bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug-induced lupus following treatment with infliximab in rheumatoid arthritis
Authors: Favalli E G , Sinigaglia L , Varenna M , Arnoldi C
Published: November 2002

After introduction of infliximab for the treatment of rheumatoid arthritis (RA), there have been many reports of patients developing asymptomatic higher rate of antinuclear antibodies and antidsDNA antibodies than in non-infliximab-treated patients. However, only five clinical drug-induced lupus (DIL) cases have been documented following treatment with infliximab, in RA and in Crohn's diseases. We report a case of a 69-year-old female with a 5 year history of RA, who was successfully treated with low-dose methotrexate (MTX) and infliximab (initially 3 mg/kg and from the fourth infusion 5 mg/kg) for 23 weeks. Before the sixth infusion, she was diagnosed with DIL by both clinical features (fever> 38°C, recurrence of active synovitis, myalgia, erythematous rash and general malaise) and laboratory findings (antinuclear antibodies 1:160, anti-double-stranded DNA positive by ELISA assay, decreased serum complement C3 and C4, hypergammaglobulinaemia, increased erythrocyte sedimentation rate). After discontinuation of treatment and therapy with oral prednisone, lupus resolved within 8 weeks.
Antiphospholipid syndrome in a patient with sarcoidosis: a case report
Authors: Singh R , Conway M D , Wilson W A
Published: November 2002

We report the case of a 72-year-old female with sarcoidosis who developed a central retinal artery occlusion in her left eye in association with persistently high titers of IgG anti-cardiolipin antibodies. Only two previous cases of antiphospholipid antibody syndrome in association with sarcoidosis have been reported. Our patient's vision stabilized on anti-coagulant therapy along with concomitant treatment of sarcoidosis-related uveitis with methotrexate.
Pregnancy outcome in 100 women with autoimmune diseases and anti-Ro/SSA antibodies: a prospective controlled study
Authors: Brucato A , Doria A , Frassi M , Castellino G , Franceschini F , Faden D , Pisoni M Pia , Solerte L , Muscarà M , Lojacono A , Motta M , Cavazzana I , Ghirardello A , Vescovi F , Tombini V , Cimaz R , Gambari P F , Meroni P L , Canesi B , Tincani A
Published: November 2002

Anti-Ro/SSA antibodies are associated with neonatal lupus but are also considered a possible cause for unexplainedpregnancy loss and adverse pregnancy outcome. In a large multicentres cohort study we have prospectivelyfollowed 100 anti-Ro/SSA positivewomen (53 systemic lupus erythematosus (SLE)) during their 122 pregnancies and 107 anti-Ro/SSA negative women (58 SLE) (140 pregnancies).Anti-Ro/SSA antibodies were tested by immunoblot and counterimmunoelectrophoresis. Mean gestational age at delivery (38 vs 37.9 weeks), prevalence of pregnancy loss (9.9 vs 18.6%), preterm birth (21.3 vs 13.9%), cesarean sections (49.2 vs 53.4%), premature rupture of membranes(4.9 vs 8.1%), preeclampsia(6.6 vs 8.1%), intrauterinegrowth retardation(0 vs 2.3%) and newborns small for gestationalage (11.5 vs 5.8%) were similar in anti-Ro/SSA positive and negative SLE mothers; findings were similar in non-SLE women. Two cases of congenital heart block were observed out of 100 anti-Ro/SSA positive women. In conclusion, anti-Ro/SSA antibodies are responsiblefor congenitalheart block but do not affect other pregnancyoutcomes,both in SLE and in non-SLE women. The general outcome of these pregnancies is now very good, if prospectively followedby multidisciplinaryteams with ample experiencein this field.
Cardiac valvular abnormalities are frequent in systemic lupus erythematosus patients with manifest arterial disease
Authors: Jensen-Urstad K , Svenungsson E , de Faire U , Silveira A , Witztum J L , Hamsten A , Frostegard J
Published: November 2002

The objective of this study was to study cardiac valve morphology and function and ventricular function in systemic lupus erythematosus(SLE) patients with and without co-existingcardiovascular disease (CVD) and in populationcontrols.Twenty-six women (52§ 8.2 years) with SLE (SLE cases) and a history of CVD (angina pectoris, myocardial infarction, cerebral infarction or intermittent claudication) were compared with 26 age-matched women with SLE but without manifest CVD (SLE controls) and 26 age-matched control women (population controls). Echocardiography was performed to assess valvular abnormalities and manifestations of ischaemic heart disease. Thirteen of the 26 SLE cases but only one of the SLE controls and one of the population controls had cardiac valvularabnormalities.Three of the SLE cases had already undergonevalve replacement and another had significant aortic insufficiency; the other nine had thickening of mainly mitral leaflets without hemodynamic significance. Among SLE cases, patients with valvular abnormalities had higher homocysteine (P < 0.001) and triglyceride (P=0.02) concentrations than patients without valvular disease. In contrast atherosclerosis as determined by IMT, oxidized LDL as measured by the monoclonal antibody E06, autoantibodiesagainst epitopesof OxLDL (aOxLDL) or phospholipids (aPL), disease duration or activity, or acute phase reactants did not differ between SLE cases with or without valvular abnormalities.Valvular abnormalitieswere not more common in SLE cases with stroke as compared to those with myocardial infarction, angina or claudication. In conclusion, valvular abnormalities are strongly associated with CVD in SLE. Raised levels of homocysteine and triglycerides characterize patients with cardiac valve abnormalities.
Behavioral and cognitive deficits occur only after prolonged exposure of mice to antiphospholipid antibodies
Authors: Shrot S , Katzav A , Korczyn A D , Litvinjuk Y , Hershenson R , Pick C G , Blank M , Zaech J , Shoenfeld Y , Sirota P , Chapman J
Published: November 2002

