EDITOR'S PICK Protein could improve recovery from heart attacks
Angiogenesis, the development of new blood vessels, is required during embryonic development and wound healing, as well as during disease processes such as tumor growth. The signals that direct angiogensis are incompletely understood, but could represent novel targets for the development of therapies that promote or inhibit this process.
In this paper, Young-Guen Kwon and colleagues, of Yonsei University in Seoul, Korea, investigated the role of two related proteins- DKK1 and DKK2- in angiogenesis. These proteins are known to have similar functions in inhibiting a particular cell signaling pathway, but Kwon and colleagues found that they played opposite roles in directing angiogenesis. Remarkably, they discovered that injection of DKK2 improved vascular regeneration in a mouse model of myocardial infarction (heart attack). The researchers are hopeful that pharmacological manipulation of DKK1 and DKK2 could be used to treat various vascular diseases.
TITLE: The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells
METABOLISM Mouse model reveals multiple roads to control blood sugar
Diabetes is a disease of uncontrolled blood sugar levels that results from absolute or relative insufficiency of the hormone insulin. Other hormones contribute to the regulation of blood sugar control and insulin release, and can also be dysregulated in diabetic patients. One of these is glucagon; diabetic patients display disordered glucagon signaling, and drugs that inhibit glucagon action are known to improve blood sugar levels in diabetic mouse models. When glucagon signaling is absent in mice, they are resistant to developing diabetes, but the interpretation of this model is complicated because the mice also have increased levels of a glucagon-related peptide called GLP-1, which itself is known to have similar physiological effects.
In order to better understand the roles of glucagon and GLP-1, Daniel Drucker and colleagues, from the University of Toronto, in Canada, generated mice in which the receptors for both had been deleted. Remarkably, the absence of GLP-1 signaling did not alter the improved glucose tolerance of mice lacking glucagon signaling. These mice had pancreatic islets that were more sensitive to other molecules that promote insulin release because they upregulate receptors for those alternative signals. The authors believe that their results demonstrate a plasticity of the many pathways that control insulin secretion.
TITLE: Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis
ENDOCRINOLOGY Insight into a common disorder of the critically ill
Critically ill patients often display characteristic changes in levels of thyroid hormones, a condition called non-thyroidal illness syndrome (NTIS). One of the initial signs of NTIS is a low level of the active hormone triiodothyronine (also called T3), and lower T3 levels correlate with poor prognosis and survival. Therefore, understanding how hormone metabolism goes awry in patients without pre-existing thyroid gland disorders could help improve the outcome of individuals who suffer from multiple diseases. Increased levels of cell signaling molecules called cytokines, particularly Interleukin-6 (IL-6), are also associated with NTIS, but how these contribute to changes in T3 levels is not understood.
In this paper, Ana Maia and colleagues, of the Universidade Federal do Rio Grande do Sul, in Porto Alegre, Brazil, examined the effect of IL-6 on the enzymes that process T3. They found that IL-6 suppressed the action of the enzymes that generate T3, and promoted the action of the enzyme that deactivates T3. In addition, the effect of IL-6 could be inhibited by antioxidants. The researchers believe that these results suggest that a state of oxidative stress, common to many acute and chronic illnesses, may underlie the activation of IL-6 and initiation of NTIS.
TITLE: IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells
ONCOLOGY Research identifies pathway involved in breast cancer metastasis
In breast cancer, lymph node metastasis is a common occurrence, and the progression of the cancer in this way is a reliable predictor of patient survival. These metastases occur first in the lymph node close to the breast called the sentinel, and then progressively move to new lymph nodes. The mechanisms that control this movement of tumor cells are not well understood, but could represent novel targets to impede the progression of metastatic cancer.
In new research, Dontscho Kerjaschki and colleagues, of the Medical University of Vienna in Austria studied samples from human breast cancer patients, and found that in order to move into new lymph nodes, tumors cells first invade the lymphatic vessels that connect them. They further found evidence in model systems that this invasion requires that tumor cells generate an enzyme called 15-lipoxygenase. The researchers believe that this work suggests that inhibition of 15-lipoxygenase and related enzymes might be an effective strategy to prevent tumor spread.
