Protein-DNA Interaction Network Yields Surprising Discovery In Regulation Of Gene Expression
Although homeodomain proteins, which control development and execution of the body’s genetic roadmap, were described 30 years ago, scientists still do not fully understand how these proteins affect gene expression.
In a paper published online in Nature, researchers at the University of California, San Diego School of Medicine reveal that homeodomain transcription factors require interaction with subnuclear structures in order to function properly.
The POU-homeodomain protein Pit1 plays an important role in animal and human life by regulating expression of hormone genes in the pituitary gland. But a common mutation in this protein causes it to lose interaction with two other proteins, Satb1 and β-catenin, and in turn disconnects it from what turns out to be a vital subnuclear structure: the matrin-3 network. This naturally occurring mutation leads to a combined pituitary hormone deficiency.
In collaboration with scientists at the Lawrence Berkeley National Laboratory, California, researchers in the M. Geoffrey Rosenfeld laboratory were able for the first time to establish the functional link between this subnuclear structure and gene activation.
“This information allows us to see in even more detail how genes are activated at the exact time and place in the body,” said Dorota Skowronska-Krawczyk, PhD, an UC San Diego School of Medicine assistant project scientist in the Department of Cellular and Molecular Medicine and first author of the paper. “This helps us understand the process of gene expression. Scientists may use this information to investigate the role of matrin-3 subnuclear network in cancer or other diseases and whether the knowledge of its function could be used to improve existing therapies or design new ones.”

Protein-DNA Interaction Network Yields Surprising Discovery In Regulation Of Gene Expression

Although homeodomain proteins, which control development and execution of the body’s genetic roadmap, were described 30 years ago, scientists still do not fully understand how these proteins affect gene expression.

In a paper published online in Nature, researchers at the University of California, San Diego School of Medicine reveal that homeodomain transcription factors require interaction with subnuclear structures in order to function properly.

The POU-homeodomain protein Pit1 plays an important role in animal and human life by regulating expression of hormone genes in the pituitary gland. But a common mutation in this protein causes it to lose interaction with two other proteins, Satb1 and β-catenin, and in turn disconnects it from what turns out to be a vital subnuclear structure: the matrin-3 network. This naturally occurring mutation leads to a combined pituitary hormone deficiency.

In collaboration with scientists at the Lawrence Berkeley National Laboratory, California, researchers in the M. Geoffrey Rosenfeld laboratory were able for the first time to establish the functional link between this subnuclear structure and gene activation.

“This information allows us to see in even more detail how genes are activated at the exact time and place in the body,” said Dorota Skowronska-Krawczyk, PhD, an UC San Diego School of Medicine assistant project scientist in the Department of Cellular and Molecular Medicine and first author of the paper. “This helps us understand the process of gene expression. Scientists may use this information to investigate the role of matrin-3 subnuclear network in cancer or other diseases and whether the knowledge of its function could be used to improve existing therapies or design new ones.”

Memorable pictures
The hippocampus is a major component of the brains of humans and other vertebrates, playing critical roles in the consolidation of information from short-term memory to long-term memory and in spatial navigation. Damage to the hippocampus, whether from oxygen starvation, diseases such as encephalitis or epilepsy or physical trauma can result in memory loss and disorientation, including anterograde amnesia – the inability to form or retain new memories.
The hippocampus is also among the first regions of the brain to be affected by Alzheimer’s disease.
The hippocampus is a many-layered splendor, as these false-color confocal micrographs of a rat hippocampus by Thomas Deerinck of the National Center for Microscopy and Imaging Research at UC San Diego brilliantly show, layer upon lovely layer of pyramidal neurons, support cells and neuronal fibers.

Memorable pictures

The hippocampus is a major component of the brains of humans and other vertebrates, playing critical roles in the consolidation of information from short-term memory to long-term memory and in spatial navigation. Damage to the hippocampus, whether from oxygen starvation, diseases such as encephalitis or epilepsy or physical trauma can result in memory loss and disorientation, including anterograde amnesia – the inability to form or retain new memories.

The hippocampus is also among the first regions of the brain to be affected by Alzheimer’s disease.

The hippocampus is a many-layered splendor, as these false-color confocal micrographs of a rat hippocampus by Thomas Deerinck of the National Center for Microscopy and Imaging Research at UC San Diego brilliantly show, layer upon lovely layer of pyramidal neurons, support cells and neuronal fibers.

Aspirin, Take TwoWhite blood cell research shows how causing and conquering inflammation are inextricably linked
Hugely popular non-steroidal anti-inflammation drugs like aspirin, naproxen (marketed as Aleve) and ibuprofen (Advil, Motrin) all work by inhibiting or killing an enzyme called cyclooxygenase – a key catalyst in production of hormone-like lipid compounds called prostaglandins that are linked to a variety of ailments, from headaches and arthritis to menstrual cramps and wound sepsis.
In a new paper, published this week in the online early edition of PNAS, researchers at the University of California, San Diego School of Medicine conclude that aspirin has a second effect: Not only does it kill cyclooxygenase, thus preventing production of the prostaglandins that cause inflammation and pain, it also prompts the enzyme to generate another compound that hastens the end of inflammation, returning the affected cells to homeostatic health.
“Aspirin causes the cyclooxygenase to make a small amount of a related product called 15-HETE,” said senior author Edward A. Dennis, PhD, Distinguished Professor of Pharmacology, Chemistry and Biochemistry. “During infection and inflammation, the 15-HETE can be converted by a second enzyme into lipoxin, which is known to help reverse inflammation and cause its resolution – a good thing.”
Specifically, Dennis and colleagues looked at the function of a type of white blood cells called macrophages, a major player in the body’s immune response to injury and infection. They found that macrophages contain the biochemical tools to not just initiate inflammation, a natural part of the immune response, but also to promote recovery from inflammation by releasing 15-HETE and converting it into lipoxin as the inflammation progresses.
Dennis said the findings may open new possibilities for anti-inflammatory therapies by developing new drugs based on analogues of lipoxin and other related molecules that promote resolution of inflammation. “If we can find ways to promote more resolution of inflammation, we can promote health,” he said.  
Image: Scanning electron micrograph of macrophage. Image courtesy of National Cancer Institute.

