Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor.

NF-κB proteins play a central and subunit-specific role in the response to DNA damage. Previous work identified p50/NF-κB1 as being necessary for cytotoxicity in response to DNA alkylation damage. Given the importance of damage-induced cell death for the maintenance of genomic stability, we examined whether Nfkb1 acts as a tumor suppressor in the setting of alkylation damage. Hprt mutation analysis demonstrates that Nfkb1(-/-) cells accumulate more alkylator-induced, but not ionizing radiation (IR)-induced, mutations than similarly treated wild-type cells. Subsequent in vivo tumor induction studies reveal that following alkylator treatment, but not IR, Nfkb1(-/-) mice develop more lymphomas than similarly treated Nfkb1(+/+) animals. Heterozygous mice develop lymphomas at an intermediate rate and retain functional p50 in their tumors, indicating that Nfkb1 acts in a haploinsufficient manner. Analysis of human cancers, including therapy-related myeloid neoplasms, demonstrates that NFKB1 mRNA expression is downregulated compared with control samples in multiple hematological malignancies. These data indicate that Nfkb1 is a haploinsufficient, pathway-specific tumor suppressor that prevents the development of hematologic malignancy in the setting of alkylation damage.

Effects of obesity on health-related quality of life in juvenile-onset systemic lupus erythematosus.

OBJECTIVE: This study evaluated the effects of obesity on health-related quality of life (HRQOL) measures in juvenile-onset systemic lupus erythematosus (jSLE). METHODS: Obesity was defined as a body mass index (BMI) ≥ 95 th percentile according to the Sex-specific Center for Disease Control BMI-For-Age Charts and determined in a multicenter cohort of jSLE patients. In this secondary analysis, the domain and summary scores of the Pediatric Quality of Life (PedsQL) Inventory and the Child Health Questionnaire (CHQ) of obese jSLE patients were compared to those of non-obese jSLE patients as well as historical obese and non-obese healthy controls. Mixed-effects modeling was performed to evaluate the relationship between obesity and HRQOL measures. RESULTS: Among the 202 jSLE patients, 25% (n = 51) were obese. Obesity had a significant negative impact on HRQOL in jSLE, even after adjusting for differences in current corticosteroid use, disease activity, disease damage, gender and race between groups. Obese jSLE patients had lower physical functioning compared to non-obese jSLE patients, and to non-obese and obese healthy controls. Compared to their non-obese counterparts, obese jSLE patients also had worse school functioning, more pain, worse social functioning and emotional functioning. Parents of obese jSLE patients worry more. The CHQ scores for obese jSLE patients were also worse compared to non-obese jSLE patients in several other domains. CONCLUSION: Our study demonstrates the detrimental effects of obesity on patient-reported outcomes in jSLE. This supports the importance of weight management for the therapeutic plan of jSLE.

c-MYC is a radiosensitive locus in human breast cells.

Ionising radiation is a potent human carcinogen. Epidemiological studies have shown that adolescent and young women are at increased risk of developing breast cancer following exposure to ionising radiation compared with older women, and that risk is dose-dependent. Although it is well understood which individuals are at risk of radiation-induced breast carcinogenesis, the molecular genetic mechanisms that underlie cell transformation are less clear. To identify genetic alterations potentially responsible for driving radiogenic breast transformation, we exposed the human breast epithelial cell line MCF-10A to fractionated doses of X-rays and examined the copy number and cytogenetic alterations. We identified numerous alterations of c-MYC that included high-level focal amplification associated with increased protein expression. c-MYC amplification was also observed in primary human mammary epithelial cells following exposure to radiation. We also demonstrate that the frequency and magnitude of c-MYC amplification and c-MYC protein expression is significantly higher in breast cancer with antecedent radiation exposure compared with breast cancer without a radiation aetiology. Our data also demonstrate extensive intratumor heterogeneity with respect to c-MYC copy number in radiogenic breast cancer, suggesting continuous evolution at this locus during disease development and progression. Taken together, these data identify c-MYC as a radiosensitive locus, implicating this oncogenic transcription factor in the aetiology of radiogenic breast cancer.

Lack of association of the TP53 Arg72Pro SNP and the MDM2 SNP309 with systemic lupus erythematosus in Caucasian, African American, and Asian children and adults.

