tbuckley/cabot-search huggingface dataset:
Phase II Clinical Trial of Interleukin-12 in Patients with Relapsed and Refractory Non-Hodgkin’s Lymphoma and Hodgkin’s Disease
Authors: Anas Younes, Barbara Pro, Michael J. Robertson, Ian W. Flinn, Jorge E. Romaguera, Fredrick Hagemeister, Nam H. Dang, Paolo Fiumara, Evelyne M. Loyer, Fernando F. Cabanillas, Peter W. McLaughlin, Maria Alma Rodriguez, Felipe Samaniego
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this study was to evaluate the clinical activity and toxicity of recombinant human Interleukin (IL)-12 in patients with relapsed and refractory non-Hodgkin’s lymphoma (NHL) or Hodgkin’s disease (HD). Experimental Design: Forty-two previously treated patients (32 patients with NHL and 10 patients with HD) were enrolled on the study. Patients were treated with either intravenous (n = 11) or subcutaneous (n = 31) administration of IL-12. The patients had received a median of three prior treatment regimens, and 16 patients had undergone prior autologous stem cell transplantation. Results: All patients were assessable for toxicity, and 39 of 42 (93%) patients were assessable for response. Six of 29 (21%) patients with NHL had a partial or complete response, whereas none of the 10 patients with HD responded. Furthermore, 15 patients had stable disease that lasted for up to 54 months. Progression-free survival in patients with indolent NHL, aggressive NHL, and HD was 6, 2, and 2.5 months, respectively. Treatment was well tolerated, and the most common toxicity was flu-like symptoms. Reversible grade 3 hepatic toxicity was observed in three patients requiring dose reduction. IL-12 therapy increased the median number of peripheral blood CD8 T lymphocytes from 423/μl to 576/μl (P = 0.0019). Furthermore, IL-12 therapy decreased serum vascular endothelial growth factor and basic fibroblast growth factor concentrations in 37% of the patients. Conclusions: The ability of recombinant human IL-12 therapy to increase the number of circulating CD8+ cells and induce clinical remissions in patients with relapsed NHL warrants further investigation of the drug.
Cancer Risk Management Practices of Noncarriers Within<i>BRCA1/2</i>Mutation–Positive Families in the Kathleen Cuningham Foundation Consortium for Research Into Familial Breast Cancer
Authors: Sarah-Jane Dawson, Melanie A. Price, Mark A. Jenkins, Joanne M. McKinley, Phyllis N. Butow, Sue-Anne McLachlan, Geoffrey J. Lindeman, Prue Weideman, Michael L. Friedlander, John L. Hopper, Kelly-Anne Phillips
Journal: Journal of Clinical Oncology (2007)

Women from BRCA mutation-positive families who do not carry the family-specific mutation are generally at average cancer risk and therefore do not require intensive risk management.Participants were female noncarriers from BRCA mutation-positive families who had responded to 3 yearly follow-up questionnaires and had chosen to either receive or not receive their genetic test result. In the former group, undertaking mammography younger than age 40 years or more than once every 2 years, clinical breast examination (CBE) more than yearly, breast self-examination (BSE) more than monthly, or any transvaginal ultrasound (TVU) or CA-125 was considered overscreening. Screening behaviors of women who did and did not know their genetic test result were compared. Logistic regression and nonparametric analyses were performed to identify demographic and psychosocial factors (respectively) associated with overscreening.Of 325 eligible women, 116 knew their mutation status and 209 did not. For the first group, proportions overscreening were mammography, 53%; CBE, 10%; BSE, 11%; TVU, 7%; and CA-125, 10%. There were no significant differences in screening behaviors between the groups. In those aware of their mutation status, parous women were more likely to overuse mammography (odds ratio [OR] = 4.4; 95% CI, 1.1 to 17; P = .03) and women with one or more first-degree relative with ovarian cancer (OC) were more likely to overuse OC screening (TVU: OR = 6.00; 95% CI, 1.0 to 35.1; P = .047, and CA-125: OR = 6.50; 95% CI, 1.49 to 28.4; P = .013).The reasons for overuse of screening (particularly mammography) by mutation noncarriers require additional elucidation given the potential for harm.
Rapid turnover of the AMP-adenosine metabolic cycle in the guinea pig heart.
Authors: K Kroll, U K Decking, K Dreikorn, J Schrader
Journal: Circulation Research (1993)

