tbuckley/cabot-search huggingface dataset:
Biological agents and gemcitabine in the treatment of breast cancer
Authors: P Morandi
Journal: Annals of Oncology (2006)

Advances in molecular biology have facilitated the identification of specific molecular abnormalities and dysfunctions in regulatory pathways in breast cancer cells that not only predict prognosis and therapeutic response but may also function as potential therapeutic targets. The rapidly growing introduction of new molecularly targeted drugs in oncology makes increasingly important to understand the effects of drugs molecular interactions. Gemcitabine (GEM), an analog of cytosine arabinoside, has an established efficacy as single agent as well as in combination in the treatment of breast cancer. GEM is a pyrimidine antimetabolite that is metabolized to difluorodeoxycytidine diphosphate (dFdCDP) and difluorodeoxycytidine triphosphate (dFdCTP). Incorporation of these nucleotides into DNA results in chain termination. dFdCTP is not readily excised by DNA exonuclease, resulting in intracellular accumulation. In addition, gemcitabine inhibits ribonucleotide reductase (RR) an enzyme that produces deoxynucleotides required for DNA synthesis. RR consists of two subunits M1 and M2, which contains the non-heme iron, necessary for the reduction reaction. Nucleoside analogues like GEM and fludarabine inhibit the M1 subunit. Several phase II studies have confirmed the activity of single-agent gemcitabine in the treatment of metastatic breast cancer. Objective response rates range from 14% to 46%, depending on the extent of previous treatment. Hematological toxicity is usually mild, with grade 4 neutropenia generally limited to < 10% of treated patients [1, 2]. The promise of therapies targeted to specific molecular abnormalities in breast cancer is currently confronted by the low than expected efficacy of the agents introduced into clinical practice One area of great interest is how to translate into human trials the synergy of these agents with chemotherapy observed in preclinical models. gemcitabine and EGFR-Tyrosine kinase inhibitors
N-Terminal Pro-Brain Natriuretic Peptide
Authors: Angela Yee-Moon Wang, Christopher Wai-Kei Lam, Cheuk-Man Yu, Mei Wang, Iris Hiu-Shuen Chan, Yan Zhang, Siu-Fai Lui, John E Sanderson
Journal: Journal of the American Society of Nephrology (2006)

A retrospective study was performed on eight dogs, one cat, and one ferret with ruptured ureters secondary to blunt trauma. The most common physical examination findings were abdominal distension/discomfort (in five of 10 animals) and gross hematuria (in five of six animals). Multiple organ injury was also common (in seven of 10 animals). Loss of retroperitoneal and peritoneal detail was the most common radiographic finding (in four of six animals). Ureteronephrectomy was the most common surgical procedure (performed in five out of seven procedures). Three of the five cases discharged were available for follow-up and have had no evidence of associated problems.
Muscle Blood Flow in Diabetes Mellitus: Evidence of Abnormality After Exercise
Authors: Ram K Menon, Andrew A Grace, William Burgoyne, Vivian A Fonseca, Ian M James, Paresh Dandona
Journal: Diabetes Care (1992)

To determine whether muscle blood flow before and after exercise is abnormal in patients with diabetes mellitus.Muscle blood flow (MBF) was measured with the 133Xe clearance technique in 15 nondiabetic subjects, 10 patients with insulin-dependent diabetes mellitus (IDDM), and 11 patients with non-insulin-dependent diabetes (NIDDM) at rest and after exercise. None of the patients had neuropathy.The median resting MBF was similar in all three groups. The median postexercise MBF was significantly greater in nondiabetic subjects (40.1 ml.min-1.100 g-1 of tissue) than in patients with IDDM (25.7 ml.min-1.100 g-1 of tissue; P less than 0.01) or NIDDM (14 ml.min-1.100 g-1 of tissue; P less than 0.01). The difference between IDDM and NIDDM was not significant.Diabetic patients have abnormalities of MBF in response to exercise. This abnormality occurs in the absence of clinical diabetic neuropathy.
Diagnostic Clinical Genome and Exome Sequencing
Authors: Jan Westerink, Frank L J Visseren, Wilko Spiering
Journal: New England Journal of Medicine (2014)

n engl j med 371;12 nejm.org september 18, 2014 1169 not. This suggests that differences with previous studies may be explained by residual confounding in those studies. Our study addresses only one piece of the complex risk–benefit equation of antidepressant use in pregnancy, during which other risks associated with antidepressant use have been well documented. Our findings certainly do not justify incautious use of such drugs in these patients. Krista F. Huybrechts, Ph.D.
The human phylome
Authors: Jaime Huerta-Cepas, Hernán Dopazo, Joaquín Dopazo, Toni Gabaldón
Journal: Genome biology (2007)

