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Aim: The aim of this study was to investigate the contribution of chromosomal microarray analysis (CMA) and next‐generation sequencing (NGS) to genetic diagnosis in fetuses with normal karyotype who underwent invasive testing for different indications. Methods: The results of invasive genetic testing performed at a tertiary center between September 2020 and March 2022 were retrospectively analyzed. Indications for invasive tests were classified as fetal structural malformation, presence of soft markers, and high risk in screening tests. CMA results were classified as pathogenic or likely pathogenic (pCNVs), benign (bCNVs), and variants of unknown clinical significance (VOUS). Results: A total of 830 invasive tests were performed and aneuploidy was detected in 11.2% of the fetuses. CMA was performed in 465 fetuses with normal karyotype, and pCNVs were detected in 6.9%. pCNVs were detected in 8.2% of fetuses with structural malformations, 6.5% in soft markers, and 4.7% in high risk in screening tests. Pathogenic variants were detected by NGS in 33.8% of fetuses with bCNVs. Conclusions: pCNVs can be significantly detected not only in fetuses with structural malformations, but also in invasive testing with other indications. NGS significantly contributes to genetic diagnosis in fetuses with structural malformations. [ABSTRACT FROM AUTHOR]

t(11;18)(q21;q21) is the most frequent chromosomal aberration specifically associated with mucosa-associated lymphoid tissue (MALT) lymphoma. The translocation fuses the API2 gene to the MALT1 gene and generates a functional API2-MALT1 transcript. The breakpoint of the fusion gene is well characterized at the transcript level but poorly understood at the genomic level and the mechanism underlying the translocation is unknown. We identified the genomic breakpoint in 19 t(11;18)-positive MALT lymphoma cases by polymerase chain reaction and sequencing and analysed the junctional sequences. The breakpoints were scattered in intron 7 and exon  8 of the API2 gene, and introns  4, 6, 7 and 8 of the MALT1 gene. Comparative sequence analysis between the API2-MALT1 fusion on der(11) and the MALT1-API2 fusion on der(18) showed extensive alterations including deletions, duplications and non-template-based insertions at the fusion junctions in all cases examined. An extensive sequence search failed to reveal any known sequence motifs that might be associated with chromosomal recombination or any novel consensus sequences at or near the breakpoints on both der(11) and der(18) except in one case, in which Alu repeats spanned the breakpoint of the MALT1-API2 fusion. Our results suggest that t(11;18) may result from illegitimate non-homologous end joining following double strand breaks. [ABSTRACT FROM AUTHOR]

The study discusses a new approach to parental agency in pediatric palliative care based on an active form of caregiving. It also explores the possibility of a positive conceptualization of parental agency in its relational context. The paper begins with an illustrative case study based on a clinical situation. This is followed by an analysis of various aspects of parental agency based on empirical studies that disclose the insufficiencies of the traditional approach to parental agency. In the next step, parental agency is analyzed from a reality‐based perspective as an activity focused on relationships and the cognitive capacity of parents vis‐a‐vis their seriously ill children. The paper also considers the importance of the cultural and social contexts in which parental agency and decision‐making take place. This agency is addressed not as individualistic in form, and nor is it exercised in terms of fixed choices. Rather, the focus is on its dynamic and future‐oriented aspects. Consequently, parental agency should be comprehended not only as a form of proxy agency representing the child's best interests but also as a complex decision‐making process in which the parents learn from their child how to become good, compassionate caregivers and at the same time good parents. [ABSTRACT FROM AUTHOR]

Currently, there is much interest in the sales and study of consumable Cannabis sativa L. products that contain relatively high levels of cannabidiol (CBD) and low levels of Δ‐9‐tetrahydrocannabinol. While there are published safety evaluations for extracts containing low concentrations of CBD, toxicological assessments for those with higher concentrations are still scant in the public domain. In this paper, genotoxicity tests and a 90‐day repeated‐dose toxicity study of an ethanolic extract of C. sativa containing ~85% CBD were performed following relevant OECD guidelines. No increased gene mutations were observed in a bacterial reverse mutation assay compared to controls up to the maximum recommended concentration of the guideline. An in vitro chromosomal aberration assay showed no positive findings in the short‐term (3 h) treatment assays. Long‐term treatment (20 h) showed an increased number of cells containing aberrations at the highest dose of 2 μg/mL, which was outside of historical control levels, but not statistically significantly different from the controls. An in vivo micronucleus study showed no genotoxic potential of the test item in mice. A 90‐day repeated‐dose gavage study using 0, 75, 125, and 175 mg/kg bw/day showed several slight findings that were considered likely to be related to an adaptive response to consumption of the extract by the animals but were not considered toxicologically relevant. These included increases in liver and adrenal weights compared to controls. The NOAEL was determined as 175 mg/kg bw/day, the highest dose tested (equivalent to approximately 150 mg/kg bw/day of CBD). A toxicological assessment of an ethanolic Cannabis sativa extract containing ~85% CBD was performed. Genotoxicity concern based on a bacterial reverse mutation assay, an in vitro chromosomal aberration assay, and an in vivo mouse micronucleus assay was considered low. A 90‐day repeated dose study in rats showed some adaptive responses but no toxicological concern. The NOAEL was 175 mg/kg bw/day, the highest dose tested. [ABSTRACT FROM AUTHOR]

Presents papers to be published in the periodical "British Journal of Haematology." Advances in the molecular and serological diagnosis of invasive fungal infection in hemato-oncology patients; Serum free light chains for monitoring multiple myeloma; Complex chromosomal abnormalities in utero.

Noninvasive prenatal testing (NIPT) has become widely available in recent years. While initially used to screen for trisomies 21, 18, and 13, the test has expanded to include a range of other conditions and will likely expand further. This paper addresses the ethical issues that arise from one particularly controversial potential use of NIPT: screening for adult‐onset conditions (AOCs). We report data from our quantitative survey of Australian NIPT users' views on the ethical issues raised by NIPT for AOCs. The survey ascertained support for NIPT for several traits and conditions including AOCs. Participants were then asked about their level of concern around implications of screening for AOCs for the future child and parent(s). Descriptive and comparative data analyses were conducted. In total, 109 respondents were included in data analysis. The majority of respondents expressed support for NIPT screening for preventable (70.9%) and nonpreventable AOCs (80.8%). Most respondents indicated concern around potential harmful impacts associated with NIPT for AOCs, including the psychological impact on the future child and on the parent(s). Despite this, the majority of participants thought that continuation of a pregnancy known to be predisposed to an AOC is ethically acceptable. The implications of these data are critically discussed and used to inform the normative claim that prospective parents should be given access to NIPT for AOCs. The study contributes to a body of research debating the ethical acceptability and regulation of various applications of NIPT as screening panels expand. [ABSTRACT FROM AUTHOR]

