Thursday
A new collaboration based at the University of Cambridge will aim to discover and develop new medicines to treat liver disease
The partnership, between the University of Cambridge and global pharmaceutical company GlaxoSmithKline (GSK), will build upon the work of researchers who have identified a molecular mechanism that plays a major role in the life-threatening liver disease that develops in a population of patients with a particular mutant gene.
Alpha-1 antitrypsin (A1AT) deficiency is one of the most common genetic disorders in the UK, affecting approximately one in 2,000 people. The A1AT protein is produced mainly in the liver and circulates to the lungs, where it serves a protective function against enzymes which can break down lung tissue.
In patients with A1AT deficiency, the protein cannot circulate freely and accumulates in the liver, leading to potentially life-threatening liver conditions including neonatal hepatitis, cirrhosis and hepatocellular carcinoma. Additionally, without A1AT circulating to the lungs, lung tissue can break down, predisposing patients to early onset emphysema. Currently, the only available treatments are liver transplantation for cirrhosis and protein replacement therapy for emphysema.
The mechanism that underlies protein accumulation in the livers of individuals with A1AT deficiency has been defined by the team led by Professor David Lomas in the University's Cambridge Institute for Medical Research (CIMR). The collaboration with GSK will combine Professor Lomas' long-term research with GSK's expertise in drug discovery and development in order to develop new therapeutics. Work on the project will be carried out both at GSK and at the CIMR.
Lung density associates with survival in alpha 1 antitrypsin deficient patients.
Abstract
INTRODUCTION:
METHODS:
RESULTS:
CONCLUSION:
KEYWORDS:
- PMID:
- 26874894
- DOI:
- 10.1016/j.rmed.2016.01.007
Monday
Serum biomarkers analyzed by LC-MS/MS as predictors for short outcome of non-small cell lung cancer patients treated with chemoradiotherapy
Abstract
By: Huang W, Ding X, Li B, Fan M, Zhou T, Sun H, Yi Y, Zhang J.
Purpose: To find potential serum biomakers that can predict clinical outcome upon treatment in non-small cell lung cancer (NSCLC) by analyzing differential proteins in serum with different sensitivity of chemoradiotherapy (CRT).Materials and Methods: Sera were collected from 37 NSCLC patients before they were treated with concurrent cisplatin-based CRT. According to the outcome of CRT, the patients were divided into sensitive group and resistant one. The proteins in sera were separated by two-dimensional gel electrophoresis after the high abundance proteins were removed from sera.
The significantly differentially expressed proteins between two groups were analyzed by liquid chromatography and tendem mass spectrometry (LC-MS/MS). Then, an additional 50 serum samples were used for ELISA analysis to validate the identified proteins that we got in the experiment.Results: Proteins in sera of each group were successfully separated on 2D gels. There were significant discrepancies in serum protein expression between NSCLC patients with different CRT sensitivity.
Among eight differently expressed proteins, six proteins were successfully identified with five of which higher expressed and one lower expressed in resistant group. The increased Alpha-1-antitrypsin (α1-AT) level in resistant group comparing to sensitive one were validated by ELISA analysis (p<0 .05=".05">
Conclusions: Proteomic approach may serve as a useful method in detecting the potential biomarkers for predicting the outcome of treatment in NSCLC patients. NSCLC patients with high alpha1-antitrypsin A1AT, α1-AT level in serum before CRT may have a worse treatment outcome.
Neoplasma 2012 Oct 16. doi: 10.4149/neo_2013_002
CT lung densitometry in young adults with alpha-1-antitrypsin deficiency
Background
Severe (PiZZ) and moderate (PiSZ) alpha-1-antitrypsin (AAT) deficiency predispose to lung emphysema, especially in smokers. We hypothesized that multi-slice computed tomography (CT) might be superior to pulmonary function tests (PFT) to detect lung emphysema in AAT-deficient individuals at the age of 32 years.
Methods
A subgroup of PiZZ and PiSZ individuals identified during the Swedish newborn screening programme in 1972–74 underwent multi-slice CT and PFT at the age of 32 years. From the CT scans the percentile density at 15% (PD15) and the relative area below –910 Hounsfield Units (RA−910 HU) were calculated. The results of PFT and CT were compared between the AAT-deficient individuals and an age-matched control group.
