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Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired by PROTAC have not only revolutionized the landscape of TPD but have the potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role in this field. A wide variety of agents spanning a broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which not only prove instrumental in overcoming the constraints of conventional small molecule entities but also provided rapidly renewing paradigms. Herein we summarize the burgeoning non-small molecule technological platforms inspired by PROTACs, including three major trajectories, to provide insights for the design strategies based on novel paradigms.

Ischemic heart failure rates rise despite decreased acute myocardial infarction (MI) mortality. Excessive myofibroblast activation post-MI leads to adverse remodeling. LIM kinases (LIMK1 and LIMK2) regulate cytoskeleton homeostasis and are pro-fibrotic markers in atrial fibrillation. However, their roles and mechanisms in postinfarction fibrosis and ventricular remodeling remain unclear. This study found that the expression of LIMKs elevated in the border zone (BZ) in mice MI models. LIMK1/2 double knockout (DKO) restrained pathological remodeling and reduced mortality by suppressing myofibroblast activation. By using adeno-associated virus (AAV) with a periostin promoter to overexpress LIMK1 or LIMK2, this study found that myofibroblast-specific LIMK2 overexpression diminished these effects in DKO mice, while LIMK1 did not. LIMK2 kinase activity was critical for myofibroblast proliferation by using AAV overexpressing mutant LIMK2 lack of kinase activity. According to phosphoproteome analysis, functional rescue experiments, co-immunoprecipitation, and protein-protein docking, LIMK2 led to the phosphorylation of β-catenin at Ser 552. LIMK2 nuclear translocation also played a role in myofibroblast proliferation after MI with the help of AAV overexpressing mutant LIMK2 without nuclear location signal. Chromatin immunoprecipitation sequencing identified that LIMK2 bound to Lrp6 promoter region in TGF-β treated cardiac fibroblasts, positively regulating Wnt signaling via Wnt receptor internalization. This study demonstrated that LIMK2 promoted myofibroblast proliferation and adverse cardiac remodeling after MI, by enhancing phospho-β-catenin (Ser552) and Lrp6 signaling. This suggested that LIMK2 could be a target for the treatment of postinfarction injury.

Beclin-1 is the firstly-identified mammalian protein of the autophagy machinery, which functions as a molecular scaffold for the assembly of PI3KC3 (class III phosphatidylinositol 3 kinase) complex, thus controlling autophagy induction and other cellular trafficking events. Notably, there is mounting evidence establishing the implications of Beclin-1 in diverse tumorigenesis processes, including tumor suppression and progression as well as resistance to cancer therapeutics and CSC (cancer stem-like cell) maintenance. More importantly, Beclin-1 has been confirmed as a potential target for the treatment of multiple cancers. In this review, we provide a comprehensive survey of the structure, functions, and regulations of Beclin-1, and we discuss recent advances in understanding the controversial roles of Beclin-1 in oncology. Moreover, we focus on summarizing the targeted Beclin-1-regulating strategies in cancer therapy, providing novel insights into a promising strategy for regulating Beclin-1 to improve cancer therapeutics in the future.

Summary: Background: The public health burden of cardiomyopathies and competency in their management by health agencies in China are not well understood. Methods: This study adopted a multi-stage sampling method for hospital selection. In the first stage, nationwide tertiary hospital recruitment was performed. As a result, 88 hospitals with the consent of the director of cardiology and access to an established electronic medical records system, were recruited. In the second stage, we sampled 66 hospitals within each geographic-economic stratification through a random sampling process. Data on (1) the outpatient and inpatient visits for cardiomyopathies between 2017 and 2021 and (2) the competency in the management of patients with cardiomyopathies, were collected. The competency of a hospital to provide cardiomyopathy care was evaluated using a specifically devised scale. Findings: The outpatient and inpatient visits for cardiomyopathies increased between 2017 and 2021 by 38.6% and 33.0%, respectively. Most hospitals had basic facilities for cardiomyopathy assessment. However, access to more complex procedures was limited, and the integrated management pathway needs improvement. Only 4 (6.1%) of the 66 participating hospitals met the criteria for being designated as a comprehensive cardiomyopathy center, and only 29 (43.9%) could be classified as a primary cardiomyopathy center. There were significant variations in competency between hospitals with different administrative and economic levels. Interpretation: The health burden of cardiomyopathies has increased significantly between 2017 and 2021 in China. Although most tertiary hospitals in China can offer basic cardiomyopathy care, more advanced facilities are not yet universally available. Moreover, inconsistencies in the management of cardiomyopathies across hospitals due to differing administrative and economic levels warrants a review of the nation allocation of medical resources. Funding: This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2023-I2M-1-001) and the National High Level Hospital Clinical Research Funding (2022-GSP-GG-17).

Hydraulic fracturing technique increases shale gas well productivity significantly. Horizontal well fracture optimization has been studied by many researchers worldwide in the past decade. However, most of these researches relied on computationally expensive numerical simulation models for objectives evaluation during the optimization process. This affects the optimization efficiency significantly. To address this issue, surrogate model methods which adapt a simple approximate model are employed to lessen the computational burden. In this study therefore, a novel intelligent variable-fidelity radial basis function (VFRBF) surrogate-assisted model for multi-objective fracture stage placement optimization, namely VFRBF-FSO, is proposed to reduce the computational burden of the numerical simulation-based production optimization. In the VFBRF-FSO method, low-fidelity (LF) and high-fidelity (HF) samples were adopted simultaneously to establish the variable-fidelity (VF) surrogate model. To the best of our knowledge, this is the first time that variable-fidelity model is used for shale gas horizontal well fracture stage placement optimization. The uniqueness of this proposed method is that a scaling factor and an augment matrix are used to integrate the LF and HF samples to increase the accuracy of the surrogate model. Moreover, two cases with different wells and well types were studied to illustrate the effectiveness and accuracy of the VFRBF-FSO method. The optimization results showed that the VFRBF-FSO method performed comparably with the HF model-based method in terms of convergence and diversity. However, the VFRBF-FSO reduced the simulation runs on the two cases with different wells and fracture types to about five times that of the HF model.

Background: Endogenous gasotransmitters are small gaseous mediators that can be generated endogenously by mammalian organisms. The dysregulation of the gasotransmitter system is associated with numerous disorders ranging from inflammatory diseases to cancers. However, the relevance of these endogenous gasotransmitters, prodrug donors and inhibitors in inflammatory dermatological disorders has not yet been thoroughly reviewed and discussed. Aim of review: This review discusses the recent progress and will provide perspectives on endogenous gasotransmitters in the context of inflammatory dermatological disorders. Key scientific concepts of review: Endogenous gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are signaling molecules that regulate several physiological and pathological processes. In addition, sulfur dioxide (SO₂), methane (CH4), hydrogen gas (H2), ammonia (NH3), and carbon dioxide (CO2) can also be generated endogenously and may take part in physiological and pathological processes. These signaling molecules regulate inflammation, vasodilation, and oxidative stress, offering therapeutic potential and attracting interest in the field of inflammatory dermatological disorders including psoriasis, atopic dermatitis, acne, rosacea, and chronic skin ulcers. The development of effective gas donors and inhibitors is a promising alternative to treat inflammatory dermatological disorders with controllable and precise delivery in the future.

