Review of the bicolora Fang and binghami Hampson species-groups of the genus Ovipennis Hampson with descriptions of five new species from Southwestern China and Indochina (Lepidoptera, Erebidae, Arctiinae, Lithosiini).

The Ovipennis bicolora Fang, 1986 and Ovipennis binghami Hampson, 1903 species-groups are reviewed. The identities of the records of O.binghami reported outside of its type locality are clarified. Ovipennis bicolora is rediscovered with the male and female genitalia illustrated for the first time. The male and female genitalia of O.thomasi ern, 2009 are illustrated for the first time and its specific status is confirmed. Five new species are described: O.hanae S.-Y. Huang, Volynkin & ern, sp. n. (Southwestern China), O.regina Volynkin, ern, S.-Y. Huang & Saldaitis, sp. n. (Northern Thailand and Southwestern China), O.takia Volynkin, S.-Y. Huang & ern, sp. n. (Western and Central Thailand), O.kitchingi Volynkin, S.-Y. Huang & ern, sp. n. (Northern Thailand), and O.sapa Volynkin, S.-Y. Huang, ern & Saldaitis, sp. n. (Northern Vietnam). Adults and genitalia of the new species are illustrated and compared with its congeners.

FASN Inhibition Decreases MHC-I Degradation and Synergizes with PD-L1 Checkpoint Blockade in Hepatocellular Carcinoma.

Immune checkpoint inhibitors (ICI) transformed the treatment landscape of hepatocellular carcinoma (HCC). Unfortunately, patients with attenuated MHC-I expression remain refractory to ICIs, and druggable targets for upregulating MHC-I are limited. Here, we found that genetic or pharmacologic inhibition of fatty acid synthase (FASN) increased MHC-I levels in HCC cells, promoting antigen presentation and stimulating antigen-specific CD8+ T-cell cytotoxicity. Mechanistically, FASN inhibition reduced palmitoylation of MHC-I that led to its lysosomal degradation. The palmitoyltransferase DHHC3 directly bound MHC-I and negatively regulated MHC-I protein levels. In an orthotopic HCC mouse model, Fasn deficiency enhanced MHC-I levels and promoted cancer cell killing by tumor-infiltrating CD8+ T cells. Moreover, the combination of two different FASN inhibitors, orlistat and TVB-2640, with anti-PD-L1 antibody robustly suppressed tumor growth in vivo. Multiplex IHC of human HCC samples and bioinformatic analysis of The Cancer Genome Atlas data further illustrated that lower expression of FASN was correlated with a higher percentage of cytotoxic CD8+ T cells. The identification of FASN as a negative regulator of MHC-I provides the rationale for combining FASN inhibitors and immunotherapy for treating HCC. SIGNIFICANCE: Inhibition of FASN increases MHC-I protein levels by suppressing its palmitoylation and lysosomal degradation, which stimulates immune activity against hepatocellular carcinoma and enhances the efficacy of immune checkpoint inhibition.

Epidemiological analysis reveals a surge in inflammatory bowel disease among children and adolescents: A global, regional, and national perspective from 1990 to 2019 - insights from the China study.

Background: The burden of inflammatory bowel disease (IBD) among children and adolescents is rising globally, with substantial variation in levels and trends of disease in different countries and regions, while data on the burden and trends were sparse in children and adolescents. We aimed to assess the trends and geographical differences in children and adolescents aged zero to 19 in 204 countries and territories over the past 30 years. Methods: Data on IBD among children and adolescents was collected from the Global Burden of Disease (GBD) 2019 database from 1990 to 2019. We used the GBD data and methodologies to describe the change in the burden of IBD among children and adolescents involving prevalence, incidence, disability-adjusted life years (DALYs), and mortality. Results: Globally, the IBD prevalence cases increased between 1990 and 2019. Annual percentage changes (AAPC) = 0.15; 95% confidence interval (CI) = 0.11-0.19, and incidence cases of IBD increased from 20 897.4 (95% CI = 17 008.6-25 520.2 in 1990 to 25 658.6 (95% CI = 21 268.5-31 075.6) in 2019, representing a 22.78% increase, DALYs cases decreased between 1990 and 2019 (AAPC = -3.02; 95% CI = -3.15 to -2.89), and mortality cases of IBD decreased from 2756.5 (95% CI = 1162.6-4484.9) in 1990 to 1208.0 (95% CI = 802.4-1651.4) in 2019, representing a 56.17% decrease. Decomposition analysis showed that IBD prevalence and incidence increased significantly, and a trend exhibited a decrease in underlying age and population-adjusted IBD DALYs and mortality rates. Correlation analysis showed that countries with high health care quality and access (HAQ) had relatively higher IBD age-standardised prevalence rate (ASPR) and age-standardised incidence rate (ASIR), but lower age-standardised DALYs rate (ASDR) and age-standardised mortality rate (ASMR). Conclusions: Global prevalence and incidence rate of IBD among children and adolescents have been increasing from 1990 to 2019, while the DALYs and mortality have been decreasing. Rising prevalence and rising incidence in areas with historically low rates will have crucial health and economic implications.