Results
Twenty-five PiZZ, 11 PiSZ and 17 PiMM individuals participated in the study. All Pi subgroups had normal lung function. The mean PD15 was 81 (SD 22) g/L in the PiZZ individuals, 96 (SD 35) g/L in the PiSZ individuals and 79 (SD 17) g/L in the PiMM individuals (ns), and the RA-910 were 30 (SD 18)%, 24 (SD 20)%, and 32 (SD 18)%, respectively (ns). For the never-smoker subgroups, in the PiZZ (n = 23), PiSZ (n = 8) and PiMM (n = 12), the mean PD15 were 95 (SD 35) g/L, 81 (SD 22) g/L, and 75 (SD 12) g/L, respectively (ns). PD15 was significantly correlated to CT derived lung size (r = −0.72; p < 0.001).
Conclusions
CT densitometry revealed no signs of emphysema and no differences between the AAT-deficient individuals identified by neonatal screening and age-matched control subjects.
Respiratory Medicine
Volume 105, Issue 1, January 2011, Pages 74-79
Severe (PiZZ) and moderate (PiSZ) alpha-1-antitrypsin (AAT) deficiency predispose to lung emphysema, especially in smokers. We hypothesized that multi-slice computed tomography (CT) might be superior to pulmonary function tests (PFT) to detect lung emphysema in AAT-deficient individuals at the age of 32 years.
Methods
A subgroup of PiZZ and PiSZ individuals identified during the Swedish newborn screening programme in 1972–74 underwent multi-slice CT and PFT at the age of 32 years. From the CT scans the percentile density at 15% (PD15) and the relative area below –910 Hounsfield Units (RA−910 HU) were calculated. The results of PFT and CT were compared between the AAT-deficient individuals and an age-matched control group.
Results
Twenty-five PiZZ, 11 PiSZ and 17 PiMM individuals participated in the study. All Pi subgroups had normal lung function. The mean PD15 was 81 (SD 22) g/L in the PiZZ individuals, 96 (SD 35) g/L in the PiSZ individuals and 79 (SD 17) g/L in the PiMM individuals (ns), and the RA-910 were 30 (SD 18)%, 24 (SD 20)%, and 32 (SD 18)%, respectively (ns). For the never-smoker subgroups, in the PiZZ (n = 23), PiSZ (n = 8) and PiMM (n = 12), the mean PD15 were 95 (SD 35) g/L, 81 (SD 22) g/L, and 75 (SD 12) g/L, respectively (ns). PD15 was significantly correlated to CT derived lung size (r = −0.72; p < 0.001).
Conclusions
CT densitometry revealed no signs of emphysema and no differences between the AAT-deficient individuals identified by neonatal screening and age-matched control subjects.
Respiratory Medicine
Volume 105, Issue 1, January 2011, Pages 74-79
Make-A-Wish grants 5-year-old's dream
By Deneesha Edwards
The Dispatch
Who ever thought wishes did not come true, doesn't know 5-year-old Walker Fritts.
Walker, whose family lives in Reeds, was granted a wish to go to Walt Disney World to see his biggest inspiration — Mickey Mouse.
The Make-A-Wish Foundation announced Wednesday at a private party at Pizza Hut that Walker and his family — his parents, Marshana and Alan Fritts, his older brother Carson, 14, and younger sister Malan, 3 — will get the chance to visit the “happiest place on earth” in Florida.
“It's very overwhelming,” said Walker's mother, Marshana Fritts. “We're very lucky to have Walker and we're very lucky Make-A-Wish Foundation is going to send us on the trip. There's other kids that deserve this too.”
Make-A-Wish starting granting wishes of children with life-threatening medical conditions in 1980. The organization grants the wishes of children to enrich the human experience with hope, strength and joy.
“This is a send-away party,” said Mary Finch, one of the foundation's grant wishers for the area. “Walker wants to see Mickey, so we're making this happen for him. We're just trying to create a happy moment. Everybody here has been instrumental in Walker's life.”
Walker is a special needs boy that was born with a genetic liver disease called Alpha 1-Antitrypsin Deficiency. Walker, who also has Down syndrome, was born five weeks premature,
Fritts said Walker has eaten with a feeding tube for most of his life, however he can eat small food items like pizza and macaroni and cheese.
Fritts said there is no cure for the disease and Walker has been on the waiting list for getting a liver transplant since he was born. She calls him a “Brenner (Children's Hospital, in Winston-Salem) baby” because he's been in and out of the hospital throughout his life.
“It's an emotional roller coaster,” she said. “We have literally stood over his bed thinking this is his last breath. There are great days. The good days are really good. The bad days are really bad. He's happy, we know his life is going to be short.”
The family arrived with his family to the restaurant in a white limousine. Close family friends, church members, teachers and administrators from Reeds Elementary School cheered the family as they arrived to the restaurant. Walker is in the special needs pre-kindergarten program at Reeds.
