SMARCB1 Gene Therapy Using a Novel Tumor-Targeted Nanomedicine Enhances Anti-Cancer Efficacy in a Mouse Model of Atypical Teratoid Rhabdoid Tumors.

Purpose: Atypical teratoid rhabdoid tumor (ATRT) is a deadly, fast-growing form of pediatric brain cancer with poor prognosis. Most ATRTs are associated with inactivation of SMARCB1, a subunit of the chromatin remodeling complex, which is involved in developmental processes. The recent identification of SMARCB1 as a tumor suppressor gene suggests that restoration of SMARCB1 could be an effective therapeutic approach. Methods: We tested SMARCB1 gene therapy in SMARCB1-deficient rhabdoid tumor cells using a novel tumor-targeted nanomedicine (termed scL-SMARCB1) to deliver wild-type SMARCB1. Our nanomedicine is a systemically administered immuno-lipid nanoparticle that can actively cross the blood-brain barrier via transferrin receptor-mediated transcytosis and selectively target tumor cells via transferrin receptor-mediated endocytosis. We studied the antitumor activity of the scL-SMARCB1 nanocomplex either as a single agent or in combination with traditional treatment modalities in preclinical models of SMARCB1-deficient ATRT. Results: Restoration of SMARCB1 expression by the scL-SMARCB1 nanocomplex blocked proliferation, and induced senescence and apoptosis in ATRT cells. Systemic administration of the scL-SMARCB1 nanocomplex demonstrated antitumor efficacy as monotherapy in mice bearing ATRT xenografts, where the expression of exogenous SMARCB1 modulates MYC-target genes. scL-SMARCB1 demonstrated even greater antitumor efficacy when combined with either cisplatin-based chemotherapy or radiation therapy, resulting in significantly improved survival of ATRT-bearing mice. Conclusion: Collectively, our data suggest that restoring SMARCB1 function via the scL-SMARCB1 nanocomplex may lead to therapeutic benefits in ATRT patients when combined with traditional chemoradiation therapies.

Concurrent sexual partnerships among African Americans in the rural south.

PURPOSE: To investigate concurrent sexual partnerships among heterosexual African Americans, 18 to 59 years old, in rural North Carolina. METHODS: Household interviews with persons randomly selected from the NC driver's license file were conducted to identify overlap among the 3 most recent sexual partnerships. RESULTS: Concurrency prevalence in the past 5 years was 53% (men) and 31% (women). Most (61%) respondents believed that a recent partner had had a concurrent partnership. Multivariate analysis revealed strong associations between concurrency and male gender, being unmarried, age of sexual debut, and incarceration of a sex partner. CONCLUSIONS: Concurrent partnerships may increase rates of heterosexual HIV among blacks in the rural Southeastern United States. Future research should examine the context that supports this network pattern.

A high proportion of genes involved in position effect variegation also affect chromosome inheritance.

Suppressors and enhancers of position effect variegation (PEV) have been linked to the establishment and maintenance of heterochromatin. The presence of centromeres and other inheritance elements in heterochromatic regions suggests that suppressors and enhancers of PEV, Su(var) s and E(var)s [collectively termed Mod(var)s], may be required for chromosome inheritance. In order to test this hypothesis, we screened 59 ethyl methanesulfonate-generated Drosophila Mod(var)s for dominant effects on the partially compromised inheritance of a minichromosome ( J21A) missing a portion of the genetically defined centromere. Nearly half of these Mod(var)s significantly increased or decreased the transmission of J21A. Analyses of homozygous mutant larval neuroblasts suggest that these mutations affect cell cycle progression and native chromosome morphology. Five out of six complementation groups tested displayed mitotic abnormalities, including phenotypes such as telomere fusions, overcondensed chromosomes, and low mitotic index. We conclude that Mod(var)s as a group are highly enriched for genes that encode essential inheritance functions. We propose that a primary function of Mod(var)s is to promote chromosome inheritance, and that the gene silencing phenotype associated with PEV may be a secondary consequence of the heterochromatic structures required to carry out these functions.

Concurrent partnerships among rural African Americans with recently reported heterosexually transmitted HIV infection.

OBJECTIVES: To investigate concurrent sexual partnerships among African Americans in North Carolina with recently reported heterosexually transmitted HIV infection. DESIGN: Population-based case series of persons with newly reported HIV infection. METHODS: Household interviews concerning sexual and other risk behaviors for HIV transmission were conducted among African Americans, 18-59 years old, who had been reported to the state health department within the preceding 6 months as having heterosexually acquired HIV infection. Dates of sexual partnerships were analyzed to identify concurrency among the 3 most recent partnerships. RESULTS: Concurrency prevalence in the past 1 and 5 years, respectively, was 45 and 63% for men and 37 and 58% for women. Most respondents (87%) believed that a recent partner had had a concurrent partnership. Multivariate analysis revealed associations between concurrency and male gender, youth, crack cocaine smoking, and incarceration of a sex partner. CONCLUSIONS: Concurrent partnerships likely accelerate heterosexual HIV transmission among blacks in the rural southeastern United States. Future research should examine the socioeconomic context that supports this network pattern.

Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates.

