tbuckley/cabot-search huggingface dataset:
In Vivo Visualization of Embryonic Stem Cell Survival, Proliferation, and Migration After Cardiac Delivery
Authors: Feng Cao, Shuan Lin, Xiaoyan Xie, Pritha Ray, Manishkumar Patel, Xianzhong Zhang, Micha Drukker, Scott J. Dylla, Andrew J. Connolly, Xiaoyuan Chen, Irving L. Weissman, Sanjiv S. Gambhir, Joseph C. Wu
Journal: Circulation (2006)

Recent studies have shown that stem cell therapy can promote tissue regeneration; however, monitoring stem cells in vivo remains problematic owing to limitations of conventional histological assays and imaging modalities.Murine embryonic stem (ES) cells were stably transduced with a lentiviral vector carrying a novel triple-fusion (TF) reporter gene that consists of firefly luciferase, monomeric red fluorescence protein, and truncated thymidine kinase (fluc-mrfp-ttk). ES cell viability, proliferation, and differentiation ability were not adversely affected by either reporter genes or reporter probes compared with nontransduced control cells (P=NS). Afterward, 1x10(7) of ES cells carrying the TF reporter gene (ES-TF) were injected into the myocardium of adult nude rats (n=20). Control animals received nontransduced ES cells (n=6). At day 4, the bioluminescence and positron emission tomography signals in study animals were 3.7x10(7)+/-5.8x10(6) photons.s(-1).cm(-2) per steradian (sr) and 0.08+/-0.03% injected dose/g, respectively (P<0.05 versus control). Both signals increased progressively from week 1 to week 4, which indicated ES cell survival and proliferation in the host. Histological analysis demonstrated the formation of intracardiac and extracardiac teratomas. Finally, animals (n=4) that were treated with intraperitoneal injection of ganciclovir (50 mg/kg) did not develop teratomas when compared with control animals (n=4) treated with saline (1 mL/kg).This is the first study to characterize ES cells that stably express fluorescence, bioluminescence, and positron emission tomography reporter genes and monitor the kinetics of ES cell survival, proliferation, and migration. This versatile imaging platform should have broad applications for basic research and clinical studies on stem cell therapy.
CCR1 blockade reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease
Authors: Daniel J. Dairaghi, Babatunde O. Oyajobi, Anjana Gupta, Brandon McCluskey, Shichang Miao, Jay P. Powers, Lisa C. Seitz, Yu Wang, Yibin Zeng, Penglie Zhang, Thomas J. Schall, Juan C. Jaen
Journal: Blood (2012)
Family History and Psychiatric Comorbidity in Persons With Compulsive Buying: Preliminary Findings
Authors: Donald W. Black, Susan Repertinger, Gary R. Gaffney, Janelle Gabel
Journal: American Journal of Psychiatry (1998)

The authors explored the family history and psychiatric comorbidity of a group of compulsive buyers who volunteered for medication studies. Compulsive buying is characterized by inappropriate shopping and spending behavior that leads to impairment.Thirty-three subjects who met the criteria of McElroy and colleagues for compulsive buying, and who scored more than two standard deviations above the mean on the Compulsive Buying Scale, were recruited. Twenty-two comparison subjects were recruited in the course of another study, and the presence of obsessive-compulsive disorder was the only reason for exclusion. Both groups were administered the Structured Clinical Interview for DSM-III-R disorders. The Family History Research Diagnostic Criteria were used to collect information about psychiatric disorders in first-degree relatives.Compulsive buyers had a mean age of 40 years; two (6%) were men. Comparison subjects had a mean age of 39 years; six (27%) were men. The two groups differed in gender distribution but not in age, marital status, or educational achievement. Compulsive buyers were more likely than comparison subjects to have lifetime mood disorders (especially major depression) and to have more than one psychiatric disorder. First-degree relatives of compulsive buyers were more likely than comparison relatives to suffer from depression, alcoholism, and a drug use disorder and to suffer more psychiatric disorders in general.These results indicate that persons who report compulsive buying behavior, and their first-degree relatives, are more likely to have a higher prevalence of psychiatric disorder than are comparison subjects.
Restricting Symptoms in the Last Year of Life
Authors: Sarwat I. Chaudhry, Terrence E. Murphy, Evelyne Gahbauer, L. Scott Sussman, Heather G. Allore, Thomas M. Gill
Journal: JAMA Internal Medicine (2013)

