JCI online early table of contents: Dec. 12, 2011

Glioblastoma multiforme (GBM) is the most common and lethal of all human brain tumors that originate in the brain. For most patients, treatment involves surgery followed by both radiation therapy and chemotherapy with temozolomide. However, many GBMs are resistant to the effects of temozolomide. A team of researchers led by Sameer Agnihotri, at the University of Toronto, Toronto, has now determined that the protein APNG can contribute to GBM resistance to the effects of temozolomide. Importantly, high levels of expression of APNG in the nucleus of ressected tumor cells correlated with poorer overall survival compared with patients lacking APNG expression. Agnihotri, and colleagues therefore suggest that monitoring APNG levels could provide insight into whether or not a patient with GBM will respond to temozolomide, although this awaits confirmation in predictive and prospective studies.

TITLE: Alkylpurine–DNA–N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients

AUTHOR CONTACT:
Sameer Agnihotri
Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada.
Phone: 416-813-6688; Fax: 416-813-8456; E-mail: sameer.agnihotri@utoronto.ca.

View this article at: http://www.jci.org/articles/view/59334?key=6384e1a132d67084e922

Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease) is an incurable adult neurodegenerative disorder that progresses to paralysis and death. Genetic mutations are the cause of disease in 5󈝶% of patients with ALS. Of immense interest, Hongxia Zhou, Xu-Gang Xia, and colleagues, at Thomas Jefferson University, Philadelphia, now show that progressive neuron degeneration can be halted in a rat model of familial ALS linked to mutations in the gene that carries the instructions for making the protein TDP-43.

Progressive motor neuron degeneration was stopped when expression of the ALS-associated mutant human TDP-43 was switched off. If expression of the mutant protein was switched off before many motor neurons had degenerated, the rats recovered function. Conversely, if expression was switched off after most motor neurons had degenerated, functional recovery was minimal. These data indicate that mutant TDP-43 in motor neurons is sufficient to promote the onset and progression of ALS and that progression of motor neuron degeneration (and thereby progression of disease) is partially reversible in the rat model.

TITLE: Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats

AUTHOR CONTACT:
Hongxia Zhou
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Phone: 215-503-5916; Fax: 215-923-3808; E-mail: Hongxia.zhou@jefferson.edu.

Xu-Gang Xia
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Phone: 215-503-9152; Fax: 215-503-7848; E-mail: xugang.xia@jefferson.edu.

View this article at: http://www.jci.org/articles/view/59130?key=d2afb40cf4f326238835

Transplant surgeons live in the hope that one day they will be able to wean at least some of their patients off the immunosuppressive drugs that must be taken to prevent rejection of a transplanted organ. A team of researchers led by Alberto Sánchez-Fueyo, at the University of Barcelona, Spain, has now identified markers that might make this possible for liver transplant recipients.

Transplant recipients must take immunosuppressive drugs for the rest of their lives to prevent rejection of their transplanted organ; this has serious negative health consequences. It would be helpful if it were possible to determine what would happen if a patient was weaned from their immunosuppressive drugs: would they reject their transplanted organ or would their immune system be sufficiently tolerant of the transplant that it would not be rejected? Sánchez-Fueyo and colleagues determined that liver transplant recipients with higher blood levels of proteins involved in handling iron (hepcidin and ferritin) could tolerate weaning from their immunosuppressive drugs. Moreover, measuring expression in the liver of genes involved in handling iron enabled Sánchez-Fueyo and colleagues to predict the outcome of immunosuppressive-drug withdrawal in an independent set of patients. They therefore suggest that they have identified a way to accurately pick out those liver transplant recipients who would be good candidates for drug-weaning protocols.

TITLE: Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation

AUTHOR CONTACT:
Alberto Sánchez-Fueyo
Hospital Clinic Barcelona, University of Barcelona, Barcelona, Spain.
Phone: 34-934872583; Fax: 34-932271779; E-mail: afueyo@clinic.ub.es.

