tbuckley/cabot-search huggingface dataset:
Polymorphism of the human C3b/C4b receptor. Identification of a third allele and analysis of receptor phenotypes in families and patients with systemic lupus erythematosus.
Authors: T R Dykman, J A Hatch, J P Atkinson
Journal: The Journal of Experimental Medicine (1984)

We have isolated C3bR from surface-labeled erythrocytes of 180 normal individuals and 45 patients with SLE. These studies have identified a previously unrecognized C3bR molecule on E with a Mr of approximately 160,000 daltons on nonreduced SDS-polyacrylamide gels. A similar receptor phenotype is also found on other C3bR-bearing peripheral blood leukocytes. Family studies demonstrate that this approximately 160,000-dalton molecule represents a third allele that is inherited in a codominant fashion at the same locus as the two previously described C3bR alleles. In unrelated normal donors a common allele (A) determines an approximately 190,000-dalton C3bR (gene frequency 0.83), a second allele (B) determines an approximately 220,000-dalton C3bR (gene frequency = 0.16), and a third rare allele (C) determines an approximately 160,000-dalton C3bR (gene frequency = 0.01). There were no major differences in gene frequencies among Caucasians and blacks or normal individuals and patients with SLE. However, compared with normal individuals, heterozygous C3bR-AC patients with SLE express large amounts of the approximately 160,000-dalton C3bR on E. Expression of C3bR molecules among heterozygous siblings is similar, suggesting that an inherited factor controls expression of the two molecules in heterozygous donors. These observations constitute an instructive example of a structural polymorphism of an integral membrane glycoprotein and provide a structural and genetic basis for further molecular and functional analyses of C3bR in normal and patient populations.
Epithelial Cell Adhesion Molecule (KSA) Expression
Authors: David B. Seligson, Allan J. Pantuck, Xueli Liu, Yunda Huang, Steven Horvath, Matthew H. T. Bui, Ken-ryu Han, Adrian J. L. Correa, Mervi Eeva, Sheila Tze, Arie S. Belldegrun, Robert A. Figlin
Journal: Clinical Cancer Research (2004)

Epithelial cell adhesion molecule (EpCAM) is a widely expressed adhesion molecule in epithelial cancers. The purpose of this study is to determine the protein expression patterns of EpCAM in renal cell carcinoma (RCC) using tissue arrays linked to a clinicopathological database to evaluate both its predictive power in patient stratification and its suitability as a potential target for immunotherapeutic treatment strategies.The University of California, Los Angeles kidney cancer tissue microarray contains specimens from 417 patients treated with nephrectomy. EpCAM protein expression in tumors and matched morphologically normal renal tissues was evaluated using anti-EpCAM immunohistochemistry. The resultant expression reactivity was correlated with clinicopathological variables.EpCAM is consistently expressed in the distal nephron on normal renal epithelium. Clear cell RCCs show minimal and infrequent EpCAM expression, whereas chromophobe and collecting duct RCCs both demonstrate intense and frequent expression. Of 318 clear cell carcinomas used in the analysis, 10% were EpCAM positive in > or = 50% of cells, and 8% of patients would be considered candidates for EpCAM-based therapy, based on high expression [> or = moderate intensity and frequent (> or = 50%) expression] and the need for systemic treatment. EpCAM expression was an independent prognostic factor for improved disease-specific survival, with a multivariate hazard ratio of 0.63 (P = 0.017; 95% confidence interval, 0.43-0.92).EpCAM is a novel prognostic molecular marker in RCC patients, and its positive expression is an independent predictor associated with improved survival. However, high expression in morphologically normal renal tissues and minimal or absent expression in clear cell carcinomas will likely limit the utility of this epithelial marker in targeted treatments of this most common RCC type.
Colorectal Cancer Mortality in Two Areas of Tuscany With Different Screening Exposures
Authors: Adele Seniori Costantini, Andrea Martini, Donella Puliti, Stefano Ciatto, Guido Castiglione, Grazia Grazzini, Marco Zappa
Journal: JNCI Journal of the National Cancer Institute (2008)

