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Background. The revascularization of small vessels using drug-eluting stents remains challenging. The use of the drug-coated balloon is an attractive therapeutic strategy in de novo lesions in small coronary vessels, particularly in the diabetic group. This study aimed to assess the outcomes of DCB-only angioplasty in small vessel disease. Methods. A total of 1198 patients with small vessel disease treated with DCB-only strategy were followed. Patients were divided into the diabetic and nondiabetic groups. Clinical and angiographical follow-up were organized at 12 months. The primary endpoints were target lesion failure and secondary major adverse cardiac events. Results. There was a significantly higher rate of target lesion failure among diabetic patients compared to nondiabetic [17 (3.9%) vs. 11 (1.4%), P = 0.006 ], taken separately, the rate of target lesion revascularization significantly differed between groups with a higher rate observed in the diabetic group [9 (2%) vs. 4 (0.5%), P = 0.014 ]. Diabetes mellitus remained an independent predictor for TLF (HR: 2.712, CI: 1.254–5.864, P = 0.011 ) and target lesion revascularization (HR: 3.698, CI: 1.112–12.298, P = 0.033 ) after adjustment. However, no significant differences were observed between groups regarding the target vessel myocardial infarction (0.6% vs. 0.1%, P = 0.110 ) and MACE [19 (4.4%) vs. 21 (2.7%), P = 0.120 ]. Conclusion. Drug-coated balloon-only treatment achieved lower incidence rates of TLF and MACE. Diabetes is an independent predictor for target lesion failure and target lesion revascularization at one year following DCB treatment in small coronary vessels. We observed no significant differences between groups regarding MACE in one year.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. HBV infection is an important risk factor for the tumorigenesis of HCC, given that the inflammatory environment is closely related to morbidity and prognosis. Consequently, it is of urgent importance to explore the immunogenomic landscape to supplement the prognosis of HCC. The expression profiles of immune‐related genes (IRGs) were integrated with 377 HCC patients to generate differentially expressed IRGs based on the Cancer Genome Atlas (TCGA) dataset. These IRGs were evaluated and assessed in terms of their diagnostic and prognostic values. A total of 32 differentially expressed immune‐related genes resulted as significantly correlated with the overall survival of HCC patients. The Gene Ontology functional enrichment analysis revealed that these genes were actively involved in cytokine‐cytokine receptor interaction. A prognostic signature based on IRGs (HSPA4, PSME3, PSMD14, FABP6, ISG20L2, TRAF3, NDRG1, NRAS, CSPG5, and IL17D) stratified patients into high-risk versus low-risk groups in terms of overall survival and remained as an independent prognostic factor in multivariate analyses after adjusting for clinical and pathologic factors. Several IRGs (HSPA4, PSME3, PSMD14, FABP6, ISG20L2, TRAF3, NDRG1, NRAS, CSPG5, and IL17D) of clinical significance were screened in the present study, revealing that the proposed clinical-immune signature is a promising risk score for predicting the prognosis of HCC.

Although drug-eluting stents are the most common interventional devices for patients with coronary disease, drug-coated balloons (DCBs) represent a novel therapeutic alternative in certain scenarios. This prospective, observational all-comers study explored the clinical outcomes of DCB use in patients with coronary lesions. All patients treated with DCBs were enrolled in this study, including patients with in-stent restenosis (ISR) or de novo lesions. The primary outcome was the target lesion revascularization (TLR) rate at one year. We enrolled 2306 patients with 2660 lesions and performed DCB angioplasty in 399 patients (17.3%) with ISR and 1907 patients (82.7%) with de novo lesions. During follow-up (366 ± 46 days), the TLR rate was lower in the de novo lesion group (1.31%) compared to the ISR group (7.02%) [odds ratio (OR) 0.176, 95% confidence interval (CI) 0.101–0.305, p

Two-step irradiance schedule (2-SIS) has been shown to significantly reduce pain during topical 5-aminolevulinic acid photodynamic therapy (ALA-PDT) on non-melanoma skin cancer (NMSC) and condyloma acuminatum (CA).1, 2 Few studies focused on 2-SIS pain control during PDT for acne.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies and rapidly progressive diseases. Exosomes and long noncoding RNAs (lncRNAs) are emerging as vital mediators in tumor cells and their microenvironment. However, the detailed roles and mechanisms of exosomal lncRNAs in PDAC progression remain unknown. Here, we aimed to clarify the clinical significance and mechanisms of exosomal lncRNA 01133 (LINC01133) in PDAC. We analyzed the expression of LINC01133 in PDAC and found that exosomal LINC01133 expression was high and positively correlated with higher TNM stage and poor overall survival rate of PDAC patients. Further research demonstrated that Periostin could increase exosome secretion and then enhance LINC01133 expression. In addition, Periostin increased p-EGFR, p-Erk, and c-myc expression, and c-myc could bind to the LINC01133 promoter region. These findings suggested that LINC01133 can be regulated by Periostin via EGFR pathway activity. We also observed that LINC01133 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. We subsequently evaluated the effect of LINC01133 on the Wnt/β-catenin pathway and confirmed that LINC01133 can interact with Enhancer Of Zeste Homolog 2 (EZH2) and then promote H3K27 trimethylation. This can further silence AXIN2 and suppress GSK3 activity, ultimately activating β-catenin. Collectively, these data indicate that exosomal LINC01133 plays an important role in pancreatic tumor progression, and targeting LINC01133 may provide a potential treatment strategy for PDAC.