Due to the poor formability of zirconium alloy, crack is one of its most common failure modes when the alloy is used for strips of spacer grids of nuclear fuel assembly during the sheet forming process. In this paper, the relationships between processing parameters (including punching speed, stamping clearance and blank-holder force (BHF)) and the crack risk of sheet forming process are discussed. A continuous forecasting model is constructed by using support vector machine regression (SVR) method. The maximum thinning ratio (TMTR), which is usually used as an index to quantitatively evaluate the crack risks during sheet forming, serves as the output while the processing parameters as the input variables of the forecasting model. The performances of the SVR model are assessed by six different regression metrics and results are compared with five other machine learning models. The evaluation results demonstrate that the SVR model has the best performance (with a relative mean error of 2.76% and the value of R20.939) and the capacity to accurately predict the maximum thinning ratio of the sheet forming process of zirconium alloys. The coupled and interactive effects of the processing parameters on the sheet forming are also analyzed through the results of the forecasting model.

The Voltaian Basin of Ghana has taken significance as a potential oil and gas basin. Since Ghana became a petroleum-producing country, every attempt is being made to understand the sedimentary basins within the country's territorial boundaries, particularly, the Voltaian Basin. This review paper investigates studies on the Voltaian Basin drawing on a comprehensive literature review based on database searches from Scopus, Web of Science, and Science Direct, among others. Several branches of geology such as mineralogy, geochemistry, igneous and metamorphic petrology, geochronology, and sedimentary geology among others were integrated to reconstruct the source of the Voltaian Basin sedimentary rocks. Application of compositional analyses to determine provenance using petrographic, mineralogical, and geochemical techniques are also discussed. Results based on articles retrieved from the comprehensive literature review summarize the findings on provenance studies; stating the sediment source and history of the rock types in the Voltaian Basin to be most likely from the Pan-African orogenic rocks having a felsic source with some inputs from metasedimentary source rocks. Findings from provenance studies further point to the depositional environment being of shallow marine source and having a fluvial to deltaic environmental features, suggesting that the depositional environment is suitable for hydrocarbon source rocks as well as reservoir rocks formation. With regards to petroleum exploration, a lot of research work needs to be done to identify the type of sedimentary organic matter present in the shales and the limestones of the Voltaian Basin. Furthermore, the rock properties that define petroleum reservoirs such as porosity, permeability, pore type, and rock compressibility as well as electrical properties of some important sandstones need to be thoroughly investigated.

Summary: The plateau pika (Ochotona curzoniae) is native to the Qinghai-Tibet Plateau. In this study, the gene that encodes a heme-binding protein in the pulmonary surfactant (PS) of the pika is identified. The protein is a homotetrameric hemoglobin (δ4) encoded by HBD (δ). HBD is expressed in alveolar epithelial type II (ATII) and type I (ATI) cells, upregulated by hypoxia. δ4 is secreted into alveolar cavities through osmiophilic multilamellar bodies. HBD expression is downregulated by RNAi, which significantly increases hypoxia-inducible factor 1α expression in lung tissue and red blood cells and hemoglobin and blood lactate concentrations but significantly decreases arterial partial pressure of oxygen (PaO2). Our results indicate that plateau pikas physiologically show hypoxemia when HBD expression is downregulated. Therefore, specific HBD expression in the lungs helps plateau pikas to obtain oxygen under hypoxia by maintaining higher PaO2. These findings provide insights into the adaptive mechanisms of plateau pikas to withstand high-altitude environments.

The corrosion resistance of zirconium alloys is closely related to the size of precipitates. β-phase quenching is the key process for controlling the precipitate size of zirconium alloy. In this study, the microstructure and the precipitates size of nuclear graded Zircaloy-4 (hereinafter called as Zr-4) alloy treated by the quenching in different cooling mediums were studied, and the critical quenching diameter of the Zr-4 alloy rod was determined by finite element method. The results showed that, the cooling rate of the β-phase quenching had small effect on the grain size of the alloy, however the size of the needle α grains increased with a decrease of cooling rate. The thickness of α grains quenched in water, quenched in oil, quenched at room temperature and quenched at 440 °C were about 1 μm, 5 μm, 9 μm, and 15 μm, respectively. When the cooling rate was high (water-quenching and oil-quenching), the precipitates formed only along the grain boundary, and with the length of less than 100 nm. When the cooling rate was low (air quenching), precipitates formed not only at the grain boundaries but also inside the grains, and the precipitates length was about 150–200 nm. When the Zr-4 alloy rod was quenched in water or oil, the maximum diameter of the specimen with suitable precipitate size (about 100–200 nm) was 140 and 97 mm, respectively. Keywords: Zr-4 alloy, βphase quenching, Cooling rate, Microstructure, Critical quenching diameter

Although human adipose derived stem cells (hADSCs) hold great promises for regenerative medicine, their key biological properties remain poorly understood. In particular, proliferation defects resulted from deep quiescence (dormancy) and senescence represent a major hurdle in hADSC production and clinical application. We have developed a model system for mechanistic dissection of hADSC quiescence and senescence. p57Kip2, a major CDK inhibitor, was highly expressed in quiescent and senescent hADSCs but its level quickly declined upon stem cell activation. p57Kip2 overexpression induced quiescence in spite of proliferative signals and its knockdown promoted cell cycle reentry even with induction of quiescence presumably through modulating the CDK2–CyclinE1 complex. Given its key role in quiescence and senescence, p57Kip2 may be exploited for innovative strategies to amplify hADSCs of high quality for clinics. Keywords: Human adipose derived stem cells, p57Kip2, Quiescence, Senescence

First-principles calculations have been carried out to investigate the adsorption of a hydrogen adatom on 24 metal doped α-Zr (0 0 0 1) surfaces in both a vacuum and an implicit solvation environment. The dopant are the elements in the 4th and 5th periods in the periodic table. Doping elements at the tail of the 4th and 5th periods can significantly reduce the hydrogen pickup in a vacuum environment. A weighted d-band center theory is used to analyze the doping effect. On the other hand, the hydrogen adsorption energies in water are relatively lower for all doped slabs and the surface adsorption of hydrogen adatom is stronger than that in a vacuum environment, especially, for the slabs with doping elements at the tail of the 4th and 5th periods. In the solvation environment, electronegativity difference affects the adsorption. Doping elements Ag, Ga, Ge, Sn, and Sb can reduce the hydrogen pickup in vacuum, while Ag and Cu can reduce the hydrogen pickup of the zirconium alloys in solvent environment.

