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Abstract Cancer cells acquire the ability to reprogram their phenotype in response to targeted therapies, yet the transition from dormancy to proliferation in drug-resistant cancers remains poorly understood. In prostate cancer, we utilized high-plasticity mouse models and enzalutamide-resistant (ENZ-R) cellular models to elucidate NR2F1 as a key factor in lineage transition and ENZ resistance. Depletion of NR2F1 drives ENZ-R cells into a relative dormancy state, characterized by reduced proliferation and heightened drug resistance, while NR2F1 overexpression yields contrasting outcomes. Transcriptional sequencing analysis of NR2F1-silenced prostate cancer cells and tissues from the Cancer Genome Atlas-prostate cancer and SU2C cohorts indicated exosomes as the most enriched cell component, with pathways implicated in steroid hormone biosynthesis and drug metabolism. Moreover, NR2F1-AS1 forms a complex with SRSF1 to upregulate NR2F1 expression, facilitating its binding with ESR1 to sustain hormonal receptor expression and enhance proliferation in ENZ-R cells. Furthermore, HnRNPA2B1 interacts with NR2F1 and NR2F1-AS1, assisting their packaging into exosomes, wherein exosomal NR2F1 and NR2F1-AS1 promote the proliferation of dormant ENZ-R cells. Our works offer novel insights into the reawaking of dormant drug-resistant cancer cells governed by NR2F1 upregulation triggered by exosome-derived NR2F1-AS1 and NR2F1, suggesting therapeutic potential for phenotype reversal. Graphical Abstract

Abstract Understanding the genomic characteristics of livestock is crucial for improving breeding efficiency and conservation efforts. However, there is a relative lack of information on the genetic makeup of local goat breeds in Henan, China. In this study, we identified runs of homozygosity (ROH), genomic inbreeding coefficients (FROH), and selection signatures in four breeds including Funiu White (FNW), Huai (HG), Lushan Bullleg (LS), and Taihang black (THB). The genomic analysis utilized a dataset of 46,278 SNP markers and 102 animals. A total of 342, 567, 1285, and 180 ROH segments were detected in FNW, HG, LS, and THB, respectively, with an average of 15.55, 29.84, 32.95, and 8.18 segments per individual. The lengths of ROH segments varied from 69.36 Mb in THB to 417.06 Mb in LS, with the most common lengths being 2-4 Mb and 4-8 Mb. The highest number of longest ROH segments (> 16 Mb) were found in LS (328) and the highest average FROH value was observed in LS (0.173), followed by HG (0.128), while the lowest FROH values were in THB (0.029) and FNW (0.070). Furthermore, the analysis of ROH islands and Composite Likelihood Ratio (CLR) identified a total of 175 significant genes. Among these, 25 genes were found to overlap, detected by both methods. These genes were associated with a diverse range of traits including reproductive ability (GPRIN3), weight (CCSER1), immune response (HERC5 and TIGD2), embryo development (NAP1L5), environmental adaptation (KLHL3, TRHDE, and IFNGR1), and milk characteristics (FAM13A). Significant Gene Ontology (GO) terms related to embryo skeletal system morphogenesis, brain ventricle development, and growth were also identified. This study helps reveal the genetic architecture of Henan goat breeds and provides valuable insights for the effective conservation and breeding programs of local goat breeds in Henan.

Abstract Background To the best of our knowledge, no study has investigated the potential joint effect of large for gestational age (LGA) and assisted reproductive technology (ART) on the long-term health of children. Methods This was a prospective cohort study that recruited children whose parents had received ART treatment in the Center for Reproductive Medicine, Shandong Provincial Hospital, affiliated to Shandong University, between January 2006 and December 2017. Linear mixed model was used to compare the main outcomes. The mediation model was used to evaluate the intermediary effect of body mass index (BMI). Results 4138 (29.5%) children born LGA and 9910 (70.5%) children born appropriate for gestational age (AGA) were included in the present study. The offspring ranged from 0.4 to 9.9 years. LGAs conceived through ART were shown to have higher BMI, blood pressure, fasting blood glucose, fasting insulin, and homeostatic model assessment of insulin resistance values, even after controlling for all covariates. The odds of overweight and insulin resistance are also higher in LGA subjects. After adjusting for all covariates, LGAs conceived through ART had BMI and BMI z-scores that were 0.48 kg/m2 and 0.34 units greater than those of AGAs, respectively. The effect of LGA on BMI was identified as early as infancy and remained consistently significant throughout pre-puberty. Conclusions Compared to AGA, LGA children conceived from ART were associated with increased cardiovascular-metabolic events, which appeared as early as infancy and with no recovery by pre-puberty.

