Harshwardhan M Thaker

Mount Sinai Medical Center, New York, New York, United States

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Publications (25)94.91 Total impact

  • Rebecca N. Baergen, Harshwardhan M Thaker, Debra S Heller
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    ABSTRACT: Abstract Objectives: Placentas have been often considered medical waste in hospitals. This view is particularly held by the patients themselves who may not understand the importance of placental examination. Hospitals have been receiving requests for placental release to patients and need to be prepared to handle these requests. Therefore, a survey was conducted to explore the experiences and practices of perinatal pathologists with respect to placental release. Methods: A survey of practicing perinatal pathologists was conducted utilizing SurveyMonkey. Questions were asked about policies in force at their particular institution, conditions of release and the purpose of release, i.e. what the disposition of the placenta was after release to the family. Results: A survey was emailed to 192 perinatal pathologists in the US and Canada utilizing SurveyMonkey. 36 responses were received. 61.1% of respondents did allow release of placentas, and those who didn't release usually reported that they didn't receive requests. In most cases, specific policies were in place, with multiple departments within the hospital having input on the creation of the policy. Parental signature was required in most cases. The most common reason for patient request was to bury the placenta although some placental release was for consumption and/or encapsulation. Conclusion: Although there are no specific religious requirements for use or burial of the placenta after delivery, there are many cultural reasons for requests. Hospitals and specific providers need to be aware of this interest, and be prepared when a request is received so a specific policy can be in place.
    Pediatric and Developmental Pathology 07/2013; 16(5). DOI:10.2350/13-05-1338-OA.1 · 0.86 Impact Factor
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    ABSTRACT: Attempts to enhance patients' immune responses to malignancies have been largely unsuccessful. We now describe an immune-escape mechanism mediated by the inhibitory receptor Ig-like transcript 3 (ILT3) that may be responsible for such failures. Using a humanized SCID mouse model, we demonstrate that soluble and membrane ILT3 induce CD8(+) T suppressor cells and prevent rejection of allogeneic tumor transplants. Furthermore, we found that patients with melanoma, and carcinomas of the colon, rectum, and pancreas produce the soluble ILT3 protein, which induces the differentiation of CD8(+) T suppressor cells and impairs T cell responses in MLC. These responses are restored by anti-ILT3 mAb or by depletion of soluble ILT3 from the serum. Immunohistochemical staining of biopsies from the tumors and metastatic lymph nodes suggests that CD68(+) tumor-associated macrophages represent the major source of soluble ILT3. Alternative splicing, resulting in the loss of the ILT3 transmembrane domain, may contribute to the release of ILT3 in the circulation. These data suggest that ILT3 depletion or blockade is crucial to the success of immunotherapy in cancer. In contrast, the inhibitory activity of soluble ILT3 on T cell alloreactivity in vitro and in vivo suggests the potential usefulness of rILT3 for immunosuppressive treatment of allograft recipients or patients with autoimmune diseases.
    The Journal of Immunology 07/2007; 178(11):7432-41. DOI:10.4049/jimmunol.178.11.7432 · 5.36 Impact Factor
  • Laxmi Baxi, Stephen Brown, Harshwardhan M Thaker
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    ABSTRACT: In the literature, conflicting reports on the significance of false-positive maternal serum multiple marker testing for trisomy 18 are encountered; however, the biology of this finding is discussed infrequently. We present such a case in association with Bloom's syndrome in the fetus. The fetus had intrauterine growth restriction, seen early in the second trimester, oligohydramnios, and was delivered at 34 weeks of gestation for impending fetal compromise. We propose that the adverse outcome of the pregnancy with false-positive serum analyte testing for trisomy 18 might result from a small-sized placenta and perhaps pathology at receptor level.
