Preliminary Validation of an Unannounced Telephone Pill Count Protocol to Measure Medication Adherence Among Young Adults With Perinatal HIV Infection.

Unannounced telephone pill counts are an objective antiretroviral therapy adherence measurement tool, but this method has not been validated in young adults (YA) living with perinatal HIV infection. Perinatally infected YA, recruited from the Child and Adolescent Self-Awareness and Health Study, agreed to unannounced telephone pill counts to measure medication adherence over 4 months and phlebotomy to measure viral load (VL). Differences in pill count adherence scores among YA with a VL of ≤20 versus >20, and demographic differences were assessed.

Association Between Psychiatric Disorders, Substance Use, and Sexual Risk Behaviors in Perinatally HIV-Exposed Youth.

As youth with perinatally acquired HIV infection age, there is a need for studies that identify predictors and correlates of sexual risk behaviors. We examined the association between psychiatric disorders and substance use disorders (SUD) with sexual risk behaviors in youth with perinatally acquired HIV infection and perinatally HIV-exposed but uninfected youth. Participants were recruited from four medical centers in New York City.

Psychiatric Disorders, Antiretroviral Medication Adherence and Viremia in a Cohort of Perinatally HIV-Infected Adolescents and Young Adults.

Background: Perinatally HIV-infected (PHIV+) adolescents and young adults (AYA) are at risk for suboptimal antiretroviral therapy (ART) adherence and mental health and substance use problems that, in HIV-infected adults, predict nonadherence. Studies on the relationship between psychiatric and substance use disorders (SUD) and adherence among PHIV+ AYA are limited, but may be important for informing evidence-based interventions to promote adherence.

Methods: Data were analyzed from 3 annual follow-up interviews (FU2-FU4, N = 179) in a longitudinal study of PHIV+ AYA.

Use of Unannounced Telephone Pill Counts to Measure Medication Adherence Among Adolescents and Young Adults Living With Perinatal HIV Infection.

Objective: To examine unannounced telephone pill counts as a measure of adherence to antiretroviral therapy among adolescents and young adults living with perinatal HIV infection.

Methods: Participants were recruited from an ongoing longitudinal study to complete four monthly, unannounced telephone pill counts. Detailed notes concerning participants' medication habits surrounding adherence were recorded.

RAS signalling through PI3-Kinase controls cell migration via modulation of Reelin expression.

RAS signalling through phosphoinositide 3-kinase (PI3-Kinase) has been shown to have an essential role in tumour initiation and maintenance. RAS also regulates cell motility and tumour invasiveness, but the role of direct RAS binding to PI3-Kinase in this remains uncertain. Here, we provide evidence that disruption of RAS interaction with PI3-Kinase p110α decreases cell motility and prevents activation of Rac GTPase.

Patterns and Correlates of Serostatus Disclosure to Sexual Partners by Perinatally-Infected Adolescents and Young Adults.

Similar to same-age peers, perinatally HIV-infected (PHIV+) youth in the US are engaging in sex, including condomless sex. Understanding decisions about serostatus disclosure to sexual partners is important to domestic and global HIV prevention efforts, since large numbers of PHIV+ children are entering adolescence and becoming sexually active. Using Social Action Theory (SAT) to inform variable selection, we examined correlates of disclosure among 98 PHIV+ adolescents/young adults in New York City.

Marijuana Use and Psychiatric Disorders in Perinatally HIV-Exposed Youth: Does HIV Matter?

Objective:  To examine longitudinal reciprocal relationships between marijuana use and psychiatric disorders, and identify the role of HIV in a sample (N = 340) of youth perinatally infected with HIV (PHIV+) and youth perinatally exposed but uninfected with HIV (PHIV-) (60.6% PHIV+; 9-16 years at baseline; 51% female). 

Methods:  Cross-lagged structural equation modeling was used to examine longitudinal associations between changes in marijuana use and changes in any behavioral, mood, and anxiety disorders at three time points across adolescence.

Barriers and facilitators to engagement of vulnerable populations in HIV primary care in New York City.

Background: Engagement in HIV care helps to maximize viral suppression, which in turn, reduces morbidity and mortality and prevents further HIV transmission. With more HIV cases than any other US city, New York City reported in 2012 that only 41% of all persons estimated to be living with HIV (PLWH) had a suppressed viral load, whereas nearly three-quarters of those in clinical care achieved viral suppression. Thus, retaining PLWH in HIV care addresses this central goal of both the US National HIV/AIDS Strategy and Governor Cuomo's plan to end the AIDS epidemic in New York State.

