tbuckley/cabot-search huggingface dataset:
Upper gastrointestinal bleeding: the trials of trials.
Authors: M J Langman
Journal: Gut (1985)

This study examines the net returns associated with collectible automobiles as an alternative asset class. The author updates and extends the literature related to the collectible automobile asset class and further examines the net returns, taking transaction and carrying costs into account and comparing them with the returns associated with financial assets. Using a sample from 2006 through 2017, the research presents empirical results related to the returns, net of costs such as sales commissions, insurance, maintenance, and storage. The findings indicate that, after accounting for such costs, holding collectible automobiles as an investment asset, during the sample period, does not produce favorable returns when compared with such financial assets as equities, bonds, and gold investments. The author also explores the nonpecuniary benefits of this alternative asset class and the efficiency of the market for collectible automobiles and sets forth a framework for future research on the topic. <b>TOPICS:</b>Real assets/alternative investments/private equity, performance measurement
Physiologic Responses as Prognostic Guides in the Use of Antidepressant Drugs
Authors: WILLIAM A. HORWITZ
Journal: American Journal of Psychiatry (1968)

Differences in opinion in regard to the effectiveness of antidepressant drugs are due partly to a lack of knowledge of how they work. The author and his colleagues studied 235 patients being treated with various antidepressants and on the basis of the patients' neurovegetative responses to the drugs (particularly the "side effect" of postural hypotension) were able to recognize reactions which served as guides to drug activity, correct dosage, prognosis, and treatment.
Assessing telomeric DNA content in pediatric cancers using whole-genome sequencing data
Authors: Matthew Parker, Xiang Chen, Armita Bahrami, James Dalton, Michael Rusch, Gang Wu, John Easton, Nai-Kong Cheung, Michael Dyer, Elaine R Mardis, Richard K Wilson, Charles Mullighan, Richard Gilbertson, Suzanne J Baker, Gerard Zambetti, David W Ellison, James R Downing, Jinghui Zhang
Journal: Genome biology (2012)

Abstract Background Telomeres are the protective arrays of tandem TTAGGG sequence and associated proteins at the termini of chromosomes. Telomeres shorten at each cell division due to the end-replication problem and are maintained above a critical threshold in malignant cancer cells to prevent cellular senescence or apoptosis. With the recent advances in massive parallel sequencing, assessing telomere content in the context of other cancer genomic aberrations becomes an attractive possibility. We present the first comprehensive analysis of telomeric DNA content change in tumors using whole-genome sequencing data from 235 pediatric cancers. Results To measure telomeric DNA content, we counted telomeric reads containing TTAGGGx4 or CCCTAAx4 and normalized to the average genomic coverage. Changes in telomeric DNA content in tumor genomes were clustered using a Bayesian Information Criterion to determine loss, no change, or gain. Using this approach, we found that the pattern of telomeric DNA alteration varies dramatically across the landscape of pediatric malignancies: telomere gain was found in 32% of solid tumors, 4% of brain tumors and 0% of hematopoietic malignancies. The results were validated by three independent experimental approaches and reveal significant association of telomere gain with the frequency of somatic sequence mutations and structural variations. Conclusions Telomere DNA content measurement using whole-genome sequencing data is a reliable approach that can generate useful insights into the landscape of the cancer genome. Measuring the change in telomeric DNA during malignant progression is likely to be a useful metric when considering telomeres in the context of the whole genome.
Molecular evolution of intergenic DNA in higher primates: pattern of DNA changes, molecular clock, and evolution of repetitive sequences.
Authors: N Maeda, C I Wu, J Bliska, J Reneke
Journal: Molecular Biology and Evolution (1988)

