Proteomic and Phosphoproteomic Analysis of Right Ventricular Hypertrophy in the Pulmonary Hypertension Rat Model.

Pulmonary arterial hypertension (PAH) is a progressive disease that affects both the lungs and heart. Right ventricle (RV) hypertrophy is a primary pathological feature of PAH; however, its underlying molecular mechanisms remain insufficiently studied. In this study, we employed tandem mass tag (TMT)-based quantitative proteomics for the integrative analysis of the proteome and phosphoproteome of the RV derived from monocrotaline-induced PAH model rats. Compared with control samples, 564 significantly upregulated proteins, 616 downregulated proteins, 622 downregulated phosphopeptides, and 683 upregulated phosphopeptides were identified (P < 0.05, abs (log2 (fold change)) > log2 1.2) in the MCT samples. The quantitative real-time polymerase chain reaction (qRT-PCR) validated the expression levels of top 20 significantly altered proteins, including Nppa (natriuretic peptides A), latent TGF-ß binding protein 2 (Ltbp2), periostin, connective tissue growth factor 2 (Ccn2), Ncam1 (neural cell adhesion molecule), quinone reductase 2 (Nqo2), and tropomodulin 4 (Tmod4). Western blotting confirmed the upregulation of Ncam1 and downregulation of Nqo2 and Tmod4 in both MCT-induced and hypoxia-induced PH rat models. Pathway enrichment analyses indicated that the altered proteins are associated with pathways, such as vesicle-mediated transport, actin cytoskeleton organization, TCA cycle, and respiratory electron transport. These significantly changed phosphoproteins were enriched in pathways such as diabetic cardiomyopathy, hypertrophic cardiomyopathy, glycolysis/gluconeogenesis, and cardiac muscle contraction. In summary, this study provides an initial analysis of the RV proteome and phosphoproteome in the progression of PAH, highlighting several RV dysfunction-associated proteins and pathways.

Survival outcomes correlate with the level of cell-free circulating DNA in ST-elevation myocardial infarction.

Background: Myocardial infarction (MI) can lead to higher cellular damage, making cell-free DNA (cfDNA) a potential biomarker for assessing disease severity. The aim of this study is to evaluate survival predictions using cfDNA measurements and assess its correlation with MI. Materials and Methods: A direct fluorescence assay was employed to measure cfDNA content in the blood samples of participants. The inclusion criteria included patients who gave informed consent, suffering from ST-elevation myocardial infraction (STEMI) based on established diagnostic criteria (joint ESC/ACC guidelines), between the age of 18 and 80 years old, and had elevated troponin biomarker levels. The study included 150 patients diagnosed with STEMI and 50 healthy volunteers as controls. Serial monitoring of patients was conducted to track their postdisease status. The rate of change of cfDNA was calculated and daily measurements for 7 days were recorded. Results: Mean levels of cfDNA were found to be 5.93 times higher in patients with STEMI compared to healthy controls, providing clear evidence of a clinical correlation between cfDNA and STEMI. Patients were further categorized based on their survival status within a 90-day period. The study observed a strong predictive relationship between the rate of change of cfDNA during daily measurements and survival outcomes. To assess its predictive capability, a receiver operating characteristics (ROC) curve analysis was performed. The ROC analysis identified an optimal cutoff value of 2.50 for cfDNA, with a sensitivity of 81.5% and specificity of 74.0% in predicting disease outcomes. Conclusion: This study demonstrates a robust association between cfDNA and STEMI, indicating that cfDNA levels can be a valuable early prognostic factor for patients. Serial measurements of cfDNA during early disease onset hold promise as an effective approach for predicting survival outcomes in MI patients.

A Novel Azo-Linked Polymer Bearing Trifluoromethyl Groups for I2 Capture.

