Abstract
STUDY QUESTION
Is embryo culture in a closed time-lapse system associated with any differences in perinatal and maternal outcomes in comparison to conventional culture and spontaneous ...conception?
SUMMARY ANSWER
There were no significant differences between time-lapse and conventional embryo culture in preterm birth (PTB, <37 weeks), low birth weight (LBW, >2500 g) and hypertensive disorders of pregnancy for singleton deliveries, the primary outcomes of this study.
WHAT IS KNOWN ALREADY
Evidence from prospective trials evaluating the safety of time-lapse incubation for clinical use show similar embryo development rates, implantation rates, and ongoing pregnancy and live birth rates when compared to conventional incubation. Few studies have investigated if uninterrupted culture can alter risks of adverse perinatal outcomes presently associated with IVF when compared to conventional culture and spontaneous conceptions.
STUDY DESIGN, SIZE, DURATION
This study is a Swedish population-based retrospective registry study, including 7379 singleton deliveries after fresh embryo transfer between 2013 and 2018 from selected IVF clinics. Perinatal outcomes of singletons born from time-lapse-cultured embryos were compared to singletons from embryos cultured in conventional incubators and 71 300 singletons from spontaneous conceptions. Main perinatal outcomes included PTB and LBW. Main maternal outcomes included hypertensive disorders of pregnancy (pregnancy hypertension and preeclampsia).
PARTICIPANTS/MATERIALS, SETTING, METHODS
From nine IVF clinics, 2683 singletons born after fresh embryo transfer in a time-lapse system were compared to 4696 singletons born after culture in a conventional incubator and 71 300 singletons born after spontaneous conception matched for year of birth, parity, and maternal age. Patient and treatment characteristics from IVF deliveries were cross-linked with the Swedish Medical Birth Register, Register of Birth Defects, National Patient Register and Statistics Sweden. Children born after sperm and oocyte donation cycles and after Preimplantation Genetic testing cycles were excluded. Odds ratio (OR) and adjusted OR were calculated, adjusting for relevant confounders.
MAIN RESULTS AND THE ROLE OF CHANCE
In the adjusted analyses, no significant differences were found for risk of PTB (adjusted OR 1.11, 95% CI 0.87–1.41) and LBW (adjusted OR 0.86, 95% CI 0.66–1.14) or hypertensive disorders of pregnancy; preeclampsia and hypertension (adjusted OR 0.99, 95% CI 0.67–1.45 and adjusted OR 0.98, 95% CI 0.62–1.53, respectively) between time-lapse and conventional incubation systems. A significantly increased risk of PTB (adjusted OR 1.31, 95% CI 1.08–1.60) and LBW (adjusted OR 1.36, 95% CI 1.08–1.72) was found for singletons born after time-lapse incubation compared to singletons born after spontaneous conceptions. In addition, a lower risk for pregnancy hypertension (adjusted OR 0.72 95% CI 0.53–0.99) but no significant difference for preeclampsia (adjusted OR 0.87, 95% CI 0.68–1.12) was found compared to spontaneous conceptions. Subgroup analyses showed that some risks were related to the day of embryo transfer, with more adverse outcomes after blastocyst transfer in comparison to cleavage stage transfer.
LIMITATIONS, REASONS FOR CAUTION
This study is retrospective in design and different clinical strategies may have been used to select specific patient groups for time-lapse versus conventional incubation. The number of patients is limited and larger datasets are required to obtain more precise estimates and adjust for possible effect of additional embryo culture variables.
WIDER IMPLICATIONS OF THE FINDINGS
Embryo culture in time-lapse systems is not associated with major differences in perinatal and maternal outcomes, compared to conventional embryo culture, suggesting that this technology is an acceptable alternative for embryo incubation.
STUDY FUNDING/COMPETING INTEREST(S)
The study was financed by a research grant from Gedeon Richter. There are no conflicts of interest for all authors to declare.
