bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen
Authors: Bajtner Estelle , Nandakumar Kutty S , Engström Åke , Holmdahl Rikard 
Published: July 2005

AbstractAntibodies against type II collagen (CII) are important in the development of collagen-induced arthritis (CIA) and possibly also in rheumatoid arthritis. We have determined the fine specificity and arthritogenicity of the antibody response to CII in chronic relapsing variants of CIA. Immunization with rat CII in B10.Q or B10.Q(BALB/c×B10.Q)F2 mice induces a chronic relapsing CIA. The antibody response to CII was determined by using triple-helical peptides of the major B cell epitopes. Each individual mouse had a unique epitope-specific response and this epitope predominance shifted distinctly during the course of the disease. In the B10.Q mice the antibodies specific for C1 and U1, and in the B10.Q(BALB/c×B10.Q)F2 mice the antibodies specific for C1, U1 and J1, correlated with the development of chronic arthritis. Injection of monoclonal antibodies against these epitopes induced relapses in chronic arthritic mice. The development of chronic relapsing arthritis, initially induced by CII immunization, is associated with an arthritogenic antibody response to certain CII epitopes.
Proteomic identification of heat shock protein 90 as a candidate target for p53 mutation reactivation by PRIMA-1 in breast cancer cells
Authors: Rehman Abdur , Chahal Manpreet S , Tang Xiaoting , Bruce James E , Pommier Yves , Daoud Sayed S 
Published: July 2005

Abstract
Introduction
A loss of p53 function resulting from mutation is prevalent in human cancers. Thus, restoration of p53 function to mutant p53 using small compounds has been extensively studied for cancer therapy. We previously reported that PRIMA-1 (for 'p53 reactivation and induction of massive apoptosis') restored the transcriptional activity of p53 target genes in breast cancer cells with a p53 mutation. By using functional proteomics approach, we sought to identify molecular targets that are involved in the restoration of normal function to mutant p53.

Methods
PRIMA-1 treated cell lysates were subjected to immunoprecipitation with DO-1 primary antibody against p53 protein, and proteins bound to p53 were separated on a denaturing gel. Bands expressed differentially between control and PRIMA-1-treated cells were then identified by matrix-assisted laser desorption ionization-time-of-flight spectrometry. Protein expression in whole cell lysates and nuclear extracts were confirmed by Western blotting. The effect of combined treatment of PRIMA-1 and adriamycin in breast cancer cells was determined with a cytotoxicity assay in vitro.

Results
PRIMA-1 treated cells distinctly expressed a protein band of 90 kDa that was identified as heat shock protein 90 (Hsp90) by the analysis of the 90 kDa band tryptic digest. Immunoblotting with isoform-specific antibodies against Hsp90 identified this band as the α isoform of Hsp90 (Hsp90α). Co-immunoprecipitation with anti-Hsp90α antibody followed by immunoblotting with DO-1 confirmed that p53 and Hsp90α were interacting proteins. PRIMA-1 treatment also resulted in the translocation of Hsp90α to the nucleus by 8 hours. Treatment of cells with PRIMA-1 alone or in combination with adriamycin, a DNA-targeted agent, resulted in increased sensitivity of tumor cells.

Conclusion
The studies demonstrate that PRIMA-1 restores the p53-Hsp90α interaction, enhances the translocation of the p53-Hsp90α complex and reactivates p53 transcriptional activity. Our preliminary evidence also suggests that PRIMA-1 could be considered in combination therapy with DNA-targeted agents for the treatment of breast cancer, especially for tumors with aberrant p53 function.
Strong evidence that the common variant S384F in BRCA2has no pathogenic relevance in hereditary breast cancer
Authors: Wappenschmidt B , Fimmers R , Rhiem K , Brosig M , Wardelmann E , Meindl A , Arnold N , Mallmann P , Schmutzler RK 
Published: July 2005

Abstract
Introduction
Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10).

Methods
For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated.

Results
We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 × 10-8 in favour of neutrality of the variant.