A 3.1-kb intergenic DNA fragment located between the psi beta-globin and delta-globin genes in the beta-globin gene cluster was cloned from gorilla, orangutan, rhesus monkey, and spider monkey, and the nucleotide sequence of each fragment was determined. The phylogeny of these four sequences, together with two previously published allelic sequences from humans and one from chimpanzee, was constructed, and the accumulation of mutations in the region was analyzed. The sites of base substitutions are not evenly distributed within the region: two Alu repeats have accumulated 0.21 + 0.02 substitutions/site with 0.15 + 0.008 substitutions/site in the remainder of the fragment. The occurrence of substitutions at neighboring sites is more frequent than would be expected if they were independent. The observed excesses disappear when ancestral -CG- dinucleotide sites are excluded. The phylogenetic relationships of the sequences indicate that the human sequence shares a most recent coancestor with the chimpanzee sequence. The data also show that great apes have accumulated fewer mutations in this part of the genome than has the rhesus monkey. The relative rates of accumulation of 12 kinds of nucleotide substitution in the region during primate evolution are asymmetric in the DNA strands. From these rates of accumulation, the origin of a simple stretch of sequence near the 3' end of the 3.1-kb fragment was deduced to be a sequence comprising 50% T and 50% C on one strand. The two oppositely oriented Alu sequences in the 3.1-kb region were inserted at their present positions before the divergence of the New-World monkeys from other lineages. Our analysis shows that the nucleotide sequences of the two Alu repeats in spider monkey are unexpectedly similar both to each other and to the deduced ancestral sequence of Alu repeats. The data suggest that there has been some type of recombinational event between the spider monkey Alu repeats but that it was not a simple gene conversion.
Phase I Dose-Escalation Study of VB-111, an Antiangiogenic Virotherapy, in Patients with Advanced Solid Tumors
Authors: Andrew J. Brenner, Yael C. Cohen, Eyal Breitbart, Livnat Bangio, John Sarantopoulos, Francis J. Giles, Ernest C. Borden, Dror Harats, Pierre L. Triozzi
Journal: Clinical Cancer Research (2013)

VB-111 is an antiangiogenic agent consisting of a nonreplicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a Fas-chimera transgene in angiogenic endothelial cells. In a phase I dose-escalation study, pharmacokinetics, pharmacodynamics, safety, and efficacy of a single dose of VB-111 in patients with advanced solid tumors were evaluated.VB-111 was administered as a single i.v. infusion at escalating doses from 1 × 10(10) (cohort 1) to 1 × 10(13) (cohort 7) viral particles (VP) in successive cohorts. Assessments included pharmacokinetic and pharmacodynamic profiles, tumor response, and overall survival.Thirty-three patients were enrolled. VB-111 was safe and well-tolerated; self-limited fever and chills were seen at doses above 3 × 10(11) VPs. Transgene expression was not detected in blood but was detected in an aspirate from a subcutaneous metastasis after treatment. One patient with papillary thyroid carcinoma had a partial response.VB-111 was safe and well tolerated in patients with advanced metastatic cancer at a single administration of up to 1 × 10(13) VPs. Evidence of transgene expression in tumor tissue and tumor response was observed.
Erythropoietin-independent erythrocyte production: signals through gp130 and c-kit dramatically promote erythropoiesis from human CD34+ cells.
Authors: X Sui, K Tsuji, S Tajima, R Tanaka, K Muraoka, Y Ebihara, K Ikebuchi, K Yasukawa, T Taga, T Kishimoto, T Nakahata
Journal: The Journal of Experimental Medicine (1996)

Erythropoietin (EPO) is the primary humoral regulator of erythropoiesis and no other factor has previously been reported to support proliferation and terminal maturation of erythroid cells from hemopoietic stem cells. Here we show that stimulation of glycoprotein (gp130) by a combination of recombinant human soluble interleukin 6 receptor (sIL-6R) and IL-6 but not sIL-6R or IL-6 alone can support proliferation, differentiation, and terminal maturation of erythroid cells in the absence of EPO from purified human CD34+ cells in suspension culture containing stem cell factor (SCF). A number of erythroid bursts and mixed erythroid colonies also developed in methylcellulose culture under the same combination. The addition of anti-gp130 monoclonal antibodies but not anti-EPO antibody to the same culture completely abrogated the generation of erythroid cells. These results clearly demonstrate that mature erythroid cells can be emerged from hemopoietic progenitors without EPO in vitro. Together with the previous reports that human sera contain detectable levels of sIL-6R, IL-6, and SCF, current data suggest that gp130 signaling in association with c-kit activation may play a role in human erythropoiesis in vivo.
Ultradeep Sequencing Analysis of Population Dynamics of Virus Escape Mutants in RNAi-Mediated Resistant Plants
Authors: Fernando Martínez, Guillaume Lafforgue, Marco J. Morelli, Fernando González-Candelas, Nam-Hai Chua, José-Antonio Daròs, Santiago F. Elena
Journal: Molecular Biology and Evolution (2012)