Background This study aimed to estimate peripheral blood lymphocyte subsets and programmed death receptor-1 positive (PD-1+) proportions of T cells, and their impact on progression free survival (PFS) and radiological response in lung cancer. Methods From May 2018 to April 2020, 34patients of the Henan Tumor Hospital who were diagnosed with advanced lung cancer were recruited to this study. Peripheral blood lymphocyte subsets and PD-1+ proportions of T cells were assessed by flow cytometry before and after treatment with immune checkpoint inhibitors (ICIs). The associations among these parameters, and PFS and clinical response were estimated by survival analysis and Fishers' exact test, respectively. Results Several lymphocyte variables and biomarkers were found to be correlated with PFS and tumor response, as assessed using the Response Evaluation Criteria in Solid Tumors (RECIST). In all 34 lung cancer participants and a subgroup of 28 participants with non-small cell lung cancer (NSCLC), higher levels of natural killer (NK) cells and higher CD4+/CD8+ cell ratios before the ICIs treatment were associated with longer PFS. Moreover, CD4+ T cells were significantly correlated with radiological response in all 34 lung cancer participants. Of the 28 NSCLC participants, those with higher levels of CD4+ T cells, CD4+/CD8+ cell ratios, absolute numbers of NK cells, and lower levels of regulatory T cells (Tregs)before treatment had better tumor response. After 2 cycles of combined ICIs treatment, both the absolute numbers of CD4+ T cells and CD45+ lymphocytes were statistically associated with PFS after being adjusted for gender and neutrophil-lymphocyte ratio (NLR) [hazard ratio (HR) =0.23, P=0.015; HR=0.30, P=0.032, respectively]. The absolute numbers of CD45+, CD3+, and CD4+ T lymphocytes were associated with radiological response treated by ICIs (P=0.038). Conclusions Our results suggested that the absolute number of NK cells and CD4+/CD8+ cells ratio before treatment could predict longer PFS and better radiological response in lung cancer patients treated with ICIs combination therapy. In addition, Tregs, as well as the other parameters in lymphocyte subsets, may also predict response.

Both tumor-infiltrating lymphocytes (TIL) and PD-1+ peripheral blood lymphocytes (PBL) are enriched for tumor-reactive clones recognizing known and unknown tumor antigens. However, the relationship between the T-cell receptor-β (TCRβ) repertoires of the TILs and T cells expanded from paired PD-1+ PBLs, and whether T cells expanded from PD-1+ PBLs can be used to treat patients with cancer as TIL substitutes remain unclear. Here, we established a highly efficient protocol to prepare polyclonal T cells from PD-1+ PBLs. A functional T-cell assay and tetramer staining revealed that cells from PD-1+ PBLs were relatively enriched for tumor-reactive T cells. Furthermore, deep TCRβ sequencing data revealed that an average of 11.29% (1.32%–29.06%; P = 0.015; n = 8) tumor-resident clonotypes were found in T cells expanded from paired PD-1+ PBLs, and the mean accumulated frequency of TIL clones found in T cells expanded from PD-1+ PBLs was 35.11% (7.23%–78.02%; P = 0.017; n = 8). Moreover, treatment of four patients, who failed multiline therapy and developed acquired resistance to anti-PD-1, with autologous T cells expanded from PD-1+ PBLs combined with anti-PD-1 antibody elicited objective responses from three of them. These results indicate that T cells expanded from PD-1+ PBLs share more clones with paired TILs and could be used to treat patients with cancer as TIL substitutes. Significance: This study harnesses the tumor reactivity of PD-1+ PBLs, developing a method to expand T cells from these clones as a potential therapeutic strategy and TIL substitute in patients with cancer. See related commentary by Ladle, p. 1940

Background Renal fibrosis is a frequent pathway leading to end-stage kidney dysfunction. In addition, renal fibrosis is the ultimate manifestation of chronic kidney diseases (CKD). Long noncoding RNAs (lncRNAs) are known to be involved in occurrence of renal fibrosis, and lncRNA plasmacytoma variant translocation 1 (PVT1) has been reported to act as a key biomarker in renal diseases. However, the role of PVT1 in renal fibrosis remains unclear. Materials and methods HK-2 cells were treated with TGF-β1 to mimic renal fibrosis in vitro. Gene and protein expressions in HK-2 cells were measured by qRT-PCR and Western-blot, respectively. ELISA was used to test the level of creatinine (CR) and blood urea nitrogen (BUN) in serum of mice. Additionally, unilateral ureteral obstruction (UUO)-induced renal fibrosis mice model was established to investigate the effect of PVT1 on renal fibrosis in vivo. Results PVT1 was upregulated in TGF-β1-treated HK-2 cells. In addition, TGF-β1-induced upregulation of α-SMA and fibronectin in HK-2 cells was significantly reversed by PVT1 knockdown. Meanwhile, PVT1 bound to miR-181a-5p in HK-2 cells. Moreover, miR-181a-5p directly targeted TGF-βR1. Furthermore, miR-181a-5p antagonist could significantly reverse the anti-fibrotic effect of PVT1 knockdown. Besides, knockdown of PVT1 notably attenuated the symptom of renal fibrosis in vivo. Conclusion Knockdown of PVT1 significantly inhibited the progression of renal fibrosis in vitro and in vivo. Thus, PVT1 may serve as a potential target for the treatment of renal fibrosis.

Pancreatic cancer is the fourth most common lethal malignancy with an overall 5-year survival rate of less than 5%. ERas, a novel Ras family member, was first identified in murine embryonic stem cells and is upregulated in various cancers. However, the expression and potential role of ERas in pancreatic cancer have not been investigated. In this study, we found that ERas mRNA and protein were upregulated in pancreatic cancer tissues and cells compared with controls. Knockdown of ERas in pancreatic cancer cells by siRNA significantly decreased cell proliferation, colony formation, migration, and invasion and promoted cell apoptosis in vitro. Epithelial–mesenchymal transition (EMT) is closely related to tumor progression. We observed a significant decrease in N-cadherin expression in pancreatic cancer cells in response to ERas gene silencing by immunofluorescence assay and western blot. Furthermore, tumor growth and EMT were inhibited in xenografts derived from pancreatic cancer cells with ERas downregulation. We further investigated the regulatory mechanisms of ERas in pancreatic cancer and found that ERas may activate the Erk/Akt signaling pathway. Moreover, Erk inhibitor decreased pancreatic cancer cells proliferation and colony formation activities. Our data suggest that targeting ERas and its relevant signaling pathways might represent a novel therapeutic approach for the treatment of pancreatic cancer. Electronic supplementary material The online version of this article (10.1007/s13577-020-00401-2) contains supplementary material, which is available to authorized users.

