JCI early table of contents for May 24, 2013

(Press-News.org) Modulating the immune system to combat metastatic cancer

Cancer cells spread and grow by avoiding detection and destruction by the immune system. Stimulation of the immune system can help to eliminate cancer cells; however, there are many factors that cause the immune system to ignore cancer cells. Regulatory T cells are immune cells that function to suppress the immune system response. In this issue of the Journal of Clinical Investigation, researchers led by Ronald Levy at Stanford University found that regulatory T cells that infiltrate tumors express proteins that can be targeted with therapeutic antibodies. Mice injected with antibodies targeting the proteins CTLA-4 and OX-40 had smaller tumors and improved survival. Moreover, treatment with these antibodies cleared both tumors at the primary site and distant metastases, including brain metastases that are usually difficult to treat. These findings suggest that therapies targeting regulatory T cells could be a promising approach in cancer treatment. In an accompanying commentary, Cristina Ghirelli and Thorsten Hagemann emphasize that in order for this approach to be clinically relevant, it will be important to show that targeting regulatory T cells in metastatic tumors also blocks growth.

TITLE:
Depleting tumor-specific Tregs at a single site eradicates disseminated tumors

AUTHOR CONTACT:
Ronald Levy
Stanford University Medical Center, Stanford, CA, USA
Phone: 650-725-6452; Fax: 650-736-1454; E-mail: levy@stanford.edu

View this article at: http://www.jci.org/articles/view/64859?key=0b844b21d3af9fbb75eb

ACCOMPANYING COMMENTARY

TITLE:
Targeting immunosuppression for cancer therapy

AUTHOR CONTACT:
Thorsten Hagemann
Barts Cancer Institute, London, UNK, GBR
Phone: +442078825795; Fax: +442078826110; E-mail: t.hagemann@qmul.ac.uk

View this article at: http://www.jci.org/articles/view/69999?key=1894a675947229d0146a

New fluorescent tools for cancer diagnosis

In recent years, microRNAs (miRNAs) and other non-coding RNAs are small molecules that help control the expression of specific proteins. In recent years they have emerged as disease biomarkers. miRNA profiles have been used to establish tissue origin for cancers of unknown primary origin, determine prognosis, monitor therapeutic responses and screen for disease, but clinically tractable, diagnostic methods for monitoring miRNA expression in patient samples are not currently available. In this issue of the Journal of Clinical Investigation, Thomas Tuschl and colleagues at Rockefeller University developed a multicolor fluorescence labeling method that can be used to visualize miRNAs in tissue sections, such as those recovered from biopsies. Using this method, Tuschl and colleagues were able to identify tumor specific miRNAs in basal cell carcinoma and Merkel cell carcinoma (accompanying image) and distinguish between FFPE sections from the two tumor types. This proof-of concept study indicates that RNA FISH could serve as a molecular diagnostic in a clinical setting. In a companion commentary, Gennadi Glinksy of Stanford University discusses how this technology could contribute to the development of RNA-based diagnostics and therapeutics.

TITLE:
Multicolor microRNA FISH effectively differentiates tumor types

AUTHOR CONTACT:
Thomas Tuschl
The Rockefeller University / HHMI, New York,USA
Phone: 2123277651; E-mail: ttuschl@rockefeller.edu

View this article at: http://www.jci.org/articles/view/68760?key=36efa8d5d66021c0e322

ACCOMPANYING COMMENTARY

TITLE:
RNA-guided diagnostics and therapeutics for next-generation individualized nanomedicine

AUTHOR CONTACT:
Gennadi Glinsky
Stanford University Medical School, Stanford, CA, USA
Phone: 858-401-3470; E-mail: gglinsky@stanford.edu

View this article at: http://www.jci.org/articles/view/69268?key=7c5b7c952e03e5ae6be5