The antiphospholipid (Hughes) syndrome (APS) includes systemic and central nervous system (CNS) pathology associated with antibodies to a complex of phospholipids and β2-glycoprotein I (β2-GPI). β2-GPI immunized mice develop systemic manifestations of APS and we presently examined CNS manifestations in this APS model. Female BALB/c mice were immunized once with β2-GPI in complete Freund's adjuvant (CFA) or with CFA alone (controls). A staircase test and a T-maze alternation test were performed to test behavior and cognition in independent groups of mice 6, 12 and 18 weeks following the immunization. The APS mice developed elevated levels of antibodies against negatively charged phospholipids and β2-GPI. Neurological impairment was detected only 18 weeks after the induction of the APS and consisted of both cognitive (53± 4 71± 3% correct choices in the T-maze alternation for APS behavioral changes (higher number of rears (18± 2 vs 7±1, P < 0.02). This is the first report of cognitive deficits in this APS model and demonstrates the time course for the development of previously described behavioral changes. The mechanism involved in these CNS manifestations remains to be elucidated.
Daylight climatology in the Athens urban environment: guidance for building designers
Authors: Kambezidis HD , Oikonomou ThI , Zevgolis D
Published: November 2002

Global and diffuse horizontal illuminance data are analysed for Athens, Greece, for the period 1992-1997. It is shown in a graphical manner that horizontal illuminance (global and diffuse) is dependent upon the time of the day and the month of the year. The diagrams are categorized according to Perraudeau’s nebulosity index, which reflects the sky cover and the climate at a given area. The cumulative frequency distribution of the parameters under all-sky types are estimated and discussed. Some examples of sky-luminance distributions using appropriate software are given. The conclusions are of potential value to local architectural practice, installations of lighting, and in developing an energy-saving policy for the Athens region.
Utilance photometry
Authors: Lynes JA
Published: November 2002

A novel relationship is postulated expressing the direct ratio of a luminaire as a function of the room index. This permits the production of an approximate table of utilization factors for a given luminaire without any need for the directional distribution of intensity to be determined. Applications of the method are discussed.
Lightness and chroma of computer simulated surfaces lit by lamps of different spectra
Authors: Xu H
Published: November 2002

By calculating the lightness and chroma of computer simulated surfaces lit by different lamps, this study shows that the average CIE 1976 chroma C* uv of surfaces lit by light of different spectral composition can be significantly different at a fixed illuminance. This study also shows the Spearman rank-order correlation is significant between the average C* uv and each of several light parameters, including gamut area, cone surface area, (S/P)1/2, and colour rendering capacity. The higher the value of any of these parameters for a lamp, the greater the average C*uv of surfaces lit under that lamp.
Advantages and disadvantages of the use of compact fluorescent lamps with electronic control gear
Authors: Topalis FV , Kostic MB , Radakovic ZR
Published: November 2002

The paper presents a comprehensive analysis dealing with the behaviour and economics of electronic compact fluorescent lamps. The economic analysis, based on the results of the test concerning the lifetime and the lamp lumen maintenance factor of electronic compact fluorescent lamps, and conducted using the cost-discount method, showed an obvious advantage for lamps of this type compared with incandescent ones. The strategic importance of the mass use of electronic compact fluorescent lamps, as well as serious power quality implications it can cause to the network, are explained in detail. Possible solutions of this problem are also presented.
Phase I Trial of the Proteasome Inhibitor PS-341 in Patients With Refractory Hematologic Malignancies
Authors: Orlowski Robert Z. , Stinchcombe Thomas E. , Mitchell Beverly S. , Shea Thomas C. , Baldwin Albert S. , Stahl Stephanie , Adams Julian , Esseltine Dixie-Lee , Elliott Peter J. , Pien Christine S. , Guerciolini Roberto , Anderson Jessica K. , Depcik-Smith Natalie D. , Bhagat Rita , Lehman Mary Jo , Novick Steven C. , O’Connor Owen A. , Soignet Steven L.
Published: November 2002

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib (previously known as PS-341) in patients with refractory hematologic malignancies.

PATIENTS AND METHODS: Patients received PS-341 twice weekly for 4 weeks at either 0.40, 1.04, 1.20, or 1.38 mg/m2, followed by a 2-week rest. The PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity.

RESULTS: Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles. DLTs at doses above the 1.04-mg/m2 MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In three of 10 patients receiving additional therapy, serious reversible adverse events appeared during cycle 2, including one episode of postural hypotension, one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed PS-341 induced 20S proteasome inhibition in a time-dependent manner, and this inhibition was also related to both the dose in milligrams per meter squared, and the absolute dose of PS-341. Among nine fully assessable patients with heavily pretreated plasma cell dyscrasias completing one cycle of therapy, there was one complete response and a reduction in paraprotein levels and/or marrow plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma and another with follicular lymphoma had shrinkage of nodal disease.

