation is a major mediator of Smad2 loss–associated EMT. Furthermore, Smad2 loss led to a significant increase in Smad4 binding to the Snail promoter, and knocking down either Smad3 or Smad4 in keratinocytes abrogated Smad2 loss–associated Snail overexpression. Our data suggest that enhanced Smad3/Smad4-mediated Snail transcription contributed to Smad2 loss–associated EMT during skin carcinogenesis.
Oncophenotypic Review and Clinical Correlates of Phosphatase and Tensin Homolog on Chromosome 10 Hamartoma Tumor Syndrome
Authors: Mrinal M. Patnaik, Sania S. Raza, Sherezade Khambatta, Peter P. Stanich, Matthew P. Goetz
Journal: Journal of Clinical Oncology (2010)

TO THE EDITOR: PTEN (phosphatase and tensin homolog on chromosome 10) hamartoma tumor syndrome (PHTS) is a rare autosomal dominant disorder encompassing four clinically distinct syndromes caused by germline mutations of the PTEN gene. PTEN is a dual-specificity phosphatase that plays a role as a tumor suppressor by negatively regulating the cell-survival signaling pathway initiated by phosphatidylinositol 3-kinase and the mitogen-activated protein kinase pathways. 1 These syndromes: Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-Like syndrome, are characterized by unregulated cellular proliferation leading to formation of benignhamartomasandmalignancies.BecauseoftherarityofPHTS, data regarding cancer risks in PHTS are limited and mostly based on small series and reports. We performed a retrospective analysis of patients who met National Comprehensive Cancer Network criteria for PHTS 2 and who presented to the Mayo Clinic between 1980and2009.Oncopathology,moleculardata,andclinicalinformation for these patients were analyzed. Forty-six patients met the criteria for PHTS. Among these, 40 patients had CS (three with Lhermitte-Duclos disease), and six had Bannayan-Riley-Ruvalcaba syndrome. Thyroid diseases were most common; there were 27 patients (58%) with benign thyroid conditions including multinodular goiters, thyroid adenomas, and hamartomas.Sevenpatients(15%)hadthyroidneoplasms.Contrarytowhat would be expected on the basis of existing literature, papillary cancers of the thyroid (n 6) were seen more often than follicular cancers
Antihypertensives reduce left ventricular hypertrophy
Authors: S. Gottlieb
Journal: BMJ (1999)

The widespread use of antihypertensive drugs in the United States since 1950 has been associated with a sharp reduction in the incidence of left ventricular hypertrophy, according to a new study published in the New England Journal of Medicine (1999;340:1221-7).

Rates of hypertension and left ventricular hypertrophy have been halved among men in the United States since antihypertensive drugs first became …
Clinical and inflammatory determinants of bronchial hyperresponsiveness in COPD
Authors: Maarten van den Berge, Judith M. Vonk, Margot Gosman, Thérèse S. Lapperre, Jiska B. Snoeck-Stroband, Peter J. Sterk, Lisette I.Z. Kunz, Pieter S. Hiemstra, Wim Timens, Nick H.T. ten Hacken, Huib A.M. Kerstjens, Dirkje S. Postma
Journal: European Respiratory Journal (2012)

Bronchial hyperresponsiveness (BHR) is regarded as a hallmark of asthma, yet it is also present in a considerable number of chronic obstructive pulmonary disease (COPD) patients. Epidemiological studies have shown that BHR provides complementary information to forced expiratory volume in 1 s (FEV 1 ) for development and progression of COPD. We hypothesised that the severity of BHR and its longitudinal changes associate with both clinical and airway inflammation measures in COPD. Our hypothesis was tested in 114 COPD patients (median age 62.9 years, smoking exposure 45.9 pack-yrs) participating in the GLUCOLD (Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease) study, which previously showed an improvement in BHR with fluticasone and fluticasone/salmeterol. At baseline, and 6 and 30 months after treatment, we investigated lung function, including body plethysmography, provocative concentration of methacholine causing a 20% fall in FEV 1 , sputum induction, and bronchial biopsies. By performing both cross-sectional and longitudinal analyses, we show that BHR in COPD is predominantly associated with residual volume/total lung capacity (a measure of air trapping) and airway inflammation reflected by the number of neutrophils, macrophages and lymphocytes in sputum and bronchial biopsies. Our findings indicate that BHR is an independent trait in COPD and provides important information on phenotype heterogeneity and disease activity.
Spanish government appeals against new law on generics in Galicia that is set to save 93m a year
Authors: A. Garcia Rada
Journal: BMJ (2011)

