bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interaction of Rotaviruses with Hsc70 during Cell Entry Is Mediated by VP5
Authors: Zárate Selene , Cuadras Mariela A. , Espinosa Rafaela , Romero Pedro , Juárez Karla O. , Camacho-Nuez Minerva , Arias Carlos F. , López Susana 
Published: June 2003

ABSTRACTRotavirus infection seems to be a multistep process in which the viruses are required to interact with several cell surface molecules to enter the cell. The virus spike protein VP4, which is cleaved by trypsin into two subunits, VP5 and VP8, is involved in some of these interactions. We have previously shown that the neuraminidase-sensitive rotavirus strain RRV initially attaches to a sialic acid-containing cell molecule through the VP8 subunit of VP4 and subsequently interacts with integrin α2β1 through VP5. After these initial contacts, the virus interacts with at least two additional proteins located at the cell surface, the integrin αvβ3 and the heat shock cognate protein Hsc70. In this work, we have shown that rotavirus RRV and its neuraminidase-resistant variant nar3 interact with Hsc70 through a VP5 domain located between amino acids 642 and 658 of the protein. This conclusion is based on the observation that a recombinant protein comprising the 300 carboxy-terminal amino acids of VP5 binds specifically to Hsc70 and a synthetic peptide containing amino acids 642 to 658 competes with the binding of the RRV and nar3 viruses to the heat shock protein. The VP5 peptide also competed with the binding to Hsc70 of the recombinant VP5 protein, and an antibody to Hsc70 reduced the binding of the recombinant protein to the surface of MA104 cells. The fact that the synthetic peptide blocks the infectivity of rotaviruses RRV and nar3 but not their binding to cells indicates that the interaction of VP5 with Hsc70 most probably occurs at a postattachment step during the virus entry process.
Ex Vivo Analysis of T-Cell Responses to Epstein-Barr Virus-Encoded Oncogene Latent Membrane Protein 1 Reveals Highly Conserved Epitope Sequences in Virus Isolates from Diverse Geographic Regions
Authors: Duraiswamy Jaikumar , Burrows Jacqueline M. , Bharadwaj Mandvi , Burrows Scott R. , Cooper Leanne , Pimtanothai Nattiya , Khanna Rajiv 
Published: June 2003

ABSTRACTEpstein-Barr virus (EBV)-encoded oncogene latent membrane protein (LMP) 1, which is consistently expressed in multiple EBV-associated malignancies, has been proposed as a potential target antigen for any future vaccine designed to control these malignancies. However, the high degree of genetic variation in the LMP1 sequence has been considered a major impediment for its use as a potential immunotherapeutic target for the treatment of EBV-associated malignancies. In the present study, we have employed a highly efficient strategy, based on ex vivo functional assays, to conduct an extensive sequence-wide analysis of LMP1-specific T-cell responses in a large panel of healthy virus carriers of diverse ethnic origin and nasopharyngeal carcinoma patients. By comparing the frequencies of T cells specific for overlapping peptides spanning LMP1, we mapped a number of novel HLA class I- and class II-restricted LMP1 T-cell epitopes, including an epitope with dual HLA class I restriction. More importantly, extensive sequence analysis of LMP1 revealed that the majority of the T-cell epitopes were highly conserved in EBV isolates from Caucasian, Papua New Guinean, African, and Southeast Asian populations, while unique geographically constrained genetic variation was observed within one HLA A2 supertype-restricted epitope. These findings indicate that conserved LMP1 epitopes should be considered in designing epitope-based immunotherapeutic strategies against EBV-associated malignancies in different ethnic populations.
Triumph of the light—isopathy and the rise of transcendental homeopathy, 1830–1920
Authors: Morrell P 
Published: June 2003