TITLE: Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse
ONCOLOGY Autoimmune reaction could help fight melanoma
One potential approach to fighting cancer involves directing the T cells of the immune system to recognize molecules produced by tumor cells (antigens) and then attack those cells, a method called immunotherapy. However, the antigens produced by tumor cells may be identical to molecules produced by non-cancerous cells, and T cell recognition of these can result in an undesirable autoimmune attack. A naturally-occurring example of this is melanoma-associated vitiligo, in which immune cells directed against a skin cancer lesion also attack healthy melanocytes, resulting destruction of those cells and patches of skin that lack normal pigmentation.
In this paper, Mary Jo Turk and colleagues, of Dartmouth Medical School and the Dartmouth-Hitchcock Medical Center in Hanover, New Hampshire, investigated how vitiligo affected T cell responses to melanoma in mice. They found that destruction of melanocytes was required for tumor immunity, and further, that the T cells associated with vitiligo provided a lasting protection against tumor growth. The researchers believe that these data show that autoimmune destruction of normal tissues is a beneficial process that occurs as the body fights cancer, and propose that inducing vitiligo in melanoma patients might enhance their natural immune response.
TITLE: Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma
IMMUNOLOGY Targeting multiple pathways improves vaccine efficacy
One of the goals of vaccine design is to elicit strong reactions from multiple groups of immune cells, both those that confer an acute response to infection, and those that will provide a lasting immune memory. To achieve this, scientists have begun physically linking molecules that activate responses through different pathways. Researchers have previously immunized mice with proteins coupled to nucleic acids (so-called conjugate vaccines) so that they might stimulate both the adaptive and innate immune responses simultaneously. However, the mechanisms that explain the improved responses to these conjugate vaccines are not completely understood.
In this paper, Bob Seder and collaborators at the National Institutes of Health in Bethesda, Maryland, found that conjugating proteins to nucleic acids increased the uptake of the vaccine by dendritic cells. In addition, they found that conjugate vaccines induced the production of cytokines that contributed to the overall response. The authors believe that this work helps to define the responses to conjugate vaccines, and suggest new methods to enhance vaccine efficacy.
TITLE: Protective T cell immunity in mice following protein-TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN, and multiple DC subsets
NEPHROLOGY Gene responsible for nephrotic syndrome and deafness identified
Nephrotic syndrome (NS) is a disorder that causes protein to leak from the blood into the urine, and a form of the disease that is resistant to treatment with steroids (SRNS) is frequent cause of end stage renal disease. SRNS has been linked to mutations in a few genes that are expressed in the podocyte cells of the kidney, but the genetic cause of the disease is unknown in the majority of cases, complicating the search for medical therapies. In new research, Friedhelm Hildebrandt and colleagues, of the Howard Hughes Medical Institute and the University of Michigan in Ann Arbor, performed genetic linkage studies to identify additional mutations that could cause SRNS. They found that in 13 patients, SRNS could be linked to mutations in the gene encoding COQ6, which is required for the synthesis CoQ10, an antioxidant enzyme with an additional role in the generation of cellular energy. Remarkably, treating these patients with CoQ10 improved renal function. Interestingly, the patients with COQ6 mutations also suffered from deafness, suggesting that this gene also plays a role in the nerve cells of the inner ear, though treatment with CoQ10 did not improve this defect. The researchers hope that by identifying the causitive mutations in NS patients, they may be better able to offer effective medical treatments.
TITLE: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness
IMMUNOLOGY Designing better CARs for cancer therapy
One new method of cancer treatment is the delivery of immune cells that have been genetically altered to express receptors that recognize tumor-specific molecules (so-called chimeric antigen receptors, CARs), and thus are directed to attack tumor cells. The addition of co-stimulatory molecules which enhance and sustain the immune response has improved the efficacy of this approach in pre-clinical studies. However, the precise design of CARs has been controversial, and it remains unclear whether they will be effective in human patients.
In new research, Gianpietro Dotti and colleagues, at Baylor College of Medicine in Houston, Texas, directly compared the efficacy of two CAR designs in patients with non-Hodgkin lymphoma. They found that the addition of the co-stimulatory molecule greatly enhanced the immune response, and made it more durable. The researchers hope that this clinical study will have far-reaching implications for the design of this type of immunotherapy.
TITLE: CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients
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