tbuckley/cabot-search huggingface dataset:
Mechanisms of iron loading and toxicity
Authors: Gregory J. Anderson
Journal: American Journal of Hematology (2007)

Normal iron homeostasis is a finely balanced system that reflects iron absorption, loss and utilization. The body has no mechanism for the active excretion of iron, so body iron levels are controlled at the point of absorption in the small intestine. Disturbances in this equilibrium, such as those leading to enhanced absorption, can have significant clinical consequences. Continued excessive iron uptake is followed by iron deposition in various tissues, ultimately leading to tissue damage, and possibly end-organ failure. In this review, current concepts in normal iron homeostasis, and iron loading are explained. The clinical consequences as well as the differences between primary and secondary iron loading are also reviewed, and some future research priorities are discussed. Am. J. Hematol., 2007. © 2007 Wiley-Liss, Inc.
Gastro-oesophageal reflux and childhood asthma: the acid test.
Authors: N M Wilson, L Charette, A H Thomson, M Silverman
Journal: Thorax (1985)

The presence of gastro-oesophageal reflux was investigated in 18 children with moderate to severe asthma by overnight oesophageal pH monitoring. Appreciable reflux was found during sleep in eight; its relevance to nocturnal asthma was not clear. On another occasion the same children were challenged in a double blind fashion with a drink of dilute hydrochloric acid (0.001 N) and the response of the airways was monitored by peak flow measurements and by histamine challenge tests. There was a significant increase in mean histamine sensitivity (p = 0.001) 90 minutes after the acid drink without any associated change in baseline peak flow rate. Eight children had a significant response to the acid drink, and a further three reacted to a more concentrated solution (0.01 N). In those asthmatic children in whom reflux is associated with a positive response to an acid drink (five out of 18 in the present study) it seems likely that reflux exacerbates nocturnal symptoms.
Multiple-Triazole–Resistant Aspergillosis
Authors: Paul E. Verweij, Emilia Mellado, Willem J.G. Melchers
Journal: New England Journal of Medicine (2007)

To the Editor: The use of voriconazole has become common for the management of invasive aspergillosis. However, therapy with voriconazole still sometimes fails, more often because of unresponsive underlying disease than because of resistance of the fungus. Since the first description of itraconazole resistance in Aspergillus fumigatus, 1 three amino acid substitutions in the 14α-sterol demethylase cyp51A gene, which is the target site for azole drugs, have been described.2 Our laboratory receives fungal isolates for identification and susceptibility testing from throughout the Netherlands. Since 2002, using Clinical and Laboratory Standards Institute methodology, we have observed an increase in the number of . . .
Addressing the American Health-Care Cost Crisis: Role of the Oncology Community
Authors: Scott D. Ramsey, Patricia A. Ganz, Veena Shankaran, Jeffrey Peppercorn, Ezekiel Emanuel
Journal: JNCI Journal of the National Cancer Institute (2013)

Health-care cost growth is unsustainable, and the current level of spending is harming our economy and our patients. This commentary describes the scope of the health-care spending problem and the particular factors in cancer care that contribute to the problem, reflecting in part presentations and discussions from an Institute of Medicine National Cancer Policy Forum Workshop held in October 2012. Presenters at the workshop identified a number of steps that the oncology community can take to reduce the rate of growth in cancer-care costs while maintaining or improving upon the quality of care. This commentary aims to highlight opportunities for the oncology community to take a leadership role in delivering affordable, high-quality cancer care.
A Caudal Proliferating Growth Center Contributes to Both Poles of the Forming Heart Tube
Authors: Gert van den Berg, Radwan Abu-Issa, Bouke A. de Boer, Mary R. Hutson, Piet A.J. de Boer, Alexandre T. Soufan, Jan M. Ruijter, Margaret L. Kirby, Maurice J.B. van den Hoff, Antoon F.M. Moorman
Journal: Circulation Research (2008)

