Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma. Although 60% of patients can be cured with a currently available combination therapy, this leaves a substantial number of patients without a cure. However, a team of researchers, led by Ari Melnick, at Weill Cornell Medical College, New York, has now identified a potential new combinatorial therapy for DLBCL. Specifically, the team found that combining an inhibitor of the protein BCL6 with either an inhibitor of HDAC proteins or an inhibitor of the Hsp90 protein enhanced killing of primary human DLBCL cells in vitro relative to the use of the BCL6 inhibitor alone. Both drug combinations also potently suppressed the growth of established human DLBCL xenografts in mice or even eradicated the tumors completely. These data provide a rational basis for designing combination therapy clinical trials in patients with DLBCL.
TITLE: BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy
AUTHOR CONTACT:
Ari Melnick
Weill Cornell Medical College, New York, New York, USA.
Phone: 212.746.7622; Fax: 212.746.8866; E-mail: amm2014@med.cornell.edu.
View this article at: http://www.jci.org/articles/view/42869?key=3f286442c25fdb9ce9e2
EDITOR'S PICK: Possible new drug targets for the genetic disorder Noonan syndrome
Noonan syndrome is a relatively common genetic disorder characterized by short stature, unique facial features, and heart defects. About 10%-15% of affected individuals have mutations in their SOS1 gene. A team of researchers, led by Raju Kucherlapati, at Harvard Medical School, Boston, has now generated mice expressing a Sos1 mutation associated with Noonan syndrome and used them to identify potential therapeutic targets for the treatment of individuals with Noonan syndrome. Specifically, the team found that the Ras/MAPK signaling pathway as well as the Rac and Stat3 proteins were activated in the hearts of the mutant mice. However the authors caution that normalizing signaling from all of these pathways and proteins might be required for successful amelioration of the entire spectrum of Noonan syndrome symptoms.
TITLE: Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation
AUTHOR CONTACT:
Raju Kucherlapati
Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.525.4445; Fax: 617.525.4440; E-mail: rkucherlapati@partners.org.
View this article at: http://www.jci.org/articles/view/43910?key=27ff3f3327b6f864e09a
BACTERIOLOGY: Easy access for cholera toxin via the flotillin proteins
Cholera is a life-threatening disease caused by the bacterium Vibrio cholerae. It is characterized by profuse watery diarrhea, vomiting, and abdominal pain. The massive watery diarrhea is caused by cholera toxin, a protein complex secreted by cholera-causing bacteria. To wreak its devastating effects, cholera toxin must enter the cells lining the small intestine. New insight into the mechanisms by which cholera toxin enters cells has now been provided by a team of researchers, led by Wayne Lencer, at Children's Hospital Boston, working in zebrafish and mammalian cells. These data provide valuable new insight into the ways in which cholera toxin causes disease.
TITLE: Intoxication of zebrafish and mammalian cells by cholera toxin depends on the flotillin/reggie proteins but not Derlin-1 or -2
AUTHOR CONTACT:
Wayne I. Lencer
Children's Hospital Boston, Boston, Massachusetts, USA.
Phone: 617.919.2573; Fax: 617.730.0495; E-mail: wayne.lencer@childrens.harvard.edu.
View this article at: http://www.jci.org/articles/view/42958?key=54d3a69b0cdaf5157376
CARDIOVASCULAR DISEASE: Promoting regression of hardening of the arteries
One of the leading causes of death in the developed world is atherosclerosis — a disease of the major arterial blood vessels that can lead to heart attack and stroke. It is often known as hardening of the arteries because deposits of fatty substances, cholesterol, cellular waste products, calcium, and other substances build up in the inner lining of an artery to form what is known as a plaque. Treatment with statins delays or halts further plaque buildup but has little effect on existing plaques. A team of researchers, led by Edward Fisher, at New York University School of Medicine, has now provided new insight into the factors involved in plaque regression in a mouse model of atherosclerosis, information that they hope might eventually lead to treatments capable of mediating atherosclerotic plaque regression.
TITLE: LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression
AUTHOR CONTACT:
Edward A. Fisher
New York University School of Medicine, New York, New York, USA.
Phone: 212.263.6631; Fax: 212.263.6632; E-mail: edward.fisher@nyumc.org.
View this article at: http://www.jci.org/articles/view/38911?key=ed957e233a8273f80445
CARDIOLOGY: How the hormone adiponectin counters stressful times for the heart
When put under stress, either acute or chronic, the heart adapts to increase its output. However, if prolonged, these adaptations can cause heart failure. Understanding natural mechanisms that protect the heart under conditions of stress is of interest because it is hoped that it will be possible to develop ways to enhance these for clinical benefit. A team of researchers, led by Barbara Ranscht, at Sanford-Burnham Medical Research Institute, La Jolla, has now provided new insight into the ways in which the hormone adiponectin protects the mouse heart under conditions of stress. Specifically, the team has identified the protein T-cadherin as the molecule on mouse heart muscle cells to which adiponectin binds to mediate its protective effects. Further analysis is required to flesh out the molecular pathways involved before it can be established experimentally whether it might be possible to modulate them for clinical benefit.
TITLE: T-cadherin is critical for adiponectin-mediated cardioprotection in mice
AUTHOR CONTACT:
Barbara Ranscht
Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
Phone: 858.646.3122; Fax: 858.646.3197; E-mail: ranscht@burnham.org.
View this article at: http://www.jci.org/articles/view/43464?key=251b421dbfb6f7ed14d6
HEMATOLOGY: Geminin: a new player in blood cell production
All cells in the blood are generated from cells known as hematopoietic stem cells. Disruption of the pathways controlling the formation of blood cells can result in leukemia, myeloproliferative disorders, and anemia. By studying mice lacking the protein geminin in blood cells and the cells from which they are generated, Thomas McGarry and colleagues, at Feinberg School of Medicine, Chicago, have provided new insight into the pathways that control blood cell production. Specifically, they find that geminin regulates the relative production of red blood cells and megakaryocytes — the cells from which platelets (cells essential for stopping bleeding) are generated. Interestingly, geminin controls this process by a mechanism that is distinct from its previously known mechanisms of action. Further studies are needed to define more concretely the molecular players with which geminin interacts to regulate blood cell production.
TITLE: Geminin deletion from hematopoietic cells causes anemia and thrombocytosis in mice
AUTHOR CONTACT:
Thomas J. McGarry
Feinberg School of Medicine, Chicago, Illinois, USA.
Phone: 312.503.4386; Fax: 312.503.0137; E-mail: t-mcgarry@northwestern.edu.
View this article at: http://www.jci.org/articles/view/43556?key=b062b3a062db8f4b5902
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