tbuckley/cabot-search huggingface dataset:
Diet and childhood asthma in a society in transition: a study in urban and rural Saudi Arabia
Authors: N. Hijazi
Journal: Thorax (2000)

<h3>BACKGROUND</h3> The causes of the worldwide increases in asthma and allergic diseases in childhood, which seem to relate to increasing prosperity, are unknown. We have previously hypothesised that a reduction in the antioxidant component of the diet is an important factor. An investigation was undertaken of dietary and other risk factors for asthma in Saudi Arabia where major lifestyle differences and prevalences of allergic disease are found in different communities. <h3>METHODS</h3> From a cross sectional study of 1444 children with a mean age of 12 (SD 1) years in Jeddah and a group of rural Saudi villages, we selected 114 cases with a history of asthma and wheeze in the last 12 months and 202 controls who had never complained of wheeze or asthma, as recorded on the ISAAC questionnaire. Risk factors for asthma and allergies (family history, social class, infections, immunisations, family size, and diet) were ascertained by questionnaire. Atopy was assessed by skin prick testing. <h3>RESULTS</h3> In univariate analyses, family history, atopy, and eating at fast food outlets were significant risk factors for wheezy illness, as were the lowest intakes of milk and vegetables and of fibre, vitamin E, calcium, magnesium, sodium, and potassium. These differences were present also in the urban children considered separately. Sex, family size, social class, infections, and parental smoking showed no relationship to risk. In multiple logistic regression analysis, urban residence, positive skin tests, family history of allergic disease, and the lowest intakes of vitamin E, magnesium and sodium related significantly and independently to risk. The lowest tertile of intake of vitamin E was associated with a threefold (95% CI 1.38 to 6.50) increase in risk when adjusted for the other factors. Intake of milk and vegetables both showed inverse linear relationships to being a case. <h3>CONCLUSIONS</h3> This study suggests that dietary factors during childhood are an important influence in determining the expression of wheezy illness, after allowing for urban/rural residence, sex, family history, and atopy. The findings are consistent with previous studies in adults and with the hypothesis that change in diet has been a determinant of the worldwide increases in asthma and allergies.
Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?
Authors: David P Minde, Zeinab Anvarian, Stefan GD Rüdiger, Madelon M Maurice
Journal: Molecular Cancer (2011)

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene strongly predispose to development of gastro-intestinal tumors. Central to the tumorigenic events in APC mutant cells is the uncontrolled stabilization and transcriptional activation of the protein β-catenin. Many questions remain as to how APC controls β-catenin degradation. Remarkably, the large C-terminal region of APC, which spans over 2000 amino acids and includes critical regions in downregulating β-catenin, is predicted to be natively unfolded. Here we discuss how this uncommonly large disordered region may help to coordinate the multiple cellular functions of APC. Recently, a significant number of germline and somatic missense mutations in the central region of APC were linked to tumorigenesis in the colon as well as extra-intestinal tissues. We classify and localize all currently known missense mutations in the APC structure. The molecular basis by which these mutations interfere with the function of APC remains unresolved. We propose several mechanisms by which cancer-related missense mutations in the large disordered domain of APC may interfere with tumor suppressor activity. Insight in the underlying molecular events will be invaluable in the development of novel strategies to counter dysregulated Wnt signaling by APC mutations in cancer.
Role of BRAF in Thyroid Oncogenesis
Authors: Lisa M. Caronia, John E. Phay, Manisha H. Shah
Journal: Clinical Cancer Research (2011)