The Spanish government and a drug industry group have brought legal proceedings against the regional government in Galicia, which in December approved a law to limit prescribing of branded drugs. The new law could save the region €93m (£78m; $125m) each year, the regional government says.

The new law in the autonomous region of Galicia, which has a population of around 2.8 million, has been in force since January. It restricts the prescription of 427 branded drugs that contain 34 active ingredients, forcing doctors to prescribe the generic versions instead.

Doctors in Galicia write 250 000 prescriptions every day, about 40 000 of which are for drugs included in the banned list. The head of the regional health department in Galicia, Pilar Farjas, of the conservative Popular …
Diversity and Evolution of Effector Loci in Natural Populations of the Plant Pathogen Melampsora lini
Authors: L. G. Barrett, P. H. Thrall, P. N. Dodds, M. van der Merwe, C. C. Linde, G. J. Lawrence, J. J. Burdon
Journal: Molecular Biology and Evolution (2009)

Genetic variation for pathogen infectivity is an important driver of disease incidence and prevalence in both natural and managed systems. Here, we use the interaction between the rust pathogen, Melampsora lini, and two host plants, Linum marginale and Linum usitatissimum, to examine how host–pathogen interactions influence the maintenance of polymorphism in genes underlying pathogen virulence. Extensive sequence variation at two effector loci (AvrP123, AvrP4) was found in M. lini isolates collected from across the native range of L. marginale in Australia, as well as in isolates collected from a second host, the cultivated species L. usitatissimum. A highly significant excess of nonsynonymous compared with synonymous polymorphism was found at both loci, suggesting that diversifying selection is important for the maintenance of the observed sequence diversity. Agrobacterium-mediated transient transformation assays were used to demonstrate that variants of both the AvrP123 and AvrP4 genes are differentially recognized by resistance genes in L. marginale. We further characterized patterns of nucleotide variation at AvrP123 and AvrP4 in 10 local populations of M. lini infecting the wild host L. marginale. Populations were significantly differentiated with respect to allelic representation at the Avr loci, suggesting the possibility of local selection maintaining distinct genetic structures between pathogen populations, whereas limited diversity may be explained via selective sweeps and demographic bottlenecks. Together, these results imply that interacting selective and nonselective factors, acting across a broad range of scales, are important for the generation and maintenance of adaptively significant variation in populations of M. lini.
IN VITRO STUDIES OF CELLULAR HYPERSENSITIVITY
Authors: Robert R. Carpenter, Michael W. Brandriss
Journal: The Journal of Experimental Medicine (1964)

Some characteristics of inhibition of cell migration induced in tissue culture by the addition of specific antigen were studied. The following characteristics were found to be shared by this type of cellular hypersensitivity and delayed cutaneous sensitivity: 1. Specificity for the carrier moiety of haptene protein conjugates. The picryl protein conjugate used to sensitize guinea pigs inhibited migration of monocytic cells from these animals. Other picrylated proteins produced little inhibition. 2. Enhancement by mycobacterial adjuvants. Incorporation of tubercle bacilli with picrylated proteins in adjuvant-antigen emulsions stimulated the development of this cellular hypersensitivity to antigen. 3. Independence of circulating antibody. In contrast to cellular hypersensitivity, serum antibody (a) reacted with any of a number of picrylated proteins, (b) developed well in the absence of mycobacterial adjuvant, and (c) persisted in unchanged titer for 5 weeks in animals sensitized with saline solutions of antigen. During this time cellular hypersensitivity decreased remarkably. The in vitro system described provides a direct method to measure cell-antigen interaction and permits study of an aspect of the immune response not mediated by humoral antibody. The relation of cellular hypersensitivity to antibody formation and delayed hypersensitivity is discussed.