Developmental Biology Volume 336, Issue 2, 15 December 2009, Pages 294-300
Abstract
The four members of the albumin gene family encode the serum transport proteins albumin, alpha-fetoprotein, α-albumin, and vitamin D-binding protein. These genes are transcribed primarily in the liver with each having a different pattern of developmental expression. The tight linkage of these genes, particularly that of albumin, alpha-fetoprotein and α-albumin, and their liver-specific expression, has led to the suggestion that these genes share common regulatory elements.
To directly examine whether the α-fetoprotein enhancer region could regulate the albumin gene family, expression of these genes was monitored in mice in which this region was deleted by homologous recombination. Our data indicate that this enhancer region is required for alpha fetoprotein and albumin activation early in liver development and α-fetoprotein reactivation during liver regeneration, but that albumin, α-albumin, and vitamin D-binding protein expression later in hepatic development is not affected by the absence of these enhancers.
We also demonstrate that RNA polymerase II loading on the α-fetoprotein and albumin promoters is reduced in the absence of this enhancer region, indicating a direct role for these enhancers in the assembly of the RNA Polymerase II complex during liver development
Tuesday
The alpha-fetoprotein enhancer region activates the albumin and alpha-fetoprotein promoters during liver development
Friday
Deliberate termination of life of newborns with spina bifida, a critical reappraisal
Objects
Deliberate termination of life of newborns (involuntary euthanasia) with meningomyelocele (MMC) is practiced openly only in the Netherlands. ‘Unbearable and hopeless suffering’ is the single most cited criterion for this termination, together with the notion that ‘there are no other proper medical means to alleviate this suffering’. In this paper, both (and other) statements are questioned, also by putting them in a broader perspective.
Methods
First, a historical overview of the treatment of newborns with MMC is presented, concentrating on the question of selection for treatment. Second, a thorough analysis is made of the criteria used for life termination. Third, a case of a newborn with a very severe MMC is presented as a ‘reference case’.
Conclusion
‘Unbearable and hopeless suffering’ cannot be applied to newborns with MMC. They are not ‘terminally ill’ and do have ‘prospects of a future’. In these end-of-life decisions, ‘quality of life judgments’ should not be applied. When such a newborn is not treated, modern palliative care always will suffice in eliminating possible discomfort. There is no reason whatsoever for active life-termination of these newborns.
Sophia Children’s Hospital, Erasmus Medical Centre, P.O.Box 2060, 3000 CB Rotterdam, The Netherlands
Deliberate termination of life of newborns (involuntary euthanasia) with meningomyelocele (MMC) is practiced openly only in the Netherlands. ‘Unbearable and hopeless suffering’ is the single most cited criterion for this termination, together with the notion that ‘there are no other proper medical means to alleviate this suffering’. In this paper, both (and other) statements are questioned, also by putting them in a broader perspective.
Methods
First, a historical overview of the treatment of newborns with MMC is presented, concentrating on the question of selection for treatment. Second, a thorough analysis is made of the criteria used for life termination. Third, a case of a newborn with a very severe MMC is presented as a ‘reference case’.
Conclusion
‘Unbearable and hopeless suffering’ cannot be applied to newborns with MMC. They are not ‘terminally ill’ and do have ‘prospects of a future’. In these end-of-life decisions, ‘quality of life judgments’ should not be applied. When such a newborn is not treated, modern palliative care always will suffice in eliminating possible discomfort. There is no reason whatsoever for active life-termination of these newborns.
Sophia Children’s Hospital, Erasmus Medical Centre, P.O.Box 2060, 3000 CB Rotterdam, The Netherlands
Thursday
Elevated Serum Levels of IGF- binding protein 2 (IGFBP-2) in patients with non-seminomatous germ cell cancer - Correlation with tumor markers Alpha-Fe
Background/Aims:
Alterations of the IGF-system have been described in different types of cancer. However, no information is available about the role of the IGF-system in patients with non-seminomatous germ cell cancer.
Methods:
Free IGF-I, IGF-II, acid-labile subunit and IGFBP-1 to -4 were analyzed by specific radioimmunoassays in 32 patients with untreated non-seminomatous germ cell cancer and compared to IGFBP-levels of 38 healthy controls. Serum-IGFBPs were analyzed by western ligand- and imuno - blotting. In 16 patients, IGFBP-profiles were measured before, during and after treatment.