Several randomized trials have demonstrated the efficacy of colorectal cancer screening by the fecal occult blood test in reducing colorectal cancer mortality, but an evaluation of population-based screening programs is still lacking. We compared the colorectal cancer mortality rates (both adjusted rates and 3-year moving average rates) during 1985-2006 for two geographic areas in the provinces of Florence and Prato in the Tuscany region of Italy that began active population-based screening for colorectal cancer at different times: the Empolese-Mugello district, in the early 1980s, and the rest of the Florence and Prato provinces, in early 2000. A log-linear Poisson model was used to estimate the annual percent change in mortality and to examine whether geographic area modified the effect of calendar year on it. The Empolese-Mugello district had a greater decrease in colorectal cancer mortality than the rest of the Florence and Prato provinces (estimated annual percent change in age-adjusted colorectal cancer mortality rate, 2.7% decrease per year [95% confidence interval {CI} = 1.7% to 3.7%] vs 1.3% decrease per year [95% CI = 0.8% to 1.7%], respectively). The interaction between calendar period and area was statistically significant (P < .001). Our results support the hypothesis that the implementation of colorectal cancer screening in the early 1980s in the Empolese-Mugello district, where approximately 17 500 people were tested each year with the fecal occult blood test, was associated with a larger reduction in colorectal cancer mortality than that observed in the rest of Florence and Prato provinces, where screening started 15-20 years later and where approximately 38 000 people were screened each year beginning in 2000.
Ser392 Phosphorylation Regulates the Oncogenic Function of Mutant p53
Authors: Damian B. S. Yap, Jung-Kuang Hsieh, Shan Zhong, Vicky Heath, Barry Gusterson, Tim Crook, Xin Lu
Journal: Cancer Research (2004)

Abstract Despite the wealth of information on the regulation of wild-type p53 function by phosphorylation, nothing is known about the biological effect of phosphorylation on mutant p53. Here we show that p53H175 is phosphorylated like wild-type p53 in cells of the same background. Ser392 nonphosphorylatable p53 mutants p53H175A392 and p53W248A392 more potently transformed rat embryo fibroblasts in cooperation with the ras oncogene than p53H175S392 and p53W248S392. p53H175A392 also had an enhanced ability to confer cellular resistance to the cytotoxic effect of cisplatin and UV radiation. This correlated with p53H175A392 being a more potent dominant negative mutant than p53H175 in inhibiting the apoptotic functions of wild-type p53. Moreover, p53H175E392, which mimics the phosphorylated form of p53H175, was less able to confer cellular resistance to DNA-damaging agents. p53H175 and p53W248 are phosphorylated like wild-type p53 in cells of the same background. Ser392 nonphosphorylated p53 was present in human breast tumors expressing mutant p53 including p53H175. Together, these results demonstrated a novel function of Ser392 phosphorylation in regulating the oncogenic function of mutant p53.
Epstein-Barr virus-encoded EBNA1 inhibits the canonical NF-κB pathway in carcinoma cells by inhibiting IKK phosphorylation
Authors: Robert Valentine, Christopher W Dawson, Chunfang Hu, Khilan M Shah, Thomas J Owen, Kathryn L Date, Sonia P Maia, Jianyong Shao, John R Arrand, Lawrence S Young, John D O'Neil
Journal: Molecular Cancer (2010)

