A newborn baby's weight loss is often used to determine how well a baby is breastfeeding, and concern about a baby which loses too much weight may result in supplementing breastfeeding with formula. However, many women receive IV fluids during labor, and new research published in BMC's open access journal International Breastfeeding Journal shows that some of a newborn's initial weight loss may be due to the infant regulating its hydration and not related to a lack of breast milk.
A group of Canadian researchers looked at relationships among the IV fluids a mother received during labor (or prior to her caesarean section), neonatal output (measured by diaper weight), and newborn weight loss. They found that during the first 24 hours following birth there was a positive association both between the IV fluids given to mothers before birth and neonatal output, and between the neonatal output and newborn weight loss. At 60 hours post birth, the time of the average lowest weight, there was a positive relationship between maternal IV fluids and newborn weight loss.
"Nurses, midwives, lactation consultants, and doctors have long wondered why some babies lose substantially more weight than others even though all babies get small amounts to eat in the beginning," said principal investigator Prof Joy Noel-Weiss from the School of Nursing at the University of Ottawa's Faculty of Health Sciences. "It appears neonates exposed to increased fluids before birth might be born overhydrated, requiring the baby to regulate his or her fluid levels during the first 24 hours after birth."
Prof Noel-Weiss added, "We should reconsider the practice of using birth weight as the baseline when calculating newborn weight loss in the first few days following birth. For mothers and their breastfed babies, accurate assessment of weight loss is important. Although more research is needed, based on our findings, we would recommend using weight measured at 24 hours post birth as a baseline."
Alongside this article, the researchers have provided a standardized method for clinicians to collect and analyze data about newborn weight loss in their own maternity site, in the hope that this protocol will help them to make informed decisions when assessing newborn weight changes.
Monday, August 15, 2011
Stem Cells Central to Pathogenesis of Mature Lymphoid Tumors
New research suggests that blood stem cells can be involved in the generation of leukemia, even when the leukemia is caused by the abnormal proliferation of mature cells. The study, published by Cell Press in the August 16th issue of the journal Cancer Cell, may guide future strategies aimed at identifying therapeutic targets for chronic lymphocytic leukemia (CLL).
CLL is a cancer of a type of mature white blood cell called a B lymphocyte. "Most human CLL cases have a precursor phase, called monoclonal B lymphocytosis (MBL), that is an asymptomatic proliferation of B cells," explains senior study author Dr. Koichi Akashi from Kyushu University Graduate School of Medical Sciences in Japan. "Our question was, if progression from MBL to CLL reflects stepwise proliferation of aberrant cells, at what stage does the first cancer-causing event occur?"
To look for the cell population with cancer-initiating activity in human CLL, Dr. Akashi and colleagues tried to find the specific developmental stage where abnormal clonal B cells first appear. They began at the beginning, with hematopoietic stem cells (HSCs). HSCs are blood stem cells that can give rise to any type of blood cell. The researchers purified HSCs from healthy individuals or HSCs from CLL patients and transplanted them into mice with a deficient immune system. In contrast to the normal HSCs, the CLL HSCs gave rise to B cells similar to those seen in MBL. Interestingly, the CLL HSCs did not have chromosomal abnormalities common to CLL, suggesting that acquisition of chromosomal abnormalities that transform MBL into CLL are secondary events.
Taken together, the findings suggest that HSCs are involved in the pathogenesis of CLL, even though CLL is a malignancy of a mature cell type. "Our data suggest that the propensity to progress to CLL is already acquired at the HSC stage," concludes Dr. Akashi. "Identification of the intrinsic abnormality of HSCs in patients with CLL should be the key to finding the ultimate therapeutic target in human CLL."
CLL is a cancer of a type of mature white blood cell called a B lymphocyte. "Most human CLL cases have a precursor phase, called monoclonal B lymphocytosis (MBL), that is an asymptomatic proliferation of B cells," explains senior study author Dr. Koichi Akashi from Kyushu University Graduate School of Medical Sciences in Japan. "Our question was, if progression from MBL to CLL reflects stepwise proliferation of aberrant cells, at what stage does the first cancer-causing event occur?"