BRAF, a cytoplasmic serine-threonine protein kinase, plays a critical role in cell signaling as an activator within the mitogen-activated protein kinase (MAPK) pathway. The most common BRAF mutation is the V600E transversion, which causes constitutive kinase activity. This mutation has been found in a multitude of human cancers, including both papillary thyroid cancer (PTC) and papillary-derived anaplastic thyroid cancer (ATC), in which it initiates follicular cell transformation. With such a high frequency of BRAF mutations in PTC (44%) and PTC-derived ATC (24%), research in BRAF(V600E) detection for diagnostic purposes has shown high sensitivity and specificity for tumor cell presence. BRAF(V600E) in PTC has also provided valuable prognostic information, as its presence has been correlated with more aggressive and iodine-resistant phenotypes. Such findings have initiated research in targeting oncogenic BRAF in cancer therapeutics. Although multiple phase II clinical trials in patients with iodine-refractory metastatic PTC have shown significant efficacy for sorafenib, a first-generation BRAF inhibitor, the mechanism by which it mediates its effect remains unclear because of multiple additional kinase targets of sorafenib. Additionally, preclinical and clinical studies investigating combination therapy with agents such as selective (PLX 4032) and potent (BAY 73-4506 and ARQ 736) small-molecule BRAF inhibitors and MAP/extracellular signal-regulated kinase (ERK) kinase inhibitors (AZD6244) hold great promise in the treatment of BRAF(V600E) cancers and may eventually play a powerful role in changing the clinical course of PTC and ATC.
Management of Hypertension
Authors: N. Burgess Record
Journal: JAMA (1980)

To the Editor.—  Physicians reading the Hypertension Detection and Follow-up Program (HDFP) (242:2562, 1979) report should feel both excited and challenged—excited because we now have evidence that pharmacologic control of even mild hypertension reduces mortality, and challenged because published evidence increasingly suggests that special treatment programs do a better job controlling high blood pressure (HBP) than do practicing physicians. 1-3   The HDFP results justify even more vigorous nationwide hypertension detection and control efforts. Occupational and community treatment programs have proved effective; where appropriate, these models should be applied as alternatives to traditional medical care. Meanwhile, is it possible that solo and small group practice physicians could achieve equally high levels of HBP detection and control if they and their patients had access to special community programs that would facilitate compliance and control?  Our experience in rural west-central Maine may help answer these questions. During the last five years, the Franklin
Azidothymidine(AZT)‐induced siderosis
Authors: Simeon Pollack, Janet Weaver
Journal: American Journal of Hematology (1993)

Abstract Azidothymidine(AZT) interferes with heme synthesis. This should upregulate the synthesis of transferrin receptors and increase the amount of iron taken up by the cell. We found a 50% increase in the iron content of liver and a 20% increase in the iron content of macrophages in AZT‐treated mice.
Influence of Donor Brain Death on Chronic Rejection of Renal Transplants in Rats
Authors: JOHANN PRATSCHKE, MARKUS J. WILHELM, IGOR LASKOWSKI, MAMORU KUSAKA, FRANCISCA BEATO, STEFAN G. TULLIUS, PETER NEUHAUS, WAYNE W. HANCOCK, NICHOLAS L. TILNEY
Journal: Journal of the American Society of Nephrology (2001)

The clinical observation that the results of kidney grafts from living donors (LD), regardless of relationship with the host, are consistently superior to those of cadavers suggests an effect of brain death (BD) on organ quality and function. This condition triggers a series of nonspecific inflammatory events that increase the intensity of the acute immunologic host responses after transplantation (Tx). Herein are examined the influences of this central injury on late changes in renal transplants in rats. A standardized model of BD was used. Groups included both allografts and isografts from normotensive braindead donors and anesthetized LD. Renal function was determined every 4 wk after Tx, at which time representative grafts were examined by morphology and by reverse transcriptase—PCR. Long-term survival of brain-dead donor transplants was significantly less than LD grafts. Proteinuria was significantly elevated in recipients of grafts from BD donors versus LD controls as early as 6 wk postoperatively and increased progressively through the 52-wk follow up. These kidneys also showed consistently more intense and progressive deterioration in renal morphology. Changes in isografts from brain-dead donors were less marked and developed at a slower tempo than in allografts but were always greater than those in controls. The transcription of cytokines was significantly increased in all brain-dead donor grafts. Donor BD accelerates the progression of long-term changes associated with kidney Tx and is an important risk factor for chronic rejection. These results explain in part the clinically noted difference in long-term function between organs from cadaver and living sources.
Lead Exposure and Behavior among Young Children in Chennai, India
Authors: Ananya Roy, David Bellinger, Howard Hu, Joel Schwartz, Adrienne S. Ettinger, Robert O. Wright, Maryse Bouchard, Kavitha Palaniappan, Kalpana Balakrishnan
Journal: Environmental Health Perspectives (2009)