Enhancing Lay Counselor Capacity to Improve Patient Outcomes with Multimedia Technology.

Multimedia technologies offer powerful tools to increase capacity of health workers to deliver standardized, effective, and engaging antiretroviral medication adherence counseling. Masivukeni-is an innovative multimedia-based, computer-driven, lay counselor-delivered intervention designed to help people living with HIV in resource-limited settings achieve optimal adherence. This pilot study examined medication adherence and key psychosocial outcomes among 55 non-adherent South African HIV+ patients, on antiretroviral therapy (ART) for at least 6 months, who were randomized to receive either Masivukeni or standard of care (SOC) counseling for ART non-adherence.

HIV treatment adherence measurement and reporting concordance in youth with perinatally acquired HIV infection and their caregivers.

We examined youth-caregiver adherence report concordance and association of different adherence self-report items with HIV RNA viral load (VL) in perinatally HIV-infected adolescents assessed in 2003-2008. Youth (n=194; 9-19 years) and their caregivers completed a multi-step 2-day recall, one item on last time medications were missed, and one item on responsibility for managing youths' medications. Across early (9-12 years), middle (13-15 years), and late (16+years) adolescence, both youth and caregivers reported having primary responsibility for youths' medication regimens and demonstrated poor to moderate youth-caregiver concordance on adherence items.

Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer.

Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung cancer cell line and analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS GTPase-activating protein encoded by the NF1 gene.

Asking only "Did you use a condom?" underestimates the prevalence of unprotected sex among perinatally HIV infected and perinatally exposed but uninfected youth.

Among young adults who use condoms, incomplete condom use (putting a condom on after beginning or taking a condom off before finishing sex) and condom failure (condom breaking or slipping off during sex) are common. Therefore, sexual behavior surveys that ask only if a condom was used are likely to underestimate the actual prevalence of unprotected sex. This study examined data from 135 sexually active perinatally HIV-infected (PHIV+) youth and perinatally exposed but uninfected (PHIV-) youth, ages 13 to 24.

PI3K pathway dependencies in endometrioid endometrial cancer cell lines.

Purpose: Endometrioid endometrial cancers (EEC) frequently harbor coexisting mutations in phosphoinositide 3-kinase (PI3K) pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to define the genetic determinants of PI3K pathway inhibitor response in EEC cells, and whether PTEN-mutant EEC cell lines rely on p110β signaling for survival.

Experimental Design: Twenty-four human EEC cell lines were characterized for their mutation profile and activation state of PI3K and mitogen-activated protein kinase (MAPK) signaling pathway proteins.

Masivukeni: development of a multimedia based antiretroviral therapy adherence intervention for counselors and patients in South Africa.

Effective medical treatment for HIV/AIDS requires patients' optimal adherence to antiretroviral therapy (ART). In resource-constrained settings, lack of adequate standardized counseling for patients on ART remains a significant barrier to adherence. Masivukeni ("Let's Wake Up" in Xhosa) is an innovative multimedia-based intervention designed to help people living with HIV in resource-limited settings achieve and maintain high levels of ART adherence.

Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies.

Oncogenic mutations in RAS genes are very common in human cancer, resulting in cells with well-characterized selective advantages, but also less well-understood vulnerabilities. We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells, but not by derivatives lacking this oncogene. Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells.

A role for p38 stress-activated protein kinase in regulation of cell growth via TORC1.

The target of rapamycin (TOR) complex 1 (TORC1) signaling pathway is a critical regulator of translation and cell growth. To identify novel components of this pathway, we performed a kinome-wide RNA interference (RNAi) screen in Drosophila melanogaster S2 cells. RNAi targeting components of the p38 stress-activated kinase cascade prevented the cell size increase elicited by depletion of the TOR negative regulator TSC2.

Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs.

Cytotoxic drug resistance is a major cause of cancer treatment failure. We report an RNA interference screen to identify genes influencing sensitivity of different cancer cell types to chemotherapeutic agents. A set of genes whose targeting leads to resistance to paclitaxel is identified, many of which are involved in the spindle assembly checkpoint.

Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice.

