Promising results with local hyperthermia of tumors

A combination of iron-oxide nanoparticles and an alternating magnetic field, which together generate heat, have activated an immune system response to tumors in mice according to an accepted manuscript by Dartmouth-Hitchcock Norris Cotton Center researchers in the journal Nanomedicine: Nanotechnology, Biology and Medicine released online on February 24, 2014.“The study demonstrates that controlled heating of one tumor can stimulate an immune response that attacks another tumor that has not had the heat treatment,” said Steve Fiering, PhD, Norris Cotton Cancer Center researcher and professor of Microbiology and Immunology, and of Genetics at the Geisel School of Medicine at Dartmouth. “This is one way to try to train the immune system to attack metastatic tumors that may not be recognized yet.”Researchers injected iron-oxide nanoparticles into the tumor and then activated those agents with magnetic energy. Researchers were able to activate antigen-presenting dendritic cells in the body’s immune system. Dendritic cells somewhat serve as “quarterbacks” for body’s immune system by calling for quick coordinated protection against an attack. The “quarterback” cells show the defensive “killer” T cells (CD8+ cells) who to attack and these cells then directly attack tumor cells and send out an alert system to engage other cells in the fight against the cancer. The combination of these two aspects of the immune response reduce risk of recurrence and discourage spreading or metastasis of the cancer. This result was observed in sites close to the primary tumor as well as distant sites. In the experiments conducted as part of this study the primary tumor resisted regrowth for one month following overheating.The magnetic hyperthermia system used was developed by co-author P. Jack Hoopes, DVM, PhD co-director of Norris Cotton Cancer Center’s Nanotechnology Working Group. “It enables very precise control of the heating to keep the temperature at a uniform 43 degrees C for as long as desired,” said Fiering. …

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Protocol developed to harvest mouse cell lines for melanoma research

Dartmouth researchers have developed a protocol that permits cells harvested from melanoma tumors in mice to grow readily in cell culture. Their findings were published in an article, Multiple murine BRafV600E melanoma cell lines with sensitivity to PLX4032, in the January 25, 2014 issue of Pigment Cell & Melanoma Research.”We anticipate that these cell lines will be extremely useful to many investigators who use mouse melanoma as a model system,” said Constance E. Brinckerhoff, PhD, professor of Medicine and of Biochemistry at the Geisel School of Medicine at Dartmouth College and a member of the Norris Cotton Cancer Center (NCCC) Mechanism Research Program.There is a lack of mouse cell lines that harbor the BRAF mutation that is so prevalent in human melanomas, and the cell lines that are available grow slowly in culture and are not representative of human melanoma cell lines. Detailed experiments on molecular mechanisms controlling mouse cell line behavior have been difficult because the currently available mouse cell lines do not grow well in culture.The Geisel researchers are the first to have developed a protocol that permits mouse melanoma cells to be harvested from tumors in the mice and to grow readily in cell culture. Importantly, these cell lines are genetically compatible with a strain of mice that are immunologically competent, while human cells need to be placed into immunologically weakened mice in order to grow. Thus, the ability to study these mouse melanoma cell lines both in culture and in mice with an intact immune system is an experimental advantage.Story Source:The above story is based on materials provided by Norris Cotton Cancer CenterDartmouth-Hitchcock Medical Center. Note: Materials may be edited for content and length.

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Monarch butterflies migration path tracked by generations for first time

Aug. 7, 2013 — Everyone knows all about the epic breeding journey taken each year by generations of monarch butterflies between Mexico and Canada, right? Not so fast, say researchers including University of Guelph biologists.Until now, linking adult butterflies and their birthplaces during a complicated annual migration spanning all of eastern North America and involving up to five generations of the iconic insects had eluded scientists.Now for the first time, researchers have mapped that migration pattern across the continent over an entire breeding season. That information might help conserve a creature increasingly threatened by loss of habitat and food sources, says Tyler Flockhart, a PhD student in U of G’s Department of Integrative Biology.”This tells us where individuals go and where they’re coming from,” he said.Flockhart is lead author of a paper published in the Proceedings of the Royal Society B with Prof. Ryan Norris and co-authors based in Saskatchewan, Colorado and Australia.Their new study traced successive generations of adult monarchs to their birthplaces between the southern United States and Ontario over a single breeding season.Before this, scientists had only a rough idea of those annual colonization patterns, said Prof. Ryan Norris, Integrative Biology. “You could have a monarch showing up in Ontario, but we didn’t know exactly where it came from.”Tracking migration patterns is vital to understanding why monarch numbers are declining and predicting the effects on the insects of milkweed plant loss, habitat destruction and other factors, he said.In 2012, the smallest-ever population of monarchs was recorded in their Mexican overwintering grounds. “They’ve been declining steadily,” said Flockhart.Monarchs normally show up in southern Ontario by June or July. This summer, few had been sighted here by the end of July.The researchers used chemical markers in butterfly wings to match “waves” of insect generations with their birthplaces. Monarch larvae eat only milkweed. …

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Disappearance of coral reefs, drastically altered marine food web on the horizon

