tbuckley/cabot-search huggingface dataset:
<i>Helicobacter pylori </i>in vivo causes structural changes in the adherent gastric mucus layer but barrier thickness is not compromised
Authors: J L Newton, N Jordan, L Oliver, V Strugala, J Pearson, O F W James, A Allen
Journal: Gut (1998)

Background —It has been proposed that a pathogenic effect of Helicobacter pylori is a weakening of the protective mucus barrier; however, this remains controversial. Aims —To clarify the effects of H pylori infection on the mucus gel barrier in vivo. Methods —Mucus gel polymeric structure and the thickness of the adherent mucus barrier were measured in endoscopic biopsy samples in subjects with and without H pylori infection. Results —There was a significant 18% reduction in the proportion of polymeric gel forming mucin in the adherent mucus layer in H pylori positive compared with negative subjects. There was no change in the adherent mucus thickness between H pylori positive and negative subjects without gastric atrophy (mean (SD): 104 (26) μm, 106 (30) μm respectively). There was however a significant reduction in mucus thickness in those H pylori positive subjects with underlying gastric atrophy (84 (13) μm, p=0.03) compared with those without atrophy. Conclusions —A partial breakdown in gel forming structure of the gastric mucus barrier does occur in H pylori infection per se but this is insufficient to cause a collapse of the mucus barrier .
Variable Levels of Normal RNA in Different Fetal Organs Carrying a Cystic Fibrosis Transmembrane Conductance Regulator Splicing Mutation
Authors: ORNIT CHIBA-FALEK, RICHARD B. PARAD, EITAN KEREM, BATSHEVA KEREM
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Disease severity varies among cystic fibrosis (CF) patients carrying the same cystic fibrosis transmembrane conductance regulator (CFTR) genotype and among organs of the same individual. It has been shown that the class V splicing mutation 3849 + 10 kb C--> T produces both normal and aberrantly spliced CFTR transcripts. We analyzed the levels of normal CFTR messenger RNA (mRNA) in different organs of an aborted fetus carrying the 3849 + 10 kb C--> T mutation, and found that they correlated with the histopathologic changes observed in these organs. We performed semiquantitative nondifferential reverse transcription-polymerase chain reaction on several organs from a 22-wk aborted CF fetus carrying the 3849 + 10 kb C--> T mutation. A very low level (1%) of normal CFTR mRNA was detected in the severely affected ileum of this fetus. Higher levels were found in the histopathologically unaffected trachea (17%), colon (19%), and lung (26%). Thus, as early as in utero, the regulation of alternative splice-site selection is an important mechanism underlying variable CF severity. Understanding of the mechanisms regulating alternative splicing in different tissues will contribute to potential therapy for patients carrying splicing mutations in CF and other human disease genes.
Clostridium perfringens enterotoxin is a superantigen reactive with human T cell receptors V beta 6.9 and V beta 22.
Authors: P Bowness, P A Moss, H Tranter, J I Bell, A J McMichael
Journal: The Journal of Experimental Medicine (1992)

Candidate superantigens were screened for their ability to induce lysis of human histocompatibility leukocyte antigen class II-positive targets by human CD8+ influenza-specific cytotoxic T cell (CTL) lines. Clostridium perfringens enterotoxin (CPET) induced major histocompatibility complex unrestricted killing by some but not all CTL lines. Using "anchored" polymerase chain reactions, CPET was shown to selectively stimulate peripheral blood lymphocytes bearing T cell receptor V beta 6.9 and V beta 22 in five healthy donors. V beta 24, V beta 21, V beta 18, V beta 5, and V beta 6.1-5 appeared to be weakly stimulated. Antigen processing was not required for CPET to induce proliferation. Like the staphylococcal enterotoxins, CPET is a major cause of food poisoning. These data suggest that superantigenic and enterotoxigenic properties may be closely linked.
Positive Feedback Loop Between PI3K-Akt-mTORC1 Signaling and the Lipogenic Pathway Boosts Akt Signaling: Induction of the Lipogenic Pathway by a Melanoma Antigen
Authors: Yoshio Yamauchi, Keiko Furukawa, Kazunori Hamamura, Koichi Furukawa
Journal: Cancer Research (2011)

