bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elevated carboxy terminal cross linked telopeptide of type I collagen in alcoholic cirrhosis: relation to liver and kidney function and bone metabolism
Authors: Møller S , Hansen M , Hillingsø J , Jensen J-E B , Henriksen J H 
Published: June 2010

BACKGROUNDThe carboxy terminal cross linked telopeptide of type I collagen (ICTP) has been put forward as a marker of bone resorption. Patients with alcoholic liver disease may have osteodystrophy.AIMSTo assess circulating and regional concentrations of ICTP in relation to liver dysfunction, bone metabolism, and fibrosis.METHODSIn 15 patients with alcoholic cirrhosis and 20 controls, hepatic venous, renal venous, and femoral arterial concentrations of ICTP, and bone mass and metabolism were measured.RESULTSCirculating ICTP was higher in patients with cirrhosis than in controls. No overall significant hepatic disposal or production was found in the patient or control groups but slightly increased production was found in a subset of patients with advanced disease. Significant renal extraction was observed in the controls, whereas only a borderline significant extraction was observed in the patients. Measurements of bone mass and metabolism indicated only a mild degree of osteodystrophy in the patients with cirrhosis. ICTP correlated significantly in the cirrhotic patients with hepatic and renal dysfunction and fibrosis, but not with measurements of bone mass or metabolism.CONCLUSIONSICTP is highly elevated in patients with cirrhosis, with no detectable hepatic net production or disposal. No relation between ICTP and markers of bone metabolism was identified, but there was a relation to indicators of liver dysfunction and fibrosis. As the cirrhotic patients conceivably only had mild osteopenia, the elevated ICTP in cirrhosis may therefore primarily reflect liver failure and hepatic fibrosis.
Bovine colostrum is a health food supplement which prevents NSAID induced gut damage
Authors: Playford R J , Floyd D N , Macdonald C E , Calnan D P , Adenekan R O , Johnson W , Goodlad R A , Marchbank T 
Published: June 2010

BACKGROUNDNon-steroidal anti-inflammatory drugs (NSAIDs) are effective for arthritis but cause gastrointestinal injury. Bovine colostrum is a rich source of growth factors and is marketed as a health food supplement.AIMSTo examine whether spray dried, defatted colostrum or milk preparations could reduce gastrointestinal injury caused by indomethacin.METHODSEffects of test solutions, administered orally, were examined using an indomethacin restraint rat model of gastric damage and an indomethacin mouse model of small intestinal injury. Effects on migration of the human colonic carcinoma cell line HT-29 and rat small intestinal cell line RIE-1 were assessed using a wounded monolayer assay system (used as an in vitro model of wound repair) and effects on proliferation determined using [3H]thymidine incorporation.RESULTSPretreatment with 0.5 or 1 ml colostral preparation reduced gastric injury by 30% and 60% respectively in rats. A milk preparation was much less efficacious. Recombinant transforming growth factor β added at a dose similar to that found in the colostrum preparation (12.5 ng/rat), reduced injury by about 60%. Addition of colostrum to drinking water (10% vol/vol) prevented villus shortening in the mouse model of small intestinal injury. Addition of milk preparation was ineffective. Colostrum increased proliferation and cell migration of RIE-1 and HT-29 cells. These effects were mainly due to constituents of the colostrum with molecular weights greater than 30 kDa.CONCLUSIONSBovine colostrum could provide a novel, inexpensive approach for the prevention and treatment of the injurious effects of NSAIDs on the gut and may also be of value for the treatment of other ulcerative conditions of the bowel.
Accuracy of screening for gastric cancer using serum pepsinogen concentrations
Authors: Kitahara F , Kobayashi K , Sato T , Kojima Y , Araki T , Fujino M A 
Published: June 2010

BACKGROUND/AIMSThe characteristics of pepsinogen screening for gastric cancer were investigated to establish a suitable cut off point for identifying gastric cancer, using endoscopic diagnosis as the yardstick.SUBJECTS/METHODSSerum pepsinogen concentrations were measured in 5113 subjects who were also screened for gastric cancer by endoscopy. The cut off point for pepsinogen was determined using receiver operator characteristics curves.RESULTSThe most suitable cut off point was a pepsinogen I concentration of less than 70 ng/ml and a ratio of pepsinogen I to pepsinogen II of less than 3.0. Using this cut off point, the sensitivity and specificity of pepsinogen screening for gastric cancer were 84.6% and 73.5% respectively. All cases of gastric cancer in patients with severe atrophic gastritis were detected. However, two of four cases of gastric cancer in patients with mild atrophic gastritis were overlooked. In subjects with mild atrophic gastritis, when gastric cancer arises within the fundic gland region, the size of the lesion determines whether it is possible to detect cancer by serum pepsinogen screening.CONCLUSIONPepsinogen screening has many advantages, including its suitability for combination with other screening methods because it is simple and inexpensive.
Microsatellite instability—a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer
Authors: Lamberti C , Kruse R , Ruelfs C , Caspari R , Wang Y , Jungck M , Mathiak M , Malayeri H R H , Friedl W , Sauerbruch T , Propping P 
Published: June 2010

BACKGROUNDClinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is based on a typical family history. As molecular genetic testing is predominantly restricted to these families, gene carriers not meeting the clinical criteria may be missed.AIMSTo examine the value of microsatellite instability (MSI) as a tool to increase the likelihood for uncovering a mismatch repair germline mutation in patients with colorectal cancer and to identify a genotype-phenotype relation in families with verified mutations.METHODSSystematic search for germline mutations (hMSH2 and hMLH1 genes) was performed in 96 patients: 57 fulfilled the Amsterdam criteria (group 1) and 12 the looser HNPCC criteria (group 2). Seventeen patients showed familial clustering of cancers (group 3) and 10 patients under 50 years had sporadic cancer (group 4), the latter of whom all exhibited MSI+ tumours.RESULTSA similar proportion of germline mutations was found in patients who fulfilled the clinical criteria of HNPCC and had MSI+ tumours (groups 1 and 2; 15/39) compared with patients who did not meet these clinical criteria but who had MSI+ tumours (groups 3 and 4; 8/27 patients). Affected relatives of patients with hMLH1 mutations showed a significantly higher frequency of colorectal cancer but a lower frequency of endometrium cancer than those with hMSH2 mutations.CONCLUSIONSMSI in tumour tissue is a useful criterion for selecting patients who should be tested for germline mutations in the mismatch repair genes hMSH2 and hMLH1 irrespective of their family history. Among carriers of hMSH2 mutations the tumour spectrum was broader than among carriers of hMLH1 mutations.
Quality of life in patients receiving home parenteral nutrition
Authors: Jeppesen P B , Langholz E , Mortensen P B 
Published: June 2010

BACKGROUND/AIMSQuality of life is an important determinant of the effectiveness of health technologies, but it has rarely been assessed in patients receiving home parenteral nutrition (HPN).PATIENTS/METHODSThe non-disease specific sickness impact profile (SIP) and the disease specific inflammatory bowel disease questionnaire (IBDQ) were used on a cohort of 49 patients receiving HPN, and the results compared with those for 36 non-HPN patients with either anatomical (<200 cm) or functional (faecal energy excretion >2.0 MJ/day (∼488 kcal/day)) short bowel.RESULTSIn the HPN patients the SIP scores were worse (higher) overall (17 (13)%v 8 (9)%) and with regard to physical (13 (15)% v 5 (8)%) and psychosocial (14 (12)% v 9 (11)%) dimensions and independent categories (20 (12)% v 9 (8)%) compared with the non-HPN patients (means (SD); all p<0.001). The IBDQ scores were worse (lower) in the HPN patients overall (5.0 (4.3–5.7)v 5.6 (4.8–6.2)) and with regard to systemic symptoms (3.8 (2.8–5.4) v 5.2 (3.9–5.9)) and emotional (5.3 (4.4–6.2) v5.8 (5.4–6.4)) and social (4.3 (3.4–5.5) v4.8 (4.5–5.8)) function (median (25–75%); all p<0.05), but only tended to be worse with regard to bowel symptoms (5.2 (4.8–6.1)v 5.7 (4.9–6.4), p = 0.08). HPN also reduced quality of life in patients with a stoma, whereas a stoma did not reduce quality of life among the non-HPN patients. Female HPN patients and HPN patients older than 45 scored worse.CONCLUSIONQuality of life is reduced in patients on HPN compared with those with anatomical or functional short bowel not receiving HPN, and compares with that reported for patients with chronic renal failure treated by dialysis.
Screening SMAD1,SMAD2, SMAD3, andSMAD5 for germline mutations in juvenile polyposis syndrome
Authors: Bevan S , Woodford-Richens K , Rozen P , Eng C , Young J , Dunlop M , Neale K , Phillips R , Markie D , Rodriguez-Bigas M , Leggett B , Sheridan E , Hodgson S , Iwama T , Eccles D , Bodmer W , Houlston R , Tomlinson I 
Published: June 2010

