EDITOR'S PICK: Anticancer drugs might be of benefit to sickle-cell patients
Sickle cell disease (SCD) is an inherited blood disorder caused by a genetic mutation that leads to the generation of a mutant form of the beta-globin chain of hemoglobin (Hb). Red blood cells containing Hb with this mutant beta-globin chain change shape upon deoxygenation and this causes them to get stuck in blood vessels, depriving the surrounding tissues of oxygen, which can lead to organ damage. Although hydroxyurea, a treatment for SCD that works by increasing fetal Hb (HbF) expression, benefits some adults with moderate and severe SCD, it does not work for all individuals. Now, hope for a new therapy for SCD has been provided by the work of Laure A. Moutouh-de Parseval and colleagues working for Celgene Corporation.
In the study, lenalidomide and pomalidomide, immunomodulatory anticancer drugs, were both shown to be more effective than hydroxyurea at inducing HbF expression by erythrocytes derived in vitro from CD34+ cells from healthy individuals. In addition, the effects of pomalidomide and hydroxyurea on HbF expression were synergistic. As pomalidomide was able to induce HbF expression in CD34+ cells from patients with SCD, the authors suggested that it might provide a new therapy for SCD, either alone or in combination with hydroxurea. Furthermore, because the induction of HbF has been shown to be of some benefit to individuals with beta-thalassemia (a hereditary anemia caused by decreased beta-globin production), the authors also suggested that pomalidomide might be a good therapeutic for the treatment of beta-hemoglobinopathies other than SCD, such as beta-thalassemia.
TITLE: Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells
AUTHOR CONTACT: Laure A. Moutouh-de Parseval
Celgene Corporation, Summit, New Jersey, USA.
Phone: (908) 673-9330; Fax: (908) 673-2774; E-mail: ldeparse@celgene.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32322
GASTROENTEROLOGY: PLE(ase) pass on the heparin: A new compound stems the tide of protein loss from the gut
Protein-losing enteropathy (PLE) is a dangerous condition involving protein leakage from the gut. Administration of heparin, which stops blood from clotting, can be used to treat individuals with the disorder, since heparin-related molecules (such as HS and Sdc1) are shed by the gut lining cells during episodes of PLE. However, the precise mechanisms of action of heparin as a treatment for PLE are unknown, and its serious side effects make long-term use unrealistic. In a new study, Hudson Freeze and his colleagues at the Burnham Institute for Medical Research, La Jolla, have identified a new, safe, and effective therapy for PLE-like disease in mice.
The authors generated mice lacking Sdc and mice lacking HS in the intestines, and found that these mice leaked protein from their gut, indicating that these molecules are essential for maintaining the integrity of the intestine and making the mice a good model to study intestinal protein leakage. Protein loss from the intestines of these mice was further increased by injection of the proteins IFN-gamma or TNF-alpha, and/or by increased venous blood pressure, all of which are known to be key players in PLE development. Treating the mice with either heparin or a modified heparin molecule that does not stop blood clotting effectively reduced protein leakage from the gut, leading the authors to recommend clinical testing of this molecule in the treatment of PLE.
TITLE: Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function
AUTHOR CONTACT: Hudson H. Freeze
Burnham Institute for Medical Research, La Jolla, California, USA
Phone: (858) 646-3142; Fax: (858) 713-6281; E-mail: hudson@burnham.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32335
PARASITOLOGY: Evasion tactics of a malaria-causing parasite revealed
Malaria caused by infection with the parasite Plasmodium falciparum is a major cause of death and morbidity. Among immune factors, antibodies that prevent P. falciparum from invading red blood cells (erythrocytes) are believed to be important components of immunity against malaria. However, the targets of these antibodies have not been well defined and there are a number of P. falciparum proteins that could be candidates because the parasite uses several different mechanisms to enter red blood cells. Determining the targets of the protective antibodies should help in the development of effective vaccines.
In a new study, James Beeson and colleagues at The Walter and Eliza Hall Institute of Medical Research, Australia, have now determined that malaria-exposed Kenyan children and adults acquire antibodies that target P. falciparum proteins involved in different red blood cell-invasion mechanisms. Furthermore, the ability of a given antibody to inhibit P. falciparum invasion of red blood cells depended on the parasite using the invasion mechanism dependent on the protein targeted by that antibody. Detailed analysis identified the targets of the inhibitory antibodies as various EBA and PfRh proteins. As antibodies that target these proteins were acquired with age, the authors suggested that P. falciparum might use various red blood cell–invasion mechanisms to evade the human immune response and that protective immunity might only be engendered by a repertoire of antibodies recognizing multiple proteins involved in different invasion mechanisms.
