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Freshwater resources are scarce in coastal areas, and using seawater as mixing water can alleviate the scarcity of freshwater resources. However, the presence of chloride ions in seawater affects the generation of hydration products and the durability of concrete structures. In order to investigate the effect of hydrated calcium silicate (C-S-H) gel and calcium hydroxide (CH) generation in seawater-mixed cement pastes under 50 °C curing, their microscopic morphology was investigated using differential scanning calorimetry analysis, X-ray diffraction (XRD), and scanning electron microscopy (SEM). The relationship between the amount of C-S-H gel and CH production and the amount of chloride ion dosing, fly ash dosing, and the age of curing were investigated. The degree of influence between hydration products and influencing factors was analyzed using the grey correlation analysis. It was shown that 50 °C curing promoted the hydration reaction and generated more hydration products compared with ASTM standard. The content of C-S-H gel and CH increased with chloride dosage. The content of C-S-H gel increased by 13.5% under 50 °C curing compared with the control group at a chloride dosage of 1.3%. Fly ash is rich in active SiO 2 and AI 2 O 3 , and other components, which can react with Ca(OH) 2 generated by cement hydration and then generate C-S-H gel. With the increase of fly ash, the content of C-S-H gel also increases, but the CH content decreases. When 25% of fly ash was doped under 50 °C curing, the C-S-H gel content increased by 5.02% compared to the control group. The CH content decreased by 31.8% compared to the control group. With the growth of the maintenance age, the hydration reaction continues, the generation of C-S-H gel and CH will continue to increase, and their microstructures will become denser. C-S-H gel and CH content increased the most by raising the curing temperature at 7 days of curing, increasing by 10.11% and 22.62%, respectively. C-S-H gel and CH content had the highest gray relation with fly ash dosing. Chloride dosage and age of maintenance had the highest correlation with CH content at room temperature maintenance of 0.788 and 0.753, respectively.

Mixing cement with seawater will cause the hydration process of cement to be different from that of ordinary cement, which will significantly affect cement's mechanical properties and durability. This article investigates the effects of chloride ion concentration, curing temperature, and nano-metakaolin content on the evolution process of Friedel's salts and ettringite (AFt) crystals in cement pastes. The study was conducted using X-ray diffraction (XRD), thermal analysis (TG), scanning electron microscopy (SEM), and mercury-intrusion porosimetry (MIP). The results show that chlorine salt can increase the production of Friedel's salt and ettringite, and the delayed AFt production increases by up to 27.95% after the addition of chlorine salt, which has an adverse effect on cement-based materials. Increasing the curing temperature and increasing the nano-metakaolin dosage increased the generation of Friedel's salt and decreased the delayed AFt generation, which resulted in a decrease in the length and diameter of the AFt crystals. After 28 days of high-temperature curing and the addition of nano-metakaolin, Friedel's salt production increased by 13.40% and 14.34%, respectively, and ettringite production decreased by 9.68% and 7.93%, respectively. Increasing the curing temperature and adding nano-metakaolin can reduce the adverse effect of delayed ettringite increases due to chloride ion binding.

With the advent of antibiotic-eluting polymeric materials for targeting recalcitrant infections, using preclinical models to study biofilm is crucial for improving the treatment efficacy in periprosthetic joint infections. The stratification of risk and severity of infections is needed to develop an effective clinical dosing framework with better outcomes. Here, using in-vivo and in-vitro implant-associated infection models, we demonstrate that methicillin-sensitive and resistant Staphylococcus aureus (MSSA and MRSA) have model-dependent distinct implant and peri-implant tissue colonization patterns. The maturity of biofilms and the location (implant vs tissue) were found to influence the antibiotic susceptibility evolution profiles of MSSA and MRSA and the models could capture the differing host-microbe interactions in vivo. Gene expression studies revealed the molecular heterogeneity of colonizing bacterial populations. The comparison and stratification of the risk and severity of infection across different preclinical models provided in this study can guide clinical dosing to effectively prevent or treat PJI., Competing Interests: O.K.M. declares the following disclosures: Royalties - Corin, Mako, Iconacy, Renovis, Arthrex, ConforMIS, Meril Healthcare, Exactech, Cambridge Polymer Group; Stake/Equity-Cambridge Polymer Group, Orthopedic Technology Group, Alchimist. E.O. declares the disclosures: Royalties-Corin, Iconacy, Renovis, Arthrex, ConforMIS, Meril Healthcare, Exactech; Paid consultant – WL Gore & Assoc; Editorial Board – JBMR; Officer/Committee- SFB, ISTA. None of these are in direct conflict with the study.