Phylogenomics analyses serve to establish evolutionary relationships among organisms and their genes. A phylome, the complete collection of all gene phylogenies in a genome, constitutes a valuable source of information, but its use in large genomes still constitutes a technical challenge. The use of phylomes also requires the development of new methods that help us to interpret them.We reconstruct here the human phylome, which includes the evolutionary relationships of all human proteins and their homologs among 39 fully sequenced eukaryotes. Phylogenetic techniques used include alignment trimming, branch length optimization, evolutionary model testing and maximum likelihood and Bayesian methods. Although differences with alternative topologies are minor, most of the trees support the Coelomata and Unikont hypotheses as well as the grouping of primates with laurasatheria to the exclusion of rodents. We assess the extent of gene duplication events and their relationship with the functional roles of the protein families involved. We find support for at least one, and probably two, rounds of whole genome duplications before vertebrate radiation. Using a novel algorithm that is independent from a species phylogeny, we derive orthology and paralogy relationships of human proteins among eukaryotic genomes.Topological variations among phylogenies for different genes are to be expected, highlighting the danger of gene-sampling effects in phylogenomic analyses. Several links can be established between the functions of gene families duplicated at certain phylogenetic splits and major evolutionary transitions in those lineages. The pipeline implemented here can be easily adapted for use in other organisms.
Involvement of a GTP-binding protein in stimulating action of angiotensin II on calcium channels in vascular smooth muscle cells.
Authors: Y Ohya, N Sperelakis
Journal: Circulation Research (1991)

The possible involvement of a GTP-binding protein in the regulation of Ca2+ channels by angiotensin II (Ang II) in vascular muscle cells was investigated by the whole-cell voltage-clamp method. Single cells were freshly isolated from guinea pig portal vein. The pipette solution contained high Cs+ to inhibit K+ currents and thereby isolate the Ca2+ channel current. Ba2+ (2 mM) was in the bath solution as a charge carrier for the Ca2+ channel. Application of Ang II (0.1-100 nM) produced an increase in peak amplitude of the Ba2+ current, with a shift of the current-voltage curve in the negative direction. These effects were inhibited by pretreatment with an antagonist of the Ang II receptor, [Sar1,Ile8]-Ang II. Presence of 0.1 mM GTP in the pipette solution stabilized the Ang II action, but 0.3-1.0 mM GDP-beta-S and 1.0 mM GTP-gamma-S inhibited it. GTP-gamma-S alone produced a slowly progressing increase in the basal (unstimulated) current amplitude. Preincubation of muscle tissues with pertussis toxin (1 micrograms/ml, for up to 6 hours at 36 degrees C) or intracellular application of preactivated pertussis toxin (1 micrograms/ml) plus NAD (1 mM) did not inhibit the Ang II action. Cholera toxin (10 micrograms/ml) also had no effect on the Ang II action. These results suggest that the Ang II stimulation of Ca2+ channels in smooth muscle of guinea pig portal vein may be mediated by a G protein that is insensitive to both pertussis toxin and cholera toxin.
Clinical Informatics
Authors: Don E. Detmer, Edward H. Shortliffe
Journal: JAMA (2014)

Only a few years ago, the mention of informatics in clinical circles generated questions regarding the rigor or relevance of the field. With the expanding interest and investment in health information technology by hospitals, health systems, and practitioners, however, interest in and acceptance of clinical informatics has increased substantially. Since 1972, the National Institutes of Health, principally through the National Library of Medicine (NLM), has supported a number of centers of excellence that focus on workforce education in computer applications and the underlying science. Additional efforts to help ensure a supply of competently trained individuals capable of maintaining progress with respect to applied clinical informatics are a recent development.
Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study
Authors: Jorge Cortes, Eric Feldman, Karen Yee, David Rizzieri, Anjali S Advani, Anthony Charman, Richard Spruyt, Martin Toal, Hagop Kantarjian
Journal: The Lancet Oncology (2013)
Agreement between observed and participant self-reported energy intake in adolescent netball players
Authors: P L S Rumbold, A St Clair-Gibson, E Stevenson, C J Dodd-Reynolds
Journal: British Journal of Sports Medicine (2010)

