GATA binding protein 2 mediated ankyrin repeat domain containing 26 high expression in myeloid-derived cell lines.

BACKGROUND: Thrombocytopenia 2, an autosomal dominant inherited disease characterized by moderate thrombocytopenia, predisposition to myeloid malignancies and normal platelet size and function, can be caused by 5'-untranslated region (UTR) point mutations in ankyrin repeat domain containing 26 (ANKRD26). Runt related transcription factor 1 (RUNX1) and friend leukemia integration 1 (FLI1) have been identified as negative regulators of ANKRD26. However, the positive regulators of ANKRD26 are still unknown. AIM: To prove the positive regulatory effect of GATA binding protein 2 (GATA2) on ANKRD26 transcription. METHODS: Human induced pluripotent stem cells derived from bone marrow (hiPSC-BM) and urothelium (hiPSC-U) were used to examine the ANKRD26 expression pattern in the early stage of differentiation. Then, transcriptome sequencing of these iPSCs and three public transcription factor (TF) databases (Cistrome DB, animal TFDB and ENCODE) were used to identify potential TF candidates for ANKRD26. Furthermore, overexpression and dual-luciferase reporter experiments were used to verify the regulatory effect of the candidate TFs on ANKRD26. Moreover, using the GENT2 platform, we analyzed the relationship between ANKRD26 expression and overall survival in cancer patients. RESULTS: In hiPSC-BMs and hiPSC-Us, we found that the transcription levels of ANKRD26 varied in the absence of RUNX1 and FLI1. We sequenced hiPSC-BM and hiPSC-U and identified 68 candidate TFs for ANKRD26. Together with three public TF databases, we found that GATA2 was the only candidate gene that could positively regulate ANKRD26. Using dual-luciferase reporter experiments, we showed that GATA2 directly binds to the 5'-UTR of ANKRD26 and promotes its transcription. There are two identified binding sites of GATA2 that are located 2 kb upstream of the TSS of ANKRD26. In addition, we discovered that high ANKRD26 expression is always related to a more favorable prognosis in breast and lung cancer patients. CONCLUSION: We first discovered that the transcription factor GATA2 plays a positive role in ANKRD26 transcription and identified its precise binding sites at the promoter region, and we revealed the importance of ANKRD26 in many tissue-derived cancers.

CPSF3 regulates alternative polyadenylation of CNIH2 to promote esophageal squamous cell carcinoma progression.

Alternative polyadenylation (APA), an important post-transcriptional regulatory mechanism, is aberrantly activated in cancer，but how APA functions in tumorigenesis remains elusive. We analyzed APA events in RNA-seq data in TCGA and reported 3'UTR alterations associated with esophageal squamous cell carcinoma (ESCC) patient prognosis and gene expression changes involving loss of tumor-suppressive miRNA binding sites. Moreover, we investigated the expression and function of cleavage and polyadenylation specific factor 3 (CPSF3), a key APA regulator in ESCC. By immunohistochemistry and qRT-PCR, we found that CPSF3 was highly expressed in ESCC tissues and associated with poor patient prognosis. Overexpression of CPSF3 enhanced, while knockdown of CPSF3 inhibited ESCC cell proliferation and migration in vitro and in vivo, as determined by colony formation, transwell assays and animal experiments. Iso-Seq and RNA-seq data analysis indicated that knockdown of CPSF3 favored use of the distal poly (A) site in the 3'UTR of Cornichon family AMPA receptor auxiliary protein 2 (CNIH2), resulting in a long-3'UTR CNIH2 isoform that produced less CNIH2 protein due to miR-125a-5p targeting and downregulating CNIH2 mRNA through a miR-125a-5p binding site in the long CNIH2 mRNA 3'UTR. Moreover, CPSF3-induced ESCC tumorigenicity was mediated by CNIH2. Taken together, CPSF3 promotes ESCC progression by upregulating CNIH2 expression through loss of miR-125a-5p-mediated CNIH2 repression through alternative splicing and polyadenylation of the CNIH2 mRNA 3'UTR.

Structural Characterization and Physiological Role of Bombyx mori Fibroinase in the Silk Gland Development.