Background Approximately 50% of spontaneous miscarriages are associated with chromosome abnormalities. Identification of these karyotypic abnormalities helps to estimate recurrence risks in future pregnancies. Chromosomal microarray analysis ( CMA) is transforming clinical cytogenetic practice with its ability to examine the human genome at increasingly high resolution. Objectives The aim of this study was to determine whether CMA testing on the products of conception following miscarriage provides better diagnostic information compared with conventional karyotyping. Search strategy MEDLINE (from 1996 to December 2012), EMBASE (from 1974 to December 2012), and CINAHL (from 1996 to December 2012) databases were searched electronically. Selection criteria Studies were selected if CMA was used on products of conception following miscarriage, alongside conventional karyotyping. Data collection and analysis Nine papers were included in the systematic review and meta-analysis. All statistical analyses were performed using stata 11.0 ( Stata Corp., College Station, TX, USA). Main results There was agreement between CMA and karyotyping in 86.0% of cases (95% CI 77.0-96.0%). CMA detected 13% (95% CI 8.0-21.0) additional chromosome abnormalities over conventional full karyotyping. In addition, traditional, full karyotyping detected 3% (95% CI 1.0-10.0%) additional abnormalities over CMA. The incidence of a variant of unknown significance ( VOUS) being detected was 2% (95% CI 1.0-10.0%). Author's conclusions Compared with karyotyping, there appears to be an increased detection rate of chromosomal abnormalities when CMA is used to analyse the products of conception; however, some of these abnormalities are VOUS, and this information should be provided when counselling women following miscarriage and when taking consent for the analysis of miscarriage products by CMA. [ABSTRACT FROM AUTHOR]

Background: Although language difficulties are one of the most distinctive characteristics of the neuropsychological profile of children with sex chromosome trisomies (SCT), the analysis of the maternal input addressed to them is a neglected topic. Aims: The present study aims to analyse the lexical, morphosyntactic, and functional features of the input addressed to children with SCT comparing them with those of the input directed to typically developing children (TD). Methods & Procedures: Participants were 38 mothers and their 8‐month‐old children, 19 with SCT and 19 TD children. Maternal utterances, collected during video‐recorded play sessions, have been transcribed and coded. Outcomes & Results: No significant differences between groups have been found in the lexical and syntactic characteristics of maternal input. However, considering the input functional features, the proportion of directives and questions was significantly higher in the maternal input addressed to children with SCT than in the input addressed to TD children whereas the opposite pattern was found in the proportion of affect‐salient speech. Conclusions & Implications: The awareness of a possible delay in their children's language development could influence the way the mothers speak to them. In particular, the functional features of maternal input could be affected. Support groups for parents of children with SCT at the preverbal stage could be useful to reassure the mothers about their role in their children's language development. What this paper addsWhat is already known on the subjectStudies in the literature identified a high percentage of language delays or impairments in children with SCT. To date, according to our knowledge, there are no studies that analyse the linguistic input addressed to these children.What this study addsThe lexical and syntactic features of maternal input addressed to 8‐month‐old children with SCT are adequate to the children's communicative skills. However, the mothers of children with SCT seem to provide additional scaffolding in their verbal input, using a lower proportion of affect‐salient speech and a higher proportion of questions. In addition, a higher proportion of directives suggests the use of a more demanding style.Clinical implications of this studyThe awareness of possible language delays could influence the functional features of input leading mothers to use a more supportive and demanding input. Support groups for parents of children with SCT at the preverbal stage could be useful to reassure the mothers about their role in their children's language development. [ABSTRACT FROM AUTHOR]

Cleft lip and palate are common craniofacial deformities. The etiology underlying these deformities is complex and multifactorial and they can occur as part of one of many chromosomal syndromes, Mendelian single gene disorders, teratogenic effects, and as yet uncharacterized syndromes. Our paper will provide an overview of the multiple genes and molecular pathways that have been implicated in palatal fusion. We believe that understanding the molecular mechanisms of cleft formation can help clinicians anticipate which patients may have difficulties healing and in the future allow them to make surgical and medical treatment decisions based on genetic information. [ABSTRACT FROM AUTHOR]

RNA sequencing (RNA-seq) provides information not only about the level of expression of individual genes but also about genomic sequences of host cells. When we use transcriptome data with whole-genome single nucleotide polymorphism (SNP) variant information, the allele frequency can show the genetic composition of the cell population and/or chromosomal aberrations. Here, I show how SNPs in mRNAs can be used to evaluate RNA-seq experiments by focusing on RNA-seq data based on a recently retracted paper on stimulus-triggered acquisition of pluripotency (STAP) cells. The analysis indicated that different types of cells and chromosomal abnormalities might have been erroneously included in the dataset. This re-evaluation showed that observing allele frequencies could help in assessing the quality of samples during a study and with retrospective evaluation of experimental quality. [ABSTRACT FROM AUTHOR]

ABSTRACT Triple X syndrome (47,XXX) is a numerical chromosomal alteration that affects 1/1,000 women, in which the woman is born with an extra X chromosome. Some oral changes have been reported in the literature, as hypodontia, influence on deposition of crown enamel and discrepancies in cephalometric measurements. Other systemic complications may lead to oral abnormalities similar to those seen in triple X patients, such as congenital hypothyroidism (CH). This paper reports a triple X syndrome case associated with CH later treated. Besides delay in cognitive and intellectual development, the patient had changes in teeth development and in cephalometric measurements with deficiencies in the maxilla and mandible. This is the first report of a triple X syndrome associated with CH. Both conditions may result in changes in dentofacial development. [ABSTRACT FROM AUTHOR]

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Chromosome abnormalities account for half of the recorded miscarriages. Data from cytogenetic analysis of the products of conception (POC) in miscarriages are reviewed in the paper. Genetic analysis of POC allows patients to be given prognostic information. Molecular genetic techniques can overcome the pitfalls of conventional karyotyping, such as culture failure and trace submicroscopic abnormalities. We compare the pros and cons when these technologies are applied to the analysis of POC after miscarriage. Guidance is also provided for future clinical applications. The objective of the review is to help clinicians understand the limitations and to optimise the usefulness of genetic analysis of POC.Tweetable Abstract: Genetics and POC of miscarriage. [ABSTRACT FROM AUTHOR]

This study provides a detailed understanding of the preclinical pharmacokinetics and metabolism of ELP‐004, an osteoclast inhibitor in development for the treatment of bone erosion. Current treatments for arthritis, including biological disease‐modifying antirheumatic drugs, are not well‐tolerated in a substantial subset of arthritis patients and are expensive; therefore, new treatments are needed. Pharmacokinetic parameters of ELP‐004 were tested with intravenous, oral, and subcutaneous administration and found to be rapidly absorbed and distributed. We found that ELP‐004 was non‐mutagenic, did not induce chromosome aberrations, non‐cardiotoxic, and had minimal off‐target effects. Using in vitro hepatic systems, we found that ELP‐004 is primarily metabolized by CYP1A2 and CYP2B6 and predicted metabolic pathways were identified. Finally, we show that ELP‐004 inhibits osteoclast differentiation without suppressing overall T‐cell function. These preclinical data will inform future development of an oral compound as well as in vivo efficacy studies in mice. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Boyd P, Rounding C, Chamberlain P, Wellesley D, Kurinczuk J. The evolution of prenatal screening and diagnosis and its impact on an unselected population over an 18-year period. BJOG 2012;119:1131-1140. Objective To review changes in and impact of prenatal screening and diagnosis Design Population-based congenital anomaly register study. Setting Oxfordshire. Population Congenital anomalies confirmed and those suspected prenatally, delivered 1991-2008. Methods Analysis of proportions of congenital anomalies confirmed and those suspected prenatally. Main outcome measures Birth prevalence, prenatal detection rates, pregnancy outcomes. Results A total of 2651 (2.3%) infants/fetuses had a congenital anomaly diagnosed. There were 3839 suspected or confirmed cases, 2847 due to a prenatal suspicion, of which 1659 had an anomaly confirmed at delivery, and 1188 false-positive diagnoses, 91% due to reporting ultrasound normal variants. The percentage of prenatal notifications rose from 48% in 1991-93 to 83-88% from 1996 to 2003 and dropped to 61% in 2006-08, partly reflecting changes in the reporting of normal variants. Reporting these increased the prenatal diagnosis rate from 53 to 63% with an increase in false-positive rate from 0.09 to 1.04%. A total of 722 (44% of prenatally detected affected fetuses) resulted in termination; 48% of these had chromosome anomalies, 34% had isolated structural anomalies, 7% had multiple anomalies, 10% had familial disorders; 42% had lethal anomalies and 58% would probably have survived the neonatal period giving an estimated 20% reduction in birth prevalence of congenital anomalies compatible with survival because of terminations. Conclusion There has been an improvement in prenatal detection of congenital anomalies over the two decades studied. The recognition that reporting normal variants, although increasing prenatal detection rates, leads to an increase in false-positive diagnoses has had an impact on practice that has redressed the balance between these two effects. [ABSTRACT FROM AUTHOR]

