tbuckley/cabot-search huggingface dataset:
Issues at the interface between primary and secondary care in the management of common respiratory disease bullet 2: Are we too ready to diagnose asthma in children?
Authors: D. J Keeley, M. Silverman
Journal: Thorax (1999)

Recurrent respiratory symptoms in children are extremely common. A proportion of those children who experience recurrent respiratory symptoms have asthma—reversible airways obstruction associated with bronchial hyperreactivity, allergic inflammation of the airways, and a response to treatment with bronchodilators and regular prophylactic inhaled anti-inflammatory agents. Since we cannot easily measure bronchial hyperresponsiveness or inflammation and clinical correlates are not specific, diagnosis often depends on response to treatment. But how big is the proportion with asthma, how does that proportion vary with age, and are we successful in applying the asthma label and giving the asthma treatments to the right group of children?

The prevalence of asthma has undoubtedly increased in industrialised countries over the last few decades. Increases in rates of physician diagnosis of asthma are partially accounted for by changes in diagnostic preference, but there is consistent survey evidence for the increasing prevalence of symptomatic wheezing. Parent reported prevalence of attacks of wheezing in Oslo children aged 6–16 increased from 3.7% to 6.8% between 1981 and 1994.1 Exercise induced bronchospasm is closely related to asthma, and the proportion of 12 year old children in Wales whose peak flow dropped by more than 25% after running doubled between 1973 and 1988.2 

It was equally clear in the 1980s that childhood asthma was underdiagnosed and undertreated. Eleven out of 31 Tyneside schoolchildren experiencing more than 12 episodes of wheezing per year and three out of 56 with 4–12 episodes per year had been offered a diagnosis of asthma by their general practitioner.3 Since then, growing awareness of the existence of childhood asthma and of the effectiveness and relative safety of regular inhaled prophylactic agents has led to considerably higher rates of diagnosis and treatment. Has the pendulum swung too far the other way? Are we now making false diagnoses …
Histone deacetylase inhibitor potentiated the ability of MTOR inhibitor to induce autophagic cell death in Burkitt leukemia/lymphoma
Authors: Li Hua Dong, Shu Cheng, Zhong Zheng, Li Wang, Yang Shen, Zhi Xiang Shen, Sai Juan Chen, Wei Li Zhao
Journal: Journal of Hematology & Oncology (2013)

Abstract Background Burkitt leukemia/lymphoma is a major subtype of aggressive B-cell lymphoma. Biological targeted therapies on this disease need to be further investigated and may help to improve the clinical outcome of the patients. Methods This study examined the anti-tumor activity of the histone deacetylases (HDAC) inhibitor valproic acid (VPA) combined with the mammalian target of rapamycin (MTOR) inhibitor temsirolimus in Burkitt leukemia/lymphoma cell lines, as well as in primary tumor cells and a murine xenograft model. Results Co-treatment of VPA and temsirolimus synergistically inhibited the tumor cell growth and triggered the autophagic cell death, with a significant inhibition of MTOR signaling and MYC oncoprotein. Functioned as a class I HDAC inhibitor, VPA potentiated the effect of temsirolimus on autophagy through inhibiting HDAC1. Molecular silencing of HDAC1 using small interfering RNA (siRNA) attenuated VPA-mediated regulation of CDKN1A, CDKN1B and LC3-I/II, regression of tumor cell growth and induction of autophagy. Meanwhile, VPA counteracted temsirolimus-induced AKT activation via HDAC3 inhibition. HDAC3 siRNA abrogated the ability of VPA to modulate AKT phosphorylation, to suppress tumor cell growth and to induce autophagy. Strong antitumor effect was also observed on primary tumor cells while sparing normal hematopoiesis ex vivo. In a murine xenograft model established with subcutaneous injection of Namalwa cells, dual treatment efficiently blocked tumor growth, inhibited MYC and induced in situ autophagy. Conclusions These findings confirmed the synergistic effect of the HDAC and MTOR inhibitors on Burkitt leukemia/lymphoma, and provided an insight into clinical application of targeting autophagy in treating MYC-associated lymphoid malignancies.
Cell Cycle in Vasculoproliferative Diseases
Authors: Vissa Sriram, Cam Patterson
Journal: Circulation (2001)

