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News From The Journal Of Clinical Investigation: July 23, 2012

ONCOLOGY
PES1 controls a balancing act in

Estrogen signaling is known to be an important driving force in many breast cancers. Estrogen can signal through two different estrogen receptors (ERs), ERα and ERβ, but the effects that engagement of each of these receptors has on cell growth and survival differs. In this issue of the JCI, Qinong Ye and colleagues, of the Beijing Institute of Biotechnology in China, describe an additional player in this process, PES1, which protects ERα from degradation but decreases the stability of ERβ, upsetting the ratio of the two receptors and promoting breast tumor growth. In the accompanying commentary Christoforos Thomas and Jan-Ake Gustaffson, of the University of Houston and the in Sweden, explain that PES1 expression in breast cancers may be a meaningful indicator of prognosis and a predictor of responsiveness to therapy.

TITLE: PES1 promotes breast cancer by differentially regulating ERα and ERβ

http://www.jci.org/articles/view/62676?key=b92cb93addaaa7955cb7

ACCOMPANYING COMMENTARY TITLE: Targeting PES1 for restoring the ERα/ERβ ratio in breast cancer

http://www.jci.org/articles/view/65133?key=a2c38637b8d0f5383a35

OPHTHALMOLOGY
A closer look at cholesterol in AMD

Age-related macular degeneration (AMD) is a major cause of blindness that can involve an over-proliferation of the blood vessels that supply the retina. Cholesterol-rich lesions are known to occur during the progression of the disease, but the link between cholesterol metabolism and AMD is unclear. In this paper, Irina Pikuleva and her team at investigated the effect of loss of CYP27A1, an enzyme involved in the processing of cholesterol, on eye physiology. They found that these mice had increased cholesterol biosynthesis in the retina, and that this promoted neovascularization. They suggest that this in part explains the connection between cholesterol deposits and blood vessel overgrowth, and that this mouse model might be useful in the development of therapeutic strategies to target the disease.

TITLE: Abnormal vascularization in mouse retina with dysregulated retinal cholesterol homeostasis

http://www.jci.org/articles/view/63816?key=e34896a82b773a52f4a2

IMMUNOLOGY
count: a numbers game

Neutrophils are white blood cells with bactericidal activity, and a drop in neutrophil count, as may occur during chemotherapy, is associated with increased risk of infection. However, despite intense research on the subject, it remains in question precisely how many neutrophils are necessary to maintain health. In this issue, a team led by Vered Rom-Kedar, of the Weizman Institute of Science in , used mathematical modeling to better understand the relationship between neutrophil concentration and bacterial population stability. They found that there was a surprising patient-to-patient variability in neutrophil killing ability that substantially contributed to determining the number of neutrophils required to stave off infection. In the accompanying commentary, Samuel Silverstein of Columbia University discusses this new equation in the light of previous attempts to calculate the critical neutrophil concentration, and suggests that this new model might be helpful in determining the treatment plans for patients at risk of systemic infection.

TITLE: Evidence for bistable bacteria-neutrophil interaction and its clinical implications

http://www.jci.org/articles/view/59832?key=c7b08d23a42849362e72

ACCOMPANYING COMMENTARY TITLE: How many neutrophils are enough (redux, redux)?

http://www.jci.org/articles/view/63939?key=d5f6ccfa4fe26fa715f9

IMMUNOLOGY
Forget-me-not: understanding the contribution of memory CD4+ T cells

Immunological memory enables to the immune system to quickly respond to foreign antigens that the body has previously encountered. Memory CD4+ T cells provide protection both independently and through interactions with other immune cells. However, understanding the specific contributions of these cells has been difficult. Here, Dr. Kai McKinstry and colleagues at the University of Massachusetts Medical School utilized B cell- and T cell-deficient mouse models to study the role of memory CD4+ T cells in the immune response to influenza A virus. They transferred memory CD4+ T cells first into wild-type and then into B cell- or T cell-deficient mice and found that these transferred T cells could provide protection against infection in each model. However, memory CD4+ T cells transfer into mice deficient in both B and T cells was ineffective against infection, suggesting that memory CD4+ T cells need to synergize with other immune cells to combat high viral doses. In the absence of other B or T cells, protection by memory CD4+ T cells was completely dependent on the cytokine IFNγ, an effect that was masked when the other T or B cells were present. Their study demonstrated that studying T cell subsets in isolation can reveal previously unrecognized functions and capabilities of different cell types and suggests a strategy to develop vaccines that enhance memory CD4+ T cell responses. In the accompanying commentary, Kobporn Boonnak and Kanta Subbarao of the National Institute of Allergy and Infectious Diseases, NIH, point out that these newly described functions of CD4+ T cells may be important in informing HIV-vaccine development.

TITLE: Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms

http://www.jci.org/articles/view/63689?key=683392a3b38beed1a465

ACCOMPANYING COMMENTARY TITLE: Memory CD4+ T cells: beyond “helper” functions

http://www.jci.org/articles/view/65208?key=ecbc925627f8a286726f

Source

Journal of Clinical Investigation