Lead exposure has long been associated with deficits in IQ among children. However, few studies have assessed the impact of lead on specific domains of behavior and cognition.We evaluated the associations between lead and different domains of neurobehavior and their relative sensitivity to lead.We determined blood lead levels using a LeadCare instrument in 756 children 3-7 years of age attending pre- and elementary schools in Chennai, India. Anxiety, social problems, inattention, hyperactivity, and attention deficit hyperactivity disorder (ADHD), as well as executive function were assessed in children by their schoolteachers using Conners' Teacher Rating Scales-39, Conners' ADHD/Diagnostic and Statistical Manual for Mental Disorders, 4th Edition Scales (CADS), and the Behavior Rating Inventory of Executive Function questionnaires, with higher scores denoting worse behavior. Analyses were carried out using multivariate generalized estimating equations with comparisons of outcome Z-scores to assess the relative strengths of the associations between log-blood lead and the different domains of behavior.Mean blood lead level was 11.4 +/- 5.3 microg/dL. Blood lead was associated with higher anxiety (beta = 0.27, p = 0.01), social problems (beta = 0.20, p = 0.02), and higher scores in the ADHD index (beta = 0.17; p = 0.05). The effect estimate was highest for global executive function (beta = 0.42; p< 0.001).Higher blood lead levels in this population of young children is associated with increased risk of neurobehavioral deficits and ADHD, with executive function and attention being particularly vulnerable domains to the effects of lead.
A Phase I-II Study of Combined Blockade of the ErbB Receptor Network with Trastuzumab and Gefitinib in Patients with HER2 (ErbB2)-Overexpressing Metastatic Breast Cancer
Authors: Carlos L. Arteaga, Anne O'Neill, Stacy L. Moulder, Michael Pins, Joseph A. Sparano, George W. Sledge, Nancy E. Davidson
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To determine the safety, and efficacy of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in combination with trastuzumab in patients with metastatic HER2-positive metastatic breast cancer. Experimental Design: Patients with HER2-overexpressing breast cancer were treated with trastuzumab 2 mg/kg/week and gefitinib 250 to 500 mg/day. The primary end point of the study was to increase the proportion progression-free from 50% to 65% at 6 months in chemotherapy-naive patients and from 50% to 70% at 3 months in patients previously treated with chemotherapy in the metastatic setting. Results: In the phase I study, all patients treated with gefitinib 500 mg/day developed grade 3 diarrhea. The phase II study was conducted using trastuzumab and gefitinib 250 mg/day. One patient achieved a complete response, 2 had a partial response, and 6 had stable disease for an overall response rate of 9% and a clinical benefit rate of 28% (9 of 32). Median time to progression (TTP) was 3 months (95% confidence interval, 2.3-4.1) in patients with no prior systemic therapy in the metastatic setting (n = 23). In patients treated with prior systemic therapy (n = 9), the median TTP of 5.3 months (95% confidence interval, 2.8-8.1). Overall median survival was 27 months. TTP was similar in EGFR-positive compared with EGFR-negative patients. Conclusions: Gefitinib 250 mg/day was the maximal dose that can be safely administered with weekly trastuzumab. Interim analysis of the efficacy suggested that the combination was unlikely to result in clinical benefit compared with trastuzumab alone. These results do not support the use of this combination in patients with HER2-positive breast cancer.
Early Impact of Human Papillomavirus Vaccination on Cervical Neoplasia--Nationwide Follow-up of Young Danish Women
Authors: B. Baldur-Felskov, C. Dehlendorff, C. Munk, S. K. Kjaer
Journal: JNCI Journal of the National Cancer Institute (2014)