The intracellular flux rate through adenosine kinase (adenosine--&gt;AMP) in the well-oxygenated heart was investigated, and the relation of the AMP-adenosine metabolic cycle (AMP&lt;--&gt;adenosine) to transmethylation (S-adenosylhomocysteine [SAH]--&gt;adenosine) and coronary flow was determined. Adenosine kinase was blocked in isolated guinea pig hearts by infusion of iodotubercidin in the presence of the adenosine deaminase blocker erythro-9-(2-hydroxy-3-nonyl)adenine (5 mumol/L). Iodotubercidin (1 nmol/L to 4 mumol/L) caused graded increases in venous effluent concentrations of adenosine, from 8 +/- 3 to 145 +/- 32 nmol/L (mean +/- SEM, n = 3), and in coronary flow, which increased to maximal levels. Flow increases were completely abolished by adenosine deaminase (5 to 10 U/mL). Interstitial adenosine concentrations, estimated using a mathematical model, increased from 22 nmol/L during control conditions to 420 nmol/L during maximal vasodilation. The possibility that iodotubercidin caused increased venous adenosine by interfering with myocardial energy metabolism was ruled out in separate 31P nuclear magnetic resonance experiments. To estimate total normoxic myocardial production of adenosine (AMP--&gt;adenosine&lt;--SAH), the time course of coronary venous adenosine release was measured during maximal inhibition of adenosine kinase with 30 mumol/L iodotubercidin. Adenosine release increased more than 15-fold over baseline, reaching a new steady-state value of 3.4 +/- 0.3 nmol.min-1 x g-1 (n = 5) after 4 minutes. In parallel experiments, the relative roles of AMP hydrolysis and transmethylation (SAH hydrolysis) were determined, using adenosine dialdehyde (10 mumol/L) to block SAH hydrolase. In these experiments, adenosine release increased to similar levels of 3.4 +/- 0.5 nmol.min-1 x g-1 (n = 6) during inhibition of adenosine deaminase and adenosine kinase. It is concluded that (1) maximal increases in coronary flow are elicited by increases in interstitial adenosine concentration to approximately 400 nmol/L, (2) more than 90% of the adenosine produced in the heart is normally rephosphorylated to AMP without escaping into the venous effluent, (3) AMP hydrolysis is the dominant pathway for cardiac adenosine production under normoxic conditions, and (4) the high rate of adenosine salvage is due to rapid turnover of a metabolic cycle between AMP and adenosine. Rapid cycling may serve to amplify the relative importance of AMP hydrolysis over transmethylation in controlling cytosolic adenosine concentrations.
Diagnostic yield of alarm features in irritable bowel syndrome and functional dyspepsia
Authors: J Hammer
Journal: Gut (2004)

<b>Objective:</b> The diagnostic value of the addition of alarm symptoms in distinguishing functional from organic gastrointestinal disease remains uncertain. We aimed to establish the value of alarm features in differentiating between organic disease and irritable bowel syndrome (IBS) and functional dyspepsia (FD). <b>Methods:</b> A total of 568 consecutive patients (63% female; mean age 44.7 years) completed a detailed symptom questionnaire and then received a complete diagnostic workup, as required. Questionnaire data were collected prospectively and audited retrospectively; the treating physician was blinded to the results of the questionnaires. Patients were coded and allocated to the following diagnostic groups: IBS, FD, organic diseases of the upper gastrointestinal tract, or organic diseases of the lower gastrointestinal tract. Logistic regression was used to identify the best subset of symptoms that discriminated organic disease from functional illness. Separate models compared IBS (n = 214) with diseases of the lower gastrointestinal tract (n = 66), and FD (n = 70) with diseases of the upper gastrointestinal tract (n = 250). <b>Results:</b> Age (50 years at symptom onset: odds ratio (OR) 2.65 (95% confidence interval 1.4–5.0); p = 0.002) and blood on the toilet paper (OR 2.7 (1.4–5.1);p = 0.002) emerged as alarm features that discriminated IBS from lower gastrointestinal illness. A diagnosis of IBS was typically associated with female sex (OR2.5 (1.3–4.6); p = 0.004), pain on six or more occasions in the previous year (OR 5.0 (2.2–11.1); p&lt;0.001), pain that radiated outside of the abdomen (OR 2.9 (1.4–6.3); p = 0.006), and pain associated with looser bowel motions (OR 2.1 (1.1–4.2); p = 0.03). A model incorporating three Manning criteria and alarm features yielded a correct diagnosis of IBS in 96% and a correct diagnosis of organic disease in 52% of cases. Alarm features did not discriminate FD from upper gastrointestinal disease. Patients with FD were significantly more likely to report upper abdominal pain (OR 3.7 (1.7–8.3); p = 0.002) and significantly less likely to report aspirin use (OR 0.26 (0.1–0.6); p = 0.001). The predictive value of symptoms in diagnosing FD was only 17%. <b>Conclusions:</b> Symptoms plus alarm features have a high predictive value for diagnosing IBS but the predictive value for a diagnosis of FD remains poor. Current criteria for the diagnosis of IBS should incorporate relevant alarm features to improve the diagnostic yield.
Insulin Degludec/Insulin Aspart Administered Once Daily at Any Meal, With Insulin Aspart at Other Meals Versus a Standard Basal-Bolus Regimen in Patients With Type 1 Diabetes
Authors: Irl B. Hirsch, Bruce Bode, Jean-Pierre Courreges, Patrik Dykiel, Edward Franek, Kjeld Hermansen, Allen King, Henriette Mersebach, Melanie Davies
Journal: Diabetes Care (2012)