A hallmark of most neurodegenerative diseases, including those caused by polyglutamine expansion, is the formation of ubiquitin (Ub)-positive protein aggregates in affected neurons. This finding suggests that the Ub system may be involved in common mechanisms underlying these otherwise unrelated diseases. Here we report the finding of ataxin-3 (Atx-3), whose mutation is implicated in the neurodegenerative disease spinocerebellar ataxia type 3, in a bioinformatics search of the human genome for components of the Ub system. We show that wild-type Atx-3 is a Ub-binding protein and that the interaction of Atx-3 with Ub is mediated by motifs homologous to those found in a proteasome subunit. Both wild-type Atx-3 and the otherwise unrelated Ub-binding protein p62/Sequestosome-1 have been shown to be sequestered into aggregates in affected neurons in several neurodegenerative diseases, but the mechanism for this recruitment has remained unclear. In this article, we show that functional Ub-binding motifs in Atx-3 and p62 proteins are required for the localization of both proteins into aggregates in a cell-based assay that recapitulates several features of polyglutamine disease. We propose that the Ub-mediated sequestration of essential Ub-binding protein(s) into aggregates may be a common mechanism contributing to the pathogenesis of neurodegenerative diseases.

Ubiquitin signals protein trafficking via interaction with a novel ubiquitin binding domain in the membrane fusion regulator, Vps9p.

The conserved vacuolar protein-sorting (Vps) pathway controls the trafficking of proteins to the vacuole/lysosome. Both the internalization of ubiquitylated cargo from the plasma membrane and its sorting at the late endosome via the Vps pathway depend on ubiquitin (Ub) binding motifs present in trafficking regulators. Here we report that Ub controls yet a third step in the Vps pathway. Vps9p, which promotes endosomal and Golgi-derived vesicle fusion, binds directly to Ub via a Cue1p-homologous (CUE) domain. The CUE domain is structurally related to the Ub-associated (UBA) domain. In an assay for vacuolar delivery of a transmembrane receptor fused to Ub, a Ub mutation impairing interaction with Vps9p led to a cytoplasmic block in receptor trafficking. This block resembled that of a receptor fused to wild-type Ub but expressed in a vps9-null background. Strikingly, this trafficking defect caused by a mutant Ub was rescued by deletion of the Vps9p CUE domain, indicating that lack of the CUE domain renders Vps9p independent of Ub for activation in vivo. We thus provide evidence for biochemical and genetic interactions between Ub and a novel Ub binding domain in Vps9p. Ub plays a positive role, whereas the CUE domain plays both positive and negative roles in Vps9p function in trafficking.

Concurrent sexual partnerships among women in the United States.

BACKGROUND: The marked racial disparity in sexually transmitted infection (STI) rates in the United States remains inadequately explained. One important factor may be concurrent sexual partnerships (relationships that overlap in time), which can transmit STIs more rapidly through a population than does sequential monogamy. METHODS: To determine prevalence, distribution, and correlates of U.S. women's involvement in concurrent partnerships, we analyzed sexual partnership data reported by the 10,847 women, age 15-44 years, in the 1995 National Survey of Family Growth. Overlapping sexual partnership dates were determined by computer program and visual review of the data. RESULTS: Prevalence of concurrent partnerships since January 1991 was 12% overall. Prevalence was lowest among currently married respondents (4%) and highest among those who were formerly married (22%), never married (19%), in the lowest income stratum (17%), age 18-24 years when interviewed (23%), or who first had sexual intercourse at age 12 or 13 (35%). Prevalence was 21% among blacks, 11% among whites, 8% among Hispanics, and 6% among Asian American and Pacific Islanders. Multiple logistic analysis substantially weakened the relationship between concurrency and black race (OR = 1.2; 95% CI = 1.1-1.4). CONCLUSIONS: Marital status in particular is strongly related to concurrency; thus, lower marriage rates among blacks and the associated higher concurrency of sexual partners may contribute to racial disparities in STI rates.

Modifiers of terminal deficiency-associated position effect variegation in Drosophila.

Terminal deletions of a Drosophila minichromosome (Dp(1;f)1187) dramatically increase the position effect variegation (PEV) of a yellow(+) body-color gene located in cis. Such terminal deficiency-associated PEV (TDA-PEV) can be suppressed by the presence of a second minichromosome, a phenomenon termed "trans-suppression." We performed a screen for mutations that modify TDA-PEV and trans-suppression. Seventy suppressors and enhancers of TDA-PEV were identified, but no modifiers of trans-suppression were recovered. Secondary analyses of the effects of these mutations on different PEV types identified 10 mutations that modify only TDA-PEV and 6 mutations that modify TDA-PEV and only one other type of PEV. One mutation, a new allele of Su(var)3-9, affects all forms of PEV, including silencing associated with the insertion of a transgene into telomeric regions (TPE). This Su(var)3-9 allele is the first modifier of PEV to affect TPE and provides a unique link between different types of gene silencing in Drosophila. The remaining mutations affected multiple PEV types, indicating that general PEV modifiers impact TDA-PEV. Modifiers of TDA-PEV may identify proteins that play important roles in general heterochromatin biology, including proteins involved in telomere structure and function and the organization of chromosomes in the interphase nucleus.