To look for the cell population with cancer-initiating activity in human CLL, Dr. Akashi and colleagues tried to find the specific developmental stage where abnormal clonal B cells first appear. They began at the beginning, with hematopoietic stem cells (HSCs). HSCs are blood stem cells that can give rise to any type of blood cell. The researchers purified HSCs from healthy individuals or HSCs from CLL patients and transplanted them into mice with a deficient immune system. In contrast to the normal HSCs, the CLL HSCs gave rise to B cells similar to those seen in MBL. Interestingly, the CLL HSCs did not have chromosomal abnormalities common to CLL, suggesting that acquisition of chromosomal abnormalities that transform MBL into CLL are secondary events.
Taken together, the findings suggest that HSCs are involved in the pathogenesis of CLL, even though CLL is a malignancy of a mature cell type. "Our data suggest that the propensity to progress to CLL is already acquired at the HSC stage," concludes Dr. Akashi. "Identification of the intrinsic abnormality of HSCs in patients with CLL should be the key to finding the ultimate therapeutic target in human CLL."
Researchers Identify a Signaling Pathway as Possible Target for Cancer Treatment
In a new study published in the August 16th issue of Developmental Cell, researchers at NYU Langone Medical Center identified a molecular mechanism that guarantees that new blood vessels form in the right place and with the proper abundance.
"We have known for a long time that blood vessels branch to give rise to new ones and that in some places of our bodies this branching occurs with a reproducible pattern. However, the mechanisms that ensure that new vessels sprout at specific locations had not been uncovered until now," said Jesús Torres-Vázquez, PhD, assistant professor of Developmental Genetics at the Skirball Institute of Biomolecular Medicine at NYU School of Medicine. "Our study illuminates the genetic basis behind the reproducible pattern of the vasculature and suggests ways in which the formation of new blood vessels could be modulated to treat certain cancers in the future."
Using the zebrafish embryo as a model system, researchers identified that Semaphorin-PlexinD1 signaling limits the formation of new blood vessels. This signaling pathway works by ensuring that blood vessels make the proper levels of soluble Flt1. Soluble Flt1 is an inhibitor of the Vascular Endothelial Growth Factor (VEGF) pathway, which promotes the growth of new blood vessels.
These findings have broad implications for human health, since changes in the level of soluble Flt1 are associated with cancer, vascular birth defects and pregnancy-related hypertension (preeclampsia).
According to researchers, the Semaphorin-PlexinD1 signaling pathway shows significant promise as a future therapeutic target for cancer treatment to slow the progression of diseases by controlling the blood vessel growth.
In addition, a related study by Dr. Torres-Vázquez illuminates how the development of the brain and its vasculature is coordinated providing greater understanding about why defects form in the brain's blood vessels and how the blood vessels of the brain form. These study findings were published in the July 2011 issue of Developmental Biology.
"We have known for a long time that blood vessels branch to give rise to new ones and that in some places of our bodies this branching occurs with a reproducible pattern. However, the mechanisms that ensure that new vessels sprout at specific locations had not been uncovered until now," said Jesús Torres-Vázquez, PhD, assistant professor of Developmental Genetics at the Skirball Institute of Biomolecular Medicine at NYU School of Medicine. "Our study illuminates the genetic basis behind the reproducible pattern of the vasculature and suggests ways in which the formation of new blood vessels could be modulated to treat certain cancers in the future."
Using the zebrafish embryo as a model system, researchers identified that Semaphorin-PlexinD1 signaling limits the formation of new blood vessels. This signaling pathway works by ensuring that blood vessels make the proper levels of soluble Flt1. Soluble Flt1 is an inhibitor of the Vascular Endothelial Growth Factor (VEGF) pathway, which promotes the growth of new blood vessels.