Plant artificial micro-RNAs (amiRs) have been engineered to target viral genomes and induce their degradation. However, the exceptional evolutionary plasticity of RNA viruses threatens the durability of the resistance conferred by these amiRs. It has recently been shown that viral populations not experiencing strong selective pressure from an antiviral amiR may already contain enough genetic variability in the target sequence to escape plant resistance in an almost deterministic manner. Furthermore, it has also been shown that viral populations exposed to subinhibitory concentrations of the antiviral amiR speed up this process. In this article, we have characterized the molecular evolutionary dynamics of an amiR target sequence in a viral genome under both conditions. The use of Illumina ultradeep sequencing has allowed us to identify virus sequence variants at frequencies as low as 2 × 10(-6) and to track their variation in time before and after the viral population was able of successfully infecting plants fully resistant to the ancestral virus. We found that every site in the amiR-target sequence of the viral genome presented variation and that the variant that eventually broke resistance was sampled among the many coexisting ones. In this system, viral evolution in fully susceptible plants results from an equilibrium between mutation and genetic drift, whereas evolution in partially resistant plants originates from more complex dynamics involving mutation, selection, and drift.
Long-Term Results of Femtosecond Laser-Assisted Sutureless Anterior Lamellar Keratoplasty
Authors: Mohamed Abou Shousha, Sonia H. Yoo, George D. Kymionis, Takeshi Ide, William Feuer, Carol L. Karp, Terrence P. O'Brien, William W. Culbertson, Eduardo Alfonso
Journal: Ophthalmology (2010)
Series on comprehensive management of end-stage COPD
Authors: N. Ambrosino, R. Goldstein
Journal: European Respiratory Journal (2007)

Chronic obstructive pulmonary disease (COPD) affects 6% of the general population and is a leading cause of morbidity and mortality worldwide. Severe and very severe disease, as defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages III and IV 1, show a prevalence of 4.5 and 2.2% in males 2, 3. COPD guidelines generally do not address patients with end-stage disease, although such patients are frequently seen in clinical practice by family physicians and respiratory specialists 2, 4. In the brief series starting in the current issue of the European Respiratory Journal , we review the management of such patients, beginning with the definition, epidemiology and natural history of their condition, as described by Viegi et al. 5.

End-stage COPD patients have the most severe airflow limitation, the highest levels of dyspnoea and the worst health-related quality of life 6. Their condition has great impact on their ability to engage in activities and on their participation in social, professional and leisure activities. Their exercise tolerance is markedly reduced by dyspnoea and fatigue, and they have frequent respiratory exacerbations, which often result in hospitalisation. Their gas exchange is usually abnormal, with hypoxaemia requiring supplemental oxygen therapy, and hypercapnia requiring consideration of ventilatory support. These are the patients most likely …
Familial Risk of Pancreatic Cancer
Authors: M. Schenk, A. G. Schwartz, E. O'Neal, M. Kinnard, J. K. Greenson, J. P. Fryzek, G. S. Ying, D. H. Garabrant
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Pancreatic cancer is the fifth leading cause of cancer-related mortality in the United States. Although smoking and age are known risk factors for pancreatic cancer, several case reports and case–control studies have suggested that there is also a familial risk. We evaluated whether a family history of pancreatic cancer increases the risk of pancreatic cancer in first-degree relatives and whether smoking and younger age at cancer diagnosis further increase this risk. Methods: We conducted in-person interviews with 247 patients (“case probands”) with pancreatic cancer and 420 population-based control probands to collect risk factor data and pancreatic cancer family history for 1816 first-degree relatives of the case probands and 3157 first-degree relatives of the control probands. We analyzed the data by unconditional logistic regression models, with adjustment for correlated data by use of generalized estimating equations. All statistical tests were two-sided. Results: A positive family history of pancreatic cancer (i.e., being related to a case proband) or ever-smoking cigarettes approximately doubled the risk of pancreatic cancer (relative risk [RR] = 2.49; 95% confidence interval [CI] = 1.32 to 4.69; RR = 2.04; 95% CI = 1.09 to 3.83, respectively). The RR increased to 8.23 (95% CI = 2.18 to 31.07) for relatives who ever smoked and were related to a case proband who was diagnosed before age 60 years. Conclusion: Routine questioning of patients about a family history of pancreatic cancer, the age of onset of this cancer in their relatives, and the patient's smoking status may identify individuals at high risk of pancreatic cancer. Future research exploring the genetic and environmental interactions associated with the risk of pancreatic cancer is critically important.
Treatment-related myelodysplasia in patients with primary brain tumors
Authors: J. M. Baehring, P. W. Marks
Journal: Neuro-Oncology (2012)

