Fluoride impairs vascular smooth muscle A7R5 cell lines via disrupting amino acids metabolism.

Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 µmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor.

Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction.

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

Intentional Watch and Wait or Organ Preservation Surgery Following Neoadjuvant Chemoradiotherapy Plus Consolidation CAPEOX for MRI-defined Low-risk Rectal Cancer: Findings From a Prospective Phase 2 Trial (PKUCH-R01 Trial, NCT02860234).

OBJECTIVE: To assess the efficacy and safety of intentional watch and wait (W&W) and organ preservation surgery following neoadjuvant chemoradiotherapy plus consolidation CAPEOX in magnetic resonance imaging (MRI)-defined low-risk rectal cancer. BACKGROUND: Clinical T2/early T3 rectal cancers can achieve high yield pathological complete response (ypCR) rates after chemoradiotherapy; thus, an intentional W&W or organ preservation strategy for good clinical responders in these subgroups can be further tested. METHODS: This prospective, single-arm, phase 2 trial enrolled patients with low-risk MRI prestaged rectal cancers, who concurrently received chemoradiation, followed by four 3-weekly cycles of CAPEOX regimen. Following reassessment, clinical complete response (cCR) or near-cCR patients underwent W&W/organ preservation surgery; the primary endpoint was a 3-year organ preservation rate. RESULTS: Of the 64 participants, 58 completed treatment, with 6.4% and 33.9% grade 3 to 4 toxicities in the radiotherapy and consolidation CAPEOX phases, respectively, during a median 39.5-month follow-up. Initial cCR, and non-cCR occurred in 33, 13, and 18 patients, respectively. Of the 31 cCR and 7 near-cCR cases managed by W&W, local regrowth occurred in 7; of these, 6 received salvage surgery. The estimated 2-year local regrowth rates were 12.9% [95% confidence interval (CI): 1.1%-24.7%] in cCR and 42.9% (95% CI: 6.2%-79.6%) in near-cCR cases, respectively. Eight patients received local excision, including 2 with regrowth salvage. Lung metastases occurred in 3 patients and multiple metastasis occurred in 1 patient; no local recurrence occurred. The estimated 3-year organ preservation rate was 67.2% (95% CI: 55.6%-78.8%). The estimated 3-year cancer-specific survival, non-regrowth disease-free survival, and stoma-free survival were 96.6% (95% CI: 92.1%-100%), 92.2% (95% CI: 85.5%-98.9%), and 82.7% (95% CI: 73.5%-91.9%), respectively. CONCLUSIONS: Chemoradiotherapy plus consolidation CAPEOX for MRI-defined low-risk rectal cancer can lead to high rates of organ preservation through intentional W&W or local excision. The oncologic safety of this strategy should be further tested.

Magnetic ε-Phosphorene for Sensing Greenhouse Gas Molecules.

It is critical for gas sensors that sense greenhouse gas molecules to have both good sensitivity and selectivity for water molecules in the ambient environment. Here, we study the charge transfer, IV curves, and electric field tuning of vanadium-doped monolayer ϵ-phosphorene as a sensor for NO, NO2, and H2O gas molecules via first-principle and transport calculations. We find that the paramagnetic toxic molecules of NO and NO2 have a high adsorption energy on V-ϵ-phosphorene, which originates from a large amount of charge transfer driven by the hybridisation of the localised spin states of the host with the molecular frontier orbital. Using the non-equilibrium Green's function, we investigate the IV responses with respect to the adsorption of different molecules to study the performance of gas molecule sensors. Our IV curves show a larger amount of changes in resistance of the paramagnetic NO and NO2 than nonmagnetic H2O gas molecules, suggesting both sensitivity and selectivity. Moreover, our calculations show that an applied external electric field (gate voltage) can effectively tune the amount of charge transfer. More charge transfer makes the sensor more sensitive to the molecule, while less charge transfer can reduce the adsorption energy and remove the adsorbed molecules, allowing for the repeated use of the sensor.

Ultrasonic washing as an abiotic elicitor to increase the phenolic content in fruits and vegetables: A review.