Recent studies have shown that the primary heart tube continues to grow by addition of cells from the coelomic wall. This growth occurs concomitantly with embryonic folding and formation of the coelomic cavity, making early heart formation morphologically complex. A scarcity of data on localized growth parameters further hampers the understanding of cardiac growth. Therefore, we investigated local proliferation during early heart formation. Firstly, we determined the cell cycle length of primary myocardium of the early heart tube to be 5.5 days, showing that this myocardium is nonproliferating and implying that initial heart formation occurs solely by addition of cells. In line with this, we show that the heart tube rapidly lengthens at its inflow by differentiation of recently divided precursor cells. To track the origin of these cells, we made quantitative 3D reconstructions of proliferation in the forming heart tube and the mesoderm of its flanking coelomic walls. These reconstructions show a single, albeit bilateral, center of rapid proliferation in the caudomedial pericardial back wall. This center expresses Islet1. Cell tracing showed that cells from this caudal growth center, besides feeding into the venous pole of the heart, also move cranially via the dorsal pericardial mesoderm and differentiate into myocardium at the arterial pole. Inhibition of caudal proliferation impairs the formation of both the atria and the right ventricle. These data show how a proliferating growth center in the caudal coelomic wall elongates the heart tube at both its venous and arterial pole, providing a morphological mechanism for early heart formation.
Monogenic diseases that can be cured by liver transplantation
Authors: Stefano Fagiuoli, Erica Daina, Lorenzo D’Antiga, Michele Colledan, Giuseppe Remuzzi
Journal: Journal of Hepatology (2013)

While the prevalence of most diseases caused by single-gene mutations is low and defines them as rare conditions, all together, monogenic diseases account for approximately 10 in every 1000 births according to the World Health Organisation.Orthotopic liver transplantation (LT) could offer a therapeutic option in monogenic diseases in two ways: by substituting for an injured liver or by supplying a tissue that can replace a mutant protein. In this respect, LT may be regarded as the correction of a disease at the level of the dysfunctional protein. Monogenic diseases that involve the liver represent a heterogeneous group of disorders. In conditions associated with predominant liver parenchymal damage (i.e., genetic cholestatic disorders, Wilson's disease, hereditary hemochromatosis, tyrosinemia, α1 antitrypsin deficiency), hepatic complications are the major source of morbidity and LT not only replaces a dysfunctional liver but also corrects the genetic defect and effectively cures the disease. A second group includes liver-based genetic disorders characterised by an architecturally near-normal liver (urea cycle disorders, Crigler-Najjar syndrome, familial amyloid polyneuropathy, primary hyperoxaluria type 1, atypical haemolytic uremic syndrome-1). In these defects, extrahepatic complications are the main source of morbidity and mortality while liver function is relatively preserved. Combined transplantation of other organs may be required, and other surgical techniques, such as domino and auxiliary liver transplantation, have been attempted. In a third group of monogenic diseases, the underlying genetic defect is expressed at a systemic level and liver involvement is just one of the clinical manifestations. In these conditions, LT might only be partially curative since the abnormal phenotype is maintained by extrahepatic synthesis of the toxic metabolites (i.e., methylmalonic acidemia, propionic acidemia).This review focuses on principles of diagnosis, management and LT results in both paediatric and adult populations of selected liver-based monogenic diseases, which represent examples of different transplantation strategies, driven by the understanding of the expression of the underlying genetic defect.
Beyond Low Plasma T3: Local Thyroid Hormone Metabolism during Inflammation and Infection
Authors: Anita Boelen, Joan Kwakkel, Eric Fliers
Journal: Endocrine Reviews (2011)

Decreased serum thyroid hormone concentrations in severely ill patients were first reported in the 1970s, but the functional meaning of the observed changes in thyroid hormone levels, together known as nonthyroidal illness syndrome (NTIS), remains enigmatic. Although the common view was that NTIS results in overall down-regulation of metabolism in order to save energy, recent work has shown a more complex picture. NTIS comprises marked variation in transcriptional and translational activity of genes involved in thyroid hormone metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. Illness-induced changes in each of these organs appear to be very different during acute or chronic inflammation, adding an additional level of complexity. Organ- and timing-specific changes in the activity of thyroid hormone deiodinating enzymes (deiodinase types 1, 2, and 3) highlight deiodinases as proactive players in the response to illness, whereas the granulocyte is a novel and potentially important cell type involved in NTIS during bacterial infection. Although acute NTIS can be seen as an adaptive response to support the immune response, NTIS may turn disadvantageous when critical illness enters a chronic phase necessitating prolonged life support. For instance, changes in thyroid hormone metabolism in muscle during critical illness may be relevant for the pathogenesis of myopathy associated with prolonged ventilator dependence. This review focuses on NTIS as a timing-related and organ-specific response to illness, occurring independently from the decrease in serum thyroid hormone levels and potentially relevant for disease progression.
Phase I/II Study of Concurrent Chemoradiotherapy for Localized Nasal Natural Killer/T-Cell Lymphoma: Japan Clinical Oncology Group Study JCOG0211
Authors: Motoko Yamaguchi, Kensei Tobinai, Masahiko Oguchi, Naoki Ishizuka, Yukio Kobayashi, Yasushi Isobe, Kenichi Ishizawa, Nobuo Maseki, Kuniaki Itoh, Noriko Usui, Izumi Wasada, Tomohiro Kinoshita, Koichi Ohshima, Yoshihiro Matsuno, Takashi Terauchi, Shigeru Nawano, Satoshi Ishikura, Yoshikazu Kagami, Tomomitsu Hotta, Kazuo Oshimi
Journal: Journal of Clinical Oncology (2009)