Studies have determined that ultrasound-activated microbubbles can increase the membrane permeability of tumor cells by triggering membrane perforation (sonoporation) to improve drug loading. However, because of the distinct cavitation events adjacent to each cell, the degree of drug loading appeared to be heterogeneous. The relationship between the long-term fate trend and the degree of drug loading remains unclear. To investigate the time-lapse viability of diversity loading cells, fluorescein isothiocyanate-dextran (FITC-dextrans) was used as a molecular model mixed with 2% v/v SonoVue microbubbles (Bracco, Milan, Italy) and exposed to various peak negative pressures (0.25 MPa, 0.6 MPa, 1.2 MPa), 1 MHz frequency and 300 μs pulse duration. To select a suitable parameter, the cavitation activity was measured, and the cell analysis was performed by flow cytometry under these acoustic pressures. The sonoporated cells were then categorized into 3 sub-groups by flow cytometry according to the various fluorescence intensity distributions to analyze their long-term fate. We observed that the stable cavitation occurred at 0.25 MPa and microbubbles underwent ultra-harmonic emission, and obvious broadband signals were observed at 0.6 MPa and 1.2 MPa, suggesting the occurs of inertial cavitation. The cell analysis further showed the maximum delivery efficiency and cell viability at 0.6 MPa, and it was selected for the following experiment. The categorization displayed that the fluorescence intensity of FITC-dextrans in sub-groups 2 and 3 were approximate 5.62-fold and 19.53-fold higher than that in sub-group 1, respectively. After separation of these sub-groups, the apoptosis and necrosis ratios in all 3 sub-groups of sonoporated cells gradually increased with increasing culture time and displayed no significant difference in either the apoptosis (p > 0.05) or necrosis (p > 0.05) ratio after 6 h and 24 h of culture, respectively. Further analysis using Western blot verified that the long-term fate of sonoporated cells involves the mitochondrial signaling proteins. These results provide better insight into the role of cavitation-enhanced permeability and a critical guide for acoustic cavitation designs.

Lipopolysaccharide (LPS) is essential for successful nodulation during the symbiosis of rhizobia and legumes. However, the detailed mechanism of the LPS in this process has not yet been clearly elucidated. In this study, the effects of common bean seed exudates on the growth, lipopolysaccharide production, and lipopolysaccharide transport genes expression (lpt) of Rhizobium anhuiense were investigated. Rhizobium anhuiense exposed to exudates showed changes in LPS electrophoretic profiles and content, whereby the LPS band was wider and the LPS content was higher in R. anhuiense treated with seed exudates. Exudates enhanced cell growth of R. anhuiense in a concentration-dependent manner; R. anhuiense exposed to higher doses of the exudate showed faster growth. Seven lpt genes of R. anhuiense were amplified and sequenced. Sequences of six lpt genes, except for lptE, were the same as those found in previously analyzed R. anhuiense strains, while lptE shared low sequence similarity with other strains. Exposure to the exudates strongly stimulated the expression of all lpt genes. Approximately 6.7- (lptG) to 301-fold (lptE) increases in the transcriptional levels were observed after only 15 min of exposure to exudates. These results indicate that seed exudates affect the LPS by making the cell wall structure more conducive to symbiotic nodulation.

The structures and stereochemistry of spiromyrrhenes A–D (1–4), isolated from Commiphora exudates, were elucidated using NMR and ECD methods. They are the first examples of hepta- and octa-cyclic heterodimers possessing C35 skeletons, for the biosynthesis of which intermolecular [4 + 2] cycloaddition has been proposed. Biological studies show that they suppress tumor stemness in esophageal cancer by inactivating the Hippo/Yap pathway.

Error calibration is one of the most important factors to realize the quadri-wave lateral shearing interferometer (QWLSI) with high accuracy. The misalignment errors of QWLSI, such as the tilt of grating and the tilt of charge coupled device (CCD), will affect the measurement accuracy. The astigmatism errors induced by the tilt of grating and CCD during the alignment process of QWLSI, which are neglected in previous studies, are analyzed and presented in analytical expressions in this paper. Firstly, the additional phase difference in X and Y directions induced by the tilt of grating and CCD are analyzed using the optical wave interference theory. Representing the phase difference in the two directions and the test wavefront with the combinations of Zernike polynomials respectively, we further obtain the analytical expressions between the Zernike coefficients of the phase difference and the Zernike coefficients of the test wavefront, according to the wavefront reconstruction theory. Then the analytical expressions for the measurement errors induced by the tilt of grating and CCD, which are mainly astigmatism, can be obtained. The analytical results show that the misalignment induced astigmatism errors are inversely proportional to the shearing ratio and proportional to the tilt angle of grating and CCD. The alignment experiment of a home-made QWLSI under null test condition is conducted to verify the correctness of the theoretical analysis. With different shearing ratios for the QWLSI, the astigmatism errors, which are induced by the tilt of grating in experimental results, are consistent with the theoretical analysis results. This paper can provide technical support for the alignment of QWLSI with small shearing ratio and high precision.