The aim was to explore the agreement over 24 h between observed and participant self-reported energy intake in adolescent netball players (habitual exercisers). Thirteen girls; age 16±1 years; stature 1.68±0.06 m; mass 61.1±8.0 kg; body mass index 21.6±2.5 kg/m 2 ; body fat 21.5±6.9%; dietary restraint 2.13±0.63 (average category for high school females)1 and maturity offset 2.7±0.5 years from peak height velocity (positive maturity offset). The participants spent 12 h at Northumbria University, from 08:00 in the morning to 20:00 in the evening. They were provided with breakfast, lunch and dinner, along with ad libitum snacks throughout the day and for the period between 20:00 and 08:00 the following morning. All items were pre weighed or measured by the observer to determine the energy intake (MJ) content. These were then numerically coded and the participants could collect food and drink items at their discretion throughout the day. The participants were instructed to inform a member of the research team of the numerical code of each item collected to later calculate observed energy intake (MJ), taking into account all leftover food or drink items. Participant recorded energy intake (MJ) was calculated using a combined self-reported, weighed food record, where all food and drink items were manually weighed or measured and recorded in a food diary by the participants and confirmed during a 24-h recall interview with the observer the following morning. Agreement between observer and participant self-reported energy intake was calculated. Energy intake mean bias±random error equated to 0.46±1.5 MJ (1.96 SD of the mean difference), therefore the 95% limits of agreement was large, ranging from −1.04 to 1.96 MJ/days. The 95% CI for bias, however, ranged from 0.00 to 0.92 MJ/days. Overall, the combined self-reported, weighed food diary and 24-h recall interview technique indicated good agreement at the group level, therefore providing a means for assessing self-reported energy intake in habitual exercisers.
The Chemokine CCL5 as a Potential Prognostic Factor Predicting Disease Progression in Stage II Breast Cancer Patients
Authors: Neora Yaal-Hahoshen, Sima Shina, Leonor Leider-Trejo, Itay Barnea, Esther L. Shabtai, Elina Azenshtein, Iulia Greenberg, Iafa Keydar, Adit Ben-Baruch
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The aim of this study was to determine the prognostic value of the chemokine CCL5, considered as a promalignancy factor in breast cancer, in predicting breast cancer progression and to evaluate its ability to strengthen the prognostic significance of other biomarkers. Experimental Design: The expression of CCL5, alone and in conjunction with estrogen receptor (ER)-α, ER-β, progesterone receptor (PR), and HER-2/neu (ErbB2), was determined in breast tumor cells by immunohistochemistry. The study included 142 breast cancer patients, including individuals in whom disease has progressed. Results: Using Cox proportional hazard models, univariate analysis suggested that, in stage I breast cancer patients, CCL5 was not a significant predictor of disease progression. In contrast, in stage II patients, the expression of CCL5 (CCL5+), the absence of ER-α (ER-α−), and the lack of PR expression (PR−) increased significantly the risk for disease progression (P = 0.0045, 0.0041, and 0.0107, respectively). The prognostic strength of CCL5, as well as of ER-α−, improved by combining them together (CCL5+/ER-α−: P = 0.0001), being highly evident in the stage IIA subgroup [CCL5+/ER-α− (P = 0.0003); ER-α− (P = 0.0315)]. In the stage II group as a whole, the combinations of CCL5−/ER-α+ and CCL5−/PR+ were highly correlated with an improved prognosis. Multivariate analysis indicated that, in stage II patients, ER-α and CCL5 were independent predictors of disease progression. Conclusions: CCL5 could be considered as a biomarker for disease progression in stage II breast cancer patients, with the CCL5+/ER-α− combination providing improved prediction of disease progression, primarily in the stage IIA subgroup.
Low Multiplicity of Infection of<i>Helicobacter pylori</i>Suppresses Apoptosis of B Lymphocytes
Authors: Francoise I. Bussiere, Rupesh Chaturvedi, Mohammad Asim, Kristen L. Hoek, Yulan Cheng, Justin Gainor, Adina Scholz, Wasif N. Khan, Keith T. Wilson
Journal: Cancer Research (2006)