Silkworm is a highly valuable insect that produces silk through secretion by a silk gland. Within this gland, a type of cathepsin L protease called Fibroinase was identified as an enzyme for hydrolyzing the primary components of silk, including fibroin and sericin. Here, we determined the crystal structure of Fibroinase fromBombyx mori at a resolution of 1.56 Å. Comparative structural analysis revealed that Fibroinase adopted a similar structural pattern with papain-type cathepsin, consisting of an N-terminal domain and a C-terminal domain. The interface between the domains forms a substrate-binding cleft, where the E64 inhibitor noncovalently binds in a novel manner. Additionally, computational simulations combined with biochemical analysis allowed us to define the binding mode and inhibition mechanism of physiological inhibitor Bombyx cysteine protease inhibitor (BCPI) with Fibroinase. Moreover, the expression profiles and RNA interference of Fibroinase indicated its critical role in removing silk proteins in the silk gland lumen and the destruction of silk gland tissue during the larval-pupal metamorphosis. These findings enhance our understanding of the structural and biochemical features of Fibroinase and its inhibitors, while also providing evidence for the physiological role of Fibroinase in silk gland development.

The MHC Class II Antigen-Processing and Presentation Pathway Is Dysregulated in Type 1 Diabetes.

Peptide loading of MHC class II (MHCII) molecules is facilitated by HLA-DM (DM), which catalyzes CLIP release, stabilizes empty MHCII, and edits the MHCII-bound peptide repertoire. HLA-DO (DO) binds to DM and modulates its activity, resulting in an altered set of peptides presented at the cell surface. MHCII-peptide presentation in individuals with type 1 diabetes (T1D) is abnormal, leading to a breakdown in tolerance; however, no direct measurement of the MHCII pathway activity in T1D patients has been performed. In this study, we measured MHCII Ag-processing pathway activity in humans by determining MHCII, MHCII-CLIP, DM, and DO levels by flow cytometry for peripheral blood B cells, dendritic cells, and monocytes from 99 T1D patients and 97 controls. Results showed that MHCII levels were similar for all three APC subsets. In contrast, MHCII-CLIP levels, independent of sex, age at blood draw, disease duration, and diagnosis age, were significantly increased for all three APCs, with B cells showing the largest increase (3.4-fold). DM and DO levels, which usually directly correlate with MHCII-CLIP levels, were unexpectedly identical in T1D patients and controls. Gene expression profiling on PBMC RNA showed that DMB mRNA was significantly elevated in T1D patients with residual C-peptide. This resulted in higher levels of DM protein in B cells and dendritic cells. DO levels were also increased, suggesting that the MHCII pathway maybe differentially regulated in individuals with residual C-peptide. Collectively, these studies show a dysregulation of the MHCII Ag-processing pathway in patients with T1D.

Formation and Evolution Mechanism of Intermetallic Compounds of Friction Stir Lap Welded Steel/Aluminum Joints.

Interfacial layers with brittle intermetallic compounds (IMC) greatly influence the performance of steel-aluminum friction stir lap welding (FSLW) joints. Thus, the formation and evolution of IMC between 7075-T6 aluminum alloy and galvanized DP590 steel in steel-aluminum FSLW joints were investigated. An FSLW numerical model was developed using the computational fluid dynamics method to analyze the interface temperature between the aluminum alloy and steel. Scanning electron microscopy (SEM) was conducted to observe the microstructure characterization and measure the IMC thickness. Phases among different joint zones were analyzed by X-ray diffraction (XRD) and energy dispersive spectroscopy (EDS). IMC layer formation was predicted by the effective Gibbs free energy model presented in this paper according to thermodynamic principles. The Monte Carlo method was utilized to predict the thickness of IMC layers. It was found that the IMC layer at the interface of the welded joint is composed of Fe2Al5, FeAl3, and Al-Zn eutectic. The IMC thickness decreased from 4.3 µm to 0.8 µm with the increasing welding speed, which was consistent with the Monte Carlo simulation results.

Detecting salivary host and microbiome RNA signature for aiding diagnosis of oral and throat cancer.