    Fetal Diagnosis and Therapy 02/2007; 22(4):318-20. DOI:10.1159/000100799 · 2.30 Impact Factor
  • Xiangyuan Wang, Laxmi Baxi, Debra Wolgemuth, Harshwardhan Thaker
    American Journal of Obstetrics and Gynecology 12/2006; 195(6). DOI:10.1016/j.ajog.2006.10.713 · 3.97 Impact Factor
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    ABSTRACT: Glycogen storage disease type IV (GSD-IV) is a rare autosomal recessive disorder due to mutations in the GBE1 gene causing deficiency of the glycogen branching enzyme (GBE). Prenatal diagnosis has occasionally been performed by the measurement of the GBE activity in cultured chorionic villi (CV) cells. Two unrelated probands with severe hypotonia at birth and death during the neonatal period were diagnosed with GSD-IV on the basis of postmortem histological findings. DNA analysis revealed truncating GBE1 mutations in both families. Prenatal diagnosis was performed in subsequent pregnancies by determination of branching enzyme activity and DNA analysis of CV or cultured amniocytes. Detailed autopsies of the affected fetuses at 14 and 24 weeks of gestation demonstrated intracellular inclusions of abnormal glycogen characteristic of GSD-IV. Prenatal diagnosis of GSD-IV by DNA analysis is highly accurate in genetically confirmed cases.
    Prenatal Diagnosis 10/2006; 26(10):951-5. DOI:10.1002/pd.1533 · 2.51 Impact Factor
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    ABSTRACT: We sought to determine the accuracy of antenatal diagnosis of twin chorionicity at a single tertiary care center and assess the consequences of incorrect diagnoses. Twins with chorionicity diagnosed by ultrasound < or = 24 weeks' gestation were retrospectively reviewed. Chorionicity was assigned by sonographic findings including placental location(s), the lambda and T-signs, and/or fetal gender(s). Postnatal diagnosis was determined by placental histopathologic examination. Medical records of antenatal-postnatal discordant chorionicities were reviewed for adverse sequelae. Chorionicity was correctly assigned antenatally in 392/410 (95.6%) twins. The sensitivity, specificity, and positive and negative predictive values of monochorionicity assessed < or = 14 weeks were 89.8%, 99.5%, 97.8%, and 97.5%. Corresponding statistical values for the second trimester were 88.0%, 94.7%, 88.0%, and 94.7%. Two cases of inaccurate antenatal diagnoses affected patient counseling or were associated with adverse clinical outcomes. Antenatal assessment of chorionicity is accurate; however, incorrect diagnoses do occur and can affect reliable patient counseling and management.
    American journal of obstetrics and gynecology 09/2006; 195(3):863-7. DOI:10.1016/j.ajog.2006.06.039 · 3.97 Impact Factor
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    ABSTRACT: Imprinted genes control fetal and placental growth in mice and in rare human syndromes, but the role of these genes in sporadic intrauterine growth restriction (IUGR) is less well-studied. We measured the ratio of mRNA from a maternally expressed imprinted gene, PHLDA2, to that from a paternally expressed imprinted gene, MEST, by Northern blotting in 38 IUGR-associated placentae and 75 non-IUGR placentae and found an increase in the PHLDA2/MEST mRNA ratio in IUGR (p=0.0001). Altered expression of PHLDA2 and MEST was not accompanied by changes in DNA methylation within their imprinting centers, and immunohistochemistry showed PHLDA2 protein appropriately restricted to villous and intermediate cytotrophoblast in the IUGR placentae. We next did a genome-wide survey of mRNA expression in 14 IUGR placentae with maternal vascular under-perfusion compared to 15 non-IUGR placentae using Affymetrix U133A microarrays. In this series six imprinted genes were differentially expressed by ANOVA with a Benjamini-Hochberg false discovery rate of 0.05, with increased expression of PHLDA2 and decreased expression of MEST, MEG3, GATM, GNAS and PLAGL1 in IUGR placentae. At lower significance, we found IGF2 mRNA decreased and CDKN1C mRNA increased in the IUGR cases. We confirmed the significant reduction in MEG3 non-translated RNA in IUGR placentae by Northern blotting. In addition to imprinted genes, the microarray data highlighted non-imprinted genes acting in endocrine signaling (LEP, CRH, HPGD, INHBA), tissue growth (IGF1), immune modulation (INDO, PSG-family genes), oxidative metabolism (GLRX), vascular function (AGTR1, DSCR1) and metabolite transport (SLC-family solute carriers) as differentially expressed in IUGR vs. non-IUGR placentae.
