Efficacy and safety of mesenchymal stem cell therapy for ovarian ageing in a mouse model.

BACKGROUND: Ovarian ageing is one of the major issues that impacts female fertility. Mesenchymal stem cell (MSC)-based therapy has made impressive progress in recent years. However, the efficacy and safety of MSCs, as nonautologous components, remain to be further verified. METHODS: Two common sources of MSCs, umbilical cord-derived MSCs (UC-MSCs) and adipose tissue-derived MSCs (AD-MSCs), were orthotopically transplanted into a mouse model of ovarian ageing to evaluate their therapeutic effects. The safety of the treatment was further evaluated, and RNA sequencing was performed to explore the underlying mechanisms involved. RESULTS: After orthotopic transplantation of MSCs into the ovary, the oestrous cycle, ovarian weight, number and proportion of primary follicles, granulosa cell proliferation, and angiogenesis were improved. The effects of AD-MSCs were superior to those of UC-MSCs in several indices, such as post-transplant granulosa cell proliferation, ovarian weight and angiogenesis. Moreover, the tumorigenesis, acute toxicity, immunogenicity and biodistribution of MSCs were evaluated, and both AD-MSCs and UC-MSCs were found to possess high safety profiles. Through RNA sequencing analysis, enhancement of the MAPK cascade was observed, and long-term effects were mainly linked to the activation of immune function. CONCLUSIONS: Orthotopic transplantation of MSCs displays significant efficacy and high safety for the treatment of ovarian ageing in mice.

Impact of homologous recombination deficiency biomarkers on outcomes in patients with early breast cancer: a systematic review protocol.

INTRODUCTION: Patients with breast cancer with homologous recombination deficiency (HRD) such as germline BRCA1/2 mutations would respond to DNA-damaging drugs. Several clinical studies have revealed that HRD biomarkers were associated with the outcomes of patients with early breast cancer (EBC). However, no systematic review has determined the prognostic role of HRD biomarkers in patients with EBC. Therefore, this study will systematically combine and analyse the results of previous studies, to facilitate the clinical use of HRD detection in EBC. METHODS AND ANALYSIS: We will search five databases including PubMed, Cochrane Library, EMBASE, OVID and Web of Science through December 2021, with no language restriction. Two reviewers will independently screen all records based on pre-established inclusion and exclusion criteria. The main outcomes include pathological complete response, disease-free survival and Ooerall survival. In addition, all studies included must contain the detection of HRD score, HRD status or HRD-related gene mutational status and protein expression. Data extraction will be carried out by two reviewers independently according to a self-designed template. The Newcastle-Ottawa Quality Assessment Scale and Jadad Scale will be used for quality assessment for cohort studies and randomised clinical trials, respectively. Review Manager V.5.3.5 will be used to perform meta-analysis. Both the Q test and I2 statistic will be used to assess heterogeneity. Subgroup and sensitivity analyses will be conducted if significant heterogeneity appears and cannot be reduced by using a random-effect model. ETHICS AND DISSEMINATION: Ethical approval is not required for a systematic review. The results will be disseminated through international and national conferences or peer-reviewed publications. PROSPERO REGISTRATION NUMBER: CRD42021286522.

Efficacy and Safety of Initial 5 Years of Adjuvant Endocrine Therapy in Postmenopausal Hormone Receptor-Positive Breast Cancer: A Systematic Review and Network Meta-Analysis.