Freedom from symptoms is an important determinant of a good death, but little is known about symptom occurrence during the last year of life.To evaluate the monthly occurrence of physical and psychological symptoms leading to restrictions in daily activities (ie, restricting symptoms) among older persons during the last year of life and to determine the associations of demographic and clinical factors with symptom occurrence.Prospective cohort study. Comprehensive assessments were completed every 18 months, and monthly interviews were conducted to assess the presence of restricting symptoms. Of 1002 nondisabled community-dwelling individuals 70 years or older in greater New Haven, Connecticut, eligible to participate, 754 agreed and were enrolled between 1998 and 1999.The primary outcome was the monthly occurrence of restricting symptoms as a dichotomous outcome. The monthly mean count of restricting symptoms was a secondary outcome.Among the 491 participants who died after their first interview and before June 30, 2011, mean age at death was 85.8 years, 61.9% were women, and 9.0% were nonwhite. The mean number of comorbid conditions was 2.4, and 73.1% had multimorbidity. The monthly occurrence of restricting symptoms was fairly constant from 12 months before death (20.4%) until 5 months before death (27.4%), when it began to increase rapidly, reaching 57.2% in the month before death. In multivariable analysis, age younger than 85 years (odds ratio [OR], 1.30 [95% CI, 1.07-1.57]), multimorbidity (OR, 1.38 [95% CI, 1.09-1.75]), and proximity to time of death (OR, 1.14 per month [95% CI, 1.11-1.16]) were significantly associated with the monthly occurrence of restricting symptoms. Participants who died of cancer had higher monthly symptom occurrence (OR, 1.80 [95% CI, 1.03-3.14]) than participants who died of sudden death, although this difference was only marginally significant (P = .04). Symptom burden did not otherwise differ substantially according to condition leading to death.Restricting symptoms are common during the last year of life, increasing substantially approximately 5 months before death. Our results highlight the importance of assessing and managing symptoms in older patients, particularly those with multimorbidity.
Modeling the Relationship between Progression-Free Survival and Overall Survival: The Phase II/III Trial
Authors: Mary W. Redman, Bryan H. Goldman, Michael LeBlanc, Anne Schott, Laurence H. Baker
Journal: Clinical Cancer Research (2013)

Abstract The standard phase II trial design has changed dramatically over the past decade. Randomized phase II studies have essentially become the standard phase II design in oncology for a variety of reasons. The use of these designs is motivated by concerns about the use of historical data to determine if a new agent or regimen shows promise of activity. However, randomized phase II designs come with the cost of increased study duration and patient resources. Progression-free survival (PFS) is an important endpoint used in many phase II designs. In many clinical settings, changes in PFS with the introduction of a new treatment may represent true benefit in terms of the gold standard outcome, overall survival (OS). The phase II/III design has been proposed as an approach to shorten the time of discovery of an active regimen. In this article, design considerations for a phase II/III trial are discussed and presented in terms of a model defining the relationship between OS and PFS. The design is also evaluated using 15 phase III trials completed in the Southwest Oncology Group (SWOG) between 1990 and 2005. The model provides a framework to evaluate the validity and properties of using a phase II/III design. In the evaluation of SWOG trials, three of four positive studies would have also proceeded to the final analysis and 10 of 11 negative studies would have stopped at the phase II analysis if a phase II/III design had been used. Through careful consideration and thorough evaluation of design properties, substantial gains could occur using this approach. Clin Cancer Res; 19(10); 2646–56. ©2013 AACR.
Improving Prospects for Targeting RAS
Authors: Harshabad Singh, Dan L. Longo, Bruce A. Chabner
Journal: Journal of Clinical Oncology (2015)