OBJECTIVE To evaluate efficacy and tolerability of a co-formulation of insulin degludec and insulin aspart (IDegAsp) with insulin aspart (IAsp) at other meals compared with basal-bolus therapy using insulin detemir (IDet) and IAsp. RESEARCH DESIGN AND METHODS Adults (n = 548) with type 1 diabetes (A1C 7.0–10.0%; BMI ≤35.0 kg/m2) were randomized 2:1 in a 26-week, multinational, parallel-group, treat-to-target trial to IDegAsp or IDet. IDegAsp was given with a meal, and IDet was given in the evening, with a second (breakfast) dose added if needed. RESULTS Non-inferiority for IDegAsp versus IDet was confirmed; A1C improved by 0.75% with IDegAsp and 0.70% with IDet to 7.6% in both groups (estimated treatment difference IDegAsp − IDet: –0.05% [95% CI –0.18 to 0.08]). There was no statistically significant difference between IDegAsp and IDet in the rates of severe hypoglycemia (0.33 and 0.42 episodes/patient-year, respectively) or overall confirmed (plasma glucose &amp;lt;3.1 mmol/L) hypoglycemia (39.17 and 44.34 episodes/patient-year, respectively). Nocturnal confirmed hypoglycemia rate was 37% lower with IDegAsp than IDet (3.71 vs. 5.72 episodes/patient-year, P &amp;lt; 0.05). Weight gain was 2.3 and 1.3 kg with IDegAsp and IDet, respectively (P &amp;lt; 0.05). Total insulin dose was 13% lower in the IDegAsp group (P &amp;lt; 0.0001). No treatment differences were detected in Health-Related Quality of Life, laboratory measurements, physical examination, vital signs, electrocardiograms, fundoscopy, or adverse events. CONCLUSIONS IDegAsp in basal-bolus therapy with IAsp at additional mealtimes improves overall glycemic control and was non-inferior to IDet, with a reduced risk of nocturnal hypoglycemia and fewer injections in comparison with IDet + IAsp basal-bolus therapy.
Tobacco-specific carcinogen NNK has an important role in lung cancer
Authors: L. Burke
Journal: Thorax (2010)

Lung cancer is the leading cause of mortality in industrialised countries and 85–90% of lung cancers are caused by cigarette smoking. DNA methyltransferase 1 (DNMT1), an enzyme that catalyses DNA methylation, is reported to be overexpressed in patients with lung and liver cancer who are smokers. The …
Characterization of Periplastidal Compartment–Targeting Signals in Chlorarachniophytes
Authors: Yoshihisa Hirakawa, Gillian H. Gile, Shuhei Ota, Patrick J. Keeling, Ken-ichiro Ishida
Journal: Molecular Biology and Evolution (2010)