Malnutrition exacerbates Giardia infection in mice

Giardia is a common parasite that frequently infects young children in the developing world. It is commonly encountered through contaminated food, soil, or water. The parasite lives inside the intestines and can cause severe diarrhea and other gastrointestinal problems and Giardia infection has been associated with developmental growth delays. Because the majority of infected individuals do not experience symptoms and frequently are infected with other pathogens, it is unclear if endemic Giardia directly stunts growth. In this issue of the Journal of Clinical Investigation, Luther Bartelt and colleagues at the University of Virginia studied the effect of Giardia infection in a malnourished host. Malnourished mice exposed to Giardia developed a worse symptoms, including inflammation, intestinal damage, and growth retardation. These findings suggest that malnourishment puts children at greater risk for symptomatic Giardia infection. In the related Attending Physician piece, Theodore Nash describes how this single infectious agent can have dramatically different effects depending on an individual's health history. As Herbert DuPont explains in the accompanying commentary, although preexisting nutritional state undoubtedly plays a role, the varying Giardia strains and host genetics are likely also contributors to the extent of disease.

TITLE:
Persistent G. lamblia impairs growth in a murine malnutrition model

AUTHOR CONTACT:
Luther Bartelt
University of Virginia, Charlottesville, VA, USA
Phone: 434-409-0652; E-mail: lab2za@virginia.edu

View this article at: http://www.jci.org/articles/view/67294?key=e1e7dcc286d4278035ce

ACCOMPANYING COMMENTARY

TITLE:
Giardia: both a harmless commensal and a devastating pathogen

AUTHOR CONTACT:
Herbert L DuPont
University of Texas, Houston, Houston, TX, USA
E-mail: hdupont@sleh.com

View this article at: http://www.jci.org/articles/view/69932?key=e48754a6b9fc60321c43

ACCOMPANYING THE ATTENDING PHYSICIAN

TITLE:
Unraveling how Giardia infections cause disease AUTHOR CONTACT:
Theodore Nash
National Institutes of Health, Bethesda, MD, USA
Phone: 301-496-6920; E-mail: theodore.nash@nih.gov

View this article at: http://www.jci.org/articles/view/69956?key=2db2037b357483546a10

Friendly bacteria tamp down the host immune response

Pathogenic bacteria typically elicit a host immune response; however, each of us lives with millions of strains of friendly bacteria (known as commensals) that do not activate the immune system or cause any symptoms. In this issue of the Journal of Clinical Investigation, researchers led by Catharina Svanborg at Lund University in Sweden propose that commensal bacteria act as guardians of their host environment, controlling the quantity and quality of host gene expression in order to prevent an immune response. To study these responses, Svanborg and colleagues used a strain of E. coli that colonizes the urinary tract but does not cause urinary tract infection symptoms. They found that, unlike bacteria that cause symptoms, the asymptomatic bacteria prevented the activation of inflammatory immune responses. This study identifies a mechanism by which commensal bacteria may establish a beneficial relationship with their host. In an accompanying Attending Physician article, Patrick Seed discusses how commensal bacteria could potentially be used as therapeutics in patients with recurrent urinary tract infections.

TITLE:
Bacterial control of host gene expression through RNA Polymerase II

AUTHOR CONTACT:
Catharina Svanborg
Labmedicin dep of Microbiology, immunology and glycobiology, Lund, SWE
Phone: +46 46 17 39 72; Fax: +46 46 13 74 68; E-mail: Catharina.Svanborg@med.lu.se

View this article at: http://www.jci.org/articles/view/66451?key=f25917427aa8c2f8df1f

ACCOMPANYING THE ATTENDING PHYSICIAN TITLE:
Anger management: bacteria soothe the savage host

AUTHOR CONTACT:
Patrick Seed
Duke Univeristy School of Medicine, Durham, NC, USA
E-mail: patrick.seed@duke.edu

View this article at: http://www.jci.org/articles/view/69647?key=a6f206b44e10bd4e877c

Familial kidney disorder reveals inner workings of a portion of the immune system

