Marlena Fejzo - Academia.edu (original) (raw)
Papers by Marlena Fejzo
Authorea (Authorea), Nov 30, 2022
Thank you for your letter 1 highlighting our study that implicates GDF15 and does not support a d... more Thank you for your letter 1 highlighting our study that implicates GDF15 and does not support a direct causal role for hCG in Hyperemesis Gravidarum (HG). 2 Both GDF15 and hCG are expressed in blastocysts and increase in the 1 st trimester, 2 so any association between the two hormones in early pregnancy is not surprising and does not imply one controls expression of the other. While it is possible hCG plays a secondary role contributing to GDF15 levels, it is unlikely to be important for HG for the following reasons:
Genomics, Aug 1, 1996
The chicken extracellular matrix glycoprotein ES/130 is necessary for epithelial—mesenchymal tran... more The chicken extracellular matrix glycoprotein ES/130 is necessary for epithelial—mesenchymal transformation in the developing heart and is also expressed in noncardiac chicken tissues such as limb and notochord. We have identified hES, the human homolog of chicken ES/130. Fluorescencein situhybridization analysis (FISH) localizes hES to human chromosome 20p11.2–p12. FISH analyses of individuals with 20p12 deletions and affected by Alagille syndrome
Molecular Microbiology, Jun 1, 1994
SummaryThe unusual longevity of the Escherichia coli ompA transcript is determined by its 5′untra... more SummaryThe unusual longevity of the Escherichia coli ompA transcript is determined by its 5′untranslated region (UTR), which functions In vivo as an mRNA stabilizer. Here we show that this 5′UTR can prolong the lifetime in E. coli of a variety of heterologous mRNAs to which it is Joined, either as a gene fusion or as an operon fusion. Statistical extrapolation suggests that it is quite likely that most E. coli mRNAs could be stabilized in this manner. We conclude that the ompA 5′ UTR impedes a major pathway for mRNA degradation in E. coli and that stabilization by fusion to this UTR does not require translational readthrough of the heterologous mRNA segment by ribosomes that initiate translation at the ompA ribosome‐binding site. Additional experiments indicate that the E. coli ribonuclease whose action is slowed by the ompA 5′ UTR is not RNase III.
American Journal of Obstetrics and Gynecology, 2023
Reproductive Toxicology, Jul 1, 2016
This is an analysis of fetal outcome in pregnancies exposed to ondansetron to treat Hyperemesis G... more This is an analysis of fetal outcome in pregnancies exposed to ondansetron to treat Hyperemesis Gravidarum (HG). In this retrospective cohort study, U.S. data on outcome were collected on 1070 pregnancies exposed to ondansetron and compared to outcomes in two control groups: 771 pregnancies in women with a history of HG with no ondansetron exposure and 1555 pregnancies with neither a history of HG nor ondansetron exposure. Ventricular septal defects were reported in 2/952 of infants in the HG/Ondansetron-exposure group and 4/1286 in the No HG/No Ondansetron-exposure group. Cleft palate was reported in 1/952 live births in the HG/Ondansetron and 2/1286 in the No HG/No Ondansetronexposure groups. Women with a history of HG who took ondansetron reported less miscarriages and terminations, and higher live birth rates. The overall results do not support evidence of teratogenicity of ondansetron.
