tbuckley/cabot-search huggingface dataset:
Lysis of Dysplastic but not Normal Oral Keratinocytes and Tissue-Engineered Epithelia with Conditionally Replicating Adenoviruses
Authors: Kamis Gaballah, Allison Hills, David Curiel, Gunnel Hallden, Paul Harrison, Max Partridge
Journal: Cancer Research (2007)

Abstract There is no effective medical treatment for oral precancer, and surgery to remove these lesions is imprecise because abnormal mucosa extends beyond the visible lesion. Development of vectors for tumor-selective viral replication has been a significant advance, and viral lysis is well suited to destruction of oral precancerous mucosa. To facilitate evaluation of new treatments, we engineered dysplastic oral epithelium using keratinocytes isolated from dysplastic lesions. We show that these model systems recapitulate the key characteristics of the clinical lesions closely, and that topical delivery of the conditionally replicating adenovirus (CRAd) dl922-947 can lyse tissue-engineered epithelia that show mild, moderate, or severe dysplasia, but normal oral epithelia are very resistant to this treatment. The lytic effect is determined by various factors, including the grade and proliferation index of the dysplastic epithelia. The presence of suprabasal cycling cells, expression of the coxsackie adenovirus receptor (CAR), the transcription cofactor p300, and other aberrations that affect the regulation of the cell cycle or apoptosis and promote viral replication may also be important. The ability of dl922-947 to destroy engineered oral dysplasia was significantly greater than that observed using wild-type adenovirus, d/1520, or viruses modified to bypass cell entry dependent on the presence of CAR. Evidence of infection in clinical dysplastic lesions was also shown ex vivo using tissue explants. We conclude that dl922-947 may provide an efficient molecular cytotoxic to dissolve oral dysplastic lesions. [Cancer Res 2007;67(15):7284–94]
Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function
Authors: Satoshi Takagi, Hiromasa Tojo, Shuhei Tomita, Shigetoshi Sano, Satoshi Itami, Mariko Hara, Shintaro Inoue, Kyoji Horie, Gen Kondoh, Ko Hosokawa, Frank J. Gonzalez, Junji Takeda
Journal: Journal of Clinical Investigation (2003)

Aryl hydrocarbon receptor nuclear translocator (ARNT), a transcription factor of the Per/AHR/ARNT/Sim family, regulates gene expression in response to environmental stimuli including xenobiotics and hypoxia. To examine its role in the epidermis, the Cre-loxP system was used to disrupt the Arnt gene in a keratinocyte-specific manner. Gene-targeted, newborn mice with almost normal appearance died neonatally of severe dehydration caused by water loss. Histology showed small changes in the architecture of cornified layers, with apparently preserved intercorneocyte lamellar structures responsible for the skin barrier function. In contrast, HPLC/ion-trap mass spectrometry revealed significant alterations in the compositions of ceramides, the major components of the lamellae. The murine epidermal ceramides normally contain 4-sphingenine and 4-hydroxysphinganine. In Arnt-null epidermis, 4-sphingenine was largely replaced by sphinganine and the amounts of ceramides with 4-hydroxysphinganine were greatly decreased, suggesting deficiency of dihydroceramide desaturases that catalyze the formation of both 4-sphingenyl and 4-hydroxysphinganyl moieties. A desaturase isoenzyme, DES-1, prefers desaturation, but DES-2 catalyzes both reactions to a similar extent. Transcript levels of Des-2, but not Des-1, were considerably decreased in cultured keratinocytes from Arnt-null epidermis. These results indicate that proper ceramide compositions through 4-desaturation regulated by ARNT are crucial for maintaining the epidermal barrier function.
No Replication of Association Between Estrogen Receptor α Gene Polymorphisms and Susceptibility to Myocardial Infarction in a Large Sample of Patients of European Descent
Authors: Werner Koch, Petra Hoppmann, Arne Pfeufer, Jakob C. Mueller, Albert Schömig, Adnan Kastrati
Journal: Circulation (2005)

