Research Round Up- Clinical & Research News - For and about the Physicians and Researchers of Brigham and Women's HospitalResearch Round Up- Clinical & Research News - For and about the Physicians and Researchers of Brigham and Women's Hospital

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Research Round up

Eculizumab Poised to Treat Preeclampsia/HELLP Syndrome

Richard Burwick, MD, MPH

In a case study reported by Richard Burwick, MD, MPH, and Bruce Feinberg, MD, of the BWH Division of Maternal Fetal Medicine, the blood disease-fighting drug, eculizumab, a targeted inhibitor of complement protein C5, showed to be an effective treatment against severe preeclampsia with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. 

A 35-year-old female patient was admitted to a hospital with severe preeclampsia with HELLP syndrome at 26 weeks gestation. She was treated with eculizumab at 1200 milligrams until treatment day 16, at which point clinicians recommended delivery of the neonate. During her course of treatment, she exhibited clinical improvement and restored normal lab results.

According to the researchers, given that pregnancy was prolonged 17 days, treatment likely resulted in a reduction of neonatal death and any associated short- and long-term health care costs.

Severe preeclampsia with HELLP syndrome is a leading cause of maternal and neonatal disease and death worldwide. Treatment strategy can be challenging given the risks: delivering the child early to preserve the mother's health puts the child at risk for premature complications vs. prolonging the pregnancy to prevent prematurity places the mother's health at risk.

"Eculizumab offers the potential to stem ongoing disease in preeclampsia while safely prolonging pregnancy for both mother and child," said Burwick.

The study was published online on Dec. 8, 2012, in Placenta.


NF1 Mechanism Provides Insight to Melanoma Development

Karen Cichowski, PhD

A study led by Karen Cichowski, PhD, and Ophelia Maertens, PhD, of the BWH Division of Genetics, provides new information on how NF1 mutations cooperate with different BRAF mutations during melanomagenesis (the formation of melanomas). The information sheds light on how loss of NF1 gene function promotes the development of this type of cancer and may desensitize tumors to BRAF inhibitors. 

In combination with other genetic changes, mutations of the BRAF gene play a significant role in the formation of melanomas. However, when these other genetic changes are absent-such as NF1 gene function-melanoma tumor development is halted by oncogene-induced senescence (a type of tumor suppression process).

When studying a genetically engineered mouse model, the researchers found that NF1 mutations prevented tumor suppression induced by the BRAF gene. This, in turn, promoted a hyperproliferation of melanocyte cells (a type of skin pigment cell) and melanoma development. The Nf1 mutations worked by disabling certain pathways, particularly PI3K and ERK.

Furthermore, the researchers note that the NF1 gene is mutated or suppressed in human melanomas with and without concurrent BRAF mutations. However, in tumors with BRAF mutations ablating NF1 decreases the sensitivity of melanoma cell lines and mouse tumors to BRAF inhibitors.

Also the researchers found that NF1 is lost in tumors from patients who had been treated with this cancer therapy, thereby demonstrating how NF1-inactivation may promote resistance to this treatment.

"It is important to not only identify the genetic alterations present in individual tumors but to understand how these alterations function together and impact therapies," said Cichowski. "This study demonstrates that NF1 loss can promote resistance to an important new therapy in melanoma (BRAF inhibitors). However, our studies also reveal a combination therapy that could be developed to overcome or prevent this resistance."   

The study was published online Nov. 21, 2012, in Cancer Discovery.

Mass Spectrometry Tool Successful in Identifying DNA-bound Proteins

The genomes of higher organisms are characterized by specific chromosomal proteins and their modifications. An ongoing challenge for scientists has been to obtain a better understanding of the rules that establish and maintain how chromatin (the DNA and proteins that make up chromosomes) are organized.

One obstacle to understanding the function of chromatin-bound protein complexes has been the potential disruption caused by removing them from the DNA for purification. This often results in the loss of weak or transient interactions with key partners.

But now a research team led by Mitzi Kuroda, PhD, of the BWH Division of Genetics, and Charlotte Wang, MD, PhD, of the BWH Department of Pathology, utilizes an approach known as chromatin-interacting protein (ChIP) mass spectrometry. The team applied this tool to affinity-purify fragmented chromatin and identify the proteins attached, using cross-linking to avoid disruption of weak interactions. 

Using this approach in a fruit fly, the researchers described the linked DNA, protein and protein modifications associated with increased gene expression of an entire chromosome.

"The ChIP-MS approach is a general one that will be applicable to the study of gene expression in human cells," said Kuroda.

The study was published online on Jan. 6, 2013, in Nature Structural & Molecular Biology.

Mitzi Kuroda, PhDCharlotte Wang, MD, PhD