Ultrasonic washing has been widely applied to the postharvest storage of fruits and vegetables as a residue-free physical washing technology, which plays an important role in improving shelf-life, safety, and nutritional value. Phenolics are a large group of phytochemicals widespread in fruits and vegetables, and they have been considered potential protective factors against some diseases because of potent antioxidative properties. Previous studies have shown that ultrasonic washing can increase the phenolic content of fruits and vegetables immediately or during storage through the induction of plant stress responses, which is of great significance for improving the functional and nutritional value of fruits and vegetables. However, the mechanisms of ultrasound as an elicitor to improve the phenolic content remain controversial. Therefore, this review summarizes the applications of ultrasonic washing to increase the phenolic content in fruits and vegetables. Meanwhile, the corresponding physiological stress response mechanisms of the phenolic accumulation in terms of immediate stress responses (i.e., higher extractability of phenolics) and late stress responses (i.e., metabolism of phenolics) are expounded. Moreover, a hypothetical model is proposed to explain phenolic biosynthesis triggered by signaling molecules produced under ultrasound stress, including primary signal (i.e., extracellular adenosine triphosphate) and secondary signals (e.g., reactive oxygen species, Ca2+ , NO, jasmonates, and ethylene). Additionally, the techno-economic feasibility of ultrasonic washing technology is also discussed. Further, challenges and trends for further development of ultrasonic washing as an abiotic elicitor applied to the postharvest storage of fruits and vegetables are presented.

Cu-Catalyzed Diarylthiolation of Ynones with Aryl Iodides and Elemental Sulfur: An Access to Tetrasubstituted (Z)-1,2-Bis(arylthio)alkenes and Benzo[b][1,4]dithiines.

A copper-catalyzed three-component reaction of ynones, aryl iodides, and elemental sulfur via a syn-addition process is established. The reaction features operational practicality, broad substrate scope, and readily accessible scale-up synthesis by affording a series of (Z)-1,2-bis(arylthio)alkenes in good to excellent yield. Moreover, benzo[b][1,4]dithiines can be also constructed efficiently by using 1,2-diiodobenzene as the coupling partner.

Tailoring Hybrid Aluminoborate Frameworks by Incorporating Multicomponent Cadmium-Amine Complexes with Various Conformations.

Inorganic-organic hybrid aluminoborates represent a subclass of porous materials, which rely on effective construction method and structure-directing agents. Herein, we prepared a series of hybrid aluminoborates through covalent decoration of unsaturated Cd2+ complexes, whose formation take advantage of chelating amine and long-chain diamine as mixed ligands. These isolated compounds, that is, [Cd(en)(1,4-dab)0.5][AlB5O10] (1a; its analogue with discrete complex [Cd(en)(dien)H2O][AlB5O10] is denoted as 1b), [Cd(1,2-dap)1.5(1,4-dabH)0.5]{Al[B5O8(OH)2](B5O10)0.5} (2), and [Cd(en)(1,3-dap)][AlB5O10] (3) feature open frameworks (1a, 1b, and 3) or a sandwich-like porous layer (2) that are constructed by AlO4 tetrahedra and [B5O10]5-/[B5O8(OH)2]3- clusters. However, they exhibit different structural features in interconnection, channel environment, and topology as a result of diversified interactions between unsaturated complexes and aluminoborate frameworks, that is, through forming two Cd-O bonds with (i) a pair of neighboring BO3 and AlO4, (ii) the same AlO4, or (iii) the same BO3. The variation in connection mode exerts essential influence on binding effects and steric hindrance that are reflected by changes in interatomic distance, bond angle, window configuration, and interlinkage of units. In addition, the incorporation of unsaturated Cd2+ complexes endows these aluminoborate materials with photoluminescence function. Compound 3 with a noncentrosymmetric structure exhibits second harmonic generation (SHG) response approximately 0.7 times that of KDP. The preparation strategy for hybrid aluminoborates proposed here combines well molecular design with templating assembly, whose synergistic effect would be crucial for drawing a rational pathway for inorganic synthesis, especially with focus on structural and functional innovation.

A Flexible NO2 Gas Sensor Based on Single-Wall Carbon Nanotube Films Doped with a High Level of Nitrogen.