Abstract The lipogenic phenotype is a metabolic hallmark of cancer cells. Sterol regulatory element–binding proteins (SREBP) are key transcriptional factors to regulate biosynthesis of cholesterol and fatty acids. It has been poorly understood how the lipogenic phenotype in cancer cells is regulated and how it augments their malignant properties. Here we describe roles of the melanoma antigen ganglioside GD3 and phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR complex 1 (mTORC1) signaling in the regulation of SREBP activity, cholesterol biosynthesis, and the integrity of lipid rafts in human melanoma cells. GD3 expression induced the activation of both SREBP-1 and SREBP-2. Consequently, HMG-CoA reductase expression and cholesterol biosynthesis increased. The activation of the SREBP pathway was independent of the oncogenic BRAF mutation. On the other hand, it was regulated by PI3K-Akt-mTORC1 signaling in human melanoma cells. Disruption of the signaling pathway resulted in the reduction of cholesterol in lipid rafts. Inhibition of the SREBP pathway attenuated Akt activation in lipid rafts and suppressed the growth of human melanoma cells in vitro and in vivo. These results suggest that PI3K-Akt-mTORC1 signaling is important for the integrity of lipid rafts by regulating SREBP activation and subsequent cholesterogenesis. We thus propose a positive feedback circuit in which PI3K-Akt-mTORC1-SREBP signaling boosts Akt signaling in human melanoma cells expressing GD3. Cancer Res; 71(14); 4989–97. ©2011 AACR.
How important is a minimal difference?
Authors: T. Troosters
Journal: European Respiratory Journal (2011)

Clinical trials typically report the mean effect of interventions with an indication of the variability or 95% confidence interval signifying whether an intervention leads to statistically significant effects. A statistical difference does not necessarily inform clinicians or policymakers as to whether patients will perceive these effects as a benefit or whether the effect is of any clinical relevance. Identifying the difference that can be considered “important” is, therefore, important and can serve as a benchmark of what constitutes a meaningful effect of an intervention. The minimal effect that would be meaningful to patients is the minimally clinically important difference (MCID), the minimal difference that reflects a true improvement (or deterioration) in an outcome is the minimally important difference (MID). In an eloquent review paper in the European Respiratory Journal, Jones 1 elaborated on the different meanings these terms can have to patients and clinicians and the different ways the M(C)ID can be assessed.

Traditionally, M(C)IDs have been calculated for patient reported outcomes, such as quality of life or symptom scales. For the St George's Respiratory Questionnaire, the MCID was calculated to be 4 (95% CI 1.6–6.4) points 1 and 3.05 (95% CI 0.39–5.71) points 2 on a scale that ranges from 0 to 100. For the Chronic Respiratory Disease Questionnaire, the MCID was found to be a 0.5 (95% CI 0.3–0.7) point improvement on the average on a seven-point Likert scale.

In this issue of the European Respiratory Journal , Puhan et al. 3 elaborate on the MID for two physiological tests: the 6-min walk distance (6MWD) and the incremental cardiopulmonary exercise test. In this case the …
Recessive LAMC3 mutations cause malformations of occipital cortical development
Authors: Tanyeri Barak, Kenneth Y Kwan, Angeliki Louvi, Veysi Demirbilek, Serap Saygı, Beyhan Tüysüz, Murim Choi, Hüseyin Boyacı, Katja Doerschner, Ying Zhu, Hande Kaymakçalan, Saliha Yılmaz, Mehmet Bakırcıoğlu, Ahmet Okay Çağlayan, Ali Kemal Öztürk, Katsuhito Yasuno, William J Brunken, Ergin Atalar, Cengiz Yalçınkaya, Alp Dinçer, Richard A Bronen, Shrikant Mane, Tayfun Özçelik, Richard P Lifton, Nenad Šestan, Kaya Bilgüvar, Murat Günel
Journal: Nature Genetics (2011)
Impact of Timing of Initiation of Dialysis on Mortality
Authors: Srinivasan Beddhu, Matthew H. Samore, Mark S. Roberts, Gregory J. Stoddard, Nirupama Ramkumar, Lisa M. Pappas, Alfred K. Cheung
Journal: Journal of the American Society of Nephrology (2003)

