In Thursday?s New York Times Andrew Pollack wrote a mostly unobjectionable, informative piece on an innovation in treatment for a variety of cancers. ?The trick he described involves attaching chemotherapeutic agents to antibodies that bind to specific markers on cancer cells ? compounds dubbed antibody-drug conjugates. ?Such therapies aim at more precise targeting of cancer drugs, which researchers, drug companies and patients hope will yield more effective results with fewer side effects.
Pollack lays out the basic technology in the piece nicely, and he frames the science within the usual sorts of anecdotes about patients on some of the drugs under trial?all pretty bog-standard medical reporting.
So why am I pissed off?
This sentence:
By harnessing?antibodies?to deliver toxic payloads to cancer cells, while largely sparing healthy cells, the drugs are a step toward the ?magic bullets? against cancer first envisioned by Paul Ehrlich, a German Nobel laureate, about 100 years ago.
Two thoughts: ?first, the lesser offense, the phrase ?envisioned by Paul Ehrlich, a German Nobel laureate,? is an attempt to assert unearned authority. ?The dreamt-of ?magic bullets? gain a quality of respectability from association with some long-dead smart guy.
That Nobel cover helps set up the second, greater claim, and the more damaging flaw in this piece: the implied outcome for someone actually receiving the hinted-at magic bullet.
Pollack, were he here, might try stop me at this point, noting that he only suggests ?a step toward? the miraculous promise of a bullet to strike cancer down ? and not that cure itself. ?And so he does.
But really, the whole framing of magic bullets ?is the problem. ?Pollack gives evidence of why this is so ? at least by implication ? later in the piece. ?The patient in his lede has breast cancer. ?for breast cancer. ?Much further down the piece we learn that the antibody-drug conjugate treatment she receives?only applies to those?20% of breast cancers that express an excess of a particular protein. ?That speaks to one reason why magic bullets remain so elusive almost half a century into the ?war on cancer:? ?cancer is not a disease. Rather it?s a family of illnesses that share the property of unconstrained cell division ? but respond often very differently to given choices of treatment.
Again, there?s no doubt in my mind that Pollack knows of the real harm to be done by talk of cures for cancer; almost all of the article is sober enough about the gains achieved so far by this approach (real, but not curative) and of the limits the given therapies face.
But even good reporters can fall prey to the easy phrase or the inaccurate shorthand of the beat. ?Sometimes it doesn?t matter. ?No one cares if a football writer uses the phrase ?smash mouth? in every piece about the Steelers-Ravens rivalry.
Cancer is different. ?The hunger for a cure is obviously and understandably overwhelming. But such hopes run straight into the basic science of cancer ? which has undone seemingly imminent magic bullets time after time.
New hope, the prospect of more time, improved quality of life, and ? with good fortune ? increased remission rates. ?Those are all fine as ways to frame the real advances in cancer therapy. ?Present them with all the optimism one may reasonable feel. ?But to imply that we?ve moved meaningfully closer to what amounts to a cure? ?Until and unless that?s really true, it is beyond misleading to suggest that particular advances offer more than they do. ?Very rapidly we?re into the territory of the cruel.
So yeah, even as a throwaway. ?Even with the imprimatur of a Nobel laureate, alive or dead. ?Even with good intentions. This kind of carelessness bugs the living crap out of me.
No snark, no jokes, a dark subject, no fun. ?Nothing new here, either; I?m guessing everyone reading this has a pretty good idea that cancer is a bear of a disease(s).
What can I say? ?This one strikes close to home.
Image: Zacharias Wagner, Crab,?from Thier Buch (Animal Book), 1641.
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THIS MORNING MY HUSBAND STARTED EXHIBITING SIGNS OF NERVOUSNESS, ANXIETY AND FEAR ABOUT THE UPCOMING BIOPSY. I HAVE BEEN ASKING FELLOW SAINTS TO PRAY WE WON?T NEED THE BIOPSY BECAUSE HIS PSA LEVELES WILL GO DOWN. INDICATING NO NEED FOR BIOPSY.? WILL YOU PRAY FOR BOB NOT TO HAVE PROSTATE CANCER AND NOT TO NEED THE BIOPSY?? I KNOW GOD DOES?NT WANT BOB TO SUFFER INSIDE. I AM ALSO ASKING IN PRAYER THAT YOU WILL PRAYER FOR INCREASED FAITH, STRENGTH AND PEACE FOR MY HUSBAND. GREATFULLY, AND BLESSINGS TO YOU.