The effects of estrogen on blood vessels are partly due to changes in vascular cell gene expression and protein synthesis that are mediated by estrogen receptors. In previous association studies, the -397T/C (rs2234693) and -351A/G (rs9340799) single nucleotide polymorphisms in the estrogen receptor alpha gene (ESR1) have been implicated in the risk of coronary atherosclerosis and myocardial infarction. To test these findings, we examined the relationship of the polymorphisms to myocardial infarction in a large sample of white patients and control individuals of predominantly European descent.The case group included 3657 patients with myocardial infarction, and the control group comprised 1211 individuals with angiographically normal coronary arteries and without signs or symptoms of myocardial infarction. TaqMan assays were used for the determination of genotypes. Genotype distributions of the -397T/C and -351A/G polymorphisms were not significantly different between the control and patient groups (P> or =0.85). The frequencies of haplotypes defined by the -397T/C and -351A/G polymorphisms were similar in the control group and the patient group (P=0.42). In addition, the distributions of haplotype-defined genotypes (diplotypes) were not significantly different between the control group and the patient group (P=0.81). Separate analyses in women and men did not reveal sex-related associations of specific genotypes or haplotypes of the polymorphisms with myocardial infarction (P> or =0.25).The results indicate that the -397T/C and -351A/G polymorphisms of ESR1 or haplotypes based on these polymorphisms are not associated with myocardial infarction in a white population.
Antiviral treatment of chronic hepatitis B virus infection: Improvement in liver disease with interferon and adenine arabinoside
Authors: George H. Scullard, Ljudevit L. Andres, Harry B. Greenberg, Joseph L. Smith, Vinod K. Sawhney, Andrew E. Neal, Anmol S. Mahal, Hans Popper, Thomas C. Merigan, William S. Robinson, Peter B. Gregory
Journal: Hepatology (1981)

Twelve of 32 patients lost HBeAg and DNA polymerase from their serum after completing antiviral therapy with interferon and/or adenine arabinoside. Three lost serum HBsAg as well. Loss of corresponding viral markers from hepatic tissue was also seen. There was improvement in symptoms, hepatic tests, and histologic findings in the 12 patients whose viral markers disappeared when compared to the 20 whose viral markers persisted despite treatment. These findings provide support for the use of antiviral agents in hepatitis B positive chronic liver disease.
Progression of Cardiovascular Autonomic Dysfunction in Patients With Type 2 Diabetes
Authors: Seung-Hyun Ko, Shin-Ae Park, Jae-Hyoung Cho, Ki-Ho Song, Kun-Ho Yoon, Bong-Yun Cha, Ho-Young Son, Ki-Dong Yoo, Keon-Woong Moon, Yong-Moon Park, Yu-Bai Ahn
Journal: Diabetes Care (2008)