Abstract Goats have achieved global prominence as essential livestock since their initial domestication, primarily owing to their remarkable adaptability to diverse environmental and production systems. Differential selection pressures influenced by climate have led to variations in their physical attributes, leaving genetic imprints within the genomes of goat breeds raised in diverse agroecological settings. In light of this, our study pursued a comprehensive analysis, merging environmental data with single nucleotide polymorphism (SNP) variations, to unearth indications of selection shaped by climate-mediated forces in goats. Through the examination of 43,300 SNPs from 51 indigenous goat breeds adapting to different climatic conditions using four analytical methods: latent factor mixed models (LFMM), F-statistics (Fst), Extended haplotype homozygosity across populations (XPEHH), and spatial analysis method (SAM), A total of 74 genes were revealed to display clear signs of selection, which are believed to be influenced by climatic conditions. Among these genes, 32 were consistently identified by at least two of the applied methods, and three genes (DENND1A, PLCB1, and ITPR2) were confirmed by all four approaches. Moreover, our investigation yielded 148 Gene Ontology (GO) terms based on these 74 genes, underlining pivotal biological pathways crucial for environmental adaptation. These pathways encompass functions like vascular smooth muscle contraction, cellular response to heat, GTPase regulator activity, rhythmic processes, and responses to temperature stimuli. Of significance, GO terms about endocrine regulation and energy metabolic responses, key for local adaptation were also uncovered, including biological processes, such as cell differentiation, regulation of peptide hormone secretion, and lipid metabolism. These findings contribute to our knowledge of the genetic structure of climate-triggered adaptation across the goat genome and have practical implications for marker-assisted breeding in goats.

Abstract Background Pulmonary primitive neuroectodermal tumor (PNET), a member of the Ewing sarcoma family of tumors, is a rare malignancy that is associated with a grim prognosis. To date, fewer than 30 cases of pulmonary PNET have been reported. In this case report, we present the clinical details of a 12-year-old girl with pulmonary PNET who underwent surgical treatment. We also conducted an analysis and summary of other relevant studies and the surgical outcomes. Case presentation In May 2018, a 12-year-old girl was admitted with symptoms of cough and blood-tinged phlegm. A computed tomography scan revealed a large mass, measuring 12.9 cm × 8.1 cm, in the right middle and lower lungs. A percutaneous lung biopsy confirmed poorly differentiated tumor cells with a nested growth pattern. Immunohistochemical staining demonstrated positive expression of CD99, CD56, Vimentin, and Synaptophysin. The patient was diagnosed with pulmonary PNET. Following three cycles of neoadjuvant chemotherapy, a substantial reduction in tumor volume was observed. Subsequently, the patient underwent a surgical procedure involving pneumonectomy and partial resection of the left atrium with the assistance of cardiopulmonary bypass. The patient was discharged 37 days after surgery. During a three-year follow-up period, she exhibited no signs of tumor recurrence and has successfully returned to school. Conclusions This case highlights the successful management of an advanced PNET with neoadjuvant chemotherapy, pneumonectomy, and partial resection of the left atrium employing cardiopulmonary bypass. The patient remained disease-free after three years. Our analysis of surgically treated cases indicates that neoadjuvant chemotherapy can contribute to improved prognoses for PNET patients. It is crucial to emphasize that complete surgical excision remains the cornerstone of treatment, underscoring the importance of surgeons considering radical surgical approaches whenever feasible for patients with pulmonary PNETs.