Abstract —Atherosclerosis and restenosis of epicardial vessels are among the greatest challenges facing the clinical cardiologist, and phenotypic modulation and proliferation of smooth muscle cells are major components of the vasculoproliferative response. Proliferation is regulated by the interplay of regulatory proteins at checkpoints in the cell cycle that alter cellular growth. Activation of the cell cycle and the genetic control of its progression are final common pathways in this process. Investigators have postulated that cell-cycle inhibition using drugs and genetic or physical methods has the potential to reverse or prevent the vasculoproliferative process. The current challenge is to translate in vitro data demonstrating the efficacy of cell-cycle inhibition to clinical trials. At present, the steps that must be taken to meet this goal are (1) to design methods of delivery of these agents to specific sites, (2) to identify appropriate cellular targets to elicit cell-cycle arrest, and (3) to improve the therapeutic ratio by minimizing potential side effects. This review discusses current concepts of the cell cycle, target-regulating mechanisms, and possible interventions in vasculoproliferative diseases. We also discuss ongoing clinical trials that use antiproliferative agents in the hope of limiting the course of these diseases, as well as the promise that antiproliferative therapy holds in the coming decade.
Balloon occluded retrograde transvenous obliteration: a feasible alternative to transjugular intrahepatic portosystemic stent shunt
Authors: A Matsumoto
Journal: Gut (2003)

We read with interest the article by Tripathi et al ( Gut 2002; 51 :270–4) on the therapeutic effect of transjugular intrahepatic portosystemic stent shunt (TIPSS) on gastric variceal bleeding. They concluded that TIPSS could only improve mortality in patients with bleeding at a portal pressure gradient (PPG) >12 mm Hg. When treating gastric varices, we should pay attention to the fact that the behaviour of these varices varies according to their location. Isolated fundal varices (FV) are confined to the fundus only (or the cardia and fundus), and are not associated with oesophageal varices. Chikamori and colleagues1 …
Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide.
Authors: Q W Xie, R Whisnant, C Nathan
Journal: The Journal of Experimental Medicine (1993)

Inducible nitric oxide synthase (iNOS) can be expressed by many types of mammalian cells in response to diverse signals acting synergistically, including cytokines and microbial products. We previously showed that induction of iNOS in mouse macrophages by interferon gamma (IFN-gamma) and lipopolysaccharide (LPS) was at the transcriptional level. From a mouse genomic library, we now cloned a 1,749-bp fragment from the 5'-flanking region of the iNOS gene, and used S1 nuclease mapping and primer extension to identify the mRNA transcription start site within it. The mRNA initiation site is preceded by a TATA box and at least 22 oligonucleotide elements homologous to consensus sequences for the binding of transcription factors involved in the inducibility of other genes by cytokines or bacterial products. These include 10 copies of IFN-gamma response element; 3 copies of gamma-activated site; 2 copies each of nuclear factor-kappa B, IFN-alpha-stimulated response element, activating protein 1, and tumor necrosis factor response element; and one X box. Plasmids in which all or the downstream one half or one third of this region of iNOS were linked to a reporter gene encoding chloramphenicol acetyltransferase were transfected into cells of the RAW264.7 macrophage-like line. All these constructs conferred inducibility of the iNOS promoter by LPS, but only the construct containing all 1,749 bp conferred synergistic inducibility by IFN-gamma plus LPS.
Targeted Cancer Gene Therapy Using a Hypoxia Inducible Factor–Dependent Oncolytic Adenovirus Armed with Interleukin-4
Authors: Dawn E. Post, Eric M. Sandberg, Michele M. Kyle, Narra Sarojini Devi, Daniel J. Brat, Zhiheng Xu, Mourad Tighiouart, Erwin G. Van Meir
Journal: Cancer Research (2007)