BACKGROUND AND AIMSJuvenile polyps occur in several Mendelian disorders, whether in association with gastrointestinal cancer alone (juvenile polyposis syndrome, JPS) or as part of known syndromes (Cowden, Gorlin, and Bannayan-Zonana) in association with developmental abnormalities, dysmorphic features, or extraintestinal tumours. Recently, some JPS families were shown to harbour germline mutations in theSMAD4 (DPC4) gene, providing further evidence for the importance of the TGFβ signalling pathway in colorectal cancer. There remains, however, considerable, unexplained genetic heterogeneity in JPS. Other members of the SMAD family are excellent candidates for JPS, especiallySMAD2 (which, likeSMAD4, is mutated somatically in colorectal cancers), SMAD3 (which causes colorectal cancer when “knocked out” in mice),SMAD5, and SMAD1.METHODSSMAD1,SMAD2, SMAD3, andSMAD5 were screened for germline mutations in 30 patients with JPS and without SMAD4mutations.RESULTSNo mutations were found in any of these genes. A G–A C89Y polymorphism with possible effects on protein function was found in SMAD3, but the frequencies of the G and A alleles did not differ between patients with JPS and controls.CONCLUSIONSIt remains to be determined whether or not this polymorphism is involved in a minor predisposition to colorectal or other carcinomas.SMAD4 may be the only member of the SMAD family which causes JPS when mutant in the germline. The other genes underlying JPS remain to be identified.
Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment
Authors: Rodrigues C M P , Marín J J G , Brites D 
Published: June 2010

BACKGROUNDData on meconium bile acid composition in newborn babies of patients with intrahepatic cholestasis of pregnancy (ICP) are relatively scant, and changes that occur on ursodeoxycholic acid (UDCA) administration have not been evaluated.AIMSTo investigate bile acid profiles in meconium of neonates from untreated and UDCA treated patients with ICP. Maternal serum bile acid composition was also analysed both at diagnosis and delivery to determine whether this influences the concentration and proportion of bile acids in the meconium.PATIENTS/METHODSThe population included eight healthy pregnant women and 16 patients with ICP, nine of which received UDCA (12.5–15.0 mg/kg body weight/day) for 15±4 days until parturition. Bile acids were assessed in the meconium by gas chromatography-mass spectrometry and in maternal serum by high performance liquid chromatography.RESULTSTotal bile acid and cholic acid concentrations in the meconium were increased (p<0.01) in newborns from patients with ICP (13.5 (5.1) and 8.4 (4.1) μmol/g respectively; mean (SEM)) as compared with controls (2.0 (0.5) and 0.8 (0.3) μmol/g respectively), reflecting the total bile acid and cholic acid levels in the maternal serum (r = 0.85 and r = 0.84, p<0.01). After UDCA administration, total bile acid concentrations decreased in the mother (∼3-fold, p<0.05) but not in the meconium. UDCA concentration in the meconium showed only a 2-fold increase after treatment, despite the much greater increase in the maternal serum (p<0.01). Lithocholic acid concentration in the meconium was not increased by UDCA treatment.CONCLUSIONSUDCA administration does not influence the concentration and proportion of bile acids in the meconium, which in turn are altered by ICP. Moreover, this beneficial treatment for the mother does not increase meconium levels of potentially toxic metabolites of UDCA such as lithocholic acid.
Microtubule-Disrupting Chemotherapeutics Result in Enhanced Proteasome-Mediated Degradation and Disappearance of Tubulin in Neural Cells
Authors: Huff Lyn M. , Sackett Dan L. , Poruchynsky Marianne S. , Fojo Tito 
Published: June 2010

Abstract
We sought to examine the effects of microtubule-targeting agents (MTA) on neural cells to better understand the problem of neurotoxicity, their principal side effect, and to possibly develop a model of clinical toxicity. Studies showed that microtubule-depolymerizing agents (MDA) not only disassembled microtubules in neural HCN2 cells but also led to rapid disappearance of tubulin, and that this was specific for MDAs. Tubulin levels decreased to 20% as early as 8 hours after adding vincristine, and to 1% to 30% (mean, 9.8 ± 7.6%; median of 7%) after 100 nmol/L vincristine for 24 hours. This disappearance was reversible. An increase in both glu-terminated and acetylated tubulin, markers of stable tubulin, preceded reaccumulation of soluble tubulin, suggesting a priority for stabilizing tubulin first as microtubules before replenishing the soluble pool. Similar results were shown with other MDAs. Furthermore, microtubule reassembly did not arise from a central focus but instead appeared to involve dispersed nucleation, as evidenced by the appearance of small, stable microtubule stubs throughout the cytoplasm. In contrast, experiments with four nonneural “normal” cell lines and four cancer cell lines resulted in microtubule destabilization but only modest tubulin degradation. Evidence for proteasome-mediated degradation was obtained by demonstrating that adding a proteasome inhibitor before vincristine prevented tubulin disappearance. In summary, MDAs lead to rapid disappearance of tubulin in neural but not in other normal or cancer cells. These results underscore the fine control that occurs in neural cells and may further our understanding of neurotoxicity following MDAs. Cancer Res; 70(14); 5870–9. ©2010 AACR.
Nrdp1-Mediated Regulation of ErbB3 Expression by the Androgen Receptor in Androgen-Dependent but not Castrate-Resistant Prostate Cancer Cells
Authors: Chen Liqun , Siddiqui Salma , Bose Swagata , Mooso Benjamin , Asuncion Alfredo , Bedolla Roble G. , Vinall Ruth , Tepper Clifford G. , Gandour-Edwards Regina , Shi XuBao , Lu Xiao-Hua , Siddiqui Javed , Chinnaiyan Arul M. , Mehra Rohit , deVere White Ralph W. , Carraway Kermit L. , Ghosh Paramita M. 
Published: June 2010