In this work, a novel three nitro-group-bearing monomer 3,6-dinitro-9-(2-trifluoromethyl-4-nitrophenyl)-carbazole (Car-3NO2 -CF3 ) via a CN coupling reaction between 3,6-dinitro-9H-carbazole (Car-2NO2 ) and 2-chloro-5-nitrobenzotrifluoride is synthesized, and obtained single crystal and single crystal analysis data for this compound. The crystal system of Car-3NO2 -CF3 is monoclinic and it has a P 21/c space group. This new monomer (Car-3NO2 -CF3 ) is also utilized to synthesize a novel azo-linked polymer (Azo-Car-CF3 ). The trifluoromethyl group has polar CF bonds, and thus it is an effective functional group for the capture of iodine. Azo-Car-CF3 has great thermal stability with a mass loss of only 10% at 414 °C, as well as good chemical stability as is demonstrated by its low solubility in common organic solvents such as tetrahydrofuran (THF), acetone, methanol, ethanol, and N,N-dimethylformamide (DMF). The specific surface area of Azo-Car-CF3 can reach as high as 335 m2  g-1 . Azo-Car-CF3 exhibits an excellent capacity for iodine adsorption and can reach up to 1198 mg g-1 in cyclohexane solution, and its adsorption capacity for iodine vapor can get to 2100 mg g-1 . In addition, ethanol can be used to trigger the release of the captured iodine to be easily released from Azo-Car-CF3 .

A randomized double blind comparison of atosiban in patients with recurrent implantation failure undergoing IVF treatment.

BACKGROUND: Patients with recurrent implantation failure (RIF) may have more uterine contractions. Several observational studies suggested that atosiban administration around embryo transfer resulted in higher pregnancy rates in RIF patients. This study aimed to evaluate the effect of atosiban given before fresh embryo transfer on pregnancy outcomes of women with RIF. METHODS: A prospective, randomized, double-blind controlled clinical trial was performed in IVF center of Shanghai First Maternity and Infant Hospital. According to a computer-generated randomization list, 194 infertile women with RIF received fresh embryo transfer between July 2017 and December 2019 were randomly allocated into the atosiban (n = 97) and the placebo (n = 97) groups. Women in the treatment group received atosiban intravenously about 30 min before embryo transfer with a bolus dose of 6.75 mg over one minute. Those in the placebo group received only normal saline infusion for the same duration. RESULTS: There was no significant difference in the live birth rate between the atosiban and placebo groups (42.3% vs 35.1%, P = 0.302, RR = 1.206 (0.844-1.723)). No significant differences were found between the two groups in the positive pregnancy test, clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and implantation rates. Similar results were found when stratified by the number of embryos previously transferred, number of previous failed embryo transfers, frequency of endometrial peristalsis on embryo transfer day (≥ 3 waves/min) or serum estradiol (E2) on the day of hCG above the median level. And, there was no correlation between the serum E2 level on the day of hCG and the frequency of endometrial peristalsis on embryo transfer day. The frequency of endometrial peristalsis on embryo transfer day, total FSH/HMG dosage and duration were the significant factors which independently predicted the likelihood of a live birth. CONCLUSIONS: These results suggested that atosiban treatment before fresh embryo transfer might not improve the live birth rate in RIF patients. TRIAL REGISTRATION: The study had been approved by the Institutional Review Board of the hospital (2017 ethics No.43) and was registered under Clinicaltrials.gov with an identifier NCT02893722.

A Bioengineering Approach for the Development of Fibroblast Growth Factor-7-Functionalized Sericin Biomaterial Applicable for the Cultivation of Keratinocytes.

Growth factors, including fibroblast growth factor-7 (FGF-7), are a group of proteins that stimulate various cellular processes and are often used with carriers to prevent the rapid loss of their activities. Sericin with great biocompatibility has been investigated as a proteinaceous carrier to enhance the stability of incorporated proteins. The difficulties in obtaining intact sericin from silkworm cocoons and the handling of growth factors with poor stability necessitate an efficient technique to incorporate the protein into a sericin-based biomaterial. Here, we report the generation of a transgenic silkworm line simultaneously expressing and incorporating FGF-7 into cocoon shells containing almost exclusively sericin. Growth-factor-functionalized sericin cocoon shells requiring simple lyophilization and pulverization processes were successfully used to induce the proliferation and migration of keratinocytes. Moreover, FGF-7 incorporated into sericin-cocoon powder exhibited remarkable stability, with more than 70% of bioactivity being retained after being stored as a suspension at 25 °C for 3 months. Transgenic sericin-cocoon powder was used to continuously supply biologically active FGF-7 to generate a three-dimensionally cultured keratinocyte model in vitro. The outcomes of this study propound a feasible approach to producing cytokine-functionalized sericin materials that are ready to use for cell cultivation.