CONCLUSION: PS-341 was well tolerated at 1.04 mg/m2 on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin’s lymphoma in this study, and merits further investigation in these populations.
Therapeutic Efficacy of Transcatheter Arterial Chemoembolization as Compared With Hepatic Resection in Hepatocellular Carcinoma Patients With Compensated Liver Function in a Hepatitis B Virus–Endemic Area: A Prospective Cohort Study
Authors: Lee Hyo-Suk , Kim Kang Mo , Yoon Jung-Hwan , Lee Tae-Rim , Suh Kyung Suk , Lee Kuhn Uk , Chung Jin Wook , Park Jae Hyung , Kim Chung Yong
Published: November 2002

PURPOSE: Identifying a special subgroup of hepatocellular carcinoma (HCC) patients who may benefit from transcatheter arterial chemoembolization (TACE) when compared with the standard treatment of hepatic resection (HR) warrants research in Asian countries.

PATIENTS AND METHODS: From January 1993 to December 1994, 182 patients with operable HCC (Child-Pugh class A and International Union Against Cancer [UICC] stage T1-3N0M0) were enrolled. After initial TACE and lipiodol computed tomography, 91 received HR and 91, who refused the operation, received repeated sessions of TACE. After stratification according to the tumor stage (UICC and Cancer of the Liver Italian Program [CLIP]) and lipiodol retention pattern, the survival rates of the two treatment groups were compared. The median follow-up period was 83 months.

RESULTS: As of December 31, 2000, 48 patients who underwent HR and 68 patients who underwent TACE had died. In a subgroup analysis according to tumor stage, the HR group survival rate was significantly higher than the TACE group in both UICC T1-2N0M0 (P = .0058) and CLIP 0 (P = .0027) subgroups. However, there was no significant difference in either UICC T3N0M0 (P = .7512) or CLIP 1-2 (P = .5366) subgroups. Even in patients with UICC T1-2N0M0 HCC, when lipiodol was compactly retained, the survival rate of the HR group was comparable to that of the TACE group (P = .0596).

CONCLUSION: TACE proved to be as effective as HR in the subpopulations with UICC T3N0M0 or CLIP 1-2 HCC and adequate liver function, and even with UICC T1-2N0M0 HCC when lipiodol was compactly retained in the tumor. In such cases, the choice of treatment modality between TACE and HR may be left to the patient’s preference.
Function and Health Status Outcomes in a Randomized Trial Comparing Preoperative and Postoperative Radiotherapy in Extremity Soft Tissue Sarcoma
Authors: Davis A.M. , O’Sullivan B. , Bell R.S. , Turcotte R. , Catton C.N. , Wunder J.S. , Chabot P. , Hammond A. , Benk V. , Isler M. , Freeman C. , Goddard K. , Bezjak A. , Kandel R.A. , Sadura A. , Day A. , James K. , Tu D. , Pater J. , Zee B.
Published: November 2002

PURPOSE: Morbidity associated with wound complications may translate into disability and quality-of-life disadvantages for patients treated with radiotherapy (RT) for soft tissue sarcoma (STS) of the extremities. Functional outcome and health status of extremity STS patients randomized in a phase III trial comparing preoperative versus postoperative RT is described.

PATIENTS AND METHODS: One hundred ninety patients with extremity STS were randomized after stratification by tumor size dichotomized at 10 cm. Function and quality of life were measured by the Musculoskeletal Tumor Society Rating Scale (MSTS), the Toronto Extremity Salvage Score (TESS), and the Short Form-36 (SF-36) at randomization, 6 weeks, and 3, 6, 12, and 24 months after surgery.

RESULTS: One hundred eighty-five patients had function data. Patients treated with postoperative RT had better function with higher MSTS (25.8 v 21.3, P < .01), TESS (69.8 v 60.6, P = .01), and SF-36 bodily pain (67.7 v 58.5, P = .03) scores at 6 weeks after surgery. There were no differences at later time points. Scores on the physical function, role-physical, and general health subscales of the SF-36 were significantly lower than Canadian normative data at all time points. After treatment arm was controlled for, MSTS change scores were predicted by a lower-extremity tumor, a large resection specimen, and motor nerve sacrifice; TESS change scores were predicted by lower-extremity tumor and prior incomplete excision. When wound complication was included in the model, patients with complications had lower MSTS and TESS scores in the first 2 years after treatment.

CONCLUSION: The timing of RT has minimal impact on the function of STS patients in the first year after surgery. Tumor characteristics and wound complications have a detrimental effect on patient function.
Safety and Pharmacokinetic Effects of TNP-470, an Angiogenesis Inhibitor, Combined With Paclitaxel in Patients With Solid Tumors: Evidence for Activity in Non–Small-Cell Lung Cancer
Authors: Herbst Roy S. , Madden Timothy L. , Tran Hai T. , Blumenschein George R. , Meyers Christina A. , Seabrooke Lee F. , Khuri Fadlo R. , Puduvalli Vinay K. , Allgood Victoria , Fritsche Herbert A. , Hinton Leslie , Newman Robert A. , Crane Elizabeth A. , Fossella Frank V. , Dordal Margaret , Goodin Thomas , Hong Waun Ki
Published: November 2002

PURPOSE: Preclinical studies suggested that the antiangiogenic agent TNP-470 was synergistic with cytotoxic therapy. TNP-470 was administered with paclitaxel to adults with solid tumors to define the safety and optimal dose of the combination regimen and to assess pharmacokinetic interactions.

PATIENTS AND METHODS: Thirty-two patients were enrolled chronologically onto one of two treatment arms. Arm A involved a fixed TNP-470 dose with escalating doses of paclitaxel, and Arm B involved a fixed paclitaxel dose with escalating doses of TNP-470. Paclitaxel and TNP-470 pharmacokinetics were evaluated along with toxicity.