View this article at: http://www.jci.org/articles/view/59411?key=af92f42e12cbd2387ba4

Many human cancers show aberrant hyperactivation of the NF-kappa-B signaling pathway, and this contributes to the development and progression of these cancers. In normal cells, NF-kappa-B activity is tightly regulated by proteins known as I-kappa-Bs; NF-kappa-B signaling even leads to expression of I-kappa-Bs. How this negative feedback loop is overcome in cancer cells has not been determined. But now, Mengfeng Li, Jun Li, and colleagues, at Sun Yat-sen University, China, have identified a mechanism by which it is overcome in human gliomas, the most common tumors arising from cells in the adult brain. Specifically, they find that the regulatory RNA miR-30* suppresses expression of I-kappa-B-alpha. Importantly, expression of miR-30e* was found to be upregulated in primary human glioma cells and correlated with tumor progression and poor survival. Thus, Li, Li, and colleagues suggest that targeting miR-30e* could provide a new approach to treating gliomas.

TITLE: MicroRNA-30e* promotes human glioma cell invasiveness in an orthotopic xenotransplantation model by disrupting the NF-kappa-B/I-kappa-B-alpha negative feedback loop

AUTHOR CONTACT:
Mengfeng Li
Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, Guangdong, China.
Phone: 86-20-87335828; Fax: 86-20-87335828; E-mail: limf@mail.sysu.edu.cn.

Jun Li
Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, Guangdong, China.
Phone: 86-20-87332748; Fax: 86-20-87331209; E-mail: lijun37@mail.sysu.edu.cn.

View this article at: http://www.jci.org/articles/view/58849?key=483b336e1aae3e232504

Many blood diseases, including sickle cell disease and hemolytic uremic syndrome, are characterized by the blockage of small blood vessels in vital organs. Among the factors causing these blockages are changes in the biophysical interactions among blood cells, blood vessel–lining cells (endothelial cells), and soluble factors. Animal models have provided much insight into blood diseases; however, in vitro systems are needed to gain deeper understanding of the biophysical changes that occur. A team of researchers led by Wilbur Lam, at Emory University School of Medicine, Atlanta, has now developed an in vitro "endothelialized" microfluidic microvasculature system that enabled them to investigate how biophysical changes in blood samples from patients with sickle cell disease cause blockage of small blood vessels. Furthermore, as Lam and colleagues were able to use their system to model the efficacy of the drug eptifibatide in preventing blood vessel obstruction in HUS, they suggest that it provides a useful tool for blood disease drug discovery.

TITLE: In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology

AUTHOR CONTACT:
Wilbur A. Lam
Emory University School of Medicine, Atlanta, Georgia, USA.
Phone: 415-385-3446; Fax: 404-727-4455; E-mail: wilbur.lam@emory.edu.

View this article at: http://www.jci.org/articles/view/58753?key=05d35c77bfff8e804d45

Ectodermal dysplasias are a group of inherited conditions in which there is abnormal development and function of the skin, hair, nails, teeth, and/or sweat glands. Individuals with ectodermal dysplasia with immune deficiency (EDI) also have a dysfunctional immune system that renders them susceptible to severe infections. EDI is caused by mutations in the NEMO gene that reduce but do not abolish expression of NEMO protein. Now, a team of researchers led by Ashish Jain, at the National Institute of Allergy and Infectious Diseases, Bethesda, has identified two patients with EDI caused by genetic mutations that are not within the NEMO gene but do markedly reduce the level of expression of NEMO. Detailed analysis of cells from these patients defined a new and unexpected function for NEMO — it controls the activity of the protein IKK-alpha in the nucleus. Importantly, the data indicate that defects in this function of NEMO result in the immune deficiency that is characteristic of EDI.

TITLE: Defective nuclear IKK-alpha function in patients with ectodermal dysplasia with immune deficiency

AUTHOR CONTACT:
Ashish Jain
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301-594-5691; Fax: 301-480-1753; E-mail: ajain@niaid.nih.gov.

View this article at: http://www.jci.org/articles/view/42534?key=05ee401b0eeda41b75be

To clear an invading microbe from the body the immune system must become activated. However, once the microbe has been cleared it is important to shut down the immune response so that it does not cause damage to healthy tissue surrounding the site of infection. In some instances, suppression of the immune response occurs before the immune system has done its job. For example, many tumors contain cells known as MDSCs that suppress antitumor immune responses. A team of researchers led by Leo Koenderman, at the University Medical Center Utrecht, The Netherlands, has now identified in humans a new population of immune system–suppressing cells characterized by high levels of expression of the proteins CD11c, CD11b, and CD16 and low levels of expression of the protein CD62L. The cells were observed in humans during acute body-wide inflammation induced by injection of a bacteria-derived toxin or by severe injury. Further analysis identified the mechanisms by which these cells suppressed the immune system, providing potential targets for preventing unwanted immune system suppression.