These findings have broad implications for human health, since changes in the level of soluble Flt1 are associated with cancer, vascular birth defects and pregnancy-related hypertension (preeclampsia).
According to researchers, the Semaphorin-PlexinD1 signaling pathway shows significant promise as a future therapeutic target for cancer treatment to slow the progression of diseases by controlling the blood vessel growth.
In addition, a related study by Dr. Torres-Vázquez illuminates how the development of the brain and its vasculature is coordinated providing greater understanding about why defects form in the brain's blood vessels and how the blood vessels of the brain form. These study findings were published in the July 2011 issue of Developmental Biology.
Childhood Eye Tumor Made Up of Hybrid Cells With Jumbled Development
A research team led by St. Jude Children's Research Hospital scientists has identified a potential new target for treatment of the childhood eye tumor retinoblastoma. Their work also settles a scientific debate by showing the cancer's cellular origins are as scrambled as the developmental pathways at work in the tumor.
Unlike other cancers that resemble a particular type of cell, researchers showed that retinoblastoma is a hybrid cell with elements of at least three different cell types. Investigators made the discovery using a variety of techniques to study 52 tumors donated by patients. The tumors were removed from a diverse group of patients, most treated at St. Jude and its international affiliates. The research appears in the August 16 edition of the scientific journal Cancer Cell.
Researchers also demonstrated that multiple, normally incompatible, developmental pathways are turned on simultaneously in retinoblastoma tumor cells. These pathways guide the fate of developing cells and determine what types of cells they become. This study found the tumor takes over at least one pathway to fuel its own growth, making it a promising drug development target.
The research provides additional insight into this rare tumor of the retina and is expected to advance understanding of retinoblastoma as well as aid development of more targeted therapies, said Michael Dyer, Ph.D., a member of the St. Jude Department of Developmental Neurobiology and the study's senior author. Justina McEvoy, Ph.D., and Jacqueline Flores-Otero, Ph.D., are co-first authors of the study and postdoctoral fellows in Dyer's laboratory.
Retinoblastoma is a tumor of the retina, which is the light-sensing membrane at the back of the eye. The tumor is found in about 5,000 individuals worldwide each year, mostly infants and toddlers. Although cure rates exceed 95 percent for patients whose cancer is contained in the eye, the prognosis is bleak if the tumor has spread.
For more than a century, scientists have tried to link the tumor's origins to one of the seven different types of cells that make up the retina. Although researchers have presented evidence to support various candidates, Dyer said the answer has remained elusive. Identifying where the tumor begins would likely speed efforts to develop new chemotherapy drugs. Increasingly, such agents are designed against particular molecular pathways active in cancer cells.
For this study, researchers took a comprehensive, unbiased approach to the search that included molecular, cellular and chemical analyses of tumor cells. Dyer and his colleagues reported that retinoblastoma tumors in both humans and mice include features from several different types of cells in the retina. The list includes cells called amacrine and horizontal interneurons, retinal progenitor cells and photoreceptors.
Investigators also screened individual cells from 192 retinoblastoma tumors to gauge the activity of about 20,000 human genes and nearly 19,000 mouse genes. The tumor cells came from the 52 patient in the study, mouse models of retinoblastoma and human tumors transplanted and growing in the eyes of mice. Scientists were surprised to find evidence in those cells that genes in multiple developmental pathways were functioning, including some pathways not normally expressed simultaneously.
Screening data are now available at no cost for use by other scientists at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE29686, "The finding that normal developmental programs are completely deregulated in this tumor is surprising and unexpected. It could also have therapeutic implications," Dyer said.
Researchers found retinoblastomas in both mice and humans have remarkably similar molecular profiles. Both involved very few genetic changes that distinguished normal cells from malignant cells. That result also sets the tumor apart from other cancers, which typically have a wider variety of genes switched on in tumor cells.