Breast cancer progression is driven by altered gene expression. We show that the RIN1 gene, which... more Breast cancer progression is driven by altered gene expression. We show that the RIN1 gene, which encodes a RAS effector regulating epithelial cell properties, is silenced in breast tumor cell lines compared with cultured human mammary epithelial cells. We also report that RIN1 is often reduced in human breast tumor cells compared with morphologically normal breast glandular cells. At least two silencing mechanisms seem to be involved. Overexpression of the transcription repressor SNAI1 (Snail) was observed in ZR75-1 cells, and SNAI1 knockdown restored RIN1 expression. In addition, DNA methylation within the RIN1 promoter and the first exon in KPL-1 cells suggested that epigenetic modifications may contribute to silencing, and demethylation was shown to restore RIN1 expression. Reexpression of RIN1 was shown to inhibit anchorage-independent growth in soft agar. In addition, RIN1 expression inhibited both the initiation and progression of tumorigenesis for two breast tumor cell lines in a mouse model, consistent with a tumor suppressor function. We also show that RIN1 acts as a negative regulator of tumor cell invasive growth and that this requires the ABL kinase–signaling function of RIN1, suggesting a mechanism through which RIN1 silencing may contribute to breast cancer progression. [Cancer Res 2007;67(24):11510–6]
Bjog: An International Journal Of Obstetrics And Gynaecology, Mar 16, 2022
ObjectiveA genome‐wide association study (GWAS) linked the placenta and appetite hormone gene GDF... more ObjectiveA genome‐wide association study (GWAS) linked the placenta and appetite hormone gene GDF15 to hyperemesis gravidarum (HG). This paradigm‐changing finding has shifted the field away from the prevailing hypotheses, but more evidence is needed. This study was performed to identify coding variants in addition to the non‐coding variants implicated by GWAS.SettingCase–control research study performed in a university setting.DesignCase–control study.PopulationHyperemesis gravidarum cases requiring intravenous fluid treatment for disease (n = 926) and controls with normal or no nausea and vomiting of pregnancy (n = 660), from the USA.MethodsWhole exome‐wide sequencing and genome informatics were performed using the standard Regeneron pipeline. All variants were compared between cases and controls using dominant, recessive, and allelic models to identify variants with exome‐wide significant p values (p < 10−6). Odds ratios and associated p values were calculated for exome‐wide significant allele(s) in subgroups of genetically predicted ancestries. Variants were filtered to identify rare pathogenic variants occurring in ≥10 cases and in no controls.Main outcome measuresIdentification of exome‐wide significant and rare genetic variant(s) associated with HG.ResultsA common coding variant in GDF15 was the only exome‐wide significant association, and a rare coding variant in GDF15 was the only predicted disease‐causing variant occurring in 10 or more cases.ConclusionsThis study confirms the GWAS finding that GDF15 is the greatest genetic risk factor for HG. The new variants identified may have implications for prediction and diagnosis. The findings provide insight into the cause, and molecular mechanisms for developing therapeutics for HG.Tweetable abstractWhole‐exome sequencing reveals placenta and vomiting hormone GDF15 most likely cause of Hyperemesis Gravidarum.
Reproductive Toxicology, 2018
This is a letter in response to the article "Publishing negative findings and the challenge of av... more This is a letter in response to the article "Publishing negative findings and the challenge of avoiding type II errors in studies of suspect teratogens: Example of a recent ondansetron publication" by Stanley Edlavitch (Reproductive Toxicology 67: 125-128). In his article, Edlavitch concludes that our study had "major issues of study design and data accuracy may be the reason that no relationship was discovered." For someone criticizing our manuscript's "accuracy," it might be a good start to actually reference the lead author's name correctly in any of the 9 times it was referenced throughout his manuscript-it's Fejzo, not Fazio. Edlavitch concludes that our manuscript had "major design flaws" and states that the manuscripts with different findings, "the studies which found increased risk (Anderka et al., 2012 and Danielsson et al., 2014) appear to be designed and analyzed carefully." In fact, Edlavitch has made completely inaccurate and misleading comments with respect to our manuscript in comparison to the studies he finds to be "designed and analyzed carefully," and I will go through one by one now and explain why his manuscript is inaccurate, biased, and frankly dishonest.
![Research paper thumbnail of Genetic Approaches Reveal a Non-Hormonal Etiology for Hyperemesis Gravidarum [7L]](https://attachments.academia-assets.com/107931538/thumbnails/1.jpg)
](Obstetrics & Gynecology, May 1, 2017
Gynecologic Oncology, Feb 1, 2021
Positive associations between alpine cushion plants and other species have been extensively studi... more Positive associations between alpine cushion plants and other species have been extensively studied. However, almost all studies have focused on the associations between macrofauna. Studies that have investigated positive associations between alpine cushion plants and rhizospheric microbes have been limited to the vegetation growing season. Here, we asked whether the positive effects that alpine cushion plants confer on rhizospheric microbe communities vary with seasons. We assessed seasonal variations in the bacterial diversity and composition in rhizosphere of two alpine cushion plants and surrounding bare ground by employing a high throughput sequencing method targeting the V3 region of bacterial 16S rRNA genes. Soil properties of the rhizosphere and the bare ground were also examined. We found that cushion rhizospheres harbored significantly more C, N, S, ammonia nitrogen, and soil moisture than the bare ground. Soil properties in cushion rhizospheres were not notably different, except for soil pH. Bacterial diversities within the same microhabitats did not vary significantly with seasons. We concluded that alpine cushion plants had positive effects on the rhizospheric bacterial communities, even though the strength of the effect varied in different cushion species. Cushion species and the soil sulfur content were probably the major factors driving the spatial distribution and structure of soil bacterial communities in the alpine communities dominated by cushion plants.