RESULTS: The combination of TNP-470 administered at 60 mg/m2three times per week and paclitaxel 225 mg/m2administered over 3 hours every 3 weeks was defined as both the maximum-tolerated dose and the optimal dose. Myelosuppression was similar to that expected with paclitaxel alone. Mild to moderate neurocognitive impairment was observed; however, the majority of changes were subclinical and reversible as determined by prestudy and poststudy neuropsychiatric test results. A clinically insignificant decrease of paclitaxel clearance was observed for the combination. Median survival for all patients was 14.1 months. Partial responses were reported in eight (25%) of 32 patients and in six (38%) of 16 patients with NSCLC, 60% of whom had received prior chemotherapy.

CONCLUSION: The combination of TNP-470 and paclitaxel, each at full single-agent dose, seems well tolerated, with minimal pharmacokinetic interaction between the two agents. Further studies of TNP-470 with chemotherapy regimens are warranted in NSCLC and other solid tumors.
Randomized Study to Evaluate the Use of High-Dose Therapy as Part of Primary Treatment for “Aggressive” Lymphoma
Authors: Kaiser Ulrich , Uebelacker Irmgard , Abel Ulrich , Birkmann Josef , Trumper Lorenz , Schmalenberg Harald , Karakas Tunca , Metzner Bernd , Hossfeld Dieter K. , Bischoff Helge G. , Franke Astrid , Reiser Marcel , Muller Peter , Mantovani Luisa , Grundeis Marc , Rothmann Frank , von Seydewitz Cay-Uwe , Mesters Rolf M. , Steinhauer Ernst U. , Krahl Dorothea , Schumacher Kurt , Kneba Michael , Baudis Michael , Schmitz Norbert , Pfab Rudiger , Koppler Hubert , Parwaresch Reza , Pfreundschuh Michael , Havemann Klaus
Published: November 2002

PURPOSE: This trial of the German High-Grade Non-Hodgkin’s Lymphoma Study Group compares the use of high-dose therapy (HDT) as part of primary treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus etoposide followed by involved-field (IF) radiotherapy in a randomized, multicenter, phase III study.

PATIENTS AND METHODS: Three hundred twelve patients with “aggressive” non-Hodgkin’s lymphoma aged ≤ 60 years with elevated serum lactate dehydrogenase levels were included from 1990 to 1997. Patients with at least a minor response after two cycles of CHOEP (CHOP + etoposide 3 × 100 mg/m2) were to receive three further cycles of CHOEP followed by IF radiotherapy (arm A) or one further cycle of CHOEP followed by autologous stem-cell transplantation and IF radiotherapy (arm B).

RESULTS: Among 158 patients randomized to arm B, 103 (65%) received HDT. The complete remission rate at the end of treatment was 62.9% in arm A and 69.9% in arm B. With a median observation time of 45.5 months, overall survival for all 312 patients was 63% after 3 years (63% for arm A, 62% for arm B; P = .68). Event-free survival was 49% for arm A versus 59% for arm B (P = .22). Relapse in arm B was associated with a significantly worse survival rate than relapse in arm A (P < .05). Relapse after HDT occurred early (median interval, 3 months). Six patients developed secondary neoplasia, three in arm A and three in arm B.

CONCLUSION: Results of the randomized trial comparing CHOP-like chemotherapy with early HDT do not support the use of HDT with carmustine, etoposide, cytarabine, and melphalan following shortened standard chemotherapy.
BRCA1/2 Genetic Testing in the Community Setting
Authors: Chen Wendy Y. , Garber Judy E. , Higham Suzanne , Schneider Katherine A. , Davis Katie B. , Deffenbaugh Amie M. , Frank Thomas S. , Gelman Rebecca S. , Li Frederick P.
Published: November 2002

PURPOSE: BRCA1/2 genetic testing has been commercially available in the United States since 1996. Most published reports described BRCA1/2 testing as research studies at large academic centers, but less is known about testing in the community. This study evaluates the process and early outcomes of BRCA1/2 genetic testing as a clinical service in the community setting.

METHODS: Surveys were mailed to women in the United States whose health care providers ordered BRCA1/2 genetic testing from Myriad Genetic Laboratories from August 1998 through July 2000. Women tested at 149 large academic centers were excluded. Main outcome measures were demographic characteristics, recall of and satisfaction with the genetic testing process, and likelihood of pursuing cancer prevention strategies.

RESULTS: Among the 646 respondents, 414 (64%) had a personal history of cancer and 505 (78%) had at least one first-degree relative with breast and/or ovarian cancer. Most subjects (82%) recalled discussions of informed consent before testing (median time, 30 minutes). Genetic results were conveyed during an office visit (57%), by telephone (39%), or by mail (3%). More than 75% of respondents were “very satisfied with the counseling received.” Cancer-free subjects with a germline mutation were more likely to consider prevention strategies after receiving the genetic results.

