Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.

Growing evidence indicates that inflammation is a contributing factor leading to cancer development. However, pathways involved in this progression are not well understood. To examine whether HIF-1alpha is a factor linking inflammation and tumorigenesis, we investigated whether the HIF-1 signaling pathway was stimulated by the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in A549 cells. We find that IL-1beta up-regulated HIF-1alpha protein under normoxia and activated the HIF-1-responsive gene vascular endothelial growth factor (VEGF) via a pathway dependent on nuclear factor kappaB (NFkB). Interestingly, although this pathway is stimulated by upstream signaling via AKT and mTOR and requires new transcription, IL-1 mediated HIF-1alpha induction also utilizes a post-transcriptional mechanism that involves antagonism of VHL-dependent HIF-1alpha degradation, which results in increased HIF-1alpha protein stability. IL-1 mediated NFkB-dependent cyclooxygenases-2 (COX-2) expression served as a positive effector for HIF-1alpha induction. Although COX-2 inhibitors attenuated IL-1 mediated HIF-1alpha induction, prostaglandin E2 (PGE2), a physiological product of COX-2, induced HIF-1alpha protein in a dose-dependent manner. Our data, therefore, demonstrate that IL-1beta up-regulates functional HIF-1alpha protein through a classical inflammatory signaling pathway involving NFkB and COX-2, culminating in up-regulation of VEGF, a potent angiogenic factor required for tumor growth and metastasis. Thus, HIF-1 is identified as a pivotal transcription factor linking the inflammatory and oncogenic pathways.

No abstract

We examined the association of sleep duration, snoring, and difficulty sleeping with cognitive function in a cohort of community-dwelling women. Women (n = 1844), aged 70 to 81 years at initial cognitive interview in 2000, are members of the Nurses' Health Study cohort. Women completed six tests of cognitive function encompassing general cognition, verbal memory, category fluency, and attention. We repeated the assessment 2 years later. We used linear regression models to obtain multivariate-adjusted mean differences in initial test performance, and in cognitive decline over time, across categories of sleep duration (< or =5,6,7,8,9+ hours/night), frequency of snoring (never, occasionally, regularly), and sleep difficulties (rarely/never, occasionally, regularly). In analyses of initial test performance, women sleeping < or =5 hours/night scored worse than women sleeping 7 hours/night (mean difference on global score combining all cognitive tests = 0.15 standard units, 95% CI: -0.28, -0.02). Women who regularly had difficulty falling or staying asleep scored 0.11 units lower on the global score (95% CI: -0.22, 0.01) compared with those who rarely had difficulty sleeping. These differences were equivalent to the mean differences in score observed between participants who were 4 to 5 years apart in age. We found no associations with snoring or with any of the sleep variables and cognitive decline over 2 years. Associations between sleep patterns and initial cognitive function may be clinically relevant given that diminished cognition is a risk factor for dementia. However, the lack of an association with prospective cognitive decline warrants further investigation.

Immunogenic cell death (ICD) is a form of cell death that activates an adaptive immune response against dead-cell-associated antigens. Cancer cells killed via ICD can elicit antitumor immunity. ICD is efficiently induced by near-infrared photo-immunotherapy (NIR-PIT) that selectively kills target-cells on which antibody-photoabsorber conjugates bind and are activated by NIR light exposure. Advanced live cell microscopies showed that NIR-PIT caused rapid and irreversible damage to the cell membrane function leading to swelling and bursting, releasing intracellular components due to the influx of water into the cell. The process also induces relocation of ICD bio markers including calreticulin, Hsp70 and Hsp90 to the cell surface and the rapid release of immunogenic signals including ATP and HMGB1 followed by maturation of immature dendritic cells. Thus, NIR-PIT is a therapy that kills tumor cells by ICD, eliciting a host immune response against tumor.

The objective of this study is to obtain and discuss in-depth information on mental health problems, including the status, barriers, and potential solutions in 1.5 and 2nd generation Asian American young adults. As a part of the Health Needs Assessment project, the researchers conducted two focus groups with 17 young adults (mainly 1.5 or 2nd generation) from eight Asian American communities (Asian Indian, Cambodian, Chinese, Indonesian, Korean, Taiwanese, Thai, and Vietnamese) in Montgomery County, Maryland. We developed a moderator's guide with open-ended questions and used it to collect qualitative data. Using a software, we organized and identified emergent themes by major categories. Participants reported a several common sources of stress that affect the mental health of Asian American young adults including: pressure to meet parental expectations of high academic achievement and live up to the “model minority” stereotype; difficulty of balancing two different cultures and communicating with parents; family obligations based on the strong family values; and discrimination or isolation due to racial or cultural background. Young Asian Americans tend not to seek professional help for their mental health problems; instead they use personal support networks—close friends, significant others, and religious community. Participants suggested that Asian cultural norms that do not consider mental problems important, and associated stigma of seeking professional care might undermine their mental health help seeking behavior. Our findings support a need for delivering culturally appropriate programs to raise awareness of mental health and cultural training for health providers to deliver culturally appropriate care.

These patterns suggest both health-damaging and health-promoting changes accompanying divorce and widowhood, and generally health-promoting changes following remarriage.

Summary Swe1 (Saccharomyces WEE1), the only “true” tyrosine kinase in budding yeast, is an Hsp90 client protein. Here we show that Swe1Wee1 phosphorylates a conserved tyrosine residue (Y24 in yeast Hsp90 and Y38 in human Hsp90α) in the N-domain of Hsp90. Phosphorylation is cell cycle-associated and modulates the ability of Hsp90 to chaperone a selected clientele, including v-Src and several other kinases. Non-phosphorylatable mutants have normal ATPase activity, support yeast viability, and productively chaperone the Hsp90 client glucocorticoid receptor. Deletion of SWE1 in yeast increases Hsp90 binding to its inhibitor geldanamycin, and pharmacologic inhibition/silencing of Wee1 sensitizes cancer cells to Hsp90 inhibitor-induced apoptosis. These findings demonstrate that Hsp90 chaperoning of distinct client proteins is differentially regulated by specific post-translational modification of a unique subcellular pool of the chaperone, and they provide a novel strategy to increase the cellular potency of Hsp90 inhibitors.