AJOG global reports, Feb 1, 2023
American Journal of Obstetrics and Gynecology, Nov 1, 2022
![Research paper thumbnail of Nausea and Vomiting of Pregnancy and HG Risk Genes Associated With Blood Levels, Sleep, Stomach Pain, and Other Traits [23N]](https://attachments.academia-assets.com/107931525/thumbnails/1.jpg)
](Obstetrics & Gynecology, May 1, 2020
The American College of Obstetrics and Gynecology recommends routine oral health care during preg... more The American College of Obstetrics and Gynecology recommends routine oral health care during pregnancy. Despite this recommendation, many pregnant women do not receive routine dental care. The reasons for discordance are complex. This study, conducted in conjunction with the ACOG District XII Committee on Healthcare of Underserved Women, surveyed ACOG District XII Fellows regarding their perceptions of factors that impact oral health care in pregnancy. METHODS: Between May and October 2019, ACOG District XII Fellows were asked to participate in an anonymous electronic survey on their practices regarding oral health in pregnancy. IRB approval was obtained. Descriptive statistics were estimated using SPSS (V25).
Gynecology & obstetrics case reports, 2016
Prompt testing and treatment followed by frequent followup with the patient until symptoms subsid... more Prompt testing and treatment followed by frequent followup with the patient until symptoms subside may help to prevent Hyperemesis Gravidarum related deaths in the future.
Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-... more Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternalGDF15gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant inGDF15which strongly predisposes mothers to HG, particularly when the fetus is wild-type, wa...
Genomics, Mar 1, 1995
Uterine leiomyomata are the most common tumors in women and can cause abnormal uterine bleeding, ... more Uterine leiomyomata are the most common tumors in women and can cause abnormal uterine bleeding, pelvic pain, and infertility. Approximately 200,000 hysterectomies are performed annually in the U.S. to relieve patients of the medical sequelae of these benign neoplasms. Our efforts have focused on cloning the t(12;14)(q14-q15;q23-q24) breakpoint in uterine leiomyoma to further our understanding of the biology of these tumors. Thirty-nine YACs and six cosmids mapping to 12q14-q15 have been mapped by fluorescence in situ hybridization to tumor metaphase chromosomes containing a t(12;14). One YAC spanned the translocation breakpoint and was mapped to tumor metaphases from a pulmonary chondroid hamartoma containing a t(12;14)(q14-q15;q23-q24) and a lipoma containing a t(12;15)(q15;q24); this YAC also spanned the breakpoint in these two tumors, suggesting that the same gene on chromosome 12 may be involved in the pathobiology of these distinct benign neoplasms.
Elsevier Masson, Dec 29, 2011
Methods in Molecular Biology, 2010
Tissue microarray technology is a new method used to analyze 100s to 1,000s of tumor samples on a... more Tissue microarray technology is a new method used to analyze 100s to 1,000s of tumor samples on a single slide allowing high throughput analysis of genes and proteins on a large cohort. The original methodology involves coring tissues from paraffin-embedded tissue donor blocks and placing them into a single paraffin block. One difficulty with paraffin-embedded tissue relates to antigenic changes in proteins and mRNA degradation induced by the fixation and embedding process. We modified this technology by using frozen tissues embedded in OCT compound as donor samples and arraying the specimens into a recipient OCT block. Tumor tissue is not fixed before embedding, and sections from the array are evaluated without fixation or postfixed according to the appropriate methodology used to analyze a specific gene at the DNA, RNA, and/or protein levels. While paraffin tissue arrays can be problematic for immunohistochemistry and for RNA in situ hybridization analyses, this method allows optimal evaluation by each technique and uniform fixation across the array panel. Frozen tissue microarrays work well for DNA, RNA, and protein analyses, and may have significant advantages over the original technology for the assessment of some genes and proteins by improving both qualitative and quantitative results.