Results:
In patients with non-seminomas, IGF-II levels were on average 1.44-fold higher than in the healthy control group (1027±48 vs. 711±30 ng/ml, P<0.0001). IGFBP-2 levels were on average 2.6 - fold higher (586±58 ng/ml vs. 226±17 ng/ml, P<0.001). During follow up, a decrease in IGFBP-2 levels was observed in all successfully treated patients, which correlated closely with the decrease of the tumor markers Alpha Fetoprotein (AFP) and Human Chorionic Gonadotropin (HCG). Additionally, in all patients with recurrent disease, a significant further increase of IGFBP-2-levels (from 358±97 ng/ml to 976±260 ng/ml) was detected. IGFBP-3 levels, as measured by RIA, were not different in patients with testicular cancer compared to controls. However, WLB-analysis demonstrated markedly decreased intact IGFBP-3 bands in untreated patients and a significant increase after successful therapy.
Conclusion:
Our results demonstrate markedly elevated IGF-II and IGFBP-2 serum levels in non-seminoma patients, showing a significant decrease after successful therapy and an increase in recurrent disease. Additionally, indirect evidence points to an increased proteolytic activity for IGFBP-3 in untreated testicular cancer patients.
Alterations of the IGF-system have been described in different types of cancer. However, no information is available about the role of the IGF-system in patients with non-seminomatous germ cell cancer.
Methods:
Free IGF-I, IGF-II, acid-labile subunit and IGFBP-1 to -4 were analyzed by specific radioimmunoassays in 32 patients with untreated non-seminomatous germ cell cancer and compared to IGFBP-levels of 38 healthy controls. Serum-IGFBPs were analyzed by western ligand- and imuno - blotting. In 16 patients, IGFBP-profiles were measured before, during and after treatment.
Results:
In patients with non-seminomas, IGF-II levels were on average 1.44-fold higher than in the healthy control group (1027±48 vs. 711±30 ng/ml, P<0.0001). IGFBP-2 levels were on average 2.6 - fold higher (586±58 ng/ml vs. 226±17 ng/ml, P<0.001). During follow up, a decrease in IGFBP-2 levels was observed in all successfully treated patients, which correlated closely with the decrease of the tumor markers Alpha Fetoprotein (AFP) and Human Chorionic Gonadotropin (HCG). Additionally, in all patients with recurrent disease, a significant further increase of IGFBP-2-levels (from 358±97 ng/ml to 976±260 ng/ml) was detected. IGFBP-3 levels, as measured by RIA, were not different in patients with testicular cancer compared to controls. However, WLB-analysis demonstrated markedly decreased intact IGFBP-3 bands in untreated patients and a significant increase after successful therapy.
Conclusion:
Our results demonstrate markedly elevated IGF-II and IGFBP-2 serum levels in non-seminoma patients, showing a significant decrease after successful therapy and an increase in recurrent disease. Additionally, indirect evidence points to an increased proteolytic activity for IGFBP-3 in untreated testicular cancer patients.
Tuesday
Targeting alpha-fetoprotein represses the proliferation of hepatoma cells via regulation of the cell cycle
Background
alpha fetoprotein (AFP) is a biomarker for primary liver cancer, yet little is known about its effect in the pathogenesis of hepatoma. We examined how AFP modulates the proliferation of hepatoma cells.
Methods
Recombinant adenovirus expressing siRNA against alpha fetoprotein (AFP) was created. The repression of cell proliferation in vitro and growth of hepatoma in vivo were examined by colony formation assay and tumor xenograft in SCID mice, respectively. Cell cycle was assayed by flow cytometry. Expression profile was determined by microarrays.
Results
siRNA targeting reduced expression of alpha fetoprotein (AFP) specifically and markedly inhibited the proliferation of hepatoma cells. Local treatment using Adv-AFPsiRNA caused significant repression of the growth of hepatoma derived HepG2 cells in xenograft in SCID mice. Knockdown of AFP resulted in an obvious delay in the G1/S transition of cell cycle, but did not affect apoptosis in HepG2 cells. Some genes related to the cell cycle, including SKP2, Cyclin D1, Csk and EBAG9 were identified.
Conclusions
The endogenous alpha fetoprotein (AFP) is a critical determinant of the growth of hepatoma cells, which functions by regulating the cell cycle. This study suggests that targeting of AFP with siRNA could be a potential therapeutic approach for hepatoma.
ARTICLE
alpha fetoprotein (AFP) is a biomarker for primary liver cancer, yet little is known about its effect in the pathogenesis of hepatoma. We examined how AFP modulates the proliferation of hepatoma cells.
Methods
Recombinant adenovirus expressing siRNA against alpha fetoprotein (AFP) was created. The repression of cell proliferation in vitro and growth of hepatoma in vivo were examined by colony formation assay and tumor xenograft in SCID mice, respectively. Cell cycle was assayed by flow cytometry. Expression profile was determined by microarrays.
