A key challenge in the development of precision medicine is defining the phenotypic consequences of pharmacological modulation of specific target macromolecules. To address this issue, a variety of ...genetic, molecular and chemical tools can be used. All of these approaches can produce misleading results if the specificity of the tools is not well understood and the proper controls are not performed. In this paper we illustrate these general themes by providing detailed studies of small molecule inhibitors of the enzymatic activity of two members of the SMYD branch of the protein lysine methyltransferases, SMYD2 and SMYD3. We show that tool compounds as well as CRISPR/Cas9 fail to reproduce many of the cell proliferation findings associated with SMYD2 and SMYD3 inhibition previously obtained with RNAi based approaches and with early stage chemical probes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The cause of meconium passage in utero is controversial, traditionally being considered evidence of fetal stress and hypoxia, and also associated with intra-amniotic inflammation/infection. It is now ...recognized to also occur in the absence of fetal stress. Autopsy studies have shown that many term stillborns (SB) have hypoxic/ischemic brain injury and other evidence of stress preceding the time period immediately before demise, including acute thymic involution (ATI); however, these findings, along with placental findings, have not been previously correlated with meconium-stained amniotic fluid (MSAF).
35 structurally normal singleton term SB (21 early term, 14 full/late term) with complete autopsies, including brain and placental examination, were identified. MSAF was visually identified at delivery and confirmed on the placental examination. Autopsy evaluation included brain injury and ATI. Placental evaluation included maternal and fetal vascular malperfusion and acute and chronic inflammatory lesions. Demographic and clinical features were compared.
18 (51%) SB had MSAF, and 17 (49%) had clear amniotic fluid (CAF). The was no significant difference in brain injury in the MSAF vs CAF group, including older gray matter injury (karyorrhexis) (67% vs 47%), recent gray matter injury (red neurons, but no karyorrhexis) (28% vs 35%), white matter injury (50% vs 29%), and hemorrhage (22% vs 24%). Severe ATI was more frequent in the MSAF vs CAF group (61% vs 24%, p = .04). There was no significant difference in placental lesions between groups, including acute maternal inflammation (39% vs 18%), acute fetal inflammation (6% vs 6%), fetal vascular malperfusion (11% vs 18%), maternal vascular malperfusion (39% vs 35%), and chronic inflammatory lesions (39% vs 29%). The MSAF group was more likely to be full/late term than early term (72% vs 28%), in contrast to the CAF group (6% vs 94%) (p = .0001). There was no difference in other clinical factors evaluated.
51% of term SB had MSAF, and, in contrast to the CAF group, these were significantly more likely to be full/late term. Brain injury was frequent in both MSAF and CAF groups, supporting hypoxia as the mechanism of demise in most of these SB. No placental lesions correlated with MSAF, including inflammation. This suggests that hypoxia is the cause of the MSAF in these SB, but that some additional biologic factor present in the full/late term SB, but not present in the early term SB, including possibly gastrointestinal maturation, is necessary for the meconium passage.
The terminology and diagnostic criteria presently used by pathologists to report invasive placentation is inconsistent and does not reflect current knowledge of the pathogenesis of the disease or the ...needs of the clinical care team. A consensus panel was convened to recommend terminology and reporting elements unified across the spectrum of PAS specimens (i.e., delivered placenta, total or partial hysterectomy with or without extrauterine tissues, curetting for retained products of conception). The proposed nomenclature under the umbrella diagnosis of placenta accreta spectrum (PAS) replaces the traditional categorical terminology (placenta accreta, increta, percreta) with a descriptive grading system that parallels the guidelines endorsed by the International Federation of Gynaecology and Obstetrics (FIGO). In addition, the nomenclature for hysterectomy specimens is separated from that for delivered placentas. The goal for each element in the system of nomenclature was to provide diagnostic criteria and guidelines for expected use in clinical practice.
Protein arginine methyltransferase-5 (PRMT5) is reported to have a role in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient ...samples derived from lymphomas, particularly mantle cell lymphoma (MCL). Here we describe the identification and characterization of a potent and selective inhibitor of PRMT5 with antiproliferative effects in both in vitro and in vivo models of MCL. EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 enzymatic activity in biochemical assays with a half-maximal inhibitory concentration (IC50) of 22 nM and broad selectivity against a panel of other histone methyltransferases. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. Oral dosing with EPZ015666 demonstrated dose-dependent antitumor activity in multiple MCL xenograft models. EPZ015666 represents a validated chemical probe for further study of PRMT5 biology and arginine methylation in cancer and other diseases.