Objectives: This study investigated a novel strategy for improving regenerative cartilage outcomes. It combines fractional laser treatment with the implantation of neocartilage generated from autologous dynamic Self-Regenerating Cartilage (dSRC)., Methods: dSRC was generated in vitro from harvested autologous swine chondrocytes. Culture was performed for 2, 4, 8, 10, and 12 weeks to study matrix maturation. Matrix formation and implant integration were also studied in vitro in swine cartilage discs using dSRC or cultured chondrocytes injected into CO 2 laser-ablated or mechanically punched holes. Cartilage discs were cultured for up to 8 weeks, harvested, and evaluated histologically and immunohistochemically., Results: The dSRC matrix was injectable by week 2, and matrices grew larger and more solid with time, generating a contiguous neocartilage matrix by week 8. Hypercellular density in dSRC at week 2 decreased over time and approached that of native cartilage by week 8. All dSRC groups exhibited high glycosaminoglycan (GAG) production, and immunohistochemical staining confirmed that the matrix was typical of normal hyaline cartilage, being rich in collagen type II. After 8 weeks in cartilage lesions in vitro, dSRC constructs generated a contiguous cartilage matrix, while isolated cultured chondrocytes exhibited only a sparse pericellular matrix. dSRC-treated lesions exhibited high GAG production compared to those treated with isolated chondrocytes., Conclusions: Isolated dSRC exhibits hyaline cartilage formation, matures over time, and generates contiguous articular cartilage matrix in fractional laser-created microenvironments in vitro, being well integrated with native cartilage.

Aims: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Chemotherapy based on gemcitabine (GEM) remains the first-line drug for patients with advanced PDAC. However, GEM resistance impairs its therapeutic effectiveness. Therefore, identifying effective therapeutic targets are urgently needed to overcome GEM resistance., Methods: The clinical significance of Tripartite Motif Containing 29 (TRIM29) was identified by exploring GEO datasets and TCGA database and its potential biological functions were predicted by GSEA analysis. The regulatory axis was established by bioinformatics analysis and validated by mechanical experiments. Then, in vitro and in vivo assays were performed to validate the roles of TRIM29 in PDAC GEM resistance., Results: High TRIM29 expression was associated with poor prognosis of PDAC and functional experiments demonstrated that TRIM29 promoted GEM resistance in PDAC GEM-resistant (GR) cells. Furthermore, we revealed that circRPS29 promoted TRIM29 expression via competitive interaction with miR-770-5p and then activated MEK/ERK signaling pathway. Additionally, both in vitro and in vivo functional experiments demonstrated that circRPS29/miR-770-5p/TRIM29 axis promoted PDAC GEM resistance via activating MEK/ERK signaling pathway., Conclusion: Our results identify the significance of the signaling axis, circRPS29/miR-770-5p/TRIM29-MEK/ERK, in PDAC GEM resistance, which will provide novel therapeutic targets for PDAC treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Arthrofibrosis is a joint disorder characterized by excessive scar formation in the joint tissues. Vitamin E is an antioxidant with potential anti-fibroblastic effect. The aim of this study was to establish an arthrofibrosis rat model after joint replacement and assess the effects of vitamin E supplementation on joint fibrosis., Methods: We simulated knee replacement in 16 male Sprague-Dawley rats. We immobilized the surgical leg with a suture in full flexion. The control groups were killed at 2 and 12 weeks (n = 5 per group), and the test group was supplemented daily with vitamin E (0.2 mg/mL) in their drinking water for 12 weeks (n = 6). We performed histological staining to investigate the presence and severity of arthrofibrosis. Immunofluorescent staining and α2-macroglobulin (α2M) enzyme-linked immunosorbent assay (ELISA) were used to assess local and systemic inflammation. Static weight bearing (total internal reflection) and range of motion (ROM) were collected for functional assessment., Results: The ROM and weight-bearing symmetry decreased after the procedure and recovered slowly with still significant deficit at the end of the study for both groups. Histological analysis confirmed fibrosis in both lateral and posterior periarticular tissue. Vitamin E supplementation showed a moderate anti-inflammatory effect on the local and systemic levels. The vitamin E group exhibited significant improvement in ROM and weight-bearing symmetry at day 84 compared to the control group., Conclusions: This model is viable for simulating arthrofibrosis after joint replacement. Vitamin E may benefit postsurgical arthrofibrosis, and further studies are needed for dosing requirements., (© 2024 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Background: Nerve xenografts harvested from transgenic α1,3-galactosyltransferase knockout (GalT-KO) pigs lack the epitope responsible for hyperacute rejection in pig-to-primate transplants. It is unknown whether these cold preserved nerve grafts support axonal regeneration in another species during and after immunosuppression. In this study, we compare outcomes between autografts and cold preserved xenografts in a rat sciatic model of nerve gap repair., Methods: Fifty male Lewis rats had a 1 cm sciatic nerve defect repaired using either: autograft and suture (n=10); 1-week or 4-week cold preserved xenograft and suture (n=10 per group); 1-week or 4-week cold preserved xenograft and photochemical tissue bonding using a human amnion wrap (PTB/HAM) (n=10 per group). Rats with xenografts were given tacrolimus until 4 months post-operatively. At 4 and 7 months, rats were euthanized and nerve sections harvested. Monthly sciatic functional index (SFI) scores were calculated., Results: All groups showed increases in SFI scores by 4 and 7 months. The autograft suture group had the highest axon density at 4 and 7 months. The largest decrease in axon density from 4 to 7 months was in the 1-week cold preserved PTB/HAM group. The only significant difference between group SFI scores occurred at 5 months, when both 1-week cold preserved groups had significantly lower scores than the 4-week cold preserved suture group., Conclusions: Our results in the rat sciatic model suggest that GalT-KO nerve xenografts may be viable alternatives to autografts and demonstrate the need for further studies of long-gap repair and comparison with acellular nerve allografts., Clinical Relevance: This proof-of-concept study in the rat sciatic model demonstrates that cold preserved GalT-KO porcine xenografts support axonal regeneration, as well as axonal viability following immunosuppression withdrawal. These results further suggest a role for both cold preservation and photochemical tissue bonding in modulating the immunological response at the nerve repair site., Competing Interests: Financial Disclosures: J.W. and M.R. are patent holders on Photochemical Tissue Bonding technology, with no received royalties, licensing or commercial income. The other authors have no disclosures or conflicts of interest., (Copyright © 2024 by the American Society of Plastic Surgeons.)