Objective: To review systematically the empirical evidence for the involvement of genetic risk factors in infantile autism. Method: We aimed at including all relevant papers written in English. We conducted a Medline search in September 2000. In addition we searched the reference lists of related papers. Results: A relatively small number of reports including family and twin studies, comorbidity, cytogenetic and molecular genetic studies were reviewed. Conclusion: As well family, twin, cytogenetic and molecular genetic studies supported the importance of genetic risk factors in infantile autism. In most individual cases probably at least a few gene variants simultaneously determine the genetic risk. Presently the most interesting chromosome regions concerning the aetiology of autism are chromosomes 7q31–35, 15q11–13 and 16p13.3 which have been suggested by different lines of genetic research. [ABSTRACT FROM AUTHOR]

Platelet-derived-growth-factor (PDGF) A-chain transcripts differing in the presence or absence of an alternative exon-derived sequence have been described. In some publications, the presence of PDGF A-chain transcripts with this exon-6-derived sequence was suggested to be tumour specific. However, in this paper it was shown by reverse-transcription polymerase-chain-reaction (PCR) analysis that both normal mesothelial cells and malignant mesothelioma cell lines predominantly express the PDGF A-chain transcript without the exon-6-derived sequence. This sequence encodes a cell-retention signal, which means that the PDGF A-chain protein is most likely to be secreted by both cell types. In cultured normal mesothelial cells, the secreted PDGF A-chain protein might be involved in autocrine growth stimulation via PDGF α receptors. However, human malignant mesothelioma cell lines only possess PDGF β receptors. If this also holds true in vivo, the PDGF A- chain protein produced and secreted by malignant mesothelial cells might have a paracrine function. In a previous paper, we described elevated expression of the PDGF A-chain transcript in human malignant mesothelioma cell lines, compared to normal mesothelial cells. In this paper, the possible reason for this elevation was studied. First, alterations at the genomic level were considered, but cytogenetic and Southern-blot analysis revealed neither consistent chromosomal aberrations, amplification nor structural rearrangement of the PDGF A-chain gene in the malignant cells. Possible differences in transcription rate of the PDGF A-chain gene, and stability of the transcript between normal and malignant cells, were therefore studied. The presence of a protein-synthesis inhibitor, cycloheximide, in the culture medium did not significantly influence the PDGF A-chain mRNA level in normal mesothelial and malignant mesothelioma cell lines. Furthermore, nuclear run-off analysis showed that nuclear PDGF A-chain mRNA levels varied in both cell types to the same extent as the levels observed in Northern blots. Taken together, this suggests that increased transcription is the most probable mechanism for the elevated mRNA level of the PDGF A-chain gene in human malignant mesothelioma cell lines. [ABSTRACT FROM AUTHOR]

Objective: The present study is aimed at introducing and evaluating MaterniCode, a state‐of‐the‐art bioinformatic pipeline for noninvasive prenatal testing (NIPT) that leverages the Ion Torrent semiconductor sequencing platform. The initiative strives to revolutionize prenatal diagnostics by offering a rapid and cost‐effective method without sacrificing accuracy. Methods: Two distinct bioinformatic strategies were employed for fetal sex determination, one of which achieved 100% accuracy. We analyzed 1225 maternal blood samples for fetal aneuploidies, benchmarking against the industry standard Illumina VeriSeq™ NIPT Solution v2. The capability of MaterniCode to detect and characterize complex chromosomal anomalies was also assessed. Results: MaterniCode achieved near‐perfect accuracy in fetal sex determination through chromosome Y (chrY)–specific gene analysis, whereas the alternative method, employing the ratio of high‐quality mapped reads on chrY relative to all reads, delivered 100% accuracy. For fetal aneuploidy detection, both the integrated WisecondorX and NIPTeR algorithms demonstrated a 100% sensitivity and specificity rate, consistent with Illumina VeriSeq™ NIPT Solution v2. The pipeline also successfully identified and precisely mapped significant chromosomal abnormalities, exemplified by a 2.4 Mb deletion on chromosome 13 and a 3 Mb duplication on chromosome 2. Conclusion: MaterniCode has proven to be an innovative and highly efficient tool in the domain of NIPT, demonstrating excellent sensitivity and specificity. Its robust capability to effectively detect a wide range of complex chromosomal aberrations, including rare and subtle variations, positions it as a promising and valuable addition to prenatal diagnostic technologies. This enhancement to diagnostic precision significantly aids clinicians in making informed decisions during pregnancy management. [ABSTRACT FROM AUTHOR]

Chromosomal aberration mostly occurs in chromosomes 21, 18 and 13, with an incidence approximately 1 out of 160 live births in humans, therefore making prenatal diagnosis necessary in clinics. Current methods have drawbacks such as time consuming, high cost, complicated operations and low sensitivity. In this paper, a novel method for rapid and accurate prenatal diagnosis of aneuploidy is proposed based on pyrosequencing, which quantitatively detects the peak height ratio (PHR) of different bases of segmental duplication. A direct polymerase chain reaction ( PCR) approach was undertaken, where a small volume of amniotic fluid was used as the starting material without DNA extraction. Single-stranded DNA was prepared from PCR products and subsequently analyzed using pyrosequencing. The PHR between target and reference chromosome of 2.2 for euploid and 3:2 for a trisomy fetus were used as reference. The reference intervals and z scores were calculated for discrimination of aneuploidy. A total of 132 samples were collected, within trisomy 21 ( n = 11), trisomy 18 ( n = 3), trisomy 13 ( n = 2), and unaffected controls ( n = 116). A set of six segmental duplications were chosen for analysis. This method had consistent results with karyotyping analysis, a correct diagnosis with 100% sensitivity and 99.9% specificity. [ABSTRACT FROM AUTHOR]