Secondary plastids are acquired by the engulfment and retention of eukaryotic algae, which results in an additional surrounding membrane or pair of membranes relative to the more familiar primary plastids of land plants. In most cases, the endocytosed alga loses its eukaryotic genome as it becomes integrated, but in two algal groups, the cryptophytes and chlorarachniophytes, the secondary plastids retain a vestigial nucleus in the periplastidal compartment (PPC), the remnant eukaryotic cytoplasm between the inner and the outer membrane pairs. Many essential housekeeping genes are missing from these reduced genomes, suggesting that they are now encoded in the host nucleus and their products are targeted to the PPC. One such nucleus-encoded, PPC-targeted protein, the translation elongation factor like (EFL) was recently identified in chlorarachniophytes. It bears an N-terminal–targeting sequence comprising a signal peptide and a transit peptide–like sequence (TPL) similar to the plastid-targeted proteins of chlorarachniophytes as well as a hydrophilic C-terminal extension rich in lysine and aspartic acid. Here, we characterize the function of the N- and C-terminal extensions of PPC-targeted EFL in transformed chlorarachniophyte cells. Using green fluorescent protein as a reporter molecule, we demonstrate that several negatively charged amino acids within the TPL are essential for accurate targeting to the PPC. Our findings further reveal that the C-terminal extension functions as a PPC retention signal in combination with an N-terminal plastid-targeting peptide, which suggests that plastid and PPC proteins may be sorted in the PPC.
Expression of epidermal growth factor receptor and human papillomavirus E6/E7 proteins in cervical carcinoma cells
Authors: G. Hu, W. Liu, J. Mendelsohn, L. M. Ellis, R. Radinsky, M. Andreeff, A. B. Deisseroth
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: Epidermal growth factor receptor (EGF-R) proteins are highly expressed in many tumors, including those of the cervix. We have observed previously that the introduction of a transcription unit containing an antisense sequence for the E6/E7 genes of human papillomavirus (HPV) 18, along with a transcription unit containing a sense complementary DNA sequence for the wild-type retinoblastoma (Rb) gene, decreased the growth of human cervical carcinoma HeLa cells (HPV 18 positive) both in vitro and in vivo . To clarify the regulatory mechanisms by which this reduction in cell proliferation occurred, we studied the expression of EGF-R proteins in these cells. Methods: Western blot and northern blot techniques were used to measure EGF-R expression, and a pulse-chase immunoprecipitation assay was used to measure the stability of EGF-R protein in HeLa cells and HeLa cells that had been transfected with the antisense E6/E7 or sense Rb sequences. Cell proliferation was measured by use of a tetrazolium-based colorimetric assay for numbers of viable cells. Results: The introduction of sense Rb or antisense E6/E7 transcription units or a combination of these two transcription units into HeLa cells dramatically decreased the level of EGF-R proteins in these cells; EGF-R levels were not affected at the transcriptional level but at the post-transcriptional level. Addition of the anti-EGF-R-specific monoclonal antibody 225mAb to HeLa cells caused 53% (95% confidence interval = 44%-62%) growth inhibition. Conclusions: These results suggest that HeLa cervical carcinoma cells are dependent on EGF-R for proliferation and that changes in functional levels of the E6/E7 HPV proteins and endogenous Rb proteins may alter the growth rate of cervical cancer cell lines by reducing the stability of EGF-R at the post-transcriptional level.
Can tissue dielectric constant measurement aid in differentiating lymphoedema from lipoedema in women with swollen legs?
Authors: S. Birkballe, M.R. Jensen, S. Noerregaard, F. Gottrup, T. Karlsmark
Journal: British Journal of Dermatology (2013)

Journal Article Can tissue dielectric constant measurement aid in differentiating lymphoedema from lipoedema in women with swollen legs? Get access S. Birkballe, S. Birkballe Department of Dermatology and Copenhagen Wound Healing Centre Copenhagen Lymphoedema Centre Bispebjerg University Hospital Bispebjerg bakke 23 DK‐2400 Copenhagen NV Denmark Correspondence Susanne Birkballe. E‐mail: susannebirkballe@dadlnet.dk Search for other works by this author on: Oxford Academic Google Scholar M.R. Jensen, M.R. Jensen Department of Dermatology and Copenhagen Wound Healing Centre Copenhagen Lymphoedema Centre Bispebjerg University Hospital Bispebjerg bakke 23 DK‐2400 Copenhagen NV DenmarkDepartment of Clinical Physiology and Nuclear Medicine Bispebjerg University Hospital Bispebjerg bakke 23 DK‐2400 Copenhagen NV Denmark Search for other works by this author on: Oxford Academic Google Scholar S. Noerregaard, S. Noerregaard Department of Dermatology and Copenhagen Wound Healing Centre Copenhagen Lymphoedema Centre Bispebjerg University Hospital Bispebjerg bakke 23 DK‐2400 Copenhagen NV Denmark Search for other works by this author on: Oxford Academic Google Scholar F. Gottrup, F. Gottrup Department of Dermatology and Copenhagen Wound Healing Centre Copenhagen Lymphoedema Centre Bispebjerg University Hospital Bispebjerg bakke 23 DK‐2400 Copenhagen NV Denmark Search for other works by this author on: Oxford Academic Google Scholar T. Karlsmark T. Karlsmark Department of Dermatology and Copenhagen Wound Healing Centre Copenhagen Lymphoedema Centre Bispebjerg University Hospital Bispebjerg bakke 23 DK‐2400 Copenhagen NV Denmark Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 170, Issue 1, 1 January 2014, Pages 96–102, https://doi.org/10.1111/bjd.12589 Published: 01 January 2014
Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α
Authors: Matthew A Brooke, Hilary J Longhurst, Vincent Plagnol, Nicholas S Kirkby, Jane A Mitchell, Franz Rüschendorf, Timothy D Warner, David P Kelsell, Thomas T MacDonald
Journal: Gut (2012)