Aims: Pancreatic cancer (PC) is a highly metastatic malignant tumor of the digestive system. Drug resistance frequently occurs during cancer treatment process. This study aimed to explore the link between chemoresistance and tumor metastasis in PC and its possible molecular and cellular mechanisms., Methods: A Metastasis and Chemoresistance Signature (MCS) scoring system was built and validated based on metastasis- and chemoresistance-related genes using gene expression data of PC, and the model was applied to single-cell RNA sequencing data. The influence of linker histone H1.2 (H1-2) on PC was explored through in vitro and in vivo experiments including proliferation, invasion, migration, drug sensitivity, rescue experiments and immunohistochemistry, emphasizing its regulation with c-MYC signaling pathway., Results: A novel MCS scoring system accurately predicted PC patient survival and was linked to chemoresistance and epithelial-mesenchymal transition (EMT) in PC single-cell RNA sequencing data. H1-2 emerged as a significant prognostic factor, with its high expression indicating increased chemoresistance and EMT. This upregulation was mediated by c-MYC, which was also found to be highly expressed in PC tissues., Conclusion: The MCS scoring system offers insights into PC chemoresistance and metastasis potential. Targeting H1-2 could enhance therapeutic strategies and improve PC patient outcomes., Competing Interests: Declaration of Competing Interest No conflict of interest exists in the submission of this manuscript. We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled. We certify that the submission is not under review by any other publication. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: To summarize current evidence about the influence of body composition on the prognosis of patients with hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) treatment., Methods: Public databases were systematically searched to identify relevant studies published from the inception of the database up to May 2023. Studies that evaluated the association between body composition and clinical outcomes in HCC patients who underwent TACE were included. A pre-designed table was applied to summarize relevant information. Meta-analysis was performed to estimate the association of body composition with overall survival., Results: Fourteen studies were included in this review, including 3631 patients (sample size range: 56-908, median 186). All body composition measurements (including skeletal muscle area, visceral and subcutaneous adipose area, and bone mineral density) were based on computer tomography. The commonly used parameter was skeletal muscle index at 3rd lumbar vertebra level (8/14). Three studies evaluated the correlations of body composition changes with the prognosis after TACE. Most studies (12/14) identified body composition parameters as an independent indicator for overall survival, progression-free survival, and treatment response rate. The hazard ratio of different body composition parameters ranged from 1.01 to 2.88, and hazard ratio of body composition changes ranged from 1.88 to 5.93. The pooled hazard ratio of sarcopenia for overall survival was 1.38 (95 %CI: 1.20-1.58)., Conclusions: Body composition seems to be an important prognostic factor for a poorer clinical outcome after TACE treatment in patients with hepatocellular carcinoma. Future prospective studies with a larger sample size are required to confirm these findings., Registration Study: This study has been prospectively registered at the PROSPERO platform (https://www.crd.york.ac.uk/prospero/) with the registration No. CRD42022345602., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Qiang Wang reports financial support was provided by 10.13039/501100004047Karolinska Institutet. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Periprosthetic joint infections occur in about 2% of patients who undergo primary total joint arthroplasty, a procedure performed over 1 million times in the United States. The gold standard of treatment is a two-stage revision. This study aimed to establish a two-stage procedure in a preclinical small animal model (rat) to test and compare the efficacy of an antibiotic-eluting material in managing infection. Joint replacement was simulated by transchondylarly implanting a polyethylene (PE) plug into the distal femur and a titanium screw in the proximal tibia. Methicillin-sensitive Staphylococcus aureus (MSSA) 10 8  CFU/mL was injected into the tibial canal and the joint space before wound closure. The control groups were killed on postoperative day (POD) 18 (n = 12) and on POD 42 (n = 4) to assess both early and later-stage outcomes in the control group. The test group underwent revision surgery on POD 18 for treatment using gentamicin-eluting polyethylene (GPE, n = 4) and was observed until POD 42 to evaluate the efficacy of treatment. Our results showed that the bone loss for the treatment group receiving GPE was significantly less than that of the control (p < 0.05), which was supported by the histology images and an AI-tool assisted infection rate evaluation. Gait metrics duty factor imbalance and hindlimb temporal symmetry were significantly different between the treatment and control groups on Day 42. This animal model was feasible for evaluating treatments for peri-prosthetic joint infections (PJI) with a revision surgery and specifically that revision surgery and local antibiotic treatment largely hindered the peri-prosthetic bone loss. Statement of clinical significance: This revision model of peri-prosthetic infection has the potential of comparatively evaluating prophylaxis and treatment strategies and devices. Antibiotic-eluting UHMWPE is devised as at tool in treating PJI while providing weight bearing and joint space preservation., (© 2023 Orthopaedic Research Society.)