Abstract Background The Epstein-Barr virus (EBV)-encoded EBNA1 protein is expressed in all EBV-associated tumours, including undifferentiated nasopharyngeal carcinoma (NPC), where it is indispensable for viral replication, genome maintenance and viral gene expression. EBNA1's transcription factor-like functions also extend to influencing the expression of cellular genes involved in pathways commonly dysregulated during oncogenesis, including elevation of AP-1 activity in NPC cell lines resulting in enhancement of angiogenesis in vitro . In this study we sought to extend these observations by examining the role of EBNA1 upon another pathway commonly deregulated during carcinogenesis; namely NF-κB. Results In this report we demonstrate that EBNA1 inhibits the canonical NF-κB pathway in carcinoma lines by inhibiting the phosphorylation of IKKα/β. In agreement with this observation we find a reduction in the phosphorylation of IκBα and reduced phosphorylation and nuclear translocation of p65, resulting in a reduction in the amount of p65 in nuclear NF-κB complexes. Similar effects were also found in carcinoma lines infected with recombinant EBV and in the EBV-positive NPC-derived cell line C666-1. Inhibition of NF-κB was dependent upon regions of EBNA1 essential for gene transactivation whilst the interaction with the deubiquitinating enzyme, USP7, was entirely dispensable. Furthermore, in agreement with EBNA1 inhibiting p65 NF-κB we demonstrate that p65 was exclusively cytoplasmic in 11 out of 11 NPC tumours studied. Conclusions Inhibition of p65 NF-κB in murine and human epidermis results in tissue hyperplasia and the development of squamous cell carcinoma. In line with this, p65 knockout fibroblasts have a transformed phenotype. Inhibition of p65 NF-κB by EBNA1 may therefore contribute to the development of NPC by inducing tissue hyperplasia. Furthermore, inhibition of NF-κB is employed by viruses as an immune evasion strategy which is also closely linked to oncogenesis during persistent viral infection. Our findings therefore further implicate EBNA1 in playing an important role in the pathogenesis of NPC.
The role of heat shock proteins in gastrointestinal diseases
Authors: V Dudeja, S M Vickers, A K Saluja
Journal: Gut (2009)

Heat shock proteins (HSPs) are a highly conserved family of proteins which inhabit almost all subcellular locations and cellular membranes. Depending on their location, these proteins perform a variety of chaperoning functions including folding of newly synthesised polypeptides. HSPs also play a major role in the protection of cells against stressful and injury-inciting stimuli. By virtue of this protective function, HSPs have been shown to prevent acinar cell injury in acute pancreatitis. Also, the levels of HSPs have been shown to be markedly elevated in various forms of cancers when compared with non-transformed cells. Further, inhibition of HSPs has been shown to induce apoptotic cell death in cancer cells suggesting that inhibition of HSPs has a potential to emerge as novel anti-cancer therapy, either as monotherapy or in combination with other chemotherapeutic agents. Several studies have suggested that HSPs can interact with and inhibit both intrinsic and extrinsic pathways of apoptosis at multiple sites. Besides the anti-apoptotic role of HSPs, recent studies suggest that they play a role in the generation of anti-cancer immunity, and attempts have been made to utilise this property of HSPs in the generation of anti-cancer vaccines. The anti-apoptotic function and mechanism of various subtypes of HSPs as well as the current status of anti-HSP therapy are discussed in this review.
How does a combined preoperative and postoperative rehabilitation programme influence the outcome of ACL reconstruction 2 years after surgery? A comparison between patients in the Delaware-Oslo ACL Cohort and the Norwegian National Knee Ligament Registry
Authors: H Grindem, L P Granan, M A Risberg, L Engebretsen, L Snyder-Mackler, I Eitzen
Journal: British Journal of Sports Medicine (2014)

Background Preoperative knee function is associated with successful postoperative outcome after anterior cruciate ligament reconstruction (ACLR). However, there are few longer term studies of patients who underwent progressive preoperative and postoperative rehabilitation compared to usual care. Objectives To compare preoperative and 2 year postoperative patient-reported outcomes (PROs) in patients undergoing progressive preoperative and postoperative rehabilitation at a sports medicine clinic compared with usual care. Methods We included patients aged 16–40 years undergoing primary unilateral ACLR. The preoperative and 2 year postoperative Knee Injury and Osteoarthritis Outcome Score (KOOS) of 84 patients undergoing progressive preoperative and postoperative rehabilitation at a sports medicine clinic (Norwegian Research Center for Active Rehabilitation (NAR) cohort) were compared with the scores of 2690 patients from the Norwegian National Knee Ligament Registry (NKLR). The analyses were adjusted for sex, age, months from injury to surgery and cartilage/meniscus injury at ACLR. Results The NAR cohort had significantly better preoperative KOOS in all subscales, with clinically relevant differences (&gt;10 points) observed in KOOS Pain, activities of daily living (ADL), Sports and Quality of Life. At 2 years, the NAR cohort still had significantly better KOOS with clinically relevant differences in KOOS Symptoms, Sports and Quality of Life. At 2 years, 85.7–94% of the patients in the NAR cohort scored within the normative range of the different KOOS subscales, compared to 51.4–75.8% of the patients in the NKLR. Conclusions Patients in a prospective cohort who underwent progressive preoperative and postoperative rehabilitation at a sports medicine clinic showed superior patient-reported outcomes both preoperatively and 2 years postoperatively compared to patients in the NKLR who received usual care.
A Case of Rupture of the Intrathoracic Portion of the Trachea
Authors: B. J. Bickford, P. W. Robertson
Journal: Thorax (1958)