Genome-wide association study reveals the genetic architecture of root hair length in maize.

BACKGROUND: Root hair, a special type of tubular-shaped cell, outgrows from root epidermal cell and plays important roles in the acquisition of nutrients and water, as well as interactions with biotic and abiotic stress. Although many genes involved in root hair development have been identified, genetic basis of natural variation in root hair growth has never been explored. RESULTS: Here, we utilized a maize association panel including 281 inbred lines with tropical, subtropical, and temperate origins to decipher the phenotypic diversity and genetic basis of root hair length. We demonstrated significant associations of root hair length with many metabolic pathways and other agronomic traits. Combining root hair phenotypes with 1.25 million single nucleotide polymorphisms (SNPs) via genome-wide association study (GWAS) revealed several candidate genes implicated in cellular signaling, polar growth, disease resistance and various metabolic pathways. CONCLUSIONS: These results illustrate the genetic basis of root hair length in maize, offering a list of candidate genes predictably contributing to root hair growth, which are invaluable resource for the future functional investigation.

Downregulation of lncRNA IGF2-AS-encoded peptide induces trophoblast - cycle arrest.

RESEARCH QUESTION: lncRNA IGF2-AS may be related to early pregnancy loss. Does lncRNA IGF2-AS affect trophoblast cell growth? The aim of the present study was to verify that lncRNA IGF2-AS encodes a polypeptide, IGF2-AS-168aa, and to study its role in the pathogenesis of trophoblasts. DESIGN: A small interfering RNA targeted to the IGF2-AS gene (si-IGF2-AS) was designed and transfected into JEG-3 and JAR cells for in-vitro gene silencing. Quantitative polymerase chain reaction and western blotting were used to determine lncRNA IGF2-AS levels in experimental cells. After IGF2-AS suppression, MTT assay was used to assess cell proliferation and apoptosis was determined by flow cytometry. Target gRNA IGF2-AS-gRNA was designed for knockout conducted the corresponding mRNA. HEK293T cells were transfected with the identified positive clone vectors. Finally, IGF2-AS-168aa was analysed by western blotting after the protein-coding region of the IGF2-AS gene was knocked out by CRISPR/Cas9 gene-editing technology. RESULTS: lncRNA IGF2-AS and IGF2-AS-168aa were significantly downregulated in JEG-3 and JAR cells transfected with si-IGF2-AS (lncRNA IGF2-AS: JAR: NC versus small interfering RNA (siRNA)-1: P = 0.019 NC versus siRNA-2: P = 0.013; JEG-3: NC versus siRNA-1: P = 0.001 NC versus siRNA-2: P = 0.004) (IGF2-AS-168aa: JAR: NC versus siRNA-1: P = 0.030 NC versus siRNA-2: P = 0.018; JEG-3: NC versus siRNA-1: P = 0.004 NC versus siRNA-2: P = 0.001). IGF2-AS gene was incapable of encoding IGF2-AS-168aa after the coding region was successfully knocked out in HEK293T cells. Flow cytometry and the MTT assay revealed that IGF2-AS gene silencing led to cell cycle block in the G1 phase, markedly decreasing cell proliferation and increasing apoptosis. CONCLUSION: The IGF2-AS gene encoded a peptide with a potential function in trophoblast cell cycle arrest.

Structural and functional characterization of the RBBP4-ZNF827 interaction and its role in NuRD recruitment to telomeres.