Treatment-related myelodysplastic syndrome (t-MDS) and treatment-related acute myelogenous leukemia (t-AML) represent rare secondary events in patients with primary tumors of the nervous system and predominantly affect those treated with alkylating agents or topoisomerase II inhibitors. Temozolomide has become the standard chemotherapeutic agent for malignant gliomas. The emergence of this alkylating agent with little acute toxicity or cumulative myelosuppression has led to off-label protracted chemotherapy for many patients with malignant and even low-grade infiltrative gliomas, raising concern for increased risk of t-MDS/t-AML in the few long-term survivors. On the basis of an extensive literature search, we provide a discussion of epidemiology, pathogenesis, clinical presentation, diagnosis, and therapy of these disorders. t-MDS/t-AML remain rare complications of chemotherapy in patients with primary brain tumors, and the vast majority of patients die of their primary neoplasm. Prospective randomized studies with long-term follow-up are required to accurately assess the risk of t-MDS/t-AML; however, unless survival in the most common gliomas substantially increases, t-MDS/t-AML incidence will likely remain low in this patient population.
A Phase I Trial and Pharmacokinetic Study of Aflibercept (VEGF Trap) in Children with Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report
Authors: Julia Glade Bender, Susan M. Blaney, Scott Borinstein, Joel M. Reid, Sylvain Baruchel, Charlotte Ahern, Ashish M. Ingle, Darrell J. Yamashiro, Alice Chen, Brenda Weigel, Peter C. Adamson, Julie R. Park
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Aflibercept is a novel decoy receptor that efficiently neutralizes circulating VEGF. A pediatric phase I trial was conducted to define the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of aflibercept. Experimental Design: Cohorts of three to six children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5, or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were conducted with the initial dose. Results: Twenty-one eligible patients were enrolled; 18 were fully evaluable for toxicity. One of six patients receiving 2.0 mg/kg/dose developed dose-limiting intratumoral hemorrhage and two of six receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the six patients receiving 2.5 mg/kg/dose developed DLTs, defining this as the MTD. The most common non-DLTs were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for &amp;gt;13 weeks. At the MTD, the ratio of free-to-bound aflibercept serum concentration was 2.10 on day 8 but only 0.44 by day 15. A rapid decrease in VEGF (P &amp;lt; 0.05) and increase in placental growth factor (PlGF; P &amp;lt; 0.05) from baseline was observed in response to aflibercept by day 2. Conclusions: The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower than the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of antitumor activity but were dose-limiting. Clin Cancer Res; 18(18); 5081–9. ©2012 AACR.
Disruption of EphA2 Receptor Tyrosine Kinase Leads to Increased Susceptibility to Carcinogenesis in Mouse Skin
Authors: Hong Guo, Hui Miao, Lizabeth Gerber, Jarnail Singh, Mitchell F. Denning, Anita C. Gilliam, Bingcheng Wang
Journal: Cancer Research (2006)