Silicosis is a progressive and chronic occupational lung disease characterized by lung inflammation, silicotic nodule formation, and diffuse pulmonary fibrosis. Emerging evidence indicates that endothelial-mesenchymal transition (EndoMT) plays a crucial role in the development of silicosis. Herein, we conducted a SiO 2 -induced EndoMT model and established a mouse model with pulmonary fibrosis by silica. We identified that SiO 2 effectively increased the expression of mesenchymal markers while decreasing the levels of endothelial markers in endothelial cells. It's further demonstrated that SiO 2 induced the PI3K/Akt signaling pathway activation via LGALS3 synthesis. Next, interfering LGALS3 blocked the process of EndoMT by inhibiting the activity of PI3K/AKT signaling. In vivo, the administration of a specific PI3K inhibitor LY294002 significantly alleviated silica-induced pulmonary fibrosis. Collectively, these results identified that the LGALS3/PI3K/AKT pathway provided a rationale target for the clinical treatment and intervention of silicosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Methylisothiazolinone (MIT) is a widely used preservative and biocide to prevent product degradation, yet its potential impact on plant growth remains poorly understood. In this study, we investigated MIT's toxic effects on Arabidopsis thaliana root growth. Exposure to MIT significantly inhibited Arabidopsis root growth, associated with reduced root meristem size and root meristem cell numbers. We explored the polar auxin transport pathway and stem cell regulation as key factors in root meristem function. Our findings demonstrated that MIT suppressed the expression of the auxin efflux carrier PIN1 and major root stem cell regulators (PLT1, PLT2, SHR, and SCR). Additionally, MIT hindered root regeneration by downregulating the quiescent center (QC) marker WOX5. Transcriptome analysis revealed MIT-induced alterations in gene expression related to oxidative stress, with physiological experiments confirming elevated reactive oxygen species (ROS) levels and increased cell death in root tips at concentrations exceeding 50 μM. In summary, this study provides critical insights into MIT's toxicity on plant root development and regeneration, primarily linked to modifications in polar auxin transport and downregulation of genes associated with root stem cell regulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Panax ginseng C.A. Mey., known for its medicinal and dietary supplement properties, primarily contains pharmacologically active ginsenosides. However, the regulatory mechanisms linking ginseng root development with ginsenoside biosynthesis are still unclear. Root meristem growth factors (RGFs) are crucial for regulating plant root growth. In our study, we identified five ginseng RGF peptide sequences from the ginseng genome and transcriptome libraries. We treated Arabidopsis and ginseng adventitious roots with exogenous Panax ginseng RGFs (PgRGFs) to assess their activities. Our results demonstrate that PgRGF1 influences gravitropic responses and reduces lateral root formation in Arabidopsis. PgRGF1 has been found to restrict the number and length of ginseng adventitious root branches in ginseng. Given the medicinal properties of ginseng, We determined the ginsenoside content and performed transcriptomic analysis of PgRGF1-treated ginseng adventitious roots. Specifically, the total ginsenoside content in ginseng adventitious roots decreased by 19.98 % and 63.71 % following treatments with 1 μM and 10 μM PgRGF1, respectively, compared to the control. The results revealed that PgRGF1 affects the accumulation of ginsenosides by regulating the expression of genes associated with auxin transportation and ginsenoside biosynthesis. These findings suggest that PgRGF1, as a peptide hormone regulator in ginseng, can modulate adventitious root growth and ginsenoside accumulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, the fibrous structure formation mechanism of soybean protein during high moisture extrusion processing was investigated using a dead-stop operation, and based on the interaction between soybean protein concentrate (SPC) and L-cysteine (CYS). The thermal properties, SDS-PAGE and particle size distribution of the samples from different extrusion zones were investigated. It was revealed that the addition of a moderate amount of CYS (0.1 %) promoted the fibrous structure formation in the SPC extrudates and optimised the textural properties of the SPC extrudates. In the extruder barrel, addition of CYS (0.1 %) promoted protein depolymerisation and unfolding in the mixing and cooking zones, and facilitated protein aggregation in the die and cooling zones. Protein solubility and raman spectroscopy revealed that disulfide bonds were principally responsible for fibrous structure formation; favoured when the intermolecular disulfide bonds (t-g-t mode) was increased. Finally, the transformation of protein conformation was revealed by secondary structure and surface hydrophobicity, which confirmed that the effect of CYS on protein conformation mainly occurred in the cooling zone. This study provides a theoretical basis for the application of CYS to regulate the fibrous structure of meat analogues., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

As a fatal occupational disease with limited therapeutic options, molecular mechanisms underpinning silicosis are still undefined. Herein, single-cell RNA sequencing of the lung tissue of silicosis mice identified two monocyte subsets, which were characterized by Cxcl10 and Mmp14 and enriched in fibrotic mouse lungs. Both Cxcl10 + and Mmp14 + monocyte subsets exhibited activation of inflammatory marker genes and positive regulation of cytokine production. Another fibrosis-unique neutrophil population characterized by Ccl3 appeared to be related to the pro-fibrotic process, specifically the "inflammatory response". Meanwhile, the proportion of monocytes and neutrophils was significantly higher in the serum of silicosis patients and slices of lung tissue from patients with silicosis further validated the over-expression of Cxcl10 and Mmp14 in monocytes, also Ccl3 in neutrophils, respectively. Mechanically, receptor-ligand interaction analysis identified the crosstalk of Cxcl10 + /Mmp14 + monocytes with Ccl3 + neutrophils promoting fibrogenesis via coupling of HBEGF-CD44 and CSF1-CSF1R. In vivo, administration of clodronate liposomes, Cxcl10 or Mmp14 siRNA-loaded liposomes, Ccl3 receptor antagonist BX471, CD44 or CSF1R neutralizing antibodies significantly alleviated silica-induced lung fibrosis. Collectively, these results demonstrate that the newly defined Cxcl10 + /Mmp14 + monocytes and Ccl3 + neutrophils participate in the silicosis process and highlight anti-receptor-ligand pair treatment as a potentially effective therapeutic strategy in managing silicosis., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) infection causes an emerging hemorrhagic fever in East Asia with a high mortality rate. Thrombocytopenia is a consistent feature of SFTS illness, but the mechanism remains elusive., Objectives: We aimed to better understand the role of platelets in the pathophysiology of SFTSV infection, including the development of thrombocytopenia., Methods: Using platelets from healthy volunteers and patients with SFTS, we evaluated the functional changes in platelets against SFTSV infection. We investigated the direct effect of glycoprotein VI on platelet-SFTSV interaction by quantitative real-time PCR, molecular docking, surface plasmon resonance spectrometry, flow cytometry, western blot, and platelet functional studies in vitro. Interactions of SFTSV and platelet-SFTSV complexes with macrophages were also determined by scanning electron microscope, quantitative real-time PCR, and flow cytometry., Results: This study is the first to demonstrate that platelets are capable of harboring and producing SFTSV particles. Structural and functional studies found that SFTSVs bind platelet glycoprotein VI to potentiate platelet activation, including platelet aggregation, adenosine triphosphate release, spreading, clot retraction, coagulation, phosphatidylserine exposure, thrombus formation, and adherence. In vitro mechanistic studies highlighted that the interaction of platelets with human THP-1 cells promoted SFTSV clearance and suppressed cytokine production in macrophages. However, unwanted SFTSV replication in macrophages reciprocally aggravated SFTSV persistence in the circulation, which may contribute to thrombocytopenia and other complications during SFTSV infection., Conclusion: These findings together highlighted the pathophysiological role of platelets in initial intrinsic defense against SFTSV infections, as well as intertwined processes with host immunity, which can also lead to thrombocytopenia and poor prognosis., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