Previous studies showed that sicker patients were initiated on dialysis at higher GFR as estimated by the Modification of Diet in Renal Disease (MDRD) formula. It was previously shown that patients with low creatinine production were malnourished and had low serum creatinine levels and creatinine clearances (CrCl) but high MDRD GFR at initiation of dialysis. Therefore, a propensity score approach was used to examine the associations of MDRD GFR and measured CrCl at the initiation of dialysis with subsequent mortality. Baseline data and outcomes were obtained from the Dialysis Morbidity Mortality Study Wave II. Propensity scores for early initiation derived by logistic regression were used in Cox models to examine mortality. Each 5-ml/min increase in MDRD GFR at initiation of dialysis in the entire cohort was associated with increased hazard of death in multivariable Cox model (hazard ratio [HR] 1.14; P = 0.002). In the subgroup of patients with reported CrCl, higher MDRD GFR was associated with increased risk of death (for each 5-ml/min increase, HR 1.27; P < 0.001) but not CrCl (for each 5-ml/min increase, HR 0.98; P = 0.81). These divergent results might reflect erroneous GFR estimation by the MDRD formula. Furthermore, these data do not support earlier initiation of dialysis. Therefore, for patients without clinical indications for initiation of dialysis, the appropriate GFR level for initiation of dialysis is unknown.
Prognostic Significance of Activated Akt Expression in Pancreatic Ductal Adenocarcinoma
Authors: Shinji Yamamoto, Yasuhiko Tomita, Yoshihiko Hoshida, Takaya Morooka, Hiroaki Nagano, Keizo Dono, Koji Umeshita, Masato Sakon, Osamu Ishikawa, Hiroaki Ohigashi, Shoji Nakamori, Morito Monden, Katsuyuki Aozasa
Journal: Clinical Cancer Research (2004)

Akt is a serine/threonine kinase that plays a central role in tumorigenesis. Among the members of Akt family, Akt2 is associated with the development of human cancers. The present study was designed to clarify the prognostic significance of Akt2 and activated Akt expression in pancreatic ductal adenocarcinoma (PDAC). In addition, activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) and the proliferation activity of tumor cells detected by Ki-67 immunohistochemistry were examined.Immunohistochemical analysis was performed on paraffin-embedded specimens from 65 patients with PDAC; 36 males and 29 females with ages ranging from 48 to 79 years (median, 66 years) of age. Expression levels of Akt2, phosphorylated Akt (p-Akt), and phosphorylated ERK 1/2 (p-ERK 1/2) were categorized as either weaker (low intensity) or equal to stronger (high intensity) compared with those in the endothelial cells of the same specimens. For Ki-67 immunohistochemistry, cases were divided into two groups: level 1, Ki-67 labeling index (LI), <20%; level 2, Ki-67 LI, > or = 20%.Twenty-six (42.6%), 28 (45.9%), 39 (63.9%), and 46 (75.4%) of the tumors showed high intensity of Akt2, p-Akt, and p-ERK 1/2 expression, and Ki-67 LI level 2, respectively. A significant positive correlation was observed between Akt2 and p-Akt expression (P < 0.01). Multivariate analysis revealed that p-Akt expression, Ki-67 LI, and histological differentiation are independent prognosticators for PDAC.p-Akt expression is a significant prognostic indicator for PDAC. Inhibition of Akt is a possible molecular approach for treatment of PDAC.
EGFR mutations in patients with brain metastases from lung cancer: Association with the efficacy of gefitinib
Authors: Shinji Shimato, Tetsuya Mitsudomi, Takayuki Kosaka, Yasushi Yatabe, Toshihiko Wakabayashi, Masaaki Mizuno, Norimoto Nakahara, Hisashi Hatano, Atsushi Natsume, Dai Ishii, Jun Yoshida
Journal: Neuro-Oncology (2006)