Abstract EphA2 receptor tyrosine kinase is frequently overexpressed in different human cancers, suggesting that it may promote tumor development and progression. However, evidence also exists that EphA2 may possess antitumorigenic properties, raising a critical question on the role of EphA2 kinase in tumorigenesis in vivo. We report here that deletion of EphA2 in mouse led to markedly enhanced susceptibility to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) two-stage skin carcinogenesis. EphA2-null mice developed skin tumors with an increased frequency and shortened latency. Moreover, tumors in homozygous knockout mice grew faster and were twice as likely to show invasive malignant progression. Haploinsufficiency of EphA2 caused an intermediate phenotype in tumor development but had little effects on invasive progression. EphA2 and ephrin-A1 exhibited compartmentalized expression pattern in mouse skin that localized EphA2/ephrin-A1 interactions to the basal layer of epidermis, which was disrupted in tumors. Loss of EphA2 increased tumor cell proliferation, whereas apoptosis was not affected. In vitro, treatment of primary keratinocytes from wild-type mice with ephrin-A1 suppressed cell proliferation and inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) activities. Both effects were abolished in EphA2-null keratinocytes, suggesting that loss of ERK inhibition by EphA2 may be one of the contributing mechanisms for increased tumor susceptibility. Interestingly, despite its tumor suppressive function, EphA2 was overexpressed in skin tumors compared with surrounding normal skin in wild-type mice, similar to the observations in human cancers. EphA2 overexpression may represent a compensatory feedback mechanism during tumorigenesis. Together, these results show that EphA2 is a novel tumor suppressor gene in mammalian skin. (Cancer Res 2006; 66(14): 7050-8)
ABC of oral bioavailability: transporters as gatekeepers in the gut
Authors: C G Dietrich
Journal: Gut (2003)

DR1 (ABCB1), MRP2 (ABCC2), and BCRP (ABCG2) are members of the family of ATP binding cassette (ABC) transporters.These are plasma membrane transporters that are expressed in various organs.The role of MDR1 and MRP2 in the hepatobiliary system is well defined; both contribute to bile formation by transport of drugs, toxins, and waste products across the canalicular membrane.As they transport exogenous and endogenous substances, they reduce the body load of potentially harmful compounds.The role of ABCG2, which is also expressed in the canalicular membrane of hepatocytes, has not yet been fully characterised.All three proteins are also expressed in the apical membrane of enterocytes where they probably control oral availability of many substances.This important ''gatekeeper'' function of ABC transporters has been recognised recently and is currently under further investigation.Expression and activity of these transporters in the gut may differ between individuals, due to genetic polymorphisms or pathological conditions.This will lead to individual differences in bioavailability of different drugs, toxins, and (food derived) carcinogens.Recent information on substrates, transport mechanisms, function, and regulation of expression of MDR1, MRP2, and BCRP in different species is summarised in this review.
Akt1 and Akt2 Play Distinct Roles in the Initiation and Metastatic Phases of Mammary Tumor Progression
Authors: Rachelle L. Dillon, Richard Marcotte, Bryan T. Hennessy, James R. Woodgett, Gordon B. Mills, William J. Muller
Journal: Cancer Research (2009)

The phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway is often dysregulated in cancer. Our previous studies have shown that coexpression of activated Akt1 with activated ErbB2 or polyoma virus middle T antigen uncoupled from the PI3K pathway (PyVmT Y315/322F) accelerates mammary tumor development but cannot rescue the metastatic phenotype associated with these models. Here, we report the generation of transgenic mice expressing activated Akt2 in the mammary epithelium. Like the mouse mammary tumor virus-Akt1 strain, mammary-specific expression of Akt2 delayed mammary gland involution. However, in contrast to Akt1, coexpression of Akt2 with activated ErbB2 or PyVmT Y315/322F in the mammary glands of transgenic mice did not affect the latency of tumor development. Strikingly, Akt2 coexpresssion markedly increased the incidence of pulmonary metastases in both tumor models, demonstrating a unique role in tumor progression. Together, these observations argue that these highly conserved kinases have distinct biological and biochemical outputs that play opposing roles in mammary tumor induction and metastasis.