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JCI early table of contents for Nov. 12, 2012

Home field advantage: Intravaginal immunization may help protect against infection

Sexually-transmitted diseases (STDs) enter the body through the mucosal epithelial cells and the ability to direct pathogen-clearing T-cells to points of infection may be the critical element in developing successful vaccines against these infections. In a study published in the Journal of Clinical Investigation, researchers led by John Schiller at the National Cancer Institute investigated the immune response to intravaginal immunization in mice infected with a form of the HPV virus carrying a model antigen. They found that intravaginal immunization significantly increased the number of immune cells present in the vaginal mucosa compared with a general immune system booster. These results indicate that site-specific vaccination enhances the local immune system response and may be useful in developing STD vaccines.

Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cells

John Schiller
National Cancer Institute, Bethesda, MD, USA
Phone: 301-594-2715; Fax: 301-480-5322; E-mail:

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HIV-1 vaccine development: pinning down a moving target

HIV-1 is a genetically diverse collection of viruses, making it a moving target in vaccine development. In a study published in the Journal of Clinical Investigation, researchers led by Brad Jones at the University of Toronto in investigated the feasibility of eliminating HIV-infected cells by targeting cellular immune responses against a human endogenous retrovirus (HERV). HERVs are the DNA remnants of ancient infectious retroviruses that became part of the germ line cells of our ancestors. Jones and colleagues found that HIV infection stimulated the expression of HERV proteins, effectively tagging HIV-infected cells. Immune cells targeted to these proteins specifically eliminated cells infected with several different strains of HIV in vitro. This study suggests that HERV-targeted immune responses should be considered in the development of HIV vaccines.

HERV-K-targeted T-cells eliminate diverse HIV-1/2 and SIV primary isolates

Brad Jones
University of Toronto, Toronto, ON, CAN
Phone: 617-777-9151; E-mail:

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Researchers find abnormal dopamine signaling in a mouse model of Angelman syndrome

Angelman syndrome (AS) is a developmental disorder characterized by intellectual disability, seizures, sleep disturbances, hand flapping, and a happy demeanor. It is caused by deletion or mutation of a gene on a maternal chromosome in the UBE3A gene. Currently, there is no effective treatment for AS, but several studies have suggested that abnormal dopamine signaling might be an underlying cause of the disorder. In a study published in the Journal of Clinical Investigation, researchers led by C.J. Malanga at the University of North Carolina at Chapel Hill engineered mice lacking maternal Ube3a and found that they exhibit behavior that correlates with abnormal dopamine signaling characterized by increased dopamine release. This study elucidates AS-associated changes in dopamine signaling that should inform clinical trials utilizing dopamine replacement therapy in AS patients.

Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome

C.J. Malanga
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Phone: 919.966.1683; Fax: 919.843.4576; E-mail:

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A new view of the immune system

Immune responses take place throughout the body and require the correct migration of particular subsets of immune cells to precise locations. In a study published in the Journal of Clinical Investigation, researchers led by Andreas Beilhack at Wrzburg University in Germany report the development of a microscopy technique that allows for the visualization of individual immune cells in intact tissues and organs. The technique, called Light Sheet Fluorescence Microscopy (LSFM), was used to monitor T-cell responses in the intestines and in mice after a bone marrow transplant. This new technology will provide insight into complex immune processes.

Mapping immune processes in intact tissues at cellular resolution

Christian Brede
Wrzburg University Clinics, Wrzburg, , DEU
Phone: +49-931-201-27638; E-mail:

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Unraveling the role of the unfolded protein response in cancer

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response known as the Unfolded Protein Response (UPR), which supports cell survival. UPR is activated at a higher frequency in mouse and human lymphomas, suggesting that it might contribute to the survival of cancer cells. In a study published in the Journal of Clinical Investigation, researchers led by Constantinos Koumenis at the University of Pennsylvania found that the oncogene c-Myc activated the UPR to increase cell survival and reduce a cell recycling process known as autophagy. By blocking c-Myc activation of the UPR in mice, Koumenis and colleagues were able to prevent the development of lymphoma. These findings suggest that inhibition of UPR may be effective in cancers characterized by enhanced c-Myc expression, such as Burkitt's lymphoma, colorectal cancer, breast cancer, and melanoma.

ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth

Constantinos Koumenis
Univ. Pennsylvania, Philadelphia, PA, USA
Phone: 215-898-0076; E-mail:

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Immune cells have differential effects on recovery after acute kidney injury

Acute kidney injury (AKI) is defined as an abrupt decrease in kidney function. The renal tubule cells are the primary targets for injury. During AKI, these cells either temporarily quit functioning or die altogether. There is increasing evidence that immune cells are the source of renal tubule damage; treatments that prevent these cells from reaching the renal tubule can reduce kidney injury. In a study published in the Journal of Clinical Investigation, researchers led by Raymond Harris at Vanderbilt University used a mouse model of AKI to study the activity of macrophages, a specific type of immune cell, in the renal tubule. They found that two different types of macrophages accumulated in the kidney. M1 macrophages enhanced inflammation and injury, while M2 macrophages promoted healing. Blocking the activity of CSF1, a growth factor that stimulates the proliferation of M2 macrophages, increased injury and delayed recovery. This study demonstrates that CSF1 plays a critical role in the recovery of the renal tubules following AKI.

CSF-1 signaling mediates recovery from acute kidney injury

Raymond C. Harris
Vanderbilt University Med Center, Nashville, TN, USA
Phone: 615 322-2150; E-mail:

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Neurodegeneration is triggered by DNA repair

Oxidative metabolism produces reactive oxygen species (ROS), highly toxic molecules that cause DNA and tissue damage. The brain is particularly susceptible to ROS damage and excessive ROS, a condition known as oxidative stress, can lead to neurodegeneration. In a study published in the Journal of Clinical Investigation, researchers led by Yusaku Nakabeppu at Kyushu University in Fukuoka, Japan investigated the role of a ROS-induced DNA lesion, 8-oxoguanine, in neurodegeneration. Nakabeppu and colleagues engineered mice that lacked different DNA repair enzymes to determine if the DNA lesion could activate cell death pathways in neurons. They found that the accumulation of 8-oxoguanine activated cell death pathways in neurons and the neuron-supporting glial cells upon repair of the DNA lesion. These findings indicate that suppression of specific DNA repair enzymes may protect the brain under conditions of oxidative stress.

8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair

Yusaku Nakabeppu
Medical Institute of Bioregulation, Kyushu University, Fukuoka, , JPN
Phone: +81-92-642-6800; Fax: +81-92-642-6791; E-mail:

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Mob mentality: loss of the protein MOB1 causes uncontrolled cell growth

Cancer is caused by an imbalance in the signals that tell cells to grow or differentiate into a specialized cell type. The Hippo signaling pathway, which regulates growth signals, is frequently mutated or inactivated in many human cancers, including trichilemmal carcinoma, a cancer that originates in hair follicles. The protein MOB1 is also frequently mutated in trichilemmal carcinoma; however its role in carcinogenesis is unclear. In a study published in the Journal of Clinical Investigation researchers led by Akira Suzuki at Kyushu University in Fukuoka, Japan investigated the role of MOB1 in Hippo signaling. Using mice with deletions or mutations in the Mob1 gene, Suzuki and colleagues found that loss of Mob1 in skin cells caused uncontrolled cell growth through dysregulation of the Hippo signaling pathway. This study establishes MOB1 as a tumor suppressor and suggests that therapeutics targeting the Hippo pathway or MOB1 might be useful in the treatment of Hippo-driven cancers, including trichilemmal carcinoma.

Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice

Akira Suzuki
Div.Cancer Genetics,Medical Institute of Bioregulation,Kyushu Univ., Fukuoka, UNK, JPN
Phone: +81-92-642-6835; Fax: +81-92-632-1499; E-mail:

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A context dependent role for Nkx2-1 in lung cancer

Mucinous adenocarcinoma is a highly invasive form of lung cancer that is associated with a decrease in a gene regulatory protein known as NKX2-1. In a study published in the Journal of Clinical Investigation, researchers led by Jeffrey Whitsett at Cincinnati Children's Hospital demonstrated that loss of one copy of the Nkx2-1 gene and the expression of an activated form of the oncogene Kras caused mucinous adenocarcinoma in mice. Interestingly, loss of one copy of Nkx2-1 in combination with the expression of another common lung-cancer associated gene, Egfr, did not cause carcinogenesis. These results suggest that the function of Nkx2-1 is context dependent and indicate that the genotype of mucinous adenocarcinomas should influence the choice of treatment.

KRAS.G12D and NKX2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung

Jeffrey Whitsett
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
Phone: 513-803-2790; E-mail:

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Contact: Jillian Hurst
Journal of Clinical Investigation

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