Carbon nanotubes (CNTs) are considered a promising candidate for the detection of toxic gases because of their high specific surface area and excellent electrical and mechanical properties. However, the detecting performance of CNT-based detectors needs to be improved because covalently bonded CNTs are usually chemically inert. We prepared a nitrogen-doped single-wall CNT (SWCNT) film by means of gas-phase fluorination followed by thermal annealing in NH3. The doped nitrogen content could be changed in the range of 2.9-9.9 at%. The N-doped SWCNT films were directly used to construct flexible and transparent gas sensors, which can work at a low voltage of 0.01 V. It was found that their NO2 detection performance was closely related to their nitrogen content. With an optimum nitrogen content of 9.8 at%, a flexible sensor had a detection limit of 500 ppb at room temperature with good cycling ability and stability during bending.

Analysis of factors correlated with spinal clinically isolated syndrome conversion to multiple sclerosis.

INTRODUCTION: The present study aims to explore the factors influencing spinal clinically isolated syndrome (CIS) conversion to multiple sclerosis (MS). MATERIAL AND METHODS: Sixty-one patients diagnosed with spinal CIS from January 2010 to November 2020 were divided into a non-progressing (CIS) group with 27 patients, and a conversion to MS (MS) group with 34 patients, based on whether they had converted to MS. The clinical presentation at onset, the Expanded Disability Status Scale (EDSS) before and after steroid therapy, the results of magnetic resonance imaging (MRI), the oligoclonal bands in cerebrospinal fluid (CSF-OCB), and the evoked potentials (EPs) were retrospectively analysed. RESULTS: Differences in gender and age were not statistically significant between the MS and CIS groups. The median time to relapse was 12 months for the MS group, with an upper quartile of 23.7 months, and 91.2% of patients relapsed within three years. In univariate analysis, patients with CIS beginning with sensory symptoms had a lower level of progression to MS (OR = 0.311). Patients with Kurtzke Functional Systems Scores (FSSs) of pyramidal functions ≥ 2 (OR = 3.582) and positive CSF-OCB (OR = 5.208) quickly progressed to MS. There was no significant difference between the two groups in terms of spinal cord lesions < 3 vertebral segments, gadolinium enhancing lesions, or abnormal EPs. The difference in the EDSS scores before and after steroid therapy was higher in the MS group than in the CIS group (p = 0.001). Differences of ≥ 1.5 in the EDSS scores before and after steroid therapy were risk factors for CIS conversion to MS (OR = 9.333). CONCLUSIONS: Patients with spinal CIS with pure sensory abnormalities at onset were less likely to convert to MS (OR = 0.311), and the risk factors were, in order of risk, the difference in EDSS score before and after steroid therapy (≥ 1.5; OR = 9.333), positive CSF-OCB (OR = 5.208), and those with an FSS of the pyramidal functions score ≥ 2; OR = 3.582). The present study serves as a simple 'first step'. Any potential predictors identified should be validated via future prospective studies.

Mixed Solvothermal Synthesis of Tn Cluster-Based Indium and Gallium Sulfides Using Versatile Ammonia or Amine Structure-Directing Agents.

Metal chalcogenide supertetrahedral Tn clusters are of current interest for their unique compositions and structures, which rely highly on the structure-directing agents. Herein, we report four novel Tn cluster-based indium and gallium sulfides, namely, [NH(CH3)3]4In4S10H4 (1), (NH3)4Ga4S6 (2), [NH3CH2CH3]5(NH2CH2CH3)2Ga11S19 (3), and [NH3CH2CH2OH]6Ga10S18·2NH2CH2CH2OH (4). All four compounds were solvothermally synthesized in mixed amine-ethanol solutions or deep eutectic solvent (DES), where ammonia/amine molecules play significant structure-directing roles in the speciation and crystal growth. (1) Being protonated, the trimethylamine and ethanolamine molecules surround the T2-[In4S10H4]4- clusters (for 1) and [Ga10S18]n6n- open framework (for 4), respectively, compensating for the negative charge of the inorganic moieties. (2) With the lone pair of electrons, the ammonia molecules in 2 coordinate directly to corner Ga3+ ions of the {Ga4S6} cage to give a neutral T2-(NH3)4Ga4S6 cluster. (3) For compound 3, part of the ethylamine molecules act as terminating ligands for the T1 and T3 units in the [Ga11S19(NH2CH2CH3)2]n5n- layer, while the rest act as interlamellar countercations upon protonation. Theoretical studies reveal the contributions of N, C, and H to the density of states (DOS) for 2 and 3 because of their hybrid structures that combine the ammonia/amine ligands with sulfide moieties together.