TRIAL REGISTRATION NUMBER
N/A
Darolutamide is a novel androgen receptor (AR) antagonist with a distinct chemical structure compared to other AR antagonists and currently in clinical Phase 3 trials for prostate cancer. Using ...cell‐based transactivation assays, we demonstrate that darolutamide, its diastereomers and its main metabolite keto‐darolutamide are strong, competitive antagonists for AR wild type, and also for several mutants identified in prostate cancer patients for which other AR antagonists show reduced antagonism or even agonism. Darolutamide, its two diastereomers and main metabolite are also strong antagonists in assays measuring AR N/C interaction and homodimerization. Molecular modeling suggests that the flexibility of darolutamide allows accommodation in the W742C/L mutated AR ligand‐binding pocket while for enzalutamide the loss of the important hydrophobic interaction with W742 leads to reduced AR interaction. This correlates with an antagonistic pattern profile of coregulator recruitment for darolutamide. In vitro efficacy studies performed with androgen‐dependent prostate cancer cell lines show that darolutamide strongly reduces cell viability and potently inhibits spheroid formation. Also, a marked down‐regulation of androgen target genes paralleled by decreased AR binding to gene regulatory regions is seen. In vivo studies reveal that oral dosing of darolutamide markedly reduces growth of the LAPC‐4 cell line‐derived xenograft and of the KuCaP‐1 patient‐derived xenograft. Altogether, these results substantiate a unique antagonistic profile of darolutamide and support further development as a prostate cancer drug.
What's new?
Comparison of genomic landscapes from primary prostate cancer and metastatic tumor shows that resistance mechanisms are centered on androgen signaling and increased synthesis. Here, the novel androgen receptor (AR) antagonist darolutamide shows strong in vitro and in vivo efficacy in different prostate cancer models. Darolutamide retains its antagonistic properties at elevated androgen levels and for several AR mutants identified in therapy‐resistant patients. A unique binding profile inside the AR ligand‐binding domain linked to the flexibility of darolutamide is proposed. Altogether, these results substantiate a unique antagonistic profile of darolutamide and support further development as a prostate cancer drug.
Abstract
Summary
Accurately identifying cell types is a critical step in single-cell sequencing analyses. Here, we present marker-based automatic cell-type annotation (MACA), a new tool for ...annotating single-cell transcriptomics datasets. We developed MACA by testing four cell-type scoring methods with two public cell-marker databases as reference in six single-cell studies. MACA compares favorably to four existing marker-based cell-type annotation methods in terms of accuracy and speed. We show that MACA can annotate a large single-nuclei RNA-seq study in minutes on human hearts with ∼290K cells. MACA scales easily to large datasets and can broadly help experts to annotate cell types in single-cell transcriptomics datasets, and we envision MACA provides a new opportunity for integration and standardization of cell-type annotation across multiple datasets.
Availability and implementation
MACA is written in python and released under GNU General Public License v3.0. The source code is available at https://github.com/ImXman/MACA.
Supplementary information
Supplementary data are available at Bioinformatics online.
Patients with heart failure with preserved ejection fraction (HFpEF) and atherosclerosis-driven coronary artery disease (CAD) will have ongoing fibrotic remodeling both in the myocardium and in ...atherosclerotic plaques. However, the functional consequences of fibrosis differ for each location. Thus, cardiac fibrosis leads to myocardial stiffening, thereby compromising cardiac function, while fibrotic remodeling stabilizes the atherosclerotic plaque, thereby reducing the risk of plaque rupture. Although there are currently no drugs targeting cardiac fibrosis, it is a field under intense investigation, and future drugs must take these considerations into account. To explore similarities and differences of fibrotic remodeling at these two locations of the heart, we review the signaling pathways that are activated in the main extracellular matrix (ECM)-producing cells, namely human cardiac fibroblasts (CFs) and vascular smooth muscle cells (VSMCs). Although these signaling pathways are highly overlapping and context-dependent, effects on ECM remodeling mainly act through two core signaling cascades: TGF-
and Angiotensin II. We complete this by summarizing the knowledge gained from clinical trials targeting these two central fibrotic pathways.
The DNA damage response (DDR) secures the integrity of the genome of eukaryotic cells. DDR deficiencies can promote tumorigenesis but concurrently may increase dependence on alternative repair ...pathways. The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DDR by activating essential signaling pathways of DNA damage repair. Here, we studied the effect of the novel selective ATR kinase inhibitor BAY 1895344 on tumor cell growth and viability. Potent antiproliferative activity was demonstrated in a broad spectrum of human tumor cell lines. BAY 1895344 exhibited strong monotherapy efficacy in cancer xenograft models that carry DNA damage repair deficiencies. The combination of BAY 1895344 with DNA damage-inducing chemotherapy or external beam radiotherapy (EBRT) showed synergistic antitumor activity. Combination treatment with BAY 1895344 and DDR inhibitors achieved strong synergistic antiproliferative activity
, and combined inhibition of ATR and PARP signaling using olaparib demonstrated synergistic antitumor activity
Furthermore, the combination of BAY 1895344 with the novel, nonsteroidal androgen receptor antagonist darolutamide resulted in significantly improved antitumor efficacy compared with respective single-agent treatments in hormone-dependent prostate cancer, and addition of EBRT resulted in even further enhanced antitumor efficacy. Thus, the ATR inhibitor BAY 1895344 may provide new therapeutic options for the treatment of cancers with certain DDR deficiencies in monotherapy and in combination with DNA damage-inducing or DNA repair-compromising cancer therapies by improving their efficacy.
