Research articles

Ron Evans and his colleagues have shown that excess thyroid hormone receptor signaling during embryonic development in mice impairs the differentiation of type I pneumocytes, a key lung cell type needed for proper gas exchange. They also show that treatment with antithyroid drugs during this stage of development rescues the defect in lung maturation, suggesting a possible therapy for some children born with respiratory distress syndrome.

The authors find that cell-intrinsic activation of Hedgehog signaling without genetic alterations is a contributing feature to the progression and chemotherapy resistance of small-cell lung carcinoma, and that Hedgehog inhibition can prevent lung cancer growth and recurrence.

Identification of the mechanisms that drive the transition from acute to chronic pain could lead to new treatments. Now, Zhizhong Pan and colleagues demonstrate that chronic pain causes epigenetic downregulation of GAD65 and results in inhibitory neurotransmission deficits in the brainstem of rats.

The placebo response involves a perceived effect of a drug that was not really received by the subject. Fabrizio Benedetti and colleagues demonstrate that the placebo response to NSAIDs in reducing pain is mediated by the endocannabinoid system in humans.

Calcineurin inhibitors, such as tacrolimus, are widely used immunosuppressive agents, but they can cause hypertension. In studies of tacrolimus-treated mice, the authors show that hypertension is due to activation of the sodium chloride transporter NCC in the kidney, causing sodium retention. They found that NCC activation also occurred in kidney transplant recipients receiving tacrolimus. The authors suggest that thiazide diuretics, which are NCC inhibitors, might counteract the hypertensive effects of this class of immunosuppressants.

Microsatellite instability (MSI) due to alterations in DNA repair genes leads to carcinogenesis, but it also correlates with better prognosis and therapy response. Little is known of the contribution of altered noncoding sequences to MSI tumorigenesis. This report identifies a deletion in an MSI intronic region leading to the expression of a truncated chaperone, which shows dominant-negative effects on its wild-type counterpart. Acting as an endogenous inhibitor of a protumorigenic chaperone, the expression of the truncated variant associates with better prognosis in humans and may contribute to the overall limited malignancy of MSI tumors.

BRCA1 loss of function is considered to promote tumorigenesis through impairment of the protein's role in DNA damage repair. By studying BRCA1 mutations that do not affect this function but still confer cancer predisposition, this report identifies a new function of BRCA1, the repression of miR-155 through modulation of HDAC activity. miR-155 increase correlates with BRCA1 loss or mutation in humans, and it likely to mediate some of the oncogenic effects of BRCA1 deficiency.

Loss of mismatch repair (MMR) genes is associated with poor cancer prognosis and has been reported to occur through genetic alterations that directly affect the expression of MMR genes such as MSH2. This report identifies a subset of leukemia patients with reduced levels of MSH2 protein but without alterations in the MSH2 gene, and it identifies concurrent deletions in regulators of MSH2 stability as potential contributors to the MSH2 deficiency and associated drug resistance in this and other cancers.

Rapidly progressive glomerulonephritis (RPGN) is a form of severe kidney injury that can lead to promptly lethal renal failure. Pierre-Louis Tharaux and colleagues report that HB-EGF is upregulated in RPGN, resulting in activation of EGFR in podocytes and their dysfunction. They further show that genetic loss of expression of HB-EGF or EGFR in a mouse model is protective, whereas pharmacological inhibition of EGFR, even after disease onset, is therapeutic. These results suggest a possible avenue of treatment for this potentially devastating condition.

Staphylococcus aureus produces pore-forming toxins, such as α-hemolysin, that damage epithelial cell layers, causing disease. In this issue, Inoshima et al. report that the cellular receptor for α-hemolysin—the metalloprotease ADAM10—is essential for lethal pneumonia caused by S. aureus infection in mice. The authors suggest that the combined effect of α-hemolysin on pore formation and in activating ADAM10 cleavage of the adherens junction protein E-cadherin disrupts the barrier function of the lung epithelium.