CONCLUSION: Virtually all respondents had a personal and/or family history of breast/ovarian cancer. Although pretest and posttest communications were not standardized, overall satisfaction with clinical breast cancer genetic testing was high. Additional follow-up will provide data on future cancer prevention practices and cancer incidence.
Limb Salvage and Amputation in Survivors of Pediatric Lower-Extremity Bone Tumors: What Are the Long-Term Implications?
Authors: Nagarajan Rajaram , Neglia Joseph P. , Clohisy Denis R. , Robison Leslie L.
Published: November 2002

ABSTRACT: The past four decades have seen tremendous progress in the treatment of pediatric and adolescent cancers. As a consequence, there are increasing numbers of adult childhood cancer survivors. This has prompted investigation into the long-term consequences of cancer treatments. One group that merits special study is the survivors of lower-extremity bone tumors. Their function and quality of life may depend in part on both the surgery and the age at which it was performed. Comparisons between studies are difficult because small numbers of patients and the use of varying research designs and methods have limited research in this area. The purpose of this article is to review the major surgical approaches to lower-limb bone tumors and their impact on pediatric patients. The results show that survival is equivalent between amputation and limb salvage. Complications occur more frequently in limb salvage. The long-term outcomes of those undergoing amputation and limb salvage have not been found to be substantially different in regard to quality of life. In conclusion, prospective long-term follow-up of pediatric patients with lower-limb tumors is needed to (1) determine in a uniform manner the long-term complications, quality of life, and functionality of this population and describe differences within this patient population based on age at diagnosis and surgical procedure, (2) identify areas of concern that are amenable to intervention, and (3) provide clinicians and future patients a better understanding of the surgical options.
Randomized Discontinuation Design: Application to Cytostatic Antineoplastic Agents
Authors: Rosner Gary L. , Stadler Walter , Ratain Mark J.
Published: November 2002

PURPOSE: Propose a phase II study design to evaluate the activity of a putative cytostatic agent, acknowledging heterogeneity of tumor growth rates in the population of patients.

METHODS: In the setting of renal cell carcinoma, some patients’ tumors will grow slowly naturally. An appropriate design has to distinguish antiproliferative activity attributable to the novel agent from indolent disease. We propose a randomized discontinuation design that initially treats all patients with the study agent (stage 1) and then randomizes in a double-blind fashion to continuing therapy or placebo only those patients whose disease is stable (stage 2). This design allows the investigators to determine if apparent slow tumor growth is attributable to the drug or to selection of patients with naturally slow-growing tumors.

RESULTS: By selecting a more homogeneous population, the randomized portion of the study requires fewer patients than would a study randomizing all patients at entry. The design also avoids potential confounding because of heterogeneous tumor growth. Because the two randomly assigned treatment groups each comprise patients with apparently slow growing tumors, any difference between the groups in disease progression after randomization is more likely a result of the study drug and less likely a result of imbalance with respect to tumor growth rates. Stopping rules during the initial open-label stage and the subsequent randomized trial stage allow one to reduce the overall sample size. Expected average tumor growth rate is an important consideration when deciding the duration of follow-up for the two stages.

CONCLUSION: The randomized discontinuation design is a feasible alternative phase II study design for determining activity of possibly cytostatic anticancer agents.
Children From Ethnic Minorities Have Benefited Equally as Other Children From Contemporary Therapy for Rhabdomyosarcoma: A Report From the Intergroup Rhabdomyosarcoma Study Group
Authors: Baker K. Scott , Anderson James R. , Lobe Thom E. , Wharam Moody D. , Qualman Stephen J. , Raney R. Beverly , Ruymann Frederick B. , Womer Richard B. , Meyer William H. , Link Michael P. , Crist William M.
Published: November 2002

PURPOSE: To define the clinical characteristics of rhabdomyosarcoma (RMS) occurring in children from ethnic minorities and determine whether these children have benefited equally from advances in therapy.

PATIENTS AND METHODS: This was a retrospective cohort analysis of children treated on the Intergroup Rhabdomyosarcoma Study Group protocols between 1984 and 1997. The clinical features and outcomes of 336 African-American children and 286 children from other ethnic minorities were compared with those of white children (n = 1,721).

RESULTS: African-American, other ethnic group, and white children enjoyed similar 5-year failure-free survivals (FFS) of 61%, 61%, and 66%, respectively, P = .15. Compared with white children, nonwhite patients more often had (1) invasive, T2 tumors (P = .03); (2) stage 2 or 3 tumors (P = .003); (3) large tumors (more than 5 cm, P < .006); and/or (4) tumors with positive regional nodes (ie, N1, P = .002). Using Cox proportional hazards analysis, seven patient risk categories were defined with significant differences in outcome. This model was then used to search for other factors associated with FFS after adjusting for these risk categories. Only T stage and age remained associated with FFS (P = .001 and P < .001, respectively). After adjusting for T stage, risk category, and age, we explored the relationship of ethnic group to FFS and found that, compared with whites, the relative risk of failure was 1.14 for African-American patients and 1.2 for other ethnic minority patients, values that are not significantly different.

CONCLUSION: Patients from ethnic minority groups more often have larger, invasive tumors with positive lymph nodes. Nevertheless, they have benefited as equally as white children from the dramatic progress in therapy of RMS.
Retinoic acid receptor β2 and neurite outgrowth in the adult mouse spinal cord in vitro
Authors: Corcoran Jonathan , So Po-Lin , Barber Robert D. , Vincent Karen J. , Mazarakis Nicholas D. , Mitrophanous Kyriacos A. , Kingsman Susan M. , Maden Malcolm
Published: November 2002