Introduction: Currently fetal nuchal translucency (NT) ≥3.5 mm is an indication for invasive testing often followed by chromosomal microarray. The aim of this study was to assess the risks for chromosomal aberrations in fetuses with an NT 3.0-3.4 mm, to determine whether invasive prenatal testing would be relevant in these cases and to assess the residual risks in fetuses with normal non-invasive prenatal test (NIPT) results.Material and Methods: A retrospective study and meta-analysis of literature cases with NT between 3.0 and 3.4 mm and 2 cohorts of pregnant women referred for invasive testing and chromosomal microarray was performed: Rotterdam region (with a risk >1:200 and NT between 3.0 and 3.4 mm) tested in the period July 2012 to June 2019 and Central Denmark region (with a risk >1:300 and NT between 3.0 and 3.4 mm) tested between September 2015 and December 2018.Results: A total of 522 fetuses were referred for invasive testing and chromosomal microarray. Meta-analysis indicated that in 1:7.4 (13.5% [95% CI 8.2%-21.5%]) fetuses a chromosomal aberration was diagnosed. Of these aberrant cases, 47/68 (69%) involved trisomy 21, 18, and 13 and would potentially be detected by all NIPT approaches. The residual risk for missing a (sub)microscopic chromosome aberration depends on the NIPT approach and is highest if NIPT was performed only for common trisomies-1:21 (4.8% [95% CI 3.2%-7.3%]). However, it may be substantially lowered if a genome-wide 10-Mb resolution NIPT test was offered (~1:464).Conclusions: Based on these data, we suggest that the NT cut-off for invasive testing could be 3.0 mm (instead of 3.5 mm) because of the high risk of 1:7.4 for a chromosomal aberration. If women were offered NIPT first, there would be a significant diagnostic delay because all abnormal NIPT results need to be confirmed by diagnostic testing. If the woman had already received a normal NIPT result, the residual risk of 1:21 to 1:464 for chromosome aberrations other than common trisomies, dependent on the NIPT approach, should be raised. If a pregnant woman declines invasive testing, but still wants a test with a broader coverage of clinically significant conditions then the genome-wide >10-Mb resolution NIPT test, which detects most aberrations, could be proposed. [ABSTRACT FROM AUTHOR]

Background: The nucleic acid targeted pathogen reduction (PR) system utilizing amustaline (S-303) and glutathione (GSH) is designed to inactivate blood-borne pathogens and leukocytes in red blood cell concentrates (PR-RBCC). Inactivation is attained after amustaline intercalates and forms covalent nucleic acid adducts preventing replication, transcription, and translation. After pathogen inactivation, amustaline spontaneously hydrolyzes to S-300, the primary negatively charged reaction product; amustaline is below quantifiable levels in PR-RBCC. GSH quenches free unreacted amustaline.Study Design and Methods: The genotoxic and carcinogenic potential of PR-RBCC, the reaction by-products, and S-300 were assessed in accordance with the International Conference on Harmonization (ICH) guidelines and performed in compliance with the Food and Drug Administration (FDA) good laboratory practice standards, 21 CFR Part 58. in vitro bacterial reverse mutagenicity and chromosomal aberration assays were performed with and without exogenous S9 metabolic activation, and in in vivo clastogenicity and carcinogenic assays using validated murine models.Results: PR-RBCCs were not genotoxic in vitro and in vivo and were non-carcinogenic in p53+/- transgenic mice transfused over 26 weeks. Estimated safety margins for human exposure ranged from >90 to >36 fold for 2 to 5 PR-RBCCs per day, respectively. PR-RBCCs and S-300 did not induce chromosome aberration in the in vivo murine bone marrow micronucleus assay at systemically toxic doses.Conclusions: PR-RBCCs did not demonstrate genotoxicity in vitro or in vivo and were not carcinogenic in vivo. These studies support the safety of PR-RBCCs and suggest that there is no measurable genotoxic hazard associated with transfusion of PR-RBCCs. [ABSTRACT FROM AUTHOR]

Arising from neural crest cells, neuroblastoma (NB) is the most common extracranial pediatric solid tumor. The clinical presentation of NB is heterogeneous, ranging from patients with asymptomatic tumor masses, who require minimal treatment, to patients with metastatic disease who are treated with multimodal therapies. Clinical outcome is also variable, with overall survival ranging from 98% to 100% in infants with stage 1 NB, to less than 30% in patients with stage 4 MYCN-amplified NB. More than 50% of patients show metastasis at diagnosis, with the involvement of different vascularized tissues, including the bone marrow (BM). In this paper, we focus on BM infiltration by NB cells, which is considered an adverse prognostic factor. In particular, we discuss the role of different biological factors that may favor the dissemination of NB cells in the BM, such as chromosomic abnormalities, gene amplification, transcription factors, cell-surface receptors, products of oncogenes, and, more importantly, cytokines and chemokines. In addition, we analyze different techniques to evaluate BM infiltration by malignant cells (i.e., flow cytometry, immunocytochemistry, and quantitative reverse transcriptase polymerase chain reaction). Finally, we review recent data regarding phenotypic and genetic characterization of BM-infiltrating malignant cells and characterization of the BM microenvironment in NB patients compared to healthy subjects. [ABSTRACT FROM AUTHOR]

Dental anomalies are the formative defects caused by genetic disturbances or environmental factors during tooth morphogenesis. Simultaneous occurrence of various multiple anomalies has been reported previously, particularly in cases of chromosomal abnormalities that often manifest with multisystem involvement. Very few cases of multiple anomalies have been documented in patients with no known generalized abnormalities. The present paper shows an unusual occurrence of a combination of dental anomalies like mandibular canine transmigration, taurodontism in permanent mandibular molars, congenital agenesis of 14 numbers of permanent teeth excluding third molars, canine impaction, primary molars with pyramidal roots, midline diastema and generalized microdontia in an apparently normal 13-year-old Indian girl. [ABSTRACT FROM AUTHOR]

Medical genetics is a field marked by fast progress. Even though it was at one point confined to a group of relatively rare diseases, today it has become a central component in the understanding of disorders and it is the subject of interest for all medical specialties. This paper, shares data on the chromosomal alterations and variations that have been diagnosed in Ecuadorian patients since 1998. A total of 2,636 individual cases have been analyzed by G-banding technique until February 2012. The present work shows this collection of data and the important findings that have appeared throughout these years in hopes that it can contribute to have a deeper understanding of the incidence of chromosomal aberrations and alterations in the Ecuadorian population. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Savvidou M, Samuel I, Syngelaki A, Poulton M, Nicolaides K. First-trimester markers of aneuploidy in women positive for HIV. BJOG 2011;118:844-848. To investigate whether the sonographic and maternal serum biochemical markers used in first-trimester screening for chromosomal abnormalities are altered in pregnancies affected by maternal HIV infection. Nested case-control study. Routine antenatal visit in a teaching hospital. Ninety HIV-positive and 450 HIV-negative pregnant women. Findings from first-trimester antenatal visit for calculation of the risk for chromosomal abnormalities were compared between HIV-positive (treated and untreated) and HIV-negative women. First-trimester maternal serum free β human chorionic gonadotrophin (free β-hCG) pregnancy-associated plasma protein-A (PAPP-A) and fetal nuchal translucency thickness (NT), were compared. There were no statistically significant differences between the HIV-positive and HIV-negative women in the median maternal levels of free β-hCG, PAPP-A and fetal NT. However, within the HIV-positive group those receiving antiretroviral treatment ( n = 41) had a significantly lower median multiple of the median (MoM) for free β-hCG (0.74, interquartile range [IQR] 0.45-1.32 MoM) than HIV-positive women on no treatment (1.03, IQR 0.76-1.85 MoM; P = 0.006) and HIV-negative women (1.0, IQR 0.68-1.47 MoM; P = 0.003). There was no correlation between the level of free β-hCG or PAPP-A and maternal viral load or CD4 count. Maternal levels of free β-hCG in treated HIV-positive pregnant women were lower compared with those in non-treated HIV-positive and HIV-negative women, whereas the PAPP-A levels and fetal NT remained unaltered. [ABSTRACT FROM AUTHOR]

The article presents abstracts on research papers which include tolerance of superfine merino wool cloth in preschool children with atopic eczema, association of the chromosome 11q13.5 variant with atopic dermatitis in Austrian patients and diagnosis and treatment of bone diseases in patients with mastocytosis, to be discussed at poster session on allergic skin diseases, mastocystosis and hereditary angioedema.