TITLE: Variation in use of erythrocyte invasion pathways by Plasmodium falciparum mediates evasion of human inhibitory antibodies
AUTHOR CONTACT: James G. Beeson
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Phone: 61-3-9345-2555; Fax: 61-3-9347-0842; E-mail: beeson@wehi.edu.au.
MEDIA CONTACT: Brad Allan
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Phone 61-3-9345-2555; Fax 61-3-9347-0852; E-mail: allan@wehi.edu.au.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32138
ONCOLOGY: Genetic analysis helps predict survival from a form of leukemia
Insight into the survival of patients with a form of leukemia known as B-CLL can be gained by analyzing the IGVH gene. Individuals without IGVH mutations (UM B-CLL) are more likely to survive for less time than those with mutations (M B-CLL). However, there is still large variability in survival of those with UM B-CLL, particularly if they are diagnosed at an early stage of the disease (low/intermediate Rai risk disease). In a new study, Diane Jelinek and colleagues at the Mayo Clinic College of Medicine, Rochester, have now identified some additional genetic factors that provide insight into the survival of individuals with low/intermediate Rai risk UM B-CLL -- if leukemic cells in individuals with low/intermediate Rai risk UM B-CLL used the IGHD3-3 gene in reading frame 2 the patients were more likely to survive for a shorter period of time. These data have identified more detailed determinants of prognosis in individuals with UM B-CLL, something that might help determine the clinical management of patients.
TITLE: Immunoglobulin diversity gene usage predicts unfavorable outcome in a subset of chronic lymphocytic leukemia patients
AUTHOR CONTACT: Diane F. Jelinek
Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Phone: (507) 284-5617; Fax: (507) 266-0981; E-mail: jelinek.diane@mayo.edu.
MEDIA CONTACT: Elizabeth Zimmermann
Mayo Clinic Cancer Center, Rochester, Minnesota, USA.
Phone: (507) 266-0810; Media (507) 284-5005; E-mail: zimmerman.elizabeth@mayo.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=32625
ONCOLOGY: The molecule GPC1 facilitates tumor metastasis
The prognosis for individuals diagnosed with pancreatic ductal adenocarcinoma (PDAC) is poor, largely because diagnosis often comes after the tumor has spread to other tissues (metastasized). New data generated by Murray Korc and colleagues at Dartmouth Hitchcock Medical Center, Lebanon, has established a role for the molecule GPC1 in driving the growth, metastasis, and angiogenesis (the growth of new blood vessels, something that is essential for a tumor to grow) of human pancreatic cancer cell lines. These data led the authors to suggest that targeting GPC1 might provide a new approach to treating individuals with PDAC.
In the study, human pancreatic cancer cell lines in which expression of GPC1 was downregulated showed reduced tumor growth, metastasis, and angiogenesis when transplanted into immunocompromised mice. A role for host GPC1 was also established, as human pancreatic cancer cell lines expressing normal levels of GPC1 showed decreased tumor growth, metastasis, and angiogenesis when transplanted into immunocompromised mice lacking GPC1. In addition, fewer metastases were detected following the transplantation of a mouse skin cancer cell line into immunocompromised mice lacking GPC1, indicating that the importance of GPC1 to tumor metastasis is not restricted to PDAC.
TITLE: Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells
AUTHOR CONTACT: Murray Korc
Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA.
Phone: (603) 650-7936; Fax: (603) 650-6122; E-mail: murray.korc@dartmouth.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32412
ONCOLOGY: We don't want cancer cells to be PC
New reserach by Abdel-Majid Khatib and colleagues at the Institut de Génétique Moléculaire, France, has demonstrated a role for a group of proteins known as proprotein convertases (PCs) in regulating the metastatic potential of human colorectal cancer cells. These data led the authors to suggest that inhibiting PCs might provide a new approach for developing strategies to prevent colorectal cancer metastasis to the liver.