To evaluate the feasibility of two-dimensional parametric parenchymal blood flow (2D-PPBF) to quantify perfusion changes in the lung parenchyma following balloon pulmonary angioplasty (BPA) for ...treatment of chronic thromboembolic pulmonary hypertension.
Overall, 35 consecutive interventions in 18 patients with 98 treated pulmonary arteries were included. To quantify changes in pulmonary blood flow using 2D-PPBF, the acquired digital subtraction angiography (DSA) series were post-processed using dedicated software. A reference region of interest (ROI; arterial inflow) in the treated pulmonary artery and a distal target ROI, including the whole lung parenchyma distal to the targeted stenosis, were placed in corresponding areas on DSA pre- and post-BPA. Half-peak density (HPD), wash-in rate (WIR), arrival to peak (AP), area under the curve (AUC), and mean transit time (MTT) were assessed. The ratios of the reference ROI to the target ROI (HPDparenchyma/HPDinflow, WIRparenchyma/WIRinflow; APparenchyma/APinflow, AUCparenchyma/AUCinflow, MTTparenchyma/MTTinflow) were calculated. The relative differences of the 2D-PPBF parameters were correlated to changes in the pulmonary flow grade score.
The pulmonary flow grade score improved significantly after BPA (1 versus 3; p<0.0001). Likewise, the mean HPDparenchyma/HPDinflow (–10.2%; p<0.0001), APparenchyma/APinflow (–24.4%; p=0.0007), and MTTparenchyma/MTTinflow (–3.5%; p=0.0449) decreased significantly, whereas WIRparenchyma/WIRinflow (+82.4%) and AUCparenchyma/AUCinflow (+58.6%) showed a significant increase (p<0.0001). Furthermore, a significant correlation between changes of the pulmonary flow grade score and changes of HPDparenchyma/HPDinflow (ρ=–0.21, p=0.04), WIRparenchyma/WIRinflow (ρ=0.43, p<0.0001), APparenchyma/APinflow (ρ=–0.22, p=0.03), AUCparenchyma/AUCinflow (ρ=0.48, p<0.0001), and MTTparenchyma/MTTinflow (ρ=–0.39, p<0.0001) could be observed.
The 2D-PPBF technique is feasible for the quantification of perfusion changes following BPA and has the potential to improve monitoring of BPA.
•Quantification of perfusion changes in treated CTEPH-lesions is feasible with 2D-PPBF.•2D-PPBF allows objective assessment in the whole parenchyma distal a treated lesion.•2D-PPBF has the potential to further optimize BPA.
An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The rationale for this study was to investigate ...the efficacy and safety of this regimen prospectively in patients with a primary myelodysplastic syndrome.
A total of 45 patients with primary myelodysplastic syndromes were conditioned with 3×14 g/m(2) treosulfan and 5×30 mg/m(2) fludarabine followed by allogeneic hematopoietic stem cell transplantation. Subtypes of myelodysplastic syndromes were refractory anemia with excess blasts-2 (44%), refractory cytopenia with multilineage dysplasia (27%), refractory anemia (9%), refractory anemia with ringed sideroblasts (4%), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (4%), refractory anemia with excess blasts-1 (2%), and myelodysplastic syndrome with isolated del (5q) (2%). The myelodysplastic syndrome was unclassified in 7% of the patients. Forty-seven percent of the patients had a favorable karyotype, 29% an unfavorable one, and 18% an intermediate karyotype. Patients were evaluated for engraftment, adverse events, graft-versus-host disease, non-relapse mortality, relapse incidence, overall survival and disease-free survival.
All but one patient showed primary engraftment of neutrophils after a median of 17 days. Non-hematologic adverse events of grade III-IV in severity included mainly infections and gastrointestinal symptoms (80% and 22% of the patients, respectively). Acute graft-versus-host disease grade II-IV developed in 24%, and extensive chronic graft-versus-host disease in 28% of the patients. After a median follow-up of 780 days, the 2-year overall and disease-free survival estimates were 71% and 67%, respectively. The 2-year cumulative incidences of non-relapse mortality and relapse were 17% and 16%, respectively.
Our safety and efficacy data suggest that treosulfan-based conditioning therapy is a promising treatment option for patients with myelodysplastic syndromes. clinicaltrials.gov identifier: NCT01062490.
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