Removal of Sr2+ Ions by a High-Capacity Indium Sulfide Exchanger Containing Permeable Layers with Large Pores.

An ethylammonium-templated indium sulfide, [CH3CH2NH3]6In8S15 (InS-2), featuring anionic layers perforated with large, 24-membered rings that facilitate the accommodation of hydrated Sr2+ ions is reported. InS-2 exhibits an excellent adsorption performance toward Sr2+ with a top-ranked capacity (qm = 143.29 mg g-1), rapid kinetics, wide pH durability (3-14), ß- and γ-radiation resistances, and a facile elution.

Chromatin accessibility analysis reveals that TFAP2A promotes angiogenesis in acquired resistance to anlotinib in lung cancer cells.

Anlotinib, a multitarget tyrosine kinase inhibitor, is effective as a third-line treatment against non-small cell lung cancer (NSCLC). However, acquired resistance occurs during its administration. To understand the molecular mechanisms of anlotinib resistance, we characterized chromatin accessibility in both the parental and anlotinib-resistant lung cancer cell line NCI-H1975 through ATAC-seq. Compared with the parental cells, we identified 2666 genomic regions with greater accessibility in anlotinib-resistant cells, in which angiogenesis-related processes and the motifs of 21 transcription factors were enriched. Among these transcription factors, TFAP2A was upregulated. TFAP2A knockdown robustly diminished tumor-induced angiogenesis and partially rescued the anti-angiogenic activity of anlotinib. Furthermore, transcriptome analysis indicated that 2280 genes were downregulated in anlotinib-resistant cells with TFAP2A knocked down, among which the PDGFR, TGF-ß, and VEGFR signaling pathways were enriched. Meanwhile, we demonstrated that TFAP2A binds to accessible sites within BMP4 and HSPG2. Collectively, this study suggests that TFAP2A accelerates anlotinib resistance by promoting tumor-induced angiogenesis.

Enhanced recovery after surgery program in the patients undergoing hepatectomy for benign liver lesions.

BACKGROUND: Enhanced recovery after surgery (ERAS) has shown effectiveness in terms of reducing the hospital stay and cost. However, the benefit of ERAS in patients undergoing hepatectomy for benign liver lesions is still unclear. METHODS: ERAS was implemented in our center since March 1st, 2018. From September 2016 to February 2018, 109 patients were enrolled into the control group, and from March 2018 to June 2019, 124 patients were enrolled into the ERAS group. All the indicators related to operation, liver functions, and postoperative outcomes were included in the analysis. RESULTS: The clinicopathologic baselines were similar in these two groups. A significantly higher proportion of patients underwent laparoscopic surgery in the ERAS group. On the whole, intraoperative blood loss (100.00 mL vs. 200.00 mL, P < 0.001), blood transfusion (3.23% vs. 10.09%, P = 0.033), total bilirubin (17.10 µmol/L vs. 21.00 µmol/L, P = 0.041), D-dimer (2.08 µg/mL vs. 2.57 µg/mL, P = 0.031), postoperative hospital stay (5.00 d vs. 6.00 d, P < 0.001), and postoperative morbidity (16.13% vs. 32.11%, P = 0.008) were significantly shorter or less in the ERAS group than those in the control group. After stratified by operation methods, ERAS group showed significantly shorter postoperative hospital stay in both open and laparoscopic operation (both P < 0.001). In patients underwent open surgery, ERAS group demonstrated significantly shorter operative duration (131.76 ± 8.75 min vs. 160.73 ± 7.23 min, P = 0.016), less intraoperative blood loss (200.00 mL vs. 450.00 mL, P = 0.008) and less postoperative morbidity (16.00% vs. 44.44%, P = 0.040). CONCLUSIONS: ERAS program may be safe and effective for the patients underwent hepatectomy, especially open surgery, for benign liver lesions.