Abstract Background Polycystic ovarian syndrome (PCOS) is recognized as the most prevalent endocrine disorder among women of reproductive age. While the utilization of assisted reproductive technology (ART) has resulted in favorable outcomes for infertility treatment in PCOS patients, the inherent pathophysiological features of the condition give rise to complications and consequences during pregnancy and delivery for both the mother and offspring. This study was to assess the correlation between maternal PCOS and various pregnancy complications and neonatal outcomes undergone ART. Methods A systematic search was conducted on PubMed, EmBase, and the Cochrane Library to identify observational studies that investigated the association between PCOS and the risk of various pregnancy complications and neonatal outcomes, including gestational diabetes mellitus (GDM), hypertension in pregnancy (PIH), preeclampsia (PE), preterm birth, abortion, congenital malformations (CA), small for gestational age (SGA), large for gestational age (LGA), low birth weight (LBW), macrosomia, neonatal intensive care unit (NICU) admission and birth weight. Eligible studies were selected based on predetermined inclusion and exclusion criteria. The meta-analysis was conducted using Review Manager and Stata software, with odds ratios (ORs) or mean difference (MD), confidence intervals (CIs), and heterogeneity (I2) being calculated. The search was conducted up to March 2023. Results A total of 33 studies with a combined sample size of 92,810 participants were identified. The findings indicate that PCOS is significantly associated with an increased risk of GDM (OR 1.51, 95% CI:1.17–1.94), PIH (OR 1.72, 95% CI:1.25–2.39), PE (OR 2.12, 95% CI:1.49–3.02), preterm birth (OR 1.29, 95% CI:1.21–1.39), and LBW (OR 1.29, 95% CI:1.14–1.47). In subgroup analyses, the risks of GDM (OR 1.80, 95% CI:1.23–2.62) and abortion (OR 1.41, 95% CI:1.08–1.84) were elevated in fresh embryo transferred (ET) subgroup, whereas elevated risk of PE (OR 1.82, 95% CI:1.17–2.83) and preterm birth (OR 1.31, 95% CI:1.21–1.42) was identified in frozen ET subgroup. Whatever with or without hyperandrogenism, patients with PCOS had a higher risk in preterm birth (OR 1.69, 95% CI: 1.31–2.18; OR 1.24, 95% CI:1.02–1.50) and abortion (OR 1.38, 95% CI:1.12–1.71; OR 1.23, 95% CI:1.06–1.43). Conclusion Our findings suggest that individuals with PCOS undergone ART are at a notably elevated risk for experiencing pregnancy complications and unfavorable neonatal outcomes. Nevertheless, to establish a definitive association between PCOS and pregnancy-related outcomes, it is necessary to conduct extensive prospective, blinded cohort studies and effectively control for confounding variables.

Abstract Background In the past decades, researchers have demonstrated the critical role of Toll-like receptors (TLRs) in the innate immune system. They recognize viral components and trigger immune signal cascades to subsequently promote the activation of the immune system. Main body Herpesviridae family members trigger TLRs to elicit cytokines in the process of infection to activate antiviral innate immune responses in host cells. This review aims to clarify the role of TLRs in the innate immunity defense against herpesviridae, and systematically describes the processes of TLR actions and herpesviridae recognition as well as the signal transduction pathways involved. Conclusions Future studies of the interactions between TLRs and herpesviridae infections, especially the subsequent signaling pathways, will not only contribute to the planning of effective antiviral therapies but also provide new molecular targets for the development of antiviral drugs.

Abstract Background A growing number of patients continue to receive total knee replacement (TKR) surgery. Nevertheless, such surgeries result in moderate to severe postoperative pain and difficulty in managing it. Musical interventions are regarded as a type of multimodal analgesia, achieving beneficial results in other clinical treatments. This study aims to evaluate the effect of musical interventions in improving short-term pain outcomes following TKR in order to determine a more reasonable and standard way of delivering musical intervention. Methods A systematic search was conducted to identify available and relevant randomized controlled trials (RCTs) regarding musical interventions compared against non-musical interventions in patients treated with TKR in Embase, MEDLINE, Cochrane Library, Web of Science, CNKI, and Wanfang Med Online up to 8 January 2020. The authors independently assessed study eligibility and risk of bias and collected the outcomes of interest to analyze. The statistical analysis was conducted using the Review Manager (RevMan) version 5.30 software. Results Eight RCTs comprised of 555 patients satisfied the inclusion criteria and were enrolled in the present study. The results showed no significant difference between the music and control groups in pain of the visual analog scale (VAS), during postoperative recovery room, back to the ward after surgery; anxiety degree of VAS; heart rate; respiratory rate; oxygen saturation; blood pressure, systolic blood pressure, and diastolic blood pressure. Nevertheless, significant differences were observed between the two groups in average increase in continuous passive motion (CPM) angles and LF/HF ratio (one kind index of heart rate variability). Conclusions Musical interventions fail to demonstrate an obvious effect in improving short-term pain outcomes following TKR. A reasonable standardization of musical interventions, including musical type, outcome measures used, outcomes measured, duration, timing and headphones or players, may improve pain outcomes with certain advantages and should be further explored after TKR.

