Asian People Reached by the Centers for Disease Control and Prevention HIV Testing Program in the United States: HIV Testing, Linkage to HIV Medical Care, and Interview for Partner Services 2014-2020.

The purpose of this analysis is to describe HIV tests and associated outcomes for Asian people reached by the Centers for Disease Control and Prevention (CDC) HIV testing program. We analyzed CDC-funded HIV tests among Asian individuals in the United States, Puerto Rico, and the U.S. Virgin Islands (2014-2020). Of the 415,560 tests, the positivity of new diagnoses was higher among males (0.49%, aPR = 7.64) than females (0.06%), and in the West (0.42%, aPR = 1.15) than in the South (0.25%). In non-health care settings, positivity was highest among men who have sex with men (MSM; 0.87%) and transgender people (0.46%). Linkage to HIV medical care among Asian people was 87.5%, and 70.7% were interviewed for partner services. Our findings suggest that improvements are crucial, particularly for Asian MSM, in linkage to care and interview for partner services.

Contributions of Community-Based Organizations Funded by the Centers for Disease Control and Prevention's HIV Testing Program.

CONTEXT: HIV testing is a critically important first step in preventing and reducing HIV transmission. Community-based organizations (CBOs) are uniquely positioned to provide HIV testing and other prevention services to populations disproportionately affected by HIV infection. OBJECTIVE: The purpose of this analysis was to assess CDC-funded health department (HD) and CBO testing programs during 2012-2017, including the number of tests and HIV positivity. DESIGN: This is an analysis of National HIV Prevention Program Monitoring and Evaluation HIV testing data submitted between 2012 and 2017 to CDC. SETTING: Sixty-one CDC-funded state and local HDs in the United States, Puerto Rico, and the US Virgin Islands and between 122 and 175 CDC-funded CBOs, depending on the year. PARTICIPANTS: Persons who received HIV testing at CDC-funded CBOs and HDs. MAIN OUTCOME MEASURE: The number of HIV tests and positivity at CBOs were compared with HDs overall and to HDs in non-health care settings that, like CBOs, include HIV risk data and are in similar locations. RESULTS: CBOs accounted for 7625 (8%) new diagnoses but conducted only 3% of the almost 19 million CDC-funded HIV tests from 2012 to 2017. Newly diagnosed HIV positivity at CBOs (1.4%) was nearly 3 times the new positivity at HDs overall (0.5%) and twice that of new positivity at HDs in non-health care settings (0.7%). A higher proportion of tests at CBOs were conducted among groups at risk, and new HIV positivity was higher for most demographic and population groups than new HIV positivity at HDs in non-health care settings. CONCLUSION: These findings demonstrate the essential role CDC-funded CBOs have in reaching, testing, and diagnosing groups at high risk for acquiring HIV infection.

HIV Testing, Linkage to HIV Medical Care, and Interviews for Partner Services Among Black Men Who Have Sex with Men - Non-Health Care Facilities, 20 Southern U.S. Jurisdictions, 2016.

Identifying HIV-infected persons who are unaware of their human immunodeficiency virus (HIV) infection status, linking them to care, and reducing health disparities are important national HIV prevention goals (1). Gay, bisexual, and other men who have sex with men (collectively referred to as MSM) accounted for 70% of HIV infection diagnoses in the United States in 2016, despite representing only 2% of the population (2,3). African American or black (black) MSM accounted for 38% of all new diagnoses of HIV infection among MSM (2). Nearly two thirds (63%) of all U.S. black MSM with diagnosed HIV infection reside in the southern United States (2), making targeted HIV prevention activities for black MSM in this region critical. Analysis of CDC-funded HIV testing data for black MSM submitted by 20 health departments in the southern United States in 2016 revealed that although black MSM received 6% of the HIV tests provided, they accounted for 36% of the new diagnoses in non-health care facilities. Among those who received new diagnoses, 67% were linked to HIV medical care within 90 days of diagnosis, which is below the 2020 national goal of linking at least 85% of persons with newly diagnosed HIV infection to care within 30 days (1). Black MSM in the southern United States are the group most affected by HIV, but only a small percentage of CDC tests in the southern United States are provided to this group. Increasing awareness of HIV status through HIV testing, especially among black MSM in the southern United States, is essential for reducing the risk for transmission and addressing disparities. HIV testing programs in the southern United States can reach more black MSM by conducting targeted risk-based testing in non-health care settings and by routine screening in agencies that also provide health care services to black MSM.

HIV Testing, Linkage to HIV Medical Care, and Interviews for Partner Services Among Women - 61 Health Department Jurisdictions, United States, Puerto Rico, and the U.S. Virgin Islands, 2015.