We investigated whether cardiovascular autonomic dysfunction was associated with glycemic control status over time in patients with type 2 diabetes.From 1999 to 2000, cardiovascular autonomic nerve function testing (AFT) was performed on patients with type 2 diabetes (n = 1,021) and was followed-up in 2006 and February 2008. Tests for cardiovascular autonomic functions measured heart rate variability parameters (expiration-to-inspiration [E/I] ratio, responses to the Valsalva maneuver, and standing). AFT scores were determined from the results of the each test as follows: 0 for normal and 1 for abnormal. We began with those who had a score of 0 and assessed the changes in total score along with biannual A1C levels.At follow-up, the development of cardiovascular autonomic dysfunction was 34.5% (E/I ratio 21.9%, Valsalva maneuver 77.8%, and posture 58.9%; n = 783). The development of cardiovascular autonomic dysfunction was higher in older patients (P < 0.001); in those with longer duration of diabetes (P < 0.001); of hypertension (P = 0.005), and of diabetic retinopathy (P < 0.001); and in those who had higher levels of microalbuminuria (P = 0.002). Logistic regression analysis revealed that the development of cardiovascular autonomic dysfunction was strongly associated with the mean A1C level during the follow-up period (mean A1C >9.0% vs. <or=7.0%, odds ratio 2.984, 95% CI 1.177-7.561; P = 0.021).The development of cardiovascular autonomic dysfunction was independently associated with microvascular complications and glycemic control status during this 7.5-year follow-up in patients with type 2 diabetes.
Identification of Cyclooxygenase-2 as a Major Actor of the Transcriptomic Adaptation of Endothelial and Tumor Cells to Cyclic Hypoxia: Effect on Angiogenesis and Metastases
Authors: Géraldine Daneau, Romain Boidot, Philippe Martinive, Olivier Feron
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Cyclic hypoxia in tumors originates from heterogeneities in RBC flux and influences not only tumor cells but also endothelial cells lining tumor blood vessels. Whether pO2 fluctuations, particularly transient reoxygenation periods, alter the well-known hypoxia-inducible factor (HIF)–dependent gene program is largely unknown. Experimental Design: We compared the transcriptomic profiles of endothelial and tumor cells exposed to cyclic hypoxia versus continuous hypoxia to uncover a possible differential effect on angiogenesis and metastases. Results: Microarray analyses identified early genes that were selectively induced by cyclic hypoxia in endothelial cells. Among them, we focused on PTGS2 because the observed increase in mRNA expression led to a significant increase in the expression and activity of cyclooxygenase-2 (COX-2; the protein product of PTGS2). HIF-1α was shown to be stabilized by cyclic hypoxia (despite reoxygenation periods) and to favor COX-2 induction as validated by the use of echinomycin and HIF-1α targeting small interfering RNA. Using a specific COX-2 inhibitor and a dedicated COX-2 targeting small interfering RNA, we documented that COX-2 accounted for the higher endothelial cell survival and angiogenic potential conferred by cyclic hypoxia. Cyclic hypoxia also led to a preferential COX-2 induction in tumor cells and, contrary to continuous hypoxia, fostered a higher metastatic take of prechallenged tumor cells. Conclusions: Our study documents that PTGS2/COX-2 is part of a cyclic hypoxia gene signature and largely accounts for the unique phenotype of endothelial and tumor cells exposed to fluctuations in pO2, thereby offering new perspectives for the clustering of tumors expressing COX-2 together with other cyclic hypoxia-responsive genes. Clin Cancer Res; 16(2); 410–9
Randomized trial of lamivudine versus entecavir in entecavir-treated patients with undetectable hepatitis B virus DNA: Outcome at 2 Years
Authors: James Fung, Ching-Lung Lai, John Yuen, Charles Cheng, Ringo Wu, Danny Ka-Ho Wong, Wai-Kay Seto, Ivan Fan-Ngai Hung, Man-Fung Yuen
Journal: Hepatology (2011)

We aimed to determine the 2-year outcomes of entecavir followed by lamivudine in patients with undetectable viral load (<12 IU/mL) and normal alanine aminotransferase (ALT) after initial entecavir treatment for at least 6 months. Patients were randomly assigned 1:1 to continue with entecavir or switch to lamivudine. Liver biochemistry and hepatitis B virus (HBV) DNA were determined at weeks 0, 4, 12, 24, 48, 72, and 96. Mutational analysis using line-probe assay were performed at weeks 0, 24, 48, and 96 and at the time of HBV DNA relapse. There was no elevation of ALT observed in any patients up to 96 weeks. At 96 weeks of follow-up, 19/25 (76%) patients in the lamivudine arm had persistently undetectable HBV DNA, compared with 25/25 (100%) patients in the entecavir arm. Six patients in the lamivudine arm had HBV DNA >20 IU/mL, occurring at a range of 12 to 96 weeks. Of these, four patients had HBV DNA of less than 100 IU/mL during rebound (three had undetectable HBV DNA after switching back to entecavir), and the remaining two patients had HBV DNA levels of 7,973 and 699 IU/mL. Three patients (12%) had evidence of drug-resistant mutations, of which two patients had rtM204I mutation and one patient had rtM204V mutation. One of these three patients had previous lamivudine exposure before entecavir treatment and one patient had questionable drug compliance.Sequential therapy using entecavir followed by lamivudine resulted in virological rebound in 24% of patients after 96 weeks. Prior optimal viral suppression with entecavir did not confer any significant advantage in patients who switched to lamivudine.
Energy expenditure and rib cage-abdominal motion in chronic obstructive pulmonary disease
Authors: JW Fitting, P Frascarolo, E Jequier, P Leuenberger
Journal: European Respiratory Journal (1989)

