Volume 20 Issue 4, April 2014

 In July, Victor Dzau will start his six-year term as president of the US Institute of Medicine (IOM). A cardiologist and researcher by training, Dzau currently serves as chancellor for health affairs at Duke University in Durham, North Carolina. Roxanne Khamsi spoke with Dzau about his vision for the IOM.

People infected with HIV who control the infection without antiretroviral drug therapy have often served as foot soldiers for science, but now science owes them some answers. If the rare good fortune of being a so-called 'HIV controller' comes with a price—namely, immune activation that raises a person's risks of developing cardiovascular disease, diabetes and other health problems—might antiretroviral medications give these patients' overactive immune systems a much-needed break? Alla Katsnelson investigates.

In the mammary gland, the stiffness of extracellular matrix (ECM) collagen is thought to influence tumor progression and clinical outcome. A new mechanism orchestrated by a microRNA circuit is shown to mediate the physical effects of the microenvironment on tumor cell progression. The findings may explain how increased breast matrix stiffness is associated with poor survival and could help identify women with aggressive breast cancer (pages 360–367).

Anemia is a debilitating condition that can be complicated by ineffective erythropoiesis. Two new studies identify GDF11 as a regulator of erythropoiesis and show that its inhibition in mouse models of anemia with ineffective erythropoiesis restores normal erythropoietic differentiation and alleviates anemia (pages 398–407 and 408–414).

Pharmacologic modulation of iron metabolism may be a potential strategy to control infection caused by the intracellular bacteria Salmonella enterica var. Typhimurium (S. typhimurium) (pages 419–424). The molecular mechanism involves the estrogen-related receptor γ (ERRγ) in the liver, which can be targeted with an inverse agonist to improve survival of infected animals.

Bariatric surgery reduces the weight of morbidly obese individuals and exerts beneficial effects on associated metabolic disorders such as type 2 diabetes. However, despite growing traction in this area of metabolic research, questions remain as to the mechanisms that lead to these benefits. New findings propose that the bile acid–activated nuclear receptor FXR mediates the metabolic improvement seen after one particular bariatric surgery approach and that this may involve alterations in the microbiome.

Certain biological features are inherent traits of cancer, yet some of them still hold mysteries for researchers and clinicians. The heterogeneity of a tumor mass is an old concept that has lately become both a puzzling factor and a feature that should be harnessed to better understand tumor vulnerabilities. Improved scientific approaches to further determine and uncover the meaning of these heterogeneous features are still needed to translate findings into ways to develop therapies, identify drug response biomarkers and stratify patients. In Bedside to Bench, Maria Kleppe and Ross L. Levine look at recent clinical cancer trials that have advanced the field and discuss main questions regarding the role of tumor heterogeneity in predicting therapeutic response and tumor progression. In addition, they raise awareness of the relevance of the interactions among different tumor entities and their contribution to the malignancy of the whole tumor. In Bench to Bedside, Kornelia Polyak peruses studies that uncover specific mutations conferring endocrine drug resistance in breast tumors and that add to our knowledge of the evolution and architecture of tumors, and she discusses how this can be used to implement drug regimens.

Mutations in Kindlin-1 result in Kindler syndrome, which is marked by skin blistering, premature skin aging and increased risk for skin cancer. Reinhard Fässler and his colleagues have developed a new mouse model of the condition, revealing new cellular and molecular mechanistic insight into the pathology of the syndrome.

Mouw et al. delineate a molecular pathway by which matrix stiffness promotes tumor malignancy. Upon matrix stiffening, integrin signaling is engaged, triggering a signaling cascade that regulates the protumorigenic microRNA miR-18a. This leads to downregulation of PTEN and activation of oncogenic signaling. The pathway provides a link between mechanotransduction, miR regulation and oncogene activation that integrates biophysical changes into tumor progression and can also be altered in human tumors.

Atherosclerotic lesions develop preferentially at sites of disturbed blood flow. As shown by Christian Weber and his coworkers, this predilection stems from effects of disturbed blood flow on endothelial expression of the microRNA miR-126-5p, which maintains the proliferative reserve of endothelial cells through repression of the Notch pathway inhibitor Dlk1.

