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Originally, the label "borderline personality disorder" was applied to patients who were thought to represent a middle ground between patients with neurotic and psychotic disorders. Increasingly, though, this area of research has focused on the heightened emotional reactivity observed in patients carrying this diagnosis, as well as the high rates with which they also meet diagnostic criteria for posttraumatic stress disorder and mood disorders.

New research by Dr. Anthony Ruocco at the University of Toronto and his colleagues paints perhaps the sharpest picture we have so far of the patterns of brain activity which may underlie the intense and unstable emotional experiences associated with this diagnosis.

In their report, the investigators describe two critical brain underpinnings of emotion dysregulation in borderline personality disorder: heightened activity in brain circuits involved in the experience of negative emotions and reduced activation of brain circuits that normally suppress negative emotion once it is generated.

To accomplish this, they undertook a meta-analysis of previously published neuroimaging studies to examine dysfunctions underlying negative emotion processing in borderline personality disorder. A thorough literature search identified 11 relevant studies from which they pooled the results to further analyse, providing data on 154 patients with borderline personality disorder and 150 healthy control subjects.

Ruocco commented, "We found compelling evidence pointing to two interconnected neural systems which may subserve symptoms of emotion dysregulation in this disorder: the first, centred on specific limbic structures, which may reflect a heightened subjective perception of the intensity of negative emotions, and the second, comprised primarily of frontal brain regions, which may be inadequately recruited to appropriately regulate emotions."

Importantly, reduced activity in a frontal area of the brain, called the subgenual anterior cingulate, may be unique to borderline personality disorder and could serve to differentiate it from other related conditions, such as recurrent major depression.

"This new report adds to the impression that people with borderline personality disorder are ‘set-up’ by their brains to have stormy emotional lives, although not necessarily unhappy or unproductive lives," commented Dr. John Krystal, Editor of Biological Psychiatry.

"Given that many of the most effective psychotherapies for borderline personality disorder work to improve emotion regulation skills, these findings could suggest that dysfunctions in critical frontal ‘control’ centres might be normalised after successful treatment," concluded Ruocco.EurekAlert

A protein known as Sp2 is key to the proper creation of neurons from stem cells, according to researchers at North Carolina State University. Understanding how this protein works could enable scientists to “program” stem cells for regeneration, which has implications for neural therapies.

Troy Ghashghaei and Jon Horowitz, both faculty in NC State’s Department of Molecular Biomedical Sciences and researchers in the Center for Comparative Medicine and Translational Research, wanted to know more about the function of Sp2, a cell cycle regulator that helps control how cells divide. Previous research from Horowitz had shown that too much Sp2 in skin-producing stem cells resulted in tumours in experimental mice. Excessive amounts of Sp2 prevented the stem cells from creating normal cell “offspring,” or skin cells. Instead, the stem cells just kept producing more stem cells, which led to tumour formation.

“We believe that Sp2 must play a fundamental role in the lives of normal stem cells,” Horowitz says. “Trouble ensues when the mechanisms that regulate its activity are overwhelmed due to its excess abundance.”

Ghashghaei and his team – led by doctoral candidate Huixuan Liang – took the opposite approach. Using genetic tools, they got rid of Sp2 in certain neural stem cells in mice, specifically those that produce the major neurons of the brain’s cerebral cortex. They found that a lack of Sp2 disrupted normal cell formation in these stem cells, and one important result was similar to Horowitz’s: the abnormal stem cells were unable to produce normal cell “offspring,” or neurons. Instead, the abnormal stem cells just created copies of themselves, which were also abnormal.

“It’s interesting that both an overabundance of this protein and a total lack of it result in similar disruptions in how stem cells divide,” Ghashghaei says. “So while this work confirms that Sp2 is absolutely necessary for stem cell function, a lot of questions still remain about what exactly it is regulating, and whether it is present in all stem cells or just a few. We also need to find out if Sp2 deletion or overabundance can produce brain tumours in our mice as in the skin.

“Finally, we are very interested in understanding how Sp2 regulates a very important decision a stem cell has to make: whether to produce more of itself or to produce offspring that can become neurons or skin cells,” Ghashghaei adds. “We hope to address those questions in our future research, because these cellular mechanisms have implications for cancer research, neurodevelopmental diseases and regenerative medicine.”North Carolina State University

Scientists from the University of Iowa and Brigham Young University (BYU) have identified a gene that may be a target for overcoming drug resistance in cancer. The finding could not only improve prognostic and diagnostic tools for evaluating cancer and monitoring patients’ response to treatment but also could lead to new therapies directed at eradicating drug-resistant cancer cells.