RAS mutations are among the most common oncogenic drivers in human cancers, affecting nearly a third of all solid tumors and around a fifth of common myeloid malignancies, but they have evaded therapeutic interventions, despite being the focus of intense research over the last three decades. Recent discoveries lend new understanding about the structure, function, and signaling of RAS and have opened new avenues for development of much needed new therapies. We discuss the various approaches under investigation to target mutant RAS proteins. The recent development of direct RAS inhibitors specific to KRAS G12C mutations represents a landmark discovery that promises to change the perception about RAS's druggability. Multiple clinical trials targeting synthetically lethal partners and/or downstream signaling partners of RAS are underway. Novel inhibitors targeting various arms of RAS processing and signaling have yielded encouraging results in the laboratory, but refinement of the drug-like properties of these molecules is required before they will be ready for the clinic.
Phase II Study of the Antibody Drug Conjugate Trastuzumab-DM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) –Positive Breast Cancer After Prior HER2-Directed Therapy
Authors: Howard A. Burris, Hope S. Rugo, Svetislava J. Vukelja, Charles L. Vogel, Rachel A. Borson, Steven Limentani, Elizabeth Tan-Chiu, Ian E. Krop, Richard A. Michaelson, Sandhya Girish, Lukas Amler, Maoxia Zheng, Yu-Waye Chu, Barbara Klencke, Joyce A. O'Shaughnessy
Journal: Journal of Clinical Oncology (2010)

The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor receptor 2 (HER2)-overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks, with evidence of efficacy, in patients with HER2-positive metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population.This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of intravenous T-DM1 (3.6 mg/kg every 3 weeks) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy.With a follow-up of ≥ 12 months among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 months), and median progression-free survival time was 4.6 months (95% CI, 3.9 to 8.6 months). The response rates were higher among patients with confirmed HER2-positive tumors (immunohistochemistry 3+ or fluorescent in situ hybridization positive) by retrospective central testing (n = 74). Higher response rates were also observed in patients whose tumors expressed ≥ median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade ≥ 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%).T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-positive MBC and is well tolerated at the recommended phase II dose.
Mammalian Target of Rapamycin, a Molecular Target in Squamous Cell Carcinomas of the Head and Neck
Authors: Panomwat Amornphimoltham, Vyomesh Patel, Akrit Sodhi, Nikolaos G. Nikitakis, John J. Sauk, Edward A. Sausville, Alfredo A. Molinolo, J. Silvio Gutkind
Journal: Cancer Research (2005)

Abstract Emerging knowledge on how the dysregulated function of signaling networks contributes to the malignant growth of squamous cell carcinoma of the head and neck (HNSCC) can now be exploited to identify novel mechanism-based anticancer treatments. In this regard, we have observed that persistent activation of the serine/threonine kinase Akt is a frequent event in HNSCC, and that blockade of its upstream kinase, 3′-phosphoinositide-dependent kinase 1, potently inhibits tumor cell growth. Akt promotes cell proliferation by its ability to coordinate mitogenic signaling with energy- and nutrient-sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian target of rapamycin (mTOR). This kinase, in turn, phosphorylates key eukaryotic translation regulators, including p70-S6 kinase and the eukaryotic translation initiation factor, 4E binding protein 1. Indeed, we show here that aberrant accumulation of the phosphorylated active form of S6, the most downstream target of the Akt-mTOR-p70-S6 kinase pathway, is a frequent event in clinical specimens from patients with HNSCC and their derived cell lines. Of interest, this enhanced level of the phosphorylated active form of S6 was rapidly reduced in HNSCC cell lines and HNSCC xenograft models at clinically relevant doses of rapamycin, which specifically inhibits mTOR. Furthermore, we observed that rapamycin displays a potent antitumor effect in vivo, as it inhibits DNA synthesis and induces the apoptotic death of HNSCC cells, ultimately resulting in tumor regression. These findings identify the Akt-mTOR pathway as a potential therapeutic target for HNSCC, and may provide the rationale for the early clinical evaluation of rapamycin and its analogues in patients with HNSCC.
Lentiginosis within plaques of linear atrophoderma of Moulin: a twin-spotting phenomenon?
Authors: E. Özkaya, K.D. Yazganoğlu
Journal: British Journal of Dermatology (2010)