Abstract Helicobacter pylori infection of the human stomach causes chronic gastritis that can lead to gastric cancer. Because activated lymphocytes persist in the gastric mucosa, and because a high multiplicity of infection (MOI) of H. pylori is needed to induce apoptosis in vitro, we speculated that resistance of lymphocytes to apoptosis is an important feature of the immune response to H. pylori. Freshly isolated mouse splenocytes underwent substantial spontaneous apoptosis and displayed a biphasic response to H. pylori, in which low MOI (1-10) markedly inhibited apoptosis, whereas high MOI (≥75) potentiated apoptosis. Low MOI reduced mitochondrial membrane depolarization, caspase-3 and caspase-9 activation, and cytochrome c release and increased Bcl-2 levels. Low MOI also induced cellular proliferation. When cells were subjected to fluorescence-activated cell sorting after coculture with H. pylori, CD19+ B cells were found to be protected from apoptosis and undergoing proliferation at low MOI, whereas CD3+ T cells did not exhibit this pattern. The protective effect of low MOI on apoptosis persisted even when B cells were isolated before activation. Immunophenotyping showed that all B-cell subsets examined were protected from apoptosis at low MOI. Additionally, gastric infection with H. pylori resulted in protection of splenic B cells from spontaneous apoptosis. Our results suggest that the low levels of H. pylori infection that occur in vivo are associated with B-cell survival and proliferation, consistent with their potential to evolve into mucosa-associated lymphoid tissue lymphoma. (Cancer Res 2006; 66(13): 6834-42)
Comparison of different hypo-osmotic swelling solutions to select viable immotile spermatozoa for potential use in intracytoplasmic sperm injection
Authors: G Verheyen
Journal: Human Reproduction Update (1997)

The hypo-osmotic swelling test, originally developed as a diagnostic sperm test, is used to discriminate viable from non-viable spermatozoa for intracytoplasmic sperm injection (ICSI) in cases of complete asthenozoospermia. In the present study, three hypo-osmotic solutions were compared, i.e. (A) Jeyendran solution containing sodium citrate and fructose; (B) a mixture of 50% culture medium and 50% milli-Q water; and (C) milli-Q water. While both the percentage of swelling and vitality assessed by eosin Y remained unchanged after 5-30 min of sperm exposure to solutions A and B, incubation in water for only 5 min was in itself detrimental. Ten frozen-thawed donor samples and 10 asthenozoospermic patient samples were exposed to the three solutions for given periods of time. Percentages of swelling and the results of the eosin Y test were well correlated for solutions B and C, but only weakly correlated for solution A. Percentage viability was further assessed by eosin Y and motility of spermatozoa after 2 h and 24 h exposure to the three solutions was compared with unexposed control spermatozoa. While a significant decrease in both parameters was observed for all three solutions in comparison with the control, sperm quality was significantly higher after exposure to solution B than after exposure to solutions A and C. It may be concluded that solution B (composed of 50% culture medium and 50% water) is to be preferred for the selection of viable immotile spermatozoa for ICSI.
Phase III Trial of Gemcitabine Plus Carboplatin Versus Single-Agent Gemcitabine in the Treatment of Locally Advanced or Metastatic Non–Small-Cell Lung Cancer: The Swedish Lung Cancer Study Group
Authors: Christer Sederholm, Gunnar Hillerdal, Kristina Lamberg, Karl Kölbeck, Monika Dufmats, Ronny Westberg, Sulochana R. Gawande
Journal: Journal of Clinical Oncology (2005)