T(15;17) is the most common chromosomal aberration in patients with acute promyelocytic leukemia (APL), leading to the formation of PML-RARα fusion gene. In a small subset of patients with APL, the RARα gene is fused with different partners. Here, we report a rare APL case with STAT5B-RARα fusion transcript. Cytomorphologic and immunophenotypic analyses showed typical features of APL. However, cytogenetic analysis showed normal karyotype, and interphase fluorescence in situ hybridization (FISH) showed PML-RARα negative. Quantitative RT-PCR also showed PML-RARα negative but STAT5B-RARα positive and sequencing analysis confirmed the result. Molecular markers including FLT3, NPM1, c-Kit and C/EBPα mutation were all negative. To our knowledge, this is the first APL patient with STAT5B-RARα in Chinese population and the fifth patient around the world according to published paper. [ABSTRACT FROM AUTHOR]

Ochratoxin A (OTA) is a toxin produced by Aspergillus and Penicillum moulds . Since OTA has not yet been evaluated in plant systems, this paper focused on describing the controversial effect OTA in an Allium root test model, which has known sensitivity to genotoxins and could be useful in toxin screening. Analyses of root growth and the root meristematic zone in response to OTA treatment were undertaken. The results show OTA toxicity to root growth at a concentration of 10 ug·ml−1 associated with inhibition of proliferation activity. Cytological changes observed in the Allium chromosome aberrations assay, at a concentration of 5.0 ug·ml−1, showed that OTA was able to induce genotoxicity at the chromosome level. These results indicate that plants cells ( Allium cepa) are very sensitive to the mycotoxin OTA, as observed at the highest concentration. Under these conditions, OTA produced toxicity and cytogenetic injury. Evidence in vitro and in vivo indicates that OTA can induce damage at the DNA level. [ABSTRACT FROM AUTHOR]

P53 mutation has been reported in various solid tumors, acute leukemia and myelodysplastic syndrome (MDS), but the diagnostic significance of p53 in MDS remains to be determined. The purpose of the present paper was to examine p53 mutation and immunostaining of the same patients, because there have been few reports of simultaneous analysis of these markers. Seven p53 mutations were observed among 37 MDS and 11 cases of overt leukemia transformed from MDS (MDS-OL). Mutated p53 mainly observed in high-risk MDS had more intense p53 staining than in MDS with wild-type p53 overexpression. Aplastic anemia (AA) produced no p53 staining. The percentage of p53 staining in MDS (71%) was higher than that of mutated p53 (11%) but did not reach 100% of MDS cases studied, therefore the authors attempted to differentiate MDS, especially refractory anemia (RA) and AA, using a combination of p53 immunostaining, hemoglobin F (HbF) immunostaining and chromosome abnormality, because HbF of erythroblasts was reportedly observed in MDS RA but not in AA. Most MDS/MDS-OL (47/48) had at least one positive marker. Among 11 AA cases, only two were positive for HbF. The present results suggest that the combination of these three markers is useful to discriminate MDS from AA. [ABSTRACT FROM AUTHOR]

Balanced reciprocal and Robertsonian translocations are the most common structural chromosomal abnormalities in humans. Generally, they are without consequence for the carrier, but for various degrees of oligoasthenoteratozoospermia in men. As these carriers can produce a significant percentage of gametes with an unbalanced combination of the parental rearrangement, there is a more or less significant risk, according to cases, of chromosomal imbalances for their offspring. Therefore, techniques were developed to study the meiotic segregation of these translocations in males. Direct investigation of human sperm chromosomes became possible by karyotyping spermatozoa after penetration of zona-free hamster oocytes and, more recently, using fluorescent in situ hybridization (FISH). This paper reviews the results obtained using these techniques in Robertsonian and reciprocal translocations. The studies on spermatozoa from translocation carriers help the comprehension of the mechanisms of the meiotic segregation. They should be integrated in the genetic exploration of the infertile men, in order to give them a personalized risk assessment of unbalanced spermatozoa, specially as a correlation was found recently between the percentage of abnormal spermatozoa and that of abnormal embryos. [ABSTRACT FROM AUTHOR]

Human germ cell tumours (GCTs) constitute a heterogeneous group of tumours that can be classified into four major subgroups. One of these subgroups encompasses (immature) teratomas and yolk sac tumours of patients under the age of 5 years. In this paper we review the various clinical, histological and cytogenetical aspects of these infantile GCTs. The primordial germ cell (PGC) has been suggested to be the cell of origin for GCTs. Infantile GCTs, however, have been suggested to originate from PGCs at a different stage of maturation than adult GCTs. The cytogenetic constitution of infantile GCTs also appears to differ from the adult GCTs and includes recurrent losses of 1p and 6q. Recently, two cases of infantile GCT were detected with constitutional 12q13 translocations. These exceptional cases may be instrumental in the search for candidate genes related to infantile and/or adult GCT development. [ABSTRACT FROM AUTHOR]

Diploid/triploid mosaicism is a dysmorphology syndrome consisting of mental retardation, truncal obesity, body and/or facial asymmetry, growth retardation, hypotonia, a small phallus, malformed low-set ears and micrognathia. In 75% of the cases, the blood karyotype is normal and the diagnosis can only be established after analysis of cultured fibroblasts. This chromosome abnormality may therefore be underdiagnosed. This paper focuses on the identification of mentally retarded and dysmorphic patients with diploid/triploid mosaicism. Detailed clinical description of well-defined patients may help in deciding if a skin biopsy for karyotyping of fibroblasts should be taken. Three new cases are presented, in which DNA marker analysis showed that the extra set of chromosomes in each case was derived from the mother. We present a review of 25 cases described in the literature and we discuss the inclusion of a second polar body into an early diploid embryo as the most likely mechanism. [ABSTRACT FROM AUTHOR]

Comparative genomic hybridization (CGH) is an established genetic method which enables a genome-wide survey of chromosomal imbalances. For each chromosome region, one obtains the information whether there is a loss or gain of genetic material, or whether there is no change at that place. Therefore, large amounts of data quickly accumulate which must be put into a logical order. Cluster analysis can be used to assign individual cases (samples) to different clusters of cases, which are similar and where each cluster may be related to a different tumour biology. Another approach consists in a clustering of chromosomal regions by rewriting the original data matrix, where the cases are written as rows and the chromosomal regions as columns, in a transposed form. In this paper we applied hierarchical cluster analysis as well as two implementations of self-organizing feature maps as classical and neuronal tools for cluster analysis of CGH data from prostatic carcinomas to such transposed data sets. Self-organizing maps are artificial neural networks with the capability to form clusters on the basis of an unsupervised learning rule. We studied a group of 48 cases of incidental carcinomas, a tumour category which has not been evaluated by CGH before. In addition we studied a group of 50 cases of pT2N0-tumours and a group of 20 pT3N0-carcinomas. The results show in all case groups three clusters of chromosomal regions, which are (i) normal or minimally affected by losses and gains, (ii) regions with many losses and few gains and (iii) regions with many gains and few losses. Moreover, for the pT2N0- and pT3N0-groups, it could be shown that the regions 6q, 8p and 13q lay all on the same cluster (associated with losses), and that the regions 9q and 20q belonged to the same cluster (associated with gains). For the incidental cancers such clear correlations could not be demonstrated. [ABSTRACT FROM AUTHOR]

Summary. This paper reviews the latest data on chromosomal abnormalities in human gametes and embryos. A close relationship between such anomalies and reproduction failure in humans has been postulated, thereby underscoring the importance of ongoing studies into the mechanisms leading to anomalies. Until recently, knowledge of chromosomal anomalies in human gametes and embryos has been limited. Newly developed strategies (in vitro fertilization combined with micromanipulation techniques followed by multicolour fluorescence in situ hybridization, and PCR analyses) allow precise investigation of this problem. This review of the available information on the etiology of chromosomal anomalies indicates that some of the genetic anomalies in human gametes and early embryos result in reproductive failure. [ABSTRACT FROM AUTHOR]