Purpose To explore a more effective treatment for localized nasal natural killer (NK)/T-cell lymphoma, we conducted a phase I/II study of concurrent chemoradiotherapy. Patients and Methods Treatments comprised concurrent radiotherapy (50 Gy) and 3 courses of dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC). Patients with a newly diagnosed stage IE or contiguous IIE disease with cervical node involvement and a performance status (PS) of 0 to 2 were eligible for enrollment. The primary end point of the phase II portion was a 2-year overall survival in patients treated with the recommended dose. Results Of the 33 patients enrolled, 10 patients were enrolled in the phase I portion and a two thirds dose of DeVIC was established as the recommended dose. Twenty-seven patients (range, 21 to 68; median, 56 years) treated with the recommended dose showed the following clinical features: male:female, 17:10; stage IE, 18; stage IIE, 9; B symptoms present, 10; elevated serum lactate dehydrogenase, 5; and PS 2, 2. With a median follow-up of 32 months, the 2-year overall survival was 78% (95% CI, 57% to 89%). This compared favorably with the historical control of radiotherapy alone (45%). Of the 26 patients assessable for a response, 20 (77%) achieved a complete response, with one partial response. The overall response rate was 81%. The most common grade 3 nonhematologic toxicity was mucositis related to radiation (30%). No treatment-related deaths were observed. Conclusion Concurrent chemoradiotherapy using multidrug resistance-nonrelated agents and etoposide is a safe and effective treatment for localized nasal NK/T-cell lymphoma and warrants further investigation.
Database of Genomic Biomarkers for Cancer Drugs and Clinical Targetability in Solid Tumors
Authors: Rodrigo Dienstmann, In Sock Jang, Brian Bot, Stephen Friend, Justin Guinney
Journal: Cancer Discovery (2015)

Abstract Summary: Comprehensive genomic profiling is expected to revolutionize cancer therapy. In this Prospective, we present the prevalence of mutations and copy-number alterations with predictive associations across solid tumors at different levels of stringency for gene–drug targetability. More than 90% of The Cancer Genome Atlas samples have potentially targetable alterations, the majority with multiple events, illustrating the challenges for treatment prioritization given the complexity of the genomic landscape. Nearly 80% of the variants in rarely mutated oncogenes are of uncertain functional significance, reflecting the gap in our understanding of the relevance of many alterations potentially linked to therapeutic actions. Access to targeted agents in early clinical trials could affect treatment decision in 75% of patients with cancer. Prospective implementation of large-scale molecular profiling and standardized reports of predictive biomarkers are fundamental steps for making precision cancer medicine a reality. Cancer Discov; 5(2); 118–23. ©2015 AACR.
Comparison of K+-channel genes within the genomes of Anopheles gambiae and Drosophila melanogaster.
Authors: Thomas J McCormack
Journal: Genome biology (2003)

