bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determinants of Sensitivity and Resistance to Rapamycin-Chemotherapy Drug Combinations In vivo
Authors: Wendel Hans-Guido , Malina Abba , Zhao Zhen , Zender Lars , Kogan Scott C. , Cordon-Cardo Carlos , Pelletier Jerry , Lowe Scott W. 
Published: August 2006

Abstract
The phosphatidylinositol-3-OH kinase [PI(3)K] pathway is frequently activated in human cancers and represents a rational target for therapeutic intervention. We have previously shown that enforced expression of Akt, which is a downstream effector of PI(3)K, could promote tumorigenesis and drug resistance in the Eμ-myc mouse lymphoma model, and that these tumors were particularly sensitive to inhibition of mammalian target of rapamycin (mTOR) with rapamycin when combined with conventional chemotherapy. We now show that reduced dosage of PTEN, a negative regulator of PI(3)K signaling, is sufficient to activate Akt, but has only a modest effect on lymphomagenesis in the same model. Nonetheless, loss of even one PTEN allele resulted in lymphomas that were resistant to conventional chemotherapy yet sensitive to rapamycin/chemotherapy combinations. These effects could be recapitulated by using RNA interference to suppress PTEN expression in lymphomas, which were previously established in the absence of PI(3)K lesions. Finally, the introduction of lesions that act downstream of mTOR (eIF4E) or disable apoptosis (Bcl-2 and loss of p53) into PTEN+/− lymphomas promoted resistance to rapamycin/chemotherapy combinations. Thus, whether activation of the PI(3)K pathway confers sensitivity or resistance to therapy depends on the therapy used as well as secondary genetic events. Understanding these genotype-response relationships in human tumors will be important for the effective use of rapamycin or other compounds targeting the PI(3)K pathway in the clinic. (Cancer Res 2006; 66(15): 7639-46)
Immunosurveillance ofErbb2Carcinogenesis in Transgenic Mice Is Concealed by a Dominant Regulatory T-Cell Self-Tolerance
Authors: Ambrosino Elena , Spadaro Michela , Iezzi Manuela , Curcio Claudia , Forni Guido , Musiani Piero , Wei Wei-Zen , Cavallo Federica 
Published: August 2006

AbstractTo assess the role of CD4+CD25+Foxp3+ regulatory T (Treg) cells in overcoming immunosurveillance of Erbb2 (HER-2/neu) mammary lesions, we studied the effects of their sustained removal in BALB/c female mice made transgenic for the rat Erbb2 (r-Erbb2) oncogene (BALB-neuT mice), which develop multiple mammary carcinomas. During the progression of these lesions, Treg cells expand in the spleen, tumor draining lymph nodes, and tumors. Repeated administration of anti-CD25 antibodies extends tumor-free survival, reduces carcinoma multiplicity, and leads to the manifestation of a natural antibody and CTL-mediated reactivity against r-Erbb2. Loss of Foxp3+ Treg cells during anti-CD25 treatment remarkably caused the disappearance of Gr1+ immature myeloid cells, suggesting a cross-talk between these two inhibitory immune cell types. Treg cell expansion associated with r-Erbb2 overexpression may be seen as a physiologic response to dampen the immune reaction elicited by local anomalous overexpression of a self-antigen. (Cancer Res 2006; 66(15): 7734-40)
Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections
Authors: Mumprecht Sabine , Matter Matthias , Pavelic Viktor , Ochsenbein Adrian F. 
Published: July 2006

Abstract
Imatinib mesylate (imatinib) is a potent inhibitor of defined tyrosine kinases (TKs) and is effective in the treatment of malignancies characterized by constitutive activation of these TKs such as chronic myeloid leukemia and gastrointestinal stromal tumors. TKs also play an important role in T-cell receptor (TCR) signal transduction. Inhibitory as well as stimulating effects of imatinib on T cells and dendritic cells have been described. Here, we analyzed the effects of imatinib treatment on antiviral immune responses in vivo. Primary cytotoxic T-cell (CTL) responses were not impaired in imatinib-treated mice after infection with lymphocytic choriomeningitis virus (LCMV) or after immunization with a tumor cell line expressing LCMV glycoprotein (LCMV-GP). Similarly, neutralizing antibody responses to vesicular stomatitis virus (VSV) were not affected. In contrast, secondary expansion of LCMV-specific memory CTLs was reduced in vitro and in vivo, resulting in impaired protection against reinfection. In addition, imatinib treatment delayed the onset of diabetes in a CTL-induced diabetes model. In summary, imatinib treatment in vivo selectively inhibits the expansion of antigen-experienced memory CTLs without affecting primary T- or B-cell responses. Therefore, imatinib may be efficacious in the suppression of CTL-mediated immunopathology in autoimmune diseases without the risk of acquiring viral infections.
Integrative roles of transforming growth factor-α in the cytoprotection mechanisms of gastric mucosal injury
Authors: Kosone Takashi , Takagi Hitoshi , Kakizaki Satoru , Sohara Naondo , Horiguchi Norio , Sato Ken , Yoneda Masashi , Takeuchi Toshiyuki , Mori Masatomo 
Published: August 2006