Aug. 5, 2013 — If history’s closest analog is any indication, the look of the oceans will change drastically in the future as the coming greenhouse world alters marine food webs and gives certain species advantages over others.Scripps Institution of Oceanography, UC San Diego, paleobiologist Richard Norris and colleagues show that the ancient greenhouse world had few large reefs, a poorly oxygenated ocean, tropical surface waters like a hot tub, and food webs that did not sustain the abundance of large sharks, whales, seabirds, and seals of the modern ocean. Aspects of this greenhouse ocean could reappear in the future if greenhouse gases continue to rise at current accelerating rates.The researchers base their projections on what is known about the “greenhouse world” of 50 million years ago when levels of greenhouse gases in the atmosphere were much higher than those that have been present during human history. Their review article appears in an Aug. 2 special edition of the journal Science titled “Natural Systems in Changing Climates.”For the past million years, atmospheric CO2 concentrations have never exceeded 280 parts per million, but industrialization, forest clearing, agriculture, and other human activities have rapidly increased concentrations of CO2 and other gases known to create a “greenhouse” effect that traps heat in the atmosphere. For several days in May 2013, CO2 levels exceeded 400 parts per million for the first time in human history and that milestone could be left well behind in the next decades. At its current pace, Earth could recreate the CO2 content of the atmosphere in the greenhouse world in just 80 years.In the greenhouse world, fossils indicate that CO2 concentrations reached 800-1,000 parts per million. Tropical ocean temperatures reached 35º C (95º F), and the polar oceans reached 12°C (53°F) — similar to current ocean temperatures offshore San Francisco. There were no polar ice sheets. Scientists have identified a “reef gap” between 42 and 57 million years ago in which complex coral reefs largely disappeared and the seabed was dominated by piles of pebble-like single-celled organisms called foraminifera.”The ‘rainforests-of-the-sea’ reefs were replaced by the ‘gravel parking lots’ of the greenhouse world,” said Norris.The greenhouse world was also marked by differences in the ocean food web with large parts of the tropical and subtropical ocean ecosystems supported by minute picoplankton instead of the larger diatoms typically found in highly productive ecosystems today. …

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Normal molecular pathway affected in poor-prognosis childhood leukemia identified

June 6, 2013 — Through genetic engineering of laboratory models, researchers at Dartmouth-Hitchcock Norris Cotton Cancer Center have uncovered a vulnerability in the way cancer cells diverge from normal regenerating cells that may help treat children with leukemia as reported in the journal PNAS on June 3, 2013. Dartmouth researchers are trying to understand the key pathways that distinguish how a normal blood cell grows and divides compared to the altered growth that occurs in leukemia. In addition to the treatment of leukemia, the work has relevance for expanding umbilical cord blood or bone marrow stem cells for transplantation.Leukemia often occurs due to chromosomal translocations, which are broken chromosomes that cause blood cells to grow uncontrollably. One gene that is involved in chromosomal translocations found at high frequency in childhood leukemia is the MLL1 (Mixed Lineage Leukemia 1) gene. Conventional chemotherapy is very ineffective at curing patients with this translocation, in contrast to other types of childhood leukemia, which are relatively curable.Using genetic engineering, the researchers generated a mouse model to discover genes that are regulated by MLL1 in hematopoietic stem cells, the cells that give rise to all white and red blood cell types. In the course of these studies, they identified several unique properties of the normal MLL1 pathway in hematopoietic stem cells that may be exploited to better treat leukemia harboring MLL1 translocations.”We discovered that many genes that depend upon the normal MLL1 protein are involved in maintaining hematopoietic stem cells, thus manipulating this pathway could be a way to expand cells from normal bone marrow or umbilical cord blood donors to improve transplantation of these cell types, which is a procedure used to treat certain chemotherapy-resistant cancers,” said Patricia Ernst, PhD, co-director Cancer Mechanisms, Dartmouth-Hitchcock Norris Cotton Cancer Center, associate professor of Genetics and of Microbiology and Immunology at the Geisel School of Medicine at Dartmouth, Hanover, NH.As principle investigator, Ernst and her team set out to discover the genetic pathways controlled by the normal form of the MLL1 protein and leukemogenic MLL1 fusion proteins specifically in hematopoietic stem cells (HSCs). Delineation of these pathways will facilitate research by her group and others aimed at developing strategies to kill leukemia cells without harming HSCs, which are often profoundly affected by current chemotherapeutic regimens. In performing this research, they also discovered a new molecular pathway that controls normal HSC biology.”We demonstrate in this study, that some direct MLL1 target genes in HSCs are affected by Menin loss (a protein involved in the inherited disorder, Multiple Endocrine Neoplasia), and some are not,” said Ernst. “This is a fundamentally important observation that demonstrates this category of chromatin modifiers utilizes different protein complexes/mechanisms to target different classes of genes in different cell types.”Ernst points out that this highly desirable outcome that would not have been predicted for this targeted therapy and may illustrate that drugs blocking the interaction of these two proteins (currently under development by other groups) leave normal hematopoiesis intact. She is working on follow-up studies of this finding.Research funded by NIH HL090036 and RR16437 as well as additional grants from American Cancer Society, Gabrielle’s Angel Foundation for Cancer Research, Lady Tata Memorial Trust, and the Lauri Strauss Leukemia Foundation.

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