Background: Rodent models are commonly employed to validate preclinical disease models through the evaluation of postoperative behavior and allodynia. Our study investigates the dynamic interplay between pain and functional recovery in the context of traumatic osteotomy and surgical repair. Specifically, we established a rat model of tibial osteotomy, followed by internal fixation using a 5-hole Y-plate with 4 screws, to explore the hypothesis that histological bone healing is closely associated with functional recovery., Objective: Our primary objective was to assess the correlation between bone healing and functional outcomes in a rat model of tibial osteotomy and plate fixation., Methods: Seventeen male Sprague-Dawley rats underwent a metaphyseal transverse osteotomy of the proximal tibia, simulating a fracture-like injury. The resultant bone defect was meticulously repaired by realigning and stabilizing the bone surfaces with the Y-plate. To comprehensively assess recovery and healing, we performed quantitative and qualitative evaluations at 2, 4, 6, and 8 weeks post-surgery. Evaluation methods included micro-CT imaging, X-ray analysis, and histological examination to monitor bone defect healing. Concurrently, we employed video recording and gait analysis to evaluate functional recovery, encompassing parameters such as temporal symmetry, hindlimb duty factor imbalance, phase dispersion, and toe spread., Results: Our findings revealed complete healing of the bone defect at 8 weeks, as confirmed by micro-CT and histological assessments. Specifically, micro-CT data showed a decline in fracture volume over time, indicating progressive healing. Histological examination demonstrated the formation of new trabecular bone and the resolution of inflammation. Importantly, specific gait analysis parameters exhibited longitudinal changes consistent with bone healing. Hindlimb duty factor imbalance, hindlimb temporal symmetry, and phase dispersion correlated strongly with the healing process, emphasizing the direct link between bone healing and functional outcomes., Conclusions: The establishment of this tibia osteotomy model underscores the association between bone healing and functional outcomes, emphasizing the feasibility of monitoring postoperative recovery using endpoint measurements. Our overarching objective is to employ this model for assessing the local efficacy of drug delivery devices in ameliorating post-surgical pain and enhancing functional recovery., (© 2023. The Author(s).)

The high prevalence of opioid addiction and the shortcomings of systemic opioids has increased the pace of the search for alternative methods of pain management. The local delivery of pain medications has started to be used as a tool for pain management and to decrease the use of systemic opioids for these patients. Here, we explored an in-situ polymerizable hydrogel system for the local delivery of analgesics and nonsteroid anti-inflammatory drugs (NSAID) for orthopaedic applications. We synthesized a series of methacrylated oligomeric polyethylene glycol-co-lactic acid polymer using microwave radiation for the delivery of bupivacaine hydrochloride as an analgesic and ketorolac tromethamine as an NSAID. We determined drug elution and gel degradation profiles in vitro. Biocompatibility was assessed against osteoblasts in vitro and by histological analysis after subcutaneous implantation for 4 weeks in vivo. Intra-articular and systemic concentrations and pharmacokinetic parameters were estimated using a two-compartment pharmacodynamic model based on in-vitro elution profiles. This type of in-situ applicable hydrogels is promising for extending the local efficacy of pain medication and further reducing the need for opioids., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: OKM: Royalties - Corin, Mako, Iconacy, Renovis, Arthrex, ConforMIS, Meril Healthcare, Exactech, Cambridge Polymer Group; Stake/Equity-Cambridge Polymer Group, Orthopaedic Technology Group, Alchimist. None of these are in direct conflict with the study. EO: Royalties-Corin, Iconacy, Renovis, Arthrex, ConforMIS, Meril Healthcare, Exactech; Paid consultant – WL Gore & Assoc; Editorial Board – JBMR; Officer/Committee- SFB, ISTA. None of these are in direct conflict with the study. MDA: Corlamlabs, None of these are in direct conflict with the study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To systematically review the efficacy of radiomics models derived from computed tomography (CT) or magnetic resonance imaging (MRI) in preoperative prediction of the histopathological grade of hepatocellular carcinoma (HCC)., Methods: Systematic literature search was performed at databases of PubMed, Web of Science, Embase, and Cochrane Library up to 30 December 2022. Studies that developed a radiomics model using preoperative CT/MRI for predicting the histopathological grade of HCC were regarded as eligible. A pre-defined table was used to extract the data related to study and patient characteristics, characteristics of radiomics modelling workflow, and the model performance metrics. Radiomics quality score and the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) were applied for research quality evaluation., Results: Eleven eligible studies were included in this review, consisting of 2245 patients (range 53-494, median 165). No studies were prospectively designed and only two studies had an external test cohort. Half of the studies (five) used CT images and the other half MRI. The median number of extracted radiomics features was 328 (range: 40-1688), which was reduced to 11 (range: 1-50) after feature selection. The commonly used classifiers were logistic regression and support vector machine (both 4/11). When evaluated on the two external test cohorts, the area under the curve of the radiomics models was 0.70 and 0.77. The median radiomics quality score was 10 (range 2-13), corresponding to 28% (range 6-36%) of the full scale. Most studies showed an unclear risk of bias as evaluated by QUADAS-2., Conclusion: Radiomics models based on preoperative CT or MRI have the potential to be used as an imaging biomarker for prediction of HCC histopathological grade. However, improved research and reporting quality is required to ensure sufficient reliability and reproducibility prior to implementation into clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Around 80% of pancreatic ductal adenocarcinoma (PDAC) patients experience recurrence after curative resection. We aimed to develop a deep-learning model based on preoperative CT images to predict early recurrence (recurrence within 12 months) in PDAC patients. The retrospective study included 435 patients with PDAC from two independent centers. A modified 3D-ResNet18 network was used for a deep learning model construction. A nomogram was constructed by incorporating deep learning model outputs and independent preoperative radiological predictors. The deep learning model provided the area under the receiver operating curve (AUC) values of 0.836, 0.736, and 0.720 in the development, internal, and external validation datasets for early recurrence prediction, respectively. Multivariate logistic analysis revealed that higher deep learning model outputs (odds ratio [OR]: 1.675; 95% CI: 1.467, 1.950; p < 0.001), cN1/2 stage (OR: 1.964; 95% CI: 1.036, 3.774; p = 0.040), and arterial involvement (OR: 2.207; 95% CI: 1.043, 4.873; p = 0.043) were independent risk factors associated with early recurrence and were used to build an integrated nomogram. The nomogram yielded AUC values of 0.855, 0.752, and 0.741 in the development, internal, and external validation datasets. In conclusion, the proposed nomogram may help predict early recurrence in PDAC patients.

