A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma

We conducted a phase 1/2 trial of high-dose 90Y-ibritumomab tiuxetan in combination with high-dose etoposide (VP-16) 40 to 60 mg/kg (day -4) and cyclophosphamide 100 mg/kg (day -2) followed by autologous stem cell transplantation (ASCT) in 31 patients with CD20+ non-Hodgkin lymphoma (NHL). Patients underwent dosimetry (day -21) with 5 mCi (185 MBq) 111In-ibritumomab tiuxetan following 250 mg/m2 rituximab, followed a week later by 90Y-ibritumomab tiuxetan to deliver a target dose of 1000 cGy to highest normal organ. Bone marrow biopsy was done on day -7 to estimate radiation dose and stem cells were reinfused when the radiation dose was estimated to be less than 5 cGy. The median 90Y-ibritumomab tiuxetan dose was 71.6 mCi (2649.2 MBq; range, 36.6-105 mCi; range, 1354.2-3885 MBq). Histology included follicular lymphoma (n = 12), diffuse large B-cell (n = 14), and mantle cell (n = 5). The median number of prior chemo-therapy treatments was 2. The treatment was well tolerated. The median times to reach an absolute neutrophil count greater than 500/microL and platelet count more than 20,000/microL were 10 days and 12 days, respectively. There were 2 deaths and 5 relapses. At a median follow-up of 22 months, the 2-year estimated overall survival and relapse-free survival rates are 92% and 78%, respectively. We conclude that high-dose 90Y-ibritumomab tiuxetan can be combined safely with high-dose etoposide and cyclophosphamide without an increase in transplant-related toxicity or delayed engraftment.     

The Scc2/Scc4 cohesin loader determines the distribution of cohesin on budding yeast chromosomes

Cohesins mediate sister chromatid cohesion and DNA repair and also function in gene regulation. Chromosomal cohesins are distributed nonrandomly, and their deposition requires the heterodimeric Scc2/Scc4 loader. Whether Scc2/Scc4 establishes nonrandom cohesin distributions on chromosomes is poorly characterized, however. To better understand the spatial regulation of cohesin association, we mapped budding yeast Scc2 and Scc4 chromosomal distributions. We find that Scc2/Scc4 resides at previously mapped cohesin-associated regions (CARs) in pericentromeric and arm regions, and that Scc2/Scc4–cohesin colocalization persists after the initial deposition of cohesins in G1/S phase. Pericentromeric Scc2/Scc4 enrichment is kinetochore-dependent, and both Scc2/Scc4 and cohesin associations are coordinately reduced in these regions following chromosome biorientation. Thus, these characteristics of Scc2/Scc4 binding closely recapitulate those of cohesin. Although present in G1, Scc2/Scc4 initially has a poor affinity for CARs, but its affinity increases as cells traverse the cell cycle. Scc2/Scc4 association with CARs is independent of cohesin, however. Taken together, these observations are inconsistent with a previous suggestion that cohesins are relocated by translocating RNA polymerases from separate loading sites to intergenic regions between convergently transcribed genes. Rather, our findings suggest that budding yeast cohesins are targeted to CARs largely by Scc2/Scc4 loader association at these locations.     

The avian heterophil

Heterophils play an indispensable role in the immune defense of the avian host. To accomplish this defense, heterophils use sophisticated mechanisms to both detect and destroy pathogenic microbes. Detection of pathogens through the toll-like receptors (TLR), FC and complement receptors, and other pathogen recognition receptors has been recently described for the avian heterophil. Upon detection of pathogens, the avian heterophil, through a network of intracellular signaling pathways and the release and response to cytokines and chemokines, responds using a repertoire of microbial killing mechanisms including production of an oxidative burst, cellular degranulation, and production of extracellular matrices of DNA and histones (HETs). In this review, the authors describe the recent advances in our understanding of the avian heterophil, its functions, receptors and signaling, identified antimicrobial products, cytokine and chemokine production, and some of the effects of genetic selection on heterophils and their functional characteristics.     

Rheumatoid arthritis: explanatory power of specific radiographic findings for patient clinical status

Radiographs of the hands and wrists of 201 patients with rheumatoid arthritis (RA) were scored for erosion, joint space narrowing, and malalignment. The explanatory power of these findings for measures of clinical status was studied with stepwise multiple linear regression analyses. Radiographic scores explained 59.2% of variation in physical joint count deformity scores, 58.5% of variation in limited motion scores, 22.5% of variation in grip strength scores, 20.5% of variation in button test scores, and 13.5% of variation for the American Rheumatism Association (ARA) Functional Class. Malalignment scores best explained variation in physical deformity, limited motion, and button test scores; joint-space-narrowing scores best explained variation in grip strength; erosion scores best explained variation in ARA Functional Class. When age, duration of disease, erythrocyte sedimentation rate, and rheumatoid factor titer were included in the regression analyses, results were similar to those without these variables. Therefore quantitative scores of specific radiographic findings are in themselves explanatory for measures of clinical status.     

In utero and childhood DDT,DDE, PBDE and PCBs exposure and sex hormones in adolescent boys: The CHAMACOS study

Dichlorodiphenyltrichloroethane (DDT), polybrominated diphenyl ether (PBDE) flame retardants, and polychlorinated biphenyls (PCBs) are believed to be endocrine-disrupting chemicals (EDCs) in humans and animals. The purpose of this study is to examine the relationship of in utero and childhood exposure to these purported EDCs and reproductive hormones in adolescent boys who participated in CHAMACOS, an ongoing birth cohort in California's Salinas Valley. We measured o,p′- and p,p′-DDT, p,p′-DDE, PBDEs and PCBs in serum collected from mothers during pregnancy or at delivery and from their sons at 9 years. We measured concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and total testosterone (T) from 234 of their sons at 12 years. In adjusted models, we found that a 10-fold increase in maternal prenatal serum concentrations of BDE-153 was associated with a 22.2% increase (95% CI: 1.0, 47.9) in FSH, a 96.6% increase (95% CI: 35.7, 184.7) in LH, and a 92.4% increase (95% CI: 20.9, 206.2) increase in T. Similarly, BDE-100 concentrations were associated with increases in boys’ LH levels. A 10-fold increase in total prenatal ΣPCBs was associated with a 64.5% increase (95% CI: 8.6, 149.0) in FSH, primarily driven by non- dioxin-like congeners. Boys' hormone levels were only marginally associated with prenatal DDT or DDE in primary models, but when boys' Tanner stage at age 12 was added to models, prenatal maternal DDT levels were associated with decreases in LH (adjusted percent change per 10-fold increase = ?18.5%, 95% CI: ?29.8, ?5.4) and T (percent change = ?18.2%, 95% CI: ?30.2, ?4.2) and DDE with LH (percent change = ?18.3%, 95% CI: ?32.9, ?0.6). Exposures measured in the children's serum at 9 years also showed associations between BDE-153 and ΣPCBs. However, there is evidence that these associations appear to be mediated by child BMI. This study suggests associations on male hormones of 12 year old boys related to exposure to certain EDC exposure prenatally. The implications on future reproductive function in puberty and adulthood should be determined.