Lonimacranaldes A and B (1 and 2), along with one biogenetically related intermediate, lonimacranalde C (3), were isolated from the flower buds of Lonicera macranthoides. Characterized by an iridoid structure and an additional C-6 unit with an aldehyde group, compounds 1 and 2 are the first examples of hybrid iridoids possessing an unexpected 6/5/6 fused tricyclic ring system, while compound 3 serves as an important precursor for their generation. The structures of lonimacranaldes A–C (1–3) were revealed by extensive spectroscopic and X-ray diffraction analyses. A plausible biogenetic pathway for them was proposed. Compound 3 showed anti-inflammatory activities by inhibiting the production of IL-6 on LPS-induced RAW 264.7 cells with an IC50 value of 6.33 μM.

Background Emerging evidence has indicated that exosomes serve as key regulators in acute myocardial infarction (AMI). This study was determined to investigate the effect of M2 macrophage-derived exosomes (M2-Exos) in AMI and the further mechanism. Methods M2 macrophages were induced and M2-exos were isolated and verified. The AMI mouse model was prepared by ligation of the left anterior descending coronary artery (LAD) and then intravenously injected with the isolated M2-exos. The mouse cardiac function was assessed by echocardiography. Hematoxylin and eosin (HE) staining and TUNEL assay were conducted to examine myocardial lesion and apoptosis in cardiac tissues. The expressions of associated molecules were detected by quantitative real time-PCR (qRT-PCR) and western blot. MTT assay, Flow cytometry and Dual-luciferase reporter assay were carried out to detect cell viability, apoptosis and the interaction of miRNA and the target. Result M2-Exos could promote cardiac repair in AMI mice. M2-Exos suppressed apoptosis and enhanced viability of hypoxia-induced cardiomyocytes through delivery of miR-1271−5p. SOX6 is a direct target of miR-1271−5p. miR-1271−5p decreased cardiomyocyte apoptosis induced by hypoxia and alleviated cardiac injury in AMI via down-regulating SOX6 expression. Conclusion We identified that M2-Exos could carry miR-1271−5p to reduce apoptosis of cardiomyocytes and promote cardiac repair via down-regulating SOX6.

Partial nephrectomy (PN) has been established as the standard treatment for T1 renal tumors, and postoperative hemorrhage due to vascular complications is a rare but potentially life-threatening complication reported after PN. Thus, this study evaluated the imaging and surgical factors associated with postoperative hemorrhage after PN and the clinical results of trans-arterial embolization. A retrospective review of the institutional PN database was performed from May 2012 to January 2019, revealing that we performed 810 PN procedures at our institution. In total, 12 patients were referred to the interventional radiology department for vascular complications after the procedure. Patients with and without transarterial embolization (TAE) were age- and sex-matched with 56 patients. Preoperative imaging characteristics and operative details were considered. Univariable and multivariable analyses were used to test their eventual association with the occurrence of hemorrhage. Furthermore, renal functions at diagnosis, after operation or embolization for TAE cases, and at the last follow-up were recorded. A diagnosis of hemorrhage was made at a median of 4 (range, 0-25) days after surgery. The majority of patients (50%) presented with gross hematuria. T test revealed higher renal tumor-parenchyma contact area (TPA) (P = .0407), Length-A (P = .0136), Length-P (P = .0267), operation time (P = .0214) and estimated blood loss (P = .0043) in patients with hemorrhage than in controls. Binary logistic regression analysis identified TPA (P = .048) and estimated blood loss (P = .042) as independent predictors for postoperative hemorrhage with an area under the ROC curve of 0.705 (64% sensitivity and 79% specificity). In conclusion, the occurrence of hemorrhage after PN was associated with a larger TPA and more estimated blood loss during the procedure. In patients who underwent selective TAE, renal function remained comparable with that of controls.

Background. Relative to nondiabetic patients, percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM) is associated with inferior clinical outcomes. We aimed to evaluate the outcomes of drug-coated balloon (DCB) in diabetic versus nondiabetic patients. Methods and Results. In this observational, prospective, multicenter study, we compared the outcomes of patients with and without DM after undergoing PCI with DCBs. Target lesion failure (TLF) was analyzed as primary endpoint. Secondary endpoints were the rates of target lesion revascularization (TLR), major adverse cardiovascular events (MACE), cardiac death, myocardial infarction (MI), and any revascularization. Propensity score matching was used to assemble a cohort of patients with similar baseline characteristics. Among 2,306 eligible patients, 578 with DM and 578 without DM had similar propensity scores and were included in the analyses. During follow-up ( 366 ± 46 days), compared with DM patients, patients without DM were associated with a lower yearly incidence of TLF (2.77% vs. 5.36%; OR, 1.991; 95% CI, 1.077 to 3.681; P = 0.025 ) and TLR (1.90% vs. 4.15%; OR, 2.233; 95% CI, 1.083 to 4.602; P = 0.026 ). No significant differences were observed with regards to rates of MACE (OR: 1.580, 95% CI: 0.912-2.735; P = 0.100 ), cardiac death (OR: 1.608, 95% CI: 0.523-4.946; P = 0.403 ), MI (OR: 4.042, 95% CI: 0.855-19.117; P = 0.057 ), and any revascularization (OR: 1.534, 95% CI: 0.983-2.393; P = 0.058 ). Conclusions. Diabetic patients experience higher TLF and TLR rates following DCB angioplasty without substantial increase in the risk of MACE, cardiac death, MI, or revascularization.

