tbuckley/cabot-search huggingface dataset:
Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival
Authors: Antonio Palumbo, Sara Bringhen, Alessandra Larocca, Davide Rossi, Francesco Di Raimondo, Valeria Magarotto, Francesca Patriarca, Anna Levi, Giulia Benevolo, Iolanda Donatella Vincelli, Mariella Grasso, Luca Franceschini, Daniela Gottardi, Renato Zambello, Vittorio Montefusco, Antonietta Pia Falcone, Paola Omedé, Roberto Marasca, Fortunato Morabito, Roberto Mina, Tommasina Guglielmelli, Chiara Nozzoli, Roberto Passera, Gianluca Gaidano, Massimo Offidani, Roberto Ria, Maria Teresa Petrucci, Pellegrino Musto, Mario Boccadoro, Michele Cavo
Journal: Journal of Clinical Oncology (2014)

Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma.We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance).In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients.Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.
Effects of Cardiac Microstructure on Propagating Electrical Waveforms
Authors: Madison S. Spach, Roger C. Barr
Journal: Circulation Research (2000)

Electrical waveforms measured during propagation at microscopic level are considerably affected by normal variations in cardiac microstructure as well as by the superfusing fluid. On the basis of evidence we present in this article, we argue that the anisotropic waveform variations discussed here are explained primarily by the associated variations in different microstructural components of myocardial architecture rather than by the effects of the perfusing bath. The results suggest that different components of myocardial architecture have preferential effects on f1.gif" BORDER="0">(max) and on the shape of the foot of the transmembrane action potential (V(m) foot). Resistive discontinuities primarily affect f1.gif" BORDER="0">(max), and an additional capacitive component in the local circuit due to the capillaries in interstitial space primarily affects V(m) foot. Resistive discontinuities also have an important influence on cardiac conduction. These discontinuities include spatial variations in the size of interstitial space (interstitial resistive discontinuities) and the role of cellular scaling (effects of cell size) when changes occur in the cellular and multicellular distribution of gap junctions during remodeling of normal mature myocardium to proarrhythmic structural substrates. The full text of this article is available at http://www.circresaha.org.
Concussion information online: evaluation of information quality, content and readability of concussion-related websites
Authors: Osman H Ahmed, S John Sullivan, Anthony G Schneiders, Paul R McCrory
Journal: British Journal of Sports Medicine (2011)

Background The internet plays an important role in the dissemination of health information to the general public. Information on orthopaedic sports medicine websites has been shown to be of a varying standard, and to date there has been no evaluation of the overall quality of concussion-related websites. Methods A four-stage methodological sampling technique was used to identify concussion-related websites. Websites were assessed for the presence of a quality standard (the HONcode ), their adherence to current expert concussion knowledge using a custom-developed concussion checklist ('CONcheck'), and their readability using the established Flesch Reading Ease (FRE) and Flesch–Kincaid Grade Level (FKGL). Results 43 Websites were identified from the search strategy with the majority (70%) not HONcode certified. A wide distribution of scores was seen for the CONcheck (0–22), FRE (16.3–77.4) and FKGL (6–17.8). Statistical analysis using independent t tests between websites with the HONcode and websites without the HONcode showed no significant differences between the two groups for CONcheck (t 41 =0.571, p=0.571), FRE (t 41 =0.808, p=0.424) and FKGL(t 41 =−0.964, p=0.341) scores. Conclusions The variability in the standard of concussion-related websites highlights the need for sports medicine website providers to consider the delivery, content and readability of information to the public.
Bridging Near and Remote Oceania: mtDNA and NRY Variation in the Solomon Islands
Authors: F. Delfin, S. Myles, Y. Choi, D. Hughes, R. Illek, M. van Oven, B. Pakendorf, M. Kayser, M. Stoneking
Journal: Molecular Biology and Evolution (2011)