The genus Datura has been used as an important traditional medicine in China, as well as in other countries worldwide. This review summarizes the latest progress and perspective of the genus Datura, from the aspects of botany, traditional uses, phytochemistry, pharmacology, and toxicology. Up to May 2022, literatures were collected from online scientific databases, including Google Scholar, PubMed, SciFinder, CNKI, ACS, and Web of Science, and information was also obtained from "Flora Republicae Populairs Sinicae", Chinese Pharmacopoeia, Chinese herbal classic books, and Ph.D. and M. Sc. dissertations. Studies on chemical constituents, pharmacological activities, and toxicity are mainly focused on D. metel, D. stramonium, and D. inoxia. Furthermore, 496 compounds have been discovered from the genus Datura, including withanolides, alkaloids, flavonoids, terpenoids, phenylpropanoids, steroids, amino acids, aromatics, and aliphatics. Among them, withanolides and alkaloids are two main active constituents. Pharmacological activities of extracts and compounds have been studied from the aspects of antitumor, antiinflammation, antioxidant, antimicrobial, antispasmodic, anticoagulant, analgesic, hypoglycemic and xanthine oxidase inhibitory activities, as well as the effects on central nervous system and immune system. Modern pharmacological studies have provided more clues to elucidate the traditional usages. The toxicity of the genus Datura is noteworthy, especially the potential toxicity on organs. This review would provide a comprehensive and constructive overview for new drug development and utilization of the genus Datura., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This study evaluated the effects of theaflavins (TFs), tea polyphenols (TP) and vitamin C (VC) on the nitrite residue amount, color, antioxidant capacity and N-nitrosamines inhibition in cured sausage. The addition of TFs, TP and VC combined with NaNO 2 respectively could significantly increase the a* value, nitroso pigment content and DPPH free radical scavenging rate, and effectively reduced the content of residual nitrite, metmyoglobin (MetMb) and total N-nitrosamines in cured sausages than treated only with NaNO 2 (P < 0.05), of which TFs group was the most significant (P < 0.05). It was indicated that the addition of TFs, TP could better inhibit the oxidation of cured sausages. UV-vis spectroscopy also showed pentacoordinate nitrosyl ferrohemochrome was the main pigment component in the samples. The results demonstrated that TFs and TP could contribute to the desired color and safety of sausage., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Current descriptive epidemiological information on classic myeloproliferative neoplasms (MPNs) is incomplete. Published data among Asian population are particularly sparse., Methods: We conducted a large population-based study to determine the incidence rates and survival patterns of MPN reported to the Singapore Cancer Registry during the period 1968-2017. Age-standardised incidence rates(ASR), overall survival, 5-/10-year relative survival ratio (RSR) were estimated. Joinpoint regression was used to evaluate quinquennial percent change (QPC) in incidence., Results: We identified 2557 individuals diagnosed with MPN including 1031 chronic myeloid leukaemia (CML), 424 polycythaemia vera (PV), 389 essential thrombocythaemia (ET), 134 primary myelofibrosis (PMF) and 579 MPN unclassifiable (MPN-U). The overall respective ASRs per 100,000 for CML, PV, ET, PMF and MPN-U were 1.24, 1.15, 1.07, 0.43, and 0.80 in 2013-2017. Males had higher ASR than females in all MPNs. A gradual rise in incidence trends of CML was observed between 1968 and 2017 (QPC 2.1%, 95% CI -0.9, 5.3). The overall incidence trends of non-CML MPNs including PV (QPC 62.9%, 95% CI 19.3, 122.6), ET (QPC 54.2%, 95% CI 23.5, 92.3) and PMF (QPC 103.5%, 95% CI 19.1, 247.6) increased sharply during 1993-2017. Survival was lower in MPNs compared with expected survival in general population: 5-year RSRs were 0.82 (95% CI 0.78, 0.86), 0.96 (95% CI 0.91, 1.01), 0.96 (95% CI 0.92, 1.01), 0.53 (95% CI 0.43, 0.65), and 0.74 (95% CI 0.68, 0.80) for CML, PV, ET, PMF and MPN-U respectively., Conclusion: CML incidence has increased marginally, whereas non-CML MPNs incidences have sharply increased. MPN patients have a lower relative survival compared to the general population, and patients with PV and ET have the most favourable relative survival. Median survival for CML patients has increased dramatically over the last 50 years., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cadmium (Cd) is a harmful element that affects plant growth and development. Genetic improvements could be applied for enhancing Cd tolerance and accumulation in plants. Here, a novel Cd stress-induced gene, NtNRAMP3, was identified in tobacco. We constructed two NtNRAMP3-knockout (KO) tobacco lines using the CRISPR/Cas9 system, which enhanced Cd tolerance and Cd accumulation in tobacco leaves compared with those in the wildtype (WT). Subcellular localization analysis suggested that NtNRAMP3 is a tonoplast protein and GUS (β-glucuronidase) histochemical analysis showed that NtNRAMP3 is highly expressed in the conductive tissue of leaves. NtNRAMP3-KO tobacco showed reduced Cd translation from vacuole to cytosol in leaves compared with the WT, and its vacuolar Cd concentration was significantly higher (20.78-22.81%) than that in the WT; in contrast, Cd concentration in the cytosol was reduced by 13.72-20.15%, preventing chlorophyll degradation and reducing reactive oxygen species accumulation in the leaves. Our findings demonstrate that NtNRAMP3 is involved in regulating Cd subcellular distribution (controlling Cd transport from vacuoles to the cytosol) and affects Cd tolerance and its accumulation in tobacco. This provides a key candidate gene to improve the phytoremediation efficiency of plants via genetic engineering., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Aims: Incomplete surgical resection of invasive non-functional pituitary adenomas (NFPAs) produces a risk of the subsequent development of complications which will require treatment with powerful drugs and adjuvant radiotherapy., Materials and Methods: The degree of invasiveness of NFPA can be established using biomarkers to help clinicians choose appropriate treatment for these patients., Results: This research explored transcriptomic and proteomic variations of non-invasive and invasive NFPAs, other forms of pituitary adenomas and evaluated exosomal genetic markers associated with these diseases. Increased expression of matrix metalloproteinase-1 (MMP1) and its formation in exosomes (exo-MMP1) were correlated with the characteristic invasiveness of NFPAs. Changes in the expression of MMP1 in the exosome was synchronized with transduction of NFPA cells. Enrichment of MMP1 stimulated migration, growth and angiogenesis in tumors through the protease-activated receptor-1 signaling pathway in cells., Conclusion: The results revealed that MMP1 activity has obligatory actions in promoting tumor invasion and angiogenesis, and that the exosome-mediated regulatory pathway for MMP1 may be a novel therapeutic target., (Copyright © 2022. Published by Elsevier B.V.)