BackgroundIn clinical trials, vaccines against human papillomavirus (HPV) have been highly effective against HPV16- or HPV18-associated cervical lesions. The quadrivalent HPV vaccine was licensed in 2006 and subsequently implemented in the Danish vaccination program. The study aim was to use individual information on HPV vaccination status to assess subsequent risk of cervical lesions.
Quantitative Cell-Free DNA, <i>KRAS</i>, and <i>BRAF</i> Mutations in Plasma from Patients with Metastatic Colorectal Cancer during Treatment with Cetuximab and Irinotecan
Authors: Karen-Lise Garm Spindler, Niels Pallisgaard, Ivan Vogelius, Anders Jakobsen
Journal: Clinical Cancer Research (2012)

The present study investigated the levels of circulating cell-free DNA (cfDNA) in plasma from patients with metastatic colorectal cancer (mCRC) in relation to third-line treatment with cetuximab and irinotecan and the quantitative relationship of cfDNA with tumor-specific mutations in plasma.Inclusion criteria were histopathologically verified chemotherapy-resistant mCRC, adequate Eastern Cooperative Oncology Group performance status, and organ function. Treatment consisted of irinotecan being administered at 350 mg/m(2) for 3 weeks and weekly administration of 250 mg/m(2) cetuximab until progression or unacceptable toxicity. A quantitative PCR method was developed to assess the number of cfDNA alleles and KRAS and BRAF mutation alleles in plasma at baseline.The study included 108 patients. Only three patients were positive for BRAF mutations. The majority of KRAS mutations detected in tumors were also found in the plasma [32 of 41 (78%)]. Plasma cfDNA and plasma mutant KRAS levels (pmKRAS) were strongly correlated (r = 0.85, P < 10(-4)). The disease control rate was 77% in patients with low cfDNA (<25% quartile) and 30% in patients with high cfDNA [>75% quartile (P = 0.009)]. Patients with pmKRAS levels higher than 75% had a disease control rate of 0% compared with 42% in patients with lower pmKRAS (P = 0.048). Cox analysis confirmed the prognostic importance of both cfDNA and pmKRAS. High levels were clear indicators of a poor outcome.KRAS analysis in plasma is a viable alternative to tissue analysis. Quantitative levels of cfDNA and pmKRAS are strongly correlated and hold promise of clinical application.
Mammographic Density and the Risk and Detection of Breast Cancer
Authors: Norman F. Boyd, Helen Guo, Lisa J. Martin, Limei Sun, Jennifer Stone, Eve Fishell, Roberta A. Jong, Greg Hislop, Anna Chiarelli, Salomon Minkin, Martin J. Yaffe
Journal: New England Journal of Medicine (2007)

Extensive mammographic density is associated with an increased risk of breast cancer and makes the detection of cancer by mammography difficult, but the influence of density on risk according to method of cancer detection is unknown.We carried out three nested case-control studies in screened populations with 1112 matched case-control pairs. We examined the association of the measured percentage of density in the baseline mammogram with risk of breast cancer, according to method of cancer detection, time since the initiation of screening, and age.As compared with women with density in less than 10% of the mammogram, women with density in 75% or more had an increased risk of breast cancer (odds ratio, 4.7; 95% confidence interval [CI], 3.0 to 7.4), whether detected by screening (odds ratio, 3.5; 95% CI, 2.0 to 6.2) or less than 12 months after a negative screening examination (odds ratio, 17.8; 95% CI, 4.8 to 65.9). Increased risk of breast cancer, whether detected by screening or other means, persisted for at least 8 years after study entry and was greater in younger than in older women. For women younger than the median age of 56 years, 26% of all breast cancers and 50% of cancers detected less than 12 months after a negative screening test were attributable to density in 50% or more of the mammogram.Extensive mammographic density is strongly associated with the risk of breast cancer detected by screening or between screening tests. A substantial fraction of breast cancers can be attributed to this risk factor.
Abstract 1104: The role of DLL4 in cancer immune-surveillance and its pathogenicity in p53-dysregulated environment
Authors: Zhixing Yao, Zaki A. Sherif
Journal: Cancer Research (2014)