Plasma-activated water: Physicochemical properties, microbial inactivation mechanisms, factors influencing antimicrobial effectiveness, and applications in the food industry.

Novel nonthermal inactivation technologies have been increasingly popular over the traditional thermal food processing methods due to their capacity in maintaining microbial safety and other quality parameters. Plasma-activated water (PAW) is a cutting-edge technology developed around a decade ago, and it has attracted considerable attention as a potential washing disinfectant. This review aims to offer an overview of the fundamentals and potential applications of PAW in the agri-food sector. A detailed description of the interactions between plasma and water can help to have a better understanding of PAW, hence the physicochemical properties of PAW are discussed. Further, this review elucidates the complex inactivation mechanisms of PAW, including oxidative stress and physical effect. In particular, the influencing factors on inactivation efficacy of PAW, including processing factors, characteristics of microorganisms, and background environment of water are extensively described. Finally, the potential applications of PAW in the food industry, such as surface decontamination for various food products, including fruits and vegetables, meat and seafood, and also the treatment on quality parameters are presented. Apart from decontamination, the applications of PAW for seed germination and plant growth, as well as meat curing are also summarized. In the end, the challenges and limitations of PAW for scale-up implementation, and future research efforts are also discussed. This review demonstrates that PAW has the potential to be successfully used in the food industry.

[Effect of Hematopoietic Pre-B-cell Leukemia Transcription Factor Interacting Protein Knockdown on Proliferation,Cell Cycle and Apoptosis in Pancreatic Cancer Cells].

Objective To unravel the role of hematopoietic pre-B-cell leukemia transcription factor interacting protein(HPIP)in the proliferation,cell cycle,and apoptosis of pancreatic ductal adenocarcinoma(PDAC)cells. Methods The HPIP expression in PDAC tissue was determined by immunohistochemical staining.Knockdown of HPIP was accomplished in MIA PaCa-2 and BxPC-3 cell lines by transient transfection of HPIP siRNA and validated by Western blotting.Cell proliferation was assessed using the cell counting kit-8 assay and colony formation assay.Cell cycle and apoptosis were detected by flow cytometry.Western blotting was performed to detect the expression levels of cyclin D1,caspase 7,and cleaved caspase 7. Results HPIP was overexpressed in PDAC tissue compared with matched adjacent pancreatic tissue(Z=-2.060,P=0.039).Knockdown of HPIP inhibited the proliferation of MIA PaCa-2 and BxPC-3 cells(all P<0.05).Knockdown of HPIP significantly reduced the positive colonies formed by MIA PaCa-2 and BxPC-3 cells(t=4.706,P=0.009;t=9.514,P=0.000).Knockdown of HPIP decreased the proportion of S phase cells(t=7.642,P=0.001;t=2.714,P=0.051)and increased the proportion of G0/G1 phase cells(t=3.244,P=0.031;t=6.095,P=0.003)in MIA PaCa-2 and BxPC-3 cells.Meanwhile,knockdown of HPIP increased the proportions of late-phase MIA PaCa-2 and BxPC-3 cells(t=24.58,P=0.000;t=36.45,P=0.000)and the overall apoptosis rate(t=29.43,P=0.000;t=43.52,P=0.000).In MIA PaCa-2 and BxPC-3 cells,knockdown of HPIP decreased the expression level of cyclin D1(t=6.705,P=0.002;t=6.238,P=0.003)and increased the expression level of cleaved caspase 7(t=3.991,P=0.016;t=6.536,P=0.002). Conclusions HPIP is overexpressed in PDAC tissue.Knockdown of HPIP inhibits the proliferation and G0/G1 to S transition of PDAC cells.Meanwhile,knockdown of HPIP promotes the apoptosis of PDAC cells.Thus,HPIP may act as an oncogene in PDAC.

Principles and recent applications of novel non-thermal processing technologies for the fish industry-a review.