Draft genome of Castanopsis chinensis, a dominant species safeguarding biodiversity in subtropical broadleaved evergreen forests.

OBJECTIVES: Castanopsis is the third largest genus in the Fagaceae family and is essentially tropical or subtropical in origin. The species in this genus are mainly canopy-dominant trees, and the key components of evergreen broadleaved forests play a crucial role in the maintenance of local biodiversity. Castanopsis chinensis, distributed from South China to Vietnam, is a representative species. It currently suffers from a high disturbance of human activity and climate change. Here, we present its assembled genome to facilitate its preliminary conservation and breeding on the genome level. DATA DESCRIPTION: The C. chinensis genome was assembled and annotated by Nanopore and MGI whole-genome sequencing and RNA-seq reads using leaf tissues. The assembly was 888,699,661 bp in length, consisting of 133 contigs and a contig N50 of 23,395,510 bp. A completeness assessment of the assembly with Benchmarking Universal Single-Copy Orthologs (BUSCO) indicated a score of 98.3%. Repetitive elements comprised 471,006,885 bp, accounting for 55.9% of the assembled sequences. A total of 51,406 genes that coded for 54,310 proteins were predicted. Multiple databases were used to functionally annotate the protein sequences.

Phytosanitary irradiation treatment of the aerial root mealybug, Pseudococcus baliteus (Hemiptera: Pseudococcidae).

The aerial root mealybug, Pseudococcus baliteus Lit (Hemiptera: Pseudococcidae), is an important invasive and quarantine pest that poses a potential threat to fruits, vegetables, and ornamental plants. As a result, phytosanitary treatments are necessary to ensure the commodities of international trade are free from these pests. To determine the minimum absorbed dose required for phytosanitary irradiation (PI) application, irradiation dose-response and large-scale confirmatory tests were conducted. Eggs that were 2, 4, and 6 days old and late gravid females (containing 0-day-old eggs) of P. baliteus were X-ray irradiated with doses of 10, 20, 40, 60, 80, 100, and 120 Gray (Gy). The efficacy of preventing egg-hatching (mortality) was compared using two-way ANOVA, 95% confidence interval overlapping and lethal dose ratio test in probit analysis. The radiotolerance sequence of mealybugs egg was found to be 0 < 2 ≈ 4 < 6-day-old eggs, and their estimated LD99.9968 values with 95% confidence interval were 132.0 (118.9-149.5), 137.6 (125.2-153.7), 145.5 (134.5-159.1), and 157.4 (144.6-173.6) Gy, respectively. Subsequently, target doses of 135 and 145 Gy were used in the confirmatory gamma radiation treatments. No F1 generation neonates developed from a total of 47,316 late females irradiated at the measured dose of 107.7-182.5 Gy, resulting in the treatment efficiency of 99.9937% at the 95% confidence level. Therefore, the highest dose of 183 Gy measured in the confirmatory tests is recommended as the minimum absorbed dose in PI treatment of P. baliteus for establishing national and international standards.

Quarantine Disinfestation of Papaya Mealybug, Paracoccus marginatus (Hemiptera: Pseudococcidae) Using Gamma and X-rays Irradiation.