Almost 8 years ago, a 84 y.o. client of ours (who did not have children or family) taught us the importance of having a "committee".? Her committee was composed of 2 friends that were her own age and 2 friends who were about 20 years younger than she.? She wisely said that it is important to form a committee of lots of varied perspectives, different ages, and people who you trust to help you with important life changing decisions.?At that time she invited?a CareForce RN to participate on her committee as she faced some disability issues.? ?Fast forward to today when I met with a elder law attorney to discuss the value of an attorney who is the legal advocate for his/her client.? We had a thoughtful discussion about legal, financial, medical, safety and emotional issues that families must address during that journey called life, and in particular the years when we are considered "elderly".? Getting advice and assistance from an attorney who is an expert in elder law can help our clients to make thoughtful and informed decisions about planning for long term care and/or estate planning.?Most definitely a qualified elder law attorney can make sure you have all of the facts before making life changing decisions.? ?Then inviting a Geriatric Care Manager, such as CareForce GCM's, to assess your medical, safety, and support needs for your long term care can inform your planning and make that committee of yours able to help you with your decisions.? Make sure you have the right members of your personal long term care committee.
In what could possibly be the best evil queen ever on film, Queen Ravena (Charlize Theron) encapsulates all the things men fear in women -- she?s manipulative, she?s clever, she?s magic, and her beauty is so great, that no man could refuse her request, no matter how corrupt it might be. Ravena was empowered with a malevolent type of dark art that comes with a ghost army and a mirror that keeps tabs on who?s the fairest in the land.
After murdering her King, Ravena throws his young daughter Snow White (Kristen Stewart) into a tower to basically let her rot. The maiden is forgotten about until she reaches a nubile age and the mirror, who takes a human form in molten gold, reveals Snow White is now fairer than she. Watch out!
This is of course unacceptable to the queen, whose power is only as strong as her beauty. The mirror instructs her to eat Snow White?s heart -- literally, chew and swallow, which Ravena has every intention of doing. She orders her non-magical brother to retrieve the young woman, but lionhearted as Snow White is, she manages to escape.
But Snow White doesn?t get too far. If there is a hell, it would be the Dark Forest in this movie. Creepy, eerie, and alive with rot, this isn?t a place a girl who?s been locked in a tower for half her life should be. But Snow White has an iron will and is determined to survive.
Meanwhile, Queen Ravena has employed -- or bribed with a lie -- the hunky Huntsman (Chris Hemsworth), whose specialty is hunting in this wicked forest of doom. He finds Snow White and manages to evade the Queen?s brother and his posse. With the help of eight dwarves (yes eight, but don?t worry, they get down to seven), they make their way to an enchanted forest complete with fairies, magical mushrooms with googly eyes, and a majestic white stag with antlers so broad, they nearly make up their own forest.
Sparing us a dopey love story, Snow White and the Huntsman is at its best with wildly smart action sequences, including the Huntsman teaching Snow White how to fight. This is a good thing, because Snow White must go against the Queen and her dark magic in order to reclaim the Queendom that is rightfully hers.
Bottom line: This Snow White is battle-ready and eager to rule. The darker parts of Queen Ravena?s magic will be too scary for younger children, but your teen daughters will delight in the best on-screen fairy tale I?ve seen this year. Enjoy!
Centegra HealthBridge is helping combat childhood obesity in McHenry County by lowering its fitness center membership age to 12 years old and continuing its Kids in Motion program.
?Illinois has the fourth-highest childhood obesity rate in the country,? said Matt Carlen, vice president of health and wellness with Centegra Health System. ?This new membership aligns with Centegra Health System?s mission to promote wellness in greater McHenry County.?
Statistics show 1 in 5 children in the state struggle with obesity.