The nucleosome remodeling and histone deacetylase (NuRD) complex is an essential multi-subunit protein complex that regulates higher-order chromatin structure. Cancers that use the alternative lengthening of telomere (ALT) pathway of telomere maintenance recruit NuRD to their telomeres. This interaction is mediated by the N-terminal domain of the zinc-finger protein ZNF827. NuRD-ZNF827 plays a vital role in the ALT pathway by creating a molecular platform for recombination-mediated repair. Disruption of NuRD binding results in loss of ALT cell viability. Here, we present the crystal structure of the NuRD subunit RBBP4 bound to the N-terminal 14 amino acids of ZNF827. RBBP4 forms a negatively charged channel that binds to ZNF827 through a network of electrostatic interactions. We identify the precise amino acids in RBBP4 required for this interaction and demonstrate that disruption of these residues prevents RBBP4 binding to both ZNF827 and telomeres, but is insufficient to decrease ALT activity. These data provide insights into the structural and functional determinants of NuRD activity at ALT telomeres.

Neurons in rat orbitofrontal cortex and medial prefrontal cortex exhibit distinct responses in reward and strategy-update in a risk-based decision-making task.

The orbitofrontal cortex (OFC) and the medial prefrontal cortex (mPFC) are known to participate in risk-based decision-making. However, whether neuronal activities of these two brain regions play similar or differential roles during different stages of risk-based decision-making process remains unknown. Here we conducted multi-channel in vivo recordings in the OFC and mPFC simultaneously when rats were performing a gambling task. Rats were trained to update strategy as the task was shifted in two stages. Behavioral testing suggests that rats exhibited different risk preferences and response latencies to food rewards during stage-1 and stage-2. Indeed, the firing patterns and numbers of non-specific neurons and nosepoking-predicting neurons were similar in OFC and mPFC. However, there were no reward-expecting neurons and significantly more reward-excitatory neurons (fired as rats received rewards) in the mPFC. Further analyses suggested that nosepoking-predicting neurons may encode the overall value of reward and strategy, whereas reward-expecting neurons show more intensive firing to a big food reward in the OFC. Nosepoking-predicting neurons in mPFC showed no correlation with decision-making strategy updating, whereas the response of reward-excitatory neurons in mPFC, which were barely observed in OFC, were inhibited during nosepoking, but were enhanced in the post-nosepoking period. These findings indicate that neurons in the OFC and mPFC exhibit distinct responses in decision-making process during reward consumption and strategy updating. Specifically, OFC encodes the overall value of a choice and is thus important for learning and strategy updating, whereas mPFC plays a key role in monitoring and execution of a strategy.

Decrease in DNA methylation 1 (DDM1) is required for the formation of m CHH islands in maize.

DNA methylation plays a crucial role in suppressing mobilization of transposable elements and regulation of gene expression. A number of studies have indicated that DNA methylation pathways and patterns exhibit distinct properties in different species, including Arabidopsis, rice, and maize. Here, we characterized the function of DDM1 in regulating genome-wide DNA methylation in maize. Two homologs of ZmDDM1 are abundantly expressed in the embryo and their simultaneous disruption caused embryo lethality with abnormalities in cell proliferation from the early stage of kernel development. We establish that ZmDDM1 is critical for DNA methylation, at CHG sites, and to a lesser extent at CG sites, in heterochromatic regions, and unexpectedly, it is required for the formation of m CHH islands. In addition, ZmDDM1 is indispensable for the presence of 24-nt siRNA, suggesting its involvement in the RdDM pathway. Our results provide novel insight into the role of ZmDDM1 in regulating the formation of m CHH islands, via the RdDM pathway maize, suggesting that, in comparison to Arabidopsis, maize may have adopted distinct mechanisms for regulating m CHH.

Progestin-primed ovarian stimulation with or without clomiphene citrate supplementation in normal ovulatory women undergoing in vitro fertilization/intracytoplasmic sperm injection: A prospective randomized controlled trial.