Paracoccus marginatus is a highly polyphagous invasive pest that poses a significant quarantine threat to tropical and subtropical countries. Infested commodities in international trade should undergo phytosanitary treatment, and irradiation is recommended as a viable alternative to replace methyl bromide fumigation. Dose-response tests were conducted on the 2-, 4-, and 6-day-old eggs and gravid females of P. marginatus using the X-ray radiation doses of 15-105 Gy with an interval of 15 Gy. Radiotolerance was compared using ANOVA, fiducial overlapping and lethal dose ratio (LDR) test, resulting in no significant difference among treatments, except for the overall mortality and LDR at LD90 (a dose causing 90% mortality at 95% confidence level). The estimated dose for LD99.9968 was 176.5-185.2 Gy, which was validated in the confirmatory tests. No nymphs emerged from a total of 60,386 gravid females exposed to a gamma radiation dose range of 146.8-185.0 Gy in the confirmatory tests. The largest dose in confirmatory tests should be the minimum threshold for phytosanitary treatment, consequently, a minimum dose of 185 Gy is recommended for the phytosanitary irradiation treatment of papaya mealybug-infested commodities, ensuring a treatment efficacy of ≥99.9950% at 95% confidence level.

A Six-Surface System to Describe Anatomy of Anterior Clinoid Process and Its Application in Anterior Clinoidectomy and Resection of Paraclinoid Meningioma.

OBJECTIVE: The anterior clinoid process (ACP) is surrounded by nerves and vessels that, together, constitute an intricate anatomical structure with variations that challenges the performance of individualized anterior clinoidectomy in treating lesions with different extents of invasion. In the present study, we established a 6-surface system for the ACP based on anatomical landmarks and analyzed its value in guiding ACP drilling and resection of paraclinoid meningiomas. METHODS: Using the anatomical characteristics of 10 dry skull specimens, we set 9 anatomical landmarks to delineate the ACP into 6 surfaces. Guided by our 6-surface system and eggshell technique, 5 colored silicone-injected anatomical specimens were dissected via a frontotemporal craniotomy to perform anterior clinoidectomy. Next, 3 typical cases of paraclinoid meningioma were selected to determine the value of using our 6-surface system in tumor resection. RESULTS: Nine points (A-H and T) were proposed to delineate the ACP surface into frontal, temporal, optic nerve, internal carotid artery, cranial nerve III, and optic strut surfaces according to the adjacent tissues. Either intradurally or extradurally, the frontal and temporal surfaces could be identified and drilled into depth, followed by skeletonization of the optic nerve, cranial nerve III, internal carotid artery, and optic strut surfaces. After the residual bone was removed, the ACP was drilled off. In surgery of paraclinoid meningiomas, our 6-surface system provided great benefit in locating the dura, nerves, and vessels, thus, increasing the safety of opening the optic canal and relaxing the oculomotor or optic nerves and allowing for individualized ACP drilling for meningioma removal. CONCLUSIONS: Our 6-surface system adds much anatomical information to the classic Dolenc triangle and can help neurosurgeons, especially junior ones, to increase their understanding of the paraclinoid spatial structure and accomplish individualized surgical procedures with high safety and minimal invasiveness.

The Origin, Differentiation, and Functions of Cancer-Associated Fibroblasts in Gastrointestinal Cancer.

Emerging evidence has shown the importance of the tumor microenvironment in tumorigenesis and progression. Cancer-associated fibroblasts (CAFs) are one of the most infiltrated stroma cells of the tumor microenvironment in gastrointestinal tumors. CAFs play crucial roles in tumor development and therapeutic response by biologically secreting soluble factors or structurally remodeling the extracellular matrix. Conceivably, CAFs may become excellent targets for tumor prevention and treatment. However, the limited knowledge of the heterogeneity of CAFs represents a huge challenge for clinically targeting CAFs. In this review, we summarize the newest understanding of gastrointestinal CAFs, with a special focus on their origin, differentiation, and function. We also discuss the current understanding of CAF subpopulations as shown by single-cell technologies.

Synthesis and Cytotoxicity Assessment against Human Colorectal Cancer Cell Lines of Quaternary 8-Dichloromethyl Protoberberine Alkaloids.