Abstract

Background
Transforming growth factor α (TGFα) protects against gastric mucosal injury and facilitates wound healing. However, its overexpression is known to induce hypertrophic gastropathy resembling Menetrier's disease in transgenic (TG) mice on an FVB background, as one of the authors reported previously. We studied another TGFα-expressing mouse line on a CD1 background, whose gastric mucosa appears normal. Since this TG mouse had a strong resistance to ethanol-induced gastric injury, we considered the long-term effect of TGFα on several gastric protection mechanisms.

Methods
TGFα-expressing transgenic (TG) mouse lines bearing human TGFα cDNA under the control of the mouse metallothionein gene I promoter were generated on a CD1 mouse background, and analyzed their ethanol injury-resistant phenotypes produced by TGFα.

Results
In the TG mucosa, blood flow was well maintained after ethanol injury. Further, neural and inducible types of NO synthases were consistently and widely expressed in the TG mucosa, compared with the limited distribution of neural type NO synthase in the luminal pit region of the wild-type (WT) mucosa. COX-2 and its upstream transcription factor NfkB were constitutively elevated in the TG mucosa even before ethanol administration, whereas they were induced in the same region of the WT mucosa only after ethanol injury. Two anti-apoptotic proteins, HSP70 and Bcl-2, were upregulated in the TG mucosa even before ethanol administration, while they were not expressed in the WT mucosa before the injury. Furthermore, pro-caspase 3 activation was inhibited in the TG mucosa, while it was converted to the active form in the WT mucosa following ethanol administration.

Conclusion
We conclude that TGFα maintains the gastric mucosal defense against gastric injury by integrating other cytoprotective mechanisms.
Total knee arthroplasty: good agreement of clinical severity scores between patients and consultants
Authors: Ebinesan Ananthan D , Sarai Bhupinder S , Walley Gayle , Bridgman Stephen , Maffulli Nicola 
Published: August 2006

Abstract

Background
Nearly 20,000 patients per year in the UK receive total knee arthroplasty (TKA). One of the problems faced by the health services of many developed countries is the length of time patients spend waiting for elective treatment. We therefore report the results of a study in which the Salisbury Priority Scoring System (SPSS) was used by both the surgeon and their patients to ascertain whether there were differences between the surgeon generated and patient generated Salisbury Priority Scores.

Methods
The Salisbury Priority Scoring System (SPSS) was used to assign relative priority to patients with knee osteoarthritis as part of a randomised controlled trial comparing the standard medial parapatellar approach versus the sub-vastus approach in TKA. The operating surgeons and each patient completed the SPSS at the same pre-assessment clinic. The SPSS assesses four criteria, namely progression of disease, pain or distress, disability or dependence on others, and loss of usual occupation. Crosstabs and agreement measures (Cohen's kappa) were performed.

Results
Overall, the four SPSS criteria showed a kappa value of 0.526, 0.796, 0.813, and 0.820, respectively, showing moderate to very good agreement between the patient and the operating consultant. Male patients showed better agreement than female patients.

Conclusion
The Salisbury Priority Scoring System is a good means of assessing patients' needs in relation to elective surgery, with high agreement between the patient and the operating surgeon.
Antisense oligonucleotide inhibition of hepatitis C virus genotype 4 replication in HepG2 cells
Authors: El Awady Mostafa K , El Din Noha G Badr , El Garf Wael T , Youssef Samar S , Omran Moataza H , El Abd Jasmin , Goueli Said A 
Published: July 2006

Abstract

Background
Hepatitis C (HCV) viral infection is a serious medical problem in Egypt and it has a devastating impact on the Egyptian economy. It is estimated that over 15% of Egyptians are infected by the virus and thus finding a cure for this disease is of utmost importance. Current therapies for hepatitis C virus (HCV) genotype 4 with interferon/ribavirin have not been successful and thus the development of alternative therapy for this genotype is disparately needed.