Abstract Background Porous-coated metaphyseal sleeves are designed to fill bone loss and facilitate osseo-integration when bone loss occurs during revision total knee arthroplasty (TKA). The purpose of this paper was to evaluate the clinical and radiographic outcomes of porous-coated metaphyseal sleeves for severe bone loss in revision TKA. Methods Form December 2014 to March 2018, we retrospectively analyzed 36 patients receiving revision TKAs. They had Anderson Orthopaedic Research Institute (AORI) Type II and III tibial bone loss and were treated with metaphyseal sleeve. The patients were followed up for a mean time of 28.5 months. The Knee Society Score (KSS), the Hospital for Special Surgery (HSS) Knee Score, Visual Analog Scale (VAS) score and the range of motion (ROM), radiographic findings of sleeve osteo-integration were also recorded. The paired t test was used to compare the KSS, the HSS knee score and VAS score before and after the revision TKAs. A value of P

Abstract Background In patients with diabetes mellitus, the urinary microalbumin-to-urine creatinine ratio (UACR) can not only predict the occurrence of diabetic nephropathy but also can be a risk factor for cardiovascular disease and renal function damage. Current studies on subclinical hypothyroidism (SCH) and UACR are mainly cross-sectional studies, and the results suggest that SCH is an independent risk factor for UACR. To further explore the longitudinal effect of SCH on UACR, we carried out this study. Methods This was a retrospective cohort study including 46 patients with type 2 diabetes mellitus and SCH in the Department of Endocrinology, The Affiliated Huai’an Hospital of Xuzhou Medical University from January 2013 to April 2018. At the same time, 96 patients with type 2 diabetes mellitus and euthyroid were chosen according to 1:2 approximately matched with age, sex and duration of diabetes mellitus. Univariate analysis, stratified analysis, and multiple linear regression analysis were used to investigate the effect of SCH on ΔUACR(ΔUACR = UACR after 1 year - baseline UACR) in patients with type 2 diabetes mellitus. Results There was no significant difference between the baseline UACR, (p > 0.05). However, the ΔUACR was significantly higher in SCH group than euthyroid group, as shown by univariate analysis, stratified analysis and multiple linear regression analysis (β:-1.071, 95% CI: − 1.713--0.428), and the difference was statistically significant (all p

Abstract Background In recent years, the incidence of carbapenem-resistant Enterobacteriaceae (CRE) infections has increased rapidly. Since the CRE strain is usually resistant to most of antimicrobial agents, patients with this infection are often accompanied by a high mortality. Therefore, it instigates a severe challenge the clinical management of infection. In this study, we study the in vitro and in vivo bactericidal activity of ceftazidime-avibactam administrated either alone or in combination with aztreonam against KPC or NDM carbapenemase-producing Klebsiella pneumoniae, and explore a new clinical therapeutic regimen for infections induced by their resistant strains. Methods The microdilution broth method was performed to analyze the minimal inhibitory concentration (MIC). The time-kill curve assay of ceftazidime-avibactam at various concentrations was conducted in 16 strains of KPC-2 and 1 strain of OXA-232 carbapenemase–producing Klebsiella pneumoniae. The in vitro synergistic bactericidal effect of ceftazidime-avibactam combined with aztreonam was determined by checkerboard assay on 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase–producing Klebsiella pneumoniae. According to calculating grade, the drugs with synergistic bactericidal effect were selected as an inhibitory concentration index. The in vitro bactericidal tests of ceftazidime-avibactam combined with aztreonam were implemented on 12 strains among them. Effect of ceftazidime-avibactam antibiotic against KPC carbapenemase–producing K. pneumoniae strain Y8 Infection was performed in the mouse model. Results The time-kill assays revealed that ceftazidime-avibactam at various concentrations of 2MIC, 4MIC and 8MIC showed significant bactericidal efficiency to the resistant bacteria strains. However, in 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase- producing Klebsiella pneumoniae, only 7 strains appeared the susceptibility to ceftazidime-avibactam treatment, MIC50 and MIC90 were 64 mg/L and 256 mg/L, respectively. Antimicrobial susceptibility testing of ceftazidime-avibactam combined with aztreonam disclosed the synergism of two drugs in 90% (27/30) strains, an additive efficiency in 3.3% (1/30) strains, and irrelevant effects in 6.6% (2/30) strains. No antagonism was found. The subsequent bactericidal tests also confirmed the results mentioned above. Therapeutic efficacy of Ceftazidime-Avibactam against K. pneumoniae strain Y8 infection in mouse indicated 70% of infection group mice died within 4 days, and all mice in this group died within 13 days. Bacterial load testing results showed that there was no significant difference in the amount of bacteria in the blood between the infected group and the treatment group. However, the spleen and liver of treatment group mice showed lower CFU counts, as compare with infected group, indicating that ceftazidime-avibactam has a significant effect on the bacteria and led to a certain therapeutic efficacy. Conclusion This study indicated ceftazidime-avibactam therapy occupied significant bactericidal effects against KPC-2 and OXA-232 carbapenemase-producing Klebsiella pneumoniae. While combined with aztreonam, the stronger synergistic bactericidal effects against NDM carbapenemase-producing Klebsiella pneumoniae were achieved.

An amendment to this paper has been published and can be accessed via the original article.