Twenty-two quaternary 8-dichloromethylprotoberberine alkaloids were synthesized from unmodified quaternary protoberberine alkaloids (QPAs) to improve their physical and chemical properties and to obtain selectively anticancer derivatives. The synthesized derivatives showed more appropriate octanol/water partition coefficients by up to values 3-4 compared to unmodified QPA substrates. In addition, these compounds exhibited significant antiproliferative activity against colorectal cancer cells and lower toxicity on normal cells, resulting in more significant selectivity indices than unmodified QPA compounds in vitro. The IC50 values of antiproliferative activity of quaternary 8-dichloromethyl-pseudoberberine 4-chlorobenzenesulfonate and quaternary 8-dichloromethyl-pseudopalmatine methanesulfonate against colorectal cancer cells are 0.31 µM and 0.41 µM, respectively, significantly stronger than those of other compounds and positive control 5-fluorouracil. These findings suggest that 8-dichloromethylation can be used as one of the modification strategies to guide the structural modification and subsequent investigation of anticancer drugs for CRC based on QPAs.

Chemoproteomics Reveals That Quaternary Protoberberine Alkaloids Inhibit Telomerase Activity Oncologically by Binding to PES1.

Natural QPAs have anti-cancer property. The prodrugs of QPAs synthesized in our work with significantly improved solubility showed significantly stronger activity in animal experiments. Nevertheless, the mechanism of action of QPAs for treating cancers remains poorly understood. Here, a chemoproteomic study reveals that QPAs non-covalently and multivalently bind to PES1 in CRC cells, which impinges on the direct interaction between hTERT and hTR in the assembly of the telomerase complex, downregulates telomerase activity, and so promotes the aging process of CRC cells. This study is beneficial for us to conduct extensively the pharmaceutical chemistry research of QPAs.

Identification of anoikis-related molecular patterns to define tumor microenvironment and predict immunotherapy response and prognosis in soft-tissue sarcoma.

Background: Soft-tissue sarcoma (STS) is a massive threat to human health due to its high morbidity and malignancy. STS also represents more than 100 histologic and molecular subtypes, with different prognosis. There is growing evidence that anoikis play a key role in the proliferation and invasion of tumors. However, the effects of anoikis in the immune landscape and the prognosis of STS remain unclear. Methods: We analyzed the genomic and transcriptomic profiling of 34 anoikis-related genes (ARGs) in patient cohort of pan-cancer and STS from The Cancer Genome Atlas (TCGA) database. Single-cell transcriptome was used to disclose the expression patterns of ARGs in specific cell types. Gene expression was further validated by real-time PCR and our own sequencing data. We established the Anoikis cluster and Anoikis subtypes by using unsupervised consensus clustering analysis. An anoikis scoring system was further built based on the differentially expressed genes (DEGs) between Anoikis clusters. The clinical and biological characteristics of different groups were evaluated. Results: The expressions of most ARGs were significantly different between STS and normal tissues. We found some common ARGs profiles across the pan-cancers. Network of 34 ARGs demonstrated the regulatory pattern and the association with immune cell infiltration. Patients from different Anoikis clusters or Anoikis subtypes displayed distinct clinical and biological characteristics. The scoring system was efficient in prediction of prognosis and immune cell infiltration. In addition, the scoring system could be used to predict immunotherapy response. Conclusion: Overall, our study thoroughly depicted the anoikis-related molecular and biological profiling and interactions of ARGs in STS. The Anoikis score model could guide the individualized management.

Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study.

Epigenetics regulates gene expression and has been confirmed to play a critical role in a variety of metabolic diseases, such as diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), osteoporosis, gout, hyperthyroidism, hypothyroidism and others. The term 'epigenetics' was firstly proposed in 1942 and with the development of technologies, the exploration of epigenetics has made great progresses. There are four main epigenetic mechanisms, including DNA methylation, histone modification, chromatin remodelling, and noncoding RNA (ncRNA), which exert different effects on metabolic diseases. Genetic and non-genetic factors, including ageing, diet, and exercise, interact with epigenetics and jointly affect the formation of a phenotype. Understanding epigenetics could be applied to diagnosing and treating metabolic diseases in the clinic, including epigenetic biomarkers, epigenetic drugs, and epigenetic editing. In this review, we introduce the brief history of epigenetics as well as the milestone events since the proposal of the term 'epigenetics'. Moreover, we summarise the research methods of epigenetics and introduce four main general mechanisms of epigenetic modulation. Furthermore, we summarise epigenetic mechanisms in metabolic diseases and introduce the interaction between epigenetics and genetic or non-genetic factors. Finally, we introduce the clinical trials and applications of epigenetics in metabolic diseases.