<h3>Objective</h3> Cryptogenic multifocal ulcerating stenosing enteritis (CMUSE) is an extremely rare, but devastating, disease of unknown aetiology. We investigated the genetic basis of this autosomal recessive condition in a pair of affected siblings who have 40-year histories of catastrophic gastrointestinal and extraintestinal disease. <h3>Design</h3> Genome-wide single-nucleotide polymorphism homozygosity mapping in the two affected family members combined with whole-exome sequencing of one affected sibling. This was followed by confirmatory Sanger sequencing of the likely disease-causing sequence variant and functional studies in affected and unaffected family members. <h3>Results</h3> Insertion/deletion variation analysis revealed the presence of a homozygous 4 bp deletion (g.155574_77delGTAA) in the <i>PLA2G4A</i> gene, located in the splice donor site directly after exon 17 (the penultimate exon) of the gene in both affected siblings. This introduces a frameshift of 10 amino acids before a premature stop codon (p.V707fsX10), which is predicted to result in the loss of 43 amino acids (residues 707–749) at the C-terminus of cytosolic phospholipase A2-α (cPLA<sub>2</sub>α). cPLA<sub>2</sub>α protein expression was undetectable in the gut of both siblings, with platelet aggregation and thromboxane A<sub>2</sub> production, as functional assays for cPLA<sub>2</sub>α activity, grossly impaired. <h3>Conclusions</h3> We have identified mutations in <i>PLA2G4A</i> as a cause of CMUSE in two affected siblings. Further studies are needed to determine if mutations in this gene are also responsible for disease of a similar phenotype in other cases.
Polymorphism in the 5′-Flanking Region of Human Glutamate-Cysteine Ligase Modifier Subunit Gene Is Associated With Myocardial Infarction
Authors: Shin-ichi Nakamura, Kiyotaka Kugiyama, Seigo Sugiyama, Shinji Miyamoto, Shun-ichi Koide, Hironobu Fukushima, Osamu Honda, Michihiro Yoshimura, Hisao Ogawa
Journal: Circulation (2002)

Background — Human glutamate-cysteine ligase (GCL) is a rate-limiting enzyme for the synthesis of glutathione that plays a crucial role in antioxidant defense mechanisms in most mammalian cells, including vascular cells. Oxidants transcriptionally upregulate GCL genes for glutathione synthesis, providing a protective mechanism against oxidative stress-induced cellular dysfunction. This study examined the hypothesis that variation in the GCL genes may be associated with coronary artery disease in which oxidative stress plays a pathogenetic role. Methods and Results — We searched for the common variants in the 5′-flanking region of the GCL modifier subunit (GCLM) gene in patients with myocardial infarction (MI). We found a polymorphism (−588C/T) in which the T allele showed lower promoter activity (40% to 50% of C allele) in response to oxidants in the luciferase reporter gene assay. Allele frequencies were determined by polymerase chain reaction-based analysis of restriction fragment length polymorphism in 429 patients with MI and 428 control subjects (as defined by angiography) in Kumamoto Prefecture, Japan. The frequency of the T polymorphism was significantly higher in the MI group than in the control group (CT and TT genotypes: 31.5% in MI group versus 19.2% in control group; P &lt;0.001). In multiple logistic regression analysis, the T polymorphism was a risk factor for MI independent of traditional coronary artery disease risk factors (odds ratio, 1.98; 95% confidence interval, 1.38 to 2.83; P &lt;0.001). Conclusions — These findings suggest that the −588T polymorphism of the GCLM gene may suppress GCLM gene induction in response to oxidants and that it is a genetic risk factor for MI.
The Pathology of Influenza Virus Infections
Authors: Jeffery K. Taubenberger, David M. Morens
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

Influenza viruses are significant human respiratory pathogens that cause both seasonal, endemic infections and periodic, unpredictable pandemics. The worst pandemic on record, in 1918, killed approximately 50 million people worldwide. Human infections caused by H5N1 highly pathogenic avian influenza viruses have raised concern about the emergence of another pandemic. The histopathology of fatal influenza virus pneumonias as documented over the past 120 years is reviewed here. Strikingly, the spectrum of pathologic changes described in the 1918 influenza pandemic is not significantly different from the histopathology observed in other less lethal pandemics or even in deaths occurring during seasonal influenza outbreaks.