OBJECTIVE: To compare the endocrinological profiles, cycle characteristics and pregnancy outcomes of progestin-primed ovarian stimulation (PPOS) with or without clomiphene citrate (CC) supplementation in normal ovulatory women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). DESIGN: Prospective randomized controlled study. PATIENT(S): A total of 320 infertile women undergoing IVF/ICSI. Medroxyprogesterone acetate (MPA) and human menopausal gonadotropin (hMG) were simultaneously administered on menstrual cycle day 3. The women were randomized into 2 equal groups with or without CC supplementation. MEASURES: The primary outcome measure was the percentage of women with profound pituitary suppression (luteinizing hormone [LH] <1.0 IU/L on the trigger day). The secondary outcomes were endocrinological profiles, cycle characteristics and pregnancy outcomes. RESULTS: The percentage of women with profound pituitary suppression was significantly lower in the study group (hMG + MPA + CC) than in the control group (hMG + MPA) (1.9% vs 33.1%, P < .001). The mean LH level during controlled ovarian stimulation (COS) was higher in the study group than in the control group (P < .001), but none of the patients in either group exhibited a premature LH surge. The doses of Gn in the study group were significantly lower than those in the control group (1334.06 ± 212.53 IU vs 1488.28 ± 325.08 IU, P < .001). The number of oocytes retrieved was similar between the 2 groups (10.03 ± 5.97 vs 10.34 ± 7.52, P > .05). No significant differences were observed in either the number of viable embryos or the pregnancy outcomes between the 2 groups. CONCLUSION(S): Clomiphene citrate is an effective adjuvant to alleviate pituitary suppression in the PPOS protocol; however, it has no impact on clinical outcomes.

New application of dydrogesterone as a part of a progestin-primed ovarian stimulation protocol for IVF: a randomized controlled trial including 516 first IVF/ICSI cycles.

STUDY QUESTION: Can dydrogesterone (DYG) be used as an alternative progestin in a progesterone primed ovarian stimulation (PPOS) protocol? SUMMARY ANSWER: DYG can be used as an appropriate alternative progestin in a PPOS protocol. WHAT IS KNOWN ALREADY: PPOS is a new ovarian stimulation regimen based on a freeze-all strategy that uses progestin as an alternative to a GnRH analog for suppressing a premature LH surge during the follicular phase. Medroxyprogesterone acetate (MPA) has been successfully used as an adjuvant to gonadotrophin in the PPOS protocol. However, the use of MPA may lead to stronger pituitary suppression and thus may require a higher dosage of hMG and a longer duration of ovarian stimulation than that of conventional ovarian stimulation protocol. STUDY DESIGN SIZE, DURATION: A prospective RCT including 516 patients was performed between November 2015 and November 2016. Computerized randomization was conducted to assign participants at a 1:1 ratio into two treatment groups: an hMG + DYG group (260 patients) or an hMG + MPA group (256 patients) followed by IVF or ICSI with the freeze-all strategy. One cycle per patient was included. The primary outcome of the trial was the number of oocytes retrieved. The sample size was chosen to detect a difference of two oocytes with a power of 90%. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients under 36 years of age with normal ovarian reserve who were undergoing their first IVF/ICSI procedure due to tubal factor infertility were randomized into two groups based on the oral progestin protocol used: hMG co-treatment with DYG (hMG + DYG) or hMG co-treatment with MPA (hMG + MPA). The different progestin was simultaneously administered at the beginning of menstrual cycle 3 (MC3). Oocyte maturation was co-triggered by administration of a GnRH agonist and hCG. All viable embryos from both protocols were cryopreserved for later transfer. Only the first frozen embryo transfer (FET) cycle was included in our study. The embryological and clinical outcomes were measured. MAIN RESULTS AND THE ROLE OF CHANCE: Basic characteristics, such as age, BMI and infertility duration, in both groups were comparable. There was no significant difference in the number (mean ± SD) of oocytes retrieved [10.8 ± 6.3 for the hMG + DYG group versus 11.1 ± 5.8 for the hMG + MPA group, P = 0.33] or the oocyte retrieval rate [74.3 ± 19.6% for the hMG + DYG group versus 75.0 ± 19.5% for the hMG + MPA group, P = 0.69] between the groups. The viable embryo rate per oocyte retrieved did not differ between the two groups [odds ratio (OR): 1.08, 95% CI: 0.97-1.21, P = 0.16]: 37.4% (1052/2815) for the hMG + DYG group versus 35.6% (1009/2837) for the hMG + MPA group. During the whole process of ovarian stimulation, the mean LH level in the hMG + DYG group was always higher than that in the hMG + MPA group (P < 0.001); however, no patient from either group experienced a premature LH surge. In addition, no patients experienced moderate or severe ovarian hyperstimulation syndrome during the ovarian stimulation. No significant difference was found in the clinical pregnancy rate of the first FET cycle between the two groups (OR: 0.82, 95% CI: 0.56-1.21, P = 0.33): 57.6% for the hMG + DYG group (125/217) versus 62.3% for the hMG + MPA group (132/212). LIMITATIONS REASONS FOR CAUTION: The patients and physician were not blinded to the study. Further, a large proportion of patients were still pregnant at the end of the clinical trial, therefore live birth rates were not observed in the follow-up period. The dose-effectiveness of DYG administration was not addressed in the trial design. WIDER IMPLICATIONS OF THE FINDINGS: DYG, which exhibits no or only weak inhibition of ovulation in normal dosage, can serve as an hMG adjuvant during ovarian stimulation. This finding suggests the possibility of a new application of DYG: as an appropriate alternative progestin for a PPOS protocol in IVF. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by The National Nature Science Foundation of China (Grant no. 81503603), Shanghai Three-year Plan on Promoting TCM Development (Grant no. ZY3-LCPT-2-2006) and the Natural Science Foundation of Shanghai (Grant nos. 15401932700 and 15ZR1424900). None of the authors declare any conflict of interest. TRIAL REGISTRATION NUMBER: Chictr.org.cn: ChiCTR-IPR-15007251. TRIAL REGISTRATION DATE: Chictr.org.cn: 22 October 2015. DATE OF FIRST PATIENT'S ENROLLMENT: 1 November 2015.

