David R. Genest

Bio: David R. Genest is an academic researcher from Harvard University. The author has contributed to research in topics: Partial Hydatidiform Mole & Chorioepithelioma. The author has an hindex of 18, co-authored 23 publications receiving 1540 citations. Previous affiliations of David R. Genest include Brigham and Women's Hospital & Wayne State University.

Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants

Abstract: Echolucent images (EL) of cerebral white matter, seen on cranial ultrasonographic scans of very low birth weight newborns, predict motor and cognitive limitations. We tested the hypothesis that markers of maternal and feto-placental infection were associated with risks of both early (diagnosed at a median age of 7 d) and late (median age = 21 d) EL in a multi-center cohort of 1078 infants or =1 after membrane rupture and who had membrane inflammation (adjusted OR not calculable), whereas the association of fetal vasculitis with late EL was seen only in infants born <1 h after membrane rupture (OR = 10.8; p = 0.05). Maternal receipt of antibiotic in the 24 h just before delivery was associated with late EL only if delivery occurred <1 h after membrane rupture (OR = 6.9; p = 0.01). Indicators of maternal infection and of a fetal inflammatory response are strongly and independently associated with EL, particularly late EL.

Discrimination of complete hydatidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57KIP2.

Abstract: The p57KIP2 protein is a cell cycle inhibitor and tumor suppressor encoded by a strongly paternally imprinted gene. We explored the utility of p57KIP2 as a diagnostic marker in hydatidiform mole, a disease likely the result of abnormal dosage and consequent misexpression of imprinted genes. Using a monoclonal antibody on paraffin-embedded, formalin-fixed tissue sections, the authors evaluated p57KIP2 expression in normal placenta and in 149 gestations including 59 complete hydatidiform moles, 39 PHMs, and 51 spontaneous losses with hydropic changes. p57KIP2 was strongly expressed in cytotrophoblast and villous mesenchyme in normal placenta, all cases of partial hydatidiform moles (39 of 39) and all spontaneous losses with hydropic changes (51 of 51). In contrast, p57KIP2 expression in cytotrophoblast and villous mesenchyme was absent or markedly decreased in 58 of 59 complete hydatidiform moles. In all gestations p57KIP2 was strongly expressed in decidua and in intervillous trophoblast islands, which served as internal positive controls for p57KIP2 immunostaining. p57KIP2 immunohistochemistry can reliably identify most cases of complete hydatidiform mole irrespective of gestational age and is thus a useful diagnostic adjunct, complementary to ploidy analysis, in the diagnosis of hydatidiform mole.

Maternal Floor Infarction and Massive Perivillous Fibrin Deposition: Histological Definitions, Association with Intrauterine Fetal Growth Restriction, and Risk of Recurrence

Abstract: Maternalfloor infarction (MFI) is a poorly understood placental lesion reportedly associated with intrauterine growth restriction (IUGR) and recurrence. In this study of MFI and the related placental disorder, massive perivillous fibrin deposition (MFD), semiquantitative histologic criteria for these diagnoses are defined and rates of IUGR and recurrence are assessed. Pathologic slides of 80 placentas diagnosed as MFI or MFD at the Brigham and Women’s Hospital (1989–99) were reviewed and reclassified as classic MFI, transmural MFD, borderline MFD, or neither MFI or MFD. The prevalence of IUGR was determined, and placental slides from additional pregnancies were reviewed to evaluate recurrence. Among 25 cases originally diagnosed as MFI, 5 (20%) were reclassified by study criteria as classic MFI, 9 (36%) as transmural or borderline MFD, and 11 (44%) as neither lesion. Among 55 cases originally diagnosed as MFD, 27 (49%) were reclassified as transmural or borderline MFD, 4 (7%) as classic MFI, and 24 (44%) as neither lesion. IUGR was identified in no case with classic MFI, in 31% of cases with transmural or borderline MFD (P = 0.02), and in 11% of cases with neither lesion. Recurrence was documented in 1 of 7 (14%) second- or third-trimester placentas. Possible recurrence was suggested in 3 of 6 (50%) first-trimester spontaneous abortion specimens. Classification of intraplacental fibrin is subjective and problematic; almost half of potential cases of MFI or MFD did not fulfill our study’s diagnostic criteria. MFD may be more common and more strongly associated with IUGR than classic MFI. Recurrence of these lesions appears to be infrequent among second- and third-trimester placentas, but may be relatively common in first-trimester spontaneous abortions.