    Placenta 06/2006; 27(6-7):540-9. DOI:10.1016/j.placenta.2005.07.004 · 3.29 Impact Factor
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    ABSTRACT: To investigate whether genetic alteration of the STK11 (serine/threonine kinase 11)/LKB1 tumor-suppressor gene is involved in the carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the entire encoding exons and flanking intronic sequences of the STK11/LKB1 gene were analysed with direct genomic sequencing of 15 HNSCC specimens. A novel missense mutation with presumed loss of heterozygosity (LOH) and 10 polymorphisms were identified in these samples. The novel mutation of STK11/LKB1 at nucleotide position 613 G --> A, which causes the amino-acid substitution from alanine to threonine at residue 205 within the catalytic kinase domain, was identified in cell line RPMI 2650. To further determine whether this point mutation affects the gene function, constructs of the wild type and A205T mutant of the STK11/LKB1 gene expression vectors were created and transfected into RPMI 2650 cells. Our results showed that the reintroduction of the wild-type but not the mutant STK11/LKB1 construct into RPMI 2650 cells induced suppression of the cell growth. The mutation also affected the kinase activity of the Stk11/Lkb1 protein. This led us to conclude that the A205T point mutation of the STK11/LKB1 gene produces functionally inactive proteins. This is the first described mutation of the STK11/LKB1 gene in HNSCC. While the mutation frequency of the STK11/LKB1 gene in HNSCC remains to be determined in future studies, our data strongly suggests that STK11/LKB1 is involved in the carcinogenesis of HNSCC.
    Oncogene 05/2006; 25(20):2937-42. DOI:10.1038/sj.onc.1209325 · 8.56 Impact Factor
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    ABSTRACT: Down syndrome (DS) is caused by trisomy 21 (+21), but the aberrations in gene expression resulting from this chromosomal aneuploidy are not yet completely understood. We used oligonucleotide microarrays to survey mRNA expression in early- and late-passage control and +21 fibroblasts and mid-gestation fetal hearts. We supplemented this analysis with northern blotting, western blotting, real-time RT-PCR, and immunohistochemistry. We found chromosome 21 genes consistently over-represented among the genes over-expressed in the +21 samples. However, these sets of over-expressed genes differed across the three cell/tissue types. The chromosome 21 gene MX1 was strongly over-expressed (mean 16-fold) in senescent +21 fibroblasts, a result verified by northern and western blotting. MX1 is an interferon target gene, and its mRNA was induced by interferons present in +21 fibroblast conditioned medium, suggesting an autocrine loop for its over-expression. By immunohistochemistry the p78MX1 protein was induced in lesional tissue of alopecia areata, an autoimmune disorder associated with DS. We found strong over-expression of the purine biosynthesis gene GART (mean 3-fold) in fetal hearts with +21 and verified this result by northern blotting and real-time RT-PCR. Different subsets of chromosome 21 genes are over-expressed in different cell types with +21, and for some genes this over-expression is non-linear (>1.5X). Hyperactive interferon signaling is a candidate pathway for cell senescence and autoimmune disorders in DS, and abnormal purine metabolism should be investigated for a potential role in cardiac defects.