Centegra?s fitness centers lowered the membership age from 14 to 12 last month with encouragement from families and physicians concerned about childhood obesity, said Kim Piraino, sales and marketing manager for the Health Bridge fitness center.
The decision was made to promote wellness and physical activity between McHenry County and Kane County youth, she said.
In recent years, a growing body of evidence has linked inflammation to the development of insulin resistance. In insulin resistance, the hormone insulin is less effective in promoting glucose uptake from the bloodstream into other tissues. Obesity is a major factor that contributes to insulin resistance, which can eventually lead to type 2 diabetes. Previous studies have shown that proinflammatory molecules found in fat tissue decreases sensitivity of tissues to insulin.
To identify drug targets that will improve insulin sensitivity, Dr. Olivia Osborn and her colleagues from the University of California in San Diego investigated the role of G protein-coupled receptor 21 (GPR21) in insulin resistance and energy homeostasis. The group compared mice without the gene encoding GPR21 to healthy control mice under normal and high-fat diet conditions. They discovered that mice lacking GPR21 had enhanced insulin sensitivity and increased energy expenditure independent of diet. This result was attributed to the reduced migration of inflammatory cells to the liver and fat tissue in the absence GPR21. Under normal diet, absence of GPR21 in the hypothalamus caused a modest decrease in body weight. This is the first study to demonstrate the negative impact of GPR21 on inflammation and insulin sensitivity. Their findings suggest that GPR21 inhibition may improve insulin resistance and enhance energy expenditure, making GPR21 inhibitors promising treatments for diabetes.
TITLE:
G proteincoupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice
View this article at: http://www.jci.org/articles/view/61953?key=dbc390c7fd2397640830
METABOLISM
Keep metabolism in mind
Metabolic regulation requires activity in the brain that controls glucose balance and food uptake. The hormones insulin, which controls glucose uptake, and leptin, which regulates energy intake and energy expenditure, are critical for mediating energy balance and influence a number of activities in the brain. Dr. Joel Elmquist and colleagues at the University of Texas in Houston wanted to specifically determine which neurons in the brain are required for regulating energy balance. The research team knew that a transcription factor called FOXO1 controlled expression of many genes in response to insulin and leptin signaling. Using genetically modified mice that lack FOXO1 in a specific area of the brain called the ventral medial nucleus of the hypothalamus, they showed that these mice are lean because of increased energy expenditure. Further, these mice had higher sensitivity to insulin in muscle, and were unable to decrease energy expenditure in response to fasting. Their data shows that the action of FOXO1 in the ventral medial nucleus of the hypothalamus is critical for appropriate regulation of energy expenditure and normal glucose balance.
TITLE:
FOXO1 in the ventromedial hypothalamus regulates energy balance
View this article at: http://www.jci.org/articles/view/62848?key=9c93a1c72137e21a5364
ONCOLOGY
The right combination: overcoming drug resistance in cancer
Overactive epidermal growth factor receptor (EGFR) signaling has been linked to the development of cancer. Several drug therapies have been developed to treat these EGFR-associated cancers; however, many patients have developed resistance to these drugs and are therefore no longer responsive to drug treatment. In a recent research article published in the Journal of Clinical Investigation, Goutham Narla and colleagues at Case Western Reserve University sought to better understand the molecular players in the EGFR signaling pathway in hopes of finding new drug targets for EGFR-associated cancers. Using cancerous human lung tissue and a mouse model of EGFR-associated lung cancer, The Narla team discovered that two tumor suppressor genes, KLF6 and FOXO1, function to disrupt overactive EGFR signaling. After treating the cancerous lung tissue and cancer-prone mice with an FDA-approved drug called trifluoperazine hydrochloride (TFP), which increases the activity of FOXO1, they restored the effectiveness of the anti-EGFR drug erlotinib and reduced tumor growth. Their work identified new drug targets for EGFR-associated cancers and suggests that combinatorial drug therapy regimens may improve treatment outcome.