Aspirin, Take Two
White blood cell research shows how causing and conquering inflammation are inextricably linked

Hugely popular non-steroidal anti-inflammation drugs like aspirin, naproxen (marketed as Aleve) and ibuprofen (Advil, Motrin) all work by inhibiting or killing an enzyme called cyclooxygenase – a key catalyst in production of hormone-like lipid compounds called prostaglandins that are linked to a variety of ailments, from headaches and arthritis to menstrual cramps and wound sepsis.

In a new paper, published this week in the online early edition of PNAS, researchers at the University of California, San Diego School of Medicine conclude that aspirin has a second effect: Not only does it kill cyclooxygenase, thus preventing production of the prostaglandins that cause inflammation and pain, it also prompts the enzyme to generate another compound that hastens the end of inflammation, returning the affected cells to homeostatic health.

“Aspirin causes the cyclooxygenase to make a small amount of a related product called 15-HETE,” said senior author Edward A. Dennis, PhD, Distinguished Professor of Pharmacology, Chemistry and Biochemistry. “During infection and inflammation, the 15-HETE can be converted by a second enzyme into lipoxin, which is known to help reverse inflammation and cause its resolution – a good thing.”

Specifically, Dennis and colleagues looked at the function of a type of white blood cells called macrophages, a major player in the body’s immune response to injury and infection. They found that macrophages contain the biochemical tools to not just initiate inflammation, a natural part of the immune response, but also to promote recovery from inflammation by releasing 15-HETE and converting it into lipoxin as the inflammation progresses.

Dennis said the findings may open new possibilities for anti-inflammatory therapies by developing new drugs based on analogues of lipoxin and other related molecules that promote resolution of inflammation. “If we can find ways to promote more resolution of inflammation, we can promote health,” he said.  

Image: Scanning electron micrograph of macrophage. Image courtesy of National Cancer Institute.

Happiness in SchizophreniaResearch suggests mental illness doesn’t preclude enjoying life
Schizophrenia is among the most severe forms of mental illness, yet some people with the disease are as happy as those in good physical and mental health according to a study led by researchers at the University of California, San Diego School of Medicine.
The study is published online this week in the journal Schizophrenia Research.
“People tend to think that happiness in schizophrenia is an oxymoron,” said senior author Dilip V. Jeste, MD, Distinguished Professor of Psychiatry and Neurosciences.
“Without discounting the suffering this disease inflicts on people, our study shows that happiness is an attainable goal for at least some schizophrenia patients,” said Jeste, who is also the Estelle and Edgar Levi Chair in Aging and director of the Sam and Rose Stein Institute for Research on Aging at UC San Diego. “This means we can help make these individuals’ lives happier.”
In a survey of people with the disease, researchers found that 37 percent of patients reported being happy all or most of the time.
Of clinical significance in terms of helping people with mental illness, the patients’ happiness was unrelated to the severity or duration of their illness, to cognitive or physical function or to socioeconomic factors such as age and education, which among healthy adults have been linked to a greater sense of well-being.
Instead, the study shows that happiness among those with chronic forms of schizophrenia is associated with positive psychological and social attributes such as resilience, optimism and lower perceived stress.
The researchers believe that these positive psychosocial attributes could be taught through behavioral modification and mindfulness training techniques.
The study is based on a survey of 72 English-speaking outpatients with schizophrenia in the San Diego area. At the time of the survey, all but nine of the patients were on at least one anti-psychotic medication and 59 percent were residents in assisted-living facilities.
The comparison group for the study included 64 healthy men and women who were part of an ongoing study on successful aging. These participants were not currently using alcohol or illicit substances and did not have diagnoses of dementia or other neurological problems. Participants ranged in age from 23 to 70 years old; the mean age for both groups was 50 years.
The survey probed respondents’ happiness during the previous week, asking them to rate statements such as “I was happy” and “I enjoyed life” on a scale from “never or rarely” to “all or most of the time.”
Responses suggest that about 37 percent of schizophrenia patients were happy most or all of the time, compared with about 83 percent for those in the comparison group.
Approximately 15 percent of schizophrenia patients reported being never or rarely happy. By contrast, none of in the comparison group reported such a low level of happiness for the week prior.
People’s self-reported happiness was then examined in relation to other factors, such as age, gender, education, living situation, medication status, anxiety levels and other mental health metrics, as well as physical health, cognitive function, and a list of “psychosocial factors” that included perceived stress, attitude toward aging, spirituality, optimism, resilience and personal mastery.
“People with schizophrenia are clearly less happy than those in the general population at large, but this is not surprising,” said lead author Barton W. Palmer, PhD, professor in the UC San Diego Department of Psychiatry. “What is impressive is that almost 40 percent of these patients are reporting happiness and that their happiness is associated with positive psychosocial attributes that can be potentially enhanced.”
Image source: happyologist

Happiness in Schizophrenia
Research suggests mental illness doesn’t preclude enjoying life

Schizophrenia is among the most severe forms of mental illness, yet some people with the disease are as happy as those in good physical and mental health according to a study led by researchers at the University of California, San Diego School of Medicine.