Purpose: To identify the optimal initial 5 years of adjuvant endocrine therapy for hormone receptor-positive postmenopausal early breast cancer (EBC) patients. Methods: We conducted a systematic search of the PubMed, Web of Science, and EMBASE to obtain relevant studies published between January 2000 and January 2022. Randomized clinical trials assessing the efficacy and safety of initial 5 years of adjuvant endocrine therapy were included. The primary outcomes were disease-free survival and overall survival and the secondary outcome was severe adverse effects (SAEs). A Bayesian network meta-analysis was carried out to indirectly compare all regimens and the value of surface under the cumulative ranking curve (SUCRA) was used to obtain rankings. Results: Eleven studies with 49,987 subjects were included. For DFS, exemestane (EXE) [hazard ratio (HR) 0.91, 95% confidence interval (95%CI) 0.87-0.96], anastrozole (ANA) (0.94, 0.90-0.97), letrozole (LET) (0.93, 0.89-0.97), tamoxifen (TAM) followed by EXE (0.91, 0.87-0.96), and TAM followed by ANA (0.92, 0.87-0.98) were more favorable than TAM, with TAM followed by EXE ranking as the first of SUCRA. For OS, only TAM followed by ANA showed significant superiority than TAM (HR 0.91, 95%CI 0.86-0.97) and ranked as the first of SUCRA. For SAEs, EXE (HR 1.72, 95%CI 1.04-2.98), ANA (1.58, 1.03-2.43), and LET (1.63, 1.02-2.57) showed greater associations with bone fracture than TAM. However, no significant difference in the incidences of cardiac events, thromboembolic events, and cerebrovascular events was found among all comparisons. Conclusion: The sequential use of aromatase inhibitors, which has the best curative effects and relatively mild side effects, may be the optimal treatment mode for hormone receptor-positive postmenopausal EBC patients. In addition, the three kinds of aromatase inhibitors achieved roughly equal efficacy, but caused different types of SAEs. Systematic Review Registration: [website], identifier [registration number].

Generation of human blastocyst-like structures from pluripotent stem cells.

Human blastocysts are comprised of the first three cell lineages of the embryo: trophectoderm, epiblast and primitive endoderm, all of which are essential for early development and organ formation. However, due to ethical concerns and restricted access to human blastocysts, a comprehensive understanding of early human embryogenesis is still lacking. To bridge this knowledge gap, a reliable model system that recapitulates early stages of human embryogenesis is needed. Here we developed a three-dimensional (3D), two-step induction protocol for generating blastocyst-like structures (EPS-blastoids) from human extended pluripotent stem (EPS) cells. Morphological and single-cell transcriptomic analyses revealed that EPS-blastoids contain key cell lineages and are transcriptionally similar to human blastocysts. Furthermore, EPS-blastoids are similar with human embryos that were cultured for 8 or 10 days in vitro, in terms of embryonic structures, cell lineages and transcriptomic profiles. In conclusion, we developed a scalable system to mimic human blastocyst development, which can potentially facilitate the study of early implantation failure that induced by developmental defects at early stage.

Comparison of the rabbit and human corneal endothelial proteomes regarding proliferative capacity.

The shortage of human donor corneas has raised important concerns about engineering of corneal endothelial cells (CECs) for clinical use. However, due to the limited proliferative capacity of human CECs, driving them into proliferation and regeneration may be difficult. Unlike human CECs, rabbit CECs have a marked proliferative capacity. To clarify the potential reason for this difference, we analysed the proteomes of four human corneal endothelium samples and four rabbit corneal endothelium samples with quantitative label-free proteomics and downstream analysis. We discovered that vitamin and selenocompound metabolism and some signaling pathways such as NF-kappa B signaling pathway differed between the samples. Moreover, TGFß, PITX2 and keratocan were distinctively expressed in rabbit samples, which might be associated with active proliferation in rabbit CECs. This study illustrates the proteomic differences between human and rabbit CECs and might promote CEC engineering strategies.

Efficacy and Safety of Pyrotinib Versus T-DM1 in HER2+ Metastatic Breast Cancer Patients Pre-Treated With Trastuzumab and a Taxane: A Bayesian Network Meta-Analysis.