TITLE:
Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response
AUTHOR CONTACT:
Goutham Narla
Case Western Reserve University and University Hospitals, Cleveland, OH, USA
Phone: 3472550885; E-mail: Goutham.Narla@mssm.edu
View this article at: http://www.jci.org/articles/view/62058?key=9eb9f31baf7df0c3365e
NEUROLOGICAL DISEASE
Finding new treatment options in inflammatory brain diseases
A team of scientist, led by Dr. Azeb Tadesse Argaw from the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, have identified a promising avenue for treating inflammatory brain diseases like multiple sclerosis. When the barrier that protects the brain, known as the blood brain barrier (BBB), becomes weak and permeable, it can lead to brain inflammation, edema and neurotoxicity. In a previous study, the group discovered that inflammatory mediators involved in brain lesion development induced angiogenic proteins in the astrocytes. This finding led them to investigate the impact of a protein that stimulates angiogenesis, vascular endothelial growth factor-A (VEGF-A), on brain permeability and inflammation. In this study, the team generated mice that have inactivated VEGF-A proteins in the astrocytes. This mouse model showed reduced BBB breakdown, decreased inflammatory cell infiltration, and increased mobility following administration of a paralytic agent. Next, the group evaluated the efficacy of a few agents in diminishing the negative effects of VEGF-A on the BBB. They discovered that systemic inhibition of endothelial nitric oxide synthase (eNOS) abolished the effects of VEGF-A on BBB breakdown. Additionally, they found that treatment with a selective eNOS inhibitor reduced drug-induced paralysis in mice. These exciting results indicate that blocking VEGF-A is an effective strategy for treating inflammatory brain diseases. Importantly, eNOS inhibitors can be given peripherally to reduce the harmful effects of VEGF-A on the brain.
TITLE:
Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease
View this article at: http://www.jci.org/articles/view/60842?key=f54bc2cb8432c10cbd88
ONCOLOGY
Tumor growth and chemoresistance are promoted by ribosomal associated protein RACK
In cells, ribosomes are responsible for translating genetic information, in the form of messenger RNA, to proteins. Coordinated translation initiation is coupled with cell cycle progression and cell growth, but excessive ribosome synthesis and translation initiation can promote cancer. Hepatocellular carcinoma is among the most common and aggressive cancers worldwide and generally displays inherently high resistance to chemotherapeutic drugs. Dr. Jianxin Gu and colleagues at Fudan University in Shanghai, China found that RACK1, the receptor for activated C-kinase 1, was highly expressed in normal liver and frequently upregulated in hepatocellular carcinoma. Aberrant expression of RACK1 contributed to chemoresistance as well as to tumor growth of hepatocellular carcinoma, effects that depended on ribosome localization of RACK1. The group went on to show that ribosomal RACK1 promoted preferential translation of the potent factors involved in growth and survival. Their results imply that RACK1 may function as an internal factor involved in the growth and survival of hepatocellular carcinoma and suggest that targeting RACK1 may be an efficacious strategy for hepatocellular carcinoma treatment.
TITLE:
Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma
AUTHOR CONTACT:
Jianxin Gu
Gene Research Center, Shanghai Medical College, Fudan University, Shanghai, , CHN
Phone: 8621-54237704; E-mail: jxgu@shmu.edu.cn
View this article at: http://www.jci.org/articles/view/58488?key=b32b824a1904ce6fbd34
Glucocorticoids (GCs) are commonly used to treat autoimmunity, but their normal roles in the immune system are not well known. Noting that GCs are naturally made in the thymus, the site where immune cells called T cells originate, Dr. Jonathan Ashwell and his group at the National Cancer Institute studied the role of GCs in T cell development and activation. They designed a mouse line in which the gene encoding the GC receptor (GR) is deleted in immature T cells. They found that the GR-deficient T cells could not respond appropriately to antigen-induced signaling. T cells generate a diverse repertoire of TCR to respond to foreign antigens in the body. Mittelstadt's group concluded that the defects were due to a shift in the TCR repertoire because they found that GR-deficient T cells responded normally when they forced to express a TCR with a fixed specificity. They demonstrated alterations in the TCR repertoire genetically, reporting a difference in the usage of particular TCR-encoding gene segments between GR-deficient and wild-type cells. The TCR repertoire is selected in the thymus where immature T cells that recognize the body's own proteins are selected against and killed. In the GR-deficient thymus, the numbers of T cells late in the maturation pathway were reduced, suggesting unusually high numbers of T cells were previously eliminated. The group concluded that the GCs in the thymus prevent inappropriate killing of T cells during development, thus providing a sufficient and diverse TCR repertoire.
