Locoregional Approaches in Cholangiocarcinoma Treatment.

Cholangiocarcinoma (CCA) is a rare hepatic malignant tumor with poor prognosis due to late detection and anatomic factors limiting the applicability of surgical resection. Without surgical resection, palliation is the most common approach. In non-surgical cases contained within the liver, locoregional therapies provide the best chance for increased survival and disease control. The most common methods, transarterial chemoembolization and transarterial radioembolization, target tumors by embolizing their blood supply and limiting the tumor's ability to metabolize. Other treatments induce direct damage via thermal ablation to tumor tissue to mediate their anti-tumor efficacy. Recent studies have begun to explore roles for these therapies outside their previous role of palliation. This review will outline the mechanisms of each of these treatments, along with their effects on overall survival, while comparing these to non-locoregional therapies.

Blood RNA signatures predict recent tuberculosis exposure in mice, macaques and humans.

Tuberculosis (TB) is the leading cause of death due to a single infectious disease. Knowing when a person was infected with Mycobacterium tuberculosis (M.tb) is critical as recent infection is the strongest clinical risk factor for progression to TB disease in immunocompetent individuals. However, time since M.tb infection is challenging to determine in routine clinical practice. To define a biomarker for recent TB exposure, we determined whether gene expression patterns in blood RNA correlated with time since M.tb infection or exposure. First, we found RNA signatures that accurately discriminated early and late time periods after experimental infection in mice and cynomolgus macaques. Next, we found a 6-gene blood RNA signature that identified recently exposed individuals in two independent human cohorts, including adult household contacts of TB cases and adolescents who recently acquired M.tb infection. Our work supports the need for future longitudinal studies of recent TB contacts to determine whether biomarkers of recent infection can provide prognostic information of TB disease risk in individuals and help map recent transmission in communities.

The Acinetobacter regulatory UmuDAb protein cleaves in response to DNA damage with chimeric LexA/UmuD characteristics.

In the DNA damage response of most bacteria, UmuD forms part of the error-prone (UmuD'(2) )C polymerase V and is activated for this function by self-cleavage after DNA damage. However, the umuD homolog (umuDAb) present throughout the Acinetobacter genus encodes an extra N-terminal region, and in Acinetobacter baylyi, regulates transcription of DNA damage-induced genes. UmuDAb expressed in cells was correspondingly larger (24 kDa) than the Escherichia coli UmuD (15 kDa). DNA damage from mitomycin C or UV exposure caused UmuDAb cleavage in both E. coli wild-type and ΔumuD cells on a timescale resembling UmuD, but did not require UmuD. Like the self-cleaving serine proteases LexA and UmuD, UmuDAb required RecA for cleavage. This cleavage produced a UmuDAb' fragment of a size consistent with the predicted cleavage site of Ala83-Gly84. Site-directed mutations at Ala83 abolished cleavage, as did mutations at either the Ser119 or Lys156 predicted enzymatic residues. Co-expression of the cleavage site mutant and an enzymatic mutant did not allow cleavage, demonstrating a strictly intramolecular mechanism of cleavage that more closely resembles the LexA-type repressors than UmuD. These data show that UmuDAb undergoes a post-translational, LexA-like cleavage event after DNA damage, possibly to achieve its regulatory action.