Publications

The Rho family of small GTPases plays a key role in the dynamic regulation of the actin cytoskeleton that underlies various important cellular functions such as shape changes, migration, and polarity. We found that Smurf1, a HECT domain E3 ubiquitin ligase, could specifically target RhoA but not Cdc42 or Rac1 for degradation. Smurf1 interacts with the dominant inactive form of RhoA, RhoA N19, which binds constitutively to guanine nucleotide exchange factors (GEFs) in vivo. Smurf1 also interacts directly with either nucleotide-free or GDP-bound RhoA in vitro; however, loading with GTPgammaS inhibits the interaction. RhoA is ubiquitinated by wild-type Smurf1 but not the catalytic mutant of Smurf1 (C699A) in vivo and in vitro, indicating that RhoA is a direct substrate of Smurf1. In this chapter, we summarize the systems and methods used in the analyses of Smurf1-regulated RhoA ubiquitination and degradation.

BACKGROUND

With recent advances in breast cancer risk reduction practices, it is increasingly important to assess both the breadth of and disparities in use across different racial/ethnic groups.

METHODS

We conducted telephone interviews with 1,700 women ages 40 to 74, from four racial/ethnic groups, without prior history of breast cancer, who received mammograms at one of five mammography facilities in San Francisco. Main outcomes measured included recognition of tamoxifen, raloxifene, genetic testing, and prophylactic surgery. Global indicators (recognition of any therapy, discussion of breast cancer risk) were developed from original outcome measures and analyzed using logistic regression.

RESULTS

Multivariate analyses indicate that race/ethnicity and interview language affected recognition of therapies and discussion of risk. White women were more likely than all other women to recognize any therapy and more likely than Asian-Americans to discuss risk. Women at high risk, who had a prior abnormal mammogram, who perceived themselves to be at high risk, or who were exposed to breast health information were more likely to discuss risk.

CONCLUSIONS

Women are aware of preventive therapies, although discussion and use is limited. Interventions to increase use of therapies should focus on those at high risk.

Large (>or=45 transplants per year) North American liver transplant centres were surveyed regarding management of hepatitis C virus (HCV). A total of 25/41 (59%) and 28/48 (58%) of centres responded to the surveys in 1998 and 2003, respectively, with 17 centres participating in both surveys. HCV was the most common indication for transplantation. Use of protocol liver biopsies was higher in 2003 and 60% used them to monitor HCV disease. Fewer centres reported modifying primary immunosuppression (IMS) for HCV-positive (vs. non-HCV) patients in 2003 (26%) vs. 1998 (56%). IMS was most frequently tacrolimus-based, but mycophenolate mofetil use increased in 2003 (52% vs. 23% in 1998). In both years, approximately 40% treated allograft rejection differently in HCV-positive recipients, with less use of OKT3 in 2003. Combination anti-HCV therapy for 12 months or more was the treatment of choice and growth factor use was common (68%). HCV-positive recipients were considered candidates for retransplantation but HCV-specific criteria were used in decision-making. Practice of centres changed over time with an increase in HCV transplantation and use of protocol liver biopsies, and a trend towards lesser modification of IMS in HCV-positive recipients. We conclude that there is considerable variability in the management of HCV among transplant programs and over time.

BACKGROUND

Homelessness and hunger are associated with poor health outcomes. Housing instability and food insecurity describe less severe problems securing housing and food.

OBJECTIVE

To determine the association between housing instability and food insecurity and access to ambulatory health care and rates of acute health care utilization.

DESIGN

Secondary data analysis of the National Survey of American Families.

PARTICIPANTS

16,651 low-income adults.

MEASUREMENT

Self-reported measures of past-year access: (1) not having a usual source of care, (2) postponing needed medical care, or (3) postponing medication; and past-year utilization: (1) not having an ambulatory care visit, (2) having emergency department (ED) visits, or (3) inpatient hospitalization.

RESULTS

23.6% of subjects had housing instability and 42.7% had food insecurity. In multivariate logistic regression models, housing instability was independently associated with not having a usual source of care (adjusted odds ratio [AOR] 1.31, 95% confidence interval [CI] 1.08 to 1.59), postponing needed medical care (AOR 1.84, 95% CI 1.46 to 2.31) and postponing medications (AOR 2.16, 95% CI 1.70 to 2.74), increased ED use (AOR: 1.43, 95% CI 1.20 to 1.70), and hospitalizations (AOR 1.30, 95% CI 1.01 to 1.67). Food insecurity was independently associated with postponing needed medical care (AOR 1.74, 95% CI 1.38 to 2.21) and postponing medications (AOR 2.15, 95% CI 1.62 to 2.85), increased ED use (AOR 1.39, 95% CI 1.17 to 1.66), and hospitalizations (AOR 1.42, 95% CI 1.09 to 1.85).

CONCLUSIONS

Housing instability and food insecurity are associated with poor access to ambulatory care and high rates of acute care. These competing life demands may lead to delays in seeking care and predispose to acute care.