Three-Dimensional HyCoSy With Perfluoropropane-Albumin Microspheres as Contrast Agents and Normal Saline Injections Into the Pelvic Cavity for Morphological Assessment of the Fallopian Tube in Infertile Women.

OBJECTIVES: To apply the three-dimensional (3D) hysterosalpingo-contrast sonography (HyCoSy) with perfluoropropane-albumin microspheres as contrast agents and normal saline injections into the pelvic cavity for assessment of the tubal patency and adhesions of fimbrial parts. METHODS: Fifty-five infertile female patients were recruited to undergo 3D HyCoSy with normal saline injected into the pelvic cavity, in which the tubal patency was observed by visualizing the spillage of contrast agents from the fimbriae, and the fimbrial adhesion was confirmed by the finger-like projections of the fimbriae and their floating and moving status. RESULTS: Of the 55 patients, bilateral tubal patency was observed in 44 (80.0%), unilateral tubal patency and the other partial occlusion in 7 (12.7%), unilateral partial occlusion and the other complete occlusion in 3 (5.4%), and bilateral complete occlusion in 1 (1.8%). The fimbrial parts were observed in 105 fallopian tubes, among which 101 were seen with the finger-like fimbriae floated and moved in the pelvic cavity, whereas 4 tubes were not because of adhesion to the pelvic cavity (n = 3) or the ovary and intestine (n = 1). More than three visible, quite long, and distributed evenly finger-like projections were present for the patent fimbrial parts; however, fewer, flat, and not evenly distributed finger-like projections were present for the adhesive tubes. No serious complications occurred during or after this procedure. CONCLUSIONS: Combination of 3D HyCoSy with normal saline injected into the pelvic cavity may be a feasible and safe procedure to assess tubal patency and adhesions of the fimbrial parts.

Luteal-phase ovarian stimulation vs conventional ovarian stimulation in patients with normal ovarian reserve treated for IVF: a large retrospective cohort study.