There is a need for novel therapies targeting hypoxic cells in tumors. These cells are associated with tumor resistance to therapy and express hypoxia inducible factor-1 (HIF-1), a transcription factor that mediates metabolic adaptation to hypoxia and activates tumor angiogenesis. We previously developed an oncolytic adenovirus (HYPR-Ad) for the specific killing of hypoxic/HIF-active tumor cells, which we now armed with an interleukin-4 gene (HYPR-Ad-IL4). We designed HYPR-Ad-IL4 by cloning the Ad E1A viral replication and IL-4 genes under the regulation of a bidirectional hypoxia/HIF-responsive promoter. The IL-4 cytokine was chosen for its ability to induce a strong host antitumor immune response and its potential antiangiogenic activity. HYPR-Ad-IL4 induced hypoxia-dependent IL-4 expression, viral replication, and conditional cytolysis of hypoxic, but not normoxic cells. The treatment of established human tumor xenografts with HYPR-Ad-IL4 resulted in rapid and maintained tumor regression with the same potency as that of wild-type dl309-Ad. HYPR-Ad-IL4-treated tumors displayed extensive necrosis, fibrosis, and widespread viral replication. Additionally, these tumors contained a distinctive leukocyte infiltrate and prominent hypoxia. The use of an oncolytic Ad that locally delivers IL-4 to tumors is novel, and we expect that HYPR-Ad-IL4 will have broad therapeutic use for all solid tumors that have hypoxia or active HIF, regardless of tissue origin or genetic alterations.
The Inflammatory Response to Cell Death
Authors: Kenneth L. Rock, Hajime Kono
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

When cells die in vivo, they trigger an inflammatory response. The ensuing hyperemia, leak of plasma proteins, and recruitment of leukocytes serve a number of useful functions in host defense and tissue repair. However, this response can also cause tissue damage and contribute to the pathogenesis of a number of diseases. Given the key role of inflammation in these processes, it is important to understand the underlying mechanisms that drive this response. Injured cells release danger signals that alert the host to cell death. Some of these molecules are recognized by cellular receptors that stimulate the generation of proinflammatory mediators. Other molecules released by dead cells stimulate the generation of mediators from extracellular sources. The resulting mediators then orchestrate the inflammatory response, eliciting its various vascular and cellular components. Dead cells also release danger signals that activate dendritic cells and promote the generation of immune responses to antigens. Here we review what is presently known about the sterile inflammatory response and its underlying mechanisms.
Expression of a Mutation Causing Hypertrophic Cardiomyopathy Disrupts Sarcomere Assembly in Adult Feline Cardiac Myocytes
Authors: A. J. Marian, Q.-T. Yu, D. L. Mann, F. L. Graham, R. Roberts
Journal: Circulation Research (1995)

Abstract Mutations in the β-myosin heavy chain (βMyHC) induce hypertrophic cardiomyopathy (HCM), cardiac hypertrophy, and sarcomere disarray, with the latter being the characteristic hallmark. Thus, we sought to determine whether expression of mutant βMyHC in adult feline cardiac myocytes, a species known to develop HCM with a phenotype identical to that in humans, induces sarcomere disarray. A full-length βMyHC cDNA was cloned from a human heart cDNA library, and an HCM-causing mutation (Arg 403 Gln) was induced in the βMyHC cDNA by site-directed mutagenesis using polymerase chain reaction (PCR). The normal and mutant βMyHC cDNAs were cloned into pΔE1spIB shuttle vector, downstream from a cytomegalovirus (CMV) promoter. Replication-deficient recombinant adenoviral constructs (Ad5/CMV/βMyHC-N and Ad5/CMV/βMyHC-403) were generated through homologous recombination of pΔE1spIB/CMV/βMyHC-N or Ad5/CMV/βMyHC-403 and pBHG10 after cotransfection in 293 host cells. Infection of COS-1 cells with the βMyHC construct resulted in the expression of a full-length myosin protein. Efficiency of infection of isolated adult cardiac myocytes was &gt;95%. Expression of the βMyHC constructs into mRNA at 48 hours after infection of feline cardiac myocytes was confirmed by reverse transcription–PCR. The net total protein and β-myosin synthesis were determined by using the amount of incorporation of [ 3 H]phenylalanine into total protein and β-myosin, respectively. Although the total amount of protein synthesis was equal among experimental groups, the net myosin synthesis at 48 hours was greater in cardiac myocytes infected with normal or mutant βMyHC constructs than control myocytes or those infected with vector alone ( P &lt;.05). Electron microscopic examination showed only minor changes in the structure of sarcomeres in all experimental groups at 48 hours after infection. However, disruption of the sarcomeric structures at 120 hours after infection with the mutant βMyHC construct was observed in ≈50% of the myocytes examined, whereas the structure of the sarcomeres remained largely intact in myocytes infected with normal βMyHC construct, adenoviral vector alone, or control cardiocytes. Similar results were confirmed by immunofluorescence using MF-20 antibody to myosin. The results of this study indicate that disruption of sarcomere assembly and myofibrillar organization due to mutant βMyHC protein is the primary defect in HCM.
Impact of Fat, Protein, and Glycemic Index on Postprandial Glucose Control in Type 1 Diabetes: Implications for Intensive Diabetes Management in the Continuous Glucose Monitoring Era
Authors: Kirstine J. Bell, Carmel E. Smart, Garry M. Steil, Jennie C. Brand-Miller, Bruce King, Howard A. Wolpert
Journal: Diabetes Care (2015)