The maternally transcribed gene p57KIP2 (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles

Abstract: Hydatidiform mole (HM) is an abnormal gestation characterized by trophoblast hyperplasia and overgrowth of placental villi. The genetic basis in the vast majority of cases is an excess of paternal to maternal genomes, suggesting that global misexpression of imprinted genes is the common molecular mechanism underlying the genesis of this condition. Although most complete HM are androgenetic in origin, a rare, frequently familial, biparental variant has been described. Here we evaluate the expression of p57(KIP2), the product of CDKN1C, an imprinted, maternally expressed gene in a series of these rare, biparental complete HM (BiCHM). We observed dramatic underexpression of p57(KIP2) in BiCHM, identical to that seen in complete HM of androgenetic origin (AnCHM). The series included two sisters, both of whom had BiCHM. Genotyping of this family identified a 15 cM region of homozygosity for 19q13.3-13.4 similar to that found in three other families with recurrent BiCHM. These results demonstrate that BiCHM, like AnCHM, result from abnormal expression of imprinted genes. In addition we provide further evidence for a major control gene on 19q13.3-13.4 which regulates expression of imprinted genes on other chromosomes.

DOC-2/hDab2, a candidate tumor suppressor gene involved in the development of gestational trophoblastic diseases.

Abstract: Gestational trophoblastic diseases comprise a spectrum of interrelated diseases including partial mole, complete mole and gestational choriocarcinoma. Using reverse transcriptase PCR (RT-PCR) analysis, we identified higher levels of DOC-2/hDab2 expression in the normal trophoblast cells in culture than in choriocarcinoma cell lines. Subsequent study using immunohistochemistry showed high levels of DOC-2/hDab2 protein expression in normal trophoblast tissues but significantly lower levels of expression in gestational trophoblastic disease tissues, particularly in complete mole and choriocarcinoma. When DOC-2/hDab2 was transfected into the choriocarcinoma cell lines, Jar, JEG and BeWo, the stable transfectants showed significantly reduced growth rate in culture. These data suggest that down regulation of DOC-2/hDab2 may play an important role in the development of gestational trophoblastic diseases.

Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting

Abstract: Imprinted genes are epigenetically marked during gametogenesis so that they are exclusively expressed from either the paternal or the maternal allele in offspring1 Imprinting prevents parthenogenesis in mammals and is often disrupted in congenital malformation syndromes, tumours and cloned animals1 Although de novo DNA methyltransferases of the Dnmt3 family are implicated in maternal imprinting2, the lethality of Dnmt3a and Dnmt3b knockout mice3 has precluded further studies We here report the disruption of Dnmt3a and Dnmt3b in germ cells, with their preservation in somatic cells, by conditional knockout technology4 Offspring from Dnmt3a conditional mutant females die in utero and lack methylation and allele-specific expression at all maternally imprinted loci examined Dnmt3a conditional mutant males show impaired spermatogenesis and lack methylation at two of three paternally imprinted loci examined in spermatogonia By contrast, Dnmt3b conditional mutants and their offspring show no apparent phenotype The phenotype of Dnmt3a conditional mutants is indistinguishable from that of Dnmt3L knockout mice2,5, except for the discrepancy in methylation at one locus These results indicate that both Dnmt3a and Dnmt3L are required for methylation of most imprinted loci in germ cells, but also suggest the involvement of other factors

Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications

Abstract: Heat shock proteins (Hsps) are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, metastasis, death, and recognition by the immune system. We review the current status of the role of Hsp expression in cancer with special emphasis on the clinical setting. Although Hsp levels are not informative at the diagnostic level, they are useful biomarkers for carcinogenesis in some tissues and signal the degree of differentiation and the aggressiveness of some cancers. In addition, the circulating levels of Hsp and anti-Hsp antibodies in cancer patients may be useful in tumor diagnosis. Furthermore, several Hsp are implicated with the prognosis of specific cancers, most notably Hsp27, whose expression is associated with poor prognosis in gastric, liver, and prostate carcinoma, and osteosarcomas, and Hsp70, which is correlated with poor prognosis in breast, endometrial, uterine cervical, and bladder carcinomas. Increased Hsp expression may also predict the response to some anticancer treatments. For example, Hsp27 and Hsp70 are implicated in resistance to chemotherapy in breast cancer, Hsp27 predicts a poor response to chemotherapy in leukemia patients, whereas Hsp70 expression predicts a better response to chemotherapy in osteosarcomas. Implication of Hsp in tumor progression and response to therapy has led to its successful targeting in therapy by 2 main strategies, including: (1) pharmacological modification of Hsp expression or molecular chaperone activity and (2) use of Hsps in anticancer vaccines, exploiting their ability to act as immunological adjuvants. In conclusion, the present times are of importance for the field of Hsps in cancer, with great contributions to both basic and clinical cancer research.