The perforation of plasma membrane by ultrasound-driven microbubbles (i.e., sonoporation) provides a temporary window for transporting macromolecules into the cytoplasm that is promising with respect to drug delivery and gene therapy. To improve the efficacy of delivery while ensuring biosafety, membrane resealing and cell recovery are required to help sonoporated cells defy membrane injury and regain their normal function. Blebs are found to accompany the recovery of sonoporated cells. However, the spatiotemporal characteristics of blebs and the underlying mechanisms remain unclear. With a customized platform for ultrasound exposure and 2-D/3-D live single-cell imaging, localized membrane perforation was induced with ultrasound-driven microbubbles, and the cellular responses were monitored using multiple fluorescent probes. The results indicated that localized blebs undergoing four phases (nucleation, expansion, pausing and retraction) on a time scale of tens of seconds to minutes were specifically involved in the reversibly sonoporated cells. The blebs spatially correlated with the membrane perforation site and temporally lagged (about tens of seconds to minutes) the resealing of perforated membrane. Their diameter (about several microns) and lifetime (about tens of seconds to minutes) positively correlated with the degree of sonoporation. Further studies revealed that intracellular calcium transients might be an upstream signal for triggering blebbing nucleation; exocytotic lysosomes not only contributed to resealing of the perforated membrane, but also to the increasing bleb volume during expansion; and actin components accumulation facilitated bleb retraction. These results provide new insight into the short-term strategies that the sonoporated cell employs to recover on membrane perforation and to remodel membrane structure and a biophysical foundation for sonoporation-based therapy.

Background. Sudden sensorineural hearing loss (SSNHL) is an otologic emergency and could lead to social difficulties and mental disorders in some patients. Although many studies have analyzed altered brain function in populations with hearing loss, little information is available about patients with idiopathic SSNHL. This study is aimed at investigating brain functional changes in SSNHL via functional magnetic resonance imaging (fMRI). Methods. Thirty-six patients with SSNHL and thirty well-matched normal hearing individuals underwent resting-state fMRI. Amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and functional connectivity (FC) values were calculated. Results. In the SSNHL patients, ALFF and fALFF were significantly increased in the bilateral putamen but decreased in the right calcarine cortex, right middle temporal gyrus (MTG), and right precentral gyrus. Widespread increases in FC were observed between brain regions, mainly including the bilateral auditory cortex, bilateral visual cortex, left striatum, left angular gyrus (AG), bilateral precuneus, and bilateral limbic lobes in patients with SSNHL. No decreased FC was observed. Conclusion. SSNHL causes functional alterations in brain regions, mainly in the striatum, auditory cortex, visual cortex, MTG, AG, precuneus, and limbic lobes within the acute period of hearing loss.

Accurately predicting the WHO classification of thymomas is urgently needed to optimize individualized therapeutic strategies. We aimed to develop and validate a combined radiomics nomogram for personalized prediction of histologic subtypes in patients with thymomas. A total of 182 thymoma patients were divided into training (n = 128) and test (n = 54) cohorts. Radiomics features were extracted from T2-weighted, T2-weighted fat suppression, and diffusion-weighted images to establish a radiomics signature in the training cohort. Multivariate logistic regression analysis was used to develop a combined radiomics nomogram that incorporated clinical, conventional MR imaging variables, apparent diffusion coefficient (ADC) value, and radiomics signature. The efficacy of clinical, conventional MR imaging, or ADC model was also evaluated respectively. The performances of different models were compared by receiver operating characteristic analysis and Delong test. The discrimination, calibration, and clinical usefulness of the combined radiomics nomogram were assessed. The radiomics signature, consisting of 14 features, achieved favorable predictive efficacy in differentiating low-risk from high-risk thymomas, outperforming clinical, conventional MR imaging, and ADC models. The combined radiomics nomogram incorporating tumor shape, ADC value, and radiomics signature yielded the best performance (training cohort: area under the curve [AUC] = 0.946, test cohort: AUC = 0.878). The calibration curve and decision curve analysis indicated the clinical utility of the combined radiomics nomogram. The radiomics signature is a useful tool that can be used to predict histologic subtypes of thymomas. The combined radiomics nomogram improved the individualized subtype prediction in patients with thymomas. • Fourteen robust features were selected to develop a radiomics signature for preoperative prediction of thymoma subtype. • MRI-based radiomics signature can differentiate low-risk thymomas from high-risk thymomas with favorable predictive efficacy compared with clinical, conventional MR imaging, and ADC models. • Combined radiomics nomogram based on tumor shape, ADC value, and radiomics signature could improve the individualized subtype prediction in patients with thymomas.

Background Autologous tumor-infiltrating lymphocytes (Tils) immunotherapy is a promising treatment in patients with advanced hepatocellular cancer. Although Tils treatment has shown great promise, their persistence and the efficacy after adoptive-transfer are insufficient and remain a challenge. Studies have demonstrated that IL-15 and Akt inhibitor can regulate T cell differentiation and memory. Here, we constructed S-15 (Super human IL-15), a fusion protein consisting of human IL-15, the sushi domain of the IL-15 receptor α chain and human IgG-Fc. Herein we compared the effects of S-15 with IL-2 or in combination with Akti on the expansion and activation of Tils. Methods Hepatocellular cancer tissues were obtained from 6 patients, Tils were expanded using IL-2, IL-2/S-15, IL-2/Akti or in combination IL-2/S-15/Akti. At day 10, anti-CD3 antibody was added to the culture media and expanded to day 25. The composition, exhaustion and T-cell differentiation markers (CD45RA/CCR7) were analyzed by flow cytometry. Results We found that IL-2/S-15/Akti expanded Tils and showed the highest percentage of central memory CD45RA−CCR7+ phenotype prior to anti-CD3 antibody activation and after anti-CD3 antibody activation. T cells cultured with IL-2/S-15/Akti exhibited a mixture of CD4+, CD8+, and CD3+CD4−CD8− T cells; S-15 in combination with Akt inhibitor downregulated the expression of PD-1+Tim-3+ on Tils and decreased the Tregs in Tils. Additionally, the Tils expanded in the presence of the Akt inhibitor and S-15 showed enhanced antitumor activity as indicated by the increase in IFN-γ producing tumor infiltrating CD8+ T cells and without comprising the Tils expansion. Conclusion Our study elucidates that IL-2/S-15/Akti expanded Tils and represent a viable source for the cellular therapy for patients with hepatocellular cancer.