Free-Standing Two-Dimensional Crystals Formed from Self-Assembled Ionic Liquids.

The fabrication of two-dimensional crystals (2DCs) has attracted very large interest because it creates materials with various surface structural features and special surface properties. Normally, this is limited to sheets networked together with strong covalent or coordination bonds. Against this understanding, we discovered macroscopic scale free-standing 2DCs in the aqueous dispersions of [Cnmim]X (X = Br, NO3; n = 14, 16, 18) using simultaneous synchrotron small- and wide-angle X-ray scattering techniques. On the other hand, the 2DCs are also a kind of novel hydrogel holding water content up to 98 wt %. This unusual phenomenon is attributed to the weak interactions between imidazole headgroups and counterions. The observation reported in this work is expected to contribute to theorists in their pursuit of the general principles governing the stability of 2D materials. It may also enlighten experimentalists in designing new free-standing 2DCs for various applications.

Profile of biological characterizations and clinical application of corneal stem/progenitor cells.

Corneal stem/progenitor cells are typical adult stem/progenitor cells. The human cornea covers the front of the eyeball, which protects the eye from the outside environment while allowing vision. The location and function demand the cornea to maintain its transparency and to continuously renew its epithelial surface by replacing injured or aged cells through a rapid turnover process in which corneal stem/progenitor cells play an important role. Corneal stem/progenitor cells include mainly corneal epithelial stem cells, corneal endothelial cell progenitors and corneal stromal stem cells. Since the discovery of corneal epithelial stem cells (also known as limbal stem cells) in 1971, an increasing number of markers for corneal stem/progenitor cells have been proposed, but there is no consensus regarding the definitive markers for them. Therefore, the identification, isolation and cultivation of these cells remain challenging without a unified approach. In this review, we systematically introduce the profile of biological characterizations, such as anatomy, characteristics, isolation, cultivation and molecular markers, and clinical applications of the three categories of corneal stem/progenitor cells.

A New Practical Method Based on MRI to Individually Localize the Transverse-Sigmoid Sinus Junction in Retrosigmoid Craniotomy: A Retrospective Before-After Study.

Background: Although the asterion has long been used as a skeletal surface marker of the transverse-sigmoid sinuses junction (TSSJ) point in the retrosigmoid approach, abundant evidence shows that the relationship between asterion and TSSJ point varies greatly. In recent years, new technologies have been developed, such as neuronavigation and three-dimensional volume rendering imaging, that can guide in exposing the TSSJ point individually. However, they are not only expensive but also difficult to apply in emergency surgery. Objective: To introduce a quick, practical, and low-cost new method for locating the TSSJ point precisely. Methods: In this retrospective before-after study, the test group located the TSSJ point with our new method during a 6-month period, while the control group used asterion as a surface landmark to estimate the TSSJ during the preceding 6 months. The primary outcome is the immediate exposure rate of the TSSJ point by the initial burr hole. Results: There were 60 patients in both control and test groups as no significant difference in the general clinical characteristics of both groups were observed. The new three-step method significantly increased the TSSJ exposure rate by initial burr hole compared with the control group (96.67% vs. 53.33%, P = 0.0002). Moreover, the total bone loss and craniotomy duration were significantly reduced by the new method. Incidence of sinus injury (10% vs. 6.6%), post-operation infection (3.33% vs. 3.33%), and CSF leakage (3.33% vs. 0%) were similar. Conclusions: The novel three-step approach accurately locates TSSJ points in retrosigmoid craniotomy, reduces bone defects, saves time, and does not increase the risk of sinus injury, infection, and CSF leakage.

Impact of Temperature Change on the Fall Armyworm, Spodoptera frugiperda under Global Climate Change.

The fall armyworm (FAW), Spodoptera frugiperda (J. E. Smith, 1797), known as an important agricultural pest around the world, is indigenous to the tropical-subtropical regions in the Western Hemisphere, although its distribution has expanded over large parts of America, Africa, Asia and Oceania in the last few years. The pest causes considerable costs annually coupled with its strong invasion propensity. Temperature is identified as the dominant abiotic factor affecting herbivorous insects. Several efforts have reported that temperature directly or indirectly influences the geographic distribution, phenology and natural enemies of the poikilothermal FAW, and thus may affect the damage to crops, e.g., the increased developmental rate accelerates the intake of crops at higher temperatures. Under some extreme temperatures, the FAW is likely to regulate various genes expression in response to environmental changes, which causes a wider viability and possibility of invasion threat. Therefore, this paper seeks to review and critically consider the variations of developmental indicators, the relationships between the FAW and its natural enemies and the temperature tolerance throughout its developmental stage at varying levels of heat/cold stress. Based on this, we discuss more environmentally friendly and economical control measures, we put forward future challenges facing climate change, we further offer statistical basics and instrumental guidance significance for informing FAW pest forecasting, risk analyses and a comprehensive management program for effective control globally.