PLoS ONE, 2013
Aberrant epidermal growth factor (EGF) signaling is associated with tumor growth in squamous cell... more Aberrant epidermal growth factor (EGF) signaling is associated with tumor growth in squamous cell carcinoma of the head and neck in humans (HNSCC), and is a major focus of targeted therapy. Cetuximab, a monoclonal antibody against EGFR, has been successful at prolonging survival but has only a 10% tumor shrinkage response rate in a clinical setting. The goal of this study was to compare dacomitinib (PF-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple HER family receptors (HER-1 (EGFR), HER-2 and HER-4 tyrosine kinases), to cetuximab, the current FDA approved anti-EGFR medication for HNSCC and erlotinib, an EGFR specific small molecule tyrosine kinase inhibitor. Dacomitinib, erlotinib and cetuximab were tested in a panel of 27 HNSCC cell lines. Treatment with 100 ug/ml of cetuximab or 1 uM of erlotinib inhibited growth by at least 50% in 7/27 cell lines, while treatment with 1 uM of dacomitinib had similar growth inhibition in 17/27 lines. Cell lines representing three levels of sensitivity to dacomitinib were further examined using Western blots, cell cycle and apoptosis analysis. Treatment with 100 nM of dacomitinib reduced EGFR activity and downstream AKT and ERK pathways more effectively than treatment with 100 ug/ml of cetuximab in all ten tested lines. Although both compounds induced apoptosis at similar levels, dacomitinib caused greater G0/G1 arrest. Sensitivity to EGFR blockade was associated with levels of EGFR and ERK and was not associated with common oncogenic mutations and copy number variations. Phosphorylated and total EGFR and ERK levels correlate with sensitivity to both cetuximab and dacomitinib. Three of the four lines in the exquisitely sensitive group had the highest levels of phosphorylated and total EGFR and ERK among the ten lines selected, while the three resistant lines collectively had the lowest levels. Neither pAKT nor tAKT was associated with sensitivity.
Authorea (Authorea), Nov 30, 2022
Thank you for your letter 1 highlighting our study that implicates GDF15 and does not support a d... more Thank you for your letter 1 highlighting our study that implicates GDF15 and does not support a direct causal role for hCG in Hyperemesis Gravidarum (HG). 2 Both GDF15 and hCG are expressed in blastocysts and increase in the 1 st trimester, 2 so any association between the two hormones in early pregnancy is not surprising and does not imply one controls expression of the other. While it is possible hCG plays a secondary role contributing to GDF15 levels, it is unlikely to be important for HG for the following reasons:
Genomics, Aug 1, 1996
The chicken extracellular matrix glycoprotein ES/130 is necessary for epithelial—mesenchymal tran... more The chicken extracellular matrix glycoprotein ES/130 is necessary for epithelial—mesenchymal transformation in the developing heart and is also expressed in noncardiac chicken tissues such as limb and notochord. We have identified hES, the human homolog of chicken ES/130. Fluorescencein situhybridization analysis (FISH) localizes hES to human chromosome 20p11.2–p12. FISH analyses of individuals with 20p12 deletions and affected by Alagille syndrome
Molecular Microbiology, Jun 1, 1994
SummaryThe unusual longevity of the Escherichia coli ompA transcript is determined by its 5′untra... more SummaryThe unusual longevity of the Escherichia coli ompA transcript is determined by its 5′untranslated region (UTR), which functions In vivo as an mRNA stabilizer. Here we show that this 5′UTR can prolong the lifetime in E. coli of a variety of heterologous mRNAs to which it is Joined, either as a gene fusion or as an operon fusion. Statistical extrapolation suggests that it is quite likely that most E. coli mRNAs could be stabilized in this manner. We conclude that the ompA 5′ UTR impedes a major pathway for mRNA degradation in E. coli and that stabilization by fusion to this UTR does not require translational readthrough of the heterologous mRNA segment by ribosomes that initiate translation at the ompA ribosome‐binding site. Additional experiments indicate that the E. coli ribonuclease whose action is slowed by the ompA 5′ UTR is not RNase III.