Conclusion
Our data provide conclusive evidence that the S384F variant is not a disease causing mutation.
Steroid use in PROWESS severe sepsis patients treated with drotrecogin alfa (activated)
Authors: Levy Howard , Laterre Pierre-Francois , Bates Becky , Qualy Rebecca L 
Published: July 2005

Abstract
Introduction
In a study conducted by Annane, patients with septic shock and unresponsive to adrenocorticotropic hormone stimulation receiving low-dose steroid therapy had prolonged survival but not significantly improved 28-day mortality. The present study examines intravenous steroid use in PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) patients meeting the Annane enrollment criteria (AEC).

Methods
Adrenocorticotropic hormone stimulation tests were not done in PROWESS. Steroids were allowed but their use was not directed. Patients were identified using AEC (all of: randomization to study drug treatment within 8 hours of shock onset; infection, fever, or hypothermia; tachycardia; systolic blood pressure <90 mmHg on vasopressors; mechanical ventilation; and one of urine <0.5 ml/kg per hour, lactic acidosis, or arterial oxygen tension/inspired fractional oxygen <280). We examined steroid use and mortality data; additional analyses were done outside the 8-hour window.

Results
Steroid-treated patients were older, had higher Acute Physiology and Chronic Health Evaluation scores and more organ dysfunctions, and were more commonly receiving mechanical ventilation. Among patients meeting AEC, regardless of steroid treatment (n = 97), mortality in the placebo and drotrecogin alfa (activated) groups was 38% (19/50) and 28% (13/47), respectively (relative risk [RR] = 0.73, 95% confidence interval [CI] 0.41–1.30). When using AEC but excluding the requirement for randomization within 8 hours of shock onset (n = 612), placebo mortality was 38% (118/313) and drotrecogin alfa (activated) mortality was 29% (88/299; RR = 0.78, 95% CI 0.62–0.98). Using AEC but excluding the 8-hour window and with steroids initiated at baseline and/or infusion (n = 228) resulted in mortality for placebo and drotrecogin alfa (activated) groups of 43% (51/118) and 33% (36/110), respectively (RR = 0.76, 95% CI 0.54–1.06).

Conclusion
Patients with severe sepsis from the PROWESS trial who were likely to respond to low-dose steroids according to the AEC were those patients at a high risk for death. However, when using the AEC, regardless of steroid use, patients exhibited a survival benefit from treatment with drotrecogin alfa (activated).
The molecular portrait of in vitro growth by meta-analysis of gene-expression profiles
Authors: Sandberg Rickard , Ernberg Ingemar 
Published: July 2005

Abstract
Background
Cell lines as model systems of tumors and tissues are essential in molecular biology, although they only approximate the properties of in vivo cells in tissues. Cell lines have been selected under in vitro conditions for a long period of time, affecting many specific cellular pathways and processes.

Results
To identify the transcriptional changes caused by long term in vitro selection, we performed a gene-expression meta-analysis and compared 60 tumor cell lines (of nine tissue origins) to 135 human tissue and 176 tumor tissue samples. Using significance analysis of microarrays we demonstrated that cell lines showed statistically significant differential expression of approximately 30% of the approximately 7,000 genes investigated compared to the tissues. Most of the differences were associated with the higher proliferation rate and the disrupted tissue organization in vitro. Thus, genes involved in cell-cycle progression, macromolecule processing and turnover, and energy metabolism were upregulated in cell lines, whereas cell adhesion molecules and membrane signaling proteins were downregulated.

Conclusion
Detailed molecular understanding of how cells adapt to the in vitro environment is important, as it will both increase our understanding of tissue organization and result in a refined molecular portrait of proliferation. It will further indicate when to use immortalized cell lines, or when it is necessary to instead use three-dimensional cultures, primary cell cultures or tissue biopsies.
The Dictyostelium genome encodes numerous RasGEFs with multiple biological roles
Authors: Wilkins Andrew , Szafranski Karol , Fraser Derek J , Bakthavatsalam Deenadayalan , Müller Rolf , Fisher Paul R , Glöckner Gernot , Eichinger Ludwig , Noegel Angelika A , Insall Robert H 
Published: July 2005

Abstract
Background
Dictyostelium discoideum is a eukaryote with a simple lifestyle and a relatively small genome whose sequence has been fully determined. It is widely used for studies on cell signaling, movement and multicellular development. Ras guanine-nucleotide exchange factors (RasGEFs) are the proteins that activate Ras and thus lie near the top of many signaling pathways. They are particularly important for signaling in development and chemotaxis in many organisms, including Dictyostelium.