Placental mesenchymal dysplasia in trisomy 21 Qureshi, Faisal; Jacques, Suzanne M.
European journal of obstetrics & gynecology and reproductive biology,
April 2020, 2020-Apr, 2020-04-00, Letnik:
247
Journal Article
-The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories.
-To establish an agreed-upon ...protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community.
-Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible.
-The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous maturation, patterns of ascending intrauterine infection, and villitis of unknown etiology were agreed upon. Topics requiring further discussion were highlighted. Ongoing developments in our understanding of the pathology of the placenta, scientific bases of the maternofetoplacental triad, and evolution of the clinical significance of defined lesions may necessitate further refinements of these consensus guidelines. The proposed structure will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
A 22-year-old woman who was 36 weeks pregnant presented with a 4-day history of cough, hemoptysis, and exertional dyspnea. She had no fever, night sweats, or weight loss. The review of system was ...otherwise negative. Her medical history was notable for a spontaneous first-trimester abortion a year ago. At that time, she had a transvaginal ultrasound scan that showed a gestational sac with no fetal movement. A post-abortion ultrasound scan revealed no residual fetal parts.
Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting ...inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.
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•GSK3368715 is a potent inhibitor of type I protein arginine methyltransferases•GSK3368715 alters exon usage and has activity against multiple cancer models•GSK3368715 synergizes with the PRMT5 inhibitor GSK3326595 to inhibit tumor growth•MTAP gene deficiency impairs PRMT5 activity, sensitizing cancer cells to GSK3368715
Fedoriw et al. show that the type I protein arginine methyltransferases (PRMT) inhibitor GSK3368715 has strong anti-cancer activity and synergizes with PRMT5 inhibition. MTAP deficiency causes accumulation of an endogenous PRMT5 inhibitor, suggesting MTAP status as a predictive biomarker for GSK3368715.
Objective To determine the frequency and type of histopathologic lesions in placentas delivered by women with a normal pregnancy outcome. Methods This retrospective cohort study included placental ...samples from 944 women with a singleton gestation who delivered at term without obstetrical complications. Placental lesions were classified into the following four categories as defined by the Society for Pediatric Pathology and by our unit: (1) acute placental inflammation, (2) chronic placental inflammation, (3) maternal vascular malperfusion and (4) fetal vascular malperfusion. Results (1) Seventy-eight percent of the placentas had lesions consistent with inflammatory or vascular lesions; (2) acute inflammatory lesions were the most prevalent, observed in 42.3% of the placentas, but only 1.0% of the lesions were severe; (3) acute inflammatory lesions were more common in the placentas of women with labor than in those without labor; (4) chronic inflammatory lesions of the placenta were present in 29.9%; and (5) maternal and fetal vascular lesions of malperfusion were detected in 35.7% and 19.7%, respectively. Two or more lesions with maternal or fetal vascular features consistent with malperfusion (high-burden lesions) were present in 7.4% and 0.7%, respectively. Conclusion Most placentas had lesions consistent with inflammatory or vascular lesions, but severe and/or high-burden lesions were infrequent. Mild placental lesions may be interpreted either as acute changes associated with parturition or as representative of a subclinical pathological process (intra-amniotic infection or sterile intra-amniotic inflammation) that did not affect the clinical course of pregnancy.
Objective: To determine frequency, stage and grade of placental histologic acute maternal inflammatory response (MIR) and fetal inflammatory response (FIR) in meconium-stained amniotic fluid (MSAF) ...in our predominantly African-American population.
Methods: Term placentas with MSAF (n = 310) were evaluated for MIR/FIR, including stage/grade, and compared with placentas with clear amniotic fluid (AF) (n = 250). MIR/FIR were also evaluated in thick compared to thin MSAF subgroups. Selected demographic and clinical features were compared.
Results: MIR and FIR were present in 57.7 and 40.3% of the MSAF compared to 44.0 and 29.2% of the clear AF group, respectively (p = .001 and .008). MIR with FIR was present in 35.8% of the MSAF compared to 25.2% of the clear AF group (p = .008); however, there was no significant difference in frequency of MIR without FIR between groups. There was no significant difference in frequency of MIR/FIR in thick compared to thin MSAF; however, thick MSAF was associated with higher FIR stage compared to thin MSAF (29.2 versus 5.4%, p = .004). This association was not seen with MIR stage or MIR/FIR grade.
Conclusions: Histologic MIR and FIR are frequent findings in MSAF. Thick MSAF is associated with higher FIR stage when compared to thin MSAF.
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