OBJECTIVE: Oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC) can go undetected resulting in late detection and poor outcomes. We describe the development and validation of CancerDetect for Oral & Throat cancer™ (CDOT), to detect markers of OSCC and/or OPSCC within a high-risk population. MATERIAL AND METHODS: We collected saliva samples from 1,175 individuals who were 50 years or older, or adults with a tobacco use history. 945 of those were used to train a classifier using machine learning methods, resulting in a salivary microbial and human metatranscriptomic signature. The classifier was then independently validated on the 230 remaining samples prospectively collected and unseen by the classifier, consisting of 20 OSCC (all stages), 76 OPSCC (all stages), and 134 negatives (including 14 pre-malignant). RESULTS: On the validation cohort, the specificity of the CDOT test was 94 %, sensitivity was 90 % for participants with OSCC, and 84.2 % for participants with OPSCC. Similar classification results were observed among people in early stage (stages I & II) vs late stage (stages III & IV). CONCLUSIONS: CDOT is a non-invasive test that can be easily administered in dentist offices, primary care centres and specialised cancer clinics for early detection of OPSCC and OSCC. This test, having received FDA's breakthrough designation for accelerated review, has the potential to enable early diagnosis, saving lives and significantly reducing healthcare expenditure.

Investigation of Pre-Aged Hardening Single-Point Incremental Forming Process and Mechanical Properties of AA6061 Aluminum Alloy.

Currently, the single-point incremental forming process often faces issues such as insufficient formability of the sheet metal and low strength of the formed parts. To address this problem, this study proposes a pre-aged hardening single-point incremental forming (PH-SPIF) process that offers several notable benefits, including shortened procedures, reduced energy consumption, and increased sheet forming limits while maintaining high mechanical properties and geometric accuracy in formed components. To investigate forming limits, an Al-Mg-Si alloy was used to form different wall angles during the PH-SPIF process. Differential scanning calorimetry (DSC) and transmission electron microscopy (TEM) analyses were conducted to characterize microstructure evolution during the PH-SPIF process. The results demonstrate that the PH-SPIF process can achieve a forming limit angle of up to 62°, with excellent geometric accuracy, and hardened component hardness reaching up to 128.5 HV, surpassing the strength of the AA6061-T6 alloy. The DSC and TEM analyses reveal numerous pre-existing thermostable GP zones in the pre-aged hardening alloys, which undergo transformation into dispersed ß" phases during the forming procedure, leading to the entanglement of numerous dislocations. The dual effects of phase transformation and plastic deformation during the PH-SPIF process significantly contribute to the desirable mechanical properties of the formed components.

Artificial intelligence-assisted ultrasound image analysis to discriminate early breast cancer in Chinese population: a retrospective, multicentre, cohort study.

Background: Early diagnosis of breast cancer has always been a difficult clinical challenge. We developed a deep-learning model EDL-BC to discriminate early breast cancer with ultrasound (US) benign findings. This study aimed to investigate how the EDL-BC model could help radiologists improve the detection rate of early breast cancer while reducing misdiagnosis. Methods: In this retrospective, multicentre cohort study, we developed an ensemble deep learning model called EDL-BC based on deep convolutional neural networks. The EDL-BC model was trained and internally validated on B-mode and color Doppler US image of 7955 lesions from 6795 patients between January 1, 2015 and December 31, 2021 in the First Affiliated Hospital of Army Medical University (SW), Chongqing, China. The model was assessed by internal and external validations, and outperformed radiologists. The model performance was validated in two independent external validation cohorts included 448 lesions from 391 patients between January 1 to December 31, 2021 in the Tangshan People's Hospital (TS), Chongqing, China, and 245 lesions from 235 patients between January 1 to December 31, 2021 in the Dazu People's Hospital (DZ), Chongqing, China. All lesions in the training and total validation cohort were US benign findings during screening and biopsy-confirmed malignant, benign, and benign with 3-year follow-up records. Six radiologists performed the clinical diagnostic performance of EDL-BC, and six radiologists independently reviewed the retrospective datasets on a web-based rating platform. Findings: The area under the receiver operating characteristic curve (AUC) of the internal validation cohort and two independent external validation cohorts for EDL-BC was 0.950 (95% confidence interval [CI]: 0.909-0.969), 0.956 (95% [CI]: 0.939-0.971), and 0.907 (95% [CI]: 0.877-0.938), respectively. The sensitivity values were 94.4% (95% [CI]: 72.7%-99.9%), 100% (95% [CI]: 69.2%-100%), and 80% (95% [CI]: 28.4%-99.5%), respectively, at 0.76. The AUC for accurate diagnosis of EDL-BC (0.945 [95% [CI]: 0.933-0.965]) and radiologists with artificial intelligence (AI) assistance (0.899 [95% [CI]: 0.883-0.913]) was significantly higher than that of the radiologists without AI assistance (0.716 [95% [CI]: 0.693-0.738]; p < 0.0001). Furthermore, there were no significant differences between the EDL-BC model and radiologists with AI assistance (p = 0.099). Interpretation: EDL-BC can identify subtle but informative elements on US images of breast lesions and can significantly improve radiologists' diagnostic performance for identifying patients with early breast cancer and benefiting the clinical practice. Funding: The National Key R&D Program of China.