Modern homeopathy dwells in a nebulous and metaphysical realm into which few non-homeopathic doctors would venture; a very different world and speaking a language virtually incomprehensible to science. Fundamentally incompatible systems, their highly sophisticated conceptions of “disease” and “cure” are sufficiently divergent to prevent their peaceful coexistence. Can the best of modern scientific medicine be reconciled with this recently resuscitated “medical Lazarus”? Could a creative dialogue be established? This article explores the development of modern homeopathic thinking between 1830 and 1920, charting a discourse within homeopathy initiated in the 1830s with reference to use of “higher potencies” and disease products (“nosodes”). Incorporation of disease products into the homeopathic mainstream killed off and supplanted the earlier allopathic version of homeopathy, encouraged the use of higher potencies, and legitimated a widespread adoption of metaphysical views within the movement, here termed “transcendental homeopathy”.Long before the birth of bacteriotherapy ... homeopathic physicians carried out investigation in their own way, and discovered similar medicines, and effected numerous cures ... Hydrophobium was proved in 1833 ... 50 years before Pasteur ... many others followed.1
Does Babbling Sound Native? Listener Responses to Vocalizations Produced by Swedish and American 12- and 18-Month-Olds
Authors: Engstrand Olle , Williams Karen , Lacerda Francisco 
Published: June 2003

Abstract
Previous studies of infants’ babbling have reported contradictory results as to the extent and timing of discernible phonetic influences of the ambient language. In the present experiment, five experienced phoneticians were asked to listen for ambient language effects on vocalizations produced by American and Swedish 12- and 18-month-olds (with 8 children in each language and age group), and to motivate their decisions in terms of word or phonetic cue perception. Group results indicated that listeners did not perceive effects of ambient language on pure babbles for either of the two age groups, whereas a clear effect appeared in both age groups given a more liberal definition of babbling. This is taken to suggest that results of ambient language listening tests may depend crucially on judgments of vocalizations’ word status. As compared to the group trends, listener responses to individual children’s vocalizations did not indicate that a majority of either 12- or 18-monthers were sufficiently native-sounding to be reliably identified on the basis of ambient language. A closer analysis of listeners’ use of phonetic cues indicated that one single phonetic property, the grave tonal word accent, was discerned by most listeners in vocalizations produced by the Swedish 18-monthers; this property was also discerned by one listener in vocalizations produced by Swedish 12-monthers. This result is consistent with the generally held belief in the primacy of tonal features in phonetic acquisition, and with experimental evidence indicating that Swedish mothers tend to enhance word accent contours in baby talk. In the final section of the paper, the results are discussed with a view to reconcile competing theories of babbling development, notably the ‘babbling drift’ and the ‘independence’ hypotheses.
Combined Treatment With Arsenic Trioxide and All-Trans-Retinoic Acid in Patients With Relapsed Acute Promyelocytic Leukemia
Authors: Raffoux Emmanuel , Rousselot Philippe , Poupon Joël , Daniel Marie-Thérèse , Cassinat Bruno , Delarue Richard , Taksin Anne-Laure , Réa Delphine , Buzyn Agnès , Tibi Annick , Lebbé Geneviève , Cimerman Patricia , Chomienne Christine , Fermand Jean-Paul , de Thé Hugues , Degos Laurent , Hermine Olivier , Dombret Hervé 
Published: June 2003

Purpose: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO. Patients and Methods: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response. Results: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity. Conclusion: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.
Randomized Trial of Adjuvant Chemotherapy With Mitomycin, Fluorouracil, and Cytosine Arabinoside Followed by Oral Fluorouracil in Serosa-Negative Gastric Cancer: Japan Clinical Oncology Group 9206–1
Authors: Nashimoto Atsushi , Nakajima Toshifusa , Furukawa Hiroshi , Kitamura Masatsugu , Kinoshita Taira , Yamamura Yoshitaka , Sasako Mitsuru , Kunii Yasuo , Motohashi Hisahiko , Yamamoto Seiichiro ,   the Gastric Cancer Surgical Study Group in the Japan Clinical Oncology Group
Published: June 2003