Drug resistance is a common problem in many metastatic cancers. It leads to failure of chemotherapy treatments and is associated with poor patient outcomes, including rapid relapse and death.

Fenghuang Zhan, Ph.D.The research team, including Fenghuang (Frank) Zhan, M.D., Ph.D., and Guido Tricot, M.D., Ph.D., from the UI, and David Bearss, Ph.D., from BYU, initially focused on identifying genes linked to the development of drug resistance in multiple myeloma, a bone marrow cancer that affects more than 20,000 Americans and causes almost 11,000 deaths annually.

Working with serial biopsied cells from 19 myeloma patients, the researchers analysed genetic changes in the cells that occurred over the course of treatment with very intensive chemotherapy drugs. This approach identified a gene called NEK2 that is strongly associated with increased drug-resistance, faster cancer growth, and poorer survival for patients.

Guido Tricot, M.D., Ph.D.Having established the relationship between high expression of the NEK2 gene and poor patient outcome in myeloma, the team then examined the relationship in other common cancers—including breast, lung, and bladder cancer—by analysing gene expression profiles from 2,500 patients’ cells with eight different cancers in Zhan’s lab.

Taking the findings back to the lab, the team then examined the effect on cancer cells of either enhancing or blocking the expression of the NEK2 gene. "In all cases, an increase in the NEK2 gene was associated with rapid death of the patient," says Tricot, who is director of Holden Comprehensive Cancer Center’s Bone Marrow Transplant and Myeloma Program at UI Hospitals and Clinics. "So this finding was not unique to myeloma; this is basically seen in every single cancer we looked at."

The research team is now developing compounds to inhibit NEK2 by collaborating with David Bearss, Ph.D., associate professor of physiology and developmental biology at BYU, in the hope that these compounds may overcome drug resistance in cancer cells. "Our studies show that over-expression of NEK2 in cancer cells significantly enhances the activity of drug efflux proteins to pump chemotherapy drugs out of cells, resulting in drug resistance. Furthermore, silencing NEK2 in cancer cells potently decreased drug resistance, induced cell-cycle arrest, cell death, and inhibited cancer cell growth in vitro and in vivo," says Zhan, UI professor of internal medicine.

“We were able to show that if we inhibit NEK2, then we can actually restore sensitivity to drugs that we use right now,” Bearss says.

Although development and clinical testing of such drugs for use in patients is not imminent, Tricot notes that the findings may have clinical use within the next several years.

"NEK2 expression may be a diagnostic or prognostic marker for drug-resistant cancer," he says. "If NEK2 is high, that would suggest that the prognosis is poorer and the patient might benefit from more aggressive treatment. The other potential use is for monitoring the cancer’s response to therapy. If NEK2 levels increase, that would suggest development of increased drug resistance and might indicate that a change of treatment would be helpful."University of Iowa Health Care

