tbuckley/cabot-search huggingface dataset:
Can This Patient Be Discharged Home? Factors Associated With At-Home Death Among Patients With Cancer
Authors: Alberto Alonso-Babarro, Eduardo Bruera, María Varela-Cerdeira, María Jesús Boya-Cristia, Rosario Madero, Isabel Torres-Vigil, Javier De Castro, Manuel González-Barón
Journal: Journal of Clinical Oncology (2011)

The purpose of this study was to identify factors associated with at-home death among patients with advanced cancer and create a decision-making model for discharging patients from an acute-care hospital.We conducted an observational cohort study to identify the association between place of death and the clinical and demographic characteristics of patients with advanced cancer who received care from a palliative home care team (PHCT) and of their primary caregivers. We used logistic regression analysis to identify the predictors of at-home death.We identified 380 patients who met the study inclusion criteria; of these, 245 patients (64%) died at home, 72 (19%) died in an acute-care hospital, 60 (16%) died in a palliative care unit, and three (1%) died in a nursing home. Median follow-up was 48 days. We included the 16 variables that were significant in univariate analysis in our decision-making model. Five variables predictive of at-home death were retained in the multivariate analysis: caregiver's preferred place of death, patients' preferred place of death, caregiver's perceived social support, number of hospital admission days, and number of PHCT visits. A subsequent reduced model including only those variables that were known at the time of discharge (caregivers' preferred place of death, patients' preferred place of death, and caregivers' perceived social support) had a sensitivity of 96% and a specificity of 81% in predicting place of death.Asking a few simple patient- and family-centered questions may help to inform the decision regarding the best place for end-of-life care and death.
Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice. Dependence on natural flanking sequences.
Authors: X C Jiang, L B Agellon, A Walsh, J L Breslow, A Tall
Journal: Journal of Clinical Investigation (1992)

To investigate the regulation of expression of the human cholesteryl ester transfer protein (CETP) gene, transgenic mice were prepared using a CETP minigene linked to the natural flanking sequences of the human CETP gene. By using a transgene containing 3.2 kb of upstream and 2.0 kb of downstream flanking sequence, five different lines of transgenic mice were generated. The abundance of CETP mRNA in various tissues was determined on standard laboratory diet or high fat, high cholesterol diets. In three lines of transgenic mice the tissues expressing the human CETP mRNA were similar to those in humans (liver, spleen, small intestine, kidney, and adipose tissue); in two lines expression was more restricted. There was a marked (4-10-fold) induction of liver CETP mRNA in response to a high fat, high cholesterol diet. The increase in hepatic CETP mRNA was accompanied by a fivefold increase in transcription rate of the CETP transgene, and a 2.5-fold increase in plasma CETP mass and activity. In contrast, CETP transgenic mice, in which the CETP minigene was linked to a metallothionein promoter rather than to its own flanking sequences, showed no change in liver CETP mRNA in response to a high cholesterol diet. Thus (a) the CETP minigene or natural flanking sequences contain elements directing authentic tissue-specific expression; (b) a high cholesterol diet induces CETP transgene transcription, causing increased hepatic CETP mRNA and plasma CETP; (c) this cholesterol response requires DNA sequences contained in the natural flanking regions of the human CETP gene.
Thymus in myasthenia gravis. Isolation of T-lymphocyte lines specific for the nicotinic acetylcholine receptor from thymuses of myasthenic patients.
Authors: A Melms, B C Schalke, T Kirchner, H K Müller-Hermelink, E Albert, H Wekerle
Journal: Journal of Clinical Investigation (1988)