    BMC Medical Genetics 03/2006; 7:24. DOI:10.1186/1471-2350-7-24 · 2.45 Impact Factor
  • J McMinn, M Wei, Y Sadovsky, H M Thaker, B Tycko
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    ABSTRACT: The PEG1 gene (a.k.a. MEST) is expressed in human placental trophoblast and endothelium, and data from knockout mice show that this gene regulates placental and fetal growth. Isoform 1 of PEG1 mRNA initiates from exon 1c and produces the long form of the MEST protein. This isoform is imprinted, with expression only from the paternal allele in many human and mouse organs, including placenta. In contrast, PEG1 isoform 2, initiating from exon 1a and producing the short form of MEST protein, is biallelically expressed (non-imprinted) in several non-placental organs. Here we show that PEG1 isoform 2 is in fact imprinted in a large subset of human placentae. A CpG island overlapping PEG1 exon 1a is unmethylated in various fetal and adult non-placental tissues, but is often substantially methylated in the placenta, with the extent of methylation in a large series approximating a normal distribution. Bisulfite conversion/sequencing indicates that the inter-individual differences reflect the relative representation of heavily methylated vs. unmethylated alleles, and RT-PCR/RFLP analysis shows strongly biased allelic expression of PEG1 isoform 2 mRNA in a majority of placentae with a high proportion of methylated alleles. These data highlight PEG1 isoform 2 as a marker for future studies of inter-individual epigenetic variation and its relation to placental and fetal growth in humans.
    Placenta 02/2006; 27(2-3):119-26. DOI:10.1016/j.placenta.2004.12.003 · 3.29 Impact Factor
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    ABSTRACT: We describe the clinical and pathologic features of an unusual case of alpha-thalassemia major in a patient who survived to term and lived for 9 days. The neonate was nonhydropic and the clinical picture was dominated by severe hypoxia with pulmonary hypertension. The diagnosis was not suspected until postnatal examination of the blood smear, which prompted the performance of hemoglobin electrophoresis and subsequent molecular confirmation. This case illustrates that alpha-thalassemia major should be in the differential diagnosis of hypoxic neonates even in the absence of hydrops.
    Pediatric and Developmental Pathology 12/2005; 8(6):706-9. DOI:10.1007/s10024-005-0063-2 · 0.86 Impact Factor
  • American Journal of Obstetrics and Gynecology 12/2005; 193(6). DOI:10.1016/j.ajog.2005.10.497 · 3.97 Impact Factor
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    ABSTRACT: To understand genetic and epigenetic pathways in Wilms' tumors, we carried out a genome scan for loss of heterozygosity (LOH) using Affymetrix 10K single nucleotide polymorphism (SNP) chips and supplemented the data with karyotype information. To score loss of imprinting (LOI) of the IGF2 gene, we assessed DNA methylation of the H19 5' differentially methylated region (DMR). Few chromosomal regions other than band 11p13 (WT1) were lost in Wilms' tumors from Denys-Drash and Wilms' tumor-aniridia syndromes, whereas sporadic Wilms' tumors showed LOH of several regions, most frequently 11p15 but also 1p, 4q, 7p, 11q, 14q, 16q, and 17p. LOI was common in the sporadic Wilms' tumors but absent in the syndromic cases. The SNP chips identified novel centers of LOH in the sporadic tumors, including a 2.4-Mb minimal region on chromosome 4q24-q25. Losses of chromosomes 1p, 14q, 16q, and 17p were more common in tumors presenting at an advanced stage; 11p15 LOH was seen at all stages, whereas LOI was associated with early-stage presentation. Wilms' tumors with LOI often completely lacked LOH in the genome-wide analysis, and in some tumors with concomitant 16q LOH and LOI, the loss of chromosome 16q was mosaic, whereas the H19 DMR methylation was complete. These findings confirm molecular differences between sporadic and syndromic Wilms' tumors, define regions of recurrent LOH, and indicate that gain of methylation at the H19 DMR is an early event in Wilms' tumorigenesis that is independent of chromosomal losses. The data further suggest a biological difference between sporadic Wilms' tumors with and without LOI.