Potassium channels are the largest and most diverse type of ion channel found in nature. The completion of the sequencing of the genomes of Drosophila melanogaster and Anopheles gambiae, which belong to the same order, the Diptera, allows us to compare and contrast K+-channel genes and gene families present within the genomes of two dipterans.This study identifies at least eight voltage-gated K+-channel genes in Anopheles, as well as three Slo-family, three Eag-family and six inward rectifier K+-channel genes. The genomic organization of K+-channel genes from Drosophila and Anopheles is well conserved. The sequence identity of the most similar K+-channel gene products between these two species ranges from 42% to 98%, with a mean value of 85%. Although most K+-channel genes in Drosophila and Anopheles are present in a 1:1 ratio, Anopheles has more genes in three K+-channel types, namely KQT, Kv3, and inward rectifier channels. Microsynteny between the genes flanking K+-channel genes in Drosophila and Anopheles was seldom observed; however, most of the K+-channel genes are indeed located at positions which a previous genome-wide comparison has designated as homologous chromosomal regions.The Anopheles genome encodes more voltage-gated and inward rectifier K+-channel genes than that of Drosophila. Despite the conservation of intron-exon boundaries, orthologs of genes flanking K+-channel genes in Drosophila are generally not found adjacent to the Anopheles K+-channel orthologs, suggesting that extensive translocation of genes has occurred since the divergence of these two organisms.
Helping Patients Decide: Ten Steps to Better Risk Communication
Authors: A. Fagerlin, B. J. Zikmund-Fisher, P. A. Ubel
Journal: JNCI Journal of the National Cancer Institute (2011)

With increasing frequency, patients are being asked to make complex decisions about cancer screening, prevention, and treatment. These decisions are fraught with emotion and cognitive difficulty simultaneously. Many Americans have low numeracy skills making the cognitive demands even greater whenever, as is often the case, patients are presented with risk statistics and asked to make comparisons between the risks and benefits of multiple options and to make informed medical decisions. In this commentary, we highlight 10 methods that have been empirically shown to improve patients’ understanding of risk and benefit information and/or their decision making. The methods range from presenting absolute risks using frequencies (rather than presenting relative risks) to using a risk format that clarifies how treatment changes risks from preexisting baseline levels to using plain language. We then provide recommendations for how health-care providers and health educators can best to communicate this complex medical information to patients, including using plain language, pictographs, and absolute risks instead of relative risks.
Variability of sputum inflammatory mediators in COPD and α<sub>1</sub>-antitrypsin deficiency
Authors: Helen Stone, Gillian McNab, Alice M. Wood, Robert A. Stockley, Elizabeth Sapey
Journal: European Respiratory Journal (2012)

There is inherent daily variability of sputum inflammatory mediators in stable-state patients with usual chronic obstructive pulmonary disease (COPD). The variability of pulmonary inflammation in patients with α(1)-antitrypsin deficiency (A1ATD) is unknown. Our study aimed to quantify this variability, in comparison to patients with usual COPD, in order to facilitate power calculations for proof of concept trials of putative specific anti-inflammatory agents in both groups. Sputum interleukin (IL)-8, myeloperoxidase (MPO), leukotriene B(4) (LTB(4)) and differential cell counts were measured in 12 usual COPD patients and 12 A1ATD patients on nine occasions over a 1-month period. All samples were obtained in the stable clinical state. There was significant daily variability in all mediators in all patients. A1ATD patients had higher sputum concentrations of IL-8 and LTB(4) compared with usual COPD, but lower levels of MPO and absolute neutrophil counts. Patients with usual COPD had more intra-patient variability, A1ATD patients demonstrated greater inter-patient variability. There are increased concentrations of pulmonary inflammatory mediators but fewer sputum neutrophils in A1ATD compared with usual COPD. The daily variability of inflammatory mediators and cell counts was significantly reduced in both groups by averaging sequential samples. This can be utilised to perform power calculations for future proof of concept studies; averaging three sequential samples appears optimum.
Suppression of dual-specificity phosphatase–2 by hypoxia increases chemoresistance and malignancy in human cancer cells
Authors: Shih-Chieh Lin, Chun-Wei Chien, Jenq-Chang Lee, Yi-Chun Yeh, Keng-Fu Hsu, Yen-Yu Lai, Shao-Chieh Lin, Shaw-Jenq Tsai
Journal: Journal of Clinical Investigation (2011)