Participation in Household Physical Activity Lowers Mortality Risk in Chinese Women and Men.

The health benefits of sport and physical exercise (SPE) have been well documented, while the influence of household physical activity (HPA) on health has received much less research attention. This study aims to provide epidemiologic insight into the role HPA plays in the development of all-cause, cardiovascular disease (CVD), respiratory disease (RESP), and cancer mortality in a nationwide cohort of Chinese adults. We conceived a prospective cohort comprising 30,791 participants aged ≥16 years from 25 provinces of China using data derived from baseline (2010) and 4 waves of follow-up (2012-2018) investigations of the China Family Panel Studies. Self-reported times of HPA and SPE were collected by interviewing participants with a standard questionnaire. Cox proportional hazard models were used to assess the associations of HPA and SPE with all-cause, CVD, RESP, and cancer mortality, adjusting for demographic and socioeconomic factors, lifestyle behaviors, and health status. A restricted cubic spline smoother was used to investigate the dose-response relationships of HPA and SPE with mortality outcomes. Sex subgroup analyses were conducted to examine the potential effect disparity between men and women. To investigate the interactive effects of HPA and SPE, we calculated the relative excess risk due to the interaction and attributable proportion of additive effects to the total observed effects. During a median follow-up of 7.2 years, a total of 1,649 deaths occurred, with 209 cases from CVD, 123 from RESP, and 323 from cancer. HPA was identified to be associated with reduced mortality outcomes, suggesting remarkably reduced risks of 43-60% in all-cause mortality, 42-50% in CVD mortality, 36-71% in RESP mortality, and 38-46% in cancer mortality. In general, higher levels of HPA tended to be associated with lower risks. An approximately inverted J-shape association was identified between HPA and all-cause and cause-specific mortality, suggesting strong evidence for potential nonlinearity. Women performing HPA had a lower risk of all-cause, CVD, and cancer mortality. We did not identify significant evidence for additive interaction between HPA and SPE. HPA is independently associated with a reduced risk of mortality in Chinese women and men. More biological studies are needed to validate our findings and clarify the mechanisms underlying the association.

Smart Phototheranostics based on Carbon Nanohorns for Precise Imaging-Guided Post-PDT toward Residual Tumor Cells after Initial Phototherapy.

As promising photonic material, phototheranostics can be activated in the laser irradiation range of tumor with sensitivity and spatiotemporal precision. However, it is difficult to completely eradicate solid tumors due to their irregularity and limited laser irradiation area. Herein, multi-stimulus responsive HA-Ce6@SWNHs were constructed with single-walled carbon nanohorns (SWNHs) and chlorine e6 (Ce6) modified hyaluronic acid (HA) via non-covalent binding. This SWNHs-based phototheranostics not only exhibited water dispersion but also could target tumor and be activated by near-infrared light for photodynamic therapy (PDT) and photothermal therapy (PTT). Additionally, HA-Ce6@SWNHs could be degraded by hyaluronidase in residual tumor cells, causing HA-Ce6 to fall off the SWNHs surfaces to restore autofluorescence, thus precisely guiding the programmed photodynamic treatments for residual tumor cells after the initial phototherapy. Thus, this work provides a rationally designed multiple-stimulus-response strategy to develop smart SWNHs-based phototheranostics for precise PDT/PTT and post-treatment imaging-guided PDT of residual tumor cells.

Diagnostic efficacy of targeted high-throughput sequencing for lower respiratory infection in preterm infants.