Journal Article Lentiginosis within plaques of linear atrophoderma of Moulin: a twin‐spotting phenomenon? Get access E. Özkaya, E. Özkaya Department of Dermatology and Venereology, Istanbul Medical Faculty, Istanbul University, 34093 Istanbul, Turkey E‐mail: profeo@istanbul.edu.tr Search for other works by this author on: Oxford Academic Google Scholar K.D. Yazganoğlu K.D. Yazganoğlu Department of Dermatology and Venereology, Istanbul Medical Faculty, Istanbul University, 34093 Istanbul, Turkey E‐mail: profeo@istanbul.edu.tr Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 163, Issue 5, 1 November 2010, Pages 1138–1140, https://doi.org/10.1111/j.1365-2133.2010.09952.x Published: 01 November 2010
Patterns and Relative Rates of Nucleotide and Insertion/Deletion Evolution at Six Chloroplast Intergenic Regions in New World Species of the Lecythidaceae
Authors: M. B. Hamilton
Journal: Molecular Biology and Evolution (2003)

Insertions and deletions (indels) in chloroplast noncoding regions are common genetic markers to estimate population structure and gene flow, although relatively little is known about indel evolution among recently diverged lineages such as within plant families. Because indel events tend to occur nonrandomly along DNA sequences, recurrent mutations may generate homoplasy for indel haplotypes. This is a potential problem for population studies, because indel haplotypes may be shared among populations after recurrent mutation as well as gene flow. Furthermore, indel haplotypes may differ in fitness and therefore be subject to natural selection detectable as rate heterogeneity among lineages. Such selection could contribute to the spatial patterning of cpDNA haplotypes, greatly complicating the interpretation of cpDNA population structure. This study examined both nucleotide and indel cpDNA variation and divergence at six noncoding regions (psbB-psbH, atpB-rbcL, trnL-trnH, rpl20-5′rps12, trnS-trnG, and trnH-psbA) in 16 individuals from eight species in the Lecythidaceae and a Sapotaceae outgroup. We described patterns of cpDNA changes, assessed the level of indel homoplasy, and tested for rate heterogeneity among lineages and regions. Although regression analysis of branch lengths suggested some degree of indel homoplasy among the most divergent lineages, there was little evidence for indel homoplasy within the Lecythidaceae. Likelihood ratio tests applied to the entire phylogenetic tree revealed a consistent pattern rejecting a molecular clock. Tajima's 1D and 2D tests revealed two taxa with consistent rate heterogeneity, one showing relatively more and one relatively fewer changes than other taxa. In general, nucleotide changes showed more evidence of rate heterogeneity than did indel changes. The rate of evolution was highly variable among the six cpDNA regions examined, with the trnS-trnG and trnH-psbA regions showing as much as 10% and 15% divergence within the Lecythidaceae. Deviations from rate homogeneity in the two taxa were constant across cpDNA regions, consistent with lineage-specific rates of evolution rather than cpDNA region-specific natural selection. There is no evidence that indels are more likely than nucleotide changes to experience homoplasy within the Lecythidaceae. These results support a neutral interpretation of cpDNA indel and nucleotide variation in population studies within species such as Corythophora alta.
Oxidants in Chronic Kidney Disease
Authors: Sudhir V. Shah, Radhakrishna Baliga, Mohan Rajapurkar, Vivian A. Fonseca
Journal: Journal of the American Society of Nephrology (2006)