Pre-operative external ventricle drainage improves neurological outcomes for patients with traumatic intracerebellar hematomas.

Objectives: Traumatic intracerebellar hematoma (TICH) is a very rare entity with a high morbidity and mortality rate, and there is no consensus on its optimal surgical management. In particular, whether and when to place external ventricle drainage in TICH patients without acute hydrocephalus pre-operation is still controversial. Methods: A single-institutional, retrospective analysis of total of 47 TICH patients with craniectomy hematoma evacuation in a tertiary medical center from January 2009 to October 2020 was performed. Primary outcomes were mortality in hospital and neurological function evaluated by GOS at discharge and 6 months after the ictus. Special attention was paid to the significance of external ventricular drainage (EVD) in TICH patients without acute hydrocephalus on admission. Results: Analysis of the clinical characteristics of the TICH patients revealed that the odds of use of EVD were seen in patients with IVH, fourth ventricle compression, and acute hydrocephalus. Placement of EVD at the bedside can significantly improve the GCS score before craniotomy, as well as the neurological score at discharge and 6 months. Compared with the only hematoma evacuation (HE) group, there is a trend that EVD can reduce hospital mortality and decrease the occurrence of delayed hydrocephalus, although the difference is not statistically significant. In addition, EVD can reduce the average NICU stay time, but has no effect on the total length of stay. Moreover, our data showed that EVD did not increase the risk of associated bleeding and intracranial infection. Interestingly, in terms of neurological function at discharge and 6 month after the ictus, even though without acute hydrocephalus on admission, the TICH patients can still benefit from EVD insertion. Conclusion: For TICH patients, perioperative EVD is safe and can significantly improve neurological prognosis. Especially for patients whose GCS dropped by more than 2 points before the operation, EVD can significantly improve the patient's GCS score, reduce the risk of herniation, and gain more time for surgical preparation. Even for TICH patients without acute hydrocephalus on admission CT scan, EVD placement still has positive clinical significance.

Increased intracellular Cl- concentration mediates neutrophil extracellular traps formation in atherosclerotic cardiovascular diseases.

Neutrophil extracellular traps (NETs) play crucial roles in atherosclerotic cardiovascular diseases such as acute coronary syndrome (ACS). Our preliminary study shows that oxidized low-density lipoprotein (oxLDL)-induced NET formation is accompanied by an elevated intracellular Cl- concentration ([Cl-]i) and reduced cystic fibrosis transmembrane conductance regulator (CFTR) expression in freshly isolated human blood neutrophils. Herein we investigated whether and how [Cl-]i regulated NET formation in vitro and in vivo. We showed that neutrophil [Cl-]i and NET levels were increased in global CFTR null (Cftr-/-) mice in the resting state, which was mimicked by intravenous injection of the CFTR inhibitor, CFTRinh-172, in wild-type mice. OxLDL-induced NET formation was aggravated by defective CFTR function. Clamping [Cl-]i at high levels directly triggered NET formation. Furthermore, we demonstrated that increased [Cl-]i by CFTRinh-172 or CFTR knockout increased the phosphorylation of serum- and glucocorticoid-inducible protein kinase 1 (SGK1) and generation of intracellular reactive oxygen species in neutrophils, and promoted oxLDL-induced NET formation and pro-inflammatory cytokine production. Consistently, peripheral blood samples obtained from atherosclerotic ApoE-/- mice or stable angina (SA) and ST-elevation ACS (STE-ACS) patients exhibited increased neutrophil [Cl-]i and SGK1 activity, decreased CFTR expression, and elevated NET levels. VX-661, a CFTR corrector, reduced the NET formation in the peripheral blood sample obtained from oxLDL-injected mice, ApoE-/- atherosclerotic mice or patients with STE-ACS by lowering neutrophil [Cl-]i. These results demonstrate that elevated neutrophil [Cl-]i during the development of atherosclerosis and ACS contributes to increased NET formation via Cl--sensitive SGK1 signaling, suggesting that defective CFTR function might be a novel therapeutic target for atherosclerotic cardiovascular diseases.

