tbuckley/cabot-search huggingface dataset:
Microsatellite Instability and Colorectal Cancer Prognosis
Authors: Piero Benatti, Roberta Gafà, Daniela Barana, Massimiliano Marino, Alessandra Scarselli, Monica Pedroni, Iva Maestri, Laura Guerzoni, Luca Roncucci, Mirco Menigatti, Barbara Roncari, Stefania Maffei, Giuseppina Rossi, Giovanni Ponti, Alessandra Santini, Lorena Losi, Carmela Di Gregorio, Cristina Oliani, Maurizio Ponz de Leon, Giovanni Lanza
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Many studies have evaluated the role of high levels of microsatellite instability (MSI) as a prognostic marker and predictor of the response to chemotherapy in colorectal cancer (CRC); however, the results are not conclusive. The aim of this study was to analyze the prognostic significance of high levels of MSI (MSI-H) in CRC patients in relation to fluorouracil-based chemotherapy. Experimental Design: In three different institutions, 1,263 patients with CRC were tested for the presence of MSI, and CRC-specific survival was then analyzed in relation to MSI status, chemotherapy, and other clinical and pathologic variables. Results: Two hundred and fifty-six tumors were MSI-H (20.3%): these were more frequently at a less advanced stage, right-sided, poorly differentiated, with mucinous phenotype, and expansive growth pattern than microsatellite stable carcinomas. Univariate and multivariate analyses of 5-year–specific survival revealed stage, tumor location, grade of differentiation, MSI, gender, and age as significant prognostic factors. The prognostic advantage of MSI tumors was particularly evident in stages II and III in which chemotherapy did not significantly affect the survival of MSI-H patients. Finally, we analyzed survival in MSI-H patients in relation to the presence of mismatch repair gene mutations. MSI-H patients with hereditary non–polyposis colorectal cancer showed a better prognosis as compared with sporadic MSI-H; however, in multivariate analysis, this difference disappeared. Conclusions: The type of genomic instability could influence the prognosis of CRC, in particular in stages II and III. Fluorouracil-based chemotherapy does not seem to improve survival among MSI-H patients. The survival benefit for patients with hereditary non–polyposis colorectal cancer is mainly determined by younger age and less advanced stage as compared with sporadic MSI-H counterpart.
A study of filicidal men
Authors: J F Campion, J M Cravens, F Covan
Journal: American Journal of Psychiatry (1988)

Twelve filicidal men were examined on a forensic psychiatric service. The majority suffered from severe mental impairments due to psychosis, neurological disorders, substance abuse, or mental retardation. Most of the filicidal acts committed by these chronically impaired men resulted from isolated explosive behavior.
Codon usage and tRNA content in unicellular and multicellular organisms.
Authors: T Ikemura
Journal: Molecular Biology and Evolution (1985)

Choices of synonymous codons in unicellular organisms are here reviewed, and differences in synonymous codon usages between Escherichia coli and the yeast Saccharomyces cerevisiae are attributed to differences in the actual populations of isoaccepting tRNAs. There exists a strong positive correlation between codon usage and tRNA content in both organisms, and the extent of this correlation relates to the protein production levels of individual genes. Codon-choice patterns are believed to have been well conserved during the course of evolution. Examination of silent substitutions and tRNA populations in Enterobacteriaceae revealed that the evolutionary constraint imposed by tRNA content on codon usage decelerated rather than accelerated the silent-substitution rate, at least insofar as pairs of taxonomically related organisms were examined. Codon-choice patterns of multicellular organisms are briefly reviewed, and diversity in G+C percentage at the third position of codons in vertebrate genes--as well as a possible causative factor in the production of this diversity--is discussed.
Pathogenic mechanisms in pulmonary fibrosis: collagen-induced migration inhibition factor production and cytotoxicity mediated by lymphocytes.
Authors: T C Kravis, A Ahmed, T E Brown, J D Fulmer, R G Crystal
Journal: Journal of Clinical Investigation (1976)