Although genetic studies have contributed greatly to our understanding of the colonization of Near and Remote Oceania, important gaps still exist. One such gap is the Solomon Islands, which extend between Bougainville and Vanuatu, thereby bridging Near and Remote Oceania, and include both Austronesian-speaking and Papuan-speaking groups. Here, we describe patterns of mitochondrial DNA (mtDNA) and nonrecombining Y chromosome (NRY) variation in over 700 individuals from 18 populations in the Solomons, including 11 Austronesian-speaking groups, 3 Papuan-speaking groups, and 4 Polynesian Outliers (descended via back migration from Polynesia). We find evidence for ancient (pre-Lapita) colonization of the Solomons in old NRY paragroups as well as from M2-M353, which probably arose in the Solomons ∼9,200 years ago and is the most frequent NRY haplogroup there. There are no consistent genetic differences between Austronesian-speaking and Papuan-speaking groups, suggesting extensive genetic contact between them. Santa Cruz, which is located in Remote Oceania, shows unusually low frequencies of mtDNA and NRY haplogroups of recent Asian ancestry. This is in apparent contradiction with expectations based on archaeological and linguistic evidence for an early (∼3,200 years ago), direct colonization of Santa Cruz by Lapita people from the Bismarck Archipelago, via a migration that "leapfrogged" over the rest of the Solomons. Polynesian Outliers show dramatic island-specific founder events involving various NRY haplogroups. We also find that NRY, but not mtDNA, genetic distance is correlated with the geographic distance between Solomons groups and that historically attested spheres of cultural interaction are associated with the recent genetic structure of Solomons groups, as revealed by mtDNA HV1 sequence and Y-STR haplotype diversity. Our results fill an important lacuna in human genetic studies of Oceania and aid in understanding the colonization and genetic history of this region.
Andropause: Is Androgen Replacement Therapy Indicated for the Aging Male?
Authors: Rabih A. Hijazi, Glenn R. Cunningham
Journal: Annual Review of Medicine (2004)

The number of men in the United States ≥65 years of age is projected to increase from 14,452,000 in 2000 to 31,343,000 in 2030. Approximately 30% of men 60–70 years of age and 70% of men 70–80 years of age have low bioavailable or free testosterone levels. Symptoms and findings of testosterone deficiency are similar to those associated with aging. They include loss of energy, depressed mood, decreased libido, erectile dysfunction, decreased muscle mass and strength, increased fat mass, frailty, osteopenia, and osteoporosis. Several small clinical trials indicate that testosterone replacement therapy can improve many of these findings; however, the studies have not been powered to assess potential risks, such as the need for invasive treatment of benign prostatic hyperplasia, development of a clinical prostate cancer, or cardiovascular events. Thus, the benefit/risk ratio of testosterone replacement therapy in aging men is not known.
Evolutionary Diversification in Polyamine Biosynthesis
Authors: E. G. Minguet, F. Vera-Sirera, A. Marina, J. Carbonell, M. A. Blazquez
Journal: Molecular Biology and Evolution (2008)

Polyamine biosynthesis is an ancient metabolic pathway present in all organisms. Aminopropyltransferases are key enzymes that mediate the synthesis of spermidine, spermine, and thermospermine. The relatively high sequence similarity between aminopropyltransferases and their similarity with putrescine N-methyltransferases (PMT) raises the question of whether they share a common ancestor or have evolved by convergence. Here we show that aminopropyltransferases and PMT are phylogenetically interconnected, and the different activities have been generated by unusually frequent events of diversification of existing functions. Although all spermidine synthases (SPDSs) derive from a common ancestor preceding the separation between prokaryotes and eukaryotes, they have been the origin of a variety of new activities. Among those, spermine synthases (SPMSs) represent a novelty independently arisen at least 3 times, in animals, fungi, and plants. The most parsimonious mechanism would involve the duplication and change of function of preexisting SPDS genes in each phylum. Although spermine is not essential for life, the repeated invention of SPMS and its conservation strongly argues for an evolutionary advantage derived from its presence. Moreover, the appearance of thermospermine synthase (tSPMS) in several genera of Archaea and Bacteria was accompanied by a loss of SPDS, suggesting that the new activity originated as a change of function of this enzyme. Surprisingly, tSPMS was later acquired by plants at an early stage of evolution by horizontal gene transfer and has proven to be essential for vascular development in tracheophytes. Finally, the synthesis of nicotine and tropane alkaloids in Solanales was favored by the origination of a new activity, PMT, as a duplication and change of function from SPDS.
Unequivocal Delineation of Clinicogenetic Subgroups and Development of a New Model for Improved Outcome Prediction in Neuroblastoma
Authors: Jo Vandesompele, Michael Baudis, Katleen De Preter, Nadine Van Roy, Peter Ambros, Nick Bown, Christian Brinkschmidt, Holger Christiansen, Valérie Combaret, Maria Łastowska, James Nicholson, Anne O'Meara, Dominique Plantaz, Raymond Stallings, Bénédicte Brichard, Caroline Van den Broecke, Sylvia De Bie, Anne De Paepe, Geneviève Laureys, Frank Speleman
Journal: Journal of Clinical Oncology (2005)