Scientists went on to show that blocking chemicals called monoamine neurotransmitters, which nerve cells normally use for communication, reduced growth in human retinoblastoma cells growing both in the laboratory and the eyes of mice. Dyer said the drugs used in this study, the anti-psychotic agents fluphenazine and chlorpromazine, better known as Thorazine, are unlikely to be used for treatment of retinoblastoma, but offer a starting point for future drug development.
The research also demonstrated that tumors transplanted directly from a patient into the same location in the eye of a mouse retained characteristics of the human tumor. The findings strengthen use of this approach for screening drugs for possible use against human cancers.
Other authors are Jiakun Zhang, Rachel Brennan, Cori Bradley, Fred Krafcik, Richard Smeyne and Amar Pani, all of St. Jude; Katie Nemeth, formerly of St. Jude; Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute, Boston; Matthew Wilson and Dianne Johnson, both of University of Tennessee Health Science Center, Memphis; Shunbin Xiong and Guillermina Lozano, both of MD Anderson Cancer Center, Houston; Julien Sage, Stanford University Medical Center, Stanford, Calif., Ligia Fu, Hospital de Ninos, Tegucigalpa, Honduras; Lotfi Louhibi, Curie Institute, Paris; and Jeff Trimarchi, Iowa State University, Ames, Iowa.
The research was supported in part by the National Institutes of Health, the American Cancer Society, the Research to Prevent Blindness Foundation and ALSAC. Dyer is a Howard Hughes Medical Institute Early Career Scientist.
Unlike other cancers that resemble a particular type of cell, researchers showed that retinoblastoma is a hybrid cell with elements of at least three different cell types. Investigators made the discovery using a variety of techniques to study 52 tumors donated by patients. The tumors were removed from a diverse group of patients, most treated at St. Jude and its international affiliates. The research appears in the August 16 edition of the scientific journal Cancer Cell.
Researchers also demonstrated that multiple, normally incompatible, developmental pathways are turned on simultaneously in retinoblastoma tumor cells. These pathways guide the fate of developing cells and determine what types of cells they become. This study found the tumor takes over at least one pathway to fuel its own growth, making it a promising drug development target.
The research provides additional insight into this rare tumor of the retina and is expected to advance understanding of retinoblastoma as well as aid development of more targeted therapies, said Michael Dyer, Ph.D., a member of the St. Jude Department of Developmental Neurobiology and the study's senior author. Justina McEvoy, Ph.D., and Jacqueline Flores-Otero, Ph.D., are co-first authors of the study and postdoctoral fellows in Dyer's laboratory.
Retinoblastoma is a tumor of the retina, which is the light-sensing membrane at the back of the eye. The tumor is found in about 5,000 individuals worldwide each year, mostly infants and toddlers. Although cure rates exceed 95 percent for patients whose cancer is contained in the eye, the prognosis is bleak if the tumor has spread.
For more than a century, scientists have tried to link the tumor's origins to one of the seven different types of cells that make up the retina. Although researchers have presented evidence to support various candidates, Dyer said the answer has remained elusive. Identifying where the tumor begins would likely speed efforts to develop new chemotherapy drugs. Increasingly, such agents are designed against particular molecular pathways active in cancer cells.
For this study, researchers took a comprehensive, unbiased approach to the search that included molecular, cellular and chemical analyses of tumor cells. Dyer and his colleagues reported that retinoblastoma tumors in both humans and mice include features from several different types of cells in the retina. The list includes cells called amacrine and horizontal interneurons, retinal progenitor cells and photoreceptors.
Investigators also screened individual cells from 192 retinoblastoma tumors to gauge the activity of about 20,000 human genes and nearly 19,000 mouse genes. The tumor cells came from the 52 patient in the study, mouse models of retinoblastoma and human tumors transplanted and growing in the eyes of mice. Scientists were surprised to find evidence in those cells that genes in multiple developmental pathways were functioning, including some pathways not normally expressed simultaneously.
