Tuesday, December 23, 2014

Penn researchers interview HIV-positive adolescents in Botswana to better understand the factors affecting adherence to antiretroviral treatments

Of the more than three million children infected with HIV, 90% live in Africa. As HIV-positive children become adolescents, it is important that antiretroviral treatments are maintained to protect their own health, as well as to safeguard the adolescents from developing resistant strains of HIV and to prevent infection of other individuals.

HIV-positive adolescents’ adherence to these treatments has been identified as a public health challenge for Botswana. However, the assessment tools testing psychosocial factors that are likely associated with poor adherence have been developed in Western countries and their constructs may not be relevant to African contexts. A new study published in PLOS ONE by Penn researchers Elizabeth Lowenthal and Karen Glanz described the cultural adaptation of these assessment tools for Botswana.

The psychosocial assessments investigate factors that may affect adolescents’ adherence to antiretroviral treatments. As Lowenthal summarized, “one of the key reasons why adolescents with HIV have higher rates of death compared with people with HIV in other age groups is that they have trouble taking their medications regularly.”

Researchers looked at the following factors by testing 7 separate assessment scales developed with Western cohorts for their applicability to Botswanan adolescents.
  • Psychological reactance- an aversion to abide by regulations that impose upon freedom and autonomy
  • Perceived stigma
  • Outcome expectancy- whether treatments were expected to improve health
  • Consideration of future consequences- the extent to which adolescents plan for their futures rather than focusing on immediate gains
  • Socio-emotional support- how adolescents receive the social and emotional support they need

The researchers interviewed 34 HIV-positive Botswanan adolescents in depth, sub grouped by age in order to talk about the factors in ways participants could understand.

The study confirmed the construct validity of some assessment tools, but highlighted four areas that caused tools to not relate to participants:
  • Socio-emotional support for the adolescents mostly came from parents rather than peers.
  • Denial of being HIV infected was more common than expected.
  • Participants were surprisingly ambivalent about taking their medicine.

Some of the tools (psychological reactance, future consequences) required major modifications to obtain construct validity for adolescents with HVI in Botswana.The assessment tools were modified during the course of the study based on participant feedback. Future research will test the association between these modified assessment tools and HIV treatment outcomes in order to provide insight into how to best support HIV infected adolescents.

First author Lowenthal suggested that the study could inform studies of adolescent adherence to other treatments as well, stating that “questions that we are able to answer in our large cohort of HIV-positive adolescents will likely be generalizable to other groups of adolescents with chronic diseases.”

-Barbara McNutt 

Monday, December 15, 2014

Penn researchers identify novel therapeutic target for kidney cancer

Kidney cancer, also known as renal cancer, is one of the ten most common cancers in both men and women. The American Cancer Society’s most recent estimates state that of the predicted 63,920 new cases of kidney cancer this year, roughly 20% of  patients will die from the disease. By far, the most common type of kidney cancer is renal cell carcinoma (RCC). The majority of RCCs are clear cell RCCs (ccRCCs), a subtype characterized by metabolic alterations, specifically increased carbohydrate and fat storage. More than 90% of ccRCCs have been found to have mutations in the von Hippel-Lindau (VHL) tumor suppressor gene; however, kidney specific VHL deletion in mice does not induce tumorigenesis or cause metabolic changes similar to those seen in ccRCC tumors. So what additional factors are needed for ccRCC tumor formation and progression? A recent study by Penn researchers published in the journal Nature identified the rate-limiting gluconeogenesis enzyme fructose-1,6-bisphosphatase (FBP1) as a key regulator of ccRCC progression.

To better understand ccRCC progression, the study’s first author, Bo Li, a post-doctoral researcher in the lab of Dr. Celeste Simon, performed metabolic profiling on human ccRCC tumors while also analyzing ccRCC metabolic gene expression profiles. Compared to the adjacent normal kidney tissue, ccRCC tumors had increased amounts of metabolites involved in sugar metabolism and significantly lower expression of carbohydrate storage genes, including FBP1. Further investigation revealed FBP1 expression was reduced in almost all tumor samples tested (>600) and reduced FBP1 expression strongly correlated with advanced tumor stage and poor patient survival. Thus, understanding the role of FBP1 in ccRCCs could significantly impact the treatment of this disease.

How do reduced levels of FBP1 promote ccRCC tumor progression? The authors found that FBP1 depletion in ccRCC cells stimulates growth and relieves inhibition of sugar breakdown (glycolysis), which provides energy for the growing cancer cells. In addition, VHL mutations associated with ccRCCs prevent the degradation of a transcription factor that responds to decreases in oxygen, known as hypoxia-inducible factor α (HIFα), thus stabilizing it. Stabilized HIFα does not cause FBP1 depletion, but its activity is tightly regulated by FBP1. This study emphasized the importance of the interaction between HIFα and FBP1, particularly when glucose and oxygen levels are low, for the formation and progression of the ccRCC.

Why is this work so important? Little is known about how changes in cell metabolism contribute to the formation and progression of ccRCC tumors. As stated by Li, “elucidating how FBP1 impacts the altered metabolic and genetic programs of ccRCC improves our knowledge of the molecular details accompanying ccRCC progression, and identifies novel therapeutic targets for this common malignancy.” Future work may focus on identifying how FBP1 is suppressed and whether reversing FBP1 suppression could improve patient outcomes. 

-Renske Erion