Diagnoses of human immunodeficiency virus (HIV) infection among women declined 17% during 2011-2015, and a total of 7,498 women received a diagnosis of HIV infection in 2015 (1). Although black or African American (black) women accounted for only 12% of the U.S. female population, 60% of women with newly diagnosed HIV infection were black (1,2). By the end of 2014, an estimated 255,900 women were living with HIV infection (3), including approximately 12% who did not know they were infected; in addition, approximately 45% of women who had received a diagnosis had not achieved viral suppression (3). HIV testing is an important public health strategy for identifying women with HIV infection and linking them to HIV medical care. Analysis of CDC-funded program data submitted by 61 health departments in 2015 indicated that among 4,749 women tested who received a diagnosis of HIV infection, 2,951 (62%) had received a diagnosis in the past (previous diagnosis), and 1,798 (38%) were receiving a diagnosis for the first time (new diagnosis). Of those who had received a previous diagnosis, 87% were not in HIV medical care at the time of the current test. Testing and identifying women who are living with HIV infection but who are not in care (regardless of when they received their first diagnosis) and rapidly linking them to care so they can receive antiretroviral therapy and become virally suppressed are essential for reducing HIV infection among all women.

The influence of urea and nitrate nutrients on the bioavailability and toxicity of nickel to Prorocentrum donghaiense (Dinophyta) and Skeletonema costatum (Bacillariophyta).

Nitrogen nutrients and nickel(Ni) are ubiquitous in aquatic environments, and they are important for primary production of ocean ecosystem. This study examined the interaction of nitrogen nutrients (specifically urea and nitrate) and Ni on chlorophyll (Chl a) concentration and photosynthesis parameters values of Prorocentrum donghaiense and Skeletonema costatum. The data presented here indicate that low concentration of Ni for P. donghaiense and S. costatum can enhance both Chl a concentration and photosynthesis parameters values when grown in urea containing environment. Despite this increase there was also an observed depression in both species tested when incubated in high concentration of Ni for P. donghaiense and S. costatum regardless of incubating in urea or nitrate. Additionally, EC50 values of Chl a and Fv/Fm for Ni at different time intervals were calculated in this study. These observations indicated that the Ni tolerance was higher in P. donghaiense as compared to S. costatum. The Ni tolerance of P. donghaiense incubated in urea was higher than that incubating in nitrate. The same phenomenon was not observed in S. costatum, which indicated that the influence of urea was dependent on the species investigated. Thus, urea input could impact Ni bioavailability and toxicity, and then affect the biodynamics thereafter.

A role for activated Cdc42 in glioblastoma multiforme invasion.

Cdc42 is a Rho-GTPase which plays a major role in regulating cell polarity and migration by specifying the localization of filopodia. However, the role of Cdc42 in GBM invasion has not been thoroughly investigated. We generated stable doxycycline-inducible clones expressing wild type (WT)-, constitutively active (CA)-, and dominant negative (DN)-Cdc42 in three different human glioma cell lines. Expression of CA-Cdc42 significantly increased the migration and invasive properties of malignant glioma cells compared to WT and DN-Cdc42 cell clones, and this was accompanied by a greater number of filopodia and focal adhesion structures which co-localize with phosphorylated focal adhesion kinase (FAK). By mass spectrometry and immunoprecipitation studies, we demonstrated that activated Cdc42 binds to IQGAP1. When implanted orthotopically in mice, the CA-Cdc42 expressing glioma cells exhibited enhanced local migration and invasion, and led to larger tumors, which significantly reduced survival. Using the Cancer Genome Atlas dataset, we determined that high Cdc42 expression is associated with poorer progression free survival, and that Cdc42 expression is highest in the proneural and neural subgroups of GBM. In summary, our studies demonstrate that activated Cdc42 is a critical determinant of the migratory and invasive phenotype of malignant gliomas, and that its effect may be mediated, at least in part, through its interaction with IQGAP1 and phosphorylated FAK.

Withania somnifera root extract inhibits mammary cancer metastasis and epithelial to mesenchymal transition.

Though clinicians can predict which patients are at risk for developing metastases, traditional therapies often prove ineffective and metastatic disease is the primary cause of cancer patient death; therefore, there is a need to develop anti-metastatic therapies that can be administered over long durations to specifically inhibit the motility of cancer cells. Withaniasomnifera root extracts (WRE) have anti-proliferative activity and the active component, Withaferin A, inhibits the pro-metastatic protein, vimentin. Vimentin is an intermediate filament protein and is part of the epithelial to mesenchymal transition (EMT) program to promote metastasis. Here, we determined whether WRE standardized to Withaferin A (sWRE) possesses anti-metastatic activity and whether it inhibits cancer motility via inhibition of vimentin and the EMT program. Several formulations of sWRE were created to enrich for Withaferin A and a stock solution of sWRE in EtOH could recover over 90% of the Withaferin A found in the original extract powder. This sWRE formulation inhibited breast cancer cell motility and invasion at concentrations less than 1µM while having negligible cytotoxicity at this dose. sWRE treatment disrupted vimentin morphology in cell lines, confirming its vimentin inhibitory activity. To determine if sWRE inhibited EMT, TGF-ß was used to induce EMT in MCF10A human mammary epithelial cells. In this case, sWRE prevented EMT induction and inhibited 3-D spheroid invasion. These studies were taken into a human xenograft and mouse mammary carcinoma model. In both models, sWRE and Withaferin A showed dose-dependent inhibition of tumor growth and metastatic lung nodule formation with minimal systemic toxicity. Taken together, these data support the hypothesis that low concentrations of sWRE inhibit cancer metastasis potentially through EMT inhibition. Moreover, these doses of sWRE have nearly no toxicity in normal mouse organs, suggesting the potential for clinical use of orally administered WRE capsules.

