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Abstract Background The number of patients with type 1 diabetes rises rapidly around the world in recent years. Maternal diabetes has a detrimental effect on reproductive outcomes due to decreased oocyte quality. However, the strategies to improve the oocyte quality and artificial reproductive technology (ART) efficiency of infertile females suffering from diabetes have not been fully studied. In this study, we aimed to examine the effects of nicotinamide mononucleotide (NMN) on oocyte maturation of mouse with type 1 diabetes mouse and explore the underlying mechanisms of NMN’s effect. Methods Streptozotocin (STZ) was used to establish the mouse models with type 1 diabetes. The successful establishment of the models was confirmed by the results of body weight test, fasting blood glucose test and haematoxylin and eosin (H&E) staining. The in vitro maturation (IVM) rate of oocytes from diabetic mice was examined. Immunofluorescence staining (IF) was performed to examine the reactive oxygen species (ROS) level, spindle/chromosome structure, mitochondrial function, actin dynamics, DNA damage and histone modification of oocytes, which are potential factors affecting the oocyte quality. The quantitative reverse transcription PCR (RT-qPCR) was used to detect the mRNA levels of Sod1, Opa1, Mfn2, Drp1, Sirt1 and Sirt3 in oocytes. Results The NMN supplementation increased the oocyte maturation rate of the mice with diabetes. Furthermore, NMN supplementation improved the oocyte quality by rescuing the actin dynamics, reversing meiotic defects, improving the mitochondrial function, reducing ROS level, suppressing DNA damage and restoring changes in histone modifications of oocytes collected from the mice with diabetes. Conclusion NMN could improve the maturation rate and quality of oocytes in STZ-induced diabetic mice, which provides a significant clue for the treatment of infertility of the patients with diabetes.

An understanding of the relationship between CO2 emissions and land use can provide a deeper understanding of how urbanization affects climate change, provide insights into sustainable urban development, and reveal CO2 emission dynamics in the context of urbanization. However, the accuracy of these predictions is limited due to the poor understanding of the influence of differences in urban hierarchy on land use transition rules. This study proposes an integrated CO2 emission prediction method that utilizes a newly developed future land use simulation (partitioned-FLUS) model and a Long Short-Term Memory (LSTM) model. Notably, the partitioned-FLUS model considers regional heterogeneities based on urban hierarchies. Based on data from the Yangtze River Delta, zonal partitioning was found to improve Kappa coefficients by at least 13% compared to conventional FLUS models. The results indicated that a significant urbanization belt was likely to form both along and south of the Yangtze River over the next 30 years; resulting in areas of concentrated CO2 emissions. The relationship between land use and CO2 emissions varied greatly between cities of different urban hierarchies. This study suggests that construction land and farmland in Level 1 and 2 cities should be reallocated to Level 3 cities, thereby reducing carbon emissions.

Abstract Background The three‐dimensional (3D) genome architecture plays a critical role inregulating gene expression. However, the specific alterations in thisarchitecture within somatotroph tumors and their implications for gene expression remain largely unexplored. Methods We employed Hi‐C and RNA‐seq analyses to compare the 3D genomic structures of somatotroph tumors with normal pituitary tissue. This comprehensive approachenabled the characterization of A/B compartments, topologically associateddomains (TADs), and chromatin loops, integrating these with gene expression patterns. Results We observed a decrease in both the frequency of chromosomal interactions andthe size of TADs in tumor tissue compared to normal tissue. Conversely, the number of TADs and chromatin loops was found to be increased in tumors. Integrated analysis of Hi‐C and RNA‐seq data demonstrated that changes inhigher‐order chromat in structure were associated with alterations in gene expression. Specifically, genes in A compartments showed higher density and increased expression relative to those in B compartments. Moreover, the weakand enhanced insulation boundaries were identified, and the associated genes were enriched in the Wnt/β‐Catenin signaling pathway. We identified the gainedand lost loops in tumor and integrated these differences with transcriptional changes to examine the functional relevance of the identified loops. Notably, we observed an enhanced insulation boundary and a greater number of loops in the TCF7L2 gene region within tumors, which was accompanied by an upregulation of TCF7L2 expression. Subsequently, TCF7L2 expression was confirmed through qRT‐PCR, and upregulated TCF7L2 prompted cell proliferation and growth hormone (GH) secretion in vitro. Conclusion Our results provide comprehensive 3D chromatin architecture maps of somatotroph tumors and offer a valuable resource for furthering the understanding of the underlying biology and mechanisms of gene expression regulation.

Introduction: Cadmium (Cd) is a hazardous environmental pollutant present in soil, water, and food. Accumulation of Cd in organisms can cause systematic injury and damage to the kidney. The Masson pine pollen aqueous extract (MPPAE) has attracted increasing attention due to its antioxidant activity and ability to enhance immunity.Methods: In this study, we investigated the potential of MPPAE to protect against Cd-induced kidney damage in rats and the underlying mechanism. The transcriptome and metabolome of rats with Cd-induced kidney damage, following treatment with MPPAE, were explored.Results: The concentrations of superoxide dismutase (SOD) and malondialdehyde (MDA) were both significantly altered after treatment with MPPAE. Furthermore, sequencing and analysis of the transcriptome and metabolome of rats with Cd-induced kidney damage, following treatment with MPPAE, revealed differential expression of numerous genes and metabolites compared with the untreated control rats. These differentially expressed genes (DEGs) included detoxification-related genes such as cytochrome P450 and the transporter. The differentially expressed metabolites (DEMs) included 4-hydroxybenzoic acid, L-ascorbate, and ciliatine. Conjoint transcriptome and metabolome analysis showed that several DEGs were correlated with DEMs.Conclusion: These preliminary findings indicate the potential of MPPAE for the treatment of toxic metal poisoning.

Introduction: Acute myocardial infarction (AMI) accounts for the majority of deaths caused by coronary artery disease (CAD). Early warning of AMI, especially for patients with stable coronary artery disease (sCAD), is urgently needed. Our previous study showed that alterations in the gut microbiota were correlated with CAD severity. Objectives: Herein, we tried to discover accurate and convenient biomarkers for AMI by combination of gut microbiota and fecal/blood/urinary metabolomics. Methods: We recruited 190 volunteers including 93 sCAD patients, 49 AMI patients, and 48 subjects with normal coronary artery (NCA), and measured their blood biochemical parameters, 16S rRNA-based gut microbiota and NMR-based fecal/blood/urinary metabolites. We further selected 20 subjects from each group and analyzed their gut microbiota by whole-metagenome shotgun sequencing. Results: Multi-omic analyses revealed that AMI patients exhibited specific changes in gut microbiota and serum/urinary/fecal metabolites as compared to subjects with sCAD or NCA. Fourteen bacterial genera and 30 metabolites (11 in feces, 10 in blood, 9 in urine) were closely related to AMI phenotypes and could accurately distinguish AMI patients from sCAD patients. Some species belonging to Alistipes, Streptococcus, Ruminococcus, Lactobacillus and Faecalibacterium were effective to distinguish AMI from sCAD and their predictive ability was confirmed in an independent cohort of CAD patients. We further selected nine indicators including 4 bacterial genera, 3 fecal and 2 urinary metabolites as a noninvasive biomarker set which can distinguish AMI from sCAD with an AUC of 0.932. Conclusion: Combination of gut microbiota and fecal/urinary metabolites provided a set of potential useful and noninvasive predictive biomarker for AMI from sCAD.