Rupture of the trachea or a large bronchus is a recognized though rare result of severe crush injuries of the chest, especially in children and young adults.Because of the rarity of reports of successful emergency surgical treatment, we present a further example of such an injury.CASE REPORT On May 13, 1956, in Western Germany, a road accident occurred in which a private car came into collision with the trailer of a lorry.The car was extensively damaged and the driver, a British soldier, was flung violently on to the steering wheel.Though dazed, he was not unconscious and was able to extricate himself from the wreckage.When admitted to hospital he was complaining of pain in the chest and he had coughed up a little blood.He had minor abrasions of the face and else- where; otherwise the chief finding was extensive bruising over the right upper chest anteriorly.Within a few hours swelling of the face and neck developed, with cyanosis of the extremities.The earliest chest radiograph (Fig. 1) showed no damage to the thoracic cage and no pneumothorax, but emphysema of the chest wall and mediastinum was obvious.Over the next three days the subcutaneous emphysema in- creased progressively and alarmingly.He was first seen by one of us (P.W. R.) on May 17, four days after the accident.At this time the emphysema was widespread.The eyes were completely closed and could not be opened, and the lips were forced apart and could not be closed.The whole body, even to the finger-tips and toes, was tensely inflated and tympanitic to percussion.The patient, who weighed 16 st.and was 6 ft. 4 in.tall (Fig. 2), resembled the man in the well-known motor-tyre advertisement.Bronchoscopy (Squadron-Leader D. G. Jones) was difficult, because the tension in the tissues of face and neck made manipulation almost impossible, but a mucosal laceration in the lower trachea was seen, though its exact extent could not be determined.A diagnosis of rupture of the lower end of the trachea was made, and it was clear that only early surgical repair could save the patient's life.He was transferred to an R.A.F.hospital, and with the .r FIG.1.-Postero-anterior radiograph of the chest on admission showing gross modiastinal and subcutaneous emphysema.FIG.2.-Appearance of the patient on admission showing gross subcutaneous emphysema.
Prediction of clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay
Authors: Marlyn J. Mayo, Julie Parkes, Beverley Adams-Huet, Burton Combes, A. S. Mills, Rodney S. Markin, Raphael Rubin, Donald Wheeler, Melissa Contos, A. B. West, Sandra Saldana, Yonas Getachew, Robert Butsch, Velimir Luketic, Marion Peters, Adrian Di Bisceglie, Nathan Bass, John Lake, Thomas Boyer, Enrique Martinez, James Boyer, Guadalupe Garcia-Tsao, David Barnes, William M. Rosenberg
Journal: Hepatology (2008)