Research led by St. Jude Children’s Research Hospital scientists has identified a possible lead in treatment of two childhood leukaemia subtypes known for their dramatic loss of chromosomes and poor treatment outcomes.
The findings also provide the first evidence of the genetic basis for this high-risk leukaemia, which is known as hypodiploid acute lymphoblastic leukaemia (ALL). Normal human cells have 46 chromosomes, half from each parent, but hypodiploid ALL is characterised by fewer than 44 chromosomes. Chromosomes are highly condensed pieces of DNA, the molecule that carries the inherited instructions for assembling and sustaining a person.
The study, the largest ever focused on hypodiploid ALL, confirmed that this tumour has distinct subtypes distinguished by the number of chromosomes lost and the submicroscopic genetic alterations they harbour. Researchers found evidence suggesting more than one-third of patients with a subtype known as low hypodiploid ALL have Li-Fraumeni syndrome. Families with Li-Fraumeni syndrome harbour inherited mutations in the TP53 tumour suppressor gene and have a high risk of a range of cancers. Hypodiploid ALL had not previously been recognised as a common manifestation of Li-Fraumeni syndrome.
Researchers reported that the major hypodiploid subtypes are both sensitive to a family of compounds that block the proliferation of cancer cells. The compounds include drugs already used to treat other cancers. The subtypes are low hypodiploid ALL, characterised by 32 to 39 chromosomes, and near haploid ALL, which has 24 to 31 chromosomes.
‘This study is a good example of the important insights that can be gained by studying the largest possible number of patients in as much detail as possible. This approach led us to key insights about these leukaemia subtypes that we would otherwise have missed,’ said the study’s senior and corresponding author, Charles Mullighan, MBBS(Hons), MSc, M.D., an associate member of the St. Jude Pathology Department. Mullighan is a Pew Scholar in Biomedical Sciences.
The near haploid and low hypodiploid ALL subtypes represent 1 to 2 percent of the estimated 3,000 pediatric ALL cases diagnosed annually in the U.S. But they account for a much larger number of ALL treatment failures. Today more than 90 percent of young ALL patients will become long-term survivors, compared to 40 percent for patients with these two high-risk subtypes. St. Jude researchers led the study in collaboration with investigators from the Children’s Oncology Group, the world’s largest organisation devoted exclusively to childhood and adolescent cancer research.
‘The cure rate for hypodiploid ALL is only about half that obtained overall for children with ALL. The findings of this study are very important and have the potential to impact how this high-risk subset of childhood ALL is treated,’ said Stephen Hunger, M.D., chair of the Children’s Oncology Group ALL committee and one of the paper’s co-authors. ‘This study grew out of the efforts of Hank Schueler, a teenager who died from hypodiploid ALL. He wanted to find ways to help treat other children with this type of leukaemia. After he passed away, his parents established a foundation to support research in hypodiploid ALL. We thought that one way to do this was to conduct the genomic analyses reported in this paper. These findings would not have been possible without Hank’s idea and without support from the Schueler family.’
Researchers used a variety of laboratory techniques to look for genetic abnormalities in cancer cells from 124 pediatric patients missing at least one chromosome. The patients included 68 with near haploid ALL and 34 with low hypodiploid ALL. Investigators also checked white blood cells collected when 89 of the 124 patients were in remission. The study included whole-genome sequencing of the entire cancer and normal genomes of 20 patients with near haploid or low hypodiploid subtypes. For another 20 patients, investigators deciphered just DNA involved in protein production. Researchers also screened cancer cells from 117 adult ALL patients, including 11 with the low hypodiploid subtype.
The whole genome sequencing was done in conjunction with the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project. The project has sequenced the complete normal and cancer genomes of more than 600 children and adolescents with some of the most aggressive and least understood cancers.
Near haploid ALL was characterised by alterations in six genes and increased activity in key pathways that help regulate cell division and development. Disruption of these pathways, known as Ras and PI3K, has been linked to other cancers. The changes were found in 71 percent of near haploid ALL patients and included deletion of the NF1 gene. The gene had not previously been linked to high-risk leukemia. Other alterations involved the genes NRAS, KRAS, MAPK1, FLT3 and PTPN11.
Low hypodiploid ALL in both adults and children was linked to mutations in the TP53 tumour suppressor gene. The gene was altered in 91 percent of pediatric patients with the ALL subtype and in 10 of the 11 adults with low hypodiploid ALL included in the study. Other common alterations involved RB1, another tumour suppressor gene.
About 38 percent of children with low hypodiploid ALL also carried TP53 abnormalities in non-cancerous blood cells. The mutations included many previously linked to Li-Fraumeni syndrome, which is characterized by changes in TP53.
Further evidence linking low hypodiploid ALL to Li-Fraumeni syndrome came when researchers found the same TP53 mutation in two generations of the same family. The father was 31 years old when he was found to have a brain tumour associated with Li-Fraumeni syndrome. His son later developed low hypodiploid ALL.
‘Identification of children with low-hypodiploid ALL and inherited TP53 mutations could help expand the use of life-saving cancer screening,’ said Linda Holmfeldt, Ph.D., a St. Jude postdoctoral fellow. She and Lei Wei, Ph.D., of the St. Jude Department of Computational Biology and formerly of Pathology, are the study’s co-first authors. ‘Screening helps save lives by finding cancers much earlier when the odds of a cure are greatest,’ Holmfeldt said. St. Jude Children’s Research Hospital