Purpose: To evaluate the survival benefit of adjuvant chemotherapy after curative resection in serosa-negative gastric cancer patients (excluding patients who were T1N0), we conducted a multicenter phase III clinical trial in which 13 cancer centers in Japan participated. Patients and Methods: From January 1993 to December 1994, 252 patients were enrolled into the study and allocated randomly to adjuvant chemotherapy or surgery alone. The chemotherapy comprised intravenous mitomycin 1.33 mg/m2, fluorouracil (FU) 166.7 mg/m2, and cytarabine 13.3 mg/m2 twice weekly for the first 3 weeks after surgery, and oral FU 134 mg/m2 daily for the next 18 months for a total dose of 67 g/m2. The primary end point was relapse-free survival. Overall survival and the site of recurrence were secondary end points. Results: Ninety-eight percent of patients underwent gastrectomy with D2 or greater lymph node dissection. There were no treatment-related deaths and few serious adverse events. There was no significant difference in relapse-free and overall survival between the arms (5-year relapse-free survival 88.8% chemotherapy v 83.7% surgery alone; P = .14 and 5-year survival 91.2% chemotherapy v 86.1% surgery alone; P = .13, respectively). Nine patients (7.1%) in the chemotherapy arm and 17 patients (13.8%) in the surgery-alone arm had cancer recurrence. Conclusion: There was no statistically significant relapse-free or overall survival benefit with this adjuvant chemotherapy for patients with macroscopically serosa-negative gastric cancer after curative resection, and there was no statistical difference between the two arms relating to the types of cancer recurrence. We do not recommend adjuvant chemotherapy with this regimen for this population in clinical practice.
Long-Term Prospective Follow-Up Study of Cardiac Function After Cardiotoxic Therapy for Malignancy in Children
Authors: Poutanen Tuija , Tikanoja Tero , Riikonen Pekka , Silvast Annuli , Perkkiö Mikko 
Published: June 2003

Purpose: To evaluate cardiac function by means of conventional and three-dimensional echocardiography (3DE) and measurement of natriuretic peptides in children and adolescents previously treated for childhood malignancy using individual follow-up data and matched control children as reference criteria. Patients and Methods: Thirty-nine survivors of childhood malignancy were examined in 1994 and 1998. The mean time from the diagnosis was 8.6 (3.9 to 16.8) years and between cardiac evaluations was 4.1 (3.3 to 5.1) years. Patients were divided into two groups according to therapies given (group I (n = 30): no cardiac irradiation, median cumulative anthracycline dose 210 mg/m2; group II (n = 9): irradiation in the cardiac region, median cumulative anthracycline dose 180 mg/m2). Results: Fractional shortening (FS) in 1994 was higher than in 1998 (32.5 ± 4.3 vs. 30.3% ± 3.3%, P = .009). 33% of patients in group I and 56% in group II in 1994 and 30% of patients in group I and 67% in group II in 1998 had N-terminal of the propeptide-atrial natriuretic peptide (NT-proANP) levels exceeding the 90th percentile of controls. In 1998, both groups (I and II) had lower ejection fraction (EF) measured by 3DE than their matched controls (52.9 ± 5.2 vs. 58.8% ± 3.1%, P < .001 and 50.0 ± 6.6 vs. 60.8% ± 3.2%, P = .024, respectively). Left atrial maximum volumes/body surface area were smaller in the patients than in controls. B-Type natriuretic peptide values did not differ significantly in either group. Conclusion: Left ventricular contractility decreases slowly even years after cardiotoxic cancer therapy in children. 3DE and NT-proANP measurements are effective methods to evaluate the cardiac function in these patients.
Soluble E-Cadherin is an Independent Pretherapeutic Factor for Long-Term Survival in Gastric Cancer
Authors: Chan Annie On-On , Chu Kent-Man , Lam Shiu-Kum , Wong Benjamin Chun-Yu , Kwok Ka-Fai , Law Simon , Ko Samuel , Hui Wai-Mo , Yueng Yui-Hung , Wong John 
Published: June 2003