“There's so many people that have helped with Walker,” Marshana Fritts said. “The Make-A-Wish Foundation does so much. There are so many kids that don't know if they'll be here for Christmas. Make-A-Wish is just a good organization.”
Mickey Mouse balloons and Make-A-Wish Foundation banners were decorated in a banquet room at Pizza Hut. There was pizza, face painting, a cake from Fancy Pastry Shop and, of course, a guest appearance from Mickey.
“We can't do this without people like Pizza Hut, they went above and beyond,” said Karen Dunlap, another wish granter for the area with the foundation. “Thank you to Pizza Hut, Fancy Pastry, At the Ritz Costume and Fantasy Limousine. We don't have a budget. We have to do it with people who are willing to help us.”
Dunlap said being a part of the foundation is a life-changing experience and the foundation is an awesome organization.
“Families go through a lot,” she said. “Just for one day or a week, we try to take all the pain away and make everyone smile and laugh.”
Lynn Conyers, the area general manager for NPC International Pizza Hut, presented the family with another surprise — free pizza for a year.
“We're honored to do this,” he said. “What a great cause and a great deal for the Make-A-Wish Foundation. It's just a honor for us to be able to do this. Walker is such a special kid. The local Pizza Hut manager, Marcia Chatin, and her staff did all the hard work today. It's been a labor of love.”
Walker's mother said her son thinks he gets to go to see Mickey Mouse because he's able to eat without the feeding tube. He has many of Mickey Mouse's toys, clothes and shoes. Marshana Fritts said Walker wasn't able to walk until he was 4, and placing Mickey Mouse stickers on his walker encouraged him.
The family will stay at the “Give Kids the World Village” for a week. They also will have tickets to Disney World, Universal Studios and Sea World. A late breakfast was arranged for Walker to have with Mickey Mouse.
“I'm speechless,” said Judy Wood, Walker's grandmother. “This is more than magical. I can't even describe what it's been like for the family up until this point. This has been a joy for them.”
The Dispatch
Who ever thought wishes did not come true, doesn't know 5-year-old Walker Fritts.
Walker, whose family lives in Reeds, was granted a wish to go to Walt Disney World to see his biggest inspiration — Mickey Mouse.
The Make-A-Wish Foundation announced Wednesday at a private party at Pizza Hut that Walker and his family — his parents, Marshana and Alan Fritts, his older brother Carson, 14, and younger sister Malan, 3 — will get the chance to visit the “happiest place on earth” in Florida.
“It's very overwhelming,” said Walker's mother, Marshana Fritts. “We're very lucky to have Walker and we're very lucky Make-A-Wish Foundation is going to send us on the trip. There's other kids that deserve this too.”
Make-A-Wish starting granting wishes of children with life-threatening medical conditions in 1980. The organization grants the wishes of children to enrich the human experience with hope, strength and joy.
“This is a send-away party,” said Mary Finch, one of the foundation's grant wishers for the area. “Walker wants to see Mickey, so we're making this happen for him. We're just trying to create a happy moment. Everybody here has been instrumental in Walker's life.”
Walker is a special needs boy that was born with a genetic liver disease called Alpha 1-Antitrypsin Deficiency. Walker, who also has Down syndrome, was born five weeks premature,
Fritts said Walker has eaten with a feeding tube for most of his life, however he can eat small food items like pizza and macaroni and cheese.
Fritts said there is no cure for the disease and Walker has been on the waiting list for getting a liver transplant since he was born. She calls him a “Brenner (Children's Hospital, in Winston-Salem) baby” because he's been in and out of the hospital throughout his life.
“It's an emotional roller coaster,” she said. “We have literally stood over his bed thinking this is his last breath. There are great days. The good days are really good. The bad days are really bad. He's happy, we know his life is going to be short.”
The family arrived with his family to the restaurant in a white limousine. Close family friends, church members, teachers and administrators from Reeds Elementary School cheered the family as they arrived to the restaurant. Walker is in the special needs pre-kindergarten program at Reeds.
“There's so many people that have helped with Walker,” Marshana Fritts said. “The Make-A-Wish Foundation does so much. There are so many kids that don't know if they'll be here for Christmas. Make-A-Wish is just a good organization.”
Mickey Mouse balloons and Make-A-Wish Foundation banners were decorated in a banquet room at Pizza Hut. There was pizza, face painting, a cake from Fancy Pastry Shop and, of course, a guest appearance from Mickey.