TITLE:
Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness
View this article at: http://www.jci.org/articles/view/63067?key=24fae67ed3776d86f2e0
NEUROLOGICAL DISEASE
Breathing abnormalities uncovered in mouse model of Leigh Syndrome
Leigh syndrome is a progressive neurodegenerative disorder affecting 1 in 40,000 live births. In up to 75% of cases, patient death is caused by respiratory arrest, but the molecular mechanisms behind breathing abnormalities are unclear.
Mutations in Leigh syndrome patients have been reported to occur in components of the mitochondrial complex I, which plays a vital role in cellular energy production, though how these mutations contribute to the development of disease is unknown. Researchers from the Howard Hughes Medical Institute at University of Washington, led by Dr. Richard Palmiter, have developed a mouse model with the hallmarks of Leigh syndrome, including progressive neurodegeneration, behavioral changes, and respiratory apnea. The researchers found that loss of murine Ndufs4, which encodes NADH dehydrogenase (ubiquinone) iron-sulfur protein 4, resulted in compromised activity of mitochondrial complex 1 and causes a fatal progressive encephalopathy. Using magnetic resonance imaging and immunohistochemistry, the researchers located signs of neuroinflammation in a specialized region of the brain known as the dorsal brainstem vestibular nucleus (VN). Selective inactivation of Ndufs4 in the VN resulted in breathing abnormalities and premature death in mice. Restoration of Ndufs4 using gene therapy in the VN corrected breathing deficits and prolonged the lifespan of knockout mice. This genetic murine model of Leigh syndrome provides new insights into the disease, indicating that compromised mitochondrial function within the VN of the brain contributes to respiration abnormalities.
TITLE:
Fatal breathing dysfunction in a mouse model of Leigh Syndrome
View this article at: http://www.jci.org/articles/view/62923?key=69fce563f91f65906283
###
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
JCI early table of contents for June 1, 2012Public release date: 1-Jun-2012 [ | E-mail | Share ]
Contact: Sarah Jackson press_releases@the-jci.org Journal of Clinical Investigation
In recent years, a growing body of evidence has linked inflammation to the development of insulin resistance. In insulin resistance, the hormone insulin is less effective in promoting glucose uptake from the bloodstream into other tissues. Obesity is a major factor that contributes to insulin resistance, which can eventually lead to type 2 diabetes. Previous studies have shown that proinflammatory molecules found in fat tissue decreases sensitivity of tissues to insulin.
To identify drug targets that will improve insulin sensitivity, Dr. Olivia Osborn and her colleagues from the University of California in San Diego investigated the role of G protein-coupled receptor 21 (GPR21) in insulin resistance and energy homeostasis. The group compared mice without the gene encoding GPR21 to healthy control mice under normal and high-fat diet conditions. They discovered that mice lacking GPR21 had enhanced insulin sensitivity and increased energy expenditure independent of diet. This result was attributed to the reduced migration of inflammatory cells to the liver and fat tissue in the absence GPR21. Under normal diet, absence of GPR21 in the hypothalamus caused a modest decrease in body weight. This is the first study to demonstrate the negative impact of GPR21 on inflammation and insulin sensitivity. Their findings suggest that GPR21 inhibition may improve insulin resistance and enhance energy expenditure, making GPR21 inhibitors promising treatments for diabetes.
TITLE:
G proteincoupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice
View this article at: http://www.jci.org/articles/view/61953?key=dbc390c7fd2397640830
METABOLISM
Keep metabolism in mind
Metabolic regulation requires activity in the brain that controls glucose balance and food uptake. The hormones insulin, which controls glucose uptake, and leptin, which regulates energy intake and energy expenditure, are critical for mediating energy balance and influence a number of activities in the brain. Dr. Joel Elmquist and colleagues at the University of Texas in Houston wanted to specifically determine which neurons in the brain are required for regulating energy balance. The research team knew that a transcription factor called FOXO1 controlled expression of many genes in response to insulin and leptin signaling. Using genetically modified mice that lack FOXO1 in a specific area of the brain called the ventral medial nucleus of the hypothalamus, they showed that these mice are lean because of increased energy expenditure. Further, these mice had higher sensitivity to insulin in muscle, and were unable to decrease energy expenditure in response to fasting. Their data shows that the action of FOXO1 in the ventral medial nucleus of the hypothalamus is critical for appropriate regulation of energy expenditure and normal glucose balance.