The p53 tumour suppressor is the central regulator of apoptosis. Previously, the functional TP53 Arg72Pro polymorphism was found to be associated with systemic lupus erythematosus (SLE) in Koreans but not Spaniards. MDM2 is the major negative regulator of p53. An intronic polymorphism in MDM2, the SNP309, attenuates p53 activity and is associated with accelerated tumour development in premenopausal women. Polymorphic variation in MDM2 has never been studied in SLE. The aim of this study is to further assess the contribution of p53-pathway genetic variation to SLE by testing the association of the TP53 Arg72Pro polymorphism and the MDM2 SNP309 with SLE in a well-characterised and ethnically diverse cohort of patients with both childhood- and adult-onset SLE (n = 314). No association was found between the TP53 Arg72Pro polymorphism and SLE in patients of European descent, Asian descent or in African Americans, nor was an association found between the MDM2 SNP309 and SLE in patients of European descent or in African Americans. In addition, there was no correlation between either variant and early-onset disease or nephritis, an index of severe disease. It is concluded that neither the TP53 Arg72Pro polymorphism nor the MDM2 SNP309 contributes significantly to either susceptibility or disease severity in SLE.

Do children with lupus have fewer male siblings?

It is widely acknowledged that genetic factors play a significant role in the pathogenesis of systemic lupus erythematosus (SLE). However, the female preponderance remains unexplained. We hypothesized that the female preponderance in childhood SLE results from selection early in the course of conception against male fetuses bearing genetic material predisposing to SLE. If this hypothesis is accurate, there should be a decreased number of male children in families with a child with SLE. Alternatively, children with SLE would have fewer male siblings. Further, this hypothesis may apply to other diseases with a female predominance such as pauciarticular onset juvenile rheumatoid arthritis (PaJRA), and not apply to diseases without female preponderance such as systemic onset juvenile rheumatoid arthritis (SoJRA). Chart review of patients with childhood onset SLE and PaJRA revealed a greater number of female children in these families compared with families of patients with SoJRA. Large-scale epidemiologic studies with precise counting of miscarriages and abortions could help to confirm these findings. Detailed studies of genetic and maternal intrauterine factors are required to conclusively prove this hypothesis.

Quality of life in children with systemic lupus erythematosus: a review.

Systemic lupus erythematosus (SLE) in children is a chronic multisystem disease with wide ranging effects on their quality of life (QOL). While SLE's impact on different arenas of life and well-being has been extensively examined in the adult population, its effect on children has not received adequate attention. This review discusses the multidimensional aspect of QOL, the biopsychosocial implications of SLE, factors complicating QOL measurement in the affected population, and the different generic and disease-specific scales used for measuring QOL and related constructs. Until now, there have not been any pediatric SLE-specific health-related QOL (HRQOL) scales. A section is devoted to a novel instrument developed specifically for measuring QOL in pediatric lupus called the Simple Measure of the Impact of Lupus Erythematosus in Youngsters (SMILEY). SMILEY is a brief, easily understood, valid, reliable and internally consistent pediatric SLE-specific QOL scale and will be a useful adjunct to clinical trials and outcomes research.

Relationship of quality of life and physical function measures with disease activity in children with systemic lupus erythematosus.

The objective of this study is to assess relationship of systemic lupus erythematosus (SLE) activity with quality of life (QOL) and physical function and determine which is more closely correlated with SLE activity in children; and identify factors critical to children's QOL. In this cross-sectional study, children with SLE and parents completed corresponding versions of physical function (Childhood Health Assessment Questionnaire CHAQ), and QOL (Pediatric Quality of Life Inventory-PedsQL Generic/Rheumatology modules) questionnaires. SLE Disease Activity Index (SLEDAI), Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI), severity, self-concept and socioeconomic status (SES) were measured. For 24 children, CHAQ scores significantly correlated with SLEDAI (rho = 0.4, p = 0.04), SDI (rho = 0.6, p = 0.004), and associated with severity (p = 0.03). PedsQL scores did not significantly correlate with above parameters. Higher self-concept/SES correlated (p < 0.05) with better physical function and QOL. For 19 parents, the only significant correlation was between SLEDAI and Worry domain-Rheumatology module (rho = 0.5, p = 0.01). Lack of strong correlation of disease activity with QOL and physical function suggests that they are different constructs with partial overlap, and should be considered collectively while evaluating the impact of SLE on children/families. Self-concept and SES should be assessed while measuring QOL in children. Larger sample is required to confirm results.

Quality of life in paediatric lupus.

Paediatric systemic lupus erythematosus (SLE) is associated with significant morbidity and has biopsychosocial implications resulting from the disease and its treatment. The aim of this study was to identify domains of quality of life (QOL) impacted by SLE in children. Children with SLE and their parents were asked a single open-ended question related to lupus. Themes derived from children's responses focused primarily on coping and maintaining control of their life despite SLE. Themes from the parents' responses were twofold: a) efforts to cope with their child having SLE; and b) appreciation/sadness in connection with their children's coping process. Qualitative exploration of different facets of QOL in these children is critical for the understanding of specific factors that assist/ease the coping process and formulating interventions for improving children's/family's self-efficacy and disease management.