Continuous glucose monitoring highlights the complexity of postprandial glucose patterns present in type 1 diabetes and points to the limitations of current approaches to mealtime insulin dosing based primarily on carbohydrate counting.A systematic review of all relevant biomedical databases, including MEDLINE, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials, was conducted to identify research on the effects of dietary fat, protein, and glycemic index (GI) on acute postprandial glucose control in type 1 diabetes and prandial insulin dosing strategies for these dietary factors.All studies examining the effect of fat (n = 7), protein (n = 7), and GI (n = 7) indicated that these dietary factors modify postprandial glycemia. Late postprandial hyperglycemia was the predominant effect of dietary fat; however, in some studies, glucose concentrations were reduced in the first 2-3 h, possibly due to delayed gastric emptying. Ten studies examining insulin bolus dose and delivery patterns required for high-fat and/or high-protein meals were identified. Because of methodological differences and limitations in experimental design, study findings were inconsistent regarding optimal bolus delivery pattern; however, the studies indicated that high-fat/protein meals require more insulin than lower-fat/protein meals with identical carbohydrate content.These studies have important implications for clinical practice and patient education and point to the need for research focused on the development of new insulin dosing algorithms based on meal composition rather than on carbohydrate content alone.
Bystander suppression of occupational hapten sensitization in rats made tolerant to ovalbumin
Authors: T Pullerits, S Lundin, Z H Cui, U Dahlgren, E Telemo, J Lötvall
Journal: European Respiratory Journal (1998)

Feeding a soluble antigen to an animal is known to cause a state of unresponsiveness against this antigen. If this antigen is given together with another antigen during the sensitization procedure, impairment of the response to the new antigen can also be seen, a phenomenon referred to as bystander suppression. The induction of tolerance against ovalbumin (OvA) and the effect of bystander suppression on the response to the hapten trimellitic anhydride (TMA), a cause of occupational asthma, were studied in Brown-Norway rats. Rats were fed either OvA-containing pellets or standard diet for 16 days before sensitization with the mixture of TMA and OvA. The animals were followed for 6 weeks after sensitization. Animals made tolerant to OvA showed a significantly suppressed delayed-type hypersensitivity (DTH) reaction against both OvA and TMA compared with the nontolerized control group at 5 weeks after sensitization, implying bystander suppression. By contrast, immunoglobulin (Ig)E and IgG antibody levels were suppressed only against OvA, whereas anti-TMA antibody levels were not affected. Airway eosinophilia after a single aerosol challenge at 6 weeks after sensitization using TMA conjugated to rat serum albumin, correlated with IgE anti-TMA levels in the group made tolerant to OvA and was not affected by OvA ingestion. In conclusion, suppressive factors released in ovalbumin-tolerant rats when they are challenged with ovalbumin, can suppress the response to trimellitic anhydride and this suppression is more pronounced for T-helper1-type responses.
Epigenetic Transdifferentiation of Normal Melanocytes by a Metastatic Melanoma Microenvironment
Authors: Elisabeth A. Seftor, Kevin M. Brown, Lynda Chin, Dawn A. Kirschmann, William W. Wheaton, Alexei Protopopov, Bin Feng, Yoganand Balagurunathan, Jeffrey M. Trent, Brian J. Nickoloff, Richard E.B. Seftor, Mary J.C. Hendrix
Journal: Cancer Research (2005)

Abstract The clinical management of cutaneous melanoma would benefit significantly from a better understanding of the molecular changes that occur during melanocytic progression to a melanoma phenotype. To gain unique insights into this process, we developed a three-dimensional in vitro model that allows observations of normal human melanocytes interacting with a metastatic melanoma matrix to determine whether these normal cells could be reprogrammed by inductive cues in the tumor cell microenvironment. The results show the epigenetic transdifferentiation of the normal melanocytic phenotype to that of an aggressive melanoma-like cell with commensurate increased migratory and invasive ability with no detectable genomic alterations. Removal of the transdifferentiated melanocytes from the inductive metastatic melanoma microenvironment results in a reversion to their normal phenotype. However, a normal melanocyte microenvironment had no epigenetic influence on the phenotype of metastatic melanoma cells. This novel approach identifies specific genes involved in the transdifferentiation of melanocytes to a more aggressive phenotype, which may offer significant therapeutic value.
The proprotein convertase PC5/6 is protective against intestinal tumorigenesis: in vivo mouse model
Authors: Xiaowei Sun, Rachid Essalmani, Nabil G Seidah, Annik Prat
Journal: Molecular Cancer (2009)

