JCI online early table of contents: Nov. 7, 2011

Type 1 diabetes is a lifelong disease characterized by high levels of sugar (glucose) in the blood. It is caused by the patient's immune system attacking and destroying the cells in their pancreas that produce the hormone insulin, which regulates blood glucose levels. Surprisingly, little is known about the mechanisms regulating the sensitivity and resistance of these cells, which are known as beta-cells, to immune system attack. However, a team of researchers led by Paola Meda, at the University of Geneva, Switzerland, has now determined that the protein connexin 36 protects mouse pancreatic beta-cells against immune molecules that are prevalent in the pancreas at the onset of type 1 diabetes. Meda and colleagues therefore suggest that promoting connexin 36 expression and/or function therapeutically might provide a way to protect beta-cells from immune system attack and thereby sustain insulin production in individuals with type 1 diabetes.

TITLE: Connexins protect mouse pancreatic beta-cells against apoptosis

AUTHOR CONTACT:
Paolo Meda
University of Geneva, Medical School, Geneva, Switzerland.
Phone: 41.22.379.52.10; Fax: 41.22.379.52.60; E-mail: paolo.meda@unige.ch.

View this article at: http://www.jci.org/articles/view/40509?key=63ae56e58268ff17ac81

Most people who die from breast cancer do not die as a result of their breast tumor but because their cancer has spread (metastasized) to other parts of their body, often their lungs or bones. A team of researchers led by Richard Kremer, at McGill University Health Centre, Montréal, has used a mouse model of human breast cancer to identify a potential new target for slowing breast tumor progression and metastasis.

The protein PTHrP is frequently found to be expressed in breast tumors, but whether it plays a role in disease progression has not been determined. Kremer and colleagues found that in one mouse model of breast cancer PTHrP promoted primary tumor initiation, tumor progression, and metastasis to other parts of the body. As neutralizing the effects of PTHrP with therapeutics known as antibodies slowed the progression and metastasis of human breast cancer cells transplanted into mice, Kremer and colleagues suggest this approach should be considered as a potential new strategy for treating people with breast cancer.

TITLE: PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

AUTHOR CONTACT:
Richard Kremer
Department of Medicine, McGill University Health Centre, Montréal, Quebec, Canada.
Phone: 514.843.1632; Fax:
514.843.1712; E-mail: richard.kremer@mcgill.ca.

MEDIA CONTACT:
Julie Robert
Public Affairs & Strategic Planning, McGill University Health Centre, Montréal, Quebec, Canada.
Phone: 514.934.1934 ext. 71381; E-mail: julie.robert@muhc.mcgill.ca.

View this article at: http://www.jci.org/articles/view/46134?key=955ea4fa37e886018bac

Pancreatic cancer is one of the most common causes of death from cancer. The majority of human pancreatic cancers are driven by activating mutations in the gene KRAS. A team of researchers led by Thorsten Hagemann, at Queen Mary University of London, United Kingdom, has now identified new molecular interactions that are important in promoting the progression of KRAS-driven pancreatic cancer in mice. Specifically, Hagemann and colleagues found that the canonical NF-kappa-B and Notch signaling pathways cooperate via the protein IKK2 to suppress the expression of PPAR-gamma, a repressor of inflammatory gene expression, thereby retaining the tumor cells in an inflammatory state that promotes tumor progression.

TITLE: Crosstalk between the canonical NF-kappa-B and Notch signaling pathways inhibits PPAR-gamma expression and promotes pancreatic cancer progression in mice

AUTHOR CONTACT:
Thorsten Hagemann
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Phone: 44.20.7882.3590; Fax: 44.20.7882.3885; E-mail: t.hagemann@qmul.ac.uk.

View this article at: http://www.jci.org/articles/view/45797?key=def6c2465693069d7b5b

Intensive research efforts are being focused on developing immune-based anticancer therapies. One approach is to therapeutically harness immune cells known as CD8+ T cells, which are key components of the natural antitumor immune response. Sid Kerkar, Nicholas Restifo, and colleagues, at the National Institutes of Health, Bethesda, recently found that engineering antitumor CD8+ T cells to secrete the proinflammatory molecule IL-12 improved their therapeutic efficacy in a mouse model of established melanoma (the most dangerous form of skin cancer). Now they have determined how the IL-12 improves the therapeutic efficacy of the antitumor CD8+ T cells. The data revealed a surprising mechanism that not only shed new light on the anticancer effects of CD8+ T cells but also provided the basis for an ongoing clinical trial in which patients with metastatic melanoma will receive T cells engineered to express IL-12 as part of their treatment.

TITLE: IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors

AUTHOR CONTACT:
Sid P. Kerkar
National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301.496.6507; Fax: 301.451.6949; E-mail: kerkars@mail.nih.gov.

Nicholas P. Restifo
National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301.496.6507; Fax: 301.451.6949; E-mail: restifon@nih.gov.

View this article at: http://www.jci.org/articles/view/58814?key=e0c8c50235809b056303

The number of individuals with type 2 diabetes is reaching epidemic proportions. The hallmark of type 2 diabetes, a high level of sugar (glucose) in the blood, is a key factor in the development of the serious complications of the disease, including kidney damage, nerve damage, and vision loss. The high level of glucose in the blood of individuals with type 2 diabetes is partly a result of increased glucose production by cells in the liver. Studies in rodents have suggested that activation of protein complexes known as KATP channels in a region of the brain known as the hypothalamus suppresses glucose production. Meredith Hawkins and colleagues, at Albert Einstein College of Medicine, New York, now show that this also occurs in humans. They therefore suggest that activating this pathway could provide a new way to reduce the level of glucose in the blood of individuals with type 2 diabetes and thereby decrease risk of serious complications.

TITLE: Activation of KATP channels suppresses glucose production in humans

AUTHOR CONTACT:
Meredith Hawkins
Albert Einstein College of Medicine, New York, New York, USA.
Phone: 718.430.3186; Fax: 718.430.8557; E-mail: meredith.hawkins@einstein.yu.edu.

View this article at: http://www.jci.org/articles/view/58035?key=e74f4aea84515bd1464d

Multiple sclerosis (MS) is a potentially debilitating inflammatory disease that affects the brain and spinal cord. Many patients with MS have an impaired sense of smell (i.e., they have olfactory deficits), and a team of researchers led by Anne Baron-Van Evercooren, at INSERM UMR-S 975, France, has now identified a potential reason why.

The SVZ is a region of the brain that supports, throughout adult life, the generation of new nerves that have very specific functions. One role of nerve cells arising from neural stem cells in the SVZ is an involvement in sensing smells. Baron-Van Evercooren and colleagues found that in a mouse model of MS, the process of nerve cell generation in the SVZ was dysregulated and fewer nerve cells involved in sensing smell were generated. The resulting olfactory deficits mimicked those observed in patients with MS. Moreover, nerve cell generation in the SVZ of patients was MS was found to be impaired. Baron-Van Evercooren and colleagues therefore suggest that the inflammation in the brain of patients with MS causes SVZ dysfunction and that this could underlie the impaired sense of smell reported by these patients.

TITLE: Inflammation-induced subventricular zone dysfunction leads to olfactory deficits in a targeted mouse model of multiple sclerosis

AUTHOR CONTACT:
Anne Baron-Van Evercooren
INSERM UMR-S 975, Hôpital Pitié-Salpêtrière, Paris, France.
Phone: 33.1.57174123; Fax: 33.1.57274788; E-mail: anne.baron@upmc.fr.

View this article at: http://www.jci.org/articles/view/59145?key=a3528f37012664885d28