Results
Although previous studies utilizing viral subgenomic or full cDNA fragments linked to reporter genes transfected into adhered cells or in a cell free system showed promise, demonstration of efficient viral replication was lacking. Thus, we utilized HepG2 cells infected with native HCV RNA genomes in a replication competent system and used antisense phosphorothioate Oligonucleotides (S-ODN) against stem loop IIId and the AUG translation start site of the viral polyprotein precursor to monitor viral replication. We were able to show complete arrest of intracellular replication of HCV-4 at 1 uM S-ODN, thus providing a proof of concept for the potential antiviral activity of S-ODN on native genomic replication of HCV genotype 4.

Conclusion
We have successfully demonstrated that by using two S-ODNs [(S-ODN1 (nt 326–348) and S-ODN-2 (nt 264–282)], we were able to completely inhibit viral replication in culture, thus confirming earlier reports on subgenomic constructs and suggesting a potential therapeutic value in HCV type 4.
Service user involvement in training: the trainees' view
Authors: Vijayakrishnan Ajay , Rutherford Joan , Miller Steve , Drummond Lynne M. 
Published: August 2006

Aims and MethodA questionnaire survey was conducted of trainees across the South-West London and St George's Basic Specialist Training Scheme in Psychiatry to explore their attitudes towards service user involvement in training.ResultsFifty-two completed questionnaires were received; 20 trainees (38%) had not attended teaching sessions where a user was present; 35 trainees (67%) were agreeable to service user involvement in examinations. Reservations concerned the objectivity of service users in examination rating and their role as an expert on assessing the trainee's skill. Awareness of user involvement strategies and policies in their trusts were not matched with actual participation.Clinical ImplicationsService users should be involved in teaching in an expert capacity and also in examinations, with safeguards regarding transparency and objectivity of the marking schemes in place.
Double-Blind, Placebo-Controlled Study of Quality of Life, Hematologic End Points, and Safety of Weekly Epoetin Alfa in Children With Cancer Receiving Myelosuppressive Chemotherapy
Authors: Razzouk Bassem I. , Hord Jeffrey D. , Hockenberry Marilyn , Hinds Pamela S. , Feusner James , Williams Denise , Rackoff Wayne R. 
Published: July 2006

Purpose To evaluate the effects of once-weekly epoetin alfa (EPO) on health-related quality of life (HRQOL), hemoglobin (Hb), transfusions, and tolerability in children with cancer. Methods Anemic patients 5 years to 18 years of age receiving myelosuppressive chemotherapy for nonmyeloid malignancies, excluding brain tumors, received intravenous EPO 600 units/kg to 900 units/kg or placebo once-weekly for 16 weeks. Patients and parents completed the pediatric health-related quality-of-life generic scales (GS) and cancer-specific scales (CS). Results One hundred eleven patients received EPO and 111 patients received placebo. Mean final values for GS total score (P = .763 among patients; P = .219 among parents) and CS domain scores (P ≥ .238; P ≥ .081, respectively) were not significantly different between treatment groups. EPO-treated patients had greater increases in Hb overall (P = .002) and were more likely to be transfusion free after 4 weeks (38.7% v 22.5%; P = .010). Change in Hb was correlated with change in PedsQL-GCS total score in the EPO group (r = 0.242; P = .018), but was not in the placebo group (r = 0.086; P = .430). Adverse events were comparable between treatment groups. Conclusion This study confirmed the tolerability and hematologic benefits of once-weekly EPO in children with cancer. No significant difference in HRQOL was detected between treatment groups, but a significant positive correlation was observed between Hb changes and HRQOL changes in the EPO group. Additional studies are warranted to assess HRQOL when anemia is managed optimally in children with cancer.
Clinical Characteristics Affect the Impact of an Uninformative DNA Test Result: The Course of Worry and Distress Experienced by Women Who Apply for Genetic Testing for Breast Cancer
Authors: van Dijk Sandra , Timmermans Daniëlle R.M. , Meijers-Heijboer Hanne , Tibben Aad , van Asperen Christi J. , Otten Wilma 
Published: July 2006