Platelet CFTR inhibition enhances arterial thrombosis via increasing intracellular Cl- concentration and activation of SGK1 signaling pathway.

Platelet hyperactivity is essential for thrombus formation in coronary artery diseases (CAD). Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients with cystic fibrosis elevates intracellular Cl- levels ([Cl-]i) and enhanced platelet hyperactivity. In this study, we explored whether alteration of [Cl-]i has a pathological role in regulating platelet hyperactivity and arterial thrombosis formation. CFTR expression was significantly decreased, while [Cl-]i was increased in platelets from CAD patients. In a FeCl3-induced mouse mesenteric arteriole thrombosis model, platelet-specific Cftr-knockout and/or pre-administration of ion channel inhibitor CFTRinh-172 increased platelet [Cl-]i, which accelerated thrombus formation, enhanced platelet aggregation and ATP release, and increased P2Y12 and PAR4 expression in platelets. Conversely, Cftr-overexpressing platelets resulted in subnormal [Cl-]i, thereby decreasing thrombosis formation. Our results showed that clamping [Cl-]i at high levels or Cftr deficiency-induced [Cl-]i increasement dramatically augmented phosphorylation (Ser422) of serum and glucocorticoid-regulated kinase (SGK1), subsequently upregulated P2Y12 and PAR4 expression via NF-κB signaling. Constitutively active mutant S422D SGK1 markedly increased P2Y12 and PAR4 expression. The specific SGK1 inhibitor GSK-650394 decreased platelet aggregation in wildtype and platelet-specific Cftr knockout mice, and platelet SGK1 phosphorylation was observed in line with increased [Cl-]i and decreased CFTR expression in CAD patients. Co-transfection of S422D SGK1 and adenovirus-induced CFTR overexpression in MEG-01 cells restored platelet activation signaling cascade. Our results suggest that [Cl-]i is a novel positive regulator of platelet activation and arterial thrombus formation via the activation of a [Cl-]i-sensitive SGK1 signaling pathway. Therefore, [Cl-]i in platelets is a novel potential biomarker for platelet hyperactivity, and CFTR may be a potential therapeutic target for platelet activation in CAD.

Hydromorphone vs sufentanil in patient-controlled analgesia for postoperative pain management: A meta-analysis.

BACKGROUND: Patient-controlled analgesia (PCA) is an effective method of postoperative pain, there have been many studies performed that have compared the efficacy of hydromorphone with continuous sufentanil. The purpose of this systematic review is to compare the efficacy and safety of hydromorphone and sufentanil. METHODS: Seven databases were searched for controlled trials to compare the efficacy and safety of hydromorphone and sufentanil. After selecting the studies, extracting the data, and assessing study quality, the meta-analysis was performed on several of the studies with RevMan 5.3. RESULTS: Thirteen studies comprised of 812 patients were found. The pain intensity of the hydromorphone group was significantly lower than that of the sufentanil group at 12 hours. With no statistical difference at 24 to 48 hours (MD12 = -1.52, 95% CI [-2.13, -1.97], P <.05). The sedation intensity of the hydromorphone group at 12, 24, and 48 hours were lower than those of the sufentanil group, with no statistical difference (MD12 = -0.03, 95% CI [-0.18, 0.12], P > .05; MD24 = -0.20, 95% CI [-0.42, 0.03], P > .05; MD48 = -0.03, 95% CI [-0.18, 0.11)], P > .05). The PCA requests in the hydromorphone group were less than that in the sufentanil group, and there was no significant difference (RR = -0.20, 95% CI [-1.93,1.53], P > .05). The incidence of adverse events in the hydromorphone group was less than that in the sufentanil group, and there was a statistical difference: (RR = 0.61, 95% CI [0.47,0.79], P < .05). CONCLUSION: Compared with sufentanil, PCA with hydromorphone was more effective in relieving pain and PCA requests 12, 24, and 48 hours after operation, and significantly reduced the incidence of adverse events, but it did not have an advantage in sedation intensity.