Objective: Perineural invasion (PNI) is associated with local recurrence, distant metastasis, and a poor prognosis in pancreatic cancer. However, rare attempt was made to identified the PNI intraoperative. To facilitate precise R0 excision of the tumor, we planned to develop a fluorescent probe for intraoperative imaging of the PNI using GAP-43 as the target and indocyanine green (ICG) as the carrier., Methods: The probe was created by binding peptide antibody and ICG. Its targeting was tested in vitro and in vivo using a co-culture model of PC12 and tumor cells to create an in vitro neural invasion model and a mouse sciatic nerve invasion model. The small animal imaging system and surgical navigation system confirmed the probe's potential clinical applicability. The sciatic nerve damage model was created to confirm the probe's targeting., Results: We used the pancreatic cancer samples and the public database to confirm that GAP-43 was preferentially overexpressed in pancreatic cancer, particularly in PNI. PC12 cells showed high GAP-43RA-PEG-ICG probe-specific absorption after being co-cultured with tumor cells in vitro. In the sciatic nerve invasion experiment, animals in probe group displayed a significantly stronger fluorescence signal at the PNI compared to ICG-NP and the contralateral normal nerves groups. Although only 60 % of mice appeared to have R0 resections by the naked eye, small animal imaging systems and surgical fluorescence navigation systems could remove the tumor with R0 precision. The injury model used in the probe imaging experimental trials demonstrated that the probe was specifically targeted to the injured nerve, regardless of whether the injury was infiltrated by a tumor or physical., Conclusion: We developed the GAP-43Ra-ICG-PEG, an active-targeting near-infrared fluorescent (NIRF) probe, that specifically binds to GAP-43-positive neural cells in an in vitro model of PNI. The probe efficiently visualized PNI lesions in pancreatic cancer in preclinical models, opening up new possibilities for NIRF-guided pancreatic surgery, particularly for PNI patients., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: One subtype of hepatocellular carcinoma (HCC), with cytokeratin 19 expression (CK19+), has shown to be more aggressive and has a poor prognosis. However, CK19+ is determined by immunohistochemical examination using a surgically resected specimen. This study is aimed at establishing a radiomics signature based on preoperative gadoxetic acid-enhanced MRI for predicting CK19 status in HCC. Patients and Methods . Clinicopathological and imaging data were retrospectively collected from patients who underwent hepatectomy between February 2015 and December 2020. Patients who underwent gadoxetic acid-enhanced MRI and had CK19 results of histopathological examination were included. Radiomics features of the manually segmented lesion during the arterial, portal venous, and hepatobiliary phases were extracted. The 10 most reproducible and robust features at each phase were selected for construction of radiomics signatures, and their performance was evaluated by analyzing the area under the curve (AUC). The goodness of fit of the model was assessed by the Hosmer-Lemeshow test., Results: A total of 110 patients were included. The incidence of CK19(+) HCC was 17% (19/110). Alpha fetoprotein was the only significant clinicopathological variable different between CK19(-) and CK19(+) groups. A majority of the selected radiomics features were wavelet filter-derived features. The AUCs of the three radiomics signatures based on arterial, portal venous, and hepatobiliary phases were 0.70 (95% CI: 0.56-0.83), 0.83 (95% CI: 0.73-0.92), and 0.89 (95% CI: 0.82-0.96), respectively. The three radiomics signatures were integrated, and the fusion signature yielded an AUC of 0.92 (95% CI: 0.86-0.98) and was used as the final model for CK19(+) prediction. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the fusion signature was 0.84, 0.89, 0.88, 0.62, and 0.96, respectively. The Hosmer-Lemeshow test showed a good fit of the fusion signature ( p > 0.05)., Conclusion: The established radiomics signature based on preoperative gadoxetic acid-enhanced MRI could be an accurate and potential imaging biomarker for HCC CK19(+) prediction., Competing Interests: The authors report no conflicts of interest in this work., (Copyright © 2023 Xiaojun Hu et al.)