“We can't do this without people like Pizza Hut, they went above and beyond,” said Karen Dunlap, another wish granter for the area with the foundation. “Thank you to Pizza Hut, Fancy Pastry, At the Ritz Costume and Fantasy Limousine. We don't have a budget. We have to do it with people who are willing to help us.”
Dunlap said being a part of the foundation is a life-changing experience and the foundation is an awesome organization.
“Families go through a lot,” she said. “Just for one day or a week, we try to take all the pain away and make everyone smile and laugh.”
Lynn Conyers, the area general manager for NPC International Pizza Hut, presented the family with another surprise — free pizza for a year.
“We're honored to do this,” he said. “What a great cause and a great deal for the Make-A-Wish Foundation. It's just a honor for us to be able to do this. Walker is such a special kid. The local Pizza Hut manager, Marcia Chatin, and her staff did all the hard work today. It's been a labor of love.”
Walker's mother said her son thinks he gets to go to see Mickey Mouse because he's able to eat without the feeding tube. He has many of Mickey Mouse's toys, clothes and shoes. Marshana Fritts said Walker wasn't able to walk until he was 4, and placing Mickey Mouse stickers on his walker encouraged him.
The family will stay at the “Give Kids the World Village” for a week. They also will have tickets to Disney World, Universal Studios and Sea World. A late breakfast was arranged for Walker to have with Mickey Mouse.
“I'm speechless,” said Judy Wood, Walker's grandmother. “This is more than magical. I can't even describe what it's been like for the family up until this point. This has been a joy for them.”
Wednesday
Alpha-1 Antitrypsin Deficiency Genetic Testing
What Is Alpha-1 Antitrypsin Deficiency?
Alpha-1 antitrypsin (AAT) is a protein normally found in the lungs and the bloodstream. It helps protect the lungs from diseases such as emphysema and chronic obstructive pulmonary disease (COPD). Some people do not make enough of this protein or they make an abnormal type of AAT, either of which can cause AAT deficiency. These people are more likely to have lung diseases and will get them at a younger-than-normal age (30 to 40 years old). Some types of abnormal AAT can also damage the liver. AAT deficiency is a rare disorder and is the only known genetic (inherited) factor that increases your chances for having lung diseases.
Alpha-1 antitrypsin deficiency is caused by a change, or mutation, in the gene that tells the body how to make alpha-1 antitrypsin. There are many kinds of possible changes in this gene, but only a few cause problems. To have this condition, you have to get the changed gene from both parents.
If you receive only one changed gene, you do not have the disease but are a carrier. The good copy of the gene you received from your other parent is enough to tell your body how to properly make alpha-1 antitrypsin. Some people who carry the changed gene may have very mild symptoms of the deficiency.
Treatment for alpha-1 antitrypsin deficiency mainly involves avoiding substances—especially cigarette smoke—that could harm your lungs. Also try to avoid dust and workplace chemicals. You also may want to avoid alcohol because of the risk of liver damage. Exercise can improve your stamina and overall health.
The only treatment available for the lack of the protein is plasma containing alpha-1 antitrypsin. This is usually given only to people who have very low levels of AAT in their blood. It is not clear that this treatment is any better than avoiding smoke and other lung-damaging chemicals. The plasma is made from the blood of many donors and is treated to reduce the chance of spreading an infectious disease. You receive the plasma through an IV, usually every 3 to 4 weeks for life.
What Is AAT Deficiency Testing?
A blood test can measure the amount of alpha-1 antitrypsin (AAT) in your blood. You may have AAT deficiency if your levels are low or if the blood test is not able to find any AAT in your blood. If your AAT level is lower than normal, the blood sample can be tested to look for abnormal types of alpha-1 antitrypsin. People who carry the changed gene may be more at risk for symptoms if they have certain types of alpha-1 antitrypsin.
Alpha-1 antitrypsin (AAT) is a protein normally found in the lungs and the bloodstream. It helps protect the lungs from diseases such as emphysema and chronic obstructive pulmonary disease (COPD). Some people do not make enough of this protein or they make an abnormal type of AAT, either of which can cause AAT deficiency. These people are more likely to have lung diseases and will get them at a younger-than-normal age (30 to 40 years old). Some types of abnormal AAT can also damage the liver. AAT deficiency is a rare disorder and is the only known genetic (inherited) factor that increases your chances for having lung diseases.
Alpha-1 antitrypsin deficiency is caused by a change, or mutation, in the gene that tells the body how to make alpha-1 antitrypsin. There are many kinds of possible changes in this gene, but only a few cause problems. To have this condition, you have to get the changed gene from both parents.