OBJECTIVE: To examine the pathogen diagnostic performance of targeted high-throughput next-gen sequencing (tNGS) in respiratory infectious diseases in preterm infants using dynamic follow-up. METHODS: Clinical samples of respiratory secretions were consecutively collected from 20 preterm infants weekly for 5 weeks, during which 10 developed bronchopulmonary dysplasia. Pathogen identification from these collected specimens was performed by both conventional cultivation and tNGS. RESULTS: We found that targeted next-generation sequencing shared a 90.9% full or partial consistency for lower respiratory pathogen detection with the traditional culture-based approach, and increased the detection rate by 105.9%. Moreover, most of the pathogens identified by tNGS were diminished in patients after treatment. CONCLUSION: This study reveals the high sensitivity and performance of targeted high-throughput sequencing for respiratory infectious disease diagnosis and pathogen identification. The trial registry number is NCT03850457, and the trial URL is https://clinicaltrials.gov/ct2/show/NCT03850457.

HSPB1 overexpression improves hypoxic-ischemic brain damage by attenuating ferroptosis in rats through promoting G6PD expression.

Heat-shock protein B (HSPB1) has a neuroprotective effect on brain injury and is a negative regulator of ferroptosis. Therefore, we infer that HSPB1 plays a protective role in hypoxic-ischemic (HI) brain damage by inhibiting ferroptosis. A neonatal rat model of hypoxic-ischemic (HI) brain damage was established. HSPB1 overexpression plasmid and the negative control were injected into the lateral ventricle of rats 48 h before HI brain damage surgery. HSPB1 and glucose-6-phosphate dehydrogenase (G6PD) levels, infarction rate, iron accumulation, apoptosis, and ferroptosis-related markers were estimated with the assistance of qRT-PCR, 2,3,5-triphenyl tetrazolium chloride (TTC) staining, Prussian blue staining, iron assay kit, TUNEL staining, and Western blot. In vitro, after transfection, HSPB1 and G6PD levels, oxygen-glucose deprivation (OGD)-mediated hippocampal neuron cell viability, apoptosis, iron content, and ferroptosis-related markers were assessed using qRT-PCR, MTT, flow cytometry, iron assay kit, and Western blot. HSPB1 and G6PD were overexpressed in the hippocampus tissues of HI rats. High expression of HSPB1 in HI rats lessened infarction rate and ferritin level, hindered iron accumulation and apoptosis, and promoted GPX4, SLC7A11, and TFR1 levels. In OGD-mediated hippocampal neuron cells, HSPB1 upregulation intensified the viability and repressed apoptosis and ferroptosis, whereas G6PD silencing reversed the effects of HSPB1 upregulation. We documented that HSPB1 overexpression unleashes neuroprotective effects via modulating G6PD expression, which offers a novel target for the prevention and treatment of HI brain damage.NEW & NOTEWORTHY HSPB1 and G6PD were overexpressed in the hippocampus tissues of HI rats. High expression of HSPB1 in HI rats mitigated infarction rate and iron accumulation. HSPB1 overexpression reduced ferritin level, attenuated apoptosis, yet augmented GPX4, SLC7A11, and TFR1 levels in the hippocampus tissues of HI rats. G6PD deletion impaired the protective role of HSPB1 overexpression against HI brain damage-induced ferroptosis.

Review of lignans from 2019 to 2021: Newly reported compounds, diverse activities, structure-activity relationships and clinical applications.

Lignans, with various biological activities, such as antitumor, antioxidant, antibacterial, and antiviral activities, are widely distributed in nature and mainly exist in the xylem of plants. In this paper, we summarized the structures and bioactivities of lignans reported in recent years (2019-2021) from five parts, including (1) a summary and classification of newly reported compounds; (2) the pharmacological activities of lignans; (3) molecular resources and activity distribution; (4) the structure-activity relationships; and (5) the clinical application of lignans. This review covers all undescribed compounds that were reported within the covered period of time and all bioactivity data about previously isolated lignans. The distribution of lignans in different plants and families is visualized, which improves the efficiency of searching for specific molecules. The diverse activities of different types of lignans provide an important reference for the rapid screening of these compounds. Discussion about the structure-activity relationships of lignans provides a direction for the structural modification of skeleton molecules. Combined with the clinical application of such molecules, this work will provide a valuable reference for pharmaceutical chemists.

Changes in tumor suppressors and inflammatory responses during hydrogen peroxide-induced senescence in rat fibroblasts.