Retinoic acid, acting through the nuclear retinoic acid receptor β2(RARβ2), stimulates neurite outgrowth from peripheral nervous system tissue that has the capacity to regenerate neurites, namely, embryonic and adult dorsal root ganglia. Similarly, in central nervous system tissue that can regenerate, namely, embryonic mouse spinal cord, retinoic acid also stimulates neurite outgrowth and RARβ2 is upregulated. By contrast, in the adult mouse spinal cord, which cannot regenerate, no such upregulation of RARβ2 by retinoic acid is observed and no neurites are extended in vitro. To test our hypothesis that the upregulation of RARβ2 is crucial to neurite regeneration, we have transduced adult mouse or rat spinal cord in vitro with a minimal equine infectious anaemia virus vector expressing RARβ2. After transduction, prolific neurite outgrowth occurs. Outgrowth does not occur when the cord is transduced with a different isoform of RARβ nor does it occur following treatment with nerve growth factor. These data demonstrate that RARβ2 is involved in neurite outgrowth, at least in vitro, and that this gene may in the future be of some therapeutic use.
Improperly folded green fluorescent protein is secreted via a non-classical pathway
Authors: Tanudji Marcel , Hevi Sarah , Chuck Steven L.
Published: November 2002

The green fluorescent protein is a cytosolic protein frequently used as a molecular tag to study protein localization in intact cells. We discovered that this protein is secreted into the medium by several but not all cell lines through a non-classical secretory pathway that is insensitive to brefeldin A. Green fluorescent protein is secreted efficiently by Chinese hamster ovary cells, with 60% of synthesized proteins secreted over 8 hours. This pathway is sensitive to changes in temperature but not to factors in serum or chemicals known to affect other non-classical protein secretion pathways. Fluorescence is observed in cells expressing green fluorescent protein, indicating that some of the protein must be fully folded in the cytosol. However, secreted green fluorescent protein is not fluorescent and therefore not folded properly. Furthermore, cellular fluorescence does not change over 6 hours whereas a significant proportion of green fluorescent protein is secreted. Thus, nascent green fluorescent protein either is folded correctly or incorrectly, and the improperly folded molecules can be exported. Non-classical secretion might be a route by which cells remove an excess of improperly folded, cytosolic proteins.
Reorganization and polarization of the meiotic bouquet-stage cell can be uncoupled from telomere clustering
Authors: Cowan Carrie R. , Carlton Peter M. , Cande W. Zacheus
Published: November 2002

Striking cellular reorganizations mark homologous pairing during meiotic prophase. We address the interdependence of chromosomal and cellular polarization during meiotic telomere clustering, the defining feature of the bouquet stage, by examining nuclear positioning and microtubule and nuclear pore reorganization. Polarization of meiotic cellular architecture was coincident with telomere clustering: microtubules were focused on the nuclear surface opposite the telomere cluster, the nucleus was positioned eccentrically in the cell such that the telomeres faced the direction of nuclear displacement and nuclear pores were clustered in a single region of the nuclear surface opposite the telomeres. Treatment of pre-bouquet stage cells with colchicine inhibited telomere clustering. Asymmetric nuclear positioning and nuclear pore clustering were normal in the presence of unclustered telomeres resulting from colchicine treatment. Nuclear pores were positioned normally with respect to the cell cortex in the absence of telomere clustering, indicating that telomere positioning is not required for polarization. This work provides evidence of meiotic cell polarization and suggests that telomeres may be positioned relative to an asymmetry present in the cell at the time of bouquet formation.
Meiotic telomere clustering is inhibited by colchicine but does not require cytoplasmic microtubules
Authors: Cowan Carrie R. , Cande W. Zacheus
Published: November 2002

Telomere clustering, the defining feature of the bouquet, is an almost universal feature of meiotic prophase, yet its mechanism remains unknown. The microtubule-depolymerizing agent colchicine was found to inhibit bouquet formation. Telomeres in colchicine-treated cells remained scattered in the nuclear periphery, whereas untreated cells exhibited a prominent telomere cluster. Colchicine administered after the bouquet had formed did not affect telomere dispersal. The effect of colchicine on bouquet formation appeared to be separable from its effect on cytoplasmic microtubules; amiprophos methyl, a highly effective plant microtubule-depolymerizing drug, did not affect telomere clustering. Inhibition of bouquet formation was limited to colchicine and the related drug podophyllotoxin out of the variety of microtubule-depolymerizing drugs tested, suggesting that the target involved in bouquet formation has a structural specificity.
Anaphase onset does not require the microtubule-dependent depletion of kinetochore and centromere-binding proteins
Authors: Canman Julie C. , Sharma Nitin , Straight Aaron , Shannon Katie B. , Fang Guowei , Salmon E. D.
Published: November 2002

Spindle checkpoint proteins, such as Mad2 and BubR1, and the motors dynein/dynactin and CENP-E usually leave kinetochores prior to anaphase onset by microtubule-dependent mechanisms. Likewise, `chromosome passenger proteins'including INCENP are depleted from the centromeres after anaphase onset and then move to the midzone complex, an event that is essential for cytokinesis. Here we test whether the cell cycle changes that occur at anaphase onset require or contribute to the depletion of kinetochore and centromere proteins independent of microtubules. This required the development of a novel non-antibody method to induce precocious anaphase onset in vivo by using a bacterially expressed fragment of the spindle checkpoint protein Mad1 capable of activating the APC/C, called GST-Mad1F10. By injecting PtK1 cells in nocodazole with GST-Mad1F10 and processing the cells for immunofluorescence microscopy after anaphase sister chromatid separation in nocodazole we found that Mad2, BubR1, cytoplasmic dynein, CENP-E and the 3F3/2 phosphoepitope remain on kinetochores. Thus depletion of these proteins (or phosphoepitope)at kinetochores is not required for anaphase onset and anaphase onset does not produce their depletion independent of microtubules. In contrast, both microtubules and anaphase onset are required for depletion of the `chromosome passenger' protein INCENP from centromeres, as INCENP does not leave the chromosomes prior to anaphase onset in the presence or absence of microtubules, but does leave the centromeres after anaphase onset in the presence of microtubules.
Visualization of translated tau protein in the axons of neuronal P19 cells and characterization of tau RNP granules
Authors: Aronov Stella , Aranda Gonzalo , Behar Leah , Ginzburg Irith
Published: November 2002