In vivo analysis of human nucleoporin repeat domain interactions.

The nuclear pore complex (NPC), assembled from ∼30 proteins termed nucleoporins (Nups), mediates selective nucleocytoplasmic trafficking. A subset of nucleoporins bear a domain with multiple phenylalanine-glycine (FG) motifs. As binding sites for transport receptors, FG Nups are critical in translocation through the NPC. Certain FG Nups are believed to associate via low-affinity, cohesive interactions to form the permeability barrier of the pore, although the form and composition of this functional barrier are debated. We used green fluorescent protein-Nup98/HoxA9 constructs with various numbers of repeats and also substituted FG domains from other nucleoporins for the Nup98 domain to directly compare cohesive interactions in live cells by fluorescence recovery after photobleaching (FRAP). We find that cohesion is a function of both number and type of FG repeats. Glycine-leucine-FG (GLFG) repeat domains are the most cohesive. FG domains from several human nucleoporins showed no interactions in this assay; however, Nup214, with numerous VFG motifs, displayed measurable cohesion by FRAP. The cohesive nature of a human nucleoporin did not necessarily correlate with that of its yeast orthologue. The Nup98 GLFG domain also functions in pore targeting through binding to Nup93, positioning the GLFG domain in the center of the NPC and supporting a role for this nucleoporin in the permeability barrier.

Nup98-homeodomain fusions interact with endogenous Nup98 during interphase and localize to kinetochores and chromosome arms during mitosis.

Chromosomal translocations involving the Nup98 gene are implicated in leukemias, especially acute myelogenous leukemia. These translocations generate chimeric fusion proteins, all of which have in common the N-terminal half of Nup98, which contains the nucleoporin FG/GLFG repeat motifs. The homeodomain group of Nup98 fusion proteins retain the C-terminus of a homeodomain transcription factor, including the homeobox responsible for DNA binding. Current models for Nup98 leukemogenesis invoke aberrant transcription resulting from recruitment of coregulators by the Nup98 repeat domain. Here we have investigated the behavior of Nup98-homeodomain fusion proteins throughout the cell cycle. At all stages, the fusion proteins exhibit a novel localization distinct from the component proteins or fragments. During interphase, there are dynamic interactions between the Nup98 fusions and endogenous Nup98 that lead to mislocalization of the intranuclear fraction of Nup98, but do not alter the level of Nup98 at the nuclear pore complex. During mitosis, no interaction between the fusion proteins and endogenous Nup98 is observed. However, the fusions are entirely concentrated at kinetochores and on chromosome arms, sites where the APC/C, a target of Nup98 regulation, is also found. Our observations suggest new possibilities for misregulation by which Nup98 translocations may contribute to cellular transformation and leukemogenesis.

Nuclear pore proteins and cancer.

Nucleocytoplasmic trafficking of macromolecules, a highly specific and tightly regulated process, occurs exclusively through the nuclear pore complex. This immense structure is assembled from approximately 30 proteins, termed nucleoporins. Here we discuss the four nucleoporins that have been linked to cancers, either through elevated expression in tumors (Nup88) or through involvement in chromosomal translocations that encode chimeric fusion proteins (Tpr, Nup98, Nup214). In each case we consider the normal function of the nucleoporin and its translocation partners, as well as what is known about their mechanistic contributions to carcinogenesis, particularly in leukemias. Studies of nucleoporin-linked cancers have revealed novel mechanisms of oncogenesis and in the future, should continue to expand our understanding of cancer biology.

Interaction of p58(PITSLRE), a G2/M-specific protein kinase, with cyclin D3.

The p58(PITSLRE) is a p34(cdc2)-related protein kinase that plays an important role in normal cell cycle progression. Elevated expression of p58(PITSLRE) in eukaryotic cells prevents them from undergoing normal cytokinesis and appears to delay them in late telophase. To investigate the molecular mechanism of p58(PITSLRE) action, we used the yeast two-hybrid system, screened a human fetal liver cDNA library, and identified cyclin D3 as an interacting partner of p58(PITSLRE). In vitro binding assay, in vivo coimmunoprecipitation, and immunofluorescence cell staining further confirmed the association of p58(PITSLRE) with cyclin D3. This binding was observed only in the G(2)/M phase but not in the G(1)/S phase of the cell cycle; meanwhile, no interaction between p110(PITSLRE) and cyclin D3 was observed in all the cell cycle. The overexpression of cyclin D3 in 7721 cells leads to an exclusively accumulation of p58(PITSLRE) in the nuclear region, affecting its cellular distribution. Histone H1 kinase activity of p58(PITSLRE) was greatly enhanced upon interaction with cyclin D3. Furthermore, kinase activity of p58(PITSLRE) was found to increase greatly in the presence of cyclin D3 using a specific substrate, beta-1,4-galactosyltransferase 1. These data provide a new clue to our understanding of the cellular function of p58(PITSLRE) and cyclin D3.