American Journal of Obstetrics and Gynecology, 2023
Reproductive Toxicology, Jul 1, 2016
This is an analysis of fetal outcome in pregnancies exposed to ondansetron to treat Hyperemesis G... more This is an analysis of fetal outcome in pregnancies exposed to ondansetron to treat Hyperemesis Gravidarum (HG). In this retrospective cohort study, U.S. data on outcome were collected on 1070 pregnancies exposed to ondansetron and compared to outcomes in two control groups: 771 pregnancies in women with a history of HG with no ondansetron exposure and 1555 pregnancies with neither a history of HG nor ondansetron exposure. Ventricular septal defects were reported in 2/952 of infants in the HG/Ondansetron-exposure group and 4/1286 in the No HG/No Ondansetron-exposure group. Cleft palate was reported in 1/952 live births in the HG/Ondansetron and 2/1286 in the No HG/No Ondansetronexposure groups. Women with a history of HG who took ondansetron reported less miscarriages and terminations, and higher live birth rates. The overall results do not support evidence of teratogenicity of ondansetron.
Breast cancer progression is driven by altered gene expression. We show that the RIN1 gene, which... more Breast cancer progression is driven by altered gene expression. We show that the RIN1 gene, which encodes a RAS effector regulating epithelial cell properties, is silenced in breast tumor cell lines compared with cultured human mammary epithelial cells. We also report that RIN1 is often reduced in human breast tumor cells compared with morphologically normal breast glandular cells. At least two silencing mechanisms seem to be involved. Overexpression of the transcription repressor SNAI1 (Snail) was observed in ZR75-1 cells, and SNAI1 knockdown restored RIN1 expression. In addition, DNA methylation within the RIN1 promoter and the first exon in KPL-1 cells suggested that epigenetic modifications may contribute to silencing, and demethylation was shown to restore RIN1 expression. Reexpression of RIN1 was shown to inhibit anchorage-independent growth in soft agar. In addition, RIN1 expression inhibited both the initiation and progression of tumorigenesis for two breast tumor cell lines in a mouse model, consistent with a tumor suppressor function. We also show that RIN1 acts as a negative regulator of tumor cell invasive growth and that this requires the ABL kinase–signaling function of RIN1, suggesting a mechanism through which RIN1 silencing may contribute to breast cancer progression. [Cancer Res 2007;67(24):11510–6]
Bjog: An International Journal Of Obstetrics And Gynaecology, Mar 16, 2022
ObjectiveA genome‐wide association study (GWAS) linked the placenta and appetite hormone gene GDF... more ObjectiveA genome‐wide association study (GWAS) linked the placenta and appetite hormone gene GDF15 to hyperemesis gravidarum (HG). This paradigm‐changing finding has shifted the field away from the prevailing hypotheses, but more evidence is needed. This study was performed to identify coding variants in addition to the non‐coding variants implicated by GWAS.SettingCase–control research study performed in a university setting.DesignCase–control study.PopulationHyperemesis gravidarum cases requiring intravenous fluid treatment for disease (n = 926) and controls with normal or no nausea and vomiting of pregnancy (n = 660), from the USA.MethodsWhole exome‐wide sequencing and genome informatics were performed using the standard Regeneron pipeline. All variants were compared between cases and controls using dominant, recessive, and allelic models to identify variants with exome‐wide significant p values (p < 10−6). Odds ratios and associated p values were calculated for exome‐wide significant allele(s) in subgroups of genetically predicted ancestries. Variants were filtered to identify rare pathogenic variants occurring in ≥10 cases and in no controls.Main outcome measuresIdentification of exome‐wide significant and rare genetic variant(s) associated with HG.ResultsA common coding variant in GDF15 was the only exome‐wide significant association, and a rare coding variant in GDF15 was the only predicted disease‐causing variant occurring in 10 or more cases.ConclusionsThis study confirms the GWAS finding that GDF15 is the greatest genetic risk factor for HG. The new variants identified may have implications for prediction and diagnosis. The findings provide insight into the cause, and molecular mechanisms for developing therapeutics for HG.Tweetable abstractWhole‐exome sequencing reveals placenta and vomiting hormone GDF15 most likely cause of Hyperemesis Gravidarum.