Results
We have searched the genome for sequences encoding RasGEFs. Despite its relative simplicity, we find that the Dictyostelium genome encodes at least 25 RasGEFs, with a few other genes encoding only parts of the RasGEF consensus domains. All appear to be expressed at some point in development. The 25 genes include a wide variety of domain structures, most of which have not been seen in other organisms. The LisH domain, which is associated with microtubule binding, is seen particularly frequently; other domains that confer interactions with the cytoskeleton are also common. Disruption of a sample of the novel genes reveals that many have clear phenotypes, including altered morphology and defects in chemotaxis, slug phototaxis and thermotaxis.

Conclusion
These results suggest that the unexpectedly large number of RasGEF genes reflects an evolutionary expansion of the range of Ras signaling rather than functional redundancy or the presence of multiple pseudogenes.
Abnormal Cytology Predicts Poor Prognosis in Cancer Patients With Pericardial Effusion
Authors: Gornik Heather L. , Gerhard-Herman Marie , Beckman Joshua A. 
Published: July 2005

Purpose Pericardial tamponade is a life-threatening disorder caused by varying medical conditions. Malignancy and complications of its treatment are a common cause of pericardial effusion. The natural history of pericardial effusion remains largely unknown. We investigated the association of malignancy with adverse outcomes after pericardiocentesis. Patients and Methods Consecutive patients undergoing pericardiocentesis at a single institution between January 1, 1999, and January 31, 2003, were included. Death was confirmed with the Social Security Death Index. Survival estimates were obtained by the Kaplan-Meier method. Cox regression was performed to determine the clinical characteristics associated with death. Results Two hundred nineteen patients underwent pericardiocentesis during the study period. The effusion was cancer-related in 43.8% of cases. Median survival was 59.6 weeks (95% CI, 24.3 to 94.8 weeks). During the follow-up period, 47.9% of patients died. Cancer-related pericardial effusion was associated with decreased survival (median, 15.1 weeks). Abnormal fluid cytology was further associated with poor prognosis among patients with malignancy (median survival, 7.3 v 29.7 weeks; P = .022). Patients with cancer-related pericardial effusion were more likely to require repeat pericardiocentesis (OR = 6.0; P = .001) and pericardial surgery (odds ratio [OR] OR = 5.7; P < .001). Cancer-related effusion and abnormal cytology were independent predictors of death in a multivariate model. Conclusion Malignancy is the most common cause of pericardial effusion in a tertiary care center. Cancer-related pericardial effusion is associated with adverse outcomes, and abnormal cytology further worsens prognosis. The poor survival among cancer patients with pericardial effusion and abnormal fluid cytology may have important implications for management.
Prediction of MYCN Amplification in Neuroblastoma Using Serum DNA and Real-Time Quantitative Polymerase Chain Reaction
Authors: Gotoh Takahiro , Hosoi Hajime , Iehara Tomoko , Kuwahara Yasumichi , Osone Shinya , Tsuchiya Kunihiko , Ohira Miki , Nakagawara Akira , Kuroda Hiroshi , Sugimoto Tohru 
Published: July 2005

Purpose MYCN amplification (MNA) indicates a poor prognosis in neuroblastoma (NB) and is routinely assayed for therapy stratification. We aimed to develop a diagnostic tool to predict MYCN status using serum DNA, which, in cancer patients, predominantly originates from tumor-released DNA. Patients and Methods Using DNA-based real-time quantitative polymerase chain reaction, we simultaneously quantified MYCN (2p24) and a reference gene, NAGK (2p12), and evaluated MYCN copy number as an MYCN/NAGK (M/N) ratio in 87 NB patients whose MYCN status had been determined by Southern blotting. Of these patients, 17 had MYCN-amplified NB, and 70 had nonamplified NB. Results The serum M/N ratio in the MNA group (median, 199.32; range, 17.1 to 901.6; 99% CI, 107.0 to 528.7) was significantly (P < .001) higher than the ratio in the non-MNA group (median, 0.87; range, 0.25 to 4.6; 99% CI, 0.82 to 1.26; Mann-Whitney U test). The sensitivity and specificity of the serum M/N ratio as a diagnostic test were both 100% when the serum M/N ratio cutoff was set at 10.0. Among six MNA patients whose clinical courses were followed, the serum ratios decreased to the normal range in the patients in remission (n = 3), whereas the ratios increased to high levels in the patients who relapsed (n = 2) or failed to achieve remission (n = 1). Conclusion Measurement of the serum M/N ratio seems to be a promising method for accurately assessing MYCN status in NB, although a larger set of patients needs to be examined to confirm this result.
Serum Proteomic Fingerprinting Discriminates Between Clinical Stages and Predicts Disease Progression in Melanoma Patients
Authors: Mian Shahid , Ugurel Selma , Parkinson Erika , Schlenzka Iris , Dryden Ian , Lancashire Lee , Ball Graham , Creaser Colin , Rees Robert , Schadendorf Dirk 
Published: July 2005