The thymus is believed to play a central role in the pathogenesis of Myasthenia gravis (MG). According to a previous hypothesis, MG is initiated within the thymus by immunogenic presentation of locally produced nicotinic acetylcholine receptor (AChR) to potentially autoimmune T cells. Data of 10 consecutive MG patients demonstrate two critical features of MG thymuses that support the concept of intrathymic activation of autoreactive, AChR-specific lymphocytes. Morphologically, the thymuses showed lympho-follicular hyperplasia in nine cases and benign thymoma in one case. The paramount feature revealed by immunohistological double marker analyses was the intimate association of myoid cells (antigen producing) with interdigitating reticulum cells (potentially antigen presenting cells), both of which were surrounded by T3+ lymphocytes in thymus medulla. All 10 thymuses contained T lymphocytes reactive with AChR. This was in contrast to the peripheral immune compartment (blood) where in only 3 of 10 patients, significant T cell responses to AChR were observed. AChR-specific T cell lines could be established from 8 of 10 thymuses, all members of the helper/inducer subset as indicated by the expression of markers T3 and T4.
Midline Carcinoma of Children and Young Adults With <i>NUT</i> Rearrangement
Authors: Christopher A. French, Jeffery L. Kutok, William C. Faquin, Jeffrey A. Toretsky, Cristina R. Antonescu, Constance A. Griffin, Vania Nose, Sara O. Vargas, Mary Moschovi, Fotini Tzortzatou-Stathopoulou, Isao Miyoshi, Antonio R. Perez-Atayde, Jon C. Aster, Jonathan A. Fletcher
Journal: Journal of Clinical Oncology (2004)

Purpose A balanced chromosomal translocation, t(15;19), resulting in the BRD4-NUT oncogene, has been identified in a lethal carcinoma of young people, a disease described primarily in case reports. We sought to amass a more definitive series of tumors with NUT and/or BRD4 gene rearrangements and to determine distinct clinicopathologic features. Patients and Methods Carcinomas (N = 98) in young individuals (median age, 32.5 years) were screened for NUT and BRD4 rearrangements using dual-color fluorescence in situ hybridization. Four published carcinomas with BRD4 and NUT rearrangements were also evaluated. Immunophenotypic analyses were performed. Results Eleven tumors had NUT gene rearrangements, including eight with BRD4-NUT fusions and three with novel rearrangements, which were designated as NUT variant. All NUT-rearranged carcinomas (NRCs) arose from midline epithelial structures, including the first example arising below the diaphragm. Patients were young (median age, 17.6 years). Squamous differentiation (seen in 82% of NRCs) was particularly striking in NUT-variant cases. In this first description of NUT-variant carcinomas, the average survival (96 weeks, n = 3) was longer than for BRD4-NUT carcinomas (28 weeks, n = 8). Strong CD34 expression was found in six of 11 NRCs but in zero of 45 NUT wild-type carcinomas. Conclusion NRCs arise from midline structures in young people, and NRCs with BRD4-NUT are highly lethal, despite intensive therapies. NUT-variant carcinomas might have a less fulminant clinical course than those with BRD4-NUT fusions. CD34 expression is characteristic in NRCs and, therefore, holds promise as a diagnostic test for this distinctive clinicopathologic entity.
Germ-Line Mutation of <i>NKX3.1</i> Cosegregates with Hereditary Prostate Cancer and Alters the Homeodomain Structure and Function
Authors: S. Lilly Zheng, Jeong-ho Ju, Bao-li Chang, Elizabeth Ortner, Jielin Sun, Sarah D. Isaacs, Jishang Sun, Kathy E. Wiley, Wennuan Liu, Micheas Zemedkun, Patrick C. Walsh, James Ferretti, James Gruschus, William B. Isaacs, Edward P. Gelmann, Jianfeng Xu
Journal: Cancer Research (2006)

Abstract NKX3.1, a gene mapped to 8p21, is a member of the NK class of homeodomain proteins and is expressed primarily in the prostate. NKX3.1 exerts a growth-suppressive and differentiating effect on prostate epithelial cells. Because of its known functions and its location within a chromosomal region where evidence for prostate cancer linkage and somatic loss of heterozygosity is found, we hypothesize that sequence variants in the NKX3.1 gene increase prostate cancer risk. To address this, we first resequenced the NKX3.1 gene in 159 probands of hereditary prostate cancer families recruited at Johns Hopkins Hospital; each family has at least three first-degree relatives affected with prostate cancer. Twenty-one germ-line variants were identified in this analysis, including one previously described common nonsynonymous change (R52C), two novel rare nonsynonymous changes (A17T and T164A), and a novel common 18-bp deletion in the promoter. Overall, the germ-line variants were significantly linked to prostate cancer, with a peak heterogeneity logarithm of odds of 2.04 (P = 0.002) at the NKX3.1 gene. The rare nonsynonymous change, T164A, located in the homeobox domain of the gene, segregated with prostate cancer in a family with three affected brothers and one unaffected brother. Importantly, nuclear magnetic resonance solution structure analysis and circular dichroism studies showed this specific mutation to affect the stability of the homeodomain of the NKX3.1 protein and decreased binding to its cognate DNA recognition sequence. These results suggest that germ-line sequence variants in NKX3.1 may play a role in susceptibility to hereditary prostate cancer and underscore a role for NKX3.1 as a prostate cancer gatekeeper. (Cancer Res 2006; 66(1): 69-77)
Pretreatment Levels of Peripheral Neutrophils and Leukocytes As Independent Predictors of Overall Survival in Patients With American Joint Committee on Cancer Stage IV Melanoma: Results of the EORTC 18951 Biochemotherapy Trial
Authors: Henrik Schmidt, Stefan Suciu, Cornelis J.A. Punt, Martin Gore, Wim Kruit, Poulam Patel, Danielle Lienard, Hans von der Maase, Alexander M.M. Eggermont, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2007)