Background: Melanocytic tumors driven by MAP2K1 in‐frame deletions are among the most recently described class of melanocytic neoplasms. The reported range of diagnoses and associated genomic aberrations in these neoplasms is wide and includes melanomas, deep penetrating melanocytomas, and pigmented epithelioid melanocytoma. However, little is known about the characteristics of these tumors, especially in the absence of well‐known second molecular "hits." Moreover, despite their frequent spitzoid cytomorphology, their potential categorization among the Spitz tumors is debatable. Materials and Methods: We conducted a retrospective search through our molecular archives to identify sequenced melanocytic tumors with MAP2K1 in‐frame deletions. We reviewed the clinical and histomorphological features of these tumors and compared them to similar neoplasms reported to date. In addition, we performed single‐nucleotide polymorphism (SNP) array testing to identify structural chromosomal aberrations. Results: Of 27 sequenced tumors, 6 (22%) showed a pathogenic MAP2K1 in‐frame deletion (with or without insertion) and were included in this series. Five (83%) were females with lesions involving the upper limb. Histopathologically, all neoplasms were compounded with plaque‐like or wedge‐shaped silhouettes, spitzoid cytomorphology, and impaired cytologic maturation. All cases showed background actinic damage with sclerotic stroma replacing solar elastosis, variable pagetoid scatter, and occasional dermal mitotic figures (range 1–2/mm2). Five cases (83%) had a small component of nevic‐looking melanocytes. Biologically, these tumors likely fall within the spectrum of unusual nevi. Five cases (83%) had a relatively high mutational burden and four (67%) showed an ultraviolet radiation signature. Four cases (67%) showed in‐frame deletion involving the p.I103_K104del locus while two cases (33%) showed in‐frame deletion involving the p.Q58_E62del locus. SNP array testing showed structural abnormalities ranging from 1 to 5 per case. Five of these cases showed a gain of chromosome 15 spanning the MAP2K1 gene locus. Discussion and Conclusion: Melanocytic tumors with MAP2K1 in‐frame deletion could represent another spectrum of melanocytic tumors with close genotypic–phenotypic correlation. They are largely characterized by a spectrum that encompasses desmoplastic Spitz nevus as shown in our series and Spitz and Clark nevus as shown by others. Evolutionary, they share many similarities with tumors with BRAF V600E mutations, suggesting they are better classified along the conventional pathway rather than the Spitz pathway despite the frequent spitzoid morphology. [ABSTRACT FROM AUTHOR]

Background and Purpose: The application of classical cytogenetic and DNA‐based molecular techniques to detect cell lineages of mosaicism derived from cultured or noncultured fetal cells may result in discordant results. This retrospective study aimed to assess the inconsistent diagnostic outcomes, technical availability, and limitations of chromosomal microarray analysis (CMA) and karyotyping for mosaicism. Methodology: A total of 75 fetuses diagnosed with mosaicism by karyotype analysis or CMA were selected, and the results from both the methods were compared and further analyzed. Results: A total of 42 (56%, 42/75) CMA results were consistent with karyotypes, consisting of 22 cases of mosaic sex chromosomal abnormalities, 8 routine autosomal aneuploidy cases, 8 other autosome aneuploidy cases, 3 large cryptic genomic rearrangements, and 1 small supernumerary marker chromosome. Discrepancy between karyotype analysis and CMA was observed in 33 (44%, 33/75) mosaicisms involving 15 sex chromosomal abnormalities, 1 routine autosomal aneuploidies, 5 other autosome aneuploidy cases, 8 large cryptic genomic rearrangements, and 4 small supernumerary marker chromosomes. Conclusion: Considering the disparities between methods as well as the cell populations analyzed, both CMA and karyotype analysis have their own advantages and disadvantages. Therefore, CMA should ideally be used in combination with karyotyping to detect more cases of mosaicism than using either test alone. [ABSTRACT FROM AUTHOR]

In this paper, the authors present the case of a 24-year-old female with ring 15 chromosome syndrome. Upon examination, the patient presented with severe mental retardation, dwarfism and microcephaly, along with other minor dysmorphic stigmata. We compared this case with three other adult female cases with this chromosomal aberration. As a result, the authors observed a somewhat dysharmonious profile between the level of mental retardation and behavioural findings in the four women, while sexual development and gonadal function seemed to be normal in all four cases. [ABSTRACT FROM AUTHOR]

Background: Pathogenic mutations in EVC or EVC2 gene can lead to Ellis‐van Creveld (EvC) syndrome, which is a rare autosomal recessive skeletal dysplasia disorder. This study aimed to determine pathogenic gene variations associated with EvC syndrome in fetuses showing ultrasound anomalies. Methods: A 32‐year‐old pregnant woman from Quanzhou, China was investigated. In her pregnancy examination, the fetus exhibited multiple fetal malformations, including a narrow thorax, short limbs, postaxial polydactyly, cardiac malformations, and separation of double renal pelvis. Karyotype, chromosomal microarray analysis and whole exome sequencing were performed for prenatal genetic etiology analysis. Results: Chromosome abnormalities and copy number variants were not observed in the fetus using karyotype and chromosomal microarray analysis. Using whole exome sequencing, two compound heterozygous variants NM_147127.5:c.[2484G>A(p.Trp828Ter)];[871‐2_894del] in EVC2 gene were identified in the fetus as pathogenic variants inherited from parents. Conclusions: The study is the first to identify two rare compound variants in EVC2 gene in a Chinese family using whole exome sequencing. The application of whole‐exome sequencing would be helpful in fetal etiological diagnosis with ultrasound anomalies. [ABSTRACT FROM AUTHOR]

Summary: Acute megakaryoblastic leukaemia (AMKL) is associated with poor prognosis. Limited information is available on its cytogenetics, molecular genetics and clinical outcome. We performed genetic analyses, evaluated prognostic factors and the value of allogeneic haematopoietic stem cell transplantation (allo‐HSCT) in a homogenous adult AMKL patient cohort. We retrospectively analysed 38 adult patients with AMKL (median age: 58 years, range: 21–80). Most received intensive treatment in AML Cooperative Group (AMLCG) trials between 2001 and 2016. Cytogenetic data showed an accumulation of adverse risk markers according to ELN 2017 and an unexpected high frequency of structural aberrations on chromosome arm 1q (33%). Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%). Complete remission rate in 33 patients receiving intensive chemotherapy was 33% and median overall survival (OS) was 33 weeks (95% CI: 21–45). Patients undergoing allo‐HSCT (n = 14) had a superior median OS (68 weeks; 95% CI: 11–126) and relapse‐free survival (RFS) of 27 weeks (95% CI: 4–50), although cumulative incidence of relapse after allo‐HSCT was high (62%). The prognosis of AMKL is determined by adverse genetic risk factors and therapy resistance. So far allo‐HSCT is the only potentially curative treatment option in this dismal AML subgroup. [ABSTRACT FROM AUTHOR]