Histopathologic grade of hepatocellular carcinoma (HCC) is an important predictor of early recurrence and poor prognosis after curative treatments. This study aims to develop a radiomics model based on preoperative gadoxetic acid-enhanced MRI for predicting HCC histopathologic grade and to validate its predictive performance in an independent external cohort. Clinical and imaging data of 403 consecutive HCC patients were retrospectively collected from two hospitals (265 and 138, respectively). Patients were categorized into poorly differentiated HCC and non-poorly differentiated HCC groups. A total of 851 radiomics features were extracted from the segmented tumor at the hepatobiliary phase images. Three classifiers, logistic regression (LR), support vector machine, and Adaboost were adopted for modeling. The areas under the curve of the three models were 0.70, 0.67, and 0.61, respectively, in the external test cohort. Alpha-fetoprotein (AFP) was the only significant clinicopathological variable associated with HCC grading (odds ratio: 2.75). When combining AFP, the LR+AFP model showed the best performance, with an AUC of 0.71 (95%CI: 0.59-0.82) in the external test cohort. A radiomics model based on gadoxetic acid-enhanced MRI was constructed in this study to discriminate HCC with different histopathologic grades. Its good performance indicates a promise in the preoperative prediction of HCC differentiation levels.

N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) is a novel lipophilic metal chelator and antioxidant used in mercury poisoning. Recent studies have suggested that NBMI may also bind to other metals such as lead and iron. Since NBMI can enter the brain, we evaluated if NBMI removes excess iron from the iron-loaded brain and ameliorates iron-induced oxidative stress. First, NBMI exhibited preferential binding to ferrous (Fe 2+ ) iron with a negligible binding affinity to ferric (Fe 3+ ) iron, indicating a selective chelation of labile iron. Second, NBMI protected SH-SY5Y human neuroblastoma cells from the cytotoxic effects of high iron. NBMI also decreased cellular labile iron and lessened the production of iron-induced reactive oxygen species in these cells. Deferiprone (DFP), a commonly used oral iron chelator, failed to prevent iron-induced cytotoxicity or labile iron accumulation. Next, we validated the efficacy of NBMI in Hfe H67D mutant mice, a mouse model of brain iron accumulation (BIA). Oral gavage of NBMI for 6 weeks decreased iron accumulation in the brain as well as liver, whereas DFP showed iron chelation only in the liver, but not in the brain. Notably, depletion of brain copper and anemia were observed in BIA mice treated with DFP, but not with NBMI, suggesting a superior safety profile of NBMI over DFP for long-term use. Collectively, our study demonstrates that NBMI provides a neuroprotective effect against BIA and has therapeutic potential for neurodegenerative diseases associated with BIA., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. Gemcitabine (Gem) has been a key chemotherapy agent for pancreatic cancer treatment by suppressing cell proliferation and inducing apoptosis. However, the overexpression of inhibitors of apoptosis (IAP) family of proteins during the carcinogenesis of pancreatic cancer can develop resistance to chemotherapy treatment and result in poor efficacy. To achieve the synergistic combinations of multiple strategies for this dismal disease, we developed a robust nanomedicine system, consisting of a photodynamic therapeutic agent (chlorine e6, Ce6) and a pro-apoptotic peptide-Gem conjugate. To have spatiotemporally controlled drug release, the pro-apoptotic peptide-Gem conjugate was designed to have a vinyldithioether linker that was sensitive to reactive oxygen species (ROS). The nanomedicine was fabricated by the direct self-assembly of the pro-apoptotic peptide-Gem conjugate with Ce6. After being delivered into tumors, the nanomedicine disassembled and rapidly released Gem, Ce6, and the pro-apoptotic peptide upon light illumination (660 nm). Both in vitro and in vivo studies in pancreatic cancer models confirmed the tumor inhibition efficacy with low systemic toxicity to animals.

Background: Although gemcitabine has been considered as the first-line drug for advanced pancreatic cancer (PC), development of resistance to gemcitabine severely limits the effectiveness of this chemotherapy, and the underlying mechanism of gemcitabine resistance remains unclear. Various factors, such as ATP binding cassette (ABC) transporters, microRNAs and their downstream signaling pathways are included in chemoresistance to gemcitabine. This study investigated the potential mechanisms of microRNAs and ABC transporters related signaling pathways for PC resistance to gemcitabine both in vivo and in vitro., Methods: Immunohistochemistry and Western blotting were applied to detect the expression of ABC transporters. Molecular docking analysis was performed to explore whether gemcitabine interacted with ABC transporters. Gain-of-function and loss-of-function analyses were performed to investigate the functions of hsa-miR-3178 in vitro and in vivo. Bioinformatics analysis, Western blotting and dual-luciferase reporter assay were used to confirm the downstream regulatory mechanisms of hsa-miR-3178., Results: We found that P-gp, BCRP and MRP1 were highly expressed in gemcitabine-resistant PC tissues and cells. Molecular docking analysis revealed that gemcitabine can bind to the ABC transporters. Hsa-miR-3178 was upregulated in gemcitabine resistance PANC-1 cells as compared to its parental PANC-1 cells. Moreover, we found that hsa-miR-3178 promoted gemcitabine resistance in PC cells. These results were also verified by animal experiments. RhoB was down-regulated in gemcitabine-resistant PC cells and it was a downstream target of hsa-miR-3178. Kaplan-Meier survival curve showed that lower RhoB expression was significantly associated with poor overall survival in PC patients. Rescue assays demonstrated that RhoB could reverse hsa-miR-3178-mediated gemcitabine resistance. Interestingly, hsa-miR-3178 promoted gemcitabine resistance in PC by activating the PI3K/Akt pathway-mediated upregulation of ABC transporters., Conclusions: Our results indicate that hsa-miR-3178 promotes gemcitabine resistance via RhoB/PI3K/Akt signaling pathway-mediated upregulation of ABC transporters. These findings suggest that hsa-miR-3178 could be a novel therapeutic target for overcoming gemcitabine resistance in PC., (© 2022. The Author(s).)