ObjectiveTo investigate the clinical and pathological factors associated with preoperative hypothalamus invasion and postoperative outcomes of adamantinomatous craniopharyngiomas (ACPs) after the expanded endonasal approach (EEA) resection.MethodsNinety-three specimens of ACPs, consisting of 71 primary and 22 recurrent tumors, were investigated for the expression of TGF-β1, SMAD2, SMAD3, and β-catenin by immunohistochemistry staining. The clinical information of relevant patients, including the extent of resection, hypothalamus invasion, endocrinopathy, complications, and prognosis, was reviewed. The relationships between the expression of these immunopathological markers and clinical factors were analyzed.ResultsEndocrinological dysfunctions were more common in recurrent patients and primary patients with hypothalamus invasion in the comparisons. For recurrent patients, the rate of gross total resection (GTR) was significantly lower than for primary patients (63.6% vs. 90.1%, P = 0.007). According to radiological and intraoperative findings, invasive ACPs (IACPs) included 48 (67.6%) cases in primary tumors. The expression of TGF-β1 and β-catenin was significantly higher in recurrent tumors (P = 0.021 and P = 0.018, respectively) and IACPs (P = 0.008 and P = 0.004, respectively). The expression level of TGF-β1 was associated with hypothalamus involvement (Puget grade, P = 0.05; Vile grade, P = 0.002), postoperative endocrinopathy (P = 0.01), and pituitary stalk preservation (P = 0.008) in primary patients. In addition, the extent of resection, treatment history, hypothalamic invasion, and level of TGF-β1 expression had significant influences on tumor recurrence/progression after surgery separately.ConclusionOur study demonstrated the potential role of TGF-β1 in the regulation of hypothalamus invasion in ACPs and the prediction of prognosis after EEA surgery. The TGF-β signaling pathway may represent a crucial mechanism in the aggressive behavior and progression of ACPs.

Abstract Background Ischemia stroke is the leading cause of disability, which is a consequence of vascular occlusion. The purpose of this study is to investigate the effect of cornin which is isolated from the fruit of Verbena officinalis L, against astrocytes autophagy induced by cerebral ischemia/reperfusion (CI/R) injury in vitro and in vivo and its potential mechanism. Methods Cornin at dose of 2.5, 5 and 10 mg/kg were intravenously injected to MCAO rats at 15 min after reperfusion. The infarction volume, blood–brain barrier (BBB), neurological severity score (mNSS), and autophagy related protein were used to evaluated the protective effects and potential mechanism of cornin in autophagy with or without phosphoinositide-3 kinase (PI3K)inhibitor LY294002 and mammalian target of rapamycin (mTOR) small interfering RNA (siRNA) at 24 h after CI/R injury. The potential protective effects and mechanism of cornin at concention of 10 ~ 1000 nM were also evaluated in oxygen glucose deprivation/reperfusion (OGD/R) in U87 cells. Results The results suggest that cornin at dose of 5 or 10 mg/kg significantly reduce the cerebral infarction volume and blood–brain barrier (BBB) leakage, and improve neurological recovery in MCAO rats. Cleaved caspase-3 and Bax levels were significantly decreased, while B-cell lymphoma-2 (Bcl-2) and the apoptosis regulator ratio (Bcl-2/Bax) were markedly increased when treated with 2.5–10 mg/kg cornin. The obvious decreased expressions of glial fibrillary acidic protein (GFAP), myosin-like BCL2 interacting protein (Beclin-1) and microtubule-associated protein light chain 3 II (LC3-II) and increased of neuronal nuclei (NeuN), sequestosome-1 (p62), phosphorylated mTOR (p-mTOR), and phosphorylated Akt (p-Akt) were observed in MCAO rats treated with 10 mg/kg cornin, which was counteracted by LY294002. The expression of autophagy-related proteins with or without LY294002 and mTOR siRNA presented the similar results as in vitro in OGD/R in U87 cells. Conclusions These results indicate that cornin improved neurological recovery after cerebral ischemia injury by preventing astrocytes autophagy induced by CI/R via the PI3K/Akt/mTOR signaling pathway.

Objective This study aimed to compare the effects of two brands of commercial vitrification carriers on pregnancy outcomes in freeze–thaw cycles. Methods We included 4871 patients who underwent a “freeze all” strategy using the commercial carriers J.Y. straw and OYASHIPS straw in the Reproductive Center of the First Hospital of Jilin University. The pregnancy outcomes of cleavage-stage embryos and blastocysts were studied separately. Detailed data and the safety of children born from mothers with the two types of carriers were also compared. Results Patients who used J.Y. straw had similar clinical pregnancy and live birth rates with one and two cleavage-stage embryo transplantation to those who used OYASHIPS straw. In patients who had blastocyst transplantation, the clinical pregnancy rate of one blastocyst transplanted in those who used OYASHIPS straw was significantly higher than that in those who used J.Y. straw (57.85% vs 47.09%). Among children born from mothers who used J.Y. straw, the congenital disability rate was significantly higher than that in those with OYASHIPS straw. Conclusion The OYASHIPS straw carrier is cheap and can achieve clinical pregnancy and live birth outcomes comparable to those of J.Y. straw. Therefore, OYASHIPS straw is a good alternative option.

Opiates produce analgesia via G-protein signaling, and adverse effects, such as respiratory depression and decreased bowel motility, by β-arrestin pathway. Oliceridine, a G protein-biased MOR agonist, only presents modest safety advantages as compared to other opiates in clinical trials, possibly due to its limited bias. Our previous study shown that LPM3480392, a full MOR biased agonist, is selective for the Gi pathway over the β-arrestin-2. In the present article, we evaluated the subacute toxicity of LPM3480392 in rats. The rats were administered with control article or LPM3480392 0.6, 1.2 or 2.4 mg/kg/day for 4 consecutive weeks followed by a 4-week recovery phase. Intravenous infusion was conducted at tail vein at 0.2, 0.4 or 0.8 mg/kg/day with a dosing volume of 10 mL/kg and 5 min/rat/dose, three times a day with an interval of approximately 4 h. The concomitant toxicokinetics study was conducted. Two unscheduled rats at 2.4 mg/kg/day died with no clear cause. For the scheduled necropsy, the major effects were associated with the MOR agonist-related pharmacodynamic properties of LPM3480392 (e.g., increased activity, increased muscle tone; decreased food consumption and body weight gain; and clinical chemistry changes related with decreased food consumption) in three LPM3480392 groups. In addition, LPM3480392 at 2.4 mg/kg/day also induced deep respiration and histopathology changes in testis and epididymis in sporadic individual rats. However, different from other opiates, LPM3480392 presents weak/no immunosuppression and the decreased adrenal gland weight, which may be due to LPM3480392’ full MOR bias. At the end of recovery phase, all findings were recovered to some extent or completely. In the toxicokinetics study, the dose-dependent elevation of drug exposure was observed, which partly explained the toxicity of high dose. In summary, LPM3480392 has exhibited good safety characteristics in this subacute toxicity study in rats.

Case studies show that earthquake-induced soil liquefaction can cause large lateral deformation of piles, leading to bridge damage. In this study, an iron and steel manufacturing by-product, slag powder, was utilized for the first time to mitigate soil liquefaction, thereby reducing the lateral deformation of piles during earthquakes. First, the liquefaction resistance of soil improved by slag powder was analyzed by cyclic triaxial tests. The results indicate that as the slag powder content increased, the soil liquefaction resistance increased. When the cyclic stress ratio is 0.2, the number of liquefaction cycles of the reinforced soil increases by 30 compared with that of the unreinforced soil. Second, a numerical modeling method of slag powder reinforced sand was proposed and validated by the cyclic triaxial test results. Third, the seismic response of piles in liquefiable soils enhanced by slag powder was evaluated using finite element analyses, and slag powder was determined to be effective in decreasing the lateral deformation of piles in liquefiable soils, the maximum displacement of the pile was reduced by 45 %. Last, an empirical formula that can easily evaluate the mitigation effect of slag powder on the lateral deformation of piles is proposed and verified by the results of finite element analysis.

It is widely recognized that macrophage cholesterol efflux mediated by the ATP-binding cassette transporter A1 (ABCA1) constitutes the initial and rate-limiting step of reverse cholesterol transport (RCT), displaying a negative correlation with the development of atherosclerosis. Although the transcriptional regulation of ABCA1 has been extensively studied in previous research, the impact of post-translational regulation on its expression remains to be elucidated. In this study, we report an AMP-activated protein kinase (AMPK) agonist called ((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-((3-hydroxyphenyl) amino)-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl dihydrogen phosphate (MP), which enhances ABCA1 expression through post-translational regulation rather than transcriptional regulation. By integrating the findings of multiple experiments, it is confirmed that MP directly binds to AMPK with a moderate binding affinity, subsequently triggering its allosteric activation. Further investigations conducted on macrophages unveil a novel mechanism through which MP modulates ABCA1 expression. Specifically, MP downregulates the Cav1.2 channel to obstruct the influx of extracellular Ca2+, thereby diminishing intracellular Ca2+ levels, suppressing calcium-activated calpain activity, and reducing the interaction strength between calpain and ABCA1. This cascade of events culminates in the deceleration of calpain-mediated degradation of ABCA1. In conclusion, MP emerges as a potentially promising candidate compound for developing agents aimed at enhancing ABCA1 stability and boosting cellular cholesterol efflux and RCT.