Thermal treatment is a traditional method for food processing, which can kill microorganisms but also lead to physicochemical and sensory quality damage, especially to temperature-sensitive foods. Nowadays consumers' increasing interest in microbial safety products with premium appearance, flavor, great nutritional value and extended shelf-life has promoted the development of emerging non-thermal food processing technologies as alternative or substitution to traditional thermal methods. Fish is an important and world-favored food but has a short shelf-life due to its extremely perishable characteristic, and the microbial spoilage and oxidative process happen rapidly just from the moment of capture, making it dependent heavily on post-harvest preservation. The applications of novel non-thermal food processing technologies, including high pressure processing (HPP), ultrasound (US), pulsed electric fields (PEF), pulsed light (PL), cold plasma (CP) and ozone can extend the shelf-life by microbial inactivation and also keep good sensory quality attributes of fish, which is of high interest for the fish industry. This review presents the principles, developments of emerging non-thermal food processing technologies, and also their applications in fish industry, with the main focus on microbial inactivation and sensory quality. The promising results showed great potential to keep microbial safety while maintaining organoleptic attributes of fish products. What's more, the strengths and weaknesses of these technologies are also discussed. The combination of different food processing technologies or with advanced packaging methods can improve antimicrobial efficacy while not significantly affect other quality properties under optimized treatment.

Activation of pluripotent genes in hepatic progenitor cells in the transition of nonalcoholic steatohepatitis to pre-malignant lesions.

Nonalcoholic steatohepatitis is considered as a precancerous condition. However, hepatic carcinogenesis from NASH is poorly understood. This study aims to investigate the activation of pluripotent genes (c-Myc, Oct-4, KLF-4, and Nanog) and morphogenic gene (Gli-1) in hepatic progenitor cells from patient specimens and in an animal model to determine the possibility of normal stem/progenitor cells becoming the origin of NASH-HCC. In this study, expression of pluripotent and morphogenic genes in human NASH-HCC tissues was significantly upregulated compared to adjacent non-tumor liver tissues. After feeding high-fat/calorie diet plus high fructose/glucose in drinking water (HFC diet plus HF/G) for up to 12 months, mice developed obesity, insulin resistance, and steatohepatitis with significant necroptotic inflammation and fibrotic progression, as well as occurrence of hyperplastic nodules with dysplasia; and this model represents pathohistologically as a transition from NASH to NASH-HCC in a pre-carcinomatous stage. High expression of pluripotent and morphogenic genes was immunohistochemically visualized in the dysplasia areas of mouse liver, where there were many OV-6-positive cells, indicating proliferation of HOCs in NASH with fibrotic progression. Moreover, oncogenic transcription factors (c-Myc, KLF-4, and Nanog) were co-localized in these hepatic progenitor cells. In conclusion, pluripotent and morphogenic genes may contribute to the reprogramming of hepatic progenitor cells in driving these cells to be the origin of NASH-HCC in a steatotic and inflamed microenvironment.

The Use of the Kurtosis-Adjusted Cumulative Noise Exposure Metric in Evaluating the Hearing Loss Risk for Complex Noise.