The study is published online this week in the journal Schizophrenia Research.

“People tend to think that happiness in schizophrenia is an oxymoron,” said senior author Dilip V. Jeste, MD, Distinguished Professor of Psychiatry and Neurosciences.

“Without discounting the suffering this disease inflicts on people, our study shows that happiness is an attainable goal for at least some schizophrenia patients,” said Jeste, who is also the Estelle and Edgar Levi Chair in Aging and director of the Sam and Rose Stein Institute for Research on Aging at UC San Diego. “This means we can help make these individuals’ lives happier.”

In a survey of people with the disease, researchers found that 37 percent of patients reported being happy all or most of the time.

Of clinical significance in terms of helping people with mental illness, the patients’ happiness was unrelated to the severity or duration of their illness, to cognitive or physical function or to socioeconomic factors such as age and education, which among healthy adults have been linked to a greater sense of well-being.

Instead, the study shows that happiness among those with chronic forms of schizophrenia is associated with positive psychological and social attributes such as resilience, optimism and lower perceived stress.

The researchers believe that these positive psychosocial attributes could be taught through behavioral modification and mindfulness training techniques.

The study is based on a survey of 72 English-speaking outpatients with schizophrenia in the San Diego area. At the time of the survey, all but nine of the patients were on at least one anti-psychotic medication and 59 percent were residents in assisted-living facilities.

The comparison group for the study included 64 healthy men and women who were part of an ongoing study on successful aging. These participants were not currently using alcohol or illicit substances and did not have diagnoses of dementia or other neurological problems. Participants ranged in age from 23 to 70 years old; the mean age for both groups was 50 years.

The survey probed respondents’ happiness during the previous week, asking them to rate statements such as “I was happy” and “I enjoyed life” on a scale from “never or rarely” to “all or most of the time.”

Responses suggest that about 37 percent of schizophrenia patients were happy most or all of the time, compared with about 83 percent for those in the comparison group.

Approximately 15 percent of schizophrenia patients reported being never or rarely happy. By contrast, none of in the comparison group reported such a low level of happiness for the week prior.

People’s self-reported happiness was then examined in relation to other factors, such as age, gender, education, living situation, medication status, anxiety levels and other mental health metrics, as well as physical health, cognitive function, and a list of “psychosocial factors” that included perceived stress, attitude toward aging, spirituality, optimism, resilience and personal mastery.

“People with schizophrenia are clearly less happy than those in the general population at large, but this is not surprising,” said lead author Barton W. Palmer, PhD, professor in the UC San Diego Department of Psychiatry. “What is impressive is that almost 40 percent of these patients are reporting happiness and that their happiness is associated with positive psychosocial attributes that can be potentially enhanced.”

Image source: happyologist

New Mouse Model Points to Therapy for Liver Disease
Non-alcoholic fatty liver disease (NAFLD) is a common affliction, affecting almost 30 percent of Americans, with a significant number suffering from its most severe form, called non-alcoholic steatohepatitis or NASH, which can lead to cirrhosis and liver cancer. In recent years, NASH has become the leading cause of liver transplantation.
Development of effective new therapies for preventing or treating NASH has been stymied by limited small animal models for the disease. In a paper published online in Cancer Cell, scientists at the University of California, San Diego School of Medicine describe a novel mouse model that closely resembles human NASH and use it to demonstrate that interference with a key inflammatory protein inhibits both the development of NASH and its progression to liver cancer.
“These findings strongly call for clinical testing of relevant drugs in human NASH and its complications,” said senior author Michael Karin, PhD, Distinguished Professor of Pharmacology in UC San Diego’s Laboratory of Gene Regulation and Signal Transduction. “Our research has shown that, at least in this mouse model, chemical compounds that include already clinically approved drugs that inhibit protein aggregation can also be used to prevent NASH caused by a high fat diet.”
The increasing prevalence of NAFLD is linked to the nation’s on-going obesity epidemic. In the past decade, the rate of obesity has doubled in adults and tripled in children, in large part due to a common diet rich in simple carbohydrates and saturated fats. NASH is characterized by inflammation and fibrosis, which damage the liver and can lead to cirrhosis, hepatocellular carcinoma (HCC), the major form of liver cancer, and loss of function. Often, the only remedy is organ transplantation.
“Developing new strategies for NASH that successfully block progression to cirrhosis or HCC required the creation of appropriate small animal models that are amenable to genetic analysis and therapeutic intervention,” said first author Hayato Nakagawa, PhD, a member of Karin’s lab who headed the research effort and is currently an assistant professor at the University of Tokyo School of Medicine. 
The resulting new mouse model takes advantage of an existing mouse strain called MUP-uPA that develops liver damage similar to humans when fed a high-fat diet (in which 60 percent of calories are fat derived) similar to the so-called “American cafeteria diet.” The mice show clinical signs characteristic of NASH within 24 weeks and full-blown HCC after 40 weeks. “The pathological characteristics of these tumors are nearly identical to those of human HCC,” said Nakagawa.
Using the new mouse model, Nakagawa and colleagues showed that a protein called tumor necrosis factor (TNF), involved in the body’s inflammatory response, plays a critical role in both NASH pathogenesis and progression to fibrosis and HCC. By interfering with TNF synthesis or its binding to its receptor, using genetic tools or an anti-psoriasis and rheumatoid arthritis drug called Enbrel, the researchers inhibited both development of NASH and its progression to HCC in the mouse model.
“Given the dramatic and persistent increase in the incidence of obesity and its consequences in the United States and elsewhere, these studies have a high impact on a major public health problem. In addition to developing a more suitable model for the study of NASH, this new work suggests some immediate targets for prevention and therapeutic intervention,” said Karin, who is an American Cancer Society Research Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.
Image source: http://1-in-10.org/nafld-a-silent-killer-associated-with-pcos