Neurobiology of Periventricular Leukomalacia in the Premature Infant

Abstract: Brain injury in the premature infant is a problem of enormous importance. Periventricular leukomalacia (PVL) is the major neuropathologic form of this brain injury and underlies most of the neurologic morbidity encountered in survivors of premature birth. Prevention of PVL now seems ultimately achievable because of recent neurobiologic insights into pathogenesis. The pathogenesis of this lesion relates to three major interacting factors. The first two of these, an incomplete state of development of the vascular supply to the cerebral white matter, and a maturation-dependent impairment in regulation of cerebral blood flow underlie a propensity for ischemic injury to cerebral white matter. The third major pathogenetic factor is the maturation-dependent vulnerability of the oligodendroglial (OL) precursor cell that represents the major cellular target in PVL. Recent neurobiologic studies show that these cells are exquisitely vulnerable to attack by free radicals, known to be generated in abundance with ischemia-reperfusion. This vulnerability of OLs is maturation-dependent, with the OL precursor cell highly vulnerable and the mature OL resistant, and appears to relate to a developmental window characterized by a combination of deficient antioxidant defenses and active acquisition of iron during OL differentiation. The result is generation of deadly reactive oxygen species and apoptotic OL death. Important contributory factors in pathogenesis interact with this central theme of vulnerability to free radical attack. Thus, the increased likelihood of PVL in the presence of intraventricular hemorrhage could relate to increases in local iron concentrations derived from the hemorrhage. The important contributory role of maternal/fetal infection or inflammation and cytokines in the pathogenesis of PVL could be related to effects on the cerebral vasculature and cerebral hemodynamics, to generation of reactive oxygen species, or to direct toxic effects on vulnerable OL precursors. A key role for elevations in extracellular glutamate, caused by ischemia-reperfusion, is suggested by demonstrations that glutamate causes toxicity to OL precursors by both nonreceptor- and receptor-mediated mechanisms. The former involves an exacerbation of the impairment in antioxidant defenses, and the latter, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor-mediated cell death. Most importantly, these new insights into the pathogenesis of PVL suggest potential preventive interventions. These include avoidance of cerebral ischemia by detection of infants with impaired cerebrovascular autoregulation, e.g. through the use of in vivo near-infrared spectroscopy, the use of free radical scavengers to prevent toxicity by reactive oxygen species, the administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor antagonists to prevent glutamate-mediated injury, or the use of maternal antibiotics or anticytokine agents to prevent toxicity from maternal/fetal infection or inflammation and cytokines.

Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis.

Abstract: ContextChorioamnionitis has been implicated in the pathogenesis of cerebral palsy, but most studies have not reported a significant association. Cystic periventricular leukomalacia (cPVL) is believed to be a precursor of cerebral palsy in preterm infants.ObjectivesTo determine whether chorioamnionitis is associated with cerebral palsy or cPVL and to examine factors that may explain differences in study results.Data SourcesSearches of MEDLINE (1966-1999), Index Medicus (1960-1965), Doctoral Dissertation Abstracts On-Line (1861-1999), bibliographies, and online conference proceedings (1999) were performed for English-language studies with titles or abstracts that discussed prenatal risk factors for cerebral palsy or cPVL.Study SelectionOf 229 initially identified publications, meta-analyses were performed on studies that addressed the association between clinical (n = 19) or histologic (n = 7) chorioamnionitis and cerebral palsy or cPVL in both preterm and full-term infants. Inclusion criteria were: presence of appropriate exposure and outcome measures, case-control or cohort study design, and provision of sufficient data to calculate relative risks (RRs) or odds ratios with 95% confidence intervals (CIs). Studies evaluating risk of cerebral palsy following maternal fever, urinary tract infection, or other maternal infection were collected, but not included in the meta-analysis.Data ExtractionInformation from individual studies was abstracted using standardized forms by 2 independent observers blinded to authors' names, journal titles, and funding sources.Data SynthesisUsing a random effects model, clinical chorioamnionitis was significantly associated with both cerebral palsy (RR, 1.9; 95% CI, 1.4-2.5) and cPVL (RR, 3.0; 95% CI, 2.2-4.0) in preterm infants. The RR of histologic chorioamnionitis and cerebral palsy was 1.6 (95% CI, 0.9-2.7) in preterm infants, and histologic chorioamnionitis was significantly associated with cPVL (RR, 2.1; 95% CI, 1.5-2.9). Among full-term infants, a positive association was found between clinical chorioamnionitis and cerebral palsy (RR, 4.7; 95% CI, 1.3-16.2). Factors explaining differences in study results included varying definitions of clinical chorioamnionitis, extent of blinding in determining exposure status, and whether individual studies adjusted for potential confounders.ConclusionOur meta-analysis indicates that chorioamnionitis is a risk factor for both cerebral palsy and cPVL.