RuleEd is a web-based editing environment which enables clinical trial eligibility rules entered as free text to be represented as a series of terms mapped to unique concepts in a controlled vocabulary. RuleEd provides interfaces for creating and refining concept mappings for terms within rules and disambiguating multiply-mapped terms. A combination of inter-active and non-interactive methods enable authors to specify eligibility rule representations with a fine level of control.

The National Center for Biomedical Ontology is a consortium that comprises leading informaticians, biologists, clinicians, and ontologists, funded by the National Institutes of Health (NIH) Roadmap, to develop innovative technology and methods that allow scientists to record, manage, and disseminate biomedical information and knowledge in machine-processable form. The goals of the Center are (1) to help unify the divergent and isolated efforts in ontology development by promoting high quality open-source, standards-based tools to create, manage, and use ontologies, (2) to create new software tools so that scientists can use ontologies to annotate and analyze biomedical data, (3) to provide a national resource for the ongoing evaluation, integration, and evolution of biomedical ontologies and associated tools and theories in the context of driving biomedical projects (DBPs), and (4) to disseminate the tools and resources of the Center and to identify, evaluate, and communicate best practices of ontology development to the biomedical community. Through the research activities within the Center, collaborations with the DBPs, and interactions with the biomedical community, our goal is to help scientists to work more effectively in the e-science paradigm, enhancing experiment design, experiment execution, data analysis, information synthesis, hypothesis generation and testing, and understand human disease.

Knee injuries are common in sports activities. Understanding the mechanisms of injury allows for better treatment of these injuries and for the development of effective prevention programmes. Tibial torque and knee flexion angle have been associated with several mechanisms of injury in the knee. This article focuses on the injury to the anterior cruciate ligament (ACL), the posterior cruciate ligament (PCL) and the meniscus of the knee as they relate to knee flexion angle and tibial torque. Hyperflexion and hyperextension with the application of tibial torque have both been implicated in the mechanism of ACL injury. A combination of anterior tibial force and internal tibial torque near full extension puts the ACL at high risk for injury. Hyperflexion also increases ACL force; however, in this position, internal and external tibial torque only minimally increase ACL force. Several successful prevention programmes have been based on these biomechanical factors. Injury to the PCL typically occurs in a flexed or hyperflexed knee position. The effects of application of a tibial torque, both internally and externally, remains controversial. Biomechanical studies have shown an increase in PCL force with knee flexion and the application of internal tibial torque, while others have shown that PCL-deficient knees have greater external tibial rotation. The meniscus must endure greater compressive loads at higher flexion angles of the knee and, as a result, are more prone to injury in these positions. In addition, ACL deficiency puts the meniscus at greater risk for injury. Reducing the forces on the ACL, PCL and meniscus during athletic activity through training, the use of appropriate equipment and safe surfaces will help to reduce injury to these structures.

BACKGROUND

This paper evaluates the replicability of an NCI-funded didactic/experiential program to increase the diversity of doctorally-prepared cancer disparities investigators.

METHODS

The program was developed and operated successfully for three years in Northern California when a replication was established at UCLA. Feasibility, process, impact, and outcome measures on UCSF and UCLA summer-institute participants were compared.

RESULTS

Average participant rankings of the influence of the program on intention to apply for a doctorate were 9.1/10 (UCSF) and 8.6/10 (UCLA). A total of 22.5% of UCSF and 10% of UCLA participants have enrolled in, been accepted by, or completed doctoral programs. Among these alumni, 68% (21/31) of UCSF and 60% (3/5) of UCLA participants plan to conduct their doctoral research in cancer control.

CONCLUSIONS

This program has been successfully replicated and has met its objective to increase the pipeline of ethnically diverse doctoral-level public health researchers. Expansion of the program to other regions of the US is feasible and indicated.

An abnormal mammography finding constitutes a stressful event that may increase vulnerability by developing or intensifying pre-existing psychological morbidity. We evaluated depressive symptoms using the Composite International Diagnostic Interview among women of four ethnic groups who had an abnormal mammography result controlling for the effect of demographic, psychosocial and medical factors on recent onset of depressive symptoms. Telephone surveys were conducted among women aged 40-80 years recruited from four clinical sites in the San Francisco Bay Area after receiving a screening mammography result that was classified as abnormal but probably benign, suspicious or highly suspicious, or indeterminate using standard criteria. Among the 910 women who completed the interview, mean age was 56 (S.D.=10), 42% were White, 19% Latina, 25% African American, and 14% Asian. Prevalence of lifetime depressive symptoms was 44%, and 11% of women had symptoms in the previous month. Multivariate logistic regression models showed that Asian ethnicity, annual income >$10 000 and weekly attendance at religious services were significantly associated with decreased depressive symptoms. Having an indeterminate result on mammography and being on disability were significantly associated with more depressive symptoms. Reporting a first episode of depression more than a year before the interview was associated with significant increase in depressive symptoms in the month prior to the interview regardless of mammography result. Women with an indeterminate interpretation on mammography were at greater risk of depressive episode in the month prior to the interview compared to women with probably benign results (odds ratio=2.41; 95% CI=1.09-5.31) or with a suspicious finding. Clinicians need to consider depression as a possible consequence after an abnormal mammography result.