Purpose: To evaluate whether pretherapeutic serum soluble E-cadherin is an independent factor predicting long-term survival in gastric cancer. Gastric cancer remains the second leading cause of cancer-related deaths in the world, but a satisfactory tumor marker is currently unavailable for gastric cancer. Soluble E-cadherin has recently been found to have prognostic value in gastric cancer. Patients and Methods: One hundred sixteen patients with histologically proven gastric adenocarcinoma were included in the trial. Pretherapeutic serum was collected, and soluble E-cadherin was assayed using a commercially available enzyme-linked immunosorbent assay kit. The patients were followed up prospectively at the outpatient clinic. Results: There were 75 men and 41 women, with a mean (± SD) age of 66 ± 14 years. Forty-eight percent of tumors were located in the gastric antrum. The median survival time was 11 months. The mean pretherapeutic value of soluble E-cadherin was 9,159 ng/mL (range, 6,002 to 10,025 ng/mL), and the mean pretherapeutic level of carcinoembryonic antigen was 11 ng/mL (range, 0.3 to 4,895 ng/mL). On multivariate analysis, soluble E-cadherin is an independent factor predicting long-term survival. Ninety percent of patients with a serum level of E-cadherin greater than 10,000 ng/mL had a survival time of less than 3 years (P = .009). Conclusion: Soluble E-cadherin is a potentially valuable pretherapeutic prognostic factor in patients with gastric cancer.
Barriers to Clinical Trial Participation by Older Women With Breast Cancer
Authors: Kemeny M. Margaret , Peterson Bercedis L. , Kornblith Alice B. , Muss Hyman B. , Wheeler Judith , Levine Ellis , Bartlett Nancy , Fleming Gini , Cohen Harvey J. 
Published: June 2003

Purpose: Although 48% of breast cancer patients are 65 years old or older, these older patients are severely underrepresented in breast cancer clinical trials. This study tested whether older patients were offered trials significantly less often than younger patients and whether older patients who were offered trials were more likely to refuse participation than younger patients. Patients and Methods: In 10 Cancer and Leukemia Group B institutions, using a retrospective case-control design, breast cancer patients eligible for an open treatment trial were paired: less than 65 years old and ≥ 65 years old. Each of the 77 pairs were matched by disease stage and treating physician. Patients were interviewed as to their reasons for participating or refusing to participate in a trial. The treating physicians were also given questionnaires about their reasons for offering or not offering a trial. Results: Sixty-eight percent of younger stage II patients were offered a trial compared with 34% of the older patients (P = .0004). In multivariate analyses, disease stage and age remained highly significant in predicting trial offering (P = .0008), when controlling for physical functioning and comorbidity. Of those offered a trial, there was no significant difference in participation between younger (56%) and older (50%) patients (P = .67). Conclusion: In a multivariate analysis including comorbid conditions, age and stage were the only predictors of whether a patient was offered a trial. The greatest impediment to enrolling older women onto trials in the setting of this study was the physicians’ perceptions about age and tolerance of toxicity.
Repeated Intravesical Instillations of an Adenoviral Vector in Patients With Locally Advanced Bladder Cancer: A Phase I Study of p53 Gene Therapy
Authors: Pagliaro Lance C. , Keyhani Afsaneh , Williams Dallas , Woods Denise , Liu Baoshun , Perrotte Paul , Slaton Joel W. , Merritt James A. , Grossman H. Barton , Dinney Colin P. 
Published: June 2003

Purpose: We investigated the feasibility, safety, and biologic activity of adenovirus-mediated p53 gene transfer in patients with locally advanced bladder cancer. Patients and Methods: Patients with measurable, locally advanced transitional-cell carcinoma of the bladder who were not candidates for cystectomy were eligible. On a 28-day cycle, intravesical instillations of INGN 201 (Ad5CMV-p53) were administered on days 1 and 4 at three dose levels (1010 particles to 1012 particles) or on either 4 or 8 consecutive days at a single dose level (1012 particles). Results: Thirteen patients received a total of 22 courses without dose-limiting toxicity. Specific transgene expression was detected by reverse transcriptase polymerase chain reaction in bladder biopsy tissue from two of seven assessable patients. There were no changes in p53, p21waf1/cip1, or bax protein levels in bladder epithelium evident from immunohistochemical analysis of 11 assessable patients. Outpatient administration of multiple courses was feasible and well tolerated. A patient with advanced superficial bladder cancer showed evidence of tumor response. Conclusion: Intravesical instillation of Ad5CMV-p53 is safe, feasible, and biologically active when administered in multiple doses to patients with bladder cancer. Observations from this study indicate that this treatment has an antitumor effect in superficial transitional-cell carcinoma. Improvements in the efficiency of gene transfer and the levels of gene expression are required to develop more effective gene therapy for bladder cancer.
Phase II Evaluation of Temozolomide and 13-cis-Retinoic Acid for the Treatment of Recurrent and Progressive Malignant Glioma: A North American Brain Tumor Consortium Study
Authors: Jaeckle Kurt A. , Hess Kenneth R. , Yung W.K. Alfred , Greenberg Harry , Fine Howard , Schiff David , Pollack Ian F. , Kuhn John , Fink Karen , Mehta Minesh , Cloughesy Timothy , Nicholas M. Kelly , Chang Susan , Prados Michael 
Published: June 2003