The universal features of the histopathology of fibrotic lung disease are derangement of parenchymal collagen and infiltration of the parenchyma with chronic inflammatory cells. To determine if this cellular reaction might be associated with autoimmunity to a consitituent of the alveolar interstitium, peripheral blood lymphocytes were exposed to human type I collagen in vitro and evaluated for the production of migration inhibition factor and cytotoxicity. Data from 18 patients with idiopathic pulmonary fibrosis, 8 patients with pulmonary fibrosis other than idiopathic pulmonary fibrosis, 12 patients with nonfibrotic lung disease, and 9 normals demonstrated that circulating lymphocytes from more than 94% of patients with fibrotic lung disease take part in processes where the recognition of collagen results in migration inhibition factor production and lysis of collagen-coated sheep red blood cells. These collagen-induced cell-mediated phenomena are obviated with human T-lymphocyte antiserum. Collagen-induced migration inhibition factor production and cytotoxicity were found in less than 20% of patients with nonfibrotic disease and were not found in normals. Qualitatively, there was no organ (lung, skin) or species (human, rabbit) collagen specificity in these assays, but human lung alpha 2 chains were recognized more often than alpha 1(I) chains. Circulating lymphocytes from patients with fibrotic disease are present in a normal T to B ratio. These lymphocytes did not incorporate [3H]thymidine when exposed to collagen but did when exposed to T-cell mitogens. These in vitro observations suggest that circulating T-lymphocytes and lung collagen may be intimately associated in the pathogenesis of human fibrotic lung disease.
α-Tocopherol Enrichment of Monocytes Decreases Agonist-Induced Adhesion to Human Endothelial Cells
Authors: Kazi Nazrul Islam, Sridevi Devaraj, Ishwarlal Jialal
Journal: Circulation (1998)

Background —Monocyte-endothelium adhesion is a crucial early event in atherogenesis. Several reports indicate that α-tocopherol (AT) is a potent antioxidant in plasma and LDL and also has intracellular effects that are antiatherogenic. Recently, it has been shown that AT supplementation results in decreased monocyte–endothelial cell adhesion. However, there is a paucity of data on the mechanisms by which AT inhibits adhesion of monocytes. We studied the effect of AT enrichment of a human monocytic cell line, U937, on adhesion to human umbilical vein endothelial cells (HUVECs). Methods and Results —Both lipopolysaccharide (LPS)– and N -formyl-methionyl-leucyl-phenylalanine (FMLP)–stimulated U937 adhesion to HUVECs were studied. AT (50 and 100 μmol/L) significantly decreased adhesion of both LPS- and FMLP-stimulated U937 cells to HUVECs (LPS-treated cells, P &lt;0.0125; FMLP-treated cells, P &lt;0.05). Expression of the adhesion molecules CD11a, CD11b, CD11c, very late antigen-4 (VLA-4), and L-selectin, as assessed by flow cytometry, was increased in the stimulated U937 cells, and AT resulted in significant reduction in the expression of CD11b and VLA-4. In addition, activation of the transcription factor nuclear factor-κB (NF-κB), as assessed by gel shift assays, was inhibited by pretreatment with AT in LPS-treated U937 cells. Conclusions —AT significantly decreases adhesion of activated monocytes to endothelial cells by decreasing expression of CD11b and VLA-4 on monocytes, possibly by inhibiting the activation of NF-κB.
COPD in the ECRHS
Authors: J Vestbo
Journal: Thorax (2004)

More work is needed on the concept of staging of COPD

As a junior doctor I once worked in a hospital where the leading consultant in medicine refused to accept the diagnosis of asthma in patients older than 40 years. To him, airflow obstruction was “asthma” in the young and “chronic bronchitis” in the elderly. While it soon became apparent that asthma does occur after the age of 40, the likelihood of significant airflow limitation occurring in young adults who have never had asthma has always seemed small to me. In this issue of Thorax De Marco et al describe the prevalence of chronic obstructive pulmonary disease (COPD) in young adults taking part in the European Community Respiratory Health Survey (ECRHS).1 They found COPD to be a considerable issue; in total, 3.6% had COPD stage I+ according to the NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD)2 and 11.8% had chronic respiratory symptoms without airflow limitation—that is, COPD GOLD stage 0.