Purpose Currently known serum biomarkers do not predict clinical outcome in melanoma. S100-β is widely established as a reliable prognostic indicator in patients with advanced metastatic disease but is of limited predictive value in tumor-free patients. This study was aimed to determine whether molecular profiling of the serum proteome could discriminate between early- and late-stage melanoma and predict disease progression. Patients and Methods Two hundred five serum samples from 101 early-stage (American Joint Committee on Cancer [AJCC] stage I) and 104 advanced stage (AJCC stage IV) melanoma patients were analyzed by matrix-assisted laser desorption/ionisation (MALDI) time-of-flight (ToF; MALDI-ToF) mass spectrometry utilizing protein chip technology and artificial neural networks (ANN). Serum samples from 55 additional patients after complete dissection of regional lymph node metastases (AJCC stage III), with 28 of 55 patients relapsing within the first year of follow-up, were analyzed in an attempt to predict disease recurrence. Serum S100-β was measured using a sandwich immunoluminometric assay. Results Analysis of 205 stage I/IV serum samples, utilizing a training set of 94 of 205 and a test set of 15 of 205 samples for 32 different ANN models, revealed correct stage assignment in 84 (88%) of 96 of a blind set of 96 of 205 serum samples. Forty-four (80%) of 55 stage III serum samples could be correctly assigned as progressors or nonprogressors using random sample cross-validation statistical methodologies. Twenty-three (82%) of 28 stage III progressors were correctly identified by MALDI-ToF combined with ANN, whereas only six (21%) of 28 could be detected by S100-β. Conclusion Validation of these findings may enable proteomic profiling to become a valuable tool for identifying high-risk melanoma patients eligible for adjuvant therapeutic interventions.
Phase II/III Study of Doxorubicin With Fluorouracil Compared With Streptozocin With Fluorouracil or Dacarbazine in the Treatment of Advanced Carcinoid Tumors: Eastern Cooperative Oncology Group Study E1281
Authors: Sun Weijing , Lipsitz Stuart , Catalano Paul , Mailliard James A. , Haller Daniel G. 
Published: July 2005

Purpose Optimal treatments for metastatic carcinoid tumor remain undefined, and the role of chemotherapy for symptomatic patients with progressive disease is uncertain. Patients and Methods Two hundred forty-nine patients with advanced carcinoid tumors were randomized to either doxorubicin with fluorouracil (FU/DOX) or streptozocin with fluorouracil (FU/STZ). Patients crossed over to the dacarbazine (DTIC) treatment after disease progression following first-line treatment (either FU/DOX or FU/STZ), and 73 patients were assigned to one of these three treatments based on their previous treatment or on abnormal baseline cardiac or renal function. Results In the randomized group, there was no difference between FU/DOX and FU/STZ in response rates (15.9% v 16%) and progression-free survival (4.5 v 5.3 months). FU/STZ (24.3 months) was superior to FU/DOX (15.7 months; P = .0267) in median survival. The response rate of crossover DTIC treatment was 8.2%, with a median survival of 11.9 months. Hematologic toxicities were the major treatment-related toxicities for both FU/DOX and FU/STZ, and mild to moderate renal toxicity was reported in 40 (34.8%) of 115 patients in the FU/STZ arm. Conclusion Response to all three treatment regimens were modest. FU/STZ improved survival compared with the doxorubicin-based regimen, suggesting that the combination should be considered to be an active regimen of therapy when chemotherapy is judged to be an option for selected patients with carcinoid tumors.
Prognostic Value of Translocation t(11;18) in Tumoral Response of Low-Grade Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue Type to Oral Chemotherapy
Authors: Lévy Michaël , Copie-Bergman Christiane , Gameiro Christine , Chaumette Marie-Thérèse , Delfau-Larue Marie-Hélène , Haioun Corinne , Charachon Antoine , Hemery François , Gaulard Philippe , Leroy Karen , Delchier Jean-Charles 
Published: July 2005