C3 glomerulopathy refers to a group of kidney conditions characterized by innappropriate activation of an immune system response mechanism known as complement. Normally the complement system helps to clear pathogens from the body. It consists of a number of small proteins that, upon immune activation, are broken up into fragments that bind to foreign material or pathogen-infected cells to trigger their destruction. In C3 glomerulopathies, the complement fragments accumulate in the kidney, causing damage. In this issue of the Journal of Clinical Investigation, Santiago Rodríguez de Córdoba and colleagues at the Centro de Investigaciones Biológicas in Madrid, Spain identifed mutations in complement regulating protein, factor H, which increased complement activation. These studies help to define how factor H functions in complement regulation and provide a greater understanding of C3 glomerulopathy pathology. As Michael Holers of the University of Colorado explains in the accompanying commentary, variants in factor H genes are linked to multiple autoimmune and inflammatory diseases. Studies like this one may help to direct the development of new therapies.

TITLE:
C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation

AUTHOR CONTACT:
Santiago Rodríguez de Córdoba
Centro de Investigaciones Biológicas (CSIC), Madrid, UNK, ESP
Phone: 34 91 8373112; E-mail: srdecordoba@cib.csic.es

View this article at: http://www.jci.org/articles/view/68280?key=10557a92827ab0d588fe

ACCOMPANYING COMMENTARY TITLE:
Human C3 glomerulopathy provides unique insights into complement factor H–related protein function

AUTHOR CONTACT:
Michael Holers
University of Colorado Denver School of Medicine, Denver, CO, USA
Phone: 303-724-7609; E-mail: Michael.Holers@ucdenver.edu

View this article at: http://www.jci.org/articles/view/69684?key=7b3a1f3b31864a612826

Bone-derived hormone and insulin influence male fertility

The bone cell-derived hormone osteocalcin promotes the production of testosterone in the mouse testis. Interestingly, osteocalcin-deficient mice exhibit increased levels of leutenizing hormone (LH), a pituitary hormone that regulates sex steroid synthesis in the testes. Additionally, osteocalcin levels appear to be linked to insulin secretion and sensitivity and circulating levels of testosterone in humans. In this issue of the Journal of Clinical Investigation, researchers led by Gerard Karsenty at Columbia University conducted a study to determine if LH and insulin regulate osteocalcin's reproductive effects. Using transgenic mice, they found that osteocalcin and LH act in two parallel pathways to stimulate testosterone synthesis. To determine the importance of osteocalcin in humans, they analyzed patients with primary testicular failure, wherein the testes do not produce enough testosterone, and a mutation in a cellular receptor that allows Leydig cells in the testes to respond to osteocalcin. This study uncovers an endocrine axis that is necessary for optimal male fertility in the mouse and suggests that osteocalcin modulates reproductive function in humans.

TITLE:
A pancreas-bone-testis axis and conservation of osteocalcin function in humans

AUTHOR CONTACT:
Gerard Karsenty
Columbia University, New York, NY, USA
Phone: 212 305 4011; E-mail: gk2172@columbia.edu

View this article at: http://www.jci.org/articles/view/65952?key=aa347e9f0247bcf117a6

Loss of RNA editing enzyme promotes melanoma growth

Dysregulated gene expression is a feature of most cancers. In this issue of the Journal of Clinical Investigation, Gal Markel and colleagues at Chaim Sheba Medical Center in Ramat-Gan, Israel, demonstrated that expression of the RNA editing enzyme ADAR1 is frequently reduced in melanoma that was linked to the development of metastases. Loss of ADAR1 enhanced the growth and tumor-forming ability of the melanoma cells. Markel and colleagues found that ADAR1 normally regulates the expression of microRNAs, molecules that help to control the expression of specific genes. In turn, microRNAs also control the expression of ADAR1. These studies demonstrate that loss of an RNA editing enzyme contributes to the development of a more aggressive, metastatic form of melanoma.

TITLE:
MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth

AUTHOR CONTACT:
Gal Markel
Chaim Sheba Medical Center, Ramat-Gan, ISR
Phone: 972-3-5304591; E-mail: markel@post.tau.ac.il

View this article at: http://www.jci.org/articles/view/62980?key=96ee313210f0982ab94b

### END