Purpose Neuroblastoma is a genetically heterogeneous pediatric tumor with a remarkably variable clinical behavior ranging from widely disseminated disease to spontaneous regression. In this study, we aimed for comprehensive genetic subgroup discovery and assessment of independent prognostic markers based on genome-wide aberrations detected by comparative genomic hybridization (CGH). Materials and Methods Published CGH data from 231 primary untreated neuroblastomas were converted to a digitized format suitable for global data mining, subgroup discovery, and multivariate survival analyses. Results In contrast to previous reports, which included only a few genetic parameters, we present here for the first time a strategy that allows unbiased evaluation of all genetic imbalances detected by CGH. The presented approach firmly established the existence of three different clinicogenetic subgroups and indicated that chromosome 17 status and tumor stage were the only independent significant predictors for patient outcome. Important new findings were: (1) a normal chromosome 17 status as a delineator of a subgroup of presumed favorable-stage tumors with highly increased risk; (2) the recognition of a survivor signature conferring 100% 5-year survival for stage 1, 2, and 4S tumors presenting with whole chromosome 17 gain; and (3) the identification of 3p deletion as a hallmark of older age at diagnosis. Conclusion We propose a new regression model for improved patient outcome prediction, incorporating tumor stage, chromosome 17, and amplification/deletion status. These findings may prove highly valuable with respect to more reliable risk assessment, evaluation of clinical results, and optimization of current treatment protocols.
Once-daily Fluticasone Furoate∗ Nasal Spray (FFNS) is Effective for the Treatment of Seasonal Allergic Rhinitis (SAR) Caused by Ragweed ∗USAN-approved name
Authors: H.B. Kaiser, R. Naclerio, J. Given, E. Philpot, T. Toler, A. Ellsworth
Journal: Journal of Allergy and Clinical Immunology (2007)
Cadmium-binding proteins of three marine molluscs and characterization of two cadmium-binding glycoproteins from the hepatopancreas of a whelk, Buccinum tenuissimum.
Authors: Y Dohi, K Kosaka, K Ohba, Y Yoneyama
Journal: Environmental Health Perspectives (1986)