New Mouse Model Points to Therapy for Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a common affliction, affecting almost 30 percent of Americans, with a significant number suffering from its most severe form, called non-alcoholic steatohepatitis or NASH, which can lead to cirrhosis and liver cancer. In recent years, NASH has become the leading cause of liver transplantation.

Development of effective new therapies for preventing or treating NASH has been stymied by limited small animal models for the disease. In a paper published online in Cancer Cell, scientists at the University of California, San Diego School of Medicine describe a novel mouse model that closely resembles human NASH and use it to demonstrate that interference with a key inflammatory protein inhibits both the development of NASH and its progression to liver cancer.

“These findings strongly call for clinical testing of relevant drugs in human NASH and its complications,” said senior author Michael Karin, PhD, Distinguished Professor of Pharmacology in UC San Diego’s Laboratory of Gene Regulation and Signal Transduction. “Our research has shown that, at least in this mouse model, chemical compounds that include already clinically approved drugs that inhibit protein aggregation can also be used to prevent NASH caused by a high fat diet.”

The increasing prevalence of NAFLD is linked to the nation’s on-going obesity epidemic. In the past decade, the rate of obesity has doubled in adults and tripled in children, in large part due to a common diet rich in simple carbohydrates and saturated fats. NASH is characterized by inflammation and fibrosis, which damage the liver and can lead to cirrhosis, hepatocellular carcinoma (HCC), the major form of liver cancer, and loss of function. Often, the only remedy is organ transplantation.

“Developing new strategies for NASH that successfully block progression to cirrhosis or HCC required the creation of appropriate small animal models that are amenable to genetic analysis and therapeutic intervention,” said first author Hayato Nakagawa, PhD, a member of Karin’s lab who headed the research effort and is currently an assistant professor at the University of Tokyo School of Medicine. 

The resulting new mouse model takes advantage of an existing mouse strain called MUP-uPA that develops liver damage similar to humans when fed a high-fat diet (in which 60 percent of calories are fat derived) similar to the so-called “American cafeteria diet.” The mice show clinical signs characteristic of NASH within 24 weeks and full-blown HCC after 40 weeks. “The pathological characteristics of these tumors are nearly identical to those of human HCC,” said Nakagawa.

Using the new mouse model, Nakagawa and colleagues showed that a protein called tumor necrosis factor (TNF), involved in the body’s inflammatory response, plays a critical role in both NASH pathogenesis and progression to fibrosis and HCC. By interfering with TNF synthesis or its binding to its receptor, using genetic tools or an anti-psoriasis and rheumatoid arthritis drug called Enbrel, the researchers inhibited both development of NASH and its progression to HCC in the mouse model.

“Given the dramatic and persistent increase in the incidence of obesity and its consequences in the United States and elsewhere, these studies have a high impact on a major public health problem. In addition to developing a more suitable model for the study of NASH, this new work suggests some immediate targets for prevention and therapeutic intervention,” said Karin, who is an American Cancer Society Research Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.

Image source: http://1-in-10.org/nafld-a-silent-killer-associated-with-pcos

New Blood: Tracing the Beginnings of Hematopoietic Stem CellsResearchers uncover earliest clues yet to development of cells that produce all adult blood cells
Hematopoietic stem cells (HSCs) give rise to all other blood cell types, but their development and how their fate is determined has long remained a mystery. In a paper published online this week in Nature, researchers at the University of California, San Diego School of Medicine elaborate upon a crucial signaling pathway and the role of key proteins, which may help clear the way to generate HSCs from human pluripotent precursors, similar to advances with other kinds of tissue stem cells. 
Principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine, and colleagues focused on the Notch signaling pathway, a system found in all animals and known to be critical to the generation of HSCs in vertebrates. “Notch signaling between emitting and receiving cells is key to establishing HSC fate during development,” said Traver. “What has not been known is where, when and how Notch signal transduction is mediated.”
Traver and colleagues discovered that the Notch signal is transduced into HSC precursor cells from signal emitting cells in the somite – embryologic tissues that eventually contribute to development of major body structures, such as skeleton, muscle and connective tissues – much earlier in the process than previously anticipated. 
More specifically, they found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling. When the researchers caused loss of function in JAM proteins in a zebrafish model, Notch signaling and HSCs were also lost. When they enforced Notch signaling through other means, HSC development was rescued.
“To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells,” said Traver. “This has been due in part to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.”
“Our studies demonstrate that Notch signaling is required much earlier than previously thought. In fact, it may be one of the earliest determinants of HSC fate. This finding strongly suggests that in vitro approaches to instruct HSC fate from induced pluripotent stem cells must focus on the Notch pathway at early time-points in the process. Our findings have also shown that JAM proteins serve as a sort of co-receptor for Notch signaling in that they are required to maintain close contact between signal-emitting and signal-receiving cells to permit strong activation of Notch in the precursors of HSCs.” 
The findings may have far-reaching implications for eventual development of hematopoietic stem cell-based therapies for diseases like leukemia and congenital blood disorders. Currently, it is not possible to create HSCs from differentiation of embryonic stem cells or induced pluripotent stem cells – pluripotent cells artificially derived from non-pluripotent cells, such as skin cells – that are being used in other therapeutic research efforts.