The study raises several questions relating to methodology, findings, and interpretation. Diagnosis and staging of COPD was done according to the GOLD guidelines2 using an FEV1 …
Evaluating the Roles of Energetic Functional Constraints on Teleost Mitochondrial-Encoded Protein Evolution
Authors: Yan-Bo Sun, Yong-Yi Shen, David M. Irwin, Ya-Ping Zhang
Journal: Molecular Biology and Evolution (2010)

Mitochondria are the power plant of cells, which play critical roles not only in energy metabolism but also in thermoregulation. These two roles have been individually suggested to influence mitochondrial DNA (mtDNA) evolution, however their relative importance is still rarely considered. Here, we conduct a comparative genomic analysis of 401 teleost complete mitochondrial genomes and test the roles of these dual functional constraints on mitochondria to provide a more complete view of mtDNA evolution. We found that mitochondrial protein–coding genes of migratory fishes have significantly smaller Ka/Ks than nonmigratory fishes. The same data set showed that the genes of fishes living in cold climates have significantly smaller Ka/Ks than tropical fishes. In contrast, these trends were not observed for two nuclear genes that are not involved in energy metabolism. The differences in selection patterns observed between mitochondrial and nuclear genes suggest that the functional constraints acting on mitochondria, due to energy metabolism and/or thermoregulation, influence the evolution of mitochondrial-encoded proteins in teleosts.
Comparison between SLC3A1 and SLC7A9 Cystinuria Patients and Carriers
Authors: Luca Dello Strologo, Elon Pras, Claudia Pontesilli, Ercole Beccia, Vittorino Ricci-Barbini, Luisa de Sanctis, Alberto Ponzone, Michele Gallucci, Luigi Bisceglia, Leopoldo Zelante, Maite Jimenez-Vidal, Mariona Font, Antonio Zorzano, Ferran Rousaud, Virginia Nunes, Paolo Gasparini, Manuel Palaci[Combining Acute Accent]n, Gianfranco Rizzoni
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Recent developments in the genetics and physiology of cystinuria do not support the traditional classification, which is based on the excretion of cystine and dibasic amino acids in obligate heterozygotes. Mutations of only two genes (SLC3A1 and SLC7A9), identified by the International Cystinuria Consortium (ICC), have been found to be responsible for all three types of the disease. The ICC set up a multinational database and collected genetic and clinical data from 224 patients affected by cystinuria, 125 with full genotype definition. Amino acid urinary excretion patterns of 189 heterozygotes with genetic definition and of 83 healthy controls were also included. All SLC3A1 carriers and 14% of SLC7A9 carriers showed a normal amino acid urinary pattern (i.e., type I phenotype). The rest of the SLC7A9 carriers showed phenotype non-I (type III, 80.5%; type II, 5.5%). This makes the traditional classification imprecise. A new classification is needed: type A, due to two mutations of SLC3A1 (rBAT) on chromosome 2 (45.2% in our database); type B, due to two mutations of SLC7A9 on chromosome 19 (53.2% in this series); and a possible third type, AB (1.6%), with one mutation on each of the above-mentioned genes. Clinical data show that cystinuria is more severe in males than in females. The two types of cystinuria (A and B) had a similar outcome in this retrospective study, but the effect of the treatment could not be analyzed. Stone events do not correlate with amino acid urinary excretion. Renal function was clearly impaired in 17% of the patients. E-mail: [email protected]
Hemizygous Disruption of <i>Cdc25A</i> Inhibits Cellular Transformation and Mammary Tumorigenesis in Mice
Authors: Dipankar Ray, Yasuhisa Terao, Dipali Nimbalkar, Hiroyuki Hirai, Evan C. Osmundson, Xianghong Zou, Roberta Franks, Konstantin Christov, Hiroaki Kiyokawa
Journal: Cancer Research (2007)