The secretory basic amino acid-specific proprotein convertases (PCs) have often been associated with cancer/metastasis. By controlling the cleavage of cancer-associated proteins, PCs play key roles in multiple steps of cancer development. Most analyses of the implication of PCs in cancer/metastasis relied on the use of in vitro overexpression systems or inhibitors that can affect more than one PC. Aside from the role of furin in salivary gland tumorigenesis, no other in vivo genetic model of PC-knockout was reported in relation to cancer development.Since PC5/6 is highly expressed in the small intestine, the present study examined its in vivo role in intestinal tumorigenesis. Analysis of human intestinal tumors at various stages showed a systematic down-regulation of PC5/6 expression. Since gene inactivation of PC5/6 leads to lethality at birth, we generated mice lacking PC5/6 in enterocytes and analyzed the impact of the presence or absence of this PC in the mouse ApcMin/+ model that develops numerous adenocarcinomas along the intestinal tract. This resulted in viable mice with almost no expression of PC5/6 in small intestine, but with no overt phenotype. The data showed that by themselves ApcMin/+ tumors express lower levels of PC5/6 mRNA, and that the lack of PC5/6 in enterocytes results in a significantly higher tumor number in the duodenum, with a similar trend in other intestinal segments. Finally, the absence of PC5/6 is also associated with a premature mortality of ApcMin/+ mice.Overall, these data suggest that intestinal PC5/6 is protective towards tumorigenesis, especially in mouse duodenum, and possibly in human colon.
Cumulative viral evolutionary changes in chronic hepatitis B virus infection precedes hepatitis B e antigen seroconversion
Authors: Yan Cheng, Stephane Guindon, Allen Rodrigo, Lin Ying Wee, Masafumi Inoue, Alex J V Thompson, Stephen Locarnini, Seng Gee Lim
Journal: Gut (2012)

To examine viral evolutionary changes and their relationship to hepatitis B e antigen (HBeAg) seroconversion.A matched case-control study of HBeAg seroconverters (n = 8) and non-seroconverters (n = 7) with adequate stored sera before seroconversion was performed. Nested PCR, cloning and sequencing of hepatitis B virus (HBV) precore/core gene was performed. Sequences were aligned using Clustal X2.0, followed by construction of phylogenetic trees using Pebble 1.0. Viral diversity, evolutionary rates and positive selection were then analysed.Baseline HBV quasispecies viral diversity was identical in seroconverters and non-seroconverters 10 years before seroconversion but started to increase approximately 3 years later. Concurrently, precore stop codon (PSC) mutations appeared. Some 2 years later, HBV-DNA declined, together with a dramatic reduction in HBeAg titres. Just before HBeAg seroconversion, seroconverters had HBV-DNA levels 2 log lower (p = 0.008), HBeAg titres 310-fold smaller (p = 0.02), PSC mutations > 25% (p < 0.001), viral evolution 8.1-fold higher (p = 0.01) and viral diversity 2.9-fold higher (p < 0.001), compared to non-seroconverters, with a 9.3-fold higher viral diversity than baseline (p = 0.011). Phylogenetic trees in seroconverters showed clustering of separate time points and longer branch lengths than non-seroconverters (p = 0.01). Positive selection was detected in five of eight seroconverters but none in non-seroconverters (p = 0.026). There was significant negative correlation between viral diversity (rs = -0.60, p < 0.001) and HBV-DNA or HBeAg (rs = -0.58, p = 0.006) levels; and positive correlation with PSC mutations (rs = 0.38, p = 0.009). Over time, the significant positive correlation was viral diversity (rs = 0.65, p < 0.001), while negative correlation was HBV-DNA (rs = -0.627, p < 0.001) and HBeAg levels (rs = -0.512, p =0.015).Cumulative viral evolutionary changes that precede HBeAg seroconversion provide insights into this event that may have implications for therapy.