    Molecular Cancer Research 10/2005; 3(9):493-502. DOI:10.1158/1541-7786.MCR-05-0082 · 4.50 Impact Factor
  • Harshwardhan M Thaker
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    ABSTRACT: The presence of a fetus in a molar pregnancy is usually an indication that it is a partial, rather than a complete, hydatidiform mole. The underlying reason for this is a basic difference in the genetic composition of the 2 types of mole. Complete moles are ‘‘androgenetic’’ conceptions, i.e., their genome is entirely paternal in origin [1]. The total absence of a maternal genetic contribution results in unopposed action of paternally expressed genes, leading to excessive trophoblastic proliferation and a very early cessation of embryonic development. Partial moles are almost all ‘‘diandric’’ triploids, with 1 maternal set and 2 paternal sets of chromosomes. The excess paternal genetic dose causes trophoblastic proliferation but is presumably kept in check by the maternal genetic contribution, which also permits the fetus to develop much further than in complete moles, sometimes well into the second trimester [2]. This marked difference in fetal viability between complete and partial moles has resulted in the dictum that ‘‘if it is a mole and if there is a fetus, then it must be a partial mole.’’ However, there are 2 important exceptions. First, the villi of early complete moles can show histologic evidence of fetal tissue, including endothelial cells, nucleated red cells, an amnion, and a yolk sac [3]. Second, a complete mole may be part of a dizygotic twin pregnancy in which the other conceptus is a normal well-developed fetus with its own nonmolar pla
    Pediatric and Developmental Pathology 04/2005; 8(2):146-7. DOI:10.1007/s10024-005-2164-3 · 0.86 Impact Factor
  • Sara E Monaco, Welton M Gersony, Harshwardhan M Thaker
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    ABSTRACT: We describe an infant with hypoplasia of the left heart diagnosed prenatally who, at birth, had signs of severe pulmonary venous obstruction. Echocardiography indicated normally connecting pulmonary veins, and showed a paradoxical right-to-left shunt across a patent oval foramen. Postmortem examination revealed that the obstruction was due to a divided left atrium, or cor triatriatum sinister, with an imperforate muscular diaphragm separating completely the two components of the divided atrium.
    Cardiology in the Young 11/2004; 14(5):553-6. DOI:10.1017/S104795110400513X · 0.86 Impact Factor
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    ABSTRACT: Hydatidiform moles are pregnancies characterized by abnormal development of both embryonic and extraembryonic tissues and are associated with the misexpression of imprinted genes. The vast majority of complete hydatidiform moles are diploid and androgenetic, whereas partial hydatidiform moles are triploid, with an extra set of chromosomes of paternal origin. Here, we present an unusual complete mole that showed strong expression of two imprinted, maternally transcribed genes, CDKN1C (encoding p57(KIP2)) and PHLDA2 (TSSC3/IPL), both part of a large imprinted gene domain on chromosome 11. Using microsatellite genotyping and fluorescent in situ hybridization, we show that this paradoxical gene expression was due to retention of a maternal copy of chromosome 11 in addition to the two paternal copies normally present in complete moles. These findings demonstrate that, despite being predominantly androgenetic, some complete moles contain small amounts of DNA of maternal origin. Furthermore, these results provide an explanation for rare false negatives that can arise when p57(KIP2) is used as a diagnostic marker for complete moles.
    Modern Pathology 10/2004; 17(9):1155-60. DOI:10.1038/modpathol.3800175 · 6.36 Impact Factor
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    ABSTRACT: To determine if immunohistochemistry for PHLDA2 (also known as IPL and TSSC3), the product of a paternally imprinted, maternally expressed gene, can be used as a tool in the differential diagnosis of molar gestations. Twenty-five cases (15 complete moles, 5 partial moles and five hydropic abortions) were stained by immunohistochemistry for PHLDA2 and scored (without knowledge of the diagnosis) for positivity in the villous cytotrophoblast and then compared to adjacent sections stained by p57KIP2 immunohistochemistry. All partial moles and hydropic abortions were positive for PHLDA2 and p57KIP2. There was strong PHLDA2 staining of the cytoplasm in virtually all cells of the villous cytotrophoblast, while p57KIP2 was localized to the nucleus in a subset of those cells. All complete moles were negative for both markers in the villous cytotrophoblast. Immunohistochemistry for PHLDA2 serves as a practical and reliable diagnostic marker for the discrimination of complete mole from partial mole and hydropic abortion. Since the immunohistochemical diagnosis of complete mole is based on a negative result, absence of staining, the use of both markers (PHLDA2 and p57KIP2) together could increase the level of confidence when making this prognostically important distinction.