Multidrug resistance (MDR) is the major cause of chemotherapy failure, which is usually caused by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2. To date, no MDR modulator has been clinically approved. Here, we found that lazertinib (YH25448; a novel third-generation tyrosine kinase inhibitor [TKI]) could enhance the anticancer efficacy of MDR transporter substrate anticancer drugs in vitr o， in vivo , and ex vivo . Mechanistically, lazertinib was shown to inhibit the drug efflux activities of ABCB1 and ABCG2 and thus increase the intracellular accumulation of the transporter substrate anticancer drug. Moreover, lazertinib was found to stimulate the ATPase activity of ABCB1/ABCG2 and inhibit the photolabeling of the transporters by 125 I-iodoarylazidoprazosin (IAAP). However, lazertinib neither changed the expression or locolization of ABCB1 and ABCG2 nor blocked the signal pathway of Akt or Erk1/2 at a drug concentration effective for MDR reversal. Overall, our results demonstrate that lazertinib effectively reverses ABCB1- or ABCG2-mediated MDR by competitively binding to the ATP-binding site and inhibiting drug efflux function. This is the first report demonstrating the novel combined use of lazertinib and conventional chemotherapeutical drugs to overcome MDR in ABCB1/ABCG2-overexpressing cancer cells., Competing Interests: The authors have no relevant competing interests to declare., (© 2022.)

Preoperative prediction of microvascular invasion (MVI) is of importance in hepatocellular carcinoma (HCC) patient treatment management. Plenty of radiomics models for MVI prediction have been proposed. This study aimed to elucidate the role of radiomics models in the prediction of MVI and to evaluate their methodological quality. The methodological quality was assessed by the Radiomics Quality Score (RQS), and the risk of bias was evaluated by the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). Twenty-two studies using CT, MRI, or PET/CT for MVI prediction were included. All were retrospective studies, and only two had an external validation cohort. The AUC values of the prediction models ranged from 0.69 to 0.94 in the test cohort. Substantial methodological heterogeneity existed, and the methodological quality was low, with an average RQS score of 10 (28% of the total). Most studies demonstrated a low or unclear risk of bias in the domains of QUADAS-2. In conclusion, a radiomics model could be an accurate and effective tool for MVI prediction in HCC patients, although the methodological quality has so far been insufficient. Future prospective studies with an external validation cohort in accordance with a standardized radiomics workflow are expected to supply a reliable model that translates into clinical utilization.

Transmembrane protease serine 4 (TMPRSS4) is upregulated in various kinds of human cancers, including pancreatic cancer. However, its biological function in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In the current study, real-time qPCR, immunohistochemical staining, Western blotting, and database (Cancer Genome Atlas and Gene Expression) analysis revealed remarkable overexpression of TMPRSS4 in PDAC tissue as compared to non-tumor tissue. The TMPRSS4 overexpression was associated with poor prognosis of PDAC patients. Moreover, multivariate analysis revealed that TMPRSS4 serves as an independent risk factor in PDAC. We performed gain-and loss-of-function analysis and found that TMPRSS4 promotes cellular proliferation and inhibits apoptosis of PDAC cells both in vitro and in vivo . Furthermore, we showed that TMPRSS4 might promote cell proliferation and inhibit apoptosis through activating ERK1/2 signaling pathway in pancreatic cancer cells. These findings were validated by using ERK1/2 phosphorylation inhibitor SCH772984 both in vitro and in vivo . Taken together, this study suggests that TMPRSS4 is a proto-oncogene, which promotes initiation and progression of PDAC by controlling cell proliferation and apoptosis. Our findings indicate that TMPRSS4 could be a promising prognostic biomarker and a therapeutic target for the treatment of pancreatic cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gu, Huang, Zhang, Wang, Tao, Yang, Zheng, Liu, Yang, Zhu, Wang and Fan.)

Pancreatic cancer (PC) is a severe disease with the highest mortality rate among various cancers. It is urgent to find an effective and accurate way to predict the survival of PC patients. Gene set variation analysis (GSVA) was used to establish and validate a miRNA set-based pathway prognostic signature for PC (miPPSPC) and a mRNA set-based pathway prognostic signature for PC (mPPSPC) in independent datasets. An optimized miPPSPC was constructed by combining clinical parameters. The miPPSPC, optimized miPPSPC and mPPSPC were established and validated to predict the survival of PC patients and showed excellent predictive ability. Four metabolic pathways and one oxidative stress pathway were identified in the miPPSPC, whereas linoleic acid metabolism and the pentose phosphate pathway were identified in the mPPSPC. Key factors of the pentose phosphate pathway and linoleic acid metabolism, G6PD and CYP2C8/9/18/19, respectively, are related to the survival of PC patients according to our tissue microarray. Thus, the miPPSPC, optimized miPPSPC and mPPSPC can predict the survival of PC patients efficiently and precisely. The metabolic and oxidative stress pathways may participate in PC progression.