Hypoxia inducible factor-1 (HIF-1) is the master transcriptional regulator of the cellular response to altered oxygen levels. HIF-1α protein is elevated in most solid tumors and contributes to poor disease outcome by promoting tumor progression, metastasis, and resistance to chemotherapy. To date, the relationship between HIF-1 and these processes, particularly chemoresistance, has remained largely unexplored. Here, we show that expression of the MAPK-specific phosphatase dual-specificity phosphatase-2 (DUSP2) is markedly reduced or completely absent in many human cancers and that its level of expression inversely correlates with that of HIF-1α and with cancer malignancy. Analysis of human cancer cell lines indicated that HIF-1α inhibited DUSP2 transcription, which resulted in prolonged phosphorylation of ERK and, hence, increased chemoresistance. Knockdown of DUSP2 increased drug resistance under normoxia, while forced expression of DUSP2 abolished hypoxia-induced chemoresistance. Further, reexpression of DUSP2 during cancer progression caused tumor regression and markedly increased drug sensitivity in mice xenografted with human tumor cell lines. Furthermore, a variety of genes involved in drug response, angiogenesis, cell survival, and apoptosis were found to be downregulated by DUSP2. Our results demonstrate that DUSP2 is a key downstream regulator of HIF-1-mediated tumor progression and chemoresistance. DUSP2 therefore may represent a novel drug target of particular relevance in tumors resistant to conventional chemotherapy.
Vulnerability to winter mortality in elderly people in Britain: population based study
Authors: Paul Wilkinson, Sam Pattenden, Ben Armstrong, Astrid Fletcher, R Sari Kovats, Punam Mangtani, Anthony J McMichael
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To examine the determinants of vulnerability to winter mortality in elderly British people. <b>Design</b> Population based cohort study (119 389 person years of follow up). <b>Setting</b> 106 general practices from the Medical Research Council trial of assessment and management of older people in Britain. <b>Participants</b> People aged ≥ 75 years. <b>Main outcome measures</b> Mortality (10 123 deaths) determined by follow up through the Office for National Statistics. <b>Results</b> Month to month variation accounted for 17% of annual all cause mortality, but only 7.8% after adjustment for temperature. The overall winter:non-winter rate ratio was 1.31 (95% confidence interval 1.26 to 1.36). There was little evidence that this ratio varied by geographical region, age, or any of the personal, socioeconomic, or clinical factors examined, with two exceptions: after adjustment for all major covariates the winter:non-winter ratio in women compared with men was 1.11 (1.00 to 1.23), and those with a self reported history of respiratory illness had a winter:non-winter ratio of 1.20 (1.08 to 1.34) times that of people without a history of respiratory illness. There was no evidence that socioeconomic deprivation or self reported financial worries were predictive of winter death. <b>Conclusion</b> Except for female sex and pre-existing respiratory illness, there was little evidence for vulnerability to winter death associated with factors thought to lead to vulnerability. The lack of socioeconomic gradient suggests that policies aimed at relief of fuel poverty may need to be supplemented by additional measures to tackle the burden of excess winter deaths in elderly people.
Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Is Required for Tumor Necrosis Factor α–Mediated Sensitization of Human Breast Cancer Cells to Chemotherapy
Authors: Jing Xu, Jun-Ying Zhou, Gen Sheng Wu
Journal: Cancer Research (2006)

Abstract Tumor necrosis factor α (TNFα) induces apoptosis and sensitizes cancer cells to chemotherapy, but the mechanism underlying its sensitization is not fully understood. Here, we report that TNFα-mediated sensitization of cancer cells to chemotherapy involves activation of the TRAIL pathway. We show that the combined treatment of breast cancer cells with TNFα and Adriamycin significantly increases cell death compared with the treatment with either agent alone. The combined treatment activated both death receptor and mitochondrial apoptotic pathways, whereas Adriamycin alone activated only the mitochondrial pathway, and TNFα failed to activate either. Furthermore, we show that TNFα induces TRAIL through a transcriptional mechanism. Using reporter gene assays in conjunction with chromatin immunoprecipitation assays, we show that TRAIL induction by TNFα is regulated via both nuclear factor-κB and Sp1 binding sites. Importantly, down-regulation of TRAIL by small interfering RNA silencing decreased TNFα-mediated Adriamycin-induced caspase activation and apoptosis, and thus enhanced breast cancer cell resistance to Adriamycin. Collectively, our results suggest that induction of TRAIL by TNFα is critical for sensitization of breast cancer cells to chemotherapy. (Cancer Res 2006; 66(20): 10092-9)