Although surgical interventions have become optional for refractory vitiligo, grafting related injuries is inevitable. Embryonic stem cell (ESC) derivatives can be used in transplantation to address this issue, but the immune rejection due to allogeneic transplantation is of great concern. To investigate the immunogenicity of ESC derived melanocytes (ES-MC), we established a co-culture system of ES-MC and allogeneic PBMC. The results showed that ES-MC were similar to human primary melanocytes, with low expression of immune related molecules, and limited capability of stimulating allogeneic lymphocytes in vitro. Taken together, our findings confirm that ES-MC are of limited immunogenicity, providing new insights into the application of ES-MC in the regenerative medicine such as treating vitiligo., Competing Interests: Declaration of competing interest There is no known conflict of interest in this manuscript., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The aim of this study is to retrospectively evaluate the safety and effectiveness of forceps-assisted removal of difficult-to-retrieve filters., Methods: Patients who underwent forceps-assisted removal of difficult-to-retrieve filters (filters that could not be successfully removed with the standard loop-snare technique) between February 2008 and February 2019 were included in this study. Patients underwent forceps-assisted filter removal either immediately after failed loop-snare removal (same procedure) or at a later time (separate procedure). Data regarding success rate, X-ray exposure time, and complications were recorded., Results: A total of 27 patients (14 men, 13 women; mean age 57.9 ± 12.6 years) were included in this study. The mean indwelling time of the filters was 10.9 ± 10.7 months. All filters were successfully removed. The mean X-ray exposure time was 25.9 ± 12.7 min (range 8-55) for all patients; the mean X-ray exposure times were 10.2 ± 2.3 min (range 8-14) for the 5 patients who underwent forceps-assisted filter removal in a separate procedure and 29.5 ± 11.2 min (range 15-55) for the 22 patients who underwent forceps-assisted filter removal immediately after failure of the loop-snare technique (P < 0.001). Two patients (8.3%) experienced extravasation of contrast material and needed no additional treatment. No major complications occurred., Conclusions: Forceps-assisted filter retrieval can be used to safely and effectively remove difficult-to-retrieve filters., (Copyright © 2019 Elsevier Inc. All rights reserved.)

To investigate the clinical characteristics of pituitary adenomas in patients under 14 years old. A total of 140 children and adolescents with pituitary adenomas were admitted to Peking Union Medical College Hospital (PUMCH) from December 1987 to December 2014, and their clinical manifestations, hormone secretions, images, pathological types, surgical complications and follow-up characteristics were analyzed. Fifty-eight (41.4%) males and 82 (58.6%) females with a mean age of 12.5 years old (range, 6-14 years old) were included. Regarding tumor type, adrenocorticotropic hormone (ACTH), prolactin (PRL), growth hormone (GH), non-functioning and multiple-secreting adenomas accounted for 35.7%, 25.7%, 12.2%, 25.7%, and 0.7% of the tumors, respectively. Microadenomas, macroadenomas and giant adenomas accounted for 33.6%, 60.0% and 6.4% of the patients, respectively. Approximately 19.3% of the adenomas included in our study were invasive. Trans-sphenoidal approach surgery (TSS) was commonly used and accounted for 97.9% of the cases in our study. Total resection was achieved in 93.6% of the patients, and subtotal resection was performed in the remaining patients. Finally, 113 patients underwent full-term follow-up until 2 years after surgery, and tumors recurred in 32 patients. TSS is the most commonly used surgical procedure in patients younger than 14 years old. No significant differences in surgical outcomes, mortality during the perioperative period or complications were observed between patients younger than 14 years old and similar patients in the general population., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Organophosphorus esters (OPEs), as one kind of emerging and toxic contaminant are ubiquitous in various environments. This study investigated the degradation of tris(2-chloroethyl) phosphate (TCEP) as a category OPEs by pyrite (FeS 2 )-activated persulfate (PS). The result shows that near-100% degradation of TCEP was achieved after 120 min in FeS 2 -PS system. The important role of Fe 2+ in the activation mechanism was confirmed by the introduction of Fe 2+ into the PS only system. Radical scavengers experiment and electron paramagnetic resonance (EPR) confirmed the presence of SO 4 ·- and ·OH，which revealed that ·OH and SO 4 ·- played major roles in TCEP degradation. The effect of various environmental factors, including pyrite and oxidant dosage, inorganic ions and pH were investigated. The result indicated that Fe 3+ and Cl - can accelerate the degradation rate of TCEP and the reaction between TCEP and FeS 2 -PS favors acidic conditions (pH>9). In addition, due to the acidification of pyrite, this system can be applied with a wide pH range. Besides, two oxidation products, C 4 H 9 Cl 2 O 4 P and C 2 H 6 ClO 4 P were identified, which suggest that hydroxylation was probably the main mechanism. This study greatly improves our understanding on TCEP removal in FeS 2 -PS system., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To investigate the clinical characteristics of hypopituitarism and its reversibility after surgery for nonfunctional pituitary adenoma (NFPA); analyze the correlation between tumor size and hypopituitarism incidence; and predict hypopituitarism by tumor volume and maximum diameter., Methods: We retrospectively reviewed 164 patients with NFPA who underwent surgical treatment at Peking Union Medical College Hospital from January 2016 to December 2016. Demographic, imaging, and endocrine data were collected during preoperative, postoperative, and long-term follow-up (21.1 ± 3.3 months) periods. Differences in hormone levels were analyzed by paired and independent samples t-tests. The cut-off values of tumor size and volume to predict hypopituitarism were calculated by receiver operating characteristic curves., Results: In total, 80.4% (132/164) of patients had anterior pituitary hypofunction and 48.4% patients had hypogonadism; the recovery rate of luteinizing hormone was 80.9%, and follicular-stimulating hormone was 60%. In total, 36.5% of patients had hypothyroidism; the recovery rate of thyroxine was 85%, free thyroxine was 87.8%, and thyroid-stimulating hormone was 100.0%. Finally, 27.4% of patients had insulin-like growth factor 1 (IGF-1)/growth hormone (GH) hypofunction, and the recovery rate of IGF-1 was 77.8%. The preoperative free thyroxine, thyroxine, GH, IGF-1, follicular-stimulating hormone, and luteinizing hormone levels were significantly lower in the giant adenoma group (n = 43) than in the large adenoma group (n = 121). The hypopituitarism predictive cut-off value of tumor volume was 3105.1 mm 3 and that of tumor diameter was 23.5 mm., Conclusions: NFPA has a significant influence on gonadal hormone, IGF-1/GH, and thyroid hormone. NFPA can cause single- or multiple-hormone reduction in each pituitary target gland. Tumor size is positively correlated with the incidence and degree of hypopituitarism. NFPA-induced hypopituitarism is significantly recovered after surgical treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

To study adaptation of largemouth bass (Micropterus salmoides) to hypoxic stress, we investigated physiological responses and lactate metabolism of the fish under acute hypoxia. The objectives of this study were to (a) observe changes in glucose, glycogen, and lactate content; (b) detect the activity of lactate dehydrogenase (LDH) in serum, brain, heart, and liver tissues; and (c) quantify the dynamic gene expression of AMP activated protein kinase alpha (AMPKα), hypoxia-inducible factor-1 alpha (HIF-1α), monocarboxylate transporter 1 (MCT1), monocarboxylate transporter 4 (MCT4), and lactate dehydrogenase-a (LDHa) following exposure to hypoxia. The fish were subjected to two hypoxia stresses (dissolved oxygen [DO] 1.20 ± 0.2 mg/L and 3.50 ± 0.3 mg/L, respectively) for 24 h. Our results showed that hypoxic stress significantly increased the decomposition of liver glycogen and significantly increased the concentration of blood glucose; however, the muscle glycogen content was not significantly decreased, which indicates that liver glycogen was the main energy source under acute hypoxia. Moreover, hypoxia led to accumulation of a large amount of lactic acid in tissues, possibly due to the activity of lactic acid dehydrogenase, but this process was delayed in the heart and brain relative to the liver. Additionally, hypoxia induced the expression of AMPKα, HIF-1α, MCT1, MCT4, and LDHa, suggesting that glycometabolism had switched from aerobic to anaerobic. Our results contribute to a better understanding of the molecular mechanisms of the response to hypoxia in largemouth bass., (Copyright © 2019. Published by Elsevier B.V.)