Introduction: B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) is the most common neoplasm in children. One of the long known recurrent rearrangements in BCP‐ALL is t(1;19)(q23;p13.3)/TCF3::PBX1. However, other TCF3 gene rearrangements were also described that are associated with significant difference in ALL prognosis. Methods: The current study aimed to analyze the spectrum of TCF3 gene rearrangements in children in Russian Federation. A cohort of 203 patients with BCP‐ALL was selected based on FISH screening and was studied by karyotyping, FISH, RT‐PCR and high throughput sequencing. Results: T(1;19)(q23;p13.3)/TCF3::PBX1 is the most common aberration in TCF3‐positive pediatric BCP‐ALL (87.7%), with its unbalanced form prevailing. It resulted from TCF3::PBX1 exon 16‐exon 3 fusion junction (86.2%) or unconventional exon 16‐exon 4 junction (1.5%). Rarer events included t(12;19)(p13;p13.3)/TCF3::ZNF384 (6.4%) and t(17;19)(q21‐q22;p13.3)/TCF3::HLF (1.5%). The latter translocations demonstrated high molecular heterogeneity and complex structure—four distinct transcripts were shown for TCF3::ZNF384 and each patient with TCF3::HLF had a unique transcript. These features hamper TCF3 rearrangement primary detection by molecular methods and brings FISH screening to the fore. A case of novel TCF3::TLX1 fusion in a patient with t(10;19)(q24;p13) was also discovered. Survival analysis within the national pediatric ALL treatment protocol demonstrated the severe prognosis of TCF3::HLF compared to both TCF3::PBX1 and TCF3::ZNF384. Conclusion: So, high molecular heterogeneity of TCF3 gene rearrangement in pediatric BCP‐ALL was demonstrated and a novel fusion gene TCF3::TLX1 was described. [ABSTRACT FROM AUTHOR]

Background: Copy number variation sequencing (CNV‐seq) could detect most chromosomal abnormalities except polyploidy, and quantitative fluorescence polymerase chain reaction (QF‐PCR) is a supplementary method to CNV‐seq in triploid detection. This study aimed to evaluate the feasibility of sequential application of CNV‐seq and QF‐PCR in genetic analysis of miscarriage and stillbirth. Methods: A total of 261 fetal specimens were analyzed by CNV‐seq, and QF‐PCR was only further performed for samples with normal female karyotype identified by CNV‐seq. Cost and turnaround time (TAT) was analyzed for sequential detection strategy. Subgroup analysis and logistic regression were carried out to evaluate the relationship between clinical characteristics (maternal age, gestational age, and number of pregnancy losses) and the occurrence of chromosomal abnormalities. Results: Abnormal results were obtained in 120 of 261 (45.98%) cases. Aneuploidy was the most common abnormality (37.55%), followed by triploidy (4.98%) and pathogenic copy number variations (pCNVs) (3.45%). CNV‐seq could detect the triploidy with male karyotype, and QF‐PCR could further identify the remaining triploidy with female karyotype. In this study, we found more male triploidies than female triploidies. With the same ability in chromosomal abnormalities detection, the cost of sequential strategy decreased by 17.35% compared with combined strategy. In subgroup analysis, significant difference was found in the frequency of total chromosomal abnormalities between early abortion group and late abortion group. Results of logistic regression showed a trend that pregnant women with advanced age, first‐time abortion, and abortion earlier than 12 weeks were more likely to detect chromosomal aberrations in their products of conception. Conclusion: Sequential application of CNV‐seq and QF‐PCR is an economic and practical strategy to identify chromosomal abnormalities in fetal tissue. [ABSTRACT FROM AUTHOR]

Pyridoxal 5′‐phosphate (PLP), the catalytically active form of vitamin B6, participates as a cofactor to one carbon (1C) pathway that produces precursors for DNA metabolism. The concerted action of PLP‐dependent serine hydroxymethyltransferase (SHMT) and thymidylate synthase (TS) leads to the biosynthesis of thymidylate (dTMP), which plays an essential function in DNA synthesis and repair. PLP deficiency causes chromosome aberrations (CABs) in Drosophila and human cells, rising the hypothesis that an altered 1C metabolism may be involved. To test this hypothesis, we used Drosophila as a model system and found, firstly, that in PLP deficient larvae SHMT activity is reduced by 40%. Second, we found that RNAi‐induced SHMT depletion causes chromosome damage rescued by PLP supplementation and strongly exacerbated by PLP depletion. RNAi‐induced TS depletion causes severe chromosome damage, but this is only slightly enhanced by PLP depletion. dTMP supplementation rescues CABs in both PLP‐deficient and PLP‐proficient SHMTRNAi. Altogether these data suggest that a reduction of SHMT activity caused by PLP deficiency contributes to chromosome damage by reducing dTMP biosynthesis. In addition, our work brings to light a gene‐nutrient interaction between SHMT decreased activity and PLP deficiency impacting on genome stability that may be translated to humans. [ABSTRACT FROM AUTHOR]

Triacylglycerol lipases are enzymes commonly used to process foods and beverages such as oils, wines, and cheeses through catalyzation of long‐chain triglyceride hydrolysis. Lipase OF derived from Candida cylindracea (strain MS‐5‐OF) is only intended for use as a processing aid in food production applications; however, it may be present at trace levels in some products. As such, the safety of Lipase OF was evaluated in this study that included a bacterial reverse mutation assay, an in vitro chromosome aberration test, and a 90‐day subchronic toxicity study in rats. In the in vitro bacterial reverse mutation and chromosome aberration assays, Lipase OF was not observed to be mutagenic at concentrations up to 5000 μg/plate and 50 μg/ml, respectively, in the presence or absence of metabolic activation. Results from the 90‐day subchronic toxicity study indicated only minimal adverse effects (i.e., increased platelet count and prothrombin time) in male rats from the high‐dose group following administration of Lipase OF via the diet at levels of 0, 1.0, 2.5, and 5.0 w/w%. The no‐observed‐adverse‐effect level (NOAEL) for Lipase OF was therefore considered 2.5 w/w% (1597.6 mg/kg body weight/day [1027.3 mg TOS/kg body weight/day]) in males and 5.0 w/w% (3700.4 mg/kg body weight/day [2379.4 mg TOS/kg body weight/day]) in females under the test conditions. Thus, the evidence presented within this study supports the safe use of Lipase OF as a processing aid in various food production applications for human consumption. Lipases derived from microorganisms can provide functional value during the manufacture of foods. The safety of Lipase OF derived from Candida cylindracea (strain MS‐5‐OF) for use as a processing aid was evaluated via two in vitro genotoxicity studies and a 90‐day subchronic toxicity study in rats. No evidence of genotoxicity was observed and a no‐observed‐adverse‐effect level of 1597.6 mg/kg body weight/day in males was identified, which supports the safe use of Lipase OF as a processing aid in foods. [ABSTRACT FROM AUTHOR]

The female characters with a 46, XY karyotype, historically termed Swyer syndrome, are commonly divided into complete and partial gonadal dysgenesis. The former is completely made up of the 46, XY chromosome, while the latter results from 45, X/46, XY mosaicism. Both of them are sex chromosome disorders and are typically characterized by delayed puberty and primary amenorrhea due to disruption of the embryonic gonads into testes. In this report, we described a young female with mos 45, X [2]/46, X, psu idic (Y) (q11.2) [48] by karyotyping. Further copy number variation sequencing (CNV-seq) and fluorescent in situ hybridization (FISH) verified her chromosome alteration. The following gonadectomy and hormone replacement therapy were carried out, and the menstrual cycle recovered along with the development of bilateral breasts and uteruses. Herein, we aim to provide clinical management strategies for the patient with Swyer syndrome in clinical practice. [ABSTRACT FROM AUTHOR]