An elevated count of blood neutrophils and monocytes recently was shown independently to predict short survival in patients with stage IV melanoma undergoing interleukin-2-based immunotherapy. In this study, we aimed to validate this finding in a large cohort of stage IV melanoma patients.For this retrospective prognostic study, the data from the European Organisation for the Research and Treatment of Cancer 18951 study were used. Patients were randomly assigned between treatment with dacarbazine, cisplatin, and interferon alfa with or without interleukin-2. Counts of neutrophils and leukocytes were analyzed together with other known prognostic factors: serum lactate dehydrogenase, performance status, metastatic site, and sex. Two multivariate prognostic factor analyses were carried out in the model: one with leukocyte counts and one with neutrophil counts.A total of 363 patients were randomly assigned and baseline blood neutrophil and leukocyte counts were available from 316 and 350 patients, respectively. A high neutrophil count (> 7.5 x 10(9)/L) was an independent prognostic factor for short overall survival (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = 0.02), and a high leukocyte count (> 10 x 10(9)/L) was an independent prognostic factor of both short overall survival (HR, 1.7; 95% CI, 1.3 to 2.4; P = 0.0005) and short progression-free survival (HR, 1.5; 95% CI, 1.1 to 2.1; P = 0.008).A high pretreatment count of neutrophils in blood was confirmed as an independent prognostic factor for short overall survival in stage IV melanoma patients undergoing interleukin-2-based immunotherapy. Furthermore, a high count of leukocytes was an independent prognostic factor for short overall survival and progression-free survival. Both parameters should be useful as stratification factors in clinical trials.
Potential Mediators of Diabetes-Related Hearing Impairment in the U.S. Population
Authors: Kathleen E. Bainbridge, Yiling J. Cheng, Catherine C. Cowie
Journal: Diabetes Care (2010)

OBJECTIVE We examined potential mediators of the reported association between diabetes and hearing impairment. RESEARCH DESIGN AND METHODS Data come from 1,508 participants, aged 40–69 years, who completed audiometric testing during 1999–2004 in the National Health and Nutrition Examination Survey (NHANES). We defined hearing impairment as the pure-tone average &amp;gt;25 decibels hearing level of pure-tone thresholds at low/mid (500, 1,000, and 2,000 Hz) and high (3,000, 4,000, 6,000, and 8,000 Hz) frequencies. Using logistic regression, we examined whether controlling for vascular or neuropathic conditions, cardiovascular risk factors, glycemia, or inflammation diminished the association between diabetes and hearing impairment. RESULTS Diabetes was associated with a 100% increased odds of low/mid-frequency hearing impairment (odds ratio 2.03 [95% CI 1.32–3.10]) and a 67% increased odds of high-frequency hearing impairment (1.67 [1.14–2.44]) in preliminary models after controlling for age, sex, race/ethnicity, education, smoking, and occupational noise exposure. Adjusting for peripheral neuropathy attenuated the association with low/mid-frequency hearing impairment (1.70 [1.02–2.82]). Adjusting for albuminuria and C-reactive protein attenuated the association with high-frequency hearing impairment (1.54 [1.02–2.32] and 1.50 [1.01–2.23], respectively). Diabetes was not associated with high-frequency hearing impairment after controlling for A1C (1.09 [0.60–1.99]) but remained associated with low/mid-frequency impairment. We found no evidence suggesting that our observed relationship between diabetes and hearing impairment is due to hypertension or dyslipidemia. CONCLUSIONS Mechanisms related to neuropathic or microvascular factors, inflammation, or hyperglycemia may be mediating the association of diabetes and hearing impairment.
Introduction to Commentaries on the Use of Placebo-Controlled Trials of New Therapies in the Treatment of Type 2 Diabetes
Authors: Charles M. Clark
Journal: Diabetes Care (2001)