Advanced oxidation processes (AOPs), such as hydroxyl radical (•OH) and sulfate radical (•SO 4 - ) mediated oxidation, are proved to be effective methods to remove the organophosphorus esters (OPEs) in wastewater effluents. However, few studies have reported about the bimolecular reaction rate constants between free radicals (•OH and •SO 4 - ) and OPEs. This issue was solved by selecting three OPEs as model compounds, the oxidation of these OPEs in UV/H 2 O 2 and UV/K 2 S 2 O 8 process were studied. Tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCPP), and tris(2,3-dichloropropyl) phosphate (TDCPP) can hardly be oxidized through direct irradiation methods using UV lamp, with the oxidation rate less than 30% after 7 h' irradiation. However, TCEP, TCPP, and TDCPP undergo degradation via UV/H 2 O 2 and UV/K 2 S 2 O 8 processes easily, the oxidation rates increased with increasing H 2 O 2 and K 2 S 2 O 8 dosage. The oxidation rates of three OPEs have been studied using competition experiments in the UV/H 2 O 2 and UV/K 2 S 2 O 8 processes. The bimolecular reaction rate constants of TCEP, TCPP and TDCPP with •OH were 2.50 × 10 10 , 3.95 × 10 10 and 2.94 × 10 10 respectively; while •SO 4 - were 3.00 × 10 7 , 1.82 × 10 7 and 2.06 × 10 7 respectively. Results showed that the simplified kinetic model involves only steady state concentration of free radicals and the molecular reaction rate contents are available for calculating the oxidation rates of OPEs in ultrapure water., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The recent emergence of Zika virus, a mosquito-borne flavivirus, in the Americas has shed light on the severe neurological diseases associated with infection, notably congenital microcephaly in newborns and Guillain-Barré syndrome in adults. Despite the recent focus on Zika virus, there are currently no approved vaccines or antiviral therapies available to treat or prevent infection. In this study we established a competitive amplified luminescent proximity homogeneous assay (ALPHAscreen) to identify small molecule inhibitors targeting the envelope protein of Zika virus (Zika E). We utilized this assay to screen two libraries of nearly 27,000 compounds and identified seven novel inhibitors of Zika E. Characterization of these primary screening leads demonstrated that inhibition of Zika virus occurs at non-cytotoxic concentrations for all seven lead compounds. In addition, we found that all seven lead compounds have potent activity against the closely related dengue virus 2 but not vesicular stomatitis virus, an unrelated enveloped virus. Biochemical experiments indicate that these compounds act by preventing E-mediated membrane fusion. This work highlights a new method for the discovery and optimization of direct-acting antivirals targeting the E protein of Zika and other flaviviruses., (Copyright © 2019. Published by Elsevier B.V.)

Objective: To investigate the clinical characteristics of delayed remission (DR) of growth hormone (GH)-secreting pituitary adenoma after transsphenoidal adenectomy and inform follow-up treatments., Methods: We retrospectively reviewed 87 patients who had undergone transsphenoidal surgery for acromegaly. Demographic, radiological, and endocrinological data were reviewed before, immediately after, 3 months after, and in the long term (2.4 ± 1.1 years) after surgery. The definition of DR was that patients did not achieve GH remission immediately, 3 months, or later after surgery, but did so in the long term without any additional postoperative treatment., Results: Fifty-one patients (58.6%) achieved long-term GH remission. There were 24 (27.6%) DR patients immediately postoperatively and 9 (10.3%) DR patients 3 months postoperatively. On average, the 24 DR patients achieved remission at 10.2 (range, 3-32) months. Immediate postoperative random and nadir GH after an oral glucose load were significantly lower in the DR group than in the nonremission group (2.73 ± 3.17 and 2.03 ± 2.59 vs. 8.05 ± 10.35 and 5.55 ± 5.91 μg/L, respectively). Three-month postoperative nadir GH was significantly lower in the DR group than in the nonremission group (1.63 ± 2.82 vs. 3.48 ± 4.25 μg/L, P = 0.007). Immediate postoperative random GH effectively predicted long-term remission (Spearman's ρ = 0.513, area under the curve = 0.905 > 0.90). However, the best predictor of long-term remission was 3-month postoperative nadir GH (Spearman's ρ = 0.728, area under the curve = 0.944 > 0.90), with 76.5% sensitivity and 97.2% specificity., Conclusions: For certain groups of patients likely to achieve DR, additional treatments should not be performed early after surgery. Prolonged follow-up and close observation could help determine the therapeutic effect of surgery and guide postoperative treatments., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Norfloxacin (NFX) is an antibacterial agent belonging to the fluoroquinolone family of drugs, known to bind bovine serum albumin (BSA). Surface-enhanced Raman scattering (SERS) and fluorescence spectroscopy in combination with molecular docking were explored to investigate the binding interaction between NFX with Bovine serum albumin (BSA) at a physiological condition. This study focused on identifying the binding site and relevant interaction mechanisms between NFX and BSA. Spectrophotometric titration with molecular docking results demonstrated that the binding site of NFX on BSA was located in sub-domain IIA. The principle binding site was identified within a hydrophobic cavity which is surrounded by the residues Leu 197, Arg 198, Ser 201, Ala 209, Trp 213, Ser 343, Leu 346, Lys 350, Ser 453, Leu 480, Val 481, and the binding force was mainly hydrophobic interaction and hydrogen bond interaction. In addition, the absorptive orientation of the NFX molecule on the colloidal surface underwent a set of changes during the process of NFX binding to BSA., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Conjugated linoleic acid (CLA)-rich triacylglycerols (TAG) have received significant attention owing to their health promoting properties. In this study, CLA-rich TAG were successfully synthesized by an immobilized mutant lipase (MAS1-H108A)-catalyzed esterification of CLA-rich fatty acids and glycerol under vacuum. MAS1-H108A was first immobilized onto ECR1030 resin. Results showed that the lipase/support ratio of 41 mg/g was suitable for the immobilization and the thermostability of immobilized MAS1-H108A was greatly enhanced. Subsequently, the immobilized MAS1-H108A was employed for the synthesis of CLA-rich TAG and 95.21% TAG with 69.19% CLA was obtained under the optimized conditions. The TAG content (95.21%) obtained by immobilized MAS1-H108A is the reported highest value thus far, which was significantly higher than that (9.26%) obtained by Novozym 435 under the same conditions. Although the TAG content comparable to the results obtained in this study could also be obtained by Novozym 435, the used enzyme amount is approximately 5-fold of the immobilized MAS1-H108A. Additionally, the immobilized MAS1-H108A exhibited excellent recyclability during esterification retaining 95.11% of its initial activity after 10 batches. Overall, such immobilized mutant lipase with superior esterification activity and recyclability has the potential to be used in oils and fats industry., (Copyright © 2018. Published by Elsevier Inc.)