Belamchinanes A-D (1-4), four triterpenoids with an unprecedented skeleton, were isolated from the seeds of Belamcanda chinensis and fully characterized. The structures of belamchinanes feature a 4/6/6/6/5 polycyclic system in which a four-membered carbocyclic ring bridges the C-1 and C-11 positions of a classical triterpenoid framework. A plausible pathway for the biosynthesis of 1-4 is proposed. Biological studies reveal that 1-4 dose-dependently protect age-related renal fibrosis in vitro .

Two new octanorlanostane-type triterpenes, euphraticanoids A and B (1 and 2), two new trinorsesquiterpenoids, euphraticanoids C and D (3 and 4), and eight known triterpenoids (5, 6, 8&ndash, 13) along with one steroid (7) were isolated from Populus euphratica resins. The structures of these new compounds, including their absolute configurations, were characterized by spectrocsopic, chemical, and computational methods. Biological evaluation revealed that compounds 4, 7&ndash, 9, 12, and 13 display neuroprotective activities in H2O2-induced HT-22 cells with 4, 8, and 9 occurring in a concentration-dependent manner and 7, 12, and 13 reaching the maximum effects at 20 &mu, M. Meanwhile, the neuroprotective properties of all isolates were accessed using glutamate-induced SH-SY5Y cells and disclosed that compounds 3, 4, 8, and 9 could dose-dependently protect neural cell injury in a concentration range of 10&ndash, 40 &mu, M. Finally, a brief structure&ndash, activity relationship was briefly discussed.

The aim of this study was to investigate the response of microtubule cytoskeleton of cells to the perforated membrane by acoustic cavitation. The changes of microtubule at subcellular level were observed in real time using an experimental platform of 1.5 MHz ultrasound exposure (13.33 µs duration and 0.70 MPa peak negative pressure). HUVEC cells exhibited different degrees of cell membrane perforation under acoustic cavitation. Our results show that: 1) After acoustic perforation, tubulin simultaneously depolymerizes with cell membrane rupture. 2) In the case of small membrane damage, tubulin could be rapidly repaired with cell membrane repair. 3) In the case of large membrane damage, tubulin could be repaired far behind the membrane repair. 4) After chelating extracellular calcium ions, the cell membrane and tubulin could not be repaired. These results provide clues for exploring the mechanism of cell membrane repair by ultrasound cavitation.

We report the use of 2H-NbS2 film as a novel counter electrode in perovskite solar cells fabricated with a cold isostatic pressing method. The 2H-NbS2 film, which was prepared through an exfoliation method followed by restacking from LixNbS2 powder, shows high electrical conductivity of 8.7 × 103 S cm−1 and work function of 5.20 eV. The two-dimensional transition metal dichalcogenide was used for the first time as a counter electrode in meso-structured perovskite solar cells. Through this process, we demonstrated a new alternative to noble metals. The perovskite solar cell base on the 2H-NbS2 counter electrode showed an open-circuit voltage of 1.046 V, comparable to that of gold, and a power conversion efficiency of 8.3%.

Conventional chemotherapy of pancreatic cancer (PaCa) suffers the problems of low drug permeability and inherent or acquired drug resistance. Development of new strategies for enhanced therapy still remains a great challenge. Herein, we report a new ultrasound-targeted microbubble destruction (UTMD)-promoted delivery system based on dendrimer-entrapped gold nanoparticles (Au DENPs) for co-delivery of gemcitabine (Gem) and miR-21 inhibitor (miR-21i). Methods: In this study, Gem-Au DENPs/miR-21i was designed and synthesized. The designed polyplexes were characterized via transmission electron microscopy (TEM), Gel retardation assay and dynamic light scattering (DLS). Then, the optimum exposure parameters were examined by an ultrasound exposure platform. The cellular uptake, cytotoxicity and anticancer effects in vitro were analyzed by confocal laser microscopy, spectra microplate reader, flow cytometry and a chemiluminescence imaging system. Lastly, the anticancer effects in vivo were evaluated by contrast-enhanced ultrasound (CEUS), hematoxylin and eosin (H&E) staining, TUNEL staining and comparison of tumor volume. Results: The results showed that the Gem-Au DENPs/miR-21i can be uptake by cancer cells and the cellular uptake was further facilitated by UTMD with an ultrasound power of 0.4 W/cm2 to enhance the cell permeability. Further, the co-delivery of Gem and miR-21i with or without UTMD treatment displayed 82-fold and 13-fold lower IC50 values than the free Gem, respectively. The UTMD-promoted co-delivery of Gem and miR-21i was further validated by in vivo treatment and showed a significant tumor volume reduction and an increase in blood perfusion of xenografted pancreatic tumors. Conclusion: The co-delivery of Gem and miR-21i using Au DENPs can be significantly promoted by UTMD technology, hence providing a promising strategy for effective pancreatic cancer treatments.

The slender cutting tools are employed in many conditions like boring and milling processes, but those machining processes often accompany with chatter phenomenon which will aggravate the machining efficiency and surface quality. The use of tuned mass damper (TMD) to damp slender tools is considered as a practical and effective way for chatter suppression. Generally, the TMD is embedded inside the hollow cutting tool with two spring-damping elements supporting the mass block at both ends. For the convenience of optimization calculation, the damped tool is generally modeled as an oscillation system with two equivalent lumped mass. With this simplified model, the difference of vibration displacements between two spring-damping elements is ignored. This makes it very difficult to tune the TMD to the best according to the optimization result in practical application especially when both cutting tool and TMD have a slender characteristic. This paper improves the optimal chatter control through a more accurate modeling method which considers the cutting tool as a cantilever Euler–Bernoulli beam and the TMD as a two degrees of freedom system including translation vibration and rotation vibration of the mass block. Based on the proposed model, the influences of the position and length of TMD on the optimal design parameters of two spring-damping elements are analyzed through a series of optimization. The results show that there are great differences in the chatter control mechanism of two spring-damping elements and it is very important to choose respective appropriate stiffness and damping parameters for two spring-damping elements in the TMD damped slender cutting tools. Only in this way can the TMD be tuned in practice to the best performance for chatter control of slender cutting tools. Furthermore, based on the simulation results and comparisons with other conventional modeling methods, the difference and superiority of tuning optimization are discussed and the accuracy and practicability of the proposed modeling method are verified with a designed damped end mill cutter and some impact tests.