If you receive only one changed gene, you do not have the disease but are a carrier. The good copy of the gene you received from your other parent is enough to tell your body how to properly make alpha-1 antitrypsin. Some people who carry the changed gene may have very mild symptoms of the deficiency.
Treatment for alpha-1 antitrypsin deficiency mainly involves avoiding substances—especially cigarette smoke—that could harm your lungs. Also try to avoid dust and workplace chemicals. You also may want to avoid alcohol because of the risk of liver damage. Exercise can improve your stamina and overall health.
The only treatment available for the lack of the protein is plasma containing alpha-1 antitrypsin. This is usually given only to people who have very low levels of AAT in their blood. It is not clear that this treatment is any better than avoiding smoke and other lung-damaging chemicals. The plasma is made from the blood of many donors and is treated to reduce the chance of spreading an infectious disease. You receive the plasma through an IV, usually every 3 to 4 weeks for life.
What Is AAT Deficiency Testing?
A blood test can measure the amount of alpha-1 antitrypsin (AAT) in your blood. You may have AAT deficiency if your levels are low or if the blood test is not able to find any AAT in your blood. If your AAT level is lower than normal, the blood sample can be tested to look for abnormal types of alpha-1 antitrypsin. People who carry the changed gene may be more at risk for symptoms if they have certain types of alpha-1 antitrypsin.
Thursday
The Role of Liver Sinusoidal Cells in Hepatocyte-Directed Gene Transfer
Frank Jacobs*, Eddie Wisse and Bart De Geest*
From the Center for Molecular and Vascular Biology,* Department of Molecular and Cellular Medicine, University of Leuven, Leuven, Belgium; and EM Unit Pathology Department and Department of Internal Medicine, University of Maastricht, Maastricht, The Netherlands
Hepatocytes are a key target for gene therapy of inborn errors of metabolism as well as of acquired diseases such as liver cancer and hepatitis. Gene transfer efficiency into hepatocytes is significantly determined by histological and functional aspects of liver sinusoidal cells. On the one hand, uptake of vectors by Kupffer cells and liver sinusoidal endothelial cells may limit hepatocyte transduction. On the other hand, the presence of fenestrae in liver sinusoidal endothelial cells provides direct access to the space of Disse and allows vectors to bind to receptors on the microvillous surface of hepatocytes. Nevertheless, the diameter of fenestrae may restrict the passage of vectors according to their size. On the basis of lege artis measurements of the diameter of fenestrae in different species, we show that the diameter of fenestrae affects the distribution of transgene DNA between sinusoidal and parenchymal liver cells after adenoviral transfer.
The small diameter of fenestrae in humans may underlie low efficiency of adenoviral transfer into hepatocytes in men. The disappearance of the unique morphological features of liver sinusoidal endothelial cells in pathological conditions like liver cirrhosis and liver cancer may further affect gene transfer efficiency. Preclinical gene transfer studies should consider species differences in the structure and function of liver sinusoidal cells as important determinants of gene transfer efficiency into hepatocytes.
From the Center for Molecular and Vascular Biology,* Department of Molecular and Cellular Medicine, University of Leuven, Leuven, Belgium; and EM Unit Pathology Department and Department of Internal Medicine, University of Maastricht, Maastricht, The Netherlands
Hepatocytes are a key target for gene therapy of inborn errors of metabolism as well as of acquired diseases such as liver cancer and hepatitis. Gene transfer efficiency into hepatocytes is significantly determined by histological and functional aspects of liver sinusoidal cells. On the one hand, uptake of vectors by Kupffer cells and liver sinusoidal endothelial cells may limit hepatocyte transduction. On the other hand, the presence of fenestrae in liver sinusoidal endothelial cells provides direct access to the space of Disse and allows vectors to bind to receptors on the microvillous surface of hepatocytes. Nevertheless, the diameter of fenestrae may restrict the passage of vectors according to their size. On the basis of lege artis measurements of the diameter of fenestrae in different species, we show that the diameter of fenestrae affects the distribution of transgene DNA between sinusoidal and parenchymal liver cells after adenoviral transfer.
The small diameter of fenestrae in humans may underlie low efficiency of adenoviral transfer into hepatocytes in men. The disappearance of the unique morphological features of liver sinusoidal endothelial cells in pathological conditions like liver cirrhosis and liver cancer may further affect gene transfer efficiency. Preclinical gene transfer studies should consider species differences in the structure and function of liver sinusoidal cells as important determinants of gene transfer efficiency into hepatocytes.
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