Objective: This study aimed to summarize the diagnosis, therapy, and prognosis of pituitary metastasis., Methods: Ten patients from the Department of Neurosurgery of the Peking Union Medical College Hospital from April 1997 to August 2014 were retrospectively analyzed., Results: The participants included 7 males (70%) and 3 females (30%), with an average age of 60.4 years. The most common initial clinical feature was visual disability (50%). The postoperative pathology reports indicated 1 case (10%) of metastatic large-cell pulmonary carcinoma, 2 cases (20%) of metastatic small cell pulmonary carcinoma, 2 cases (20%) of clear cell renal carcinoma metastasis, and 5 cases (50%) of metastasis of adenocarcinomas from different areas. All the patients underwent a thorough follow-up, and the average survival was 144 days., Conclusions: Pituitary metastasis is a rare disease. Its diagnosis depends on the clinical manifestations and radiologic results. The primary therapeutic method is surgery and subsequent radiotherapy and chemotherapy; however, the prognosis of this disease is poor., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Melatonin (N-acetyl-5-methoxytryptamine) has been reported to suppress epithelial-mesenchymal transition and cancer stem cells in some types of cancer. However, the effects of melatonin on the osteosarcoma stem cells, epithelial-mesenchymal transition and metastasis of osteosarcoma are still not clear. The present study was conducted to dissect the activity of melatonin on the osteosarcoma stem cells and the underlying mechanisms., Main Methods: MTT, wound healing, transwell assay and western blotting were conducted to determine the effect of melatonin on osteosarcoma cell invasion and migration and downregulation of SOX9-mediated signaling. Tumor spheroid assay and FACS analysis were performed to analyze the inhibition of the osteosarcoma stem cells. In vivo model for tumor formation and metastasis from single cell clone was used to evaluate the suppression of osteosarcoma stem cells by melatonin., Key Findings: We demonstrated that melatonin potently suppresses the migration and invasion of osteosarcoma cells. Furthermore, melatonin significantly inhibits the sarcosphere formation of osteosarcoma stem cells and regulates EMT markers of osteosarcoma cells. In vivo mice model showed that melatonin significantly inhibits the initiation and metastasis of osteosarcoma. SOX9 is the key transcription factor mediating the effect of melatonin. Melatonin inhibited of cancer stem cell by down-regulation of SOX9-mediated signaling pathway in osteosarcoma., Significance: Collectively, these results deepen the understanding of the biological functions of melatonin and provide new insights for the intervention of osteosarcoma stem cells., (Copyright © 2018. Published by Elsevier Inc.)

Aims: We aim to validate the AJCC 8th edition prognostic staging system for breast cancer in an Asian setting., Methods: Clinico-pathologic information and cancer-specific survival (CSS) outcomes of 6287 stage I to III patients with invasive breast cancer who underwent upfront surgery at SingHealth institutions in Singapore from 2006 to 2014 were analyzed. Survival distributions for the different staging systems were estimated by the Kaplan-Meier method and compared using the log-rank tests. Multivariable Cox proportional hazards models were used, with Akaike Information Criterion (AIC) and Harrell's Concordance Index (C-index) to compare both staging systems. Among patients with positive hormone-receptor status, 84.8% received endocrine therapy. Among the cohort, 60.3% of received chemotherapy; 82.1% of node positive patients received chemotherapy and 86.0% of HER2-enriched patients in whom chemotherapy was also indicated received adjuvant HER2-targeted therapy. Ninety-seven percent of patients received anthracyclines and/or taxanes containing chemotherapy regime., Results: The median follow up was 64 months. 2921 patients (46.5%) were discordant between the anatomic and prognostic systems of which 363 (5.8%) were upstaged and 2558 (40.7%) were down-staged. For all patients, stages in both the prognostic and anatomic systems were discriminating for 5-year CSS. Controlling for age, ethnicity and receipt of chemotherapy, the prognostic staging system model (AIC = 7538.87, C = 0.79) presented slightly better explanation and concordance of survival times than the anatomic staging system model (AIC = 7607.31, C = 0.77)., Conclusion: The prognostic staging system was better than the anatomic staging system in predicting outcomes but the anatomic system remains relevant due to its ease of use., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To investigate pituitary abscess (PA) magnetic resonance imaging (MRI) features to improve the neuroradiologic and diagnostic knowledge of this rare disease and guide follow-up treatments., Methods: Clinical data were collected for 51 patients with PA, and MRI data were quantitatively reviewed in a retrospective analysis. Clinical factors were analyzed to investigate their relevance., Results: PA neuroimaging showed special radiologic features, including hypointensity or isointensity on T1-weighted imaging (30 patients, 58.8%), isointensity or hyperintensity on T2-weighted imaging (39 patients, 76.5%), and disappearance of the posterior pituitary bright spot in most patients (44 patients, 86.3%). After gadolinium injection, rim or rimlike enhancement was observed in 82.4% of patients (n = 42). Half of those patients showed typical rim enhancement (profound peripheral enhancement with internal hypointensity); others showed atypical rim enhancement with special signs, such as enhanced, thick abscess wall and hyperintense flocculent or cottonlike foci within the internal hypointense region. Almost all patients (96.1%) presented at least 1 sign of adjacent anatomic structure invasion, including peripheral meninges enhancement, pituitary stalk thickening, and paranasal sinus mucosa enhancement. Rank correlation analysis of the clinical time course and MRI characteristics of PA showed a Spearman correlation coefficient of 0.270, indicating borderline significance (P = 0.055)., Conclusions: Classic MRI characteristics of PA show T1 signal hypointensity or isointensity, T2 signal isointensity or hyperintensity, and peripheral rim enhancement after gadolinium injection. The MRI appearance of PA may reflect the abscess liquefaction and formation. Despite its profound significance for differential diagnosis, adjacent structure invasion is generally ignored by clinicians., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To investigate the clinical features of somatotrophic adenoma in children younger than 14 years and to evaluate the short-term and long-term outcomes of transsphenoidal surgery., Methods: This single-center retrospective study included 22 patients with somatotrophic adenoma who were admitted to our institution between January 1997 and January 2017. The patients' demographics, hormone levels, imaging characteristics, surgical outcomes, and follow-up data were summarized., Results: The average age of patients at diagnosis was 10.3 years, and the average disease duration was 42.5 months. Growth acceleration was observed in 90.9% of patients. Mixed somatolactotrophic adenoma was identified in 36.4% of patients. In total, 77.3% of tumors on imaging were macroadenomas or giant adenoma, and 50% were invasive. Twenty-one patients underwent tumor resection, and the remission rate after a single transsphenoidal surgery was 45%. Preoperative growth hormone levels (P = 0.017), growth hormone nadir (P = 0.003), and tumor size (P = 0.026) were the most likely influencing factors associated with the surgical remission rate. Postoperative cerebral spinal fluid leakage (15%) was the main complication of transsphenoidal surgery. During a median follow-up period of 42.5 months, 72.7% of the patients obtained remission after monotherapy or combined treatment, and no recurrence was observed., Conclusions: Somatotrophic adenomas in children younger than 14 years tend to be macroadenomas with a shorter disease duration than that observed in adults. Transsphenoidal surgery is safe and effective and could represent a preferred treatment option. The combination of surgery, medication, and radiation is recommended to achieve optimal long-term outcomes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To investigate the incidence, bacteriologic features, and risk factors of posttranssphenoidal surgery (post-TSS) meningitis and/or bacteremia., Methods: This retrospective study included 3242 patients who underwent TSS for pituitary adenoma at the Department of Neurosurgery of Peking Union Medical College Hospital between January 2012 and December 2016. Clinical data for patients with and without post-TSS meningitis and/or bacteremia were compared and analyzed., Results: Meningitis and bacteremia developed after 27 (0.8%) and 26 (0.8%) procedures, respectively, and 6 patients (0.2%) developed both. Gram-positive organisms (coagulase-negative staphylococci, Streptococcus pneumonia, and S viridans) predominated in meningitis, whereas gram-negative organisms (Klebsiella pneumonia, Enterobacter aerogenes, and Escherichia coli) predominated in bacteremia. All identified species were sensitive to amikacin, imipenem, and meropenem. Antibiotic treatment cured 52 patients (7 died). In a multivariate analysis, the risk of meningitis and/or bacteremia was independently associated with diabetes (P < 0.001; odds ratio [OR], 6.06), previous surgery at the same location (P < 0.001; OR, 4.23), intraoperative cerebrospinal fluid leakage (P < 0.001l; OR, 4.63), and an endoscopic approach (P = 0.001; OR, 2.50)., Conclusions: Meningitis and/or bacteremia remain critical postoperative complications of TSS for pituitary adenoma. The pathogens with drug sensitivity to antibiotics differed between meningitis and bacteremia. Early blood and cerebrospinal fluid bacterial cultures, drug susceptibility analyses, and appropriate antibiotic treatment can help control the rate of infection., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Transsphenoid surgery (TSS) is a standard treatment modality for Cushing's disease (CD). However, postoperative remission and recurrence rates vary among studies. Here we analyze the diagnosis and outcomes of 341 patients with a preoperative diagnosis of CD undergoing TSS in a single center over a 3-year period., Methods: A total of 341 patients were enrolled. Clinical manifestations, imaging results, laboratory workups, and results of inferior petrosal sinus sampling (IPSS) were obtained. Outcomes were obtained with a follow-up length from 12 to 36 months., Results: The tumors were mainly of Knosp level 0 (68.57%). The sensitivity of MRI, combined low-dose and high-dose dexamethasone suppression test and IPSS in the diagnosis were 90.83%, 88.53% and 95.57%. The concordance of lateralization by MRI and by IPSS were 78.96% and 61.34% compared with surgery. 2., Outcomes: The overall remission rate was 78.89% (N = 289). Patients undergoing the first TSS (N = 234) had a remission rate of 86.36% for macroadenomas (N = 22) and 83.2% for microadenomas (N = 212). Patients undergoing a second TSS (N = 55) had lower rate of remission of 50.00% for macroadenomas (N = 6) and 61.22% for microadenomas (N = 49). For patients with invasive tumors, the overall remission rate was 26.92% (N = 26), 20.0% for macroadenomas (n = 20) and 50.0% for microadenomas (N = 6). The recurrence rate was 2.42%., Conclusions: Pituitary imaging, endocrinological workups and IPSS are sensitive and specific diagnostic modalities for CD, but the lateralization efficacy of MRI and IPSS are unsatisfactory. A higher rate of remission relies on gross resections of tumors., (Copyright © 2017. Published by Elsevier Inc.)