Abstract Background This study aimed to explore the incidence and influencing factors for early pregnancy loss (EPL) in infertility patients with first pregnancy undergoing in vitro fertilization (IVF) embryo transfer cycles in Jilin province, China. Methods A retrospective study of 2709 first pregnancy embryo transfer cycles collected from January 2016 to January 2021 was performed. The cycles were divided into the EPL group (n = 411) and the live birth group (n = 2298) according to the cycle outcomes. Results The EPL rate of the first-time pregnancies for infertility patients undergoing fresh/frozen-thaw embryo transfer cycle was 14.1%. Female patients aged 40 and older had increased odds of EPL compared to those under 35 (OR = 3.97, 95%CI: 2.80–7.55). Female patients with a body mass index (BMI) of 25 or greater were more likely to have EPLs than those in the normal BMI range (OR = 1.32, 95%CI: 1.03–1.70). The odds of EPL after frozen-thaw embryo transfer were higher than those after fresh embryo transfer (OR = 1.59, 95%CI: 1.11–2.27). A thin endometrium on the day of embryo transfer increased the odds of EPL (OR = 1.84, 95%CI: 1.01–3.33). Transferring more than two embryos had lower odds of EPL than single-embryo transfer (OR = 0.67, 95%CI: 0.50–0.90). Compared with other infertility diagnoses, tubal factor alone was associated with lower odds of EPL (OR = 0.72, 95%CI: 0.53–0.98). Conclusions The risk factors for EPL were age 40 and older, obesity, frozen-thaw cycle, thin endometrium, and non-isolated tubal factor.

Abstract Background Mice with humanized livers are important models to study drug toxicology testing, development of hepatitis virus treatments, and hepatocyte transplantation therapy. However, the huge difference between mouse and human in size and anatomy limited the application of humanized mice in investigating human diseases. Therefore, it is urgent to construct humanized livers in pigs to precisely investigate hepatocyte regeneration and human hepatocyte therapy. CRISPR/Cas9 system and somatic cell cloning technology were used to generate two pig models with FAH deficiency and exhibiting severe immunodeficiency (FAH/RAG1 and FAH/RAG1/IL2RG deficiency). Human primary hepatocytes were then successfully transplanted into the FG pig model and constructed two pigs with human liver. Results The constructed FAH/RAG1/IL2RG triple-knockout pig models were characterized by chronic liver injury and severe immunodeficiency. Importantly, the FG pigs transplanted with primary human hepatocytes produced human albumin in a time dependent manner as early as 1 week after transplantation. Furthermore, the colonization of human hepatocytes was confirmed by immunochemistry staining. Conclusions We successfully generated pig models with severe immunodeficiency that could construct human liver tissues.

An efficient palladium-catalyzed sulfonylative coupling for the synthesis of benzyl(allyl) sulfones from sulfonyl hydrazides and carbonates was developed. The novel methodology employs easily accessible chemical feedstocks including stable and readily available arylsulfonyl hydrazides and benzyl(allyl) carbonates. A variety of benzyl(allyl) sulfones could be obtained in good to excellent yields in the presence of Pd(dppf)Cl2 without additional base under mild conditions.

Alkali-activated slag (AAS), an environmentally friendly material, has recently attracted increasing attention for applications in soil improvement. However, most of the studies focused on the geomechanical behavior of non-liquefiable soils strengthened with AAS. The objectives of this study are to examine whether AAS is effective for strengthening liquefiable soil and to evaluate the effectiveness of AAS in deep soil mixing (DSM) technology for mitigation of liquefaction. The mechanical properties and microscale mechanism of the improvement of liquefiable soil by AAS under standard curing, water curing, and seawater curing conditions are studied first. Then, the strengthening effect of the DSM technique using the soil-AAS mixture on the soil-pile-superstructure system is studied by three-dimensional numerical analyses. The results show that the compressive strength of the soil-AAS mixture is much greater than that of the soil-cement mixture. Compressive strength of 32 MPa was obtained for a soil-ASS mixture with 25% slag content under 28-day standard curing. Moreover, the DSM technique using the soil-AAS mixture is an effective method for liquefaction mitigation; the maximum lateral displacement of the pile during shaking can be reduced by half when the area improvement ratio is 20 %.

Abusive supervision could negatively influence individual work attitudes, behaviors, and work outcomes. Self-efficacy and work engagement can help to increase nursing performance. But few studies have attempted to determine the specific mechanism between them in China. The objective is to analyze the levels of abusive supervision, self-efficacy, and work engagement, and to explore the relationship between these three variables among Chinese clinical registered nurses. A predictive, cross-sectional quantitative survey was performed in a convenience sample of 923 Chinese clinical nurses. The instruments included the Demographic Data Questionnaire, Abusive Supervision Scale, Self-efficacy Scale and Work Engagement Scale. A total of 702 valid questionnaires were returned, yielding a favorable response rate of 76.1%. The level of abusive supervision was at the mid-low level, with a mean of 1.55. The nurses presented a relative high level of self-efficacy (M = 4.97) and work engagement (M = 5.01). A statistically significant negative correlation between abusive supervision and self-efficacy (r = −0.21, p

Objective: To explore the method of eliminating donor-specific anti-HLA antibodies (DSA) in haploidentical stem cell transplantation (haplo-SCT). Methods: We present a refractory B-cell acute lymphoblastic leukemia (ALL) patient who had strongly positive DSA, but had no human leukocyte antigen–matched donor. Although CD38 expression on leukemia cells was negative, daratumumab combined with etoposide and venetoclax therapy was chosen for her. Results: She achieved a significant decrease in DSA levels and complete remission on the combination therapy with daratumumab. She then received a haplo-SCT from a daughter as a donor and had a successful engraftment of donor stem cell. In haplo-SCT, strongly positive DSA levels, directed against donor HLA antigens, could be significantly reduced by daratumumab therapy before transplantation and successfully bridge subsequent haplo-SCT. Conclusion: Although CD38 expression is negative in leukemia cells, refractory B-ALL patients may still benefit from combination therapy with daratumumab. We need further clinical observation.

ObjectiveTo determine risk factors and management for the development of a postoperative cerebrospinal fluid (CSF) leak after an endoscopic endonasal surgery (EES) for pituitary adenomas.MethodsThe clinical data of 400 patients who underwent EES for resection of pituitary adenomas from December 2018 to November 2019 in the Department of Neurosurgery of Beijing Tiantan Hospital were retrospectively reviewed. Age, gender, body mass index (BMI), tumor size, Knosp grade, suprasellar extension grade, sellar floor erosion grade, repeated transsphenoidal surgery, intraoperative CSF leak, use of pedicled nasoseptal flap and lumbar drain were collected and analyzed.ResultsPostoperative CSF leak occurred in 14 of 400 patients (3.5%). Age, gender, BMI, tumor size, Knosp grade and repeated transsphenoidal surgery were not risk factors for CSF leak. Suprasellar extension grade (≥B 6.0% vs.