OBJECTIVE: To test a kurtosis-adjusted cumulative noise exposure (CNE) metric for use in evaluating the risk of hearing loss among workers exposed to industrial noises. Specifically, to evaluate whether the kurtosis-adjusted CNE (1) provides a better association with observed industrial noise-induced hearing loss, and (2) provides a single metric applicable to both complex (non-Gaussian [non-G]) and continuous or steady state (Gaussian [G]) noise exposures for predicting noise-induced hearing loss (dose-response curves). DESIGN: Audiometric and noise exposure data were acquired on a population of screened workers (N = 341) from two steel manufacturing plants located in Zhejiang province and a textile manufacturing plant located in Henan province, China. All the subjects from the two steel manufacturing plants (N = 178) were exposed to complex noise, whereas the subjects from textile manufacturing plant (N = 163) were exposed to a G continuous noise. Each subject was given an otologic examination to determine their pure-tone HTL and had their personal 8-hr equivalent A-weighted noise exposure (LAeq) and full-shift noise kurtosis statistic (which is sensitive to the peaks and temporal characteristics of noise exposures) measured. For each subject, an unadjusted and kurtosis-adjusted CNE index for the years worked was created. Multiple linear regression analysis controlling for age was used to determine the relationship between CNE (unadjusted and kurtosis adjusted) and the mean HTL at 3, 4, and 6 kHz (HTL346) among the complex noise-exposed group. In addition, each subject's HTLs from 0.5 to 8.0 kHz were age and sex adjusted using Annex A (ISO-1999) to determine whether they had adjusted high-frequency noise-induced hearing loss (AHFNIHL), defined as an adjusted HTL shift of 30 dB or greater at 3.0, 4.0, or 6.0 kHz in either ear. Dose-response curves for AHFNIHL were developed separately for workers exposed to G and non-G noise using both unadjusted and adjusted CNE as the exposure matric. RESULTS: Multiple linear regression analysis among complex exposed workers demonstrated that the correlation between HTL3,4,6 and CNE controlling for age was improved when using the kurtosis-adjusted CNE compared with the unadjusted CNE (R = 0.386 versus 0.350) and that noise accounted for a greater proportion of hearing loss. In addition, although dose-response curves for AHFNIHL were distinctly different when using unadjusted CNE, they overlapped when using the kurtosis-adjusted CNE. CONCLUSIONS: For the same exposure level, the prevalence of NIHL is greater in workers exposed to complex noise environments than in workers exposed to a continuous noise. Kurtosis adjustment of CNE improved the correlation with NIHL and provided a single metric for dose-response effects across different types of noise. The kurtosis-adjusted CNE may be a reasonable candidate for use in NIHL risk assessment across a wide variety of noise environments.

Capn4 contributes to tumour growth and metastasis of hepatocellular carcinoma by activation of the FAK-Src signalling pathways.

Calpain small subunit 1 (Capn4) has been identified as a major gene that promotes metastasis of hepatocellular carcinoma (HCC). However, the mechanism by which Capn4 promotes progression of HCC is not understood. In this study, we found that Capn4 expression was increased in highly metastatic HCC cell lines and in tumour tissue from HCC patients compared to healthy patient tissue. Over-expression of Capn4 in HCC cells enhanced tumour cell growth in vitro and increased invasiveness, tumourigenicity and lung metastasis in vivo. Protein microarray analyses showed that expression of multiple proteins was regulated by Capn4. Interestingly, Capn4 was found to physically associate with FAK and promoted hyperactivity of the FAK-Src signalling pathway via increased phosphorylation of specific tyrosine residues of FAK, Src and p130Cas. Knock-down of Capn4 expression suppressed the malignant behaviour of HCC cells and inhibited the FAK-Src signalling pathway. Furthermore, Capn4-mediated invasion and metastasis of HCC cells required up-regulation of matrix metalloproteinase-2 (MMP2) through activation of this signalling pathway. Our clinical data revealed that Capn4 expression correlated well with the levels of phospho-FAK, and over-expression of both Capn4 and phospho-FAK correlates with the poorest survival outcomes in HCC. In conclusion, our data showed that Capn4 can contribute to HCC growth and metastasis via activation of the FAK-Src signalling pathway and MMP2.

Scrotal sparganosis mimicking scrotal teratoma in an infant: a case report and literature review.

Sparganosis is an infection with a parasitic tapeworm larva that occurs by eating infected foods or drinking contaminated water. The larvae can migrate to a tissue or muscle in the chest, abdominal wall, extremities, eyes, brain, urinary tract, pleura, pericardium, spinal canal, or scrotum. Herein, we report a 5-month old infant with scrotal sparganosis who was initially suspected to have a scrotal inflammatory mass with a history of applying raw frog meat into the umbilicus. Preoperative ultrasound examinations and computed tomography (CT) scanning misdiagnosed the mass as a scrotal teratoma. The scrotal mass was surgically removed, and the histopathology proved it to be scrotal sparganosis. This case displays the youngest patient ever reported with scrotal sparganosis, and the first description of CT characteristics of scrotal sparganosis. A detailed medical history is necessary for patients with scrotal masses suspected of sparganosis. In addition, ultrasound and CT examinations are helpful to rule out other causes of a scrotal mass.