TITLE: A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1

AUTHOR CONTACT:
Leo Koenderman
University Medical Center Utrecht, Utrecht, The Netherlands.
Phone: 31-88-7557255; Fax: 31-88-7555415; E-mail: l.koenderman@umcutrecht.nl.

View this article at: http://www.jci.org/articles/view/57990?key=ffff831d2c7a509bd694

One of the first immune cells to respond to an invading microbe is the neutrophil. Numbers of these cells are tightly regulated because of their importance as a first responder. In healthy individuals, more than 1 × 109 neutrophils per kilogram body weight are released from the bone marrow every day; an equivalent number must be cleared from the circulation to ensure numbers remain constant. A team of researchers — led by Steven Bensinger and Peter Tontonoz, at UCLA, Los Angeles — has now determined that proteins known as LXRs are key regulators of neutrophil clearance and production in mice and identified the molecular pathways by which the LXRs do so. As dysregulation of neutrophil clearance has been implicated in the development of lupus, future studies will focus on determining whether modulating LXR signaling can modify disease in animal models of lupus.

TITLE: Coordinate regulation of neutrophil homeostasis by liver X receptors in mice

AUTHOR CONTACT:
Steven J. Bensinger
David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
Phone: 310-825-9885; Fax: 310-267-6267; E-mail: sbensinger@mednet.ucla.edu.

Peter Tontonoz
David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
Phone: 310-206-4546; Fax: 310-267-0382; E-mail: ptontonoz@mednet.ucla.edu.

View this article at: http://www.jci.org/articles/view/58393?key=abc382b18a21deb76dfb

HIV-1 infection is characterized by the loss of key immune cells known as CD4+ T cells. Combined antiretroviral therapy (cART) largely restores CD4+ T cell numbers in the blood, but the gut remains substantially depleted of these cells. A team of researchers led by Pierre Delobel, at INSERM, UMR1043, France, has now determined that the inefficient restoration of CD4+ T cell numbers in the gut of cART-treated HIV-infected individuals is likely to be a result of a lack of recruitment of CD4+ T cells; in particular, those CD4+ T cells that express the proteins CCR9 and beta-7. Moreover, this is probably because expression of the molecule CCL25, which attracts CD4+ T cells expressing the protein CCR9, is decreased in the small intestine of HIV-infected individuals. These data provide a potential explanation for the inefficient restoration of gut CD4+ T cell numbers in HIV-infected individuals receiving effective cART, something that was poorly understood.

TITLE: Altered CD4+ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals

AUTHOR CONTACT:
Pierre Delobel
INSERM, UMR1043, Toulouse, France.
Phone: 33-5-61-77-75-08; Fax: 33-5-61-77-21-38; E-mail: delobel.p@chu-toulouse.fr.

View this article at: http://www.jci.org/articles/view/59011?key=a0a1ec7e537acfb05110

The process of transplanting an organ is complex. Despite great care, some cells of the organ die during the harvesting and implantation procedures. These dead cells activate a branch of the organ recipient's immune system known as the innate immune system. This impairs the ability of the organ recipient's immune system to tolerate the new organ, which can lead to rapid rejection of the transplanted organ (acute transplant rejection). A team of researchers led by Daniel Goldstein, at Yale University School of Medicine, New Haven, has now determined that release of the protein haptoglobin from dying skin cells activates the innate immune system and accelerates transplant rejection in a mouse model of skin transplantation. As there are three major variants of haptoglobin in humans, Goldstein and colleagues suggest that it would be interesting to determine whether differential expression of these haptoglobin variants influences rejection of transplanted hearts in humans.

TITLE: Haptoglobin activates innate immunity to enhance acute transplant rejection in mice

AUTHOR CONTACT:
Daniel R. Goldstein
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203-785-3271; Fax: 203-785-7567; E-mail: daniel.goldstein@yale.edu.

View this article at: http://www.jci.org/articles/view/58344?key=68e86efe8058c7046e4b