Cell proliferation and senescence are processes induced by oxidative stress. In this study, we aimed to establish a cellular model of rapid proliferation and senescence of rat tail-tip fibroblasts by hydrogen peroxide (H2O2), a well-known oxidant. On this basis, changes in oxidative stress, inflammatory response and cell cycle of fibroblasts were studied. After H2O2 treatment, cell counting and flow cytometry results showed that 50 µM of H2O2 for 12 h and 100 µM for 8 h effectively promoted fibroblast proliferation, while 500 µM rapidly led to cell cycle arrest. In addition, stimulation with H2O2 at a concentration of 50 µM also promoted the inflammatory effects of the cells. At a concentration of 100 µM H2O2, the cellular antioxidant system began to collapse at 8 h and began to affect cellular activity. 500 µM of H2O2 at 4 h the levels of senescence-associated ß-galactosidase, a marker of senescence and oxidative stress, were almost positive in fibroblasts. In addition, we found that the risk of fibroblasts carcinogenesis increased with increased H2O2 stimulation. The results of this study indicate that H2O2 can cause rapid proliferation and senescence of fibroblasts and that its mechanism of action may be mainly through influencing cellular antioxidant systems, cellular inflammatory responses and cell cycle.

PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8+T cells and promoting fatty acid metabolism.

BACKGROUND: The phosphatidylinositol 3-kinase (PI3K) is frequently hyperactivated in cancer and plays important roles in both malignant and immune cells. The effect of PI3Kα inhibitors on the tumor microenvironment (TME) remains largely unknown. Here, we investigated the modulation of the TME by a clinical PI3Kα-specific inhibitor CYH33. METHODS: The activity of CYH33 against a panel of murine tumors in the immune-competent context or athymic mice was detected. Single-cell RNA sequencing and multi-parameter flow cytometry were performed to determine the immune profiling of TME. The effect of CYH33 on immune cells was conducted with primary murine cells. RESULTS: CYH33 exhibited more potent antitumor activity in immune-competent context. CYH33 enhanced the infiltration and activation of CD8+T and CD4+T cells, while attenuating M2-like macrophages and regulatory CD4+T cells. Increase in memory T cells was confirmed by the induction of long-term immune memory on CYH33 treatment. Mechanistically, CYH33 relieved the suppressed expansion of CD8+T cells via preferential polarization of the macrophages to the M1 phenotype. CYH33 promoted fatty acid (FA) metabolism in the TME, while FA enhanced the activity of CD8+T cells in vitro. The combination of CYH33 with the FA synthase (FASN) inhibitor C75 synergistically inhibited tumor growth with enhanced host immunity. CONCLUSIONS: CYH33 induces immune activation and synergizes with FASN inhibitor to further promote the antitumor immunity, which gains novel insights into how PI3K inhibitors exert their activity by modulating TME and provides a rationale for the concurrent targeting of PI3K and FASN in breast cancer treatment.

pVHL promotes lysosomal degradation of YAP in lung adenocarcinoma.

Yes-associated protein (YAP) is a vital transcriptional co-activator that activates cell proliferation and evasion of apoptosis for the promotion of tumorigenesis. The von Hippel-Lindau tumor suppressor protein (pVHL), as a critical component of E3 ubiquitin ligase, targets various substrates to regulate tumor progression. However, the precise molecular mechanisms of pVHL during tumorigenesis remain largely unclear. Herein, we found that there was a significant negative correlation between pVHL and YAP at protein level in the TCGA-LUAD dataset and our cohort. Over-expression of pVHL decreased YAP protein expression and reduced its transcriptional activity. Further study indicated that pVHL did not affect YAP mRNA level but decreased YAP protein stability in a lysosome-dependent manner. In addition, the pVHL-mediated degradation of YAP inhibited cellular proliferation, migration, and enhanced chemosensitivity to cisplatin in lung adenocarcinoma cells. Interestingly, the pVHL-mediated YAP degradation was blocked by elevated O-GlcNAcylation. Collectively, our findings demonstrate that pVHL modulates the lysosomal degradation of YAP, and may provide more clues to better understanding the tumor suppressive effects of pVHL.

Up-regulation of FUT8 inhibits TGF-ß1-induced activation of hepatic stellate cells during liver fibrogenesis.