As the editor in chief of Diabetes Care , I was stimulated by the thoughtful letter of David S.H. Bell (1) questioning the value and ethics of placebo-controlled trials in the development of new therapeutic agents for the treatment of hyperglycemia in type 2 diabetes, and I decided to look into this issue more in depth. I asked three people to give their perspectives on this issue. The first response, …
Phylogenetic evidence for horizontal transmission of group I introns in the nuclear ribosomal DNA of mushroom-forming fungi
Authors: D S Hibbett
Journal: Molecular Biology and Evolution (1996)

Group I introns were discovered inserted at the same position in the nuclear small-subunit ribosomal DNA (nuc-ssu-rDNA) in several species of homobasidiomycetes (mushroom-forming fungi). Based on conserved intron sequences, a pair of intron-specific primers was designed for PCR amplification and sequencing of intron-containing rDNA repeats. Using the intron-specific primers together with flanking rDNA primers, a PCR assay was conducted to determine presence or absence of introns in 39 species of homobasidiomycetes. Introns were confined to the genera Panellus, Clavicorona, and Lentinellus. Phylogenetic analyses of nuc-ssu-rDNA and mitochondrial ssu-rDNA sequences suggest that Clavicorona and Lentinellus are closely related, but that Panellus is not closely related to these. The simplest explanation for the distribution of the introns is that they have been twice independently gained via horizontal transmission, once on the lineage leading to Panellus, and once on the lineage leading to Lentinellus and Clavicorona. BLAST searches using the introns from Panellus and Lentinellus as query sequences retrieved 16 other similar group I introns of nuc-ssu-rDNA and nuclear large-subunit rDNA (nuc-lsu-rDNA) from fungal and green algal hosts. Phylogenetic analyses of intron sequences suggest that the mushroom introns are monophyletic, and are nested within a clade that contains four other introns that insert at the same position as the mushroom introns, two from different groups of fungi and two from green algae. The distribution of host lineages and insertion sites among the introns suggests that horizontal and vertical transmission, homing, and transposition have been factors in intron evolution. As distinctive, heritable features of nuclear rDNAs in certain lineages, group I introns have promise as phylogenetic markers. Nevertheless, the possibility of horizontal transmission and homing also suggest that their use poses certain pitfalls.
Triplet Combination With Irinotecan Plus Oxaliplatin Plus Continuous-Infusion Fluorouracil and Leucovorin as First-Line Treatment in Metastatic Colorectal Cancer: A Multicenter Phase II Trial
Authors: J. Souglakos, D. Mavroudis, S. Kakolyris, Ch. Kourousis, N. Vardakis, N. Androulakis, S. Agelaki, K. Kalbakis, D. Tsetis, N. Athanasiadis, G. Samonis, V. Georgoulias
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To evaluate the efficacy and tolerance of irinotecan (CPT-11) in combination with oxaliplatin (l-OHP) plus fluorouracil (5-FU)/leucovorin (LV) (de Gramont regimen) as first-line treatment of metastatic colorectal cancer (MCC). PATIENTS AND METHODS: Thirty-one patients with MCC who had not received prior therapy for metastatic disease were enrolled. Their median age was 60 years; performance status (World Health Organization) was 0 in 12, 1 in 14, and 2 in five patients; 19 patients (61%) had prior surgery, and 14 (45%) had adjuvant chemotherapy. CPT-11 was administered on day 1 at 150 mg/m 2 as a 90-minute intravenous (IV) infusion; l-OHP was administered on day 2 at 65 mg/m 2 as a 2-hour IV infusion; and on days 2 and 3, LV 200 mg/m 2 preceded 5-FU administration of 400 mg/m 2 /d initial IV bolus dose followed by 600 mg/m 2 /d 22-hour IV continuous infusion. The regimen was repeated every 2 weeks. RESULTS: All patients were assessable for toxicity and 30 for response to treatment. Complete response was achieved in two patients (6.5%) and partial response in 16 (51.6%) (overall response rate, 58.1%; 95% confidence interval, 40.7% to 75.4%); eight patients (25.8%) had stable disease, and five (16.1%) had disease progression. The median duration of response was 9 months, and the median time to disease progression was 13 months. Neutropenia grade 3 to 4 occurred in 14 patients (45%) and febrile neutropenia in two (6%). Diarrhea grade 3 to 4 was observed in 10 patients (32%), neurotoxicity grade 3 to 4 in three (9%), and asthenia grade 3 in two (10%). No treatment-related death has occurred. CONCLUSION: The triplet combination of 5-FU/LV + CPT-11 + l-OHP is a highly active regimen with manageable toxicity as front-line treatment in MCC.
Diagnosis and treatment of invasive pulmonary aspergillosis in neutropenic patients
Authors: F. Reichenberger, J.M. Habicht, A. Gratwohl, M. Tamm
Journal: European Respiratory Journal (2001)