The prognosis for patients with advanced stage ovarian cancer is poor. Here, Gooitzen van Dam and colleagues demonstrate the first human application of a tumor-specific intraoperative fluorescence imaging methodology using a folate receptor-α (FR-α)-targeted fluorescent agent that exploits the overexpression of FR-α in the majority of epithelial ovarian cancers. It is hoped this approach may lead to improved intraoperative staging and more radical cytoreductive surgery.

Whether there exists a human memory T cell population with stem cell–like properties of self-renewal and multipotency is under active investigation. Here Gattinoni et al. characterize a subset of human T cells that phenotypically resemble naive T cells yet have properties associated with memory T cells. These T cells show enhanced ability to self renew and to give rise to differentiated memory cell subsets, suggesting a stem cell–like functionality.

To date, the dogma in the field has been that RANKL, an essential cytokine in osteoclast maturation, is released by osteoblasts as a way to coordinate bone growth and bone loss during adult bone remodeling. Now, Hiroshi Takayanagi and colleagues, as well as Charles O'Brien and colleagues, have independently found that osteocytes are the predominant source of RANKL in the adult mouse. As RANKL signaling is a key target in treating osteoporosis, these results have potentially important implications for disease management.

People with brain cancers called gliomas often have seizures due to secretion of the excitatory neurotransmitter glutamate from the tumor. Now, Harald Sontheimer and his colleagues report that blockade of a cystine-glutamate transporter in tumor cells by an FDA-approved drug can reduce glioma-induced epilepsy in mice.

To date, the dogma in the field has been that RANKL, an essential cytokine in osteoclast maturation, is released by osteoblasts as a way to coordinate bone growth and bone loss during adult bone remodeling. Now, Hiroshi Takayanagi and colleagues, as well as Charles O'Brien and colleagues, have independently found that osteocytes are the predominant source of RANKL in the adult mouse. As RANKL signaling is a key target in treating osteoporosis, these results have potentially important implications for disease management.

This report describes the isolation and in vitro expansion of human colon stem cells from normal tissues. Cells with high levels of the membrane receptor EPHB2 are shown to have characteristics of intestinal stem cells, and the authors optimize culture conditions that allow their in vitro expansion as multipotent cells capable of differentiation into several intestinal lineages.

The activation of stress kinases, such as p38 MAPK, is believed to be detrimental to normal cellular processes. However, Umut Ozcan and his colleagues now show that p38 MAPK is actually beneficial, as in mice it increases the mRNA stability and nuclear localization of Xbp1s, a crucial factor in resolving endoplasmic reticulum stress and improving glucose homeostasis. These results suggest a possible indirect way of targeting XBP1s in the treatment of type 2 diabetes.

New vaccine candidates are urgently needed for the control and prevention of Mycobacterium tuberculosis (Mtb) infection. Kari Sweeney and her colleagues now report that an attenuated strain of Mycobacterium smegmatis expressing the esx-3 genes from Mtb induces effective CD4⁺ T cell dependent immunity against infection with Mtb in mice. The study offers a new avenue for the identification of protective immunogens in Mtb infection and a candidate vaccine platform warranting further study.

By exploiting the thermoreversible properties of the US Food and Drug Administration–approved poloxamer 407 (triblock polymer) and 2-octylcyanoacrylate bioadhesive, Edward Chang et al. have developed a new method of sutureless vascular anastomosis, even in vessels with a diameter of less than 1.0 mm. This nonmechanical, sutureless approach compared favorably to the standard hand-sewn approach in long-term (two-year) rat studies.

Imatinib has been proposed as a therapy for gastrointestinal stromal tumors, owing to its side effects on KIT, a kinase often mutated in this type of tumor. This report shows that a key aspect of imatinib's effect is its modulation of antitumor immune responses by a mechanism regulating Ido expression. Combining imatinib with CTLA-4 blockade emerges as a potential efficacious therapeutic approach for gastrointestinal stromal tumors.