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Quantifying the total-body virus burden in HIV-infected individuals is necessary to understand viral persistence and guide development of cure strategies. Here, Estes et al. find a high burden of residual virus in tissues of SIV-infected monkeys and HIV-infected humans, and evidence of low-level viral replication, even under antiretroviral therapy.
Amplification of chromosome 1q21.3 distinguishes cells with tumor-initiating capacity that drive tumor recurrence across different breast cancer subtypes. A droplet digital PCR assay in circulating free tumor DNA identifies patients with early-stage cancer at high risk of relapse and predicts response to therapy in the metastatic setting. Pharmacological blockade of targets within this amplicon using a clinically available compound prevents tumor recurrence, suggesting a potential therapeutic approach to improve the clinical management of patients harboring 1q21.3-amplified breast tumors.
Factors secreted by metastatic a primary tumors induce an early phenotypic switch in perivascular cells at distant pre-metastatic niches. By using sophisticated lineage-tracing mouse models, the authors demonstrate that enhanced KLF4 expression in these cells increases their ability to proliferate and migrate away from the vasculature, and augments fibronectin deposition, which contributes to metastatic growth. These findings increase the mechanistic understanding of the metastatic process and uncover a role for perivascular plasticity that could be targeted to prevent metastasis.
Transcriptomic profiling using a newly-developed cre-inducible method to biotinylate wild-type and mutant MeCP2 protein highlights the cellular heterogeneity of transcriptional changes in rodent models of Rett Syndrome, including cell-type- and subcellular compartment-specific differences in male brains and X-linked mosaicism in female brains.
A silent single-nucleotide variant (SNV) affecting the transcription of a long noncoding RNA (lncRNA EGFR-AS1) within the EGFR coding region alters the EGFR isoform ratio and modulates oncogene addiction and response to EGFR tyrosine kinase inhibitors in squamous-cell cancers. Proof-of-concept validation in patients supports the notion that this SNV and levels of the lncRNA could be used to predict response to therapy in a clinical setting. These results, together with findings by Bal et al., uncover the functional role of noncoding RNAs in modulating the response to targeted therapies in cancer.
Simultaneous activation of Wnt and Shh pathways in murine neural precursor cells results in the formation of embryonal tumors with multilayered rosettes (ETMR) that recapitulate the histological and molecular features of human tumors. This novel mouse model represents a platform for evaluating therapeutic approaches for this rare malignant pediatric brain tumor, and provides novel insights into the cell of origin and molecular mechanisms driving the disease.
GDF15 has potent anti-obesity effects, but its receptor was unknown. GFRAL has now been identified as the receptor and mediates GDF15's effects through central actions in the hindbrain.
GDF15 has potent anti-obesity effects, but its receptor was unknown. GFRAL has now been identified as the receptor that mediates GDF15's effects via central actions in the hindbrain.
Different mutations found in endometrial and prostate tumors affecting the substrate-recognition domain of SPOP, a component of the E3 ubiquitin ligase complex, result in opposing degradation activity of BET proteins and response to BET inhibitors. This work, along with findings by Zhang et al. and Dai et al., highlights the divergent effects of recurrent mutations affecting different residues within the same functional domain of SPOP and provides scientific rationale to guide the administration of BET inhibitors in endometrial and prostate cancer patients harboring SPOP mutations.
IFITM3 encodes an antiviral protein that blocks entry of influenza A virus into cells. Paul Thomas and colleagues report that SNP rs34481144 in the 5′ UTR of IFITM3 is an expression quantitative trait locus for this gene and that the risk allele is associated with lower IFITM3 expression and severe influenza disease.
Resistance to ERK signaling inhibitors in BRAFV600E-mutant melanomas and lung cancers is achieved by parallel convergent mechanisms, including amplification of the mutant allele in extrachromosomal elements, that allow tumors to adapt while maintaining their intratumor heterogeneity. Intermittent treatment with a combination of RAF, MEK and ERK inhibitors imposes a higher selective pressure than sequential therapy and produces the strongest antitumor effects while minimizing toxicity. These findings warrant evaluating the effectiveness of this combinatorial regimen in patients, to improve treatment responses and delay the emergence of drug resistance.
Number of IL-9-expressing ILC2s are elevated in patients with inflammatory arthritis during remission, and these cells are critical in mice for the resolution of inflammatory arthritis via regulatory T cell induction. Delivery of DNA minicircles encoding IL-9 into inflamed joints ameliorates mouse experimental arthritis, suggesting possible therapeutic applications.
The kinase Plk1 has been studied primarily as a mitotic regulator in dividing cells, but de Cárcer et al. find that Plk1 deficiency or inhibition in mice causes nonmitotic defects in the vasculature, including aortic aneurysm and rupture, as well as defective vascular smooth muscle contractility. These results recommend a note of caution in the clinical use of PLK1 inhibitors as anticancer agents.
Repair of defects in the common bile duct is hampered by a lack of healthy donor tissue. Developing human extrahepatic cholangiocyte organoids and testing them in mouse models may provide a way to overcome this limitation.
In a mouse model of spinal cord injury, reactive astrogliosis is found to be context dependent and reversible. Blockade of type I collagen–reactive astrocyte interactions prevents astrocyte scar formation and facilitates functional recovery after injury.
Composition of gut bacteria and serum metabolites in young, obese individuals is partially restored following weight loss surgery, including Bacteroides thetaiotaomicron, which decreases serum glutamate levels and fat mass gain in mice.
Current mouse models of nonalcoholic steatohepatitis are limited, making identification and preclinical testing of new treatments challenging. Housing mice at thermoneutrality leads to less stress, a stronger immune response and better modeling of this condition.
During cold stimulation, cholesterol is converted to bile acids in an alternative pathway. The bile acids then alter the microbiota, which in turn promotes more heat generation.