PURPOSE: To compare the efficacy and safety between pyrotinib (Pyr) and trastuzumab emtansine (T-DM1) in pre-treated human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) patients. METHODS: A comprehensive literature search of the PubMed, EMBASE, and Web of Science was performed in August 2020. Randomized clinical trials comparing the efficacy and safety between different anti-HER2 regimens in patients pre-treated with trastuzumab (Tra) and a taxane in metastatic settings (≤second-line treatment) were included. A fixed effects network meta-analysis based on the Bayesian inferential framework was conducted for progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and grade ≥3 adverse events (AEs). Values of surface under cumulative ranking probability curve (SUCRA) were calculated to offer a ranking of all regimens. RESULTS: Twelve studies with 4,353 subjects were identified. Nine regimens were included into the network: T-DM1, lapatinib-capecitabine (Lap-Cap), Tra-Cap, Cap, neratinib (Ner), pertuzumab (Per)-Tra-Cap, Pyr-Cap, atezolizumab (Ate)-T-DM1, and Ner-Cap. For PFS, Pyr-Cap was more favorable than T-DM1 (hazard ratio, 95% confidence interval: 0.77, 0.70-0.86), Lap-Cap (0.64, 0.59-0.69), Tra-Cap (0.63, 0.56-0.70), Cap (0.50, 0.45-0.56), Ner (0.59, 0.51-0.69), Per-Tra-Cap (0.68, 0.59-0.79), and Ner-Cap (0.72, 0.64-0.81). For OS, Pyr-Cap showed further improvement than Lap-Cap (hazard ratio, 95% confidence interval: 0.71, 0.52-0.99), Cap (0.68, 0.49-0.96), and Ner (0.65, 0.45-0.94). For ORR, Pyr-Cap was significantly superior than Cap (odds ratio, 95% confidence interval: 7.87, 1.22-56.51). No significant difference was observed in grade ≥3 AEs among all the regimens. Pyr-Cap ranked in the highest in PFS, OS, ORR, and grade ≥3 AEs (SUCRA = 99.4, 89.7, 86.4, and 89.3%). CONCLUSIONS: These results indicate that Pyr may be more effective than T-DM1 in HER2+ MBC patients pre-treated with Tra and a taxane. However, it may be associated with more grade ≥3 AEs.

Brain transcriptomics of nonhuman primates: A review.

The brain is one of the most important and intricate organs in our bodies. Interpreting brain function and illustrating the changes and molecular mechanisms during physiological or pathological processes are essential but sometimes difficult to achieve. In addition to histology, ethology and pharmacology, the development of transcriptomics alleviates this condition by enabling high-throughput observation of the brain at various levels of anatomical specificity. Moreover, because human brain samples are scarce, the brains of nonhuman primates are important alternative models. Here in this review, we summarize the applications of transcriptomics in nonhuman primate brain studies, including investigations of brain development, aging, toxic effects and diseases. Overall, as a powerful tool with developmental potential, transcriptomics has been widely utilized in neuroscience.

Transcriptomic analysis reveals gender differences in gene expression profiling of the hypothalamus of rhesus macaque with aging.

Due to the current delay in childbearing, the importance of elucidating the underlying mechanisms for reproductive aging has increased. Human fertility is considered to be controlled by hormones secreted by the hypothalamic-pituitary-gonadal axis. To clarify the changes in hypothalamic gene expression with increasing age, we performed paired-end strand-specific total RNA sequencing for the hypothalamus tissues of rhesus. We found that hypothalamic gene expression in females was more susceptible to aging than that in males, and reproductive aging in females and males might have different regulatory mechanisms. Intriguingly, the expression of most of the hormones secreted by hypothalamus showed no significant difference among the macaques grouped by age and gender. Moreover, the age-related housekeeping genes in females were enriched in neurodegenerative disorders- and metabolic-related pathways. This study provides evidence that aging may influence hypothalamic gene expression through different mechanisms in females and males and may involve some nonhormonal pathways, which helps further elucidate the process of reproductive aging and improve clinical fertility assessment in mid-aged women.

Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects.

Endocrine therapy is the main treatment option for estrogen receptor-positive (ER+) breast cancer (BC). Compared with other clinical subtypes, ER+ BC patients usually have a more favorable prognosis. However, almost all ER+ BCpatients develop endocrine resistance and disease progression eventually. A large number of studies based on liquid biopsy suggest that ESR1 mutations may play a key role in this process. For patients with ER+ metastatic BC (MBC), ESR1 is an important prognostic factor and may associate with the resistance to endocrine therapy, like aromatase inhibitors. The advances of sequencing technologies allow us to conduct longitudinal monitoring of disease and unveil the clinical implications of each ESR1 sub-clone in ER+ MBC. Moreover, since the ESR1-related endocrine resistance has not been fully addressed by existing agents, more potent cornerstone drugs should be developed as soon as possible. Herein, we reviewed the recent progress of detecting ESR1 mutations based on liquid biopsy and different sequencing technologies in ER+ MBC and discussed its clinical impacts and prospects.