OBJECTIVE: We have previously reported a new luteal-phase ovarian stimulation (LPS) strategy for infertility treatment. The purpose of this study was to systematically assess the efficiency and safety of this strategy by comparing it with conventional ovarian stimulation protocols. DESIGN: Retrospective cohort study. SUBJECTS: Patients with normal ovarian reserve undergoing ovum pick-up (OPU) cycles between April 2012 and September 2013 were enrolled: 708 patients underwent the LPS protocol compared with 745 patients who underwent the mild treatment protocol and 1287 patients who underwent the short-term protocol. MEASUREMENTS: Number of mature oocytes retrieved and top-quality embryos obtained, implantation rate, pregnancy rate, live birth and ongoing pregnancy rate and neonatal outcomes. RESULTS: The numbers of mature oocytes retrieved and top-quality embryos obtained per OPU cycle were significantly increased in the LPS group (10·9 ± 7·6 and 4·6 ± 4·3, respectively) compared with the mild treatment group (3·7 ± 3·0 and 1·8 ± 1·8, respectively, both P < 0·001) or the short-term group (9·1 ± 5·5 and 3·7 ± 3·1, respectively, both P < 0·001). Moreover, the total gonadotrophin used was also the highest in the LPS group. No significant differences were identified in the implantation rate (35·5% vs 34·8%, P > 0·05), pregnancy rate (46·2% vs 43·7%, P > 0·05) or live birth and ongoing pregnancy rate (44·4% vs 41·7%, P > 0·05) per frozen-thawed embryo transfer (FET) cycle in the LPS and mild treatment groups, respectively. However, the LPS protocol achieved a higher implantation rate (35·5% vs 31·8%, P = 0·012), pregnancy rate (46·2% vs 41·9%, P = 0·041), and live birth and ongoing pregnancy rate (44·4% vs 39·2%, P = 0·012) compared with the short-term protocol. Neonatal outcomes in the LPS group were similar to the other two groups. CONCLUSIONS: The available data suggest that LPS is a feasible strategy for infertility treatment and complements the available follicular-phase ovarian stimulation strategies.

Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol).

Previous studies have shown that existing antral follicles in the luteal phase enable ovarian stimulation. In a pilot study, the efficacy of double stimulations during the follicular and luteal phases in women with poor ovarian response was explored (defined according to the Bologna criteria). Thirty-eight women began with mild ovarian stimulation. After the first oocyte retrieval, human menopausal gonadotrophin and letrozole were administrated to stimulate follicle development, and oocyte retrieval was carried out a second time when dominant follicles had matured. The primary outcome measured was the number of oocytes retrieved: stage one 1.7 ± 1.0; stage two 3.5 ± 3.2. From the double stimulation, 167 oocytes were collected and 26 out of 38 (68.4%) succeeded in producing one to six viable embryos cryopreserved for later transfer. Twenty-one women underwent 23 cryopreserved embryo transfers, resulting in 13 clinical pregnancies. The study shows that double ovarian stimulations in the same menstrual cycle provide more opportunities for retrieving oocytes in poor responders. The stimulation can start in the luteal phase resulting in retrieval of more oocytes in a short period of time. This offers new hope for women with poor ovarian response and newly diagnosed cancer patients needing fertility preservation.

A randomized controlled trial to compare the live birth rate of the first frozen embryo transfer following the progestin-primed ovarian stimulation protocol vs. the antagonist protocol in women with an anticipated high ovarian response.