TITLE:
FOXO1 in the ventromedial hypothalamus regulates energy balance
View this article at: http://www.jci.org/articles/view/62848?key=9c93a1c72137e21a5364
ONCOLOGY
The right combination: overcoming drug resistance in cancer
Overactive epidermal growth factor receptor (EGFR) signaling has been linked to the development of cancer. Several drug therapies have been developed to treat these EGFR-associated cancers; however, many patients have developed resistance to these drugs and are therefore no longer responsive to drug treatment. In a recent research article published in the Journal of Clinical Investigation, Goutham Narla and colleagues at Case Western Reserve University sought to better understand the molecular players in the EGFR signaling pathway in hopes of finding new drug targets for EGFR-associated cancers. Using cancerous human lung tissue and a mouse model of EGFR-associated lung cancer, The Narla team discovered that two tumor suppressor genes, KLF6 and FOXO1, function to disrupt overactive EGFR signaling. After treating the cancerous lung tissue and cancer-prone mice with an FDA-approved drug called trifluoperazine hydrochloride (TFP), which increases the activity of FOXO1, they restored the effectiveness of the anti-EGFR drug erlotinib and reduced tumor growth. Their work identified new drug targets for EGFR-associated cancers and suggests that combinatorial drug therapy regimens may improve treatment outcome.
TITLE:
Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response
AUTHOR CONTACT:
Goutham Narla
Case Western Reserve University and University Hospitals, Cleveland, OH, USA
Phone: 3472550885; E-mail: Goutham.Narla@mssm.edu
View this article at: http://www.jci.org/articles/view/62058?key=9eb9f31baf7df0c3365e
NEUROLOGICAL DISEASE
Finding new treatment options in inflammatory brain diseases
A team of scientist, led by Dr. Azeb Tadesse Argaw from the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, have identified a promising avenue for treating inflammatory brain diseases like multiple sclerosis. When the barrier that protects the brain, known as the blood brain barrier (BBB), becomes weak and permeable, it can lead to brain inflammation, edema and neurotoxicity. In a previous study, the group discovered that inflammatory mediators involved in brain lesion development induced angiogenic proteins in the astrocytes. This finding led them to investigate the impact of a protein that stimulates angiogenesis, vascular endothelial growth factor-A (VEGF-A), on brain permeability and inflammation. In this study, the team generated mice that have inactivated VEGF-A proteins in the astrocytes. This mouse model showed reduced BBB breakdown, decreased inflammatory cell infiltration, and increased mobility following administration of a paralytic agent. Next, the group evaluated the efficacy of a few agents in diminishing the negative effects of VEGF-A on the BBB. They discovered that systemic inhibition of endothelial nitric oxide synthase (eNOS) abolished the effects of VEGF-A on BBB breakdown. Additionally, they found that treatment with a selective eNOS inhibitor reduced drug-induced paralysis in mice. These exciting results indicate that blocking VEGF-A is an effective strategy for treating inflammatory brain diseases. Importantly, eNOS inhibitors can be given peripherally to reduce the harmful effects of VEGF-A on the brain.