Invasive pulmonary aspergillosis is a major cause of morbidity and mortality in neutropenic patients. Microbiological and serological tests are of limited value. The diagnosis should be considered in neutropenic patients with fever not responding to antibiotics, and typical findings on thoracic computed tomography scan. Whenever possible, diagnosis should be confirmed by tissue examination. Newer techniques, such as polymerase chain reaction may change the current diagnostic approach. Therapeutic strategies consist of prophylaxis in risk groups and the early application of antifungal agents in suspected or probable disease. Amphotericin B as desoxycholate or lipid formulation is the current standard medication in invasive infection, although it has major side effects. Its role is challenged by the new azole derivates, such as itraconazole and voriconazole, and the new echinocandins. Additional therapies with cytokines, such as granulocyte macrophage colony stimulating factor and interferon‐γ, and with granulocyte transfusions are under evaluation. In selected cases lung resection is of proven diagnostic and therapeutic value. This paper analyses the current understanding of the pathogenesis and epidemiology of invasive aspergillosis and reviews the actual diagnostic and therapeutic strategies for invasive pulmonary aspergillosis in neutropenic patients.
Genetic Manipulation of Periostin Expression in the Heart Does Not Affect Myocyte Content, Cell Cycle Activity, or Cardiac Repair
Authors: Angela Lorts, Jennifer A. Schwanekamp, John W. Elrod, Michelle A. Sargent, Jeffery D. Molkentin
Journal: Circulation Research (2008)

Following a pathological insult, the adult mammalian heart undergoes hypertrophic growth and remodeling of the extracellular matrix. Although a small subpopulation of cardiomyocytes can reenter the cell cycle following cardiac injury, the myocardium is largely thought to be incapable of significant regeneration. Periostin, an extracellular matrix protein, has recently been proposed to induce reentry of differentiated cardiomyocytes back into the cell cycle and promote meaningful repair following myocardial infarction. Here, we show that although periostin is induced in the heart following injury, it does not stimulate DNA synthesis, mitosis, or cytokinesis of cardiomyocytes in vitro or in vivo. Mice lacking the gene encoding periostin and mice with inducible overexpression of full-length periostin were analyzed at baseline and after myocardial infarction. There was no difference in heart size or a change in cardiomyocyte number in either periostin transgenic or gene-targeted mice at baseline. Quantification of proliferating myocytes in the periinfarct area showed no difference between periostin-overexpressing and -null mice compared with strain-matched controls. In support of these observations, neither overexpression of periostin in cell culture, via an adenoviral vector, nor stimulation with recombinant protein induced DNA synthesis, mitosis, or cytokinesis. Periostin is a regulator of cardiac remodeling and hypertrophy and may be a reasonable pharmacological target to mitigate heart failure, but manipulation of this protein appears to have no obvious effect on myocardial regeneration.
Evidence of Dysfunction of Endothelial Progenitors in Pulmonary Arterial Hypertension
Authors: Mark Toshner, Robert Voswinckel, Mark Southwood, Rafia Al-Lamki, Luke S. G. Howard, Denis Marchesan, Jun Yang, Jay Suntharalingam, Elaine Soon, Andrew Exley, Susan Stewart, Markus Hecker, Zhenping Zhu, Ursula Gehling, Werner Seeger, Joanna Pepke-Zaba, Nicholas W. Morrell
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Severe pulmonary arterial hypertension (PAH) is characterized by the formation of plexiform lesions and concentric intimal fibrosis in small pulmonary arteries. The origin of cells contributing to these vascular lesions is uncertain. Endogenous endothelial progenitor cells are potential contributors to this process.