The cadmium-binding proteins were shown to exist in the hepatopancreas of three molluscs, a whelk, Buccinum tenuissimum, a turbo, Batillus cornutus, and a squid, Todarodes pacificus. Cadmium was efficiently accumulated in nature to a mean concentration of 119, 33, and 50 micrograms/g wet tissue in the hepatopancreas of three species of molluscs, and 30%, 11%, and 43% of the element in each tissue of whelk, turbo, and squid was extracted to the soluble fraction, respectively. Separation of the soluble fraction by Sephadex G-75 in the presence of 2-mercaptoethanol revealed that cadmium was mainly bound to the protein fraction FII of molecular weight 10,000. Two cytoplasmic cadmium-binding glycoproteins from the hepatopancreas of Buccinum tenuissimum were purified to homogeneity by Sephadex G-75 gel filtration and double DEAE-Sephadex A-25 chromatographies in the presence of 2-mercaptoethanol. These two cadmium-binding glycoproteins, termed FIIA and FIIB, had molecular weights of 8000 and 13,000 and consisted of 52 and 94 amino acid residues, respectively. Three and two cysteine residues in FIIA and FIIB, respectively, were found and two more half-cystine were also detected in FIIB. The sugar contents of FIIA and FIIB were about 20.5% and 8.7% by weight, respectively, consisting of galactose, mannose, fucose, and amino sugar. Both showed strong metal-binding ability, especially for cadmium, copper, and mercury.
Hemodynamic Effects of Endothelin-1 and Big Endothelin-1 in Chronic Hemodialysis Patients
Authors: ASTRID OTTOSSON-SEEBERGER, GUNVOR AHLBORG, ANETTE HEMSÉN, JAN M. LUNDBERG, ANDERS ALVESTRAND
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Increased plasma concentrations of endothelin-1 (ET-1) and big endothelin-1 (big ET-1) have been reported in patients with end-stage renal failure (ESRD). In the present study, which included hemodialysis (HD) patients with ( n = 21) and without ( n = 32) ischemic heart disease, the putative association between plasma levels of ET-1 and big ET-1 and ischemic heart disease and the influence of the dialysis procedure on ET concentrations was investigated. This study also examined in an additional five HD patients without cardiac disease whether intravenously infused ET-1 and big ET-1 (0.2, 1, and 4 pmol/kg per min, each dose for 20 min) preserve their vasoactive potency and whether exogenous big ET-1, which in healthy humans is converted in the kidney, is still converted to ET-1 in ESRD. HD patients with ischemic heart disease demonstrated higher plasma levels of ET-1 and big ET-1 than HD patients without this disorder, and HD reduced plasma ET-1 and big ET-1 concentrations. In HD patients, the big ET-1 infusion, resulting in a 1.5-fold increase in plasma ET-1, caused a more marked and prolonged rise in mean arterial BP than ET-1 (20% versus 13%, P = 0.0001) and a slightly smaller but more prolonged decrease in estimated splanchnic blood flow than ET-1 (37% versus 44%, P = 0.02). Furthermore, big ET-1 lowered heart rate by 9% ( P = 0.01) but ET-1 did not. Plasma half-lives of ET-1 and big ET-1 were longer in HD patients than in healthy humans. Thus, ET-1 and big ET-1 preserve their vasoactive potency, and circulating big ET-1 is still converted to active ET-1 in ESRD. Consequently, the increased plasma levels of ET-1 and big ET-1 noted in HD patients, especially in patients with ischemic heart disease, might play a role in the development of uremic cardiovascular complications.
Analysis of the <i>DPYD</i> Gene Implicated in 5-Fluorouracil Catabolism in a Cohort of Caucasian Individuals
Authors: Katharina Seck, Silvia Riemer, Ronald Kates, Tobias Ullrich, Verena Lutz, Nadia Harbeck, Manfred Schmitt, Marion Kiechle, Robert Diasio, Eva Gross
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Complete or partial loss of dihydropyrimidine dehydrogenase (DPD) function has been described in cancer patients with intolerance to fluoropyrimidine drugs like 5-fluorouracil (5-FU) or Xeloda. The intention of this population study is to assess and to evaluate gene variations in the entire coding region of the dihydropyrimidine dehydrogenase gene (DPYD), which could be implicated in DPD malfunction. Experimental Design: A cohort of 157 individuals was genotyped by denaturing high-performance liquid chromatography; 100 of these genotypes were compared with functional studies on DPD activity and mRNA expression. Results: Twenty-three variants in coding and noncoding regions of the DPYD gene were detected, giving rise to 15 common haplotypes with a frequency of &amp;gt;1%. Rare sequence alterations included a frameshift mutation (295-298delTCAT) and three novel point mutations, 1218G&amp;gt;A (Met406Ile), 1236G&amp;gt;A (Glu412Glu), and 3067C&amp;gt;T (Pro1023Ser). DPD enzyme activity showed high variation in the analyzed population and correlated with DPD mRNA expression. In particular, the novel variants were not accompanied with decreased enzyme activity. However, a statistically significant deviation from the median DPD activity of the population was associated with the mutations 1601G&amp;gt;A (Ser534Asn) and 2846A&amp;gt;T (Asp949Val). Conclusion: This work presents an analysis of DPYD gene variations in a large cohort of Caucasians. The results reflect the genetic and enzymatic variability of DPD in the population and may contribute to further insight into the pharmacogenetic disorder of DPD deficiency.
<i>CRHR1</i> Polymorphisms Predict Bone Density in Survivors of Acute Lymphoblastic Leukemia
Authors: Terreia S. Jones, Sue C. Kaste, Wei Liu, Cheng Cheng, Wenjian Yang, Kelan G. Tantisira, Ching-Hon Pui, Mary V. Relling
Journal: Journal of Clinical Oncology (2008)