Screening data are now available at no cost for use by other scientists at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE29686, "The finding that normal developmental programs are completely deregulated in this tumor is surprising and unexpected. It could also have therapeutic implications," Dyer said.
Researchers found retinoblastomas in both mice and humans have remarkably similar molecular profiles. Both involved very few genetic changes that distinguished normal cells from malignant cells. That result also sets the tumor apart from other cancers, which typically have a wider variety of genes switched on in tumor cells.
Scientists went on to show that blocking chemicals called monoamine neurotransmitters, which nerve cells normally use for communication, reduced growth in human retinoblastoma cells growing both in the laboratory and the eyes of mice. Dyer said the drugs used in this study, the anti-psychotic agents fluphenazine and chlorpromazine, better known as Thorazine, are unlikely to be used for treatment of retinoblastoma, but offer a starting point for future drug development.
The research also demonstrated that tumors transplanted directly from a patient into the same location in the eye of a mouse retained characteristics of the human tumor. The findings strengthen use of this approach for screening drugs for possible use against human cancers.
Other authors are Jiakun Zhang, Rachel Brennan, Cori Bradley, Fred Krafcik, Richard Smeyne and Amar Pani, all of St. Jude; Katie Nemeth, formerly of St. Jude; Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute, Boston; Matthew Wilson and Dianne Johnson, both of University of Tennessee Health Science Center, Memphis; Shunbin Xiong and Guillermina Lozano, both of MD Anderson Cancer Center, Houston; Julien Sage, Stanford University Medical Center, Stanford, Calif., Ligia Fu, Hospital de Ninos, Tegucigalpa, Honduras; Lotfi Louhibi, Curie Institute, Paris; and Jeff Trimarchi, Iowa State University, Ames, Iowa.
The research was supported in part by the National Institutes of Health, the American Cancer Society, the Research to Prevent Blindness Foundation and ALSAC. Dyer is a Howard Hughes Medical Institute Early Career Scientist.
New Insight Into the Regulation of Stem Cells and Cancer Cells
Scientists at the Gladstone Institutes have gained new insight into the delicate relationship between two proteins that, when out of balance, can prevent the normal development of stem cells in the heart and may also be important in some types of cancer.
The news, being announced in a paper published online in Nature Cell Biology, adds to the understanding of the role of stem cells in embryonic heart development, and how that process could be manipulated to create new heart muscle in the future. This paper also provides another example of how the same signals controlling stem cells in the embryo are those that can cause human cancers, providing new insight into treating this devastating disease.
"These findings reveal an unexpected cross-talk between two important proteins that together regulate the growth of many types of stem cells, including cardiac stem cells," said Deepak Srivastava, MD, senior author and director of Gladstone's cardiovascular research. "More than 35,000 babies are born each year with congenital heart defects, and there are nearly 5 million adults who suffer from heart failure in the United States. We hope that our research can lead to new hope for all those impacted by these diseases."
Further, these findings underscore the value of the "basic" research -- the kind in which Gladstone specializes -- in which scientists focus on improving our fundamental understanding of biology. Basic research is not necessarily targeted at a specific drug target, for example, as "applied" research often is. But basic research does often lead to breakthroughs that can significantly improve human health.
"We weren't at all focused on cancer as we created and carried out our experiments," said Chulan Kwon, PhD, who led the work at Gladstone and is now an assistant professor at Johns Hopkins University School of Medicine. "But it is gratifying that while expanding our basic knowledge of how these two proteins interact, we have increased the chances of being able to offer new solutions for those suffering from colorectal cancer."
In the paper, Dr. Srivastava and his colleagues describe how Notch and Beta-Catenin, the two proteins in question, together contribute to the regulation of cell growth and fetal development. When the protein called Notch interacted with Beta-Catenin, it results in degradation of Beta-catenin, which in turn regulates the growth of both stem cells and cancer cells. Conversely, when Notch and Beta-Catenin didn't interact, stem cells expanded out of control. Disruption of the balance of these two proteins can lead to a malformed heart during embryonic development. And in adults, over-active Beta-Catenin can promote abnormal cell growth in the intestinal wall, opening the door for colon cancer.