Four previously unreported sesquiterpenoid diasteromers, arteannoides U–X (1–4), together with one new norsesquiterpenoid 5 (arteannoide Y) and one undescribed rearranged cadinene sesquiterpenoid 6 (arteannoide Z) were obtained from the dried aerial parts of Artemisia annua (Qinghao). Notably, arteannoides U–X (1–4) are four stereoisomers that possess the same molecules and the same planar connectivity, but differ from each other in configuration at a certain stereocenter. Their accurate structures were unambiguously identified and distinguished by extensive spectroscopic analyses, NMR calculations with DP4+ analysis, electronic circular dichroism (ECD) calculations and X-ray diffraction analyses. Compounds 1, 3, and 4 showed inhibitory activities against the production of inflammatory cytokines (PGE2, NO, IL-6 and TNF-α) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages.

Background T lymphocytes play an indispensably important role in clearing virus and tumor antigen. There is little knowledge about impacts of inhibitory molecules with cytokine on tumor-infiltrating CD4+ T-cells in the presence of gastric cancer (GC). This study investigated the distribution of tumor-infiltrating T-cells subset and the differentiation as well as inhibitory phenotype of T-cells from blood and tissues of GC patients. Materials and methods Patients with GC diagnosed on the basis of pre-operative staging and laparotomy findings were approached for enrollment between 2014 and 2015 at the Affiliated Cancer Hospital of Zhengzhou University, China. Phenotypic analysis based on isolation of tumor-infiltrating lymphocytes and intracellular IFN-γ staining assay is conducted. Statistical analysis is performed to show significance. Results The results showed that the percentage of CD4+ T-cells among CD3+ cells in tumors was significantly higher than that in the matched paraneoplastic tissue. CD4+ CD25high CD127low regulatory T-cells (Tregs), PD-1+, Tim-3+, and PD-1+ Tim-3+ cells were up-regulated on tumor infiltrating T-cells from patients with GC compared to their expressions on corresponding peripheral blood and peritumoral T-cells. Blockades of PD-1+ and Tim-3+ were effective in restoring tumor infiltrating T-cells’ production of interferon-gamma (IFN-γ). Combined PD-1+ and Tim-3+ inhibition had a synergistic effect on IFN-γ secretion by CD4+ T-cells. Conclusion The results suggested that the composition, inhibitors, and location of the immune infiltrate should be considered when evaluating antitumor immunotherapy. A new insight into the mechanisms underlying T cell dysfunction is provided.

A novel 7-O-7′ type mesomeric neolignan, meso-asarolignan A (1), six pairs of new neolignan enantiomers, (±)-asarolignan B–G (2a/2b, 3a/3b, 4–6, 7a/7b), along with 16 known analogues (8–23) were isolated from the rhizomes of Acorus tatarinowii. The structures of the new compounds were elucidated by extensive analysis of spectroscopic, X-ray diffraction, and computational data. Compounds 1–3 represent rare examples of naturally occurring lignans with a 7-O-7′ linkage pattern. All isolated compounds were assayed for their anti-neuroinflammatory effects on tumor necrosis factor α (TNF-α) production in an activated murine microglia cell line. Compounds 7(a/b), 14(a/b), 16, 20, and 22 reduced TNF-α levels without high cell toxicity in LPS-activated BV-2 cells.

Previous studies reported that long-term nociceptive stimulation could result in neurovascular coupling (NVC) dysfunction in brain, but these studies were based mainly on unimodal imaging biomarkers, thus could not comprehensively reflect NVC dysfunction. We investigated the potential NVC dysfunction in chronic migraine by exploring the relationship between neuronal activity and cerebral perfusion maps. The Pearson correlation coefficients between these 2 maps were defined as the NVC biomarkers. NVC biomarkers in migraineurs were significantly lower in left inferior parietal gyrus (IPG), left superior marginal gyrus (SMG) and left angular gyrus (AG), but significantly higher in right superior occipital gyrus (SOG), right superior parietal gyrus (SPG), and precuneus. These brain regions were located mainly in parietal or occipital lobes and were related to visual or sensory information processing. ALFF-CBF in right SPG was positively correlated with disease history and that in right precuneus was negatively correlated with migraine persisting time. fALFF-CBF in left SMG and AG were negatively related to headache frequency and positively related to health condition and disease history. In conclusion, multi-modal MRI could be used to detect NVC dysfunction in chronic migraine patients, which is a new method to assess the impact of chronic pain on the brain.

Four new compounds including two new sesquiterpenoid dimers, commiphoroids E (1) and F (2), a new triterpenoid (3), and a new sesquiterpenoid (4), along with three known terpenoids (5&minus, 7) were isolated from Resina Commiphora, whose structures were identified by NMR spectra, HRESIMS, and X-ray diffraction analysis. Compounds 1 and 2 both bear an O-bridge ring and feature a plausible [4 + 2] Diels&ndash, Alder cycloaddition reaction. Antimycobacterial activities show that all the tested compounds (200 &mu, M) could inhibit the growth of both sensitive and clinically multi-drug resistant (MDR) isolated strains. In addition, cellular toxicity of the isolates against human cancer cells and THP-1 monocyte cells was examined.