Abstract
Patients with advanced prostate cancer (PCa) are initially susceptible to androgen withdrawal (AW), but ultimately develop resistance to this therapy (castration-resistant PCa, CRPC). Here, we show that AW can promote CRPC development by increasing the levels of the receptor tyrosine kinase ErbB3 in androgen-dependent PCa, resulting in AW-resistant cell cycle progression and increased androgen receptor (AR) transcriptional activity. CRPC cell lines and human PCa tissue overexpressed ErbB3, whereas downregulation of ErbB3 prevented CRPC cell growth. Investigation of the mechanism by which AW augments ErbB3, using normal prostate-derived pRNS-1-1 cells, and androgen-dependent PCa lines LNCaP, PC346C, and CWR22 mouse xenografts, revealed that the AR suppresses ErbB3 protein levels, whereas AW relieves this suppression, showing for the first time the negative regulation of ErbB3 by AR. We show that AR activation promotes ErbB3 degradation in androgen-dependent cells, and that this effect is mediated by AR-dependent transcriptional upregulation of neuregulin receptor degradation protein-1 (Nrdp1), an E3 ubiquitin ligase that targets ErbB3 for degradation but whose role in PCa has not been previously examined. Therefore, AW decreases Nrdp1 expression, promoting ErbB3 protein accumulation, and leading to AR-independent proliferation. However, in CRPC sublines of LNCaP and CWR22, which strongly overexpress the AR, ErbB3 levels remain elevated due to constitutive suppression of Nrdp1, which prevents AR regulation of Nrdp1. Our observations point to a model of CRPC development in which progression of PCa to castration resistance is associated with the inability of AR to transcriptionally regulate Nrdp1, and predict that inhibition of ErbB3 during AW may impair CRPC development. Cancer Res; 70(14); 5994–6003. ©2010 AACR.
Tumor Antigen Epitopes Interpreted by the Immune System as Self or Abnormal-Self Differentially Affect Cancer Vaccine Responses
Authors: Ryan Sean O. , Turner Michael S. , Gariépy Jean , Finn Olivera J. 
Published: June 2010

AbstractEpitope selection is an important consideration in the design of cancer vaccines, but factors affecting selection are not fully understood. We compared the immune responses to peptides and glycopeptides from the common human tumor antigen MUC1, a mucin that is coated with O-linked carbohydrates in its variable number of tandem repeats (VNTR) region. MUC1 expressed on tumor cells is characteristically underglycosylated, creating peptide and glycopeptide neoepitopes that are recognized by the immune system. The response to VNTR peptides is weaker in MUC1-transgenic mice (MUC1-Tg mice) than in wild-type (WT) mice, whereas the response to VNTR glycopeptides is equally strong in the two strains. Thus, glycopeptides seem to be recognized as foreign, whereas peptides, although immunogenic, are perceived as self. To explore this further, we generated MUC1 peptide– and glycopeptide–specific T-cell receptor transgenic mice and studied the function of their CD4 T cells when adoptively transferred into MUC1-Tg or WT mice. Peptide-specific T-cell precursors were not centrally deleted in MUC1-Tg mice and did not acquire a T regulatory phenotype. However, their response to the cognate peptide was reduced in MUC1-Tg mice compared with WT mice. In contrast, glycopeptide-specific CD4 T cells responded equally well in the two hosts and, when simultaneously activated, also enhanced the peptide-specific T-cell responses. Our data show that the immune system differentially recognizes various epitopes of tumor-associated antigens either as self or as foreign, and this controls the strength of antitumor immunity. This represents an important consideration for designing safe and effective cancer vaccines. Cancer Res; 70(14); 5788–96. ©2010 AACR.
MEK Inhibitor PD0325901 Significantly Reduces the Growth of Papillary Thyroid Carcinoma Cells In vitro and In vivo
Authors: Henderson Ying C. , Chen Yunyun , Frederick Mitchell J. , Lai Stephen Y. , Clayman Gary L. 
Published: June 2010

