Key Points• Acquired pathogenic mutations in SAMHD1 are found in up to 11% of relapsed/refractory patients with CLL. • SAMHD1 is mobilized to sites of DNA damage.SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase and a nuclease that restricts HIV-1 in noncycling cells. Germ-line mutations in SAMHD1 have been described in patients with Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal whole genome sequencing study of chronic lymphocytic leukemia (CLL), we revealed a SAMHD1 mutation as a potential founding event. Here, we describe an AGS patient carrying a pathogenic germ-line SAMHD1 mutation who developed CLL at 24 years of age. Using clinical trial samples, we show that acquired SAMHD1 mutations are associated with high variant allele frequency and reduced SAMHD1 expression and occur in 11% of relapsed/refractory CLL patients. We provide evidence that SAMHD1 regulates cell proliferation and survival and engages in specific protein interactions in response to DNA damage. We propose that SAMHD1 may have a function in DNA repair and that the presence of SAMHD1 mutations in CLL promotes leukemia development. (Blood. 2014;123(7):1021-1031)

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Human immunodeficiency virus type 1 (HIV‐1) transcription relies on its transactivating Tat protein. Although devoid of a signal sequence, Tat is released by infected cells and secreted Tat can affect uninfected cells, thereby contributing to HIV‐1 pathogenesis. The mechanism and the efficiency of Tat export remained to be documented. Here, we show that, in HIV‐1‐infected primary CD4+ T‐cells that are the main targets of the virus, Tat accumulates at the plasma membrane because of its specific binding to phosphatidylinositol‐4,5‐bisphosphate (PI(4,5)P2). This interaction is driven by a specific motif of the Tat basic domain that recognizes a single PI(4,5)P2 molecule and is stabilized by membrane insertion of Tat tryptophan side chain. This original recognition mechanism enables binding to membrane‐embedded PI(4,5)P2 only, but with an unusually high affinity that allows Tat to perturb the PI(4,5)P2‐mediated recruitment of cellular proteins. Tat–PI(4,5)P2 interaction is strictly required for Tat secretion, a process that is very efficient, as ∼2/3 of Tat are exported by HIV‐1‐infected cells during their lifespan. The function of extracellular Tat in HIV‐1 infection might thus be more significant than earlier thought.

OBJECTIVES To evaluate the extent to which preexisting mental disorders influence diagnosis, treatment, and survival in older adults with colon cancer. DESIGN Retrospective cohort study. SETTING The Surveillance, Epidemiology and End Results (SEER)–Medicare linked database. PARTICIPANTS Eighty thousand six hundred seventy participants, aged 67 and older with a diagnosis of colon cancer. MEASUREMENTS The association between the presence of a preexisting mental disorder and the stage of colon cancer at diagnosis, receipt of cancer treatment, and overall and colon cancer-specific mortality were assessed using Cox proportional hazards regression and logistic regression. RESULTS Participants with mental disorders were more likely to have been diagnosed with colon cancer at autopsy (4.4% vs 1.1%; P<.001) and at an unknown stage of cancer (14.6% vs 6.2%; P<.001); to have received no surgery, chemotherapy, or radiation therapy (adjusted risk ratio (ARR) =2.09, 95% confidence interval (CI) =1.86–2.35); and to have received no chemotherapy for Stage 3 cancer (ARR =1.63, 95% CI =1.49–1.79). The rate of overall mortality (hazard ratio (HR) =1.33, 95% CI =1.31–1.36) and colon cancer-specific mortality (HR =1.23, 95% CI =1.19–1.27) was substantially higher in participants with a preexisting mental disorder than in their counterparts. All of these associations were particularly pronounced in participants with psychotic disorders and those with dementia. CONCLUSION Public health initiatives are needed to improve colon cancer detection and treatment in older adults with mental disorders.

Measurement invariance across young adults from Hong Kong and Taiwan among three internet-related addiction scales: Bergen Social Media Addiction Scale (BSMAS), Smartphone Application-Based Addiction Scale (SABAS), and Internet Gaming Disorder Scale-Short Form (IGDS-SF9) (Study Part A)