New Blood: Tracing the Beginnings of Hematopoietic Stem Cells
Researchers uncover earliest clues yet to development of cells that produce all adult blood cells

Hematopoietic stem cells (HSCs) give rise to all other blood cell types, but their development and how their fate is determined has long remained a mystery. In a paper published online this week in Nature, researchers at the University of California, San Diego School of Medicine elaborate upon a crucial signaling pathway and the role of key proteins, which may help clear the way to generate HSCs from human pluripotent precursors, similar to advances with other kinds of tissue stem cells. 

Principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine, and colleagues focused on the Notch signaling pathway, a system found in all animals and known to be critical to the generation of HSCs in vertebrates. “Notch signaling between emitting and receiving cells is key to establishing HSC fate during development,” said Traver. “What has not been known is where, when and how Notch signal transduction is mediated.”

Traver and colleagues discovered that the Notch signal is transduced into HSC precursor cells from signal emitting cells in the somite – embryologic tissues that eventually contribute to development of major body structures, such as skeleton, muscle and connective tissues – much earlier in the process than previously anticipated. 

More specifically, they found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling. When the researchers caused loss of function in JAM proteins in a zebrafish model, Notch signaling and HSCs were also lost. When they enforced Notch signaling through other means, HSC development was rescued.

“To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells,” said Traver. “This has been due in part to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.”

“Our studies demonstrate that Notch signaling is required much earlier than previously thought. In fact, it may be one of the earliest determinants of HSC fate. This finding strongly suggests that in vitro approaches to instruct HSC fate from induced pluripotent stem cells must focus on the Notch pathway at early time-points in the process. Our findings have also shown that JAM proteins serve as a sort of co-receptor for Notch signaling in that they are required to maintain close contact between signal-emitting and signal-receiving cells to permit strong activation of Notch in the precursors of HSCs.” 

The findings may have far-reaching implications for eventual development of hematopoietic stem cell-based therapies for diseases like leukemia and congenital blood disorders. Currently, it is not possible to create HSCs from differentiation of embryonic stem cells or induced pluripotent stem cells – pluripotent cells artificially derived from non-pluripotent cells, such as skin cells – that are being used in other therapeutic research efforts.

A New Way To Control Tumor Growth
Almost all high-risk, poor-prognosis cancers have high infiltration of macrophages, immune system cells that promote tumor growth and metastasis by secreting growth factors required for tumor progression. 
A new study in Molecular Cancer Research by scientists at the University of California, San Diego School of Medicine shows that an emerging class of anticancer treatments known as PI-3K inhibitors degrade the HIF1 alpha protein as well as block tumor-induced angiogenesis and inhibit pro-angiogenic factors secreted by macrophages. The study may offer a potential therapy for treating deadly hypoxic tumors.
“Our study indicates that PI-3K inhibitors are excellent candidates for the treatment of cancers where macrophages promote tumor progression,” said lead author Shweta Joshi, PhD, postdoctoral researcher. “This is good news because it means that some new cancer therapies may help patients in more ways than was initially realized.”
“These HIF1 proteins are major players in driving the cancer state,” said co-author Donald Durden, MD, PhD, professor and vice chair for research in the Department of Pediatrics and research director, Division of Hematology/Oncology at the UC San Diego Moores Cancer Center.
“Hypoxic regions of tumors are characterized by an increased accumulation of macrophages which contributes to tumor angiogenesis and tumor progression. That is why our observation is so important, because it reveals an entirely new way of controlling tumor growth promoted by macrophages.”
Above image: An electron micrograph of a macrophage.

A New Way To Control Tumor Growth

Almost all high-risk, poor-prognosis cancers have high infiltration of macrophages, immune system cells that promote tumor growth and metastasis by secreting growth factors required for tumor progression. 

A new study in Molecular Cancer Research by scientists at the University of California, San Diego School of Medicine shows that an emerging class of anticancer treatments known as PI-3K inhibitors degrade the HIF1 alpha protein as well as block tumor-induced angiogenesis and inhibit pro-angiogenic factors secreted by macrophages. The study may offer a potential therapy for treating deadly hypoxic tumors.

“Our study indicates that PI-3K inhibitors are excellent candidates for the treatment of cancers where macrophages promote tumor progression,” said lead author Shweta Joshi, PhD, postdoctoral researcher. “This is good news because it means that some new cancer therapies may help patients in more ways than was initially realized.”

“These HIF1 proteins are major players in driving the cancer state,” said co-author Donald Durden, MD, PhD, professor and vice chair for research in the Department of Pediatrics and research director, Division of Hematology/Oncology at the UC San Diego Moores Cancer Center.

“Hypoxic regions of tumors are characterized by an increased accumulation of macrophages which contributes to tumor angiogenesis and tumor progression. That is why our observation is so important, because it reveals an entirely new way of controlling tumor growth promoted by macrophages.”

Above image: An electron micrograph of a macrophage.