Purpose Corticosteroids are a critical component of therapy for acute lymphoblastic leukemia (ALL) but are associated with late effects, such as osteoporosis. Risk factors remain poorly defined. Because CRHR1 polymorphisms have been associated with other corticosteroid effects, our goal was to define whether CRHR1 polymorphisms predict which patients with ALL are likely to develop bone mineral deficits. Patients and Methods The mean bone mineral density z scores of 309 long-term survivors of ALL were determined by quantitative computed tomography of the trabecular lumbar spine. We analyzed whether CRHR1 genotypes, adjusted for sex, ALL treatment regimen, and weight, could predict bone density. Results We found that three single nucleotide polymorphisms (SNPs), all in linkage disequilibrium, were associated with bone density in a sex-specific manner. Bone density was lower in males (P = .001), in nonblack patients (P &lt; .08), in those who were not overweight (P &lt; .001), and in those who received intensive antimetabolites and glucocorticoids (P &lt; .001). After adjustment for these features, the G allele at the rs1876828 SNP was associated with lower z scores (P = .02) in males but tended to have the opposite association in females (P = .09). Conclusion CRHR1 polymorphisms may impact the risk of bone density deficits in patients treated with corticosteroids and antimetabolites in a sex-specific manner.
The Human Major Histocompatibility Complex and Endocrine Disease*
Authors: NADIR R. FARID, JOHN C. BEAR
Journal: Endocrine Reviews (1981)

ARELATIONSHIP is found between loci in the major histocompatibility complex (MHC) and susceptibility to several endocrine disorders. For the more common endocrine diseases the relationship is evidenced in statistical associations of disease with specific alleles, for which several explanations are possible. The most likely is that these associations indicate the influence of immune response genes in linkage disequilibrium with the marker allele, but this is by no means proven. A pervasive association is noted of the DR3 allele of the histocompatibility (HLA)-DR system with autoimmune endocrine disease; this may be by way of immunological facilitation rather than disease-specific predisposition. A more specific association between DR4 and insulindependent diabetes mellitus (IDDM) is seen, suggesting the existence of a diabetogenic gene in or near the MHC. Likewise, the association of DR5 with goitrous (and DR3 with atrophic) thyroiditis suggests a possible link to the mechanism of goiter formation. These associations, when explained, will probably account for a substantial part, but not all, of individual variation in endocrine disease susceptibility.
Clinical management of older people with non-small cell lung cancer in England
Authors: Paul Beckett, Matthew Callister, Laila J Tata, Richard Harrison, Michael D Peake, Roz Stanley, Ian Woolhouse, Mark Slade, Richard B Hubbard
Journal: Thorax (2012)

Data for 25261 patients with non-small cell lung cancer whose details were submitted to the National Lung Cancer Audit in England were analysed to assess the effect of age at diagnosis on their clinical management, after accounting for sex, stage, performance status and comorbidity. Multivariate logistic regression showed the odds of having histocytological confirmation and anticancer treatment decreased progressively with age, and was also lower in women. It is likely that these results have a multifactorial explanation, and further research into the attitudes of patients, carers and healthcare professionals, and clinical trials of treatment in older populations, are necessary.