Results
siRNA targeting reduced expression of alpha fetoprotein (AFP) specifically and markedly inhibited the proliferation of hepatoma cells. Local treatment using Adv-AFPsiRNA caused significant repression of the growth of hepatoma derived HepG2 cells in xenograft in SCID mice. Knockdown of AFP resulted in an obvious delay in the G1/S transition of cell cycle, but did not affect apoptosis in HepG2 cells. Some genes related to the cell cycle, including SKP2, Cyclin D1, Csk and EBAG9 were identified.
Conclusions
The endogenous alpha fetoprotein (AFP) is a critical determinant of the growth of hepatoma cells, which functions by regulating the cell cycle. This study suggests that targeting of AFP with siRNA could be a potential therapeutic approach for hepatoma.
ARTICLE
Monday
Serum alpha-fetoprotein (AFP) levels in breastfed infants with prolonged indirect hyperbilirubinemia
Abstract
The aim of this prospective study was to verify normal serum alpha-fetoprotein (AFP) levels in jaundiced breastfed infants with indirect hyperbilirubinemia.
Methods
The study was conducted in clinically jaundiced breastfed infants, 20, or more, days old, referred to our outpatient ambulatory. Inclusion criteria were: birth at term after a physiologic pregnancy, with an Apgar score > 7 at 1 and 5 min, no evidence of congenital anomalies or diseases, direct bilirubin < 1 mg/dl, normal values of alpha-1-antitrypsin, glucose-6-phosphate dehydrogenase, thyroid stimulating hormone, triiodothyronine, tyroxine, and normal growth. 30 non-jaundiced breastfed infants age–weight-matched, were used as control group.
Results
98 jaundiced breastfed infants satisfied inclusion criteria. Their mean serum concentration of AFP was significantly higher than control infants (3548 vs 1095 ng/ml, p < 0.001). Serum AFP levels of jaundiced infants were directly associated with serum indirect bilirubin and γ-glutamyltranspeptidase concentrations.
Conclusions
The most probable explanation of elevated AFP in jaundiced breastfed infants may be the presence in human milk of one or more factors which affect hepatocyte growth and/or function. Based on our finding we demonstrated that in jaundiced breastfed infants normal range of serum AFP levels are higher than previously published data for healthy infants. Our data can be useful for a right interpretation of AFP levels in breastfed infants with prolonged jaundiced and may be used to avoid unnecessary investigations.
Rosa Manganaroa, Lucia Marsegliaa, Carmelo Mamìa, Giuseppe Saittaa, Romana Garganob and Marina Gemellia, ,
ARTICLE
The aim of this prospective study was to verify normal serum alpha-fetoprotein (AFP) levels in jaundiced breastfed infants with indirect hyperbilirubinemia.
Methods
The study was conducted in clinically jaundiced breastfed infants, 20, or more, days old, referred to our outpatient ambulatory. Inclusion criteria were: birth at term after a physiologic pregnancy, with an Apgar score > 7 at 1 and 5 min, no evidence of congenital anomalies or diseases, direct bilirubin < 1 mg/dl, normal values of alpha-1-antitrypsin, glucose-6-phosphate dehydrogenase, thyroid stimulating hormone, triiodothyronine, tyroxine, and normal growth. 30 non-jaundiced breastfed infants age–weight-matched, were used as control group.
Results
98 jaundiced breastfed infants satisfied inclusion criteria. Their mean serum concentration of AFP was significantly higher than control infants (3548 vs 1095 ng/ml, p < 0.001). Serum AFP levels of jaundiced infants were directly associated with serum indirect bilirubin and γ-glutamyltranspeptidase concentrations.
Conclusions
The most probable explanation of elevated AFP in jaundiced breastfed infants may be the presence in human milk of one or more factors which affect hepatocyte growth and/or function. Based on our finding we demonstrated that in jaundiced breastfed infants normal range of serum AFP levels are higher than previously published data for healthy infants. Our data can be useful for a right interpretation of AFP levels in breastfed infants with prolonged jaundiced and may be used to avoid unnecessary investigations.
Rosa Manganaroa, Lucia Marsegliaa, Carmelo Mamìa, Giuseppe Saittaa, Romana Garganob and Marina Gemellia, ,
ARTICLE
Wednesday
ANENCEPHALY - Birth Defect
What is Anencephaly?
Anencephaly is a defect in the closure of the neural tube during fetal development. The neural tube is a narrow channel that folds and closes between the 3rd and 4th weeks of pregnancy to form the brain and spinal cord of the embryo. Anencephaly occurs when the "cephalic" or head end of the neural tube fails to close, resulting in the absence of a major portion of the brain, skull, and scalp. Infants with this disorder are born without a forebrain (the front part of the brain) and a cerebrum (the thinking and coordinating part of the brain). The remaining brain tissue is often exposed--not covered by bone or skin. A baby born with anencephaly is usually blind, deaf, unconscious, and unable to feel pain. Although some individuals with anencephaly may be born with a rudimentary brain stem, the lack of a functioning cerebrum permanently rules out the possibility of ever gaining consciousness. Reflex actions such as breathing and responses to sound or touch may occur.