Zhikun Zhang,1 Rong Zhang,2 Peng Qin,3 Liwen Tan4 1Mental Health Center, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; 2Department of Psychiatry, Staff Hospital of Zhongyuan Oil Field Company, Puyang, Henan, China; 3Department of Psychiatry, Changde Rehabilitation Hospital, Changde, Hunan, China; 4Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China Purpose: This study aimed to investigate cognitive functioning, negative symptoms, and the relationships in schizophrenia (SP) pedigrees and to explore the effect of genetic loading on those endophenotypes.Patients and methods: Forty-four patients with SP, 81 first-degree non-psychotic relatives of patients from simplex and multiplex families, 14 matched control probands, and 29 first-degree relatives of the patients from communities were assessed by the vocabulary subtest (VS) of Wechsler Adult Intelligence Scale, memory span subtests of the Multiple Memory Assessment Scale (MMAS), Wisconsin Card Sorting Test (WCST), Continuous Performance Test (CPT), and Negative Scale of Positive and Negative Syndrome Scale.Results: Compared with controls, patients with SP and their relatives had worse performances in WCST and CPT, and more serious negative symptoms. Patients from multiple families performed poorly on most tests while patients from simplex families had impairments only on the parameters of CPT and WSCT as compared to control probands. Patients from multiple families differed significantly from the patients from simplex families in the digit span and word span of MMAS. After controlling for education, in comparison with relatives of control probands, relatives from multiple families showed impairments in VS, multiple domains of CPT, whereas relatives from simplex families had lower scores on the VS and more total cards and random errors in WSCT. The performances of most tests were linked to negative symptoms in patients with SP. For patients with SP, VS, correct numbers and categories in the WCST, and visual and acoustic errors in the CPT predicted 68.8% of the variability in negative symptoms.Conclusion: Our findings support that cognitive deficits and negative symptoms may be markers of hereditary susceptibility of SP and aggravate as the degree of genetic load increases. There are certain relationships between cognitive deficits and negative symptoms in patients with SP. Keywords: schizophrenia, first-degree relatives, cognitive function, negative symptoms, genetic load

Aim This study aims to determine the characteristics and severity of suicide mortality in Inner Mongolia between 2008 and 2015. Methods The death data between 2008 and 2015 was collected from the Death Registry System, 1 and the suicide mortality were calculated. Suicide mortality for total of eight years and two periods (2008–2011 and 2012–2015) were tested by the X 2 - test. Logistic regression analysis was used to test the risk of suicide between these two observation periods by gender and region. The age-specific suicide mortality was displayed through a semi-logarithmic line chart using Pearson's correlation coefficients. Then, the prohibited pesticides and proportion of organophosphorus pesticides were calculated. Results The suicide mortality (7.20/10 5 ) in 2008–2011 was higher than the suicide mortality (4.84/10 5 ) in 2012–2015 ( X 2 = 62.28, P = 0.00). Intentional self-poisoning by and exposure to pesticides 2 and intentional self-harm by hanging 3 were the two main ways of suicide, accounting for nearly 80%. The all-cause suicide mortality increased with age ( r = 0.837, P = 0.005) in 2008–2011 and ( r = 0.863, P = 0.003) in 2012–2015, and suicide mortality was higher in males than in females. Limitation The DRS did not provide the pesticides used by people who committed suicide by pesticide poisoning. Conclusion Suicide mortality dropped like a waterfall in Inner Mongolia between 2008 and 2015, and the most obvious drop was pesticide suicide.The general drop in suicide mortality, especially the drop in pesticide poisoning suicide mortality, may be attributable to social policies that benefited the residents and the prohibition of selected pesticides. Favorable policies can effectively decrease suicide mortality.

The aim of this study is to illustrate how lysosome exocytosis would be involved in membrane blebbing to reseal the perforated membrane by acoustic cavitation. Using a customized platform for 1.5-MHz ultrasound exposure (13.33-μs duration and 0.70-MPa peak negative pressure)and recording cellular responses of the Hela cervical cancer cell at the single cell level. Our results revealed: 1)The dynamics of blebbing at the perforation site induced by reversible sonoporation includes three phases: immediate expansion, long-time stationary, rapid retraction on the time scale of about hundreds of seconds. 2)The temporal-duration and spatial size of the bleb were positively correlated with the degree of the reversible sonoporation. 3)During the expansion of blebbing, lysosomes were delivered to the membrane surface by exocytosis, and then fused with membrane to facilitate resealing. These findings provide new evidence to reveal the resealing mechanism of the perforated membrane by acoustic cavitation.

A high power 755 nm continuous-wave (CW) laser with high beam quality based on the Alexandrite crystal was demonstrated. The Alexandrite lasers single-end-pumped by 638 nm laser diodes (LDs) and 532 nm solid-state laser were studied comparatively, then the CW output power, optical-to-optical conversion efficiency, and slope efficiency pumped by 638 nm LDs were 3.9 W, 19.7%, and 23.7%, respectively, while they were 2.1 W, 10.0%, and 12.9%, at nearly the same conditions except that it was pumped by 532 nm solid-state laser. The results show that the Alexandrite laser pumped with 638 nm LDs can obtain higher CW output power and higher conversion efficiency. Moreover, a CW output power of 6.2 W at 755 nm of Alexandrite laser double-end-pumped by a 638 nm LDs was achieved with the optical-to-optical conversion efficiency and the slope efficiency of 16.3% and 24.2%, respectively. The beam quality factor M2 was better than 1.47 at the CW output power of 5.0 W, which was the highest CW output power of Alexandrite laser with the diffraction limit to the best. This high power and high beam quality 755 nm Alexandrite laser provides the fundamental frequency source for the development of CW ultraviolet lasers.