Floroindole confers protection against cecal ligation and puncture-induced sepsis via inhibition of NF-kB p65 phosphorylation

Purpose: To investigate the protective effect of floroindole against cecal ligation and puncture (CLP)- induced sepsis, as well as the underlying mechanism of action. Methods: Thirty-five 10–week-old male Wistar rats weighing 190 - 210 g (mean: 200.00 ± 10.10 g) were used for this study. The rats were randomly assigned to seven groups of five rats each, viz, normal control group, and six CLP groups. The CLP groups were those subjected to cecal ligation and puncture (CLP). The first 5 CLP groups received 2, 4, 6, 8 or 10 mg/kg floroindole, respectively, 1 h after CLP, via intraperitoneal route (i.p.) while the 6th CLP group served as untreated control. Western blotting, enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qRT-PCR) were used for the assessment of the expression levels of tumor necrosis factor-α (TNF- α), interleukn-6 (IL-6), nucleotide-binding oligomerization domain 2 (NOD2) and p-NF-κB p65. Results: Cecal ligation and puncture (CLP) significantly and time-dependently upregulated the expressions of TNF-α, IL-6 and NOD2 in intestinal tissues of rats (p < 0.05). However, treatment with floroindole significantly, and dose-dependently down-regulated CLP-induced expressions of these proteins (p < 0.05). Treatment of rats with floroindole also significantly and dose-dependently inhibited CLP-induced phosphorylation of NF-κB p65 in rat ileum (p < 0.05). Conclusion: The results obtained in this study demonstrate that floroindole confers some degree of protection against CLP-induced sepsis via inhibition of NF-κB p65 phosphorylation

Advanced development of biomarkers for immunotherapy in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Mono-immunotherapy and combination therapy with immune checkpoint inhibitors (ICIs) and multitargeted tyrosine kinase inhibitors (TKIs) or anti-vascular endothelial growth factor (anti-VEGF) inhibitors have become new standard therapies in advanced HCC (aHCC). However, the clinical benefit of these treatments is still limited. Thus, proper biomarkers which can predict treatment response to immunotherapy to maximize clinical benefit while sparing unnecessary toxicity are urgently needed. Contrary to other malignancies, up until now, no acknowledged biomarkers are available to predict resistance or response to immunotherapy for HCC patients. Furthermore, biomarkers, which are established in other cancer types, such as programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB), have no stable predictive effect in HCC. Thus, plenty of research focusing on biomarkers for HCC is under exploration. In this review, we summarize the predictive and prognostic biomarkers as well as the potential predictive mechanism in order to guide future research direction for biomarker exploration and clinical treatment options in HCC

JWA Deficiency Suppresses Dimethylbenz[a]Anthracene-Phorbol Ester Induced Skin Papillomas via Inactivation of MAPK Pathway in Mice

Our previous studies indicated that JWA plays an important role in DNA damage repair, cell migration, and regulation of MAPKs. In this study, we investigated the role of JWA in chemical carcinogenesis using conditional JWA knockout (JWAΔ2/Δ2) mice and two-stage model of skin carcinogenesis. Our results indicated that JWAΔ2/Δ2 mice were resistant to the development of skin papillomas initiated by 7, 12-dimethylbenz(a)anthracene (DMBA) followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). In JWAΔ2/Δ2 mice, the induction of papilloma was delayed, and the tumor number and size were reduced. In primary keratinocytes from JWAΔ2/Δ2 mice, DMBA exposure induced more intensive DNA damage, while TPA-promoted cell proliferation was reduced. The further mechanistic studies showed that JWA deficiency blocked TPA-induced activation of MAPKs and its downstream transcription factor Elk1 both in vitro and in vivo. JWAΔ2/Δ2 mice are resistance to tumorigenesis induced by DMBA/TPA probably through inhibition of transcription factor Elk1 via MAPKs. These results highlight the importance of JWA in skin homeostasis and in the process of skin tumor development

Numerical Simulation of the Fracture Propagation Mechanism during Supercritical Carbon Dioxide Fracturing in Shale Reservoirs

AbstractTo investigate the fracture propagation mechanism during supercritical CO2 fracturing in shale reservoirs, a numerical model was proposed based on the displacement discontinuity method. The Peng–Robinson equation was introduced to determine the variations in CO2 properties during the fracturing process. Considering natural fracture distribution in shale reservoirs, the fracture propagation mechanisms during supercritical CO2 fracturing in shale reservoirs under different horizontal stress differences and matrix permeabilities were analyzed. The influence of the proportion of CO2 preenergizing on fracture morphology was discussed. The results obtained via numerical simulation show that supercritical CO2 is beneficial to create a more complex fracture network by activating natural fractures under the same horizontal stress difference. CO2 easily penetrates into the matrix near the fracture surfaces, increasing reservoir energy. However, when the permeability of shale reservoirs exceeds 0.04×10−3 μm2, substantial filtration of CO2 into the reservoir matrix occurs near the well bore, limiting the activation of natural fractures around the fracture tip. A higher proportion of CO2 preenergizing during fracturing is conducive to improve the fracture complexity while reducing the fracture aperture

Improvement of Bondability by Depressing the Inhomogeneous Distribution of Nanoparticles in a Sintering Bonding Process with Silver Nanoparticles

Low-temperature bonding by sintering of Ag nanoparticles (NPs) is a promising lead-free bonding technique used in the electronic packaging industry. In this work, we prepare Ag nanoparticle (NP) paste using both an aqueous method and a polyol method. Sintering bonding trials were then conducted using different forms of Ag NPs. The results showed that use of the aqueous-based Ag NP paste led to inhomogeneous distribution of NPs, known as the ''coffee-ring effect.'' This led to low strength of fabricated joints. We investigated the influence of the coffeering effect and ways to depress it by changing the bonding material composition. Our results show that, when using polyol-based Ag NP paste as the bonding material, the coffee-ring effect was successfully depressed due to increased Marangoni flow. The corresponding shear strength of joints was increased significantly to 50 MPa at bonding temperature of 250°C

Effectiveness of 3-dimensional shoulder ultrasound in the diagnosis of rotator cuff tears: A meta-analysis

Background: Numerous quantitatively based studies measuring the accuracy of 3D shoulder ultrasound (US) for the diagnosis of rotator cuff tears remain inconclusive. In order to determine how effective 3D shoulder US is for detecting rotator cuff tears, a meta-analysis was performed systematically. Methods: Six electronic databases, PubMed/Medline, Embase, Cochrane Library, CNKI, VIP data, and Wanfang data, were utilized to retrieve articles praising the diagnostic value of 3D shoulder US for use in detecting rotator cuff tears. After screening and diluting out the articles that met inclusion criteria to be used for statistical analysis, the pooled evaluation indexes including sensitivity, specificity, and diagnostic odds ratio (DOR) as well as the summary receiver operating characteristic curve (SROC) were calculated utilizing Meta-Disc v.1.4. Results: Screening determined that out of 4220, 7 studies involving a total of 282 patients were deemed viable for inclusion in the meta-analysis. The results of the analysis showed that the sensitivity and specificity were at 94% and 83%, respectively, with a DOR of 60.06, Q* index of 0.9058 and the area under SROC of 0.9609. Additionally, a satisfactory accuracy of 3D shoulder US was observed in detecting full-and partial-thickness rotator cuff tears. Conclusion: This meta-analysis suggests that 3D shoulder US is very effective and highly accurate to detect full-thickness rotator cuff tears, but may lack accuracy in the diagnosis of partial tears