Abstract Primary biliary cirrhosis (PBC) is sometimes diagnosed based on a positive antimitochondrial antibody in the appropriate clinical setting without a liver biopsy. Although a liver biopsy can assess the extent of liver fibrosis and provide prognostic information, serum fibrosis markers avoid biopsy complications and sampling error and provide results as a continuous variable, which may be more precise than categorical histological stages. The current study was undertaken to evaluate serum fibrosis markers as predictors of clinical progression in a large cohort of PBC patients. Serial liver biopsy specimens and serum samples were collected every 2 years in 161 PBC subjects for a median of 7.3 years. Clinical progression was defined as development of one or more of the following events: varices, variceal bleed, ascites, encephalopathy, liver transplantation, or liver-related death. Serum hyaluronic acid, tissue inhibitor of metalloproteinase 1, and procollagen III aminopeptide were measured and entered into the previously validated enhanced liver fibrosis (ELF) algorithm. The ability of ELF, histological fibrosis, bilirubin, Model for End-Stage Liver Disease (MELD), and Mayo Risk Score to differentiate between individuals who would experience a clinical event from those who would not was evaluated at different time points. Event-free survival was significantly lower in those with high baseline ELF. Each 1-point increase in ELF was associated with a threefold increase in future complications. The prognostic performance of all tests was similar when performed close to the time of the first event. However, at earlier times in the disease process (4 and 6 years before the first event), the prognostic performance of ELF was significantly better than MELD or Mayo R score. Conclusion: The ELF algorithm is a highly accurate noninvasive measure of PBC disease severity that provides useful long-term prognostic information. (Hepatology 2008.)
First-Line Gefitinib for Patients With Advanced Non–Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations Without Indication for Chemotherapy
Authors: Akira Inoue, Kunihiko Kobayashi, Kazuhiro Usui, Makoto Maemondo, Shoji Okinaga, Iwao Mikami, Masahiro Ando, Koichi Yamazaki, Yasuo Saijo, Akihiko Gemma, Hitoshi Miyazawa, Tomoaki Tanaka, Kenji Ikebuchi, Toshihiro Nukiwa, Satoshi Morita, Koichi Hagiwara
Journal: Journal of Clinical Oncology (2009)

This multicenter phase II study was undertaken to investigate the efficacy and feasibility of gefitinib for patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations without indication for chemotherapy as a result of poor performance status (PS).Chemotherapy-naïve patients with poor PS (patients 20 to 74 years of age with Eastern Cooperative Oncology Group PS 3 to 4, 75 to 79 years of age with PS 2 to 4, and >or= 80 years of age with PS 1 to 4) who had EGFR mutations examined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method were enrolled and received gefitinib (250 mg/d) alone.Between February 2006 and May 2007, 30 patients with NSCLC and poor PS, including 22 patients with PS 3 to 4, were enrolled. The overall response rate was 66% (90% CI, 51% to 80%), and the disease control rate was 90%. PS improvement rate was 79% (P < .00005); in particular, 68% of the 22 patients improved from >or= PS 3 at baseline to <or= PS 1. The median progression-free survival, median survival time, and 1-year survival rate were 6.5 months, 17.8 months, and 63%, respectively. No treatment-related deaths were observed.This is the first report indicating that EGFR mutation-positive patients with extremely poor PS benefit from first-line gefitinib. Because there previously has been no standard treatment for these patients with short life expectancy other than best supportive care, examination of EGFR mutations as a biomarker is recommended in this patient population.
Plasma Glucose Concentration and Prediction of Future Risk of Type 2 Diabetes
Authors: Muhammad A. Abdul-Ghani, Ralph A. DeFronzo
Journal: Diabetes Care (2009)

The prevalence of type 2 diabetes has increased in recent decades to epidemic proportions. About 150 million individuals worldwide had type 2 diabetes in 2000, and this number is expected to increase to ∼300 million by the year 2025 (1). Because of the chronic course of type 2 diabetes and the significant morbidity and mortality associated with the vascular complications of the disease, type 2 diabetes has become not only a serious public health threat, but also a heavy economic burden on the health care system. The total annual cost of diabetes care in the U.S. was estimated to be $175 billion in the year 2007, and this number is expected to increase further with the increasing incidence of the disease (2).

Recent clinical trials have reported a reduction in the incidence of type 2 diabetes with lifestyle intervention (3,4) and pharmacotherapy (4,5) in subjects with IGT. These results suggest that primary prevention of type 2 diabetes could be an effective strategy to restrain the epidemic increase in the disease prevalence and reduce the economic burden it poses on the health care system.

Accurate identification of subjects at increased risk for future type 2 diabetes is essential for an early prevention program. It minimizes the number of subjects in the intervention program while improving the efficacy and the cost-effectiveness of the intervention. An impaired glucose tolerance (IGT) test was introduced in 1979 as an intermediate state in the transition in glucose homeostasis from normal to overt diabetes (6). Subjects with IGT have increased risk for future type 2 diabetes (7). Thus, all previous intervention trials that have tested the efficacy of prevention strategies have recruited subjects with IGT (3–5). Although, in general, subjects with IGT have an increased risk for future type 2 …