We present a differential diagnosis of an intracranial lesion following haploidentical stem cell transplantation (haplo-SCT) in a female patient with acute lymphoblastic leukemia (ALL). This patient received an anti-CD19-chimeric antigen receptor (CAR) T-cell therapy for refractory B-cell ALL and obtained minimal residual disease (MRD)-positive (0.03%) complete remission (CR). Then the patient received a bridging therapy of haplo-SCT. After bridging therapy, the patient maintained MRD-negative and full donor chimerism in bone marrow (BM) and was negative for Epstein–Barr virus (EBV)-DNA copy in peripheral blood. At 91 days after haplo-SCT, the patient presented with dizziness and fatigue and magnetic resonance imaging (MRI) demonstrated an intracranial lesion. The diagnosis of isolated extramedullary relapse (IEMR) was temporarily considered. Then next-generation sequencing (NGS) identified positive EBV-DNA in the cerebrospinal fluid, although EBV-DNA in the peripheral blood was negative. Furthermore, the positive EBV-DNA by NGS and complete donor chimerism in the brain tissue confirmed the diagnosis of central nervous system post-transplant lymphoproliferative disorder (CNS-PTLD). However, the EBV-encoded small RNAs (EBERs) in situ hybridization was sparsely positive. The patient was subsequently treated with anti-CD22-CAR T cells in combination with Zanubrutinib, but the disease progressed quickly and died. Donor chimerism examination of focal biopsy provides important evidence for diagnosing PTLD. Furthermore, NGS detection of EBV-DNA in local lesions is more valuable for diagnosing PTLD than detection of EBV-DNA in the peripheral blood. Trial registration: The patient was enrolled in a clinical trial of ChiCTR1800019622 and ChiCTR1800019298 .

PurposeTumor consistency is important for pituitary neuroendocrine tumors (PitNETs) resection to improve surgical outcomes. In this study, we evaluated the T2-WI of PitNETs and defined a specific T2-WI signaling manifestation, the “Mosaic sign,” to predict tumor consistency and resection of PitNETs.DesignA retrospective review of MRI and tumor histology of 137 consecutive patients who underwent endoscopic endonasal resection for PitNETs was performed.MethodsThe “Mosaic sign” was defined by the ratio of the tumor itself T2-WI signals, and characterized by multiple intratumor hyperintense dots. The degree of tumor resection was an assessment by postoperative MRI examination. The presence of the “Mosaic sign” was compared with patients' basic information, tumor consistency, tumor pathological staining, and surgical result. To determine whether the presence or absence of “Mosaic sign” could predict tumor consistency and guide surgical resection of tumors.ResultsStatistical analysis showed that the consistency of the tumor and the degree of resection were correlated with the “Mosaic sign”. In the 137 cases of T2-WI, 43 had “Mosaic sign”, 39 cases had soft tumor consistency, and 4 were classified as fibrous, of which 42 were completely resected and 1 was subtotal resected. Of the 94 patients without “Mosaic sign”, the consistency of tumor of 54 cases were classified as soft, the remaining 40 cases were fibrous, 80 cases were completely resected, and 14 cases were subtotal resected. Postoperative cerebrospinal fluid leakage occurred in 1 patient. The number of corticotroph adenomas in the group of “Mosaic sign” was higher, with the statistical difference between the two groups (P = 0.0343).ConclusionsThe presence of the “Mosaic sign” in T2-WI may provide preoperative information for pituitary adenomas consistency and effectively guide surgical approaches.

A novel and low-cost foam gauging pig was proposed for the issue that the foam pig cannot accurately judge the deformation of the pipeline and remove stubborn residual substances in the pigging process, which may lead to inaccurate results of detection instruments used later or even blockage of the pipeline. Magnetic flux leakage detection principle was used to place magnetic blocks in the polyurethane layer of foam pig, and Hall element was used to measure the change of magnetic field during deformation to obtain the height, form and other characteristics of residual substances for diameter measuring in advance. The design allows the accurate detection of scaling and deformation in the pipeline under complex working conditions to prevent blocking. With the operating foam gauging pig as the research object, ABAQUS software was used to simulate its deformation when encountering residual substances. The results show that when a certain deformation occurs, the larger the density and the thinner the thickness of the foam at the outer layer, or the smaller the density and thicker the foam at the inner layer of the pig, the more accurate the measured displacement variation results will be.

Abstract Background Endonasal endoscopic skull base surgery has undergone rapid technological developments and is now widely performed, but its strengths and weaknesses deserve further investigation and deliberation. This study was performed to investigate the surgical indications, complications, and technical advantages and disadvantages of endonasal endoscopic skull base surgery. Methods The clinical data of 1886 endoscopic endonasal skull base surgeries performed in our ward at Beijing Tiantan Hospital from June 2006 to June 2016 were retrospectively analyzed. Results One thousand ninety-three (73.4%, 1490) pituitary adenomas, 54 (24.9%, 217) chordomas, 28 (80.0%, 35) craniopharyngiomas, and 15 (83.3%, 18) meningiomas underwent total resection. Two patients died postoperatively, both having pituitary adenomas. Other postoperative complications included olfactory disorders (n = 226, 11.9%), postoperative cerebrospinal fluid leakage (n = 78, 4.1%), hypopituitarism (n = 74, 3.9%), diabetes insipidus (n = 64, 3.4%), intracranial infection (n = 36, 1.9%), epistaxis (n = 24, 1.3%), vascular injury (n = 8, 0.4%), optic nerve injury (n = 8, 0.4%), and oculomotor movement impairment (n = 4, 0.2%). In total, 1517 (80.4%) patients were followed up for 6 to 126 months (average, 42.5 months) postoperatively. A total of 196 (13.2%) pituitary adenomas and 13 (37.1%) craniopharyngiomas recurred but no meningiomas recurred. Chordomas recurred in 97 (44.7%) patients, in whom 5-year survival rate was 65%. Conclusion Endoscopic surgery is an innovative surgical technique and the first choice for most midline extradural lesions such as chordomas, and an excellent choice for pituitary adenomas. It probably will be a good technique for many kinds of craniopharyngiomas and a common technique for most of skull base meningiomas, so the surgical indications of these cases should be chosen carefully to make good use of its respective advantages.

The genetic basis of prolactinomas remains poorly understood. Here, the authors find a recurrent hotspot somatic mutation in the splicing factor 3 subunit B1 (SF3B1 R625H ) in prolactinomas, and show that this mutation causes aberrant splicing of ESRRG mRNA leading to up-regulation of prolactin.

Although haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT) has achieved similar survival to HLA-identical sibling donor (ISD) transplantation, the delayed hematopoietic engraftment as well as higher incidence of graft-versus-host-disease (GVHD), results in prolonged hospitalization, higher costs, and increased morbidity. In this study, a prospective, non-randomized clinical study was designed to evaluate the outcomes of patients who underwent HID HSCT supported by cord blood or ISD HSCT. Between May 2017 and November 2020, 113 patients were enrolled to undergo HID HSCT supported by cord blood (n=88) or ISD HSCT (n=25). The cumulative incidence of neutrophil and platelet engraftment at 30days was comparable in these two groups. Importantly, there was no significant difference in the cumulative incidence of grade II-IV aGVHD at 100days (20.5% [95% confidence interval [CI]: 12.2%–28.8%] versus 12.0% [95% CI: 0.2%–23.8%], P = 0.32) and cGVHD at 1 year (19.5% [95% CI: 11.2%–27.8%] versus 16.6% [[95% CI: 1.3%–31.9%] P = 0.70) between the two groups. Among the HID and ISD groups, the 2-year disease free survival was 76.8 and 80.0% ( P = 0.83), the 2-year overall survival was 82.4 and 88.0% ( P = 0.66), the 2-year GVHD-free, relapse-free survival was 68.9 and 75.3% ( P = 0.62), respectively. Our results indicate that HID transplantation supported by cord blood may offer a good alternative to ISD HSCT for patients with hematopoietic malignancies. Trial registration: Effect of co-infusion third party umbilical cord blood stem cells on haploidentical hematopoietic stem cell transplantation https://www.chictr.org.cn Reg. No. ChiCTR-OIN-17011426.