TITLE:
Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease
View this article at: http://www.jci.org/articles/view/60842?key=f54bc2cb8432c10cbd88
ONCOLOGY
Tumor growth and chemoresistance are promoted by ribosomal associated protein RACK
In cells, ribosomes are responsible for translating genetic information, in the form of messenger RNA, to proteins. Coordinated translation initiation is coupled with cell cycle progression and cell growth, but excessive ribosome synthesis and translation initiation can promote cancer. Hepatocellular carcinoma is among the most common and aggressive cancers worldwide and generally displays inherently high resistance to chemotherapeutic drugs. Dr. Jianxin Gu and colleagues at Fudan University in Shanghai, China found that RACK1, the receptor for activated C-kinase 1, was highly expressed in normal liver and frequently upregulated in hepatocellular carcinoma. Aberrant expression of RACK1 contributed to chemoresistance as well as to tumor growth of hepatocellular carcinoma, effects that depended on ribosome localization of RACK1. The group went on to show that ribosomal RACK1 promoted preferential translation of the potent factors involved in growth and survival. Their results imply that RACK1 may function as an internal factor involved in the growth and survival of hepatocellular carcinoma and suggest that targeting RACK1 may be an efficacious strategy for hepatocellular carcinoma treatment.
TITLE:
Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma
AUTHOR CONTACT:
Jianxin Gu
Gene Research Center, Shanghai Medical College, Fudan University, Shanghai, , CHN
Phone: 8621-54237704; E-mail: jxgu@shmu.edu.cn
View this article at: http://www.jci.org/articles/view/58488?key=b32b824a1904ce6fbd34
Glucocorticoids (GCs) are commonly used to treat autoimmunity, but their normal roles in the immune system are not well known. Noting that GCs are naturally made in the thymus, the site where immune cells called T cells originate, Dr. Jonathan Ashwell and his group at the National Cancer Institute studied the role of GCs in T cell development and activation. They designed a mouse line in which the gene encoding the GC receptor (GR) is deleted in immature T cells. They found that the GR-deficient T cells could not respond appropriately to antigen-induced signaling. T cells generate a diverse repertoire of TCR to respond to foreign antigens in the body. Mittelstadt's group concluded that the defects were due to a shift in the TCR repertoire because they found that GR-deficient T cells responded normally when they forced to express a TCR with a fixed specificity. They demonstrated alterations in the TCR repertoire genetically, reporting a difference in the usage of particular TCR-encoding gene segments between GR-deficient and wild-type cells. The TCR repertoire is selected in the thymus where immature T cells that recognize the body's own proteins are selected against and killed. In the GR-deficient thymus, the numbers of T cells late in the maturation pathway were reduced, suggesting unusually high numbers of T cells were previously eliminated. The group concluded that the GCs in the thymus prevent inappropriate killing of T cells during development, thus providing a sufficient and diverse TCR repertoire.
TITLE:
Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness
View this article at: http://www.jci.org/articles/view/63067?key=24fae67ed3776d86f2e0
NEUROLOGICAL DISEASE
Breathing abnormalities uncovered in mouse model of Leigh Syndrome
Leigh syndrome is a progressive neurodegenerative disorder affecting 1 in 40,000 live births. In up to 75% of cases, patient death is caused by respiratory arrest, but the molecular mechanisms behind breathing abnormalities are unclear.
Mutations in Leigh syndrome patients have been reported to occur in components of the mitochondrial complex I, which plays a vital role in cellular energy production, though how these mutations contribute to the development of disease is unknown. Researchers from the Howard Hughes Medical Institute at University of Washington, led by Dr. Richard Palmiter, have developed a mouse model with the hallmarks of Leigh syndrome, including progressive neurodegeneration, behavioral changes, and respiratory apnea. The researchers found that loss of murine Ndufs4, which encodes NADH dehydrogenase (ubiquinone) iron-sulfur protein 4, resulted in compromised activity of mitochondrial complex 1 and causes a fatal progressive encephalopathy. Using magnetic resonance imaging and immunohistochemistry, the researchers located signs of neuroinflammation in a specialized region of the brain known as the dorsal brainstem vestibular nucleus (VN). Selective inactivation of Ndufs4 in the VN resulted in breathing abnormalities and premature death in mice. Restoration of Ndufs4 using gene therapy in the VN corrected breathing deficits and prolonged the lifespan of knockout mice. This genetic murine model of Leigh syndrome provides new insights into the disease, indicating that compromised mitochondrial function within the VN of the brain contributes to respiration abnormalities.
TITLE:
Fatal breathing dysfunction in a mouse model of Leigh Syndrome
View this article at: http://www.jci.org/articles/view/62923?key=69fce563f91f65906283
###
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
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Public release date: 1-Jun-2012
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