This phase III study compared overall survival in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) when treated with single-agent gemcitabine versus gemcitabine/carboplatin. Secondary objectives were to compare response, time to progression, toxicity, and quality of life.Chemotherapy-naive patients received either gemcitabine alone (1,250 mg/m2 on days 1 and 8; gemcitabine arm) or with carboplatin (area under the curve 5 on day 1; GC arm) every 21 days.Demographics and disease characteristics of 334 randomly assigned patients were comparable on both arms. An intent-to-treat analysis showed significantly better overall survival (log-rank P = .0205) and 2-year survival (15% v 5%; P = .009) favoring the GC arm. Per Cox multivariate analysis, only two covariates, treatment arm (GC v G) and baseline performance status (0 or 1 v 2), independently influenced survival. Per-protocol analyses showed significantly longer median time to progression (5.7 v 3.9 months; P = .0001) and significantly higher objective response rate (29.6 v 11.3%; P < .0001) in the GC arm. Grade 3 to 4 leucopenia and thrombocytopenia were significantly more pronounced in the GC arm (P for both variables < .001) but importantly without associated increases in fever, infection, bleeding, or hospitalizations. There was no discernible difference in global quality-of-life patterns between treatment arms.In advanced NSCLC, gemcitabine/carboplatin therapy resulted in significant survival benefit compared with single-agent gemcitabine without undue increase in toxicity.
Overweight/obesity and vitamin D deficiency contribute to the global burden of low back pain
Authors: William B Grant
Journal: Annals of the Rheumatic Diseases (2014)

The paper by Hoy and colleagues presents the global burden of low back pain [LBP].1 From Table 3 of this paper, it appears that the regions with the highest tertile of prevalence for males and females are Australasia, Central Europe, Eastern Europe, Latin America tropical, North Africa/Middle East and Western Europe, while the regions in the lowest tertile are the Caribbean, East Asia, Latin American Andean, central and southern, North America high income, Southeast Asia, and Sub-Saharan Africa east. Given the enormous magnitude of the problem, the authors stated ‘There is an urgent need to increase our understanding, and attemptto mitigate the growing burden of LBP’.

While the paper did not discuss possible causes of LBP, two are reasonably well known: …
Protective Immunity Does Not Correlate with the Hierarchy of Virus-specific Cytotoxic T Cell Responses to Naturally Processed Peptides
Authors: A. Gallimore
Journal: The Journal of Experimental Medicine (1998)

Infection of C57BL/6 mice with lymphocytic choriomeningitis virus (LCMV) stimulates major histocompatibility complex class I-restricted cytotoxic T cells (CTLs), which normally resolve the infection.Three peptide epitopes derived from LCMV have been shown to bind the mouse class I molecule H-2 D b and to stimulate CTL responses in LCMV-infected mice.This report describes the identity and abundance of each CTL epitope after their elution from LCMV-infected cells.Based on this information, peptide abundance was found to correlate with the magnitude of each CTL response generated after infection with LCMV.Subsequent experiments, performed to determine the antiviral capacity of each CTL specificity, indicate that the quantitative hierarchy of CTL activity does not correlate with the ability to protect against LCMV infection.This report, therefore, indicates that immunodominant epitopes should be defined, not only by the strength of the CTL response that they stimulate, but also by the ability of the CTLs to protect against infection.
Acetylcholine reversal of isoproterenol-stimulated sodium currents in rabbit ventricular myocytes.
Authors: J J Matsuda, H C Lee, E F Shibata
Journal: Circulation Research (1993)

We have recently shown that beta-adrenergic agonists enhance the cardiac sodium current (INa) in rabbits through dual G-protein regulatory pathways. To determine if muscarinic cholinergic receptor stimulation can also modulate INa, we studied the effects of acetylcholine (ACh) and carbachol on INa in enzymatically dispersed rabbit ventricular myocytes. Whole-cell patch-clamp experiments done at room temperature using 20 mM [Na+]o showed that 100 nM isoproterenol increased INa and accelerated current decay as previously described. ACh (1 microM) or carbachol (1 microM) significantly reversed the stimulatory isoproterenol effects at test potentials throughout the INa activation range and at holding potentials negative to -80 mV. This effect was completely inhibited by atropine (1 microM) and was confirmed by studying single-channel INa from cell-attached patches. When INa was stimulated by forskolin (1 microM), carbachol (1 microM) significantly reversed the effect. The muscarinic-mediated inhibition of INa was inhibited by pertussis toxin (0.1 or 1.0 microgram/ml) incubation (12-15 hours), suggesting that the effect was inhibitory G-protein dependent. Further investigation of the ACh inhibitory mechanism revealed that ACh alone had no effect on INa and that when cells were dialyzed with cAMP (5 microM), ACh failed to inhibit INa. Furthermore, cGMP failed to inhibit the effect of isoproterenol on INa. These data suggest that ACh acts at or proximal to adenylate cyclase stimulation. Thus, rabbit cardiac Na+ channels are regulated by muscarinic agonists in a fashion similar to cardiac Ca2+ channels.