Dr. Srivastava, who is also a professor of pediatrics at the University of California-San Francisco (UCSF), said his group has already begun additional research meant to uncover what other proteins impact Notch and Beta-Catenin in the body. Gladstone, which is affiliated with UCSF, is a leading and independent biomedical-research organization that focuses on cardiovascular disease, neurodegenerative disease and viral infections.
"We hope that this research will lead us to new potential therapies for cancer, and towards a better understanding of heart defects in newborns," said Paul Cheng, who co-led the study and is an MD/PhD student at the UCSF School of Medicine and who works at Gladstone.
Other scientists who participated in the research at Gladstone include Isabelle King, Peter Andersen and Vishal Nigam. Funding for the research came from a wide variety of organizations, including the American Heart Association, the National Institutes of Health, the William Younger Family Foundation, and the California Institute for Regenerative Medicine.
The news, being announced in a paper published online in Nature Cell Biology, adds to the understanding of the role of stem cells in embryonic heart development, and how that process could be manipulated to create new heart muscle in the future. This paper also provides another example of how the same signals controlling stem cells in the embryo are those that can cause human cancers, providing new insight into treating this devastating disease.
"These findings reveal an unexpected cross-talk between two important proteins that together regulate the growth of many types of stem cells, including cardiac stem cells," said Deepak Srivastava, MD, senior author and director of Gladstone's cardiovascular research. "More than 35,000 babies are born each year with congenital heart defects, and there are nearly 5 million adults who suffer from heart failure in the United States. We hope that our research can lead to new hope for all those impacted by these diseases."
Further, these findings underscore the value of the "basic" research -- the kind in which Gladstone specializes -- in which scientists focus on improving our fundamental understanding of biology. Basic research is not necessarily targeted at a specific drug target, for example, as "applied" research often is. But basic research does often lead to breakthroughs that can significantly improve human health.
"We weren't at all focused on cancer as we created and carried out our experiments," said Chulan Kwon, PhD, who led the work at Gladstone and is now an assistant professor at Johns Hopkins University School of Medicine. "But it is gratifying that while expanding our basic knowledge of how these two proteins interact, we have increased the chances of being able to offer new solutions for those suffering from colorectal cancer."
In the paper, Dr. Srivastava and his colleagues describe how Notch and Beta-Catenin, the two proteins in question, together contribute to the regulation of cell growth and fetal development. When the protein called Notch interacted with Beta-Catenin, it results in degradation of Beta-catenin, which in turn regulates the growth of both stem cells and cancer cells. Conversely, when Notch and Beta-Catenin didn't interact, stem cells expanded out of control. Disruption of the balance of these two proteins can lead to a malformed heart during embryonic development. And in adults, over-active Beta-Catenin can promote abnormal cell growth in the intestinal wall, opening the door for colon cancer.
Dr. Srivastava, who is also a professor of pediatrics at the University of California-San Francisco (UCSF), said his group has already begun additional research meant to uncover what other proteins impact Notch and Beta-Catenin in the body. Gladstone, which is affiliated with UCSF, is a leading and independent biomedical-research organization that focuses on cardiovascular disease, neurodegenerative disease and viral infections.
"We hope that this research will lead us to new potential therapies for cancer, and towards a better understanding of heart defects in newborns," said Paul Cheng, who co-led the study and is an MD/PhD student at the UCSF School of Medicine and who works at Gladstone.
Other scientists who participated in the research at Gladstone include Isabelle King, Peter Andersen and Vishal Nigam. Funding for the research came from a wide variety of organizations, including the American Heart Association, the National Institutes of Health, the William Younger Family Foundation, and the California Institute for Regenerative Medicine.
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