Purpose DNA mutation testing for breast cancer usually yields an uninformative result, which is a negative result in the absence of a known BRCA mutation within the family. However, few data are available on the psychological impact of this result. Moreover, the clinical heterogeneity within this group has not yet been considered. This study provides prospective data about the course of cancer-specific worry and distress for different groups of test applicants. Patients and Methods All DNA test applicants (n = 238) completed three questionnaires: before and 1 and 7 months after disclosure of a DNA mutation test. With repeated-measures analysis of variance, differences were assessed between BRCA1/2-positive women (n = 42), BRCA1/2–true-negative women (n = 43), and women with an uninformative test result (n = 153). Results On the group level, women with an uninformative result seemed to be reassured after disclosure (P < .001), but to a lesser extent than those women who received a true-negative result. However, not all women with an uninformative result reacted similarly: higher levels of worry and distress could be explained by relatively straightforward clinical variables, namely a personal history of cancer (P ≤ .001) and a higher pedigree-based risk (P ≤ .005). Furthermore, these clinical variables determined whether these women were either comparable to women who received a true-negative result or to BRCA mutation carriers. Conclusion Women with an uninformative result form a heterogeneous group of test applicants. The subpopulation of those with both a personal history of cancer and a relatively high pedigree-based risk expressed the highest levels of worry 7 months after DNA testing.
Prospective Study of Incidence and Severity of Epiphora and Canalicular Stenosis in Patients With Metastatic Breast Cancer Receiving Docetaxel
Authors: Esmaeli Bita , Amin Sapna , Valero Vicente , Adinin Rosnie , Arbuckle Rebecca , Banay Roberto , Do Kim-Anh , Rivera Edgardo 
Published: July 2006

Purpose To determine the incidence and severity of epiphora and canalicular stenosis in patients receiving docetaxel weekly or every 3 weeks. Patients and Methods In this prospective trial, each patient underwent an ophthalmologic examination and probing and irrigation of the lacrimal drainage apparatus at baseline and every 4 to 6 weeks after initiation of docetaxel. During each visit, epiphora and canalicular stenosis were graded. Patients with epiphora were treated with tobramycin and dexamethasone drops. If epiphora worsened or if findings on probing and irrigation suggested further canalicular narrowing, silicone intubation was offered. Results Twenty-eight patients received docetaxel weekly, and 28 patients received docetaxel every 3 weeks. Eighteen patients (64%) who received weekly docetaxel developed epiphora. Epiphora was mild in seven patients, moderate in five, and severe in six. Nine patients had resolution of epiphora with tobramycin and dexamethasone administration. Nine patients had worsened canalicular stenosis; six underwent surgery. The median cumulative docetaxel dose was 496.5 mg at onset of epiphora and 889.5 mg at surgery. Eleven patients (39%) who received docetaxel every 3 weeks developed epiphora. The median cumulative docetaxel dose at onset of epiphora in this group was 420 mg. Epiphora was mild in nine patients, moderate in one, and severe in one. Nine patients had resolution of epiphora with tobramycin and dexamethasone administration. Two patients underwent surgery. Conclusion Epiphora occurred in 64% of patients in the weekly group and in 39% of patients in the every-3-weeks group. Moderate or severe canalicular stenosis was seen in about one-third of patients in the weekly group and in none of the patients in the every-3-weeks group.
Residual Disease Monitoring in Childhood Acute Myeloid Leukemia by Multiparameter Flow Cytometry: The MRD-AML-BFM Study Group
Authors: Langebrake Claudia , Creutzig Ursula , Dworzak Michael , Hrusak Ondrej , Mejstrikova Ester , Griesinger Frank , Zimmermann Martin , Reinhardt Dirk 
Published: July 2006