Localization of tau mRNA to the axon requires the axonal localization cis signal (ALS), which is located within the 3′ untranslated region, and trans-acting binding proteins, which are part of the observed granular structures in neuronal cells. In this study, using both biochemical and morphological methods, we show that the granules contain tau mRNA, HuD RNA-binding protein, which stabilizes mRNA, and KIF3A, a member of the kinesin microtubule-associated motor protein family involved in anterograde transport. The granules are detected along the axon and accumulate in the growth cone. Inhibition of KIF3A expression caused neurite retraction and inhibited tau mRNA axonal targeting. Taken together, these results suggest that HuD and KIF3A proteins are present in the tau mRNA axonal granules and suggest an additional function for the kinesin motor family in the microtubule-dependent translocation of RNA granules. Localized tau-GFP expression was blocked by a protein synthesis inhibitor, and upon release from inhibition, nascent tau-GFP`hot spots' were directly observed in the axon and growth cones. These observations are consistent with local protein synthesis in the axon resulting from the transported tau mRNA.
Osteoclast spreading kinetics are correlated with an oscillatory activation of a calcium-dependent potassium current
Authors: Espinosa Leon , Paret Laurent , Ojeda Carlos , Tourneur Yves , Delmas Pierre D. , Chenu Chantal
Published: November 2002

Cell movement and spreading involve calcium-dependent processes and ionic channel activation. During bone resorption, osteoclasts alternate between spread, motile and resorptive phases. We investigated whether the electrical membrane properties of osteoclasts were linked to their membrane morphological changes. Rabbit osteoclasts were recorded by time-lapse videomicroscopy performed simultaneously with patch-clamp whole cell and single channel recordings. Original image analysis methods were developed and used to demonstrate for the first time an oscillatory activation of a spontaneous membrane current in osteoclasts, which is directly correlated to the membrane movement rate. This current was identified as a calcium-dependent potassium current (IKCa) that is sensitive to both charybdotoxin and apamin and was generated by a channel with unitary conductance of approximately 25±2 pS. Blockade of this current also decreased osteoclast spreading and inhibited bone resorption in vitro, demonstrating a physiological role for this current in osteoclast activity. These results establish for the first time a temporal correlation between lamellipodia formation kinetics and spontaneous peaks of IKCa, which are both involved in the control of osteoclast spreading and bone resorption.
Metalloproteinase inhibitors: biological actions and therapeutic opportunities
Authors: Baker Andrew H. , Edwards Dylan R. , Murphy Gillian
Published: November 2002

Tissue inhibitors of metalloproteinases (TIMPs) are the major cellular inhibitors of the matrix metalloproteinase (MMP) sub-family, exhibiting varying efficacy against different members, as well as different tissue expression patterns and modes of regulation. Other proteins have modest inhibitory activity against some of the MMPs, including domains of netrins,the procollagen C-terminal proteinase enhancer (PCPE), the reversion-inducing cysteine-rich protein with Kazal motifs (RECK), and tissue factor pathway inhibitor (TFPI-2), but their physiological significance is not at all clear.α2-Macroglobulin, thrombospondin-1 and thrombospondin-2 can bind to some MMPs and act as agents for their removal from the extracellular environment. In contrast, few effective inhibitors of other members of the metzincin family, the astacins or the distintegrin metalloproteinases, ADAMs have been identified.

Many of these MMP inhibitors, including the TIMPs, possess other biological activities which may not be related to their inhibitory capacities. These need to be thoroughly characterized in order to allow informed development of MMP inhibitors as potential therapeutic agents. Over activity of MMPs has been implicated in many diseases, including those of the cardiovascular system,arthritis and cancer. The development of synthetic small molecule inhibitors has been actively pursued for some time, but the concept of the use of the natural inhibitors, such as the TIMPs, in gene based therapies is being assessed in animal models and should provide useful insights into the cell biology of degradative diseases.
The growth ofDrosophilabristles and laterals is not restricted to the tip or base
Authors: Fei Xiaoyin , He Biao , Adler Paul N.
Published: November 2002

The highly elongated bristles of Drosophila have proven to be a valuable model system for studying cellular morphogenesis. Extending bristles contain a series of large bundles of actin filaments juxtaposed to the plasma membrane and centrally located microtubules. Models to explain the extension of the bristle have principally focused on the assembly of actin filaments at the distal tip of the bristle. We have used time-lapse observations of wild-type and mutant bristles and the related arista laterals and come to the conclusion that growth takes place throughout the growing cellular extension. This distributed growth can explain the behavior of split laterals and the shape changes seen at the tip during bristle and lateral outgrowth. Inhibitor studies suggest that the microtubule cytoskeleton is essential for maintaining the highly biased axial growth of these structures. We have used fluorescence recovery after photo-bleaching to study the dynamics of the cytoskeleton during bristle growth. Our experiments show that actin bundles in growing bristles are quite stable and move in a retrograde fashion. The bristle microtubules are less stable. The retrograde movement of the peripheral actin appears to be counterbalanced by the distally directed movement of cytoplasm in the center of the bristle.
Spatial organisation and behaviour of the parental chromosome sets in the nuclei of Saccharomyces cerevisiae × S. paradoxus hybrids
Authors: Lorenz Alexander , Fuchs Jörg , Trelles-Sticken Edgar , Scherthan Harry , Loidl Josef
Published: November 2002