Reproductive Toxicology, 2018
This is a letter in response to the article "Publishing negative findings and the challenge of av... more This is a letter in response to the article "Publishing negative findings and the challenge of avoiding type II errors in studies of suspect teratogens: Example of a recent ondansetron publication" by Stanley Edlavitch (Reproductive Toxicology 67: 125-128). In his article, Edlavitch concludes that our study had "major issues of study design and data accuracy may be the reason that no relationship was discovered." For someone criticizing our manuscript's "accuracy," it might be a good start to actually reference the lead author's name correctly in any of the 9 times it was referenced throughout his manuscript-it's Fejzo, not Fazio. Edlavitch concludes that our manuscript had "major design flaws" and states that the manuscripts with different findings, "the studies which found increased risk (Anderka et al., 2012 and Danielsson et al., 2014) appear to be designed and analyzed carefully." In fact, Edlavitch has made completely inaccurate and misleading comments with respect to our manuscript in comparison to the studies he finds to be "designed and analyzed carefully," and I will go through one by one now and explain why his manuscript is inaccurate, biased, and frankly dishonest.
Obstetrics & Gynecology, May 1, 2017
Gynecologic Oncology, Feb 1, 2021
Positive associations between alpine cushion plants and other species have been extensively studi... more Positive associations between alpine cushion plants and other species have been extensively studied. However, almost all studies have focused on the associations between macrofauna. Studies that have investigated positive associations between alpine cushion plants and rhizospheric microbes have been limited to the vegetation growing season. Here, we asked whether the positive effects that alpine cushion plants confer on rhizospheric microbe communities vary with seasons. We assessed seasonal variations in the bacterial diversity and composition in rhizosphere of two alpine cushion plants and surrounding bare ground by employing a high throughput sequencing method targeting the V3 region of bacterial 16S rRNA genes. Soil properties of the rhizosphere and the bare ground were also examined. We found that cushion rhizospheres harbored significantly more C, N, S, ammonia nitrogen, and soil moisture than the bare ground. Soil properties in cushion rhizospheres were not notably different, except for soil pH. Bacterial diversities within the same microhabitats did not vary significantly with seasons. We concluded that alpine cushion plants had positive effects on the rhizospheric bacterial communities, even though the strength of the effect varied in different cushion species. Cushion species and the soil sulfur content were probably the major factors driving the spatial distribution and structure of soil bacterial communities in the alpine communities dominated by cushion plants.
AJOG global reports, Feb 1, 2023
American Journal of Obstetrics and Gynecology, Nov 1, 2022
Obstetrics & Gynecology, May 1, 2020
The American College of Obstetrics and Gynecology recommends routine oral health care during preg... more The American College of Obstetrics and Gynecology recommends routine oral health care during pregnancy. Despite this recommendation, many pregnant women do not receive routine dental care. The reasons for discordance are complex. This study, conducted in conjunction with the ACOG District XII Committee on Healthcare of Underserved Women, surveyed ACOG District XII Fellows regarding their perceptions of factors that impact oral health care in pregnancy. METHODS: Between May and October 2019, ACOG District XII Fellows were asked to participate in an anonymous electronic survey on their practices regarding oral health in pregnancy. IRB approval was obtained. Descriptive statistics were estimated using SPSS (V25).
Gynecology & obstetrics case reports, 2016
Prompt testing and treatment followed by frequent followup with the patient until symptoms subsid... more Prompt testing and treatment followed by frequent followup with the patient until symptoms subside may help to prevent Hyperemesis Gravidarum related deaths in the future.
Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-... more Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternalGDF15gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant inGDF15which strongly predisposes mothers to HG, particularly when the fetus is wild-type, wa...