Epigenome editing by CRISPR/Cas9 in clinical settings: possibilities and challenges.

Epigenome editing is a promising approach for both basic research and clinical application. With the convergence of techniques from different fields, regulating gene expression artificially becomes possible. From a clinical point of view, targeted epigenome editing by CRISPR/Cas9 of disease-related genes offers novel therapeutic avenues for many diseases. In this review, we summarize the EpiEffectors used in epigenome editing by CRISPR/Cas9, current applications of epigenome editing and progress made in this field. Moreover, application challenges such as off-target effects, inefficient delivery, stability and immunogenicity are discussed. In conclusion, epigenome editing by CRISPR/Cas9 has broad prospects in the clinic, and future work will promote the application of this technology.

Efficacy of long-term noninvasive positive pressure ventilation in stable hypercapnic COPD patients with respiratory failure: a meta-analysis of randomized controlled trials.

INTRODUCTION: The efficacy of long-term noninvasive positive pressure ventilation (NPPV) in stable hypercapnic COPD patients with respiratory failure remains unclear. The aim of this meta-analysis was to critically assess the efficacy of long-term NPPV on mortality, acute exacerbation, exercise capacity, symptoms and significant physiological parameters (lung function, respiratory muscle function and gas exchange). PATIENTS AND METHODS: We performed an electronic literature search using the PubMed, Cochrane Library, Embase, OVID and Chinese Biomedical Literature Database in May 2017. Studies comparing treatment effects of NPPV with oxygen therapy in stable hypercapnic COPD patients with respiratory failure were conducted, and at least one of the following parameters were reviewed: frequency of acute exacerbation, mortality, lung function, respiratory muscle function, gas exchange, exercise capacity. RESULTS: Seven studies with 810 subjects were identified. The partial pressure of arterial carbon dioxide (PaCO2) significantly decreased in patients who received long-term NPPV (weighted mean difference [WMD] -3.73, 95% CI: -5.83 to -1.64, P=0.0005). No significant difference was found in mortality, partial pressure of arterial oxygen (PaO2), frequency of acute exacerbation, lung function, respiratory muscle function and exercise capacity. The subgroup analysis showed that NPPV significantly improved the survival of patients when it was targeted at greatly reducing hypercapnia (WMD 0.35, 95% CI: 0.19 to 0.64, P=0.0006). CONCLUSION: The results indicate that long-term NPPV decreases the PaCO2 of stable hypercapnic COPD patients with respiratory failure and improves mortality with the aim of reducing PaCO2.

Secondary systemic lupus erythematosus after thymoma resection misdiagnosed as medically unexplained dyspnoea: A case report.

RATIONALE: Secondary systemic lupus erythematosus (SLE) is an exceedingly rare complication of thymoma resection and is difficult to diagnose because of the insidious and nonspecific clinical manifestations. A case of SLE that occurs secondary to thymoma resection is described in this report. PATIENT CONCERNS: A 43-year-old male came to our hospital with the sole symptom of dyspnea after thymoma resection initially. However, other atypical lesions of SLE occurred over time. DIAGNOSES: Antinuclear antibody spectrum test showed positive results and the diagnosis of SLE was obtained. INTERVENTIONS: Initially the patient was treated for medically unexplained dyspnea (MUD) without much improvement. Following the diagnosis, the methylprednisolone pulse therapy and therapies of immunoglobulin and cyclophosphamide were adopted for the treatment. OUTCOMES: Finally, the patient's symptoms faded rapidly and favorable prognosis has been maintained till now. LESSONS: This case highlights the importance of a serious and comprehensive analysis before we give the diagnosis of MUD. Additionally, ignorance of secondary SLE after thymoma resection should be prevented to avoid a delayed diagnosis and treatment.