In the study, in vitro analysis indicated that inhibiting the function of PCs in both a human and murine colon carcinoma cell line blocked a number of cellular events known to be crucial for colorectal cancer metastasis. In addition, media collected from cultures of the human colon carcinoma cell line in which PC function was inhibited failed to enable colorectal tumor cells to stick to endothelial cells, a critical step in metastasis. The in vivo significance of these observations was demonstrated by the observation that when the human colon carcinoma cell line in which PC function was inhibited was injected into immunocompromised mice it generated fewer liver metastases than the parental cells in which PCC function was normal.
TITLE: Selective inhibition of proprotein convertases represses the metastatic potential of human colorectal tumor cells
AUTHOR CONTACT: Abdel-Majid Khatib
Institut de Génétique Moléculaire, Paris, France.
Phone: 33-1-42-49-92-60; Fax: 33-1-42-49-48-38; E-mail: Majid.Khatib@stlouis.inserm.fr.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32040
IMMUNOLOGY: Have your wheat, and eat it, too: A subset of immune cells provides hope for patients with celiac disease
Celiac disease is a disorder in which the body mounts an immune response against its small intestine following consumption of foods containing gluten. It is known that patients suffering from celiac disease have a pronounced abundance of immune cells called IELs bearing the protein TCR-alpha-beta in their small intestine. These cells are thought to mediate the immune response to gluten. In addition, celiac patients also have increased numbers of TCR-gamma-delta IELs; however, the role of these cells in celiac disease has not been well understood. In a new study, John Manavalan and his colleagues at Columbia University College of Physicians and Surgeons, New York, have demonstrated that TCR-gamma-delta IELs may be important in suppressing the aberrant immune response and enhancing tolerance to wheat gluten in patients with celiac disease.
The researchers examined cells taken from the intestines of patients with either active celiac disease or with celiac disease treated by adherence to a gluten-free diet. They found that the number of TCR-gamma-delta IELs was higher in patients on the gluten-free diet. The TCR-gamma-delta IELs from patients on the gluten-free diet were shown to secrete TGF-beta, a protein typically secreted by immune cells that protect the body from mounting immune responses against innocuous particles or its own tissues. In addition, when IELs expressing either TCR-gamma-delta or TCR-alpha-beta were mixed, TGF-beta secreted by the TCR-gamma-delta cells suppressed the expression of molecules by which the TCR-alpha-beta IELs mediate their toxic effects on the intestine. The authors therefore suggested that further understanding of the mechanism by which TCR-gamma-delta IELs regulate TCR-alpha-beta IELs may help in the identification of new therapies for individuals suffering from celiac disease.
TITLE: Small intestinal CD8+TCR-gamma-delta+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease
AUTHOR CONTACT: John S. Manavalan
Columbia University College of Physicians and Surgeons, New York, New York, USA
Phone: (212) 851-4599; Fax: (212) 851-4590; E-mail: jm2074@columbia.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30989
INFLAMMATION: L(ea)PS and bounds to understanding the body's response to blood poisoning
Septic shock is caused by uncontrolled inflammation throughout the whole body in response to severe infection. For Gram-negative bacteria septic shock is mainly caused by the inflammatory response to the bacterial endotoxin LPS. Left untreated, septic shock can lead to organ failure and death. Previous attempts to identify the mechanisms responsible for LPS removal during septic shock have been unsuccessful. In a new study, Deneys van der Westhuyzen and colleagues from the University of Kentucky Medical Center, Lexington have revealed how the cholesterol metabolism-related protein SR-BI may be vital in the body's defense against LPS-induced septic shock.
SR-BI-deficient mice had an uncontrollable inflammatory response following LPS challenge, with a higher subsequent mortality rate compared with normal animals. Researchers addressed the reason for this increased inflammation, and found reduced production of glucocorticoid hormones, which attenuate the pro-inflammatory response to foreign substances in the blood, in response to LPS challenge and infection with Gram-negative bacteria. Additionally, although SR-BI-deficient mice were able to neutralize LPS, its clearance from the body by the liver was reduced. From these results, the authors concluded that SR-BI serves an important protective mechanism in the body, mediating LPS removal while also ensuring anti-inflammatory glucocorticoid production.
TITLE: SR-BI protects against endotoxemia in mice through its roles in glucocorticoid production and hepatic clearance
AUTHOR CONTACT: Deneys R. van der Westhuyzen
University of Kentucky Medical Center, Lexington, Kentucky, USA
Phone: (859) 323-4933 ext. 81397; Fax: (859) 257-3646; E-mail: dvwest1@uky.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31539
Journal
Journal of Clinical Investigation