Study Question: Is there an association between different mitochondrial DNA (mtDNA) genotypes and female infertility or ovarian response, and is the appearance of variants in the oocytes favored by medically assisted reproduction (MAR) techniques?
Summary Answer: Ovarian response was negatively associated with global non-synonymous protein-coding homoplasmic variants but positively associated with haplogroup K; the number of oocytes retrieved in a cycle correlates with the number of heteroplasmic variants in the oocytes, principally with variants located in the hypervariable (HV) region and rRNA loci, as well as non-synonymous protein-coding variants.
What Is Known Already: Several genes have been shown to be positively associated with infertility, and there is growing concern that MAR may facilitate the transmission of these harmful variants to offspring, thereby passing on infertility. The potential role of mtDNA variants in these two perspectives remains poorly understood.
The ancient cemetery of Pommerœul, Belgium, was classified as Gallo-Roman in the 1970s', yielding 76 cremation graves and one inhumation. However, subsequent radiocarbon analyses dated the inhumation to the Late Neolithic (4-3 millennium calBC). We report osteoarchaeological analysis indicating that the inhumation was composed of bones from multiple individuals, afterwards buried as "one".
View Article and Find Full Text PDFAbout 70% of human cleavage stage embryos show chromosomal mosaicism, falling to 20% in blastocysts. Chromosomally mosaic human blastocysts can implant and lead to healthy new-borns with normal karyotypes. Studies in mouse embryos and human gastruloids showed that aneuploid cells are eliminated from the epiblast by p53-mediated apoptosis while being tolerated in the trophectoderm.
View Article and Find Full Text PDFThe International Staging System for multiple myeloma recently underwent a second revision (R2-ISS) to include gain/amplification of 1q21 and account for the additive prognostic significance of multiple high-risk features. The phase 3 ICARIA-MM (isatuximab-pomalidomide-dexamethasone vs. pomalidomide-dexamethasone) and IKEMA (isatuximab-carfilzomib-dexamethasone vs.
View Article and Find Full Text PDFAlthough more than 140 genes have been associated with non-syndromic hereditary hearing loss (HL), at least half of the cases remain unexplained in medical genetic testing. One reason is that pathogenic variants are located in 'novel' deafness genes. A variant prioritization approach was used to identify novel (candidate) genes for HL.
View Article and Find Full Text PDFThere is accumulating evidence of BCMA and GPRC5D loss after treatment with T-cell redirecting therapies in patients with relapsed/refractory multiple myeloma (RRMM). While complete CD38 loss is not observed upon relapses after treatment with anti-CD38 monoclonal antibodies (mAb), there is downregulation of surface CD38 expression and decreased number and function of NK cells, which renders these patients resistant to retreatment with anti-CD38 mAb. Here, we provide preclinical evidence that RRMM patients previously exposed to anti-CD38 mAb could benefit from T-cell-based immunotherapy that depend less on CD38 antigen density and NK-cell activity, such as the novel CD38/CD3xCD28 trispecific T-cell engager, SAR442257.
View Article and Find Full Text PDFStudy Question: Is there a difference in clinical pregnancy rates (CPRs) in good prognosis patients after single embryo transfer (SET) on Day 5, in case of stable culture at 36.6°C or 37.1°C?
Summary Answer: CPR (with heartbeat at 7 weeks) after blastocyst transfer do not differ after culturing at 36.
Objectives: Cluster of differentiation 38 (CD38) is a key target on multiple myeloma (MM) cells. This multi-centre, Phase 1, single-agent study (NCT04000282) investigated SAR442085, a novel fragment crystallisable (Fc)-modified anti-CD38 monoclonal antibody (mAb), with enhanced affinity towards Fc-gamma receptor on effector cells in patients with relapsed and/or refractory (RR) MM.
Methods: This study comprised two parts: Part-A (dose-escalation involving anti-CD38 mAb pre-treated and naïve patients) and Part-B (dose expansion).
Background: The genetic composition of embryos generated by in vitro fertilization (IVF) can be examined with preimplantation genetic testing (PGT). Until recently, PGT was limited to detecting single-gene, high-risk pathogenic variants, large structural variants, and aneuploidy. Recent advances have made genome-wide genotyping of IVF embryos feasible and affordable, raising the possibility of screening embryos for their risk of polygenic diseases such as breast cancer, hypertension, diabetes, or schizophrenia.
View Article and Find Full Text PDFCurrent treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients.
View Article and Find Full Text PDFUnlabelled: T cell-engaging antibodies (TCEs) are showing promising efficacy in relapsed/refractory multiple myeloma, even in patients that relapsed after B-cell maturation antigen (BCMA)-targeted therapy. Patients with multiple myeloma may have compromised T-cell health unaccounted for by preclinical models. Here, we use Myeloma Drug Sensitivity Testing (My-DST) for ex vivo measurement of anti-multiple myeloma cytotoxicity for the trispecific CD38/CD28xCD3 TCE SAR442257 through activation of the patients' own endogenous T cells to inform clinical development of the compound in multiple myeloma.