Pictured: MRI technology was used to identify and locate a probable tumor (outlined in yellow) during a targeted prostate biopsy for a patient who had previously had multiple negative biopsies but had persistently high PSA levels. Resulting biospy confirmed presence of high-grade cancer.
Prostate Cancer Diagnosis Improves with MRI Technology UC San Diego Health System is the first to use new tool in San Diego
Oncologists at UC San Diego Moores Cancer Center are the first in San Diego to meld magnetic resonance imaging (MRI) technology with a traditional ultrasound prostate exam to create a three-dimensional map of the prostate that allows physicians to view growths that were previously undetectable.
An ultrasound machine provides an imperfect view of the prostate, resulting in an under-diagnosis of cancer, said J. Kellogg Parsons, MD, MHS, the UC San Diego Health System urologic oncologist who, along with Christopher Kane, MD, chair of the Department of Urology and Karim Kader, MD, PhD, urologic oncologist, is pioneering the new technology at Moores Cancer Center.
“With an ultrasound exam, we are typically unable to see the most suspicious areas of the prostate so we end up sampling different parts of the prostate that statistically speaking are more likely to have cancer,” said Parsons, who is also an associate professor in the Department of Urology at UC San Diego School of Medicine. “The MRI is a game-changer. It allows us to target the biopsy needles exactly where we think the cancer is located. It’s more precise.”
Armondo Lopez, a patient at Moores Cancer Center, had been given a clean bill of health using the traditional ultrasound biopsy method, but when his prostate-specific antigen (PSA) levels, a protein that is often elevated in men with prostate cancer, started to rise he began to worry. Parsons recommended a MRI-guided prostate biopsy. The new technology led to the diagnosis of an aggressive prostate cancer located in an area normally not visible using the ultrasound machine alone. The tumor was still in its early stage and treatable, said Parsons.
An early diagnosis typically improves a patient’s prognosis. In the United States, prostate cancer is the second leading cause of cancer death in men with more than 29,000 estimated deaths expected this year. The average age at the time of diagnosis is about 66.
More here

Pictured: MRI technology was used to identify and locate a probable tumor (outlined in yellow) during a targeted prostate biopsy for a patient who had previously had multiple negative biopsies but had persistently high PSA levels. Resulting biospy confirmed presence of high-grade cancer.

Prostate Cancer Diagnosis Improves with MRI Technology
UC San Diego Health System is the first to use new tool in San Diego

Oncologists at UC San Diego Moores Cancer Center are the first in San Diego to meld magnetic resonance imaging (MRI) technology with a traditional ultrasound prostate exam to create a three-dimensional map of the prostate that allows physicians to view growths that were previously undetectable.

An ultrasound machine provides an imperfect view of the prostate, resulting in an under-diagnosis of cancer, said J. Kellogg Parsons, MD, MHS, the UC San Diego Health System urologic oncologist who, along with Christopher Kane, MD, chair of the Department of Urology and Karim Kader, MD, PhD, urologic oncologist, is pioneering the new technology at Moores Cancer Center.

“With an ultrasound exam, we are typically unable to see the most suspicious areas of the prostate so we end up sampling different parts of the prostate that statistically speaking are more likely to have cancer,” said Parsons, who is also an associate professor in the Department of Urology at UC San Diego School of Medicine. “The MRI is a game-changer. It allows us to target the biopsy needles exactly where we think the cancer is located. It’s more precise.”

Armondo Lopez, a patient at Moores Cancer Center, had been given a clean bill of health using the traditional ultrasound biopsy method, but when his prostate-specific antigen (PSA) levels, a protein that is often elevated in men with prostate cancer, started to rise he began to worry. Parsons recommended a MRI-guided prostate biopsy. The new technology led to the diagnosis of an aggressive prostate cancer located in an area normally not visible using the ultrasound machine alone. The tumor was still in its early stage and treatable, said Parsons.

An early diagnosis typically improves a patient’s prognosis. In the United States, prostate cancer is the second leading cause of cancer death in men with more than 29,000 estimated deaths expected this year. The average age at the time of diagnosis is about 66.

More here

Adipose for a picture
Adiposity on a grand scale is a familiar sight. It describes more than one-third of American adults, categorized by the U.S. Centers for Disease Control and Prevention as obese.
Turns out that fat on the microscopic scale isn’t any more attractive, at least not these adipocytes (fat cells) captured in an electron micrograph by Steve Gschmeissner.

Adipose for a picture

Adiposity on a grand scale is a familiar sight. It describes more than one-third of American adults, categorized by the U.S. Centers for Disease Control and Prevention as obese.

Turns out that fat on the microscopic scale isn’t any more attractive, at least not these adipocytes (fat cells) captured in an electron micrograph by Steve Gschmeissner.