We demonstrate that the genomes of Saccharomyces cerevisiae and S. paradoxus are sufficiently divergent to allow their differential labeling by genomic in situ hybridisation (GISH). The cytological discrimination of the genomes allowed us to study the merging of the two genomes during hybrid mating. GISH revealed that in hybrid nuclei the two genomes are intermixed. In hybrid meiosis, extensive intraspectific nonhomologous pairing takes place. GISH on chromosome addition and substitution strains (with chromosomes of S. paradoxus added to or replacing the homoeologous chromosome of an otherwise S. cerevisiaebackground) was used to delineate individual chromosomes at interphase and to examine various aspects of chromosome structure and arrangement.
Get a ligand, get a life: integrins, signaling and cell survival
Authors: Stupack Dwayne G. , Cheresh David A.
Published: November 2002

Programmed cell death is crucial for the development and maintenance of multicellular organisms. The decision to live, or to die, depends, at the cellular level, upon the cell's interaction with extracellular cues that trigger cell signaling pathways promoting survival or death. The extracellular matrix (ECM) influences the execution of the apoptotic program through the actions of adhesion receptors. Among these, integrins initiate a variety of downstream signaling events in response to ECM ligation. Integrins directly activate survival pathways via the PI 3-kinase and MAPK pathways and act as essential cofactors for their stimulation by growth factors. Conversely,elevated integrin expression in the absence of appropriate ligands, or in the presence of natural or synthetic antagonists, can promote apoptosis under otherwise permissive growth conditions. Integrins thus act in a crucial biosensory role, coordinating survival or death responses as a function of ECM composition. This dual function provides an elegant mechanism through which tissue-remodeling events may regulate cell death or survival in a temporal,ECM-governed manner.
Neuronal calcium sensor 1 and phosphatidylinositol 4-OH kinase βinteract in neuronal cells and are translocated to membranes during nucleotide-evoked exocytosis
Authors: Taverna Elena , Francolini Maura , Jeromin Andreas , Hilfiker Sabine , Roder John , Rosa Patrizia
Published: November 2002

Neuronal calcium sensor 1 (NCS-1) belongs to a family of EF-hand calcium-binding proteins and is mainly expressed in neurons and neuroendocrine cells, where it causes facilitation of neurotransmitter release through unknown mechanisms. The yeast homologue of NCS-1 has been demonstrated to interact with and regulate the activity of yeast phosphatidylinositol 4-OH kinase β (PI4Kβ). However, in neurons and neurosecretory cells NCS-1 has not unequivocally been shown to interact with PI4Kβ. Here we have compared the subcellular distribution of NCS-1 and PI4Kβ and investigated whether they are capable of forming complexes. In neurons, both proteins are widely distributed and are present in perikarya and, to a lesser extent, in nerve terminals. A consistent portion of NCS-1 and PIK4β is cytosolic,whereas a portion of both proteins appears to be associated with the membranes of the endoplasmic reticulum and the Golgi complex. Very small amounts of NCS-1 and PI4Kβ are present in synaptic vesicles. Our results further demonstrate that in neurosecretory cells, endogenous NCS-1 and PIK4βinteract to form a complex that can be immunoisolated from membrane as well as from cytosolic fractions. Moreover, both proteins can be recruited to membranes when cells are treated with nucleotide receptor agonists known to increase polyphosphoinositide turnover and concomitantly induce exocytosis of secretory vesicles. Finally, in PC12 cells overexpressing NCS-1, the amount of PI4Kβ associated with the membranes is increased concomitantly with the increased levels of NCS-1 detected in the same membrane fractions. Together,these findings demonstrate that mammalian NCS-1 and PI4Kβ interact under physiological conditions, which suggest a possible role for NCS-1 in the translocation of PI4Kβ to target membranes.
On the importance of being co-transcriptional
Authors: Neugebauer Karla M.
Published: November 2002

Intense research in recent years has shown that many pre-mRNA processing events are co-transcriptional or at least begin during RNA synthesis by RNA polymerase II (Pol II). But is it important that pre-mRNA processing occurs co-transcriptionally? Whereas Pol II directs 5′ capping of mRNA by binding to and recruiting all three capping activities to transcription units,co-transcriptional splicing is not obligatory. In some cases, such as alternative splicing, splicing may occur post-transcriptionally owing to the slower kinetics of splicing unfavorable introns. Despite recent models in which splicing factors are bound directly to the C-terminal domain (CTD) of Pol II, little evidence supports that view. Instead, interactions between snRNPs and transcription elongation factors provide the strongest molecular evidence for a physical link between transcription and splicing. Transcription termination depends on polyadenylation signals, but, like splicing,polyadenylation per se probably begins co-transcriptionally and continues post-transcriptionally. Nascent RNA plays an important role in determining which transcripts are polyadenylated and which alternative terminal exon is used. A recent addition to co-transcriptional RNA processing is a possible RNA surveillance step prior to release of the mRNP from the transcription unit,which appears to coordinate nuclear transport with mRNA processing and may be mediated by components of the nuclear exosome.