Genomics, Mar 1, 1995
Uterine leiomyomata are the most common tumors in women and can cause abnormal uterine bleeding, ... more Uterine leiomyomata are the most common tumors in women and can cause abnormal uterine bleeding, pelvic pain, and infertility. Approximately 200,000 hysterectomies are performed annually in the U.S. to relieve patients of the medical sequelae of these benign neoplasms. Our efforts have focused on cloning the t(12;14)(q14-q15;q23-q24) breakpoint in uterine leiomyoma to further our understanding of the biology of these tumors. Thirty-nine YACs and six cosmids mapping to 12q14-q15 have been mapped by fluorescence in situ hybridization to tumor metaphase chromosomes containing a t(12;14). One YAC spanned the translocation breakpoint and was mapped to tumor metaphases from a pulmonary chondroid hamartoma containing a t(12;14)(q14-q15;q23-q24) and a lipoma containing a t(12;15)(q15;q24); this YAC also spanned the breakpoint in these two tumors, suggesting that the same gene on chromosome 12 may be involved in the pathobiology of these distinct benign neoplasms.
Elsevier Masson, Dec 29, 2011
Methods in Molecular Biology, 2010
Tissue microarray technology is a new method used to analyze 100s to 1,000s of tumor samples on a... more Tissue microarray technology is a new method used to analyze 100s to 1,000s of tumor samples on a single slide allowing high throughput analysis of genes and proteins on a large cohort. The original methodology involves coring tissues from paraffin-embedded tissue donor blocks and placing them into a single paraffin block. One difficulty with paraffin-embedded tissue relates to antigenic changes in proteins and mRNA degradation induced by the fixation and embedding process. We modified this technology by using frozen tissues embedded in OCT compound as donor samples and arraying the specimens into a recipient OCT block. Tumor tissue is not fixed before embedding, and sections from the array are evaluated without fixation or postfixed according to the appropriate methodology used to analyze a specific gene at the DNA, RNA, and/or protein levels. While paraffin tissue arrays can be problematic for immunohistochemistry and for RNA in situ hybridization analyses, this method allows optimal evaluation by each technique and uniform fixation across the array panel. Frozen tissue microarrays work well for DNA, RNA, and protein analyses, and may have significant advantages over the original technology for the assessment of some genes and proteins by improving both qualitative and quantitative results.
PLoS ONE, 2013
Aberrant epidermal growth factor (EGF) signaling is associated with tumor growth in squamous cell... more Aberrant epidermal growth factor (EGF) signaling is associated with tumor growth in squamous cell carcinoma of the head and neck in humans (HNSCC), and is a major focus of targeted therapy. Cetuximab, a monoclonal antibody against EGFR, has been successful at prolonging survival but has only a 10% tumor shrinkage response rate in a clinical setting. The goal of this study was to compare dacomitinib (PF-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple HER family receptors (HER-1 (EGFR), HER-2 and HER-4 tyrosine kinases), to cetuximab, the current FDA approved anti-EGFR medication for HNSCC and erlotinib, an EGFR specific small molecule tyrosine kinase inhibitor. Dacomitinib, erlotinib and cetuximab were tested in a panel of 27 HNSCC cell lines. Treatment with 100 ug/ml of cetuximab or 1 uM of erlotinib inhibited growth by at least 50% in 7/27 cell lines, while treatment with 1 uM of dacomitinib had similar growth inhibition in 17/27 lines. Cell lines representing three levels of sensitivity to dacomitinib were further examined using Western blots, cell cycle and apoptosis analysis. Treatment with 100 nM of dacomitinib reduced EGFR activity and downstream AKT and ERK pathways more effectively than treatment with 100 ug/ml of cetuximab in all ten tested lines. Although both compounds induced apoptosis at similar levels, dacomitinib caused greater G0/G1 arrest. Sensitivity to EGFR blockade was associated with levels of EGFR and ERK and was not associated with common oncogenic mutations and copy number variations. Phosphorylated and total EGFR and ERK levels correlate with sensitivity to both cetuximab and dacomitinib. Three of the four lines in the exquisitely sensitive group had the highest levels of phosphorylated and total EGFR and ERK among the ten lines selected, while the three resistant lines collectively had the lowest levels. Neither pAKT nor tAKT was associated with sensitivity.