Purpose To determine the impact of translocation t(11;18) on response to oral alkylating agents in gastric mucosa-associated lymphoid tissue lymphoma (GML). Patients and Methods Fifty-three patients with a GML were studied. Helicobacter pylori--positive patients (n = 34) received anti–H pylori treatment and H pylori–negative patients (n = 19) or patients who failed to respond to anti–H pylori treatment received oral alkylating agents. t(11;18) was detected by reverse transcription polymerase chain reaction from frozen gastric biopsies. Results t(11;18) was detected in 32% of patients. It was more prevalent in H pylori--negative as compared with H pylori--positive patients (12 of 19 v five of 34 patients; P = .0005). Among 31 H pylori–eradicated patients, t(11;18) was detected in three patients, all of whom experienced treatment failure, and it was absent in 28 patients: 21 patients (75%) were in remission and seven patients (25%) experienced treatment failure (P = .03). Among 21 patients who received an alkylating agent, t(11;18) was detected in 12 patients: five patients (42%) were in remission and seven patients (58%) experienced treatment failure. t(11;18) was absent in nine patients: eight patients (89%) were in remission and one patient (11%) experienced treatment failure by the end of treatment. Four patients in remission relapsed during follow-up (median, 7 years): they all had t(11;18). Durable remission was obtained in eight (89%) of the nine patients without t(11;18) versus one of the 12 patients (8%) with t(11;18) (P = .0003). Conclusion Presence of t(11;18) in GML is predictive of resistance to oral alkylating agents, with less than 10% of durable remission at long-term follow-up.
Blood Pressure and Body Mass Index in Long-Term Survivors of Testicular Cancer
Authors: Sagstuen H. , Aass N. , Fosså S.D. , Dahl O. , Klepp O. , Wist E.A. , Wilsgaard T. , Bremnes R.M. 
Published: July 2005

Purpose To evaluate blood pressure and body mass index (BMI) in long-term survivors of testicular cancer (TC) treated with different modalities. Patients and Methods One thousand eight hundred fourteen patients treated for unilateral TC in Norway (1980 to 1994) were invited to participate in a follow-up study (1998 to 2002), including measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP), and BMI. Of these patients, 1,289 patients (71%) participated in the study. The patients were categorized into four treatment groups: surgery (n = 242), radiotherapy (n = 547), and two chemotherapy groups, cumulative cisplatin dose ≤ 850 mg (n = 402) and cumulative cisplatin dose more than 850 mg (n = 98). A control group consisted of healthy males from the Tromsø Population Study (n = 2,847). Results At diagnosis, age-adjusted regression analyses showed no differences between the treatment groups for any variables. After a median follow-up time of 11.2 years, age-adjusted SBP and DBP were significantly higher for both chemotherapy groups compared with the surgery group. Chemotherapy-treated patients had increased odds for hypertension at follow-up compared with the surgery group, and the odds were highest for the cisplatin more than 850 mg group (odds ratio = 2.4; 95% CI, 1.4 to 4.0). The cisplatin more than 850 mg group had a significantly higher 10-year BMI increase and a higher prevalence of obesity at follow-up than the surgery group. Compared with healthy controls, chemotherapy-treated patients had, at follow-up, increased SBP, increased DBP, excessive BMI increase, and a higher prevalence of hypertension. Conclusion Five to 20 years after therapy, cured TC patients treated with cisplatin-based chemotherapy had significantly higher levels of blood pressure, a higher prevalence of hypertension, and an excessive weight gain compared with patients treated with other modalities and compared with healthy controls.