Chronic kidney disease is a worldwide public health problem that affects approximately 10% of the US adult population and is associated with a high prevalence of cardiovascular disease and high economic cost. Chronic renal insufficiency, once established, tends to progress to end-stage kidney disease, suggesting some common mechanisms for ultimately causing scarring and further nephron loss. This review defines the term reactive oxygen metabolites (ROM), or oxidants, and presents the available experimental evidence in support of the role of oxidants in diabetic and nondiabetic glomerular disease and their role in tubulointerstitial damage that accompanies progression. It concludes by reviewing the limited human data that provide some proof of concept that the observations in experimental models may be relevant to human disease.
Age-related increases in PGD2 expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice
Authors: Jincun Zhao, Jingxian Zhao, Kevin Legge, Stanley Perlman
Journal: Journal of Clinical Investigation (2011)

The morbidity and mortality associated with respiratory virus infection is felt most keenly among the elderly. T cells are necessary for viral clearance, and many age-dependent intrinsic T cell defects have been documented. However, the development of robust T cell responses in the lung also requires respiratory DCs (rDCs), which must process antigen and migrate to draining LNs (DLNs), and little is known about age-related defects in these T cell-extrinsic functions. Here, we show that increases in prostaglandin D(2) (PGD(2)) expression in mouse lungs upon aging correlate with a progressive impairment in rDC migration to DLNs. Decreased rDC migration resulted in diminished T cell responses and more severe clinical disease in older mice infected with respiratory viruses. Diminished rDC migration associated with virus-specific defects in T cell responses and was not a result of cell-intrinsic defect, rather it reflected the observed age-dependent increases in PGD(2) expression. Blocking PGD(2) function with small-molecule antagonists enhanced rDC migration, T cell responses, and survival. This effect correlated with upregulation on rDCs of CCR7, a chemokine receptor involved in DC chemotaxis. Our results suggest that inhibiting PGD(2) function may be a useful approach to enhance T cell responses against respiratory viruses in older humans.
Effect of an inhaled glucocorticosteroid on mast cell and smooth muscle beta 2 adrenergic tolerance in mild asthma.
Authors: D H Yates, M Worsdell, P J Barnes
Journal: Thorax (1998)

BACKGROUND: Regular inhaled beta 2 agonist therapy is associated with loss of bronchoprotection to indirect bronchial provocation challenges such as allergen or adenosine monophosphate (AMP), while directly acting challenge is less affected, implying preferential mast cell tolerance. Glucocorticosteroids may reverse such beta 2 adrenoreceptor tolerance and upregulate mast cell beta 2 adrenoceptor function. METHODS: The effect of single high dose glucocorticosteroids on terbutaline induced loss of bronchoprotection was studied in a placebo controlled, double blind, cross-over study. Fifteen asthmatic subjects who were not taking inhaled glucocorticosteroids underwent two 10-day treatment periods with terbutaline (500 micrograms four times daily via Turbohaler), each followed by a single dose of inhaled budesonide (800 micrograms via Turbohaler) or identical placebo. RESULTS: Regular treatment with terbutaline resulted in significant loss of bronchoprotection to AMP (mean difference (95% CI) -1.7 (-3.0 to 0.4) doubling dilutions) but not to methacholine (mean difference -0.1 (-1.0 to 0.8) doubling dilutions). Single high dose budesonide increased the protective effect of terbutaline more to AMP than to methacholine challenge (+0.76 (0.3) doubling dilutions compared with +0.13 (0.4) doubling dilutions, respectively). The mean (SE) difference between budesonide and placebo for methacholine challenge was 0.08 (0.14) whereas that for AMP was 0.075 (0.15); p = NS. The difference in PC20 was not statistically significant when compared with placebo for either challenge agent. CONCLUSIONS: Inhaled glucocorticosteroids in a single dose had no significant effect in restoring terbutaline induced loss of bronchoprotection, implying that mast cell beta 2 adrenoceptor sensitivity is not restored by a single dose of an inhaled glucocorticosteroid in asthma.