ObjectThe trans lamina terminalis approach (TLTA) has been described as a way to remove third ventricular tumors. The aim of this paper was to analyze the feasible outcomes of TLTA applied to tumors extending into the third ventricle in our institute.MethodsSuprasellar tumors (n = 149) were treated by the extended endonasal approach from September 2019 to December 2020 in Beijing Tiantan Hospital. Eleven of the tumors were treated by TLTA or TLTA via the trans-chiasm-pituitary corridor (TCPC). The surgical technique notes of TLTA were described and indications and outcomes of the approach were analyzed.ResultsThere were 11 patients enrolled in the study, six with papillary craniopharyngiomas, two with adamantinomatous craniopharyngiomas, one with a germinal cell tumor (GCT), one with cavernous malformation and one with chordoid glioma. Four of the patients received a radical resection by TLTA alone, while seven of them received TLTA via the TCPC. Gross total resection was achieved in eight patients (72.7%), and partial resection in three patients (27.3%). Visual function was improved in four of the 11 patients (36.4%), was unchanged in five patients (45.5%), and deteriorated in two patients (18.2%). New-onset hypopituitarism occurred in seven patients (63.3%) and new-onset diabetes insipidus occurred in two patients (18.2%). Electrocyte imbalance were observed in six patients (54.5%) at post-operative week 2. There were no surgery-related deaths or cerebrospinal fluid leaks. Postoperative intracranial infection was observed in one patient (9.1%), and during the follow-up period, tumor recurrence occurred in one patient (9.1%).ConclusionThe expanded TLTA provides a feasible suprachiasm corridor to remove tumors extending into the third ventricle, especially for craniopharyngiomas. Sound understanding of the major strengths and limitations of this approach, as well as strategies for complication avoidance, is necessary for its safe and effective application.

Toludesvenlafaxine hydrochloride dihydrate is a novel chemical entity and a potential triple monoamine reuptake inhibitor. This study characterized the in vitro triple reuptake inhibition activity, antidepressant-like activity in animals, and pharmacokinetic profiles in rats of toludesvenlafaxine. Binding affinity was determined using human serotonin transporter (SERT) protein, norepinephrine transporter (NET) protein and dopamine transporter (DAT) protein, and the reuptake inhibition was determined using Chinese hamster ovary cells expressing human SERT, NET and DAT. The antidepressant-like activity was examined in rat chronic unpredictable mild stress model and olfactory bulbectomized model. In rats, the tissue distribution and pharmacokinetic parameters were determined. Toludesvenlafaxine had high binding affinity on SERT, NET and DAT, and significantly inhibited the reuptake of serotonin (IC50 = 31.4 ± 0.4 nM), norepinephrine (IC50 = 586.7 ± 83.6 nM) and dopamine (IC50 = 733.2 ± 10.3 nM) in vitro. Toludesvenlafaxine demonstrated significant antidepressant-like effects in rat models at 8–16 mg/kg. In addition, toludesvenlafaxine significantly reduced serum corticosterone and significantly increased testosterone levels in rats. Toludesvenlafaxine was quickly absorbed and converted to O-desvenlafaxine (ODV) after oral administration, both of which were selectively distributed into the hypothalamus with high concentration. Plasma ODV exposure was proportionally related to the doses after oral dosing. These results suggest that toludesvenlafaxine is a triple reuptake inhibitor with relatively fast-acting antidepressant-like activity and good therapeutic profile including improvement of anhedonia and sexual function.

Post-transplant lymphoproliferative disease (PTLD) often exhibits poor prognosis and high mortality, and there are no uniform guidelines for the treatment of this disease. Anti-CD19 chimeric antigen receptor (CAR) T cells show significant efficacy in treatment of relapse/refractory diffuse large B-cell lymphoma (DLBCL). Treatment using anti-CD19-CAR T-cell therapy in PTLD has been limited by immunosuppressants and has not been widely employed. In this study, a refractory post kidney transplant DLBCL patient with a high tumor burden was enrolled in a clinical trial of anti-CD19-CAR T-cell therapy. The tacrolimus dose was not decreased during combination chemotherapy, as the creatinine level of the patient increased. To improve the function of autologous T cells, combination therapy with anti-CD19-CAR T cells and programmed cell death 1 (PD-1) inhibitors was selected. After treatment with the combination therapy, the patient was diagnosed with grade 1 cytokine release syndrome and grade 3 immune effector cell-associated neurotoxicity syndrome. The amplification peak of anti-CD19-CAR T cells reached 9.01% on day 7. With PD-1 inhibitor maintenance therapy, his disease was maintained in partial remission for 18 weeks. However, his tumor suddenly increased in size, and he discontinued the treatment, including radiation therapy. The anti-CD19-CAR T cell and PD-1 inhibitors have a combined effect on PTLD, and this combination therapy needs to be further explored.

Somatotroph adenomas are the leading cause of acromegaly, with the nearly sparsely granulated somatotroph subtype belonging to high-risk adenomas, and they are less responsive to medical treatment. The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. In this study, we identified the characteristic profiling of the integrated stress response in translocation and translation initiation factor activity in somatotroph adenomas, normal pituitary, or other adenoma subtypes through proteomics. Immunohistochemistry exhibited the differential significance and the priority of eukaryotic translation initiation factor 2β (EIF2β) in somatotroph adenomas compared with gonadotroph and corticotroph adenomas. Differentially expressed genes based on the level of EIF2β in somatotroph adenomas were revealed. MetaSape pathways showed that EIF2β was involved in regulating growth and cell activation, immune system, and extracellular matrix organization processes. The correlation analysis showed Spearman correlation coefficients of r = 0.611 (p < 0.001) for EIF2β and eukaryotic translation initiation factor 2 alpha kinase 1 (HRI), r = 0.765 (p < 0.001) for eukaryotic translation initiation factor 2 alpha kinase 2 (PKR), r = 0.813 (p < 0.001) for eukaryotic translation initiation factor 2 alpha kinase 3 (PERK), r = 0.728 (p < 0.001) for GCN2, and r = 0.732 (p < 0.001) for signal transducer and activator of transcription 3 (STAT3). Furthermore, the invasive potential in patients with a high EIF2β was greater than that in patients with a low EIF2β (7/10 vs. 4/18, p = 0.038), with a lower immune-cell infiltration probability (p < 0.05). The ESTIMATE algorithm showed that the levels of activation of the EIF2 pathway were negatively correlated with the immune score in somatotroph adenomas (p < 0.001). In in vitro experiments, the knockdown of EIF2β changed the phenotype of somatotroph adenomas, including cell proliferation, migration, and the secretion ability of growth hormone/insulin-like growth factor-1. In this study, we demonstrate that the ISR is pivotal in somatotroph adenomas and provide a rationale for implementing ISR-based regimens in future treatment strategies.

Natural deep eutectic solvents (NADESs) coupled with microwave-assisted extraction (MAE) were applied to extract total flavonoid compounds from spent sweet potato (Ipomoea batatas L.) leaves. In this study, ten different NADESs were successfully synthesized for the MAE. Based on single-factor experiments, the response surface methodology (RSM) was applied, and the microwave power, extraction temperature, extraction time, and solid–liquid ratio were further evaluated in order to optimize the yields of total flavonoid compounds. Besides, the extracts were recovered by macroporous resin for the biological activity detection of flavonoid compounds. As a result, NADES-2, synthesized by choline chloride and malic acid (molar ratio 1:2), exhibited the highest extraction yield. After that, the NADES-2-based MAE process was optimized and the optimal conditions were as follows: microwave power of 470 W, extraction temperature of 54 °C, extraction time of 21 min, and solid–liquid ratio of 70 mg/mL. The extraction yield (40.21 ± 0.23 mg rutin equivalents/g sweet potato leaves) of the model validation experiment was demonstrated to be in accordance with the predicted value (40.49 mg rutin equivalents/g sweet potato leaves). In addition, flavonoid compounds were efficiently recovered from NADES-extracts with a high recovery yield (>85%) using AB-8 macroporous resin. The bioactivity experiments in vitro confirmed that total flavonoid compounds had good DPPH and O2−· radical-scavenging activity, as well as inhibitory effects on E. coli, S. aureus, E. carotovora, and B. subtilis. In conclusion, this study provides a green and efficient method to extract flavonoid compounds from spent sweet potato leaves, providing technical support for the development and utilization of sweet potato leaves’ waste.