View Article and Find Full Text PDFChildren conceived through assisted reproductive technologies (ART) have an elevated risk of lower birthweight, yet the underlying cause remains unclear. Our study explores mitochondrial DNA (mtDNA) variants as contributors to birthweight differences by impacting mitochondrial function during prenatal development. We deep-sequenced the mtDNA of 451 ART and spontaneously conceived (SC) individuals, 157 mother-child pairs and 113 individual oocytes from either natural menstrual cycles or after ovarian stimulation (OS) and find that ART individuals carried a different mtDNA genotype than SC individuals, with more de novo non-synonymous variants.
View Article and Find Full Text PDFBackground: CD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved-daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites.
Aim: Among the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38-mediated T-cell activation.
Despite over 40 years following the first birth from medically assisted reproduction (MAR) technologies, mechanisms underlying the key developmental events during the first 7 days of human development, such as signaling pathway contribution, are remaining a mystery. An in-depth mechanistic understanding of how the human preimplantation embryo develops would support the optimization of embryo quality assessment methods and culturing conditions, thereby increasing the success rate of MAR. However, the limited availability of human embryos, legitimate ethical concerns, and regulations still present an obstacle toward our advancement of knowledge.
View Article and Find Full Text PDFPurpose: To study the prevalence, level, and nature of sleep problems and fatigue experienced by Usher syndrome type 2a (USH2a) patients.
Design: Cross-sectional study.
Participants: Fifty-six genetically confirmed Dutch patients with syndromic USH2a and 120 healthy controls.
Study Question: What have we learnt after 10 years of electronic witnessing?
Summary Answer: When applied correctly, an electronic witnessing system can replace manual witnessing in the medically assisted reproduction lab to prevent sample mix-up.
What Is Known Already: Electronic witnessing systems have been implemented to improve the correct identification, processing, and traceability of biological materials. When non-matching samples are simultaneously present in a single workstation, a mismatch event is generated to prevent sample mix-up.
Study Question: Which processes and transcription factors specify the first and second lineage segregation events during human preimplantation development?
Summary Answer: Differentiation into trophectoderm (TE) cells can be initiated independently of polarity; moreover, TEAD1 and YAP1 co-localize in (precursor) TE and primitive endoderm (PrE) cells, suggesting a role in both the first and the second lineage segregation events.
What Is Known Already: We know that polarity, YAP1/GATA3 signalling and phospholipase C signalling play a key role in TE initiation in compacted human embryos, however, little is known about the TEAD family of transcription factors that become activated by YAP1 and, especially, whether they play a role during epiblast (EPI) and PrE formation. In mouse embryos, polarized outer cells show nuclear TEAD4/YAP1 activity that upregulates Cdx2 and Gata3 expression while inner cells exclude YAP1 which upregulates Sox2 expression.
Background: A 12-nucleotide in-frame deletion was recently identified as a relatively common and highly penetrant cause of autosomal dominant non-syndromic sensorineural hearing loss, type DFNA21, in the Netherlands. The associated hearing phenotype is variable. The allele frequency (AF) of 0.
View Article and Find Full Text PDFOur understanding of the molecular events driving cell specification in early mammalian development relies mainly on mouse studies, and it remains unclear whether these mechanisms are conserved across mammals, including humans. We have shown that the establishment of cell polarity via aPKC is a conserved event in the initiation of the trophectoderm (TE) placental programme in mouse, cow and human embryos. However, the mechanisms transducing cell polarity into cell fate in cow and human embryos are unknown.
View Article and Find Full Text PDFBackground: Given the incurable nature of multiple myeloma (MM), efforts are made to improve the efficacy of anti-CD38 monoclonal antibodies via combinations with other potentially synergistic therapies. This Phase 1/2 trial (NCT03194867) was designed to determine whether cemiplimab (anti-PD-1) enhances the anti-myeloma activity of isatuximab (anti-CD38) in patients with relapsed and refractory multiple myeloma (RRMM), to confirm the feasibility of the combination, determine its efficacy, and further evaluate its safety.
Methods: Patients received isatuximab 10 mg/kg once weekly for 4 weeks followed by every 2 weeks (Isa), or isatuximab 10 mg/kg plus cemiplimab 250 mg every 2 (Isa + CemiQ2W) or every 4 weeks (Isa + CemiQ4W).
The aim of this study is to contribute to a better description of the genotypic and phenotypic spectrum of DFNA6/14/38 and aid in counseling future patients identified with this variant. Therefore, we describe the genotype and phenotype in a large Dutch-German family (W21-1472) with autosomal dominant non-syndromic, low-frequency sensorineural hearing loss (LFSNHL). Exome sequencing and targeted analysis of a hearing impairment gene panel were used to genetically screen the proband.
View Article and Find Full Text PDFThis study compares 16 vowel-normalization methods for purposes of sociophonetic research. Most of the previous work in this domain has focused on the performance of normalization methods on steady-state vowels. By contrast, this study explicitly considers dynamic formant trajectories, using generalized additive models to model these nonlinearly.
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