The resting energy expenditure (REE) was measured by indirect calorimetry in 10 patients with chronic obstructive pulmonary disease (COPD) in stable clinical state and in 10 normal subjects. In order to avoid artefactually increased values, REE was obtained from prolonged measurements in steady state using a ventilated hood, without facial apparatus. The REE of COPD patients was significantly increased to 117% of predicted basal metabolic rate and to 125% of the control group values. Rib cage and abdominal movements were measured in COPD patients by inductance plethysmography and expressed with three indices: rib cage contribution to tidal volume (RC/VT), variability in compartmental contribution to tidal volume (SD RC/VT), and maximal compartmental amplitude/tidal volume ratio (MCA/VT). No correlation was found between REE and any of the indices of rib cage and abdominal motion. We conclude that the REE is increased in patients with COPD in stable clinical state, but is not related to the degree of abnormal rib cage-abdominal motion.
Vitamin D Is Required for IFN-γ–Mediated Antimicrobial Activity of Human Macrophages
Authors: Mario Fabri, Steffen Stenger, Dong-Min Shin, Jae-Min Yuk, Philip T. Liu, Susan Realegeno, Hye-Mi Lee, Stephan R. Krutzik, Mirjam Schenk, Peter A. Sieling, Rosane Teles, Dennis Montoya, Shankar S. Iyer, Heiko Bruns, David M. Lewinsohn, Bruce W. Hollis, Martin Hewison, John S. Adams, Andreas Steinmeyer, Ulrich Zügel, Genhong Cheng, Eun-Kyeong Jo, Barry R. Bloom, Robert L. Modlin
Journal: Science Translational Medicine (2011)

Control of tuberculosis worldwide depends on our understanding of human immune mechanisms, which combat the infection. Acquired T cell responses are critical for host defense against microbial pathogens, yet the mechanisms by which they act in humans remain unclear. We report that T cells, by the release of interferon-γ (IFN-γ), induce autophagy, phagosomal maturation, the production of antimicrobial peptides such as cathelicidin, and antimicrobial activity against Mycobacterium tuberculosis in human macrophages via a vitamin D-dependent pathway. IFN-γ induced the antimicrobial pathway in human macrophages cultured in vitamin D-sufficient sera, but not in sera from African-Americans that have lower amounts of vitamin D and who are more susceptible to tuberculosis. In vitro supplementation of vitamin D-deficient serum with 25-hydroxyvitamin D3 restored IFN-γ-induced antimicrobial peptide expression, autophagy, phagosome-lysosome fusion, and antimicrobial activity. These results suggest a mechanism in which vitamin D is required for acquired immunity to overcome the ability of intracellular pathogens to evade macrophage-mediated antimicrobial responses. The present findings underscore the importance of adequate amounts of vitamin D in all human populations for sustaining both innate and acquired immunity against infection.
Acute Charcot foot
Authors: P. Baglioni, M. Malik, O. E. Okosieme
Journal: BMJ (2012)