Engeletin is a natural derivative of Smilax glabra rhizomilax that exhibits anti-inflammatory activity and suppresses lipid peroxidation. In the present study, we sought to elucidate the mechanistic basis for the neuroprotective and pro-angiogenic activity of engeltin in a human umbilical vein endothelial cells (HUVECs) oxygen-glucose deprivation and reoxygenation (OGD/R) model system and a middle cerebral artery occlusion (MCAO) rat model of cerebral ischemia and reperfusion injury. These analyses revealed that engeletin (10, 20, or 40 mg/kg) was able to reduce the infarct volume, increase cerebral blood flow, improve neurological function, and bolster the expression of vascular endothelial growth factor (VEGF), vasohibin-2 (Vash-2), angiopoietin-1 (Ang-1), phosphorylated human angiopoietin receptor tyrosine kinase 2 (p-Tie2), and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) in MCAO rats. Similarly, engeletin (100, 200, or 400 nM) markedly enhanced the migration, tube formation, and VEGF expression of HUVECs in an OGD/R model system, while the VEGF receptor (R) inhibitor axitinib reversed the observed changes in HUVEC tube formation activity and Vash-2, VEGF, and CD31 expression. These data suggested that engeletin exhibited significant neuroprotective effects against cerebral ischemia and reperfusion injury in rats, and improved cerebrovascular angiogenesis by modulating the VEGF/vasohibin and Ang-1/Tie-2 pathways.

Abstract Background Several different technologies are used for prenatal screening procedures and genetic diagnostic technologies. We aimed to investigate the rates of chromosomal abnormalities in cases with different abnormal prenatal indications and to determine the relationships between fetal chromosomal abnormalities and indicators of prenatal abnormalities in Northeast China. Methods We evaluated 4953 16- to 23-week singleton gestation cases using amniocentesis and a total of 3583 participants received serological screening. Fetal chromosomal analyses were performed for all samples using fluorescence in situ hybridization and karyotyping. Results Among these samples, 204 (4.12%) had fetal chromosomal abnormalities. A total of 3583 participants received serological screening, among whom 102 (2.85%) exhibited positive results. A total of 309 participants had ultrasonography; 42 (13.6%) of these had abnormalities. Among 97 participants who had non-invasive prenatal testing (NIPT), 59 (61%) had positive results. Among 1265 participants with advanced maternal age, 78 (6.2%) had abnormal results. Conclusion The serological screening and NIPT that were included in the prenatal screening methods all had false positive and false negative rates. Although they are both prenatal screening techniques, maternal serum screening cannot be replaced by NIPT. The pregnancy women should accept NIPT in a qualified prenatal diagnostic center. We recommend that pregnant women at high or critical risk undergoing prenatal screening should confirm the fetal karyotype through amniocentesis. Moreover, if women receive a positive result via NIPT, they should not have a pregnancy termination without undergoing further prenatal diagnosis.

Abstract Background Pituitary adenoma and meningioma are the most common benign tumors in the central nervous system. Pituitary adenoma associated with meningioma (PAM) is a rare disease and the clinical features and mechanisms of PAM are unclear. Methods We summarized the clinical data of 57 PAM patients and compared with sporadic pituitary adenoma (SPA) and sporadic meningioma (SM). 5 pituitary adenomas of PAM and 5 SPAs were performed ceRNA microarray. qRT-PCR, Western Blot, siMEN1 and rapamycin inhibition experiment were validated for ceRNA microarray. Results Clinical variable analyses revealed that significant correlations between PAM and female sex as well as older age when compared with SPA and significant correlations between PAM and transitional meningioma as well as older age when compared with SM. Additionally, the characteristics of PAM were significantly different for MEN1 patients. Functional experiments showed lower expression of MEN1 can upregulate mTOR signaling, in accordance with the result of ceRNA microarray. Rapamycin treatment promotes apoptosis in primary pituitary adenoma and meningioma cells of PAM. Conclusions MEN1 plays an important role in PAM by upregulating mTOR signaling pathway. Rapamycin represents a potential therapeutic strategy for PAM in the future.

Abstract Background To investigate the relationship between cyclin B1 (CCNB1) gene expression and cavernous sinus invasion in pituitary adenomas. Methods Twenty-four pituitary adenoma tissue samples were examined by RT-qPCR and Western blot to assess the mRNA expression levels and protein levels of CCNB1, E-cadherin and N-cadherin. Correlation analyses between the expression levels of E-cadherin, N-cadherin and CCNB1 were performed. After lentivirus-mediated knockdown of CCNB1 in rat pituitary adenoma cell lines (GH3 and GT1-1), cell function changes were studied. The relationship between CCNB1 and epithelial-mesenchymal transition (EMT) was further verified by animal experiments. Results CCNB1 and N-cadherin gene expression were significantly higher in the invasive pituitary adenomas than in the non-invasive pituitary adenomas. Conversely, E-cadherin expression in the invasive pituitary adenomas was significantly lower. CCNB1 gene expression was downregulated in the GH3 and GT1-1 pituitary adenoma cell lines; N-cadherin expression was also decreased, but E-cadherin expression was increased. These results were confirmed in vivo. After downregulation of CCNB1, cell invasion and migration was significantly reduced in Transwell experiments. Conclusion High CCNB1 expression in pituitary adenoma affects cavernous sinus invasion through EMT.

A novel AMP-activated protein kinase (AMPK) activator, IMM-H007 (H007), has been reported to reduce serum lipid levels and inhibit lipid accumulation in the liver in hyperlipidemic animal models. However, how H007 ameliorates hepatic steatosis and inflammation remains unknown. In the present study, H007, at 200 mg/kg, reduced hepatic lipid levels and the levels of collagenous fiber in the liver in high-fat diet (HFD)-fed hamsters compared to those in the HFD group. Meanwhile, compared to the controls, H007 significantly inhibited sterol-regulatory element binding protein (SREBP)-1c and acetyl CoA carboxylase (ACC) expression by upregulating the AMPK activity, suppressing the saturated fatty acid accumulation and increasing polyunsaturated fatty acid synthesis in the liver. Compared to the controls, H007 treatment inhibited the expression of monocyte chemotactic protein (MCP-1) in fatty acid-treated HepG2 cells; suppressed leukocyte adherence and rolling on the liver microvasculature; and suppressed hepatic macrophage infiltration. H007 also suppressed the expression of nuclear factor-κB (NF-κB) p65 in fatty acid- and lipopolysaccharide-treated HepG2 cells compared to that in the controls by activating AMPK. These data suggested that H007 had a beneficial effect by improving the lipid composition in the liver and inhibiting inflammatory cell trafficking in the development of nonalcoholic fatty liver disease. Keywords: AMPK activator, Hepatic lipid metabolism, Leukocyte trafficking, Hepatic steatosis, Inflammation

Low birth efficiency and developmental abnormalities in embryos derived using round spermatid injection (ROSI) limit the clinical application of this method. Further, the underlying molecular mechanisms remain elusive and warrant further in-depth study. In this study, the embryonic day (E) 11.5 mouse fetuses and corresponding placentas derived upon using ROSI, intracytoplasmic sperm injection (ICSI), and natural in vivo fertilized (control) embryos were collected. Transcriptome and DNA methylation profiles were analyzed and compared using RNA-sequencing (RNA-seq) and whole-genome bisulfite sequencing, respectively. RNA-seq results revealed similar gene expression profiles in the ROSI, ICSI, and control fetuses and placentas. Compared with the other two groups, seven differentially expressed genes (DEGs) were identified in ROSI fetuses, and ten DEGs were identified in the corresponding placentas. However, no differences in CpG methylation were observed in fetuses and placentas from the three groups. Imprinting control region methylation and imprinted gene expression were the same between the three fetus and placenta groups. Although 49 repetitive DNA sequences (RS) were abnormally activated in ROSI fetuses, RS DNA methylation did not differ between the three groups. Interestingly, abnormal hypermethylation in promoter regions and low expression of Fggy and Rec8 were correlated with a crown-rump length less than 6 mm in one ROSI fetus. Our study demonstrates that the transcriptome and DNA methylation in ROSI-derived E11.5 mouse fetuses and placentas were comparable with those in the other two groups. However, some abnormally expressed genes in the ROSI fetus and placenta warrant further investigation to elucidate their effect on the development of ROSI-derived embryos.