Combined intravenous methotrexate and cyclophosphamide for refractory childhood lupus nephritis.

OBJECTIVE: To evaluate the efficacy and safety of combining monthly intravenous methotrexate (IV MTX) with monthly IV cyclophosphamide (CYTX; given on the same day) for the treatment of children who develop recurrent diffuse proliferative glomerulonephritis secondary to systemic lupus erythematosus during or after the standard 3 year course of IV CYTX. METHODS: Five children were treated with nine monthly doses of IV CYTX (750-1000 mg/m(2)/month) and IV MTX (50-300 mg/m(2)/month) given on the same day. Their clinical and laboratory measurements were collected every other week throughout the nine months. RESULTS: All children improved dramatically. SLEDAI scores decreased from an average of 13.8 to 4.4, mean (SD) serum creatinine level fell from 100 (60) to 80 (40) micro mol/l, and serum albumin rose from 28 (11) g/l to 41 (6) g/l, while the mean (SD) C3 level increased from 0.5 (0.1) g/l to 0.9 (0.4) g/l. Clinical improvement persisted after 4 years' follow up despite discontinuing MTX and CYTX after 9 months. The average daily dose of corticosteroids has been reduced from 27.6 mg/day at the start of treatment to 12.5 mg/day at follow up. CONCLUSION: Combined IV MTX and IV CYTX treatment effectively controls recurrent or refractory lupus nephritis in children with significant disease activity after treatment with IV CYTX alone.

Benign outcome of RSV infection in children with cancer.

BACKGROUND: High case-fatality rates have been reported among adults who develop respiratory syncytial virus (RSV) infection while being treated for oncologic diseases, particularly after bone marrow transplantation. Previous reports of RSV infection among children with primary and acquired immunodeficiencies describe increased morbidity compared with that seen in immunocompetent children, but there have been few reports describing the outcome of RSV infection specifically among pediatric oncology patients. METHODS: We retrospectively reviewed the charts of all children being treated by the Pediatric Oncology Service at Memorial Sloan-Kettering Cancer Center who had positive tests for RSV between the Fall of 1994 and the Spring of 1998. Patients on the BMT Service were excluded from this analysis. RESULTS: Eighteen RSV infections were identified among pediatric oncology patients, who were being treated with aggressive, predominantly alkylator-based chemotherapy for a variety of oncologic diagnoses. Nine episodes of RSV infection (50%) were treated with specific antiviral therapy. Only one death less than 100 days from the diagnosis of RSV infection occurred among these 18 patients and was attributed to progressive leukemia. The remaining patients recovered fully, although three were readmitted with respiratory symptoms within two weeks of discharge. Seven patients had concurrent infection with other pathogenic organisms. CONCLUSIONS: In striking contrast with the outcome of RSV infection in adult oncology patients, there may be low mortality associated with RSV infection in pediatric oncology patients. It is possible that scheduled anti-neoplastic therapy need not be delayed for these patients when the diagnosis of RSV infection is made.

Systemic lupus erythematosus in a pediatric patient with congenital acquired immunodeficiency syndrome.

The coexistence of congenital HIV infection with primary rheumatologic disease is rare. We have described a child with congenital AIDS and concurrent systemic lupus erythematosus who presented with small vessel vasculitis with no renal involvement. Oral corticosteroid therapy resulted in significant improvement in her clinical state. The child also responded strongly to potent antiretroviral therapy both virologically and immunologically.

Neonatal lupus erythematosus in triplets.

Neonatal lupus erythematosus (NLE) is an inflammatory syndrome in the fetus or neonate associated with the presence of anti-Ro(SSA) and anti-La(SSB) antibodies in the mother. It is characterized by a combination of dermatologic, hematologic, hepatic, and cardiac manifestations. NLE has been reported in twins; we describe neonatal lupus erythematosus occurring in triplets.

Advances in the medical treatment of juvenile rheumatoid arthritis.

Juvenile rheumatoid arthritis (JRA) remains a challenge for clinicians. Nonsteroidal anti-inflammatory drugs and corticosteroids remain the mainstays of therapy, but concerns persist about side effects and the ability of these agents to prevent progression of bony disease. In recent years, novel treatments have been developed and quickly discarded because of unexpected toxicities or lack of efficacy. However, recent studies have shown that methotrexate and sulfasalazine are relatively safe and effective for JRA. Newly developed drugs, such as selective cyclooxygenase-2 inhibitors and soluble tumor necrosis factor receptor, whose development has stemmed from a more basic understanding of pathophysiology, may provide better disease control with fewer side effects. Finally, novel therapies, such as stem cell transplantation, may offer hope for children with JRA, especially systemic-onset JRA, whose disease has been refractory to conventional therapy.