A 38 year old man was referred by his general practitioner to our diabetes foot clinic with a swollen red foot (fig 1⇓).He had had type 1 diabetes for 25 years, complicated with retinopathy, peripheral neuropathy, and nephropathy, and was being worked up for dialysis following a failed pancreas-kidney transplant.The absence of pain together with preserved pulses and intact skin raised a suspicion of acute Charcot foot.A plain radiograph of the foot showed fractures through the necks of the first three metatarsals (fig 2⇓).We offloaded the foot in a total contact cast and advised the patient to limit weight bearing.Magnetic resonance imaging (MRI) subsequently confirmed neuroarthropathic changes of acute Charcot (fig 3⇓). What is acute Charcot foot?Charcot's neuroarthropathy is a destructive process of bone and joint, typically seen in a foot that has lost its protective sensory innervation.The classic description of this disabling condition by Jean-Martin Charcot in 1883 was in patients with tabes dorsalis, but nowadays most cases of Charcot foot occur as a complication of diabetes mellitus.The chronic stage of the disease is easily recognisable, but the acute phase can present a diagnostic challenge. 1In a recent series the diagnosis of acute Charcot foot was missed before specialist referral in 19 of 20 patients. 2In another report, referring clinicians failed to diagnose Charcot foot in 19 of 24 cases seen in a specialist diabetes foot clinic. 3 Why is acute Charcot foot missed?The acute phase of a Charcot foot may not be considered or may be mistaken for more common causes of leg or foot swelling, such as cellulitis, gout, deep venous thrombosis, or sprains. 2 The misdiagnosis of ankle sprain is particularly common if the patient recalls a history of trivial injury.Standard radiographs may show no abnormalities at this stage, contributing to delays in diagnosis. 3Practice PRACTICE Key points • Suspect acute Charcot foot in a patient with diabetes and neuropathy who presents with a swollen warm foot
Differential Toll-like receptor-dependent collagenase expression in chondrocytes
Authors: Q Zhang, W Hui, G J Litherland, M J Barter, R Davidson, C Darrah, S T Donell, I M Clark, T E Cawston, J H Robinson, A D Rowan, D A Young
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objectives:</h3> To characterise the catabolic response of osteoarthritic chondrocytes to Toll-like receptor (TLR) ligands. <h3>Methods:</h3> Induction of the collagenases, matrix metalloproteinase (MMP)1 and MMP13, by TLR ligands was assessed in chondrocytes by real-time reverse transcriptase (RT)-PCR. TLR signalling pathway activation and their involvement in collagenase induction were confirmed by immunoblotting and use of pathway inhibitors and siRNA. TLR expression was compared in the femoral head cartilage of normal controls and patients with osteoarthritis (OA) by real-time RT-PCR. <h3>Results:</h3> Ligands for TLR6/2 and TLR3 showed the greatest upregulation of MMP1 and MMP13 respectively, although all TLR ligands upregulated these MMPs. MMP1 and MMP13 induction by TLR3 and TLR1/2 or TLR6/2 ligands were dependent on Trif and MyD88, respectively. These inductions were dependent upon the nuclear factor (NF)κB pathway, but were differentially inhibited by various mitogen-activated protein kinase inhibitors, with MMP13 induction most reliant on the extracellular signal-regulated kinase pathway. In addition, ligands for TLR1/2 and TLR6/2, but not TLR3, induced significant collagenolysis in a cartilage resorption assay. Finally, TLR2 was significantly downregulated and TLR3 upregulated in OA, compared to normal, cartilage. <h3>Conclusions:</h3> Activation of chondrocyte TLRs leads to differential collagenase gene activation. Treatment of chondrocytes with TLR1/2 or TLR6/2 ligands resulted in collagen resorption. The modulated expression of chondrocyte TLR2 and TLR3 in OA cartilage, compared to normal, may reflect a response to repair cartilage or prevent further extracellular matrix destruction. These data suggest modulation of TLR-mediated signalling as a potential therapeutic strategy for the treatment of OA.
Reflections on the Rise in Asthma Morbidity and Mortality
Authors: A. Sonia Buist
Journal: JAMA (1990)