Human MSX1 gene is mapped to chromosome 4 and encodes a 303aa homeobox protein MSX1. MSX1 expression appears during early tooth development of vertebrate embryogenesis. Mutations in this protein are related to human tooth anomalie, cleft lip and palate and congenital ectodermal dysplasia syndrome. Most of the confirmed pathogenic mutations are located in exon2 encoded homeobox domain. Here, we report the establishment of MSX1 gene knockout human embryonic stem (hES) cell lines by CRISPR-Cas9 technology. These cell lines provide good materials for further studies of the roles MSX1 plays in human tooth development and congenital tooth agenesis., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate outcomes and identified risk factors affecting cure and intraoperative cerebrospinal fluid leak after transsphenoidal surgery using a new classification for growth hormone-secreting pituitary adenoma associated with empty sella., Methods: In this retrospective cohort study, 51 patients enrolled from January 2010 to June 2016 were categorized into 3 groups using a new classification scheme: grade A, whole tumor occupation area beneath a horizontal line drawn along the lowest level of empty sella; grade B, tumor occupation area that crossed the horizontal line on 1 side; and grade C, tumor occupation area that crossed the horizontal line on 2 sides. Clinical data were collected and analyzed., Results: Cure rate for grade A patients (88.24%; 15/17) was significantly higher than cure rate for grade B (55.00%; 11/20) and grade C (50.00%; 7/14) patients. Occurrence of cerebrospinal fluid leaks in grade C patients (35.71%; 5/14) was higher than in grade A patients (5.88%; 1/17). Logistic regression analysis indicated that risk factors affecting cure included large maximum tumor diameter (P = 0.009, odds ratio [OR] = 1.222), high preoperative fasting growth hormone level (P = 0.031, OR = 1.088), and high classification (P = 0.017, OR = 4.485). Risk factor affecting intraoperative cerebrospinal fluid leak was high classification (P = 0.039, OR = 3.580)., Conclusions: Transsphenoidal surgery is the current optimal treatment strategy. Empty sella increases the difficulty of surgery with a higher incidence of complications. The new classification scheme was better for predicting the surgical outcome for this disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Since 1965, polybrominated diphenyl ethers (PBDEs) have been used internationally as flame-retardant additives. PBDEs were recently withdrawn from commerce in North America and Europe due to their environmental persistence, bioaccumulative properties and endocrine-disrupting effects. Generations exposed perinatally to the highest environmental doses of PBDE account for one-fifth of the total United States population. While, toxicity of PBDE for the male reproductive system has been demonstrated in several human and animal studies, the long-lasting effects of perinatal exposures on male reproduction are still poorly understood. In this study, pregnant Wistar rats were exposed to 0.2mg/kg 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) from gestation day 8 until postnatal day 21. Male reproductive outcomes were analyzed on postnatal day 120 in offspring. Exposed animals had significantly smaller testes, displayed decreased sperm production per testis weight, had significantly increased percentage of morphologically abnormal spermatozoa, and showed an increase in spermatozoa head size. Perinatal BDE-47 exposure led to significant changes in testes transcriptome, including suppression of genes essential for spermatogenesis and activation of immune response genes. In particular, we observed a 4-fold average decrease in expression of protamine and transition protein genes in testes, suggesting that histone-protamine exchange may be dysregulated during spermatogenesis, resulting in an aberrant sperm epigenome. The possibility of long-lasting effects of developmental PBDE exposures calls for additional studies to build a foundation for the development of preventive and protective interventions against the environmentally-induced decline in fertility., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The pharmacokinetic profile of gallocatechin-7-gallate (J10688) was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD) rats received 1, 3, and 10 mg/kg (i.v.) of J10688 and plasma drug concentrations were determined by a high performance liquid chromatography-mass spectrometry (LC-MS) method. The pharmacokinetic software Data Analysis System (Version 3.0) was used to calculate the pharmacokinetic parameters. For different i.v. doses of J10688, the mean peak plasma concentration (C 0) values ranged from 11.26 to 50.82 mg/L, and mean area under the concentration-time curve (AUC0-t ) values ranged from 1.75 to 11.80 (mg·h/L). J10688 lacked dose-dependent pharmacokinetic properties within doses between 1 and 10 mg/kg, based on the power model. The method developed in this study was sensitive, precise, and stable. The pharmacokinetic properties of J10688 in SD rats were shown to have rapid distribution and clearance values. These pharmacokinetic results may contribute to an improved understanding of the pharmacological actions of J10688.