Ras proteins signal through direct interaction with a number of effector enzymes, including type I phosphoinositide (PI) 3-kinases. Although the ability of Ras to control PI 3-kinase has been well established in manipulated cell culture models, evidence for a role of the interaction of endogenous Ras with PI 3-kinase in normal and malignant cell growth in vivo has been lacking. Here we generate mice with mutations in the Pi3kca gene encoding the catalytic p110alpha isoform that block its interaction with Ras.

Predicting the Onset of Sexual and Drug Risk Behaviors in HIV-Negative Youths with HIV-Positive Mothers: The Role of Contextual, Self-Regulation, and Social-Interaction Factors.

HIV-negative, inner-city adolescents with HIV-infected parents are considered to be at high risk for acquiring HIV themselves. Using a modified theory of health behavior, this study examined the effects of maternal HIV infection and psychosocial variables on the onset of sexual and drug risk behavior in 144 HIV-negative adolescents with and without HIV-positive mothers. Adolescents and their mothers were interviewed when the youths were 10-14 years old and again when they were 13-19 years old.

Moving from theory to research to practice. Implementing an effective dyadic intervention to improve antiretroviral adherence for clinic patients.

There is a dearth of evidence on the relative efficacy of intervention modalities to improve and maintain patient adherence to antiretroviral medications. Although empiric findings from research on HIV/AIDS, other diseases, and chronic medical conditions consistently demonstrate that social support plays an important role in facilitating adherence, few HIV/AIDS interventions have directly targeted this factor. Ewart's social action theory emphasizes the role of social relationships in behavior change and provides a comprehensive and useful guide to the development of interventions for adherence.

Exoenzyme S of Pseudomonas aeruginosa is not able to induce apoptosis when cells express activated proteins, such as Ras or protein kinase B/Akt.

Intracellular targeting of the Pseudomonas aeruginosa toxins, such as exoenzyme S (ExoS), cause cell death, as well as morphological and physiological changes in various tissue culture cells and animal models. In this report we have investigated the mechanism behind ExoS-mediated cell death. In order to address this issue, we have used cell lines expressing activated forms of various components of the Ras signalling pathway in order to evaluate the importance of the Ras pathway for viability and survival upon ExoS infection.

Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells.

The ability of activated Ras to induce growth arrest of human ovarian surface epithelial (HOSE) cells via induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) has been used to screen for Ras pathway signaling components using a library of RNA interference (RNAi) vectors targeting the kinome. Two known Ras-regulated kinases were identified, phosphoinositide 3-kinase p110alpha and ribosomal protein S6 kinase p70(S6K1), plus the MAP kinase kinase kinase kinase MINK, which had not previously been implicated in Ras signaling. MINK is activated after Ras induction via a mechanism involving reactive oxygen species and mediates stimulation of the stress-activated protein kinase p38 MAPK downstream of the Raf/ERK pathway.

CUTL1 is a target of TGF(beta) signaling that enhances cancer cell motility and invasiveness.

CUTL1, also known as CDP, Cut, or Cux-1, is a homeodomain transcriptional regulator known to be involved in development and cell cycle progression. Here we report that CUTL1 activity is associated with increased migration and invasiveness in numerous tumor cell lines, both in vitro and in vivo. Furthermore, we identify CUTL1 as a transcriptional target of transforming growth factor beta and a mediator of its promigratory effects.

The transcriptional response to Raf activation is almost completely dependent on Mitogen-activated Protein Kinase Kinase activity and shows a major autocrine component.

The Raf protein kinases are major effectors of Ras GTPases and key components of the transcriptional response to serum factors, acting at least in part through the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. It has recently been suggested that Raf also may trigger other as yet uncharacterized signaling pathways. Here, we have used cDNA microarrays to dissect changes in gene expression induced by activation of inducible c-Raf-1 constructs in human mammary epithelial and ovarian epithelial cells.

Fibroblast growth factor 2-mediated translational control of IAPs blocks mitochondrial release of Smac/DIABLO and apoptosis in small cell lung cancer cells.

The mitochondrial release of cytochrome c and Smac/DIABLO has been implicated in the activation of apoptosis in response to cell stress. Smac promotes cytochrome c-induced activation of caspases by sequestering the inhibitor of apoptosis protein (IAP) family of potent caspase suppressors. Differential release from mitochondria of cytochrome c and Smac can occur, but the underlying mechanism and physiological significance of this are unclear.