Obesity is marked by a state of low-grade inflammation, including the accumulation of macrophages in the adipose tissue, which results in insulin resistance. Kathryn Moore and her colleagues now show that the neuronal guidance molecule, netrin-1, is upregulated in fat cells during obesity and leads to the retention of macrophages in this tissue. They also show that its genetic deletion in mice prevents the development of insulin resistance by a high-fat diet.

Type 1 diabetes (T1D) and type 2 diabetes (T2D) are both hallmarked by loss of insulin-producing pancreatic beta cells. Kathrin Maedler and her colleagues now show that the kinase MST1 is upregulated by diabetic conditions in beta cells, resulting in their dysfunction and their apoptosis. They also show that genetic knockout of the gene encoding Mst1 results in protection from diabetes in T1D and T2D mouse models.

Michael Dussiot et al. show that an activin receptor IIA ligand trap ameliorates anemia in a mouse model of β-thalassemia by blocking the deleterious effects of GDF11. Mechanistically, GDF11 inactivation reversed ineffective erythropoiesis by promoting terminal erythroblast differentiation and by inducing apoptosis of immature erythroblasts. Also in this issue, Rajasekhar Suragani et al. show related findings using a modified activin receptor IIB ligand trap.

Rajasekhar Suragani et al. show that a modified activin receptor IIB ligand trap increases red blood cell numbers in mice, rats and monkeys and ameliorates anemia in mice and rats, including in a mouse model of myelodysplastic syndromes. The ligand trap binds to the cytokine GDF11 and acts by inhibiting Smad2/3 signaling, thereby reversing ineffective erythropoiesis. Also in this issue, Michael Dussiot et al. show related findings using a wild-type activin receptor IIA ligand trap.

Howard Federoff and colleagues have identified a ten-metabolite profile in the blood that can determine with 90% certainty whether a cognitively normal elderly person will go on to develop dementia symptoms in the next 2–3 years. The findings could help with patient selection for clinical trials aimed at preventing dementia.

Mammals respond to bacterial infection by inducing the expression of hepcidin, which restricts serum iron levels through its effects on macrophage iron export and thereby limits systemic bacterial growth. Kim et al. now report that the macrophage-tropic pathogen Salmonella typhimurium exploits this pathway by triggering the expression of estrogen-related receptor-γ (ERR-γ), which they show increases hepcidin expression and enhances S. typhimurium growth.

Latency-reversing agents (LRAs) have been tested in HIV-1–infected individuals in the hopes of activating the latent viral reservoir and contributing to efforts to eradicate the virus. Robert F. Siliciano and his colleagues now report that most individual LRAs fail to reactivate latent virus in cells from infected individuals and that in vitro models of latency do not adequately reflect the ability of these agents to induce latent virus ex vivo.

Alain Thierry and his colleagues offer a new allele-specific, quantitative PCR–based method designed for the detection of point mutations and determination of mutation load using circulating cell-free DNA isolated from blood. In a blinded study of patients with colorectal cancer, the method exhibited 98% specificity and 92% sensitivity for the seven KRAS point mutations tested and compared favorably with other routinely used detection methods. The approach should help in patients selection for anti-EGFR treatments and for monitoring resistance.

The work of Michael Angelo and colleagues uses multiplexed ion beam imaging (MIBI) to localize and visualize protein expression in a manner analogous to immunohistochemistry (IHC) while circumventing some of the limitations of conventional IHC with clinical samples. MIBI uses secondary ion mass spectrometry to image antibodies tagged with isotopically pure elemental metal reporters, expanding the number of targets that can be analyzed simultaneously to about 100. The approach, used here to image breast tumor tissue sections, offers over a five-log dynamic range and compatibility with standard formalin-fixed, paraffin-embedded tissue sections.

A new technique that allows high-resolution in vivo imaging of myelinated fibers without the use of a fluorescent marker is described by Aaron Schain and colleagues. This label-free approach, which does not require histological or immunocytochemical staining, uses spectral confocal reflectance microscopy, can be performed on a conventional confocal microscope and can be used for deep-tissue transcranial imaging up to 400 μm deep, longitudinally tracking fine changes in axonal myelination. It has potential for the in vivo analysis of normal myelin development, as well as demyelinating diseases of the CNS and peripheral nervous system.