Abstract CDC25A phosphatase activates multiple cyclin-dependent kinases (CDK) during cell cycle progression. Inactivation of CDC25A by ubiquitin-mediated degradation is a major mechanism of DNA damage-induced S-G2 checkpoint. Although increased CDC25A expression has been reported in various human cancer tissues, it remains unclear whether CDC25A activation is a critical rate-limiting step of carcinogenesis. To assess the role for CDC25A in cell cycle control and carcinogenesis, we used a Cdc25A-null mouse strain we recently generated. Whereas Cdc25A−/− mice exhibit early embryonic lethality, Cdc25A+/− mice show no appreciable developmental defect. Cdc25A+/− mouse embryonic fibroblasts (MEF) exhibit normal kinetics of cell cycle progression at early passages, modestly enhanced G2 checkpoint response to DNA damage, and shortened proliferative life span, compared with wild-type MEFs. Importantly, Cdc25A+/− MEFs are significantly resistant to malignant transformation induced by coexpression of H-rasV12 and a dominant negative p53 mutant. The rate-limiting role for CDC25A in transformation is further supported by decreased transformation efficiency in MCF-10A human mammary epithelial cells stably expressing CDC25A small interfering RNA. Consistently, Cdc25A+/− mice show substantially prolonged latency in mammary tumorigenesis induced by MMTV-H-ras or MMTV-neu transgene, whereas MMTV-myc–induced tumorigenesis is not significantly affected by Cdc25A heterozygosity. Mammary tissues of Cdc25A+/−;MMTV-neu mice before tumor development display less proliferative response to the oncogene with increased tyrosine phosphorylation of CDK1/2, but show no significant change in apoptosis. These results suggest that Cdc25A plays a rate-limiting role in transformation and tumor initiation mediated by ras activation. [Cancer Res 2007;67(14):6605–11]
Beyond the correspondence metaphor: When accuracy cannot be assessed
Authors: Ian R. Newby, Michael Ross
Journal: Behavioral and Brain Sciences (1996)

Abstract Koriat &amp; Goldsmith propose that the correspondence metaphor captures the essence of everyday memory research. We suggest that correspondence is often not at issue because objective assessments of everyday events are frequently lacking. In these cases, other questions arise, such as how individuals evaluate the validity of memories and the significance they attach to those evaluations.
International Guidelines for Management of Metastatic Breast Cancer: Can Metastatic Breast Cancer Be Cured?
Authors: O. Pagani, E. Senkus, W. Wood, M. Colleoni, T. Cufer, S. Kyriakides, A. Costa, E. P. Winer, F. Cardoso
Journal: JNCI Journal of the National Cancer Institute (2010)

A distinctive subset of metastatic breast cancer (MBC) is oligometastatic disease, which is characterized by single or few detectable metastatic lesions. The existing treatment guidelines for patients with localized MBC include surgery, radiotherapy, and regional chemotherapy. The European School of Oncology–Metastatic Breast Cancer Task Force addressed the management of these patients in its first consensus recommendations published in 2007. The Task Force endorsed the possibility of a more aggressive and multidisciplinary approach for patients with oligometastatic disease, stressing also the need for clinical trials in this patient population. At the sixth European Breast Cancer Conference, held in Berlin in March 2008, the second public session on MBC guidelines addressed the controversial issue of whether MBC can be cured. In this commentary, we summarize the discussion and related recommendations regarding the available therapeutic options that are possibly associated with cure in these patients. In particular, data on local (surgery and radiotherapy) and chemotherapy options are discussed. Large retrospective series show an association between surgical removal of the primary tumor or of lung metastases and improved long-term outcome in patients with oligometastatic disease. In the absence of data from prospective randomized studies, removal of the primary tumor or isolated metastatic lesions may be an attractive therapeutic strategy in this subset of patients, offering rapid disease control and potential for survival benefit. Some improvement in outcome may also be achieved with optimization of systemic therapies, possibly in combination with optimal local treatment.
Site of Gene Action in Susceptibility to Estrogen-induced Testicular Interstitial-Cell Tumors of Mice
Authors: John J. Trentin, W. U. Gardner
Journal: Cancer Research (1958)