Novel Study Maps Infant Brain Growth In First Three Months of Life Using MRI TechnologyResults may be key in identifying and treating earliest signs of neurodevelopmental disordersA recent study conducted by researchers at the University of California, San Diego School of Medicine and the University of Hawaii demonstrates a new approach to measuring early brain development of infants, resulting in more accurate whole brain growth charts and providing the first estimates for growth trajectories of subcortical areas during the first three months after birth. Assessing the size, asymmetry and rate of growth of different brain regions could be key in detecting and treating the earliest signs of neurodevelopmental disorders, such as autism or perinatal brain injury.
The study will be published in JAMA Neurology on August 11.
For the first time, researchers used magnetic resonance imaging (MRI) of the newborn brain to calculate the volume of multiple brain regions and to map out regional growth trajectories during the infant’s first 90 days of life. The study followed the brain growth of full term and premature babies with no neurological or major health issues.
“A better understanding of when and how neurodevelopmental disorders arise in the postnatal period may help assist in therapeutic development, while being able to quantify related changes in structure size would likely facilitate monitoring response to therapeutic intervention. Early intervention during a period of high neuroplasticity could mitigate the severity of the disorders in later years,” said Dominic Holland, PhD, first author of the study and researcher in the Department of Neurosciences at UC San Diego School of Medicine.
For more than two centuries, clinicians have tracked brain growth by measuring the outside of the infant’s head with a measuring tape. The results are then plotted on a percentile chart to indicate if normal growth patterns exist. While the measurement is helpful for observing growth, it does not reveal if the individual structures within the brain are developing normally.
On average, researchers found the newborn brain grows one percent each day immediately following birth but slows to 0.4 percent per day by three months. In general for both sexes, the cerebellum, which is involved in motor control, grew at the highest rate, more than doubling volume in 90 days. The hippocampus grew at the slowest rate, increasing in volume by only 47 percent in 90 days, suggesting that the development of episodic memory is not as important at this stage of life.
“We found that being born a week premature, for example, resulted in a brain four to five percent smaller than expected for a full term baby. The brains of premature babies actually grow faster than those of term-born babies, but that’s because they’re effectively younger – and younger means faster growth,” said Holland.  “At 90 days post-delivery, however, premature brains were still two percent smaller. The brain’s rapid growth rates near birth suggest that inducing early labor, if not clinically warranted, may have a negative effect on the infant’s neurodevelopment.”
The study also found that many asymmetries in the brain are already established in the early postnatal period, including the right hippocampus being larger than the left, which historically, has been suggested to occur in the early adolescent years. Cerebral asymmetry is associated with functions such as dexterity and language abilities.
Next steps involve continuing to make advances in the application of different MRI modalities to examine the newborn brain. MRI provides high quality images of different types of tissue and does not involve radiation, like computed tomography (CT). Future research will investigate how brain structure sizes at birth and subsequent growth rates are altered as a result of alcohol and drug consumption during pregnancy.
“Our findings give us a deeper understanding of the relationship between brain structure and function when both are developing rapidly during the most dynamic postnatal growth phase for the human brain,” said Holland.
Image courtesy of NMMG

Novel Study Maps Infant Brain Growth In First Three Months of Life Using MRI Technology
Results may be key in identifying and treating earliest signs of neurodevelopmental disorders

A recent study conducted by researchers at the University of California, San Diego School of Medicine and the University of Hawaii demonstrates a new approach to measuring early brain development of infants, resulting in more accurate whole brain growth charts and providing the first estimates for growth trajectories of subcortical areas during the first three months after birth. Assessing the size, asymmetry and rate of growth of different brain regions could be key in detecting and treating the earliest signs of neurodevelopmental disorders, such as autism or perinatal brain injury.

The study will be published in JAMA Neurology on August 11.

For the first time, researchers used magnetic resonance imaging (MRI) of the newborn brain to calculate the volume of multiple brain regions and to map out regional growth trajectories during the infant’s first 90 days of life. The study followed the brain growth of full term and premature babies with no neurological or major health issues.

“A better understanding of when and how neurodevelopmental disorders arise in the postnatal period may help assist in therapeutic development, while being able to quantify related changes in structure size would likely facilitate monitoring response to therapeutic intervention. Early intervention during a period of high neuroplasticity could mitigate the severity of the disorders in later years,” said Dominic Holland, PhD, first author of the study and researcher in the Department of Neurosciences at UC San Diego School of Medicine.

For more than two centuries, clinicians have tracked brain growth by measuring the outside of the infant’s head with a measuring tape. The results are then plotted on a percentile chart to indicate if normal growth patterns exist. While the measurement is helpful for observing growth, it does not reveal if the individual structures within the brain are developing normally.

On average, researchers found the newborn brain grows one percent each day immediately following birth but slows to 0.4 percent per day by three months. In general for both sexes, the cerebellum, which is involved in motor control, grew at the highest rate, more than doubling volume in 90 days. The hippocampus grew at the slowest rate, increasing in volume by only 47 percent in 90 days, suggesting that the development of episodic memory is not as important at this stage of life.

“We found that being born a week premature, for example, resulted in a brain four to five percent smaller than expected for a full term baby. The brains of premature babies actually grow faster than those of term-born babies, but that’s because they’re effectively younger – and younger means faster growth,” said Holland.  “At 90 days post-delivery, however, premature brains were still two percent smaller. The brain’s rapid growth rates near birth suggest that inducing early labor, if not clinically warranted, may have a negative effect on the infant’s neurodevelopment.”

The study also found that many asymmetries in the brain are already established in the early postnatal period, including the right hippocampus being larger than the left, which historically, has been suggested to occur in the early adolescent years. Cerebral asymmetry is associated with functions such as dexterity and language abilities.

Next steps involve continuing to make advances in the application of different MRI modalities to examine the newborn brain. MRI provides high quality images of different types of tissue and does not involve radiation, like computed tomography (CT). Future research will investigate how brain structure sizes at birth and subsequent growth rates are altered as a result of alcohol and drug consumption during pregnancy.

“Our findings give us a deeper understanding of the relationship between brain structure and function when both are developing rapidly during the most dynamic postnatal growth phase for the human brain,” said Holland.