Abstract Recent advances in cancer studies reveal that tumorigenesis results from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome characterized by mutation of the TP53 tumor suppressor gene (locus 17p13.1). The p53 transcription factor responds to diverse cellular stresses by regulating target genes that induce apoptosis, cell cycle arrest, DNA repair, and senescence. LFS can provide powerful insights into our understanding of somatic mutations present in sporadic cancers as well as the de-regulation of cell signaling pathways. We will be using LFS cells and mice as models to build on our previous discovery that showed a balanced reciprocal translocation between chromosomes 11q23 and 15q15 in LFS patients' skin fibroblast cells. In our present study, analysis of the breakpoint region reveals that in LFS, breast cancer (MCF7) and neuroblastoma (IMR32) cell lines, there is a dramatically increased activation in the expression of cancer susceptibility candidate 5 gene (CASC5), a part of kinetochore-microtubule attachments associated with cell proliferation. Furthermore, there was an abrogation in the expression of a critical protein, Delta-like ligand-4 (DLL4), in LFS normal skin fibroblasts of TP53 mutation carriers and non-carriers. There was also a down-regulation of DLL4 in unrelated breast cancer and neuroblastoma cell lines by DNA hypermethylation. DLL4 is a ligand for Notch family of receptors with crucial functions in normal development, immune surveillance and tissue homeostasis. TP53 and CTCF (a transcription factor involved in chromatin architecture) have a direct activator effect at the DLL4 promoter. Notch/DLL4 plays a key role in the generation of hematopoietic stem cells during embryonic development and regulates the T cell lineage and subsequent stages of thymopoiesis. WNT2 is also down-regulated in LFS cell lines and abolished in MCF7. Whereas Notch signaling controls cell fate specification in a variety of cell contexts during embryonic and postnatal development, Wnt signaling plays a critical role in cell differentiation and proliferation. Both Notch and Wnt pathways are activated by oncogenic mutations and dysregulated in cancer. The long-term objective of this research is to develop a critical understanding of the mechanisms by which p53 regulates cancer immune-surveillance through cross-talk with the tumor microenvironment so that therapeutic agents can be developed to curtail cancer progression. Citation Format: Zhixing Yao, Zaki A. Sherif. The role of DLL4 in cancer immune-surveillance and its pathogenicity in p53-dysregulated environment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1104. doi:10.1158/1538-7445.AM2014-1104
Recombination of hepatitis B virus DNA in patients with HIV
Authors: Guillaume Fallot, Boris Halgand, Elisabeth Garnier, Michel Branger, Anne Gervais, Anne-Marie Roque-Afonso, Valérie Thiers, Eric Billaud, Sophie Matheron, Didier Samuel, Cyrille Féray
Journal: Gut (2011)

<h3>Introduction</h3> Hepatitis B is a major cause of death in patients with HIV who usually receive drugs active against hepatitis B virus (HBV). The variability of HBV DNA over time has been little studied. Recombination between different HBV genotypes has been described in many cross-sectional studies, but the frequency of intergenotypic and intragenotypic recombinations in individual patients is unknown. <h3>Methods</h3> 32 HIV-positive and 11 HIV-negative patients who remained HBV viraemic despite antiviral therapy for at least 1 year were studied. Genotyping was based on line probe assays and genotype-specific PCR. The variability of HBV DNA over time was examined with restriction length and single-strand conformational polymorphism (RFLP-SSCP). HBV DNA sequences obtained by cloning a 2800 bp PCR fragment were analysed for phylogenetic parameters (diversity and selection pressure) and recombination was detected with RDP3 software. <h3>Results</h3> Large fragments of HBV DNA could be amplified at two different time points in 33 patients. Marked quasi-species modifications occurred in 14 patients. In seven of these patients and in one patient with no change detectable by RFLP-SSCP, the 2800 bp fragment was cloned at two time points at least. In four (57%) of these seven patients, various intergenotypic or intragenotypic recombination events were detected between subvariants present in the initial quasi-species. Recombinant fragments mostly harboured antiviral resistance determinants and reflected a large increase in diversity and in positive selection pressure on the entire HBV quasi-species. <h3>Conclusions</h3> In coinfected patients, HBV DNA recombination events are frequent during antiviral therapy, corresponding to increased positive selection pressure on the HBV quasi-species and to conservation of antiviral resistance mutations. In this population and at the individual level, recombination is a significant source of HBV genetic variability.