Liver fibrosis is a continuous wound healing response caused by chronic liver injury, and the activation of hepatic stellate cells (HSCs) is considered as the main event for it. Core fucosylation catalyzed by FUT8 refers to adding the fucosyl moiety to the innermost GlcNAc residue of N-linked oligosaccharides and is involved in many biological processes such as cell differentiation, migration, and signaling transduction. Aberrant core fucosylation is associated with a variety of diseases including cardiovascular disease, tumors and neuroinflammation, but much less is understood in liver fibrosis. Herein, we reported FUT8 mRNA level was increased in patients with liver fibrosis from GEO database and positively correlated with fibrosis progression. FUT8 expression and the core fucosylation were also elevated in TAA-induced mouse liver fibrosis model, and were mainly distributed in the fibrous septum of mouse liver. TGF-ß1, as the most pro-fibrogenic cytokine, could promote the expression of FUT8 and total core fucosylation levels in HSCs in vitro. However, up-regulation of FUT8 in turn inhibited TGF-ß1-induced trans-differentiation, migration and pro-fibrogenic signaling pathways in HSCs. In conclusion, our results suggest that the up-regulation of FUT8 inhibits TGF-ß1-induced HSC activation in a negative feedback loop, and provide potential new therapeutic strategy for liver fibrosis by targeting FUT8.

Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells.

Phosphoinositide-3 kinase alpha-specific inhibitors (PI3Kαi) displayed promising potential for the treatment of esophageal squamous cell carcinoma (ESCC) with frequent activation in PI3K signaling. However, acquired resistance is likely to develop and limit the efficacy of PI3Kαi like other targeted therapies. To identify genomic adaptation to PI3Kαi, we applied whole-genome sequencing and detected gene mutation and amplification in four lines of ESCC cells established with adapted resistance to a novel PI3Kαi CYH33. Particularly, HRASG12S mutation was found in KYSE180C cells. Overexpression of HRASG12S in ESCC parental cells rendered resistance to CYH33. By contrast, down-regulation of HRASG12S restored the sensitivity of KYSE180C1 cells to CYH33, and combination of CYH33 and MEK162 displayed synergistic effect against KYSE180C1 cells and xenografts. Furthermore, elevated mTORC1, mitogen-activated protein kinase (MAPK), and c-Myc signaling pathways were found in resistant cells by RNA sequencing and combination of CYH33 and RAD001, MEK162, or OTX015 overcame the resistance to CYH33, which was accompanied with enhanced inhibition on S6, extracellular signal-regulated kinase 1 (ERK), or c-Myc, respectively. Overall, we characterized the adaptations to PI3Kαi in ESCC cells and identified combinatorial regimens that may circumvent resistance.

Modulation of the 5-HT3A receptor current by desacylbaldrinal.

The serotonin (5-hydroxytryptamine) type 3 receptor is an important target in the control of digestive dysfunction such as anorexia and bulimia, and 5-HT3 receptor antagonists are effective against eating disorder and the early-phase chemotherapy and radiotherapy evoked vomiting. Our previous research of Valeriana jatamansi revealed the presence of iridoids, which showed potent antitumor activities. Here, we explored the effects of 10π aromatic iridoid desacylbaldrinal isolated from V. jatamansi on the 5-HT3 receptor current. We performed whole cell recordings of 5-HT3A receptor currents in the presence of the compound. The result indicated that desacylbaldrinal inhibited the 5-HT-mediated 5-HT3A receptor current.

A case report of neonatal orbital peripheral primitive neuroectodermal tumor and literature review.

Primitive neuroectodermal tumors are rare malignant neoplasms from primitive neural crest cells. Most primitive neuroectodermal tumors occur in the central and sympathetic nervous systems. We report a Chinese newborn patient presenting a huge unilateral proptosis after birth, diagnosed as orbital peripheral primitive neuroectodermal tumor by histopathology and immunohistochemistry. Our case is the first reported case of orbital peripheral primitive neuroectodermal tumor diagnosed in the newborn period. The clinical manifestations, radiological findings, histopathologic, and immunohistochemistry results are described in detail. We also conducted a literature search focusing on primitive neuroectodermal tumor of the orbit. To the best of our knowledge, all articles with English abstracts were reviewed here.