Gefitinib—a specific inhibitor of epidermal growth factor receptor (EGFR)-associated tyrosine kinase—has demonstrated efficacy in a subgroup of patients with non-small-cell lung carcinoma (NSCLC) who fail conventional chemotherapy. It is also reported to have an antitumor effect in brain metastases from NSCLC. Additionally, EGFR mutations have shown a strong association with gefitinib sensitivity for NSCLC. Here, we assessed the efficacy of gefitinib in brain metastases from NSCLC and evaluated the association of this efficacy with EGFR mutations. We retrospectively reviewed eight cases in which patients were suffering from brain metastases before the initiation of gefitinib treatment. Brain tumor response could be evaluated by MRI in these patients; EGFR gene analyses were also available. We evaluated whether objective tumor response was observed after gefitinib treatment and assessed the efficacy of gefitinib as effective, noneffective, or not assessable in consideration of the influence of previous radiotherapy. Of the eight patients, the efficacy of gefitinib was assessed as effective in three and as noneffective in three. All three patients demonstrating effective efficacy had EGFR mutations in the tyrosine kinase domain (deletion mutation in two patients and point mutation in one patients), whereas none of the three patients demonstrating noneffective efficacy had EGFR mutations. Gefitinib appears to be effective in treating brain metastases in a subgroup of patients. Our data suggested a possible association between the efficacy of gefitinib in the treatment of brain metastases and EGFR mutations.
Is vitamin D (Vit D) a marker of severity of recurrent wheezing/asthma in infants?
Authors: Marilyn Urrutia Pereira, Jennifer B.G. Avila, Dirceu Solé
Journal: European Respiratory Journal (2013)

Background : Vit D low serum levels have been linked to respiratory diseases including recurrent wheezing and asthma. We evaluate the impact of Vit D in recurrent wheezy (RW) children followed in the Pediatric Program for Prevention of Asthma (PIPA) in the city of Uruguaiana, Brazil

Methods : Parents/caregivers of RW children (3 or > episodes;3-47 months old) referred to PIPA project had a written validate questionnaire filled in (International Study of Wheezing in Infants) and a blood sample collected for the determination of serum level of Vit D (Electro-chemiluminescence; normal = 30 ng/ml). According to Vit D they were split into: N1 (≥30ng/ml, N=124) and D2 (<30ng/ml, N=98).

Results : Vit D mean serum level for N1 (42.7ng/ml) were significantly higher than D2 (22.9ng/ml). Except for current weight (12.5±4.5 x 11.6±3.5), the two groups were similar regarding: current age (months) (20.4±12.9 x 22.9±13.8), current height (cm) (83.6±16.7 x 81.2±12.3), age at first episode (months) (4.7±3.9 x 4.7±3.8), nightime awakenings/week (22.2% vs. 22.5%; Odds Ratio (OR): 1.01 (95%CI:0.61-1.69), emergency room visits (67.5% vs. 67.8%; OR:0.99 (95%CI:0,82-1.21), hospitalization for severe wheeze (18.8% vs. 19.0%, OR:0.98 (95%CI:0.56-1.74), physician-diagnosed asthma (28.2% vs. 38.2%, OR:0.74 (95%CI:0.50-1.09), hospitalization for pneumonia (17.2% vs. 12.5% ; OR:1.38 (95%CI:0.71-2.66) for N1 x D2, respectively.