Purpose Monitoring of residual disease (RD) by flow cytometry in childhood acute myeloid leukemia (AML) may predict outcome. However, the optimal time points for investigation, the best antibody combinations, and most importantly, the clinical impact of RD analysis remain unclear. Patients and Methods Five hundred forty-two specimens of 150 children enrolled in the AML-Berlin-Frankfurt-Muenster (BFM) 98 study were analyzed by four-color immunophenotyping at up to four predefined time points during treatment. For each of the 12 leukemia-associated immunophenotypes and time points, a threshold level based on a previous retrospective analysis of another cohort of children with AML and on control bone marrows was determined. Results Regarding all four time points, there is a statistically significant difference in the 3-year event-free survival (EFS) in those children presenting with immunologically detectable blasts at 3 or more time points. The levels at bone marrow puncture (BMP) 1 and BMP2 turned out to have the most significant predictive value for 3-year-EFS: 71% ± 6% versus 48% ± 9%, PLog-Rank = .029 and 70% ± 6% versus 50% ± 7%, PLog-Rank = .033), resulting in a more than two-fold risk of relapse. In a multivariate analysis, using a combined risk classification based on morphologically determined blasts at BMP1 and BMP2, French-American-British classification, and cytogenetics, the influence of immunologically determined RD was no longer statistically significant. Conclusion RD monitoring before second induction has the same predictive value as examining levels at four different time points during intensive chemotherapy. Compared with commonly defined risk factors in the AML-BFM studies, flow cytometry does not provide additional information for outcome prediction, but may be helpful to evaluate the remission status at day 28.
Phase I Single-Dose Study of Intracavitary-Administered Iodine-131-TM-601 in Adults With Recurrent High-Grade Glioma
Authors: Mamelak Adam N. , Rosenfeld Steven , Bucholz Richard , Raubitschek Andrew , Nabors L. Burt , Fiveash John B. , Shen Sui , Khazaeli M.B. , Colcher David , Liu An , Osman Medhat , Guthrie Bart , Schade-Bijur Susan , Hablitz Diana M. , Alvarez Vernon L. , Gonda Matthew A. 
Published: July 2006

Purpose TM-601 binds to malignant brain tumor cells with high affinity and does not seem to bind to normal brain tissue. Preclinical studies suggest that iodine-131 (131I) –TM-601 may be an effective targeted therapy for the treatment of glioma. We evaluated the safety, biodistribution, and dosimetry of intracavitary-administered 131I-TM-601 in patients with recurrent glioma. Patients and Methods Eighteen adult patients (17 with glioblastoma multiforme and one with anaplastic astrocytoma) with histologically documented recurrent glioma and a Karnofsky performance status of ≥ 60% who were eligible for cytoreductive craniotomy were enrolled. An intracavitary catheter with subcutaneous reservoir was placed in the tumor cavity during surgery. Two weeks after surgery, patients received a single dose of 131I-TM-601 from one of three dosing panels (0.25, 0.50, or 1.0 mg of TM-601), each labeled with 10 mCi of 131I. Results Intracavitary administration was well tolerated, with no dose-limiting toxicities observed. 131I-TM-601 bound to the tumor periphery and demonstrated long-term retention at the tumor with minimal uptake in any other organ system. Nonbound peptide was eliminated from the body within 24 to 48 hours. Only minor adverse events were reported during the 22 days after administration. At day 180, four patients had radiographic stable disease, and one had a partial response. Two of these patients further improved and were without evidence of disease for more than 30 months. Conclusion A single dose of 10 mCi 131I-TM-601 was well tolerated for 0.25 to 1.0 mg TM-601 and may have an antitumoral effect. Dosimetry and biodistribution from this first trial suggest that phase II studies of 131I-TM-601 are indicated.
Decision Analysis for Prophylactic Cranial Irradiation for Patients With Small-Cell Lung Cancer
Authors: Lee J. Jack , Bekele B. Nebiyou , Zhou Xian , Cantor Scott B. , Komaki Ritsuko , Lee Jin Soo 
Published: July 2006

Purpose Prophylactic cranial irradiation (PCI) has been shown to provide survival benefit in patients with limited disease small-cell lung cancer (LD-SCLC) who have achieved complete response. However, PCI may also produce long-term neurotoxicity (NT). The benefits and risks of PCI in LD-SCLC are evaluated. Methods We developed a decision-analytic model to compare quality-adjusted life expectancy (QALE) in a cohort of SCLC patients who do or do not receive PCI by varying survival rates and the frequency and severity of PCI-related NT. Sensitivity analyses were applied to examine the robustness of the optimal decision. Results At current published survival rates (26% 5-year survival rate with PCI and 22% without PCI) and a low NT rate, PCI offered a benefit over no PCI (QALE = 4.31 and 3.70 for mild NT severity; QALE = 4.09 and 3.70 for substantial NT severity, respectively). With a moderate NT rate, PCI was still preferred. If the PCI survival rate increased to 40%, PCI outperformed no PCI with a mild NT severity. However, no PCI was preferred over PCI (QALE = 5.72 v 5.47) with substantial NT severity. Two-way sensitivity analyses showed that PCI was preferred for low NT rates, mild NT severity, and low long-term survival rates. Otherwise, no PCI was preferred. Conclusion The current data suggest PCI offers better QALE than no PCI in LD-SCLC patients who have achieved complete response. As the survival rate for SCLC patients continues to improve, NT rate and NT severity must be controlled to maintain a favorable benefit-risk ratio for recommending PCI.