Intermittent intravenous cyclophosphamide arrests progression of the renal chronicity index in childhood systemic lupus erythematosus.

OBJECTIVE: To assess prospectively the safety and efficacy of a 36-month course of systematic bolus intravenous cyclophosphamide therapy (IVCY) for children with lupus nephritis. STUDY DESIGN: Sixteen children with lupus nephritis were treated with IVCY for 36 months. Renal biopsies performed before and after treatment were scored for activity and chronicity. SLEDAI scores, laboratory measures, and prednisone dosage were recorded at the time of each treatment. RESULTS: After 36 months of IVCY therapy, the renal biopsy activity index decreased from 9 +/- 4 to 1 +/- 1 (P <.001) without a change in chronicity. The mean creatinine clearance increased from 90 +/- 23 to 107 +/- 23 mL/min/1.73 mol/L(2) (P <.01), and the mean 24-hour urine protein excretion decreased from 2.0 +/- 2.4 g/24 h to 0.5 +/- 0.7 g/24 h (P <.05). The mean SLEDAI score decreased from 19 +/- 5.2 to 2.9 +/- 3.1 (P <.001). The mean prednisone dosage decreased from 35.5 +/- 20 mg/d to 14.0 +/- 3 mg/d (P <.001). No significant complications occurred. CONCLUSIONS: Thirty-six months of systematic IVCY therapy led to decreased renal biopsy activity without progression of chronicity, with excellent disease control and a greater than 50% reduction in mean corticosteroid dose.

Molecular cloning of a gene required for DNA replication in Ustilago maydis.

TSD2, a gene necessary for DNA synthesis in Ustilago maydis, was cloned by complementation of the temperature sensitive growth defect of a mutant known previously as pol1-1 and renamed here tsd2-1. Linkage analysis established that the cloned fragment contained an allele of tsd2-1 and not a suppressor. DNA sequence determination of the cloned DNA fragment indicated the presence of a single large uninterrupted open reading frame capable of encoding a protein of 845 amino acids without homology to any known gene involved in DNA synthesis. TSD2 was found to be cell cycle-regulated and mRNA levels peaked in early S or G1 phase.

The REC1 gene of Ustilago maydis, which encodes a 3'-->5' exonuclease, couples DNA repair and completion of DNA synthesis to a mitotic checkpoint.

Mutation in the REC1 gene of Ustilago maydis results in extreme sensitivity to killing by ultraviolet light. The lethality of the rec1-1 mutant was found to be partially suppressed if irradiated cells were held artificially in G2-phase by addition of a microtubule inhibitor. This mutant was also found to be sensitive to killing when DNA synthesis was inhibited by external means through addition of hydroxyurea or by genetic control in a temperature-sensitive mutant strain defective in DNA synthesis. Flow cytometric analysis of exponentially growing cultures indicated that wild-type cells accumulated in G2 after UV irradiation, while rec1-1 cells appeared to exit from G2 and accumulate in G1/S. Analysis of mRNA levels in synchronized cells indicated that the REC1 gene is periodically expressed with the cell cycle and reaches maximal levels at G1/S. The results are interpreted to mean that a G2-M checkpoint is disabled in the rec1-1 mutant. It is proposed that the REC1 gene product functions in a surveillance system operating during S-phase and G2 to find and repair stretches of DNA with compromised integrity and to communicate with the cell cycle apparatus.

Levels of soluble Fas/APO-1/CD95 in systemic lupus erythematosus and juvenile rheumatoid arthritis.

OBJECTIVE: To quantify soluble Fas/APO-1 (sFas/APO-1) protein in the serum of patients with systemic lupus erythematosus (SLE) and juvenile rheumatoid arthritis (JRA). METHODS: Soluble Fas/APO-1 was quantified using a sandwich enzyme-linked immunosorbent assay. Disease activity in SLE patients was assessed by the SLE Disease Activity Index. RESULTS: Increased serum sFas/APO-1 levels were observed in only 1 of the 27 SLE patients (4%) and 3 of the 10 JRA patients (30%). CONCLUSION: Increased levels of sFas/APO-1 occurred infrequently in SLE, and the levels were lower than 10 ng/ml. Increased levels of sFas/APO-1 are not specific for SLE. Soluble Fas/APO-1 is unlikely to be of major pathogenetic significance in SLE.