OBJECTIVE: To compare the live birth rate of the first frozen embryo transfer (FET) after ovarian stimulation by the progestin-primed ovarian stimulation (PPOS) protocol vs. the antagonist protocol in women with an anticipated high ovarian response who were undergoing in vitro fertilization. DESIGN: Randomized controlled trial. SETTING: A tertiary assisted reproduction center. PATIENTS: Women with infertility aged <43 years undergoing the first in vitro fertilization cycle and having antral follicle count of >15. INTERVENTIONS: Medroxyprogesterone 10 mg daily was given from the start of ovarian stimulation until the day of ovulation trigger in the PPOS protocol. In the antagonist protocol, an antagonist 0.25 mg daily was given from the sixth day of ovarian stimulation until the day of ovulation trigger. Blinding was not possible for women or physicians but the biostatistician was blinded to the group assignment. MAIN OUTCOME MEASURE: Live birth rate of the first FET cycle. RESULTS: A total of 784 women were recruited from June 2020 and October 2021 and assigned randomly in a 1:1 ratio into two groups: PPOS group (n = 392) and antagonist group (n = 392). Embryo transfer was either cancelled or postponed in 62 women (62/392, 15.8%) in the PPOS group and 65 (65/392, 16.6%) in the antagonist group because of no transferable embryos or no FET within 6 months after randomization. The two groups were similar in demographic characteristics and the numbers of oocytes obtained or fertilized, cleaving embryos, good-quality embryos at day 3, blastocysts developed, and embryos or blastocysts frozen. There was no statistically significant difference in the live birth rate of the first FET cycle between the PPOS and antagonist groups on the basis of both the intention-to-treat analysis (37.5.0% [147/392] vs. 32.7% [128/392]; relative risk, 1.148 [95% confidence interval, 0.949-1.390]) and per-protocol analysis (44.5% [147/330] vs. 39.1% [128/327]; relative risk, 1.138 [95% confidence interval, 0.950-1.364]). Both groups showed comparable clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy, and cumulative live birth rates. CONCLUSION: The live birth rates of the first FET following the PPOS and antagonist protocols were comparable in women with an anticipated high ovarian response. CLINICAL TRIAL REGISTRATION NUMBER: NCT04414761 (ClinicalTrials.gov).

The effect of dapagliflozin on anemia in elderly patients with heart failure by bioinformatics analysis.

BACKGROUND: Anemia associated with heart failure is frequent and can exacerbate the symptoms of heart failure. Dapagliflozin is the first SGLT-2 inhibitor with significant cardiovascular protection. However, the effect of dapagliflozin on anemia in elderly patients with heart failure is unknown. OBJECTIVE: We aimed to study the effect of dapagliflozin on anemia in elderly patients with heart failure by bioinformatics analysis. METHODS: The target genes were determined, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The protein-protein interaction (PPI) network and modules were constructed. The dapagliflozin-targets network in anemia and heart failure was constructed. Molecular docking experiments between dapagliflozin and its key target AKT1 were performed. RESULTS: We found 1 dapagliflozin related target gene and 2 disease related genes. Totally, 134 target genes of dapagliflozin on anemia in elderly patients with heart failure were determined. The pathways may involve lipid and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications, hepatitis B, insulin signaling pathway, fluid shear stress and atherosclerosis, neurotrophin signaling pathway, insulin resistance, toxoplasmosis, colorectal cancer, and EGFR tyrosine kinase inhibitor resistance. The hub genes in network were AKT1, TP53, GAPDH, TNF, CASP3, EGFR, and MAPK3. The structure of dapagliflozin and AKT1 molecular docking was exhibited. CONCLUSIONS: The hub genes in network were AKT1, TP53, GAPDH, TNF, CASP3, EGFR, and MAPK3. The structure of dapagliflozin and AKT1 molecular docking was exhibited.

Transcriptomic profiling highlights cell proliferation in the progression of experimental pulmonary hypertension in rats.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remolding and occlusion, leading to the elevated pulmonary arterial pressures, right ventricular hypertrophy, and eventual heart failure if left untreated. Understanding the molecular mechanisms underlying the development and progression of pulmonary hypertension (PH) is crucial for devising efficient therapeutic approaches for the disease. Lung homogenates were collected weekly and underwent RNA-sequencing in the monocrotaline (MCT)-induced PH rat model to explore genes associated with PH progression. Statistical analyses revealed 1038, 1244, and 3125 significantly altered genes (P < 0.05, abs (log2fold change) > log21.5) between control and MCT-exposed rats during the first, second, and third week, respectively. Pathway enrichment analyses revealed involvement of cell cycle and innate immune system for the upregulated genes, GPCR and VEGF signaling for the downregulated genes. Furthermore, qRT-PCR validated upregulation of representative genes associated with cell cycle including Cdc25c (cell division cycle 25C), Cdc45, Top2a (topoisomerase IIα), Ccna2 (cyclin A2) and Ccnb1 (cyclin B1). Western blot and immunofluorescence analysis confirmed increases in PCNA, Ccna2, Top2a, along with other proliferation markers in the lung tissue of MCT-treated rats. In summary, RNA sequencing data highlights the significance of cell proliferation in progression of rodent PH.