Purpose: Temozolomide (TMZ) and 13-cis-retinoic acid (cRA) have shown activity in prior single-agent trials of recurrent malignant gliomas (MG). This phase II trial evaluated efficacy and toxicity of combination temozolomide and cRA treatment in recurrent MG. Patients and Methods: Adults with recurrent supratentorial MG for whom surgery, radiation, and/or chemotherapy failed were eligible. Treatment included oral TMZ 150 or 200 mg/m2/d, days 1 through 5, and cRA 100 mg/m2/d, days 1 to 21, every 28 days. Primary end point was progression-free survival at 6 months (PFS 6); secondary end points included response, survival, and PFS12. Results: Eighty-eight eligible patients (glioblastoma multiforme [n = 40]; anaplastic gliomas [n = 48; astrocytoma, 28; oligodendroglioma, 14; mixed glioma, six]) received treatment. PFS 6 was 43% (95% confidence interval [CI], 33% to 54%) and PFS12 was 16% (95% CI, 10% to 26%). Median overall PFS was 19 weeks (95% CI, 16 to 27 weeks), and median overall survival (OS) was 47 weeks (95% CI, 36 to 58 weeks). OS was 46% (95% CI, 36% to 57%) at 52 weeks and 21% (95% CI, 13% to 31%) at 104 weeks. Of 84 assessable patients, there were two (3%) complete responses and eight (12%) partial responses (complete plus partial response, 15%). Among 499 treatment cycles, the most common grade 3/4 events included granulocytopenia (1.8%), thrombocytopenia (1.4%), and hypertriglyceridemia (1.2%). Conclusion: TMZ and cRA were active, exceeding our 20% thresholds for PFS 6 success, assuming 20% improvement over our previously reported database (glioblastoma multiforme: expected, 30%; observed, 32%; anaplastic glioma: expected, 40%; observed, 50%).
Immunization With Melan-A Peptide-Pulsed Peripheral Blood Mononuclear Cells Plus Recombinant Human Interleukin-12 Induces Clinical Activity and T-Cell Responses in Advanced Melanoma
Authors: Peterson Amy C. , Harlin Helena , Gajewski Thomas F. 
Published: June 2003

Purpose: Preclinical studies showed that immunization with peripheral blood mononuclear cells (PBMC) loaded with tumor antigen peptides plus interleukin-12 (IL-12) induced CD8+T-cell responses and tumor rejection. We recently determined that recombinant human (rh) IL-12 at 30 to 100 ng/kg is effective as a vaccine adjuvant in patients. A phase II study of immunization with Melan-A peptide-pulsed PBMC + rhIL-12 was conducted in 20 patients with advanced melanoma.Patients and Methods: Patients were HLA-A2–positive and had documented Melan-A expression. Immunization was performed every 3 weeks with clinical re-evaluation every three cycles. Immune responses were measured by ELISpot assay before and after treatment and through the first three cycles, and were correlated with clinical outcome.Results: Most patients had received prior therapy and had visceral metastases. Nonetheless, two patients achieved a complete response, five patients achieved a minor or mixed response, and four patients had stable disease. The median survival was 12.25 months for all patients and was not yet reached for those with a normal lactate dehydrogenase. There were no grade 3 or 4 toxicities. Measurement of specific CD8+T-cell responses by direct ex vivo ELISpot revealed a significant increase in interferon gamma–producing T cells against Melan-A (P = .015) after vaccination, but not against an Epstein-Barr virus control peptide (P = .86). There was a correlation between the magnitude of the increase in Melan-A–specific cells and clinical response (P = .046).Conclusion: This immunization approach may be more straightforward than dendritic cell strategies and seems to have clinical activity that can be correlated to a biologic end point.