Morbidity and mortality for asthma appear to be on the increase in the United States and many other Western countries.<sup>1-7</sup>The prevalence of this common condition may also be increasing.<sup>8,9</sup>These trends are worrisome, because they come at a time when morbidity and mortality from many chronic diseases are decreasing, when we think we have a fairly sound understanding of the pathophysiology of asthma, and when we believe we have more effective drugs for its management. Asthma mortality rates declined in the United States and Canada from 1965 through 1978 and then started to rise again. From 1980 to 1987, total deaths from asthma in the United States increased from 2891 to 4360.3 This represents a 31% increase in the death rate, from 1.3/100 000 population to 1.7/100 000. The rate for females increased more rapidly than the rate for males, and death rates were generally higher for
Annexin V autoantibodies in rheumatoid arthritis.
Authors: M.I Rodríguez-García, J.A Fernández, A Rodríguez, M.P Fernández, C Gutierrez, J.C Torre-Alonso
Journal: Annals of the Rheumatic Diseases (1996)

To investigate the occurrence of anti-annexin V autoantibodies in sera of patients with rheumatoid arthritis to assess involvement with the disease and any relation to glucocorticoid treatment. Anti-annexin V antibodies were measured by an enzyme linked immunosorbent assay (ELISA) which used the purified human recombinant protein as antigen. Concentrations of anti-annexin V autoantibodies, predominantly of the IgG class, were significantly raised in sera from patients with rheumatoid arthritis compared to normal controls. This was not correlated with other indices of disease activity such as erythrocyte sedimentation rate or C reactive protein and was unrelated to glucocorticoid treatment. Extracellular annexin V provides an antigenic stimulus for autoantibody production and its in vivo expression is independent of glucocorticoid control. Such autoantibodies may have a detrimental role in the arthritic condition by interfering with putative functions of annexin V, including collagen type II binding, inhibition of phospholipase A2 activity, and Fc receptor activity.
Fibroblast growth enhancing activity of tumor necrosis factor and its relationship to other polypeptide growth factors.
Authors: J Vilcek, V J Palombella, D Henriksen-DeStefano, C Swenson, R Feinman, M Hirai, M Tsujimoto
Journal: The Journal of Experimental Medicine (1986)

Tumor necrosis factor (TNF) is a monocyte-derived protein cytotoxic or cytostatic for some tumor cell lines. Here we show that highly purified E. coli-derived recombinant human TNF stimulated the growth of human FS-4 diploid fibroblasts. Stimulation of cell growth was demonstrable at a TNF concentration of 10 pg/ml (3 X 10(-13) M). Maximal stimulation was attained at TNF concentrations of 10 ng/ml (3 X 10(-10) M) or higher. Growth-stimulatory activity of TNF was inhibited by an mAb neutralizing the cytotoxic activity of TNF. Growth stimulation was not inhibited by another mAb specific for TNF, lacking neutralizing activity for the cytotoxic activity of TNF. Growth stimulation by TNF was more marked and more sustained in the presence of greater than or equal to 10% FCS than in medium with less than or equal to 5% FCS. Addition of TNF to confluent FS-4 cultures also produced a marked stimulation of cell growth in the presence of fresh FCS, while a much less marked stimulation was seen in the absence of FCS. Stimulation of confluent cultures by TNF in serum-free medium was enhanced by insulin, suggesting that insulin or insulin-like growth factor(s) in the serum can act synergistically with TNF in producing growth stimulation. While the growth-stimulatory effects of TNF and insulin were synergistic, the actions of TNF and epidermal growth factor (EGF) were less than additive, suggesting that TNF and EGF may activate identical or similar pathways. We conclude that stimulation of cell growth is probably a physiological function of TNF, and that the cytotoxic and cytostatic actions of TNF may be the result of an anomalous growth signal transduction in neoplastic cells lacking the constraints of normal growth control mechanisms.