Background: 3q29 deletion syndrome is associated with mild to moderate intellectual disability as well as comorbid psychopathology such as ADHD, anxiety, ASD and schizophrenia. A greater understanding of specific profiles that could increase risk for psychopathology is necessary in order to best understand and support individuals with 3q29 deletion syndrome. The goal of this study was to thus carefully outline the strengths and weaknesses of these individuals. A second goal was to ask whether the cognitive impact of the deletion predicted psychopathology in other domains. Methods: We systematically evaluated cognitive ability, adaptive behaviour and psychopathology in 32 individuals with the canonical 3q29 deletion using gold‐standard instruments and a standardised phenotyping protocol. Results: Mean full scale IQ was 73 (range 40–99). Verbal subtest score (mean 80, range 31–106) was slightly higher and had a greater range than non‐verbal subtest score (mean 75, range 53–98). Spatial ability was evaluated in a subset (n = 24) and was lower than verbal and non‐verbal ability (mean 71, range 34–108). There was an average 14‐point difference between verbal and non‐verbal subset scores; 60% of the time the verbal subset score was higher than the non‐verbal subset score. Study subjects with a verbal ability subtest score lower than the non‐verbal subtest score were four times more likely to have a diagnosis of intellectual disability (suggestive, P value 0.07). The age at which a child first spoke two‐word phrases was strongly associated with measures of verbal ability (P value 2.56e‐07). Cognitive ability was correlated with adaptive behaviour measures (correlation 0.42, P value 0.02). However, although group means found equivalent scores, there was, on average, a 10‐point gap between these skills (range −33 to 33), in either direction, in about 50% of the sample, suggesting that cognitive measures only partially inform adaptive ability. Cognitive ability scores did not have any significant relationship to cumulative burden of psychopathology nor to individual neurodevelopmental or psychiatric diagnoses. Conclusions: Individuals with 3q29 deletion syndrome have a complex pattern of cognitive disability. Two‐thirds of individuals with the deletion will exhibit significant strength in verbal ability; this may mask deficits in non‐verbal reasoning, leading to an overestimation of overall ability. Deficits in verbal ability may be the driver of intellectual disability diagnosis. Cognitive ability is not a strong indicator of other neurodevelopmental or psychiatric impairment; thus, individuals with 3q29 deletion syndrome who exhibit IQ scores within the normal range should receive all recommended behavioural evaluations. [ABSTRACT FROM AUTHOR]

Objectives: Recently, the Mayo Clinic introduced a new staging system (the Mayo Additive Staging System [MASS]) for patients with newly diagnosed multiple myeloma (NDMM) based on the number of high‐risk (HR) abnormalities, including HR IgH translocations, 1q gain/amplification, chromosome 17 abnormalities, International Staging System (ISS)‐III, and elevated lactate dehydrogenase. Patients with 0, 1, or ≥2 HR abnormalities were defined as stage I, II, or III, respectively. We aimed to validate the real‐world prognostic value of the MASS. Methods: We retrospectively analyzed the cytogenetic and laboratory results of 544 patients with NDMM at a single center. Results: Ninety (16.5%) patients had no HR factors (MASS I), 193 (35.5%) had 1 HR factor (MASS II), and 261 (48%) had ≥2 HR factors (MASS III). The median progression‐free survival (PFS) and overall survival (OS) times were 48, 28, and 20 months and 137, 73, and 39 months in the three groups, respectively (p <.001). In the subgroup analysis, patients had different OS outcomes based on the MASS when grouped by age, renal function, or therapeutic regimens. The MASS identified patients with the worst outcomes among those rated revised ISS II. Conclusion: The MASS system is a reliable risk stratification tool for patients with NDMM in real‐world clinical practice. [ABSTRACT FROM AUTHOR]

Long-term cigarette smoking causes various human diseases, including respiratory disease, cancer, and gastrointestinal (GI) disorders. Alterations in gene expression and variable splicing processes induced by smoking are associated with the development of diseases. This study applied advanced machine learning methods to identify the isoforms with important roles in distinguishing smokers from former smokers based on the expression profile of isoforms from current and former smokers collected in one previous study. These isoforms were deemed as features, which were first analyzed by the Boruta to select features highly correlated with the target variables. Then, the selected features were evaluated by four feature ranking algorithms, resulting in four feature lists. The incremental feature selection method was applied to each list for obtaining the optimal feature subsets and building high-performance classification models. Furthermore, a series of classification rules were accessed by decision tree with the highest performance. Eventually, the rationality of the mined isoforms (features) and classification rules was verified by reviewing previous research. Features such as isoforms ENST00000464835 (expressed by LRRN3), ENST00000622663 (expressed by SASH1), and ENST00000284311 (expressed by GPR15), and pathways (cytotoxicity mediated by natural killer cell and cytokine–cytokine receptor interaction) revealed by the enrichment analysis, were highly relevant to smoking response, suggesting the robustness of our analysis pipeline. [ABSTRACT FROM AUTHOR]

Background and Objectives: In Japan, cord blood is used for more than half of all unrelated stem cell transplantations. The public cord blood banks (CBBs) have been collecting information on cord blood transplantation‐related adverse events from physicians on a voluntary basis, without common definitions of the adverse reactions. The aims of this study were to compare two classification systems to improve the reporting system and to clarify the actual risk from cord blood infusion, which can then provide the impetus to take appropriate measures to reduce adverse events. Materials and Methods: We classified the reports according to existing criteria; one is the Proposed Standard Definitions for Surveillance of Non‐Infectious Adverse Transfusion Reactions by the International Society of Blood Transfusion (ISBT) Working Party on Haemovigilance, and the other is the Common Terminology Criteria for Adverse Events (CTCAE). There were 140 cases with adverse events reported from April 2014 through March 2019. Results: Twelve cases, such as donor‐derived leukaemia/myelodysplastic syndromes (MDS) and chromosomal aberrations reported after engraftment, were excluded from this analysis. Of the 128 cases with adverse events at cord blood infusion, the CTCAE and ISBT criteria could not classify 6 cases and 68 cases, respectively. Classifying by the CTCAE, the most common side effect was hypertension in 35 cases, followed by anaphylaxis, allergic reactions, nausea, urticaria, etc. Serious adverse events (grades 4 and 5) were mainly anaphylaxis, with a frequency of 0.23%. Conclusion: It is necessary not only to provide information on adverse events but also to standardize the reporting of adverse events to support measures to reduce them. [ABSTRACT FROM AUTHOR]

Background: Oligohydramnios or polyhydramnios, is associated with chromosomal aberrations, particularly aneuploidy. However, its correlation with copy number variation (CNV) remains unclear. Methods: We retrospectively analyzed 428 cases with an abnormal level of amniotic fluid, comprising of 139 cases of single ultrasound findings (SU group) and 289 cases of multiple ultrasound findings (MU group), by CNV sequencing (CNV‐Seq) and followed their pregnancy outcomes. Results: The overall detection rate of clinically significant findings was 8%, with 5% in the SU group and 11% in MU group. Besides, 18 microdeletion/microduplication syndromes were detected, with the highest rate of renal cysts and diabetes syndrome (22%, 4/18). Also, the rate of termination of pregnancy in MU group was much higher than that in the SU group (29% vs. 10%, ***p < 0.001), and in the MU‐oligohydramnios subgroup, it was the highest (34%), regardless of cases with chromosomal anomaly and lost to follow‐up. Conclusion: Our results showed that the abnormal level of amniotic fluid, especially combined with other ultrasound abnormalities, is closely related to chromosomal abnormalities and genetic CNVs. CNV‐Seq may be useful in investigating pregnancies with an abnormal amniotic fluid level. [ABSTRACT FROM AUTHOR]