    The Journal of reproductive medicine 09/2004; 49(8):630-6. · 0.58 Impact Factor
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    ABSTRACT: Endothelial dysfunction characterizes heart failure (HF). Simvastatin (Sim) increases endothelial nitric oxide (NO) independent of lipid-lowering. We evaluated the effect of Sim on cardiac function, apoptosis, and NO availability in HF. Five-month-old cardiomyopathic (CM) hamsters were divided into 2 groups: Sim (20 mg/kg, 6 weeks, n = 6) and Untreated (n = 6). Age-matched normal hamsters served as controls (n = 6). Serial echocardiograms were performed to measure LV function. Myocardial apoptosis, eNOS, and capillary density were measured at 6 weeks. Cardiomyopathic hamsters had lower LV shortening fraction (SF) compared with controls (17 +/- 3% vs 59 +/- 2%), higher LV end-diastolic volume (30 +/- 3 vs 6 +/- 2 mL/m2), and lower LV mass/volume ratio (0.5 +/- 0.04 vs 0.72 +/- 0.02 mg/ml, P < 0.001). During follow-up, SF decreased (9 +/- 2%) and LV volume increased (38 +/- 1 mL/m2) in untreated hamsters (P < 0.05 from baseline) but did not change significantly in the Sim group (P < 0.05 vs untreated). Myocardial caspase-3 activity was higher and apoptotic nuclear density was lower in Sim compared with untreated CM hamsters (0.072 +/- 0.02% vs 0.107 +/- 0.03%, P < 0.01). Myocardial capillary density was highest in the Sim group (P < 0.05). eNOS expression was not different between groups. Sim retards the progression of HF in CM hamsters. This may be related to an increase in coronary microvasculature, increase in NO availability, and decreased apoptosis.
    Journal of Cardiovascular Pharmacology 03/2004; 43(3):454-61. DOI:10.1097/00005344-200403000-00018 · 2.11 Impact Factor
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    ABSTRACT: Radiofrequency ablation is a minimally invasive technique that has been used in selective reduction of acardiac twins. We report a case in which radiofrequency ablation was used to selectively reduce a monochorionic twin discordant for an abnormality.
    American Journal of Obstetrics and Gynecology 03/2004; 190(2):575-6. DOI:10.1016/j.ajog.2003.08.010 · 3.97 Impact Factor
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    ABSTRACT: We describe the clinical course, echocardiography, angiography, and histopathology of a female infant with pulmonary atresia and intact ventricular septum (PA/IVS) with complete coronary ostial atresia and right ventricle-dependent coronary circulation who survived for 7 weeks after palliative surgery. The patient expired from myocardial insufficiency while waiting for a donor heart. Postmortem examination demonstrated atretic coronary ostia, ventricular sinusoids, and myocardial infarctions of various ages. This report suggests that neonates with PA/IVS who have this extreme form of coronary abnormality may potentially be managed medically and surgically until cardiac transplantation is available.
    Pediatric Cardiology 02/2004; 25(1):67-9. DOI:10.1007/s00246-003-0517-0 · 1.55 Impact Factor

Publication Stats

679 Citations
94.91 Total Impact Points

Institutions

  • 2013
    • Mount Sinai Medical Center
      New York, New York, United States
  • 2004–2006
    • CUNY Graduate Center
      New York, New York, United States
  • 2002–2006
    • Columbia University
      • • Department of Obstetrics and Gynecology
      • • Division of Pediatric Cardiology
      • • College of Physicians and Surgeons
      • • Department of Medicine
      New York, New York, United States
  • 2005
    • University of Toronto
      Toronto, Ontario, Canada