Conclusions : Although there was a trend toward more severity among patients with lower levels of Vit D this difference was not significant. Long-term studies are necessary for more reliable conclusions about the role of Vit D in these patients.
Hydrocortisone Infusion for Severe Community-acquired Pneumonia
Authors: Marco Confalonieri, Rosario Urbino, Alfredo Potena, Marco Piattella, Piercarlo Parigi, Giacomo Puccio, Rossana Della Porta, Carbone Giorgio, Francesco Blasi, Reba Umberger, G. Umberto Meduri
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

We hypothesize that hydrocortisone infusion in severe community-acquired pneumonia attenuates systemic inflammation and leads to earlier resolution of pneumonia and a reduction in sepsis-related complications. In a multicenter trial, patients admitted to the Intensive Care Unit (ICU) with severe community-acquired pneumonia received protocol-guided antibiotic treatment and were randomly assigned to hydrocortisone infusion or placebo. Hydrocortisone was given as an intravenous 200-mg bolus followed by infusion at a rate of 10 mg/hour for 7 days. Primary end-points of the study were improvement in PaO2:FIO2 (PaO2:FIO2 > 300 or ⩾ 100 increase from study entry) and multiple organ dysfunction syndrome (MODS) score by Study Day 8 and reduction in delayed septic shock. Forty-six patients entered the study. At study entry, the hydrocortisone group had lower PaO2:FIO2, and higher chest radiograph score and C-reactive protein level. By Study Day 8, treated patients had, compared with control subjects, a significant improvement in PaO2:FIO2 (p = 0.002) and chest radiograph score (p < 0.0001), and a significant reduction in C-reactive protein levels (p = 0.01), MODS score (p = 0.003), and delayed septic shock (p = 0.001). Hydrocortisone treatment was associated with a significant reduction in length of hospital stay (p = 0.03) and mortality (p = 0.009).
Antileukemic Activity of Lysophosphatidic Acid Acyltransferase-β Inhibitor CT32228 in Chronic Myelogenous Leukemia Sensitive and Resistant to Imatinib
Authors: Paul La Rosée, Taiping Jia, Shadmer Demehri, Nicolai Härtel, Peter de Vries, Lynn Bonham, David Hollenback, Jack W. Singer, Junia V. Melo, Brian J. Druker, Michael W. Deininger
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Lysophosphatidic acid acyltransferase (LPAAT)-β catalyzes the conversion of lysophosphatidic acid to phosphatidic acid, an essential component of several signaling pathways, including the Ras/mitogen-activated protein kinase pathway. Inhibition of LPAAT-β induces growth arrest and apoptosis in cancer cell lines, implicating LPAAT-β as a potential drug target in neoplasia. Experimental Design: In this study, we investigated the effects of CT32228, a specific LPAAT-β inhibitor, on BCR-ABL-transformed cell lines and primary cells from patients with chronic myelogenous leukemia. Results: CT32228 had antiproliferative activity against BCR-ABL-positive cell lines in the nanomolar dose range, evidenced by cell cycle arrest in G2-M and induction of apoptosis. Treatment of K562 cells with CT32228 led to inhibition of extracellular signal-regulated kinase 1/2 phosphorylation, consistent with inhibition of mitogen-activated protein kinase signaling. Importantly, CT32228 was highly active in cell lines resistant to the Bcr-Abl kinase inhibitor imatinib. Combination of CT32228 with imatinib produced additive inhibition of proliferation in cell lines with residual sensitivity toward imatinib. In short-term cultures in the absence of growth factors, CT32228 preferentially inhibited the growth of granulocyte-macrophage colony-forming units from chronic myelogenous leukemia patients compared with healthy controls. Conclusion: These data establish LPAAT-β as a potential drug target for the treatment of BCR-ABL-positive leukemias.
Systems Approach to Neurodegenerative Disease Biomarker Discovery
Authors: Christopher Lausted, Inyoul Lee, Yong Zhou, Shizhen Qin, Jaeyun Sung, Nathan D. Price, Leroy Hood, Kai Wang
Journal: The Annual Review of Pharmacology and Toxicology (2013)

