Research articles

During pregnancy, women often become insulin resistant, thus requiring an expansion of pancreatic beta cell mass to provide more insulin. Michael German and his colleagues now report that lactogenic hormones drive the expression of serotonin in the beta cells to induce this increase in beta cell mass.

A prognostic gene expression signature predicts metastasis in individuals with sarcomas and other tumor types more accurately than existing tools.

Glycosphingolipid modulation may be a new approach to treat polycystic kidney disease. Blocking glucosylceramide accumulation with a glucosylceramide synthase inhibitor inhibits cyst formation in mouse models of the disease through inhibition of Akt-mediated signaling and by interfering with the cell cycle machinery.

A critical donor organ shortage currently limits the treatment of patients with severe liver failure. Building on earlier work with decellularized hearts, Basak Uygun et al. have developed a transplantable liver graft using a decellularized liver matrix. This approach preserves the structural and functional characteristics of the native microvascular network, supports efficient recellularization and, when transplanted into rats, allows the viability and metabolic function of hepatocytes to be maintained.

Using pair-end transcriptome sequencing, this study provides the identification of Raf pathway gene rearrangements in a small proportion of prostate and gastric cancers and in melanomas. The fusion proteins show tumorigenic potential and represent a unique activating alteration of this oncogenic pathway, which seems to be mutually exclusive from known cancer-associated Raf mutations. This suggests that therapeutic Raf inhibition can be expanded to this fusion-harboring subset of solid tumors.

Using the skin epidermis as a model for studies of epithelial biology and tumorigenesis and lentiviruses carrying RNAi or Cre recombinase, Beronja and colleagues describe a noninvasive, in vivo method for cell type–specific loss-of-function studies in the surface epithelia of mouse embryos. This approach can be used for the rapid functional assay of genes, the dissection of genetic interactions within complex regulatory pathways, and the study of the role of putative tumor suppressors and oncogenes in regulating growth control.

Immunologically targeting α-lactalbumin, a breast-specific protein highly expressed in breast carcinomas but absent from nonlactating mammary cells, provides protection against breast cancer in mice. This strategy may protect women against breast cancer in their post–child-bearing years, when lactation is readily avoidable and risk for developing breast cancer is high.

Spinal cord injury leads to flaccid paralysis resulting from the loss of descending serotonergic modulation. Murray et al. demonstrate that spontaneous recovery of motoneuron excitability is associated with alternative mRNA editing and increased expression of constitutively active 5HT_2C serotonin receptors. Activation of these receptors leads to large persistent calcium currents, sustained muscle contractions and restoration of locomotion. However, in the absence of descending modulation from the brain, this leads to spasticity. Inhibiting constitutive 5-HT receptor activity is effective in reducing spasticity in rats and humans following spinal cord injury.

Basophils initiate T helper type 2 responses after exposure to allergens and IgE immune complexes. Juan Rivera and his colleagues find that elevated amounts of IgE in Lyn^−/− mice drive basophil activation, secretion of T helper type 2 cytokines and production of autoantibodies, leading to a lupus-like phenotype in mice and to glomerulonephritis. Depletion of basophils or deficiencies in IgE or interleukin-4 are sufficient to reduce autoantibody production and prevent kidney damage. Data from subjects with SLE suggest that increased IgE levels and activated basophils may contribute to disease.

Fan et al. present a method to dissect the cellular immune response to transplanted tissue by tracking various T cell populations in both the circulatory compartment by in vivo flow cytometry and at the graft site by endoscopic confocal microscopy. The allograft response was followed for two weeks in a mouse model in which pancreatic islet transplants were placed beneath the renal capsule. This approach may help to develop treatment options that improve transplantation outcomes.

The transcription factor ATF5 is associated with malignancy in glioblastomas. In this report, the authors devise a unique shRNA screen to identify and characterize the upstream regulators and downstream effectors of ATF5 in brain tumors. ATF5 upregulation is mediated by a concomitant increase in FRS2, PAK1 and CREB3L2 and promotes survival by elevating Mcl1 expression. This pathway represents a novel therapeutic target validated by the antitumor efficiency of the Raf kinase inhibitor sorafenib.

In two studies from teams led by Hiroshi Kawaguchi and Jang-Soo Chun, a role for HIF-2α in osteoarthritis has been uncovered. Along with identifying the molecular mechanism, the teams found that HIF-2α expression is increased in human osteoarthritic tissue, and mice deficient for the protein are protected in two osteoarthritis models, suggesting that HIF-2A could be a therapeutic target.

In two studies from teams led by Hiroshi Kawaguchi and Jang-Soo Chun, a role for HIF-2α in osteoarthritis has been uncovered. Along with identifying the molecular mechanism, the teams found that HIF-2α expression is increased in human osteoarthritic tissue, and mice deficient for the protein are protected in two osteoarthritis models, suggesting that HIF-2α could be a therapeutic target.

The treatment options for sepsis are limited in scope and efficacy, resulting in frequent human fatalities. Liew and colleagues now report that interleukin-33 is a promising therapeutic strategy that increases neutrophil recruitment to the site of infection and bacterial clearance and decreases mortality in a mouse model of sepsis.

Transplant arteriosclerosis is a leading cause of transplanted organ dysfunction. Human regulatory T cells expanded ex vivo can prevent transplant arteriosclerosis in a mouse model by preventing the immune infiltration of the graft.

Rubin Tuder and his colleagues show that cigarette smoke induces expression of Rtp801 (also known as Redd1), a hypoxia-inducible protein that inhibits mTOR activity and enhances oxidative stress–mediated cell death. They also show that mice deficient in Rtp801 are protected from cigarette smoke–induced lung injury, thus suggesting the protein as a target to prevent emphysema.

Adeno-associated virus serotype 6–mediated transduction requires the epidermal growth factor receptor.

This study dissects the contribution of TLR signaling to intestinal tumorigenesis. MyD88 signaling, known to be required for tumorigenesis in Apc^min/+ mice, is shown to be triggered by ligands from the microflora. MyD88-mediated activation of the MEK-ERK cascade stabilizes c-Myc by preventing its ubiquitin-mediated degradation. The findings link oncogenic c-Myc function to immune signaling and uncover MEK inhibition as a new therapeutic strategy to treat intestinal tumors.

In a mouse model of systemic autoimmunity, the damage-associated molecular pattern molecules Mrp8 and Mrp14 are essential for the induction of autoreactive CD8⁺ T cells and for disease development in a TLR4– and IL-17–dependent manner. A similar mechanism might be at play in people with cutaneous lupus erythematosus.

In this work, Björn Lamprecht et al. found that survival of Hodgkin's lymphoma cells requires activity of the growth factor receptor CSF1R. Transcription of the gene encoding CSF1R was unexpectedly discovered to originate in a specific class of long terminal repeat, a type of repetitive element present in the genome. Transcriptional initiation from this class of long terminal repeats was widely activated in Hodgkin's lymphoma cells, which the authors traced to defects in epigenetic silencing (517–518).