Abstract
Papillary thyroid carcinomas (PTC) are the most common type of thyroid malignancy. Most PTC carry one of the two mutations, RET/PTC rearrangement or BRAF mutation. Both mutations are able to activate the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling transduction pathway leading to cellular proliferation, differentiation, and apoptosis. PD0325901 is a specific MEK1/2 inhibitor and therefore is a promising drug to treat thyroid cancers with either RET/PTC or BRAF mutation. In this study we tested the effects of PD0325901 on PTC cells harboring either mutation in vitro by growth curves and Western blots and in vivo using a murine orthotopic xenograft model. We found that 50% growth inhibition (GI50) by PD0325901 was 11 nmol/L for the PTC cells with the RET/PTC1 rearrangement and 6.3 nmol/L for PTC cells with a BRAF mutation, with both concentrations readily achievable in serum. After 1 week of oral administration of PD0325901 (20–25 mg/kg/day) in mice, no tumor growth was detected in mice inoculated with PTC cells bearing a BRAF mutation. For PTC with the RET/PTC1 rearrangement, the average tumor volume of the orthotopic tumor was reduced by 58% as compared with controls. In conclusion, our data suggested that PTC cells carrying a BRAF mutation were more sensitive to PD0325901 than were PTC cells carrying the RET/PTC1 rearrangement. Our findings support the clinical evaluation of PD0325901 for patients with PTC and potentially other carcinomas with BRAF mutations. Mol Cancer Ther; 9(7); 1968–76. ©2010 AACR.
Land Surface Heating and the North American Monsoon Anticyclone: Model Evaluation from Diurnal to Seasonal
Authors: Kelly Patrick , Mapes Brian 
Published: June 2010

Abstract
Data from several regional and global models (including model-based analysis data) are compared with field data from the North American Monsoon Experiment (NAME), from observational sites as well as satellite retrievals. On the regional scale (NAME tier 1.5), sensible heating is shown to exceed latent and is furthermore concentrated in the lower half of the troposphere, so in considering the North American monsoon (NAM) midlevel anticyclone, the authors focus on radiative and turbulent energy fluxes at the surface. Models exhibit large discrepancies in their simulation of the mean diurnal cycle of these fluxes as well as in their sensitivity of evaporative fraction to recent rainfall. Most of the models examined have too much net radiation due to excessive shortwave surface flux (too little cloud) and too much sensible heating. These high biases in sensible heating appear to drive overpredictions of both the daily and seasonal rise of 500-hPa heights in the NAM anticyclone. This diurnal–seasonal resemblance suggests that calibrating surface heating processes using readily field-observed diurnal variations could lead to improvements in seasonal-time-scale NAM simulations.
Drug-dependent clearance of human platelets in the NOD/scid mouse by antibodies from patients with drug-induced immune thrombocytopenia
Authors: Bougie Daniel W. , Nayak Dhirendra , Boylan Brian , Newman Peter J. , Aster Richard H. 
Published: June 2010

AbstractDrug-induced immune thrombocytopenia (DITP) is a relatively common and sometimes life-threatening condition caused by antibodies that bind avidly to platelets only when drug is present. How drug-dependent antibodies (DDAbs) are induced and how drugs promote their interaction with platelets are poorly understood, and methods for detecting DDAbs are suboptimal. A small animal model of DITP could provide a new tool for addressing these and other questions concerning pathogenesis and diagnosis. We examined whether the nonobese diabetic/severe combined immunodeficient (NOD/scid) mouse, which lacks xenoantibodies and therefore allows infused human platelets to circulate, can be used to study drug-dependent clearance of platelets by DDAbs in vivo. In this report, we show that the NOD/scid model is suitable for this purpose and describe studies to optimize its sensitivity for drug-dependent human antibody detection. We further show that the mouse can produce metabolites of acetaminophen and naproxen for which certain drug-dependent antibodies are specific in quantities sufficient to enable these antibodies to cause platelet destruction. The findings indicate that the NOD/scid mouse can provide a unique tool for studying DITP pathogenesis and may be particularly valuable for identifying metabolite-specific antibodies capable of causing immune thrombocytopenia or hemolytic anemia.