Biomarkers are essential for performing early diagnosis, monitoring neurodegenerative disease progression, gauging responses to therapies, and stratifying neurodegenerative diseases into their different subtypes. A wide range of molecular markers are under investigation in tissues and biofluids as well as through imaging; moreover, many are prominent proteins present in cerebrospinal fluid. However, in more frequently and easily collected fluids such as plasma, these proteins show only a modest correlation with disease and thus lack the necessary sensitivity or specificity for clinical use. High-throughput and quantitative proteomic technologies and systems-driven approaches to biofluid analysis are now being utilized in the search for better biomarkers. Biomarker discovery involves many critical steps including study design, sample preparation, protein and peptide separation and identification, and bioinformatics and data integration issues that must be carefully controlled before independent confirmation and validation. In this review, we summarize current proteomic and nucleic acid technologies involved in the discovery of biomarkers of neurodegenerative diseases, particularly Alzheimer's, Parkinson's, Huntington's, and prion diseases.
Nontraumatic chylothorax and previous cancer: a role for positron emission tomography?
Authors: A. Garcia-Zamalloa
Journal: European Respiratory Journal (2005)

tomography scan revealed bilateral multiple cystic lesions with thin smooth walls of varying sizes.However, the male sex prompted us to exclude a more sinister cause for the lesions [2], and upon further questioning the patient had complained of right thigh pain for several weeks.Examination revealed a fixed soft tissue mass in the mid-thigh.Histology from the thigh mass biopsy and bilateral video-assisted thoracic surgery bullectomy [3] confirmed pulmonary epithelioid sarcoma metastases.Subsequent investigations showed no other organ was involved.The pulmonary lesions progressed over a 5-yr period, eventually leading to respiratory failure.Pulmonary cysts as the sole metastatic manifestation of sarcomas are rare, with ,20 cases reported [4].The cysts are usually thin walled, without debris and slow growing (fig.1).Typically, the cystic lesions are not evident on chest radiographs, but are well visualised on computed tomography scans, where they may mimic benign bullous disease.The diagnosis may not be established until patients present with pneumothorax necessitating surgical intervention and biopsy [3,5].Clinicians should be aware of this important differential diagnosis of bilateral pulmonary cystic lesions, and exclude metastatic sarcoma in the assessment of their patients.
Are Older Cancer Patients Being Referred to Oncologists? A Mail Questionnaire of Ontario Primary Care Practitioners to Evaluate Their Referral Patterns
Authors: Carol A. Townsley, Kendra Naidoo, Gregory R. Pond, Wendy Melnick, Sharon E. Straus, Lillian L. Siu
Journal: Journal of Clinical Oncology (2003)

Purpose: Understanding why older patients are frequently underrepresented in cancer services use and clinical research may help to increase their participation in clinical trials and eventually result in better cancer care for this vulnerable population. Methods: To identify potential barriers that may prevent older cancer patients from being referred from a primary care physician (PCP) to an oncology specialist, a self-administered questionnaire was mailed to 9,312 PCPs throughout Ontario. Results: With a one-time mailing, 2,240 questionnaires were returned (response rate, 24%) of which 2,089 (93%) were assessable. Although 86% of respondents would refer most older patients with early-stage, potentially curable cancers to oncologists, only 65% would refer those with advanced-stage, potentially incurable cancers. The factors that most influence referral decisions of PCPs are patient’s desire to be referred (69%), type (54%) and stage (49%) of cancer, and severity of cancer symptoms (49%). Other factors including age do not seem to influence the referral decision. Approximately 9% of respondents found it difficult to refer older cancer patients to oncology specialists, with the most commonly cited barriers being the length of waiting lists, mandatory tissue diagnosis before referral, and the belief that oncologists seldom relate to PCPs. Conclusion: Most PCPs stated that they would refer all elderly patients with cancer to oncologists and that referral decisions were based mainly on patients’ wishes. Continued efforts are needed to overcome barriers in the referral process and to understand the perspectives of elderly patients to enhance their cancer care.