Background: Chromosomal abnormalities play an important role in the diagnosis and prognosis of patients with myelodysplastic syndromes (MDSs). The single-nucleotide polymorphism array (SNP-A) technique has gained popularity due to its improved resolution compared to that of metaphase cytogenetic (MC) analysis.Methods: A total of 376 individuals were recruited from two medical centers in China, including 350 patients and 26 healthy individuals. Among these patients, 200 were diagnosed with de novo MDS, 25 with myeloproliferative neoplasm (MPN), 63 with primary acute myeloid leukemia (AML), and 62 with idiopathic cytopenia of undetermined significance (ICUS). We evaluated the significance of abnormal chromosomes detected by SNP-A in the diagnosis and prognosis of MDS-related disorders.Results: (1) When certain chromosomal abnormalities could not be detected by conventional MC methods, these abnormalities could be detected more efficiently by the SNP-A method. With SNP-A, the detection rates of submicroscopic or cryptic aberrations in the MDS, MPN, and AML patients with normal MC findings were 32.8, 30.8, and 30%, respectively. (2) The chromosomal abnormalities detected by SNP-A had a very important value for the prognosis of patients with MDSs, especially in the low-risk group. The survival of patients with abnormal chromosomes detected by SNP-A was significantly lower than that of patients with no detected chromosomal abnormalities; this difference was observed in overall survival (OS) (P = 0.001) and progression-free survival (PFS) [24 months vs. not reach (NR); P = 0.008]. The patients with multiple chromosomal abnormalities detected by SNP-A had an inferior prognosis, and SNP-A abnormalities (≥3 per patient) were found to be an independent predictor of poor prognosis in patients with MDSs [hazard ratio (HR) = 2.40, P = 0.002]. (3) Patients with ICUS may progress to myeloid malignancies, but most patients often maintain a stable ICUS status for many years without progression. An ICUS patient found to have an MDS-related karyotype would be rediagnosed with MDS. SNP-A can efficiently detect chromosomal abnormalities, which would be important for assessing the evolution of ICUS. In our study, 17 ICUS patients with SNP-A-detected abnormalities developed typical MDSs.Conclusions: SNP-A can help evaluate the prognosis of patients with MDSs and better assess the risk of disease progression for patients with ICUS.

The increased PD-L1 expression induces poorer prognosis in melanoma. The small molecule inhibitors of PD-1/PD-L1 pathways have been an encouraging drug development strategy because of good affinity and oral bioavailability without immunogenicity and immunotoxicities of PD-1/PD-L1 antibodies. In this study, we studied the effects of PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, on PD-1/PD-L1 binding and the cytokines secretion in human CD3+ cells in vitro. We also investigated the antitumor and immunomodulatory activity of PCC0208025 and the pharmacokinetics properties in B16-F10 melanoma-bearing mice. The results showed that PCC0208025 inhibited the PD-1/PD-L1 proteins binding, and rescued PD-L1-mediated inhibition of IFN-γ production in human CD3+ T cells in vitro. Furthermore, in B16-F10 melanoma-bearing mice, PCC0208025 presented the antitumor effects, enhanced IFN-γ levels in plasma, increased the frequency of CD3+CD8+ T and CD8+IFN-γ+ T and the ratios of CD8+/Treg, and deceased the CD4+CD25+CD127low/- (Treg) number in tumor. Pharmacokinetics study found that PCC0208025 was absorbed and distributed into the tumors with much higher concentrations than those of the blockade against PD-1/PD-L1 binding. Our work suggests that PCC0208025 exhibited anti-tumor effects through inhibiting Treg expansion and increasing cytotoxic activity of tumor-infiltrating CD8+ T cells by the blockade of PD-1/PD-L1 binding, which may provide the pharmacological basis to develop small molecule inhibitors of PD-1/PD-L1 binding for PCC0208025 as a lead compound.

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease caused mainly by LDL receptor (Ldlr) gene mutations. Unlike FH patients, heterozygous Ldlr knockout (KO) mice do not show a dominant FH trait. Hamsters, like humans, have the cholesteryl ester transfer protein, intestine-only ApoB editing and low hepatic cholesterol synthesis. Here, we generated Ldlr-ablated hamsters using CRISPR/Cas9 technology. Homozygous Ldlr KO hamsters on a chow diet developed hypercholesterolemia with LDL as the dominant lipoprotein and spontaneous atherosclerosis. On a high-cholesterol/high-fat (HCHF) diet, these animals exhibited severe hyperlipidemia and atherosclerotic lesions in the aorta and coronary arteries. Moreover, the heterozygous Ldlr KO hamsters on a short-term HCHF diet also had overt hypercholesterolemia, which could be effectively ameliorated with several lipid-lowering drugs. Importantly, heterozygotes on 3-month HCHF diets developed accelerated lesions in the aortas and coronary arteries. Our findings demonstrate that the Ldlr KO hamster is an animal model of choice for human FH and has great potential in translational research of hyperlipidemia and coronary heart disease.

Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in humans, is characterized by the accumulation of triacylglycerols (TGs) in hepatocytes. We tested whether 2′,3′,5′‐tri‐acetyl‐N6‐(3‐hydroxylaniline) adenosine (IMM‐H007) can eliminate hepatic steatosis in hamsters fed a high‐fat diet (HFD), as a model of NAFLD. Compared with HFD‐only controls, IMM‐H007 treatment significantly lowered serum levels of TG, total cholesterol, and free fatty acids (FFAs) in hamsters fed the HFD, with a prominent decrease in levels of serum transaminases and fasting insulin, without affecting fasting glucose levels. Moreover, 1H‐MRI and histopathological analyses revealed that hepatic lipid accumulation and fibrosis were improved by IMM‐H007 treatment. These changes were accompanied by improvement of insulin resistance and oxidative stress, and attenuation of inflammation. IMM‐H007 reduced expression of proteins involved in uptake of hepatic fatty acids and lipogenesis, and increased very low density lipoprotein secretion and expression of proteins responsible for fatty acid oxidation and autophagy. In studies in vivo, IMM‐H007 inhibited fatty acid import into hepatocytes and liver lipogenesis, and concomitantly stimulated fatty acid oxidation, autophagy, and export of hepatic lipids. These data suggest that IMM‐H007 resolves hepatic steatosis in HFD‐fed hamsters by the regulation of lipid metabolism. Thus, IMM‐H007 has therapeutic potential for NAFLD.

HDL plays crucial roles at multiple stages of the pathogenesis of atherosclerosis. AMP-activated protein kinase (AMPK) is a therapeutic candidate for the treatment of cardiovascular disease. However, the effect of AMPK activation on HDL functionality has not been established in vivo. We assessed the effects of pharmacological AMPK activation using A-769662, AICAR, metformin, and IMM-H007 on the atheroprotective functions of HDL in apoE-deficient (apoE−/−) mice fed with a high-fat diet. After administration, there were no changes in serum lipid levels among the groups. However, mice treated with AMPK activators showed significantly enhanced reverse cholesterol transport in vivo and in vitro. AMPK activation also increased the expression of ABCA1 and ABCG1 in macrophages and scavenger receptor class B type I and LCAT in the liver. HDL from AMPK activation mice exhibited lower HDL inflammatory index and myeloperoxidase activity and higher paraoxonase 1 activity than HDL from untreated mice, implying superior antioxidant and anti-inflammatory capacities. Pharmacological AMPK activation also induced polarization of macrophages to the M2 state and reduced plasma lipid peroxidation, inflammatory cytokine production, and atherosclerotic plaque formation in apoE−/− mice. These observations suggest that pharmacological AMPK activation enhances the anti-atherogenic properties of HDL in vivo. This likely represents a key mechanism by which AMPK activation attenuates atherosclerosis.

AMP-activated protein kinase (AMPK), known as a sensor and a master of cellular energy balance, integrates various regulatory signals including anabolic and catabolic metabolic processes. Accompanying the application of genetic methods and a plethora of AMPK agonists, rapid progress has identified AMPK as an attractive therapeutic target for several human diseases, such as cancer, type 2 diabetes, atherosclerosis, myocardial ischemia/reperfusion injury and neurodegenerative disease. The role of AMPK in metabolic and energetic modulation both at the intracellular and whole body levels has been reviewed elsewhere. In the present review, we summarize and update the paradoxical role of AMPK implicated in the diseases mentioned above and put forward the challenge encountered. Thus it will be expected to provide important clues for exploring rational methods of intervention in human diseases.