Image courtesy of NMMG

About

News from UC San Diego Health Sciences
Media Contacts: 619-543-6163
HealthSciComm@ucsd.edu

Blogroll

  • katiecouric
  • laboratoryequipment
  • amnhnyc
  • medindia
  • infographicjournal
  • austinstatesman
  • yahoonews
  • azspot
  • forbes
  • wayfaringmd
  • neurosciencestuff
  • onaissues
  • nprradiopictures
  • lakeconews
  • npr
  • pozmagazine
  • currentsinbiology
  • newyorker
  • sciencefriday
  • aspiringdoctors
  • oupacademic
  • abcworldnews
  • think-progress
  • libertasacademica
  • scientificillustration
  • usagov
  • theweekmagazine
  • forum-network
  • huffingtonpost
  • thebrainscoop
  • actgnetwork
  • explore-blog
  • awomaninscience
  • fastcompany
  • nbcnightlynews
  • msnbc
  • mothernaturenetwork
  • afro-dominicano
  • prnewswire
  • instagram
  • scienceyoucanlove
  • smithsonianmag
  • todaysdocument
  • wnyc
  • md-admissions
  • longform
  • scinerds
  • post-mitotic
  • nydailynews
  • mathcat345
  • pulitzercenter
  • pubhealth
  • breakingnews
  • cranquis
  • nursingmonkeymomma
  • dodgemedlin
  • doublejack
  • prochoiceamerica
  • comedycentral
  • latimes
  • medicalstate
  • exploratorium
  • nursefocker
  • thisisfusion
  • whitehouse
  • mindblowingscience
  • therumpus
  • scishow
  • guardian
  • missmdisme
  • medresearch
  • kqedscience
  • publicradiointernational
  • shortformblog
  • staff
  • sdzoo
  • photojojo
  • rollingstone
  • theonion
  • thevancouversun
  • natgeofound
  • medicalschool
  • theskygazer
  • timemagazine
  • plannedparenthood
  • jtotheizzoe
  • sesamestreet
  • artandsciencejournal
  • ucsdspecialcollections
  • scipak
  • nprfreshair
  • sdzsafaripark
  • aarp
  • officialssay
  • nbcnews
  • 3rdofmay
  • newshour
  • unicef
  • thisissandiego
  • pbstv
  • americanpublicmedia
  • cancerninja
  • nypl
  • thedailyshow
  • cenwatchglass
  • usatoday
  • buzzfeed
  • csmonitor
  • thescienceblog
  • ucresearch
  • tballardbrown
  • psydoctor8
  • nprontheroad
  • usnews
  • sciencenetlinks
  • yaleuniversity
  • mashablehq
  • madsweat
  • cnbc
  • timelightbox
  • today
  • artneuroscience
  • bbsrc
  • anaofta
  • seltzerlizard
  • scientificthought
  • melon-collies
  • inothernews
  • ucsdcrossculturalcenter
  • boston
  • wnycradiolab
  • wired
  • tmagazine
  • columbusdispatch
  • statedept
  • science-junkie
  • journalofajournalist
  • princeton-medbloro
  • ucsciencetoday
  • wsudiscovery
  • nprglobalhealth
  • newsweek
  • ari-abroad
  • salon
  • shortyawards
  • pbsthisdayinhistory
  • newswatchtv
  • washingtonexaminer
  • molecularlifesciences
  • codeit
  • nysci
  • peacecorps
  • scienceisbeauty
  • doctorswithoutborders
  • ucsdzone
  • scienceandfood
  • blamoscience
  • researchchla
  • ucrhub
  • sciencesoup
  • markcoatney
  • highcountrynews
  • reuters
  • pritheworld
  • jayparkinsonmd
  • robertreich
  • minnpost
  • ottawahealth
  • bbglasses
  • fyeahmedlab
  • science-and-logic
  • queerability
  • blue-lights-and-tea
  • alscientist
  • fuckyeahneuroscience
  • htdeverything
  • houseofmind
  • mediamed
  • psychotherapy
  • phdr
  • mediclopedia
  • topherchris
  • kateoplis
  • soupsoup
  • brookhavenlab
  • ohscience
  • lewisandquark
  • biocanvas
  • artpoweratucsd
  • ucsdcancer
  • denverpost
  • motherjones
  • discoverynews
  • michiganengineering
  • oh4theloveofscience
  • healthcareinfoguide
  • nurse-on-duty
  • skunkbear
  • thenewrepublic
  • wgbhnews
  • theatlantic
  • colchrishadfield
  • fuckyeahcardiovascularsystem
  • fuckyeahnervoussystem
  • stemcellculture
  • sciencenote
  • matthewkeys
  • hospitalreina
  • robotmuesli
  • pneupnurse
  • ziyadnazem
  • medethicslady
  • themedicalchronicles
  • kpcc
  • ohyeahdevelopmentalbiology
  • ucsdcareerservicescenter
  • science
  • pacificstand
  • clearscience
  • bitesizedbiology
  • poptech
  • futureofscience
  • galindoyadira
  • genannetics
  • ucsd
  • ucsdmedialab
  • joshherigon
  • thescienceofreality
  • ladyjournos
  • articulomortis
  • sciencechicks
  • auditoryinsomniac
  • chronicleofhighered
  • vetstail
  • neurolove
  • ajebsary
  • neuroanatomyblog
  • goodideapublichealth
  • tedx
  • huffpostscience
  • thecoloradopursuit
  • brainmtters
  • bobedwardsradio
  • paraphyletic
  • sci-fact
  • nationalpost
  • carlzimmer
  • life
  • dailymedical
  • oceanportal
  • bklynmed
  • wellcomebrains
  • aljazeera
  • reportingonhealth
  • ucsfbioengineering
  • coolhealthinfographics
  • thedailywhat
  • villagevoice
  • nbclatino
  • guardiancomment
  • scientificbritain
  • adschu