To determine whether genetic susceptibility to estrogen-induced testicular tumors is determined by the testis itself, or by other host factors, testes from the susceptible A strain or the resistant C3H strain were transplanted into the susceptible F1 hybrid (castrated and estrogenized). Tumors arose in much higher incidence in testes from the susceptible strain than in those from the resistant strain, indicating that the site of gene action for tumor susceptibility or resistance in this and several other systems reviewed resides largely in the end organ.
Guidelines of the American College of Obstetricians and Gynecologists for exercise during pregnancy and the postpartum period
Authors: R Artal, M O'Toole
Journal: British Journal of Sports Medicine (2003)

The cardiac action potential is generated by a concerted action of different ion channels and transporters. Dysfunction of any of these membrane proteins can give rise to cardiac arrhythmias, which is particularly true for the repolarizing potassium channels. We suggest that an increased repolarization current could be a new antiarrhythmic principle, because it possibly would attenuate afterdepolarizations, ischemic leak currents, and re-entry phenomena. Repolarization of the cardiac myocytes is crucially dependent on the late rapid delayed rectifier current (I<sub>Kr</sub>) conducted by <i>ether-a-go-go</i>-related gene (ERG) potassium channels. We have developed the diphenylurea compound 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643) and tested whether this small organic molecule could increase the activity of human ERG (HERG) channels expressed heterologously. In <i>Xenopus laevis</i> oocytes, NS1643 increased both steady-state and tail current at all voltages tested. The EC<sub>50</sub> value for HERG channel activation was 10.5 μM. These results were reproduced on HERG channels expressed in mammalian human embryonic kidney 293 cells. In guinea pig cardiomyocytes, studied by patch clamp, application of 10 μM NS1643 activated I<sub>Kr</sub> and significantly decreased the action potential duration to 65% of the control values. The effect could be reverted by application of the specific HERG channel inhibitor 4′-[[1-[2-(6-methyl-2-pyridyl)ethyl]-4-piperidinyl]carbonyl]-methanesulfonanilide (E-4031) at 100 nM. Application of NS1643 also resulted in a prolonged postrepolarization refractory time. Finally, cardiomyocytes exposed to NS1643 resisted reactivation by small depolarizing currents mimicking early afterdepolarizations. In conclusion, HERG channel activation by small molecules such as NS1643 increases the repolarization reserve and presents an interesting new antiarrhythmic approach.
P150 How well do patients with chronic respiratory failure secondary to COPD and their carers adapt to long-term oxygen therapy at home?
Authors: C. Wrench
Journal: Thorax (2010)

<h3>Introduction and objectives</h3> Long-term oxygen therapy for the treatment chronic respiratory failure requires a commitment by patients to use 15 h oxygen per day and yet little is known about the impact of this demanding treatment on daily living. A phenomenological appro/ach was used to explore the personal experiences of patients starting long-term oxygen therapy at home and their carers. All patients had a primary diagnosis of COPD with chronic respiratory failure and had completed formal oxygen assessment in the Oxygen Assessment Clinic. The study was ethically approved. <h3>Methods</h3> The research tool was a single, semi-structured recorded interview carried out within the participants’ own home within 4 weeks of commencing oxygen. Participants were recruited from clinic over a 2-month period and consisted of seven patient participants (6 female, 1 male) and four carer participants (3 female, 1 male). For the purpose of this study, a carer was defined as someone who had daily contact with the patient. A semi-structured interview was carried out in the participants9 own home. Interviews were recorded and then transcribed verbatim. Patients and carers were interviewed separately to ensure confidentiality. Due to the chronic breathlessness of the patient participants, interview times were limited to between 30 and 45 min. Analysis was carried out using Colaizzi9s seven stage process (1978). <h3>Results</h3> Patient participants described emotions ranging from initial fear, anger, and frustration to final acceptance. This journey was echoed in the experiences of the carers and shared elements of the grieving process (Kubler–Ross). Some patients and carers had begun to develop coping strategies to help with day-to-day activities, such as using ambulatory oxygen to complete simple chores or using breathing exercises to relax. <h3>Conclusions</h3> The impact of long-term oxygen therapy on the participants of this study, both emotionally and physically, was considerable. Formal oxygen assessment is undoubtedly essential but patients and their carers need additional educational and emotional support from an experienced Health Care Professional, particularly during the initial stages of their treatment.