An alpha-fetoprotein (AFP) blood test checks the level of AFP in a pregnant woman's blood. AFP is a substance made in the liver of a unborn baby (fetus). The amount of AFP in the blood of a pregnant woman can help see whether the baby may have such problems as spina bifida and anencephaly. An AFP test can also be done as part of a screening test to find other chromosomal problems, such as Down syndrome (trisomy 21) or Edward syndrome (trisomy 18). An AFP test can find an omphalocele, a congenital problem in which some of the baby's intestines stick out through the belly wall.
Normally, low levels of AFP can be found in the blood of a pregnant woman. No AFP (or only a very low level) is generally found in the blood of healthy men or healthy, nonpregnant women.
Anencephaly is a defect in the closure of the neural tube during fetal development. The neural tube is a narrow channel that folds and closes between the 3rd and 4th weeks of pregnancy to form the brain and spinal cord of the embryo. Anencephaly occurs when the "cephalic" or head end of the neural tube fails to close, resulting in the absence of a major portion of the brain, skull, and scalp. Infants with this disorder are born without a forebrain (the front part of the brain) and a cerebrum (the thinking and coordinating part of the brain). The remaining brain tissue is often exposed--not covered by bone or skin. A baby born with anencephaly is usually blind, deaf, unconscious, and unable to feel pain. Although some individuals with anencephaly may be born with a rudimentary brain stem, the lack of a functioning cerebrum permanently rules out the possibility of ever gaining consciousness. Reflex actions such as breathing and responses to sound or touch may occur.
An alpha-fetoprotein (AFP) blood test checks the level of AFP in a pregnant woman's blood. AFP is a substance made in the liver of a unborn baby (fetus). The amount of AFP in the blood of a pregnant woman can help see whether the baby may have such problems as spina bifida and anencephaly. An AFP test can also be done as part of a screening test to find other chromosomal problems, such as Down syndrome (trisomy 21) or Edward syndrome (trisomy 18). An AFP test can find an omphalocele, a congenital problem in which some of the baby's intestines stick out through the belly wall.
Normally, low levels of AFP can be found in the blood of a pregnant woman. No AFP (or only a very low level) is generally found in the blood of healthy men or healthy, nonpregnant women.
Monday
Single nucleotide polymorphism in the promoter region of human alpha-fetoprotein (AFP) gene and its significance in hepatocellular carcinoma (HCC)
Variations of serum alpha fetoprotein afp levels in hepatocellular carcinoma patients and cell lines are likely due to the differential activity of enhancer/silencer elements that control AFP. To understand the potential mechanism underlying the differential expression of AFP, we have examined the sequence of the AFP promoter in HCC.
Results
Three novel SNPs in the promoter region of the AFP gene , which have not been previously reported, were found at positions −330, −401 and −692. The level of serum alpha fetoprotein was significantly higher in HCC patients with the CT genotype of 330 SNP or the AG genotype of the 401 SNP. The genotype of CG in 692 SNP was also associated with a significant elevated level of serum alpha fetoprotein , and further this genotype appeared to be associated with the high risk of HCC development. 401 SNP and 692 SNP were located at the positions of known binding sites for transcription factors that have a role in the production of alpha fetoprotein and the growth of tumors .
Conclusions
The novel polymorphisms identified in the promoter region of the AFP gene may be pathologically significant in HCC.
Department of Surgery, The Chinese University of Hong Kong , Prince of Wales Hospital, Shatin, New Territories, Hong Kong
Results
Three novel SNPs in the promoter region of the AFP gene , which have not been previously reported, were found at positions −330, −401 and −692. The level of serum alpha fetoprotein was significantly higher in HCC patients with the CT genotype of 330 SNP or the AG genotype of the 401 SNP. The genotype of CG in 692 SNP was also associated with a significant elevated level of serum alpha fetoprotein , and further this genotype appeared to be associated with the high risk of HCC development. 401 SNP and 692 SNP were located at the positions of known binding sites for transcription factors that have a role in the production of alpha fetoprotein and the growth of tumors .
Conclusions
The novel polymorphisms identified in the promoter region of the AFP gene may be pathologically significant in HCC.
Department of Surgery, The Chinese University of Hong Kong , Prince of Wales Hospital, Shatin, New Territories, Hong Kong
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