Hierarchical, nanoporous graphitic membranes are synthetically challenging yet attractive materials, due to their structural integrity. Here, the authors fabricate freestanding, porous carbon membranes with single-crystal-like graphitic order which serve as water splitting electrocatalysts upon cobalt doping.

Objective This study aimed to assess the value of measuring the tubule diameter during microdissection testicular sperm extraction (micro-TESE) in predicting outcomes in patients with Sertoli cell-only syndrome (SCOS). Methods Fifty-six consecutive patients with SCOS were included. Patients were classified into two groups on the basis of the diameter of seminiferous tubules measured against 5/0 surgical suture (≥100 µm or

The low-density lipoprotein receptor (LDLR) plays a critical role in the liver for the clearance of plasma low-density lipoprotein (LDL). Its deficiency causes hypercholesterolemia in many models. To facilitate the usage of rats as animal models for the discovery of cholesterol-lowering drugs, we took a genetic approach to delete the LDLR in rats aiming to increase plasma LDL cholesterol (LDL-C). An LDLR knockout rat was generated via zinc-finger nuclease technology, which harbors a 19-basepair deletion in the seventh exon of the ldlr gene. As expected, deletion of the LDLR elevated total cholesterol and total triglyceride in the plasma, and caused a tenfold increase of plasma LDL-C and a fourfold increase of plasma very low-density lipoprotein (VLDL-C). A lipidomics analysis revealed that deletion of the LDLR affected hepatic lipid metabolism, particularly lysophosphatidylcholines, free fatty acids and sphingolipids in the liver. Cholesterol ester (CE) 20:4 also displayed a significant increase in the LDLR knockout rats. Taken together, the LDLR knockout rat offers a new model of hypercholesterolemia, and the lipidomics analysis reveals hepatic lipid signatures associating with deficiency of the LDL receptor.

ABCA1 plays a key role in the initial lipidation of apoA-I, which generates circulating HDL cholesterol. Whereas it is known that the transcriptional upregulation of ABCA1 promotes HDL formation and reverse cholesterol transport (RCT), it is not known how the inhibition of ABCA1 protein degradation impacts HDL function. Employing the small molecule triacetyl-3-hydroxyphenyladenosine (IMM-H007), we determined how the attenuation of ABCA1 protein degradation affects HDL cholesterol efflux capacity, RCT, and atherosclerotic lesion formation. Pulse-chase analysis revealed that IMM-H007 inhibits ABCA1 degradation and facilitates its cell-surface localization in macrophages, and additional studies in macrophages showed that IMM-H007 thereby promotes cholesterol efflux. IMM-H007 treatment of Paigen diet-fed mice caused an increase in circulating HDL level, it increased the cholesterol efflux capacity of HDL, and it enhanced in vivo RCT from macrophages to the plasma, liver, and feces. Furthermore, ABCA1 degradation suppression by IMM-H007 reduced atherosclerotic plaque formation in apoE−/− mice. Thus, via effects on both ABCA1-expressing cells and circulating HDL function, the inhibition of ABCA1 protein degradation by IMM-H007 promotes HDL cholesterol efflux capacity and RCT and attenuates atherogenesis. IMM-H007 potentially represents a lead compound for the development of agents to augment HDL function.

As the major active ingredient of Cordyceps militaris, cordycepin (3′-deoxyadenosine) has been well documented to alleviate inflammation and oxidative stress both in vitro and in vivo. To explore the potential protective effect of cordycepin in fulminant hepatic failure, mice were pretreated with cordycepin for 3 weeks followed by D-galactosamine (GalN)/lipopolysaccharide (LPS) injection. Then we found cordycepin (200 mg/kg) administration elevated survival rate, improved liver function, and suppressed hepatocyte apoptosis and necrosis in mice with severe hepatic damage by GalN/LPS treatment. Further, cordycepin inhibited hepatic neutrophil and macrophage infiltration and prevented proinflammatory cytokine production possibly through suppressing TLR4 and NF-κB signaling transduction. The blockade of reactive oxygen species (ROS) and lipid peroxidation production by cordycepin was associated with the decrease of NAD(P)H oxidase (NOX) activity. Besides, cordycepin significantly prevented excessive autophagy induced by GalN/LPS in the liver. These data suggested that cordycepin could be a promising therapeutic agent for GalN/LPS-induced hepatotoxicity.

At present, in the treatment of non-small cell lung cancer (NSCLC), targeted therapy has an important status. After epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs), crizotinib targeted at EML4-ALK fusion gene becomes a significant drug of molecular targeted therapy in NSCLC. Phase I and II clinical trials prove that crizotinib is effective for treatment of activating EML4-ALK mutation in advanced NSCLC patients, little side-effect, and well tolerated. Recently, crizotinib can inhibit ROS1 receptor tyrosine kinase and show extraordinary significant antitumor activity in ROS1-rearranged NSCLC. Drug resistance also exists in crizotinib. The mechanism of drug resistance needs further research. In this study, a review is performed in the mechanism and pharmacokinetics of crizotinib, and the clinical progress of treatment in advanced NSCLC.

2', 3', 5'-Tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine (also known as WS070117) is a new adenosine analog that displays anti-hyperlipidemic activity both in vitro and in vivo experiments as shown in many preliminary studies. Due to its new structure, little is known about the metabolism of WS070117. Hence, the in vivo metabolites of WS070117 in rat urine following oral administration were investigated. Identification of the metabolites was conducted using the combination of high-performance liquid chromatography (HPLC) coupled with diode array detector (DAD), ion trap electrospray ionization-mass spectrometry (ESI-MS), and off-line microprobe nuclear magnetic resonance (NMR) measurements. Seven metabolites were obtained as pure compounds at the sub-milligram to milligram levels. Results of structure elucidation unambiguously revealed that the phase I metabolite, N6-(3-hydroxyphenyl) adenosine (M8), was a hydrolysate of WS070117 by hydrolysis on the three ester groups. N6-(3-hydr-oxyphenyl) adenine (M7), also one of the phase I metabolites, was the derivative of M8 by the loss of ribofuranose. In addition to two phase I metabolites, there were five phase II metabolites of WS070117 found in rat urine. 8-hydroxy-N6-(3-hydroxy-phenyl) adenosine (M6) was the product of M7 by hydrolysis at position 8. The other four were elucidated to be N6-(3-O-β-D-glucuronyphenyl) adenine (M2), N8-hydroxy-N6-(3-O-sulfophenyl) adenine (M3), N6-(3-O-β-D-glucuronyphenyl) adenosine (M4), and N6-(3-O- sulfophenyl) adenosine (M5). Phase II metabolic pathways were proven to consist of hydroxylation, glucuronidation and sulfation. This study provides new and valuable information on the metabolism of WS070117, and also demonstrates the HPLC/MS/off-line microprobe NMR approach as a robust means for rapid identification of metabolites.

Tris-(2,3-dibromopropyl) isocyanurate (TDBP-TAZTO), an emerging brominated flame retardant, possesses the characteristics of candidate persistent organic pollutants and has displayed toxicity to fish and rodents. TDBP-TAZTO can pass through the blood brain barrier and accumulate in brain. However, the neurotoxicity of TDBP-TAZTO has not yet studied in rodents. We hypothesize that TDBP-TAZTO could induce the neurotoxicity in rat hippocampal neurons. The male adult rats were exposed to TDBP-TAZTO of 5 and 50 mg/kg by gavage, daily for 6 months. TDBP-TAZTO resulted in cognitive impairment and depression-like behaviors, which may be related with TDBP-TAZTO-induced hypothalamic-pituitary-adrenal axis hyperactivation, upregulation of inflammatory and oxidative stress markers, overexpression of pro-apoptotic proteins, downexpression of neurogenesis-related proteins in hippocampus, and hippocampal neurons damage in DG, CA1 and CA3 areas. Our findings suggested that TDBP-TAZTO induces significant hippocampal neurotoxicity, which provokes cognitive impairment and depression-like behaviors in adult rats. Therefore, this research will contribute to evaluate the neurotoxic effects of TDBP-TAZTO in human.