Background: Understanding the internal anatomy of the liver remains a major challenge in anatomical liver resection. Although virtual hepatectomy and indocyanine green (ICG) fluorescence imaging techniques have been widely used in hepatobiliary surgery, limitations in their application for real-time navigation persist., Objective: The aim of the present study was to evaluate the feasibility and clinical utility of the novel laparoscopic hepatectomy navigation system (LHNS), which fuses preoperative three-dimensional (3D) models with ICG fluorescence imaging to achieve real-time surgical navigation., Methods: We conducted a retrospective review of clinical outcome for 64 patients who underwent laparoscopic hepatectomy from January 2018 to December 2018, including 30 patients who underwent the procedure using the LHNS (LHNS group) and 34 patients who underwent the procedure without LHNS guidance (Non-LHNS group)., Results: There was no significant difference in preoperative characteristics between the two groups. The LHNS group had a significantly less blood loss (285.0 ± 163.0 mL vs. 391.1 ± 242.0 mL; P = 0.047), less intraoperative blood transfusion rate (13.3% vs. 38.2%; P = 0.045), and shorter postoperative hospital stay (7.8 ± 2.1 days vs. 10.6 ± 3.8 days; P < 0.001) than the Non-LHNS group. There was no statistical difference in operative time and the overall complication rate between the two groups. The liver transection line was clearly delineated by the LHNS in 27 patients; however, the projection of boundary was unclear in 2 cases, and in 1 case, the boundary was not clearly displayed by ICG fluorescence imaging., Conclusions: We developed the LHNS to address limitations of current intraoperative imaging systems. The LHNS is hopefully to become a promising real-time navigation system for laparoscopic hepatectomy.

Nucleic acid-based therapeutics, including the use of messenger RNA (mRNA) as a drug molecule, has tremendous potential in the treatment of chronic diseases, such as age-related neurodegenerative diseases. In this study, we have developed a cationic liposomal formulation of mRNA and evaluated the potential of intranasal delivery to the brain in murine model. Preliminary in vitro studies in J774A.1 murine macrophages showed GFP expression up to 24 h and stably expressed GFP protein in the cytosol. Upon intranasal administration of GFP-mRNA/cationic liposomes (3 mg/kg dose) in mice, there was significantly higher GFP-mRNA expression in the brain post 24 h as compared to either naked mRNA or the vehicle-treated group. Luciferase mRNA encapsulated in cationic liposomes was used for quantification of mRNA expression distribution in the brain. The results showed increased luciferase activity in the whole brain in a dose-dependent manner. Specifically, the luciferase-mRNA/cationic liposome group (3 mg/kg dose) showed significantly higher luciferase activity in the cortex, striatum, and midbrain regions as compared with the control groups, with minimal systemic exposure. Overall, the results of this study demonstrate the feasibility of brain-specific, nonviral mRNA delivery for the treatment of various neurological disorders.

The majority of periprosthetic joint infections occur shortly after primary joint replacement (<3 months) and require the removal of all implant components for the treatment period (~4 months). A clinically relevant animal model of periprosthetic infection should, therefore, establish an infection with implant components in place. Here, we describe a joint replacement model in the rat with ultrahigh molecular weight polyethylene (UHMWPE) and titanium components inoculated at the time of surgery by methicillin-sensitive Staphylococcus aureus (S. aureus), which is one of the main causative microorganisms of periprosthetic joint infections. We monitored the animals for 4 weeks by measuring gait, weight-bearing symmetry, von Frey testing, and micro-CT as our primary endpoint analyses. We also assessed the infection ex vivo using colony counts on the implant surfaces and histology of the surrounding tissues. The results confirmed the presence of a local infection for 4 weeks with osteolysis, loosening of the implants, and clinical infection indicators such as redness, swelling, and increased temperature. The utility of specific gait analysis parameters, especially temporal symmetry, hindlimb duty factor imbalance, and phase dispersion was identified in this model for assessing the longitudinal progression of the infection, and these metrics correlated with weight-bearing asymmetry. We propose to use this model to study the efficacy of using different local delivery regimens of antimicrobials on addressing periprosthetic joint infections. Statement of clinical significance: We have established a preclinical joint surgery model, in which postoperative recovery can be monitored over a multi-week course by assessing gait, weight-bearing, and allodynia. This model can be used to study the efficacy of different combinations of implant materials and medication regimens. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:1101-1112, 2020., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: To identify key microRNAs (miRNAs) and their target mRNAs related to gemcitabine-resistant pancreatic cancer (PC) and investigate the association between gemcitabine-resistant-related miRNAs and mRNAs and immune infiltration., Methods: Expression profiles of miRNAs and mRNAs were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed miRNAs and mRNAs (referred to as "DEmiRNAs" and "DEmRNAs", respectively) were distinguished between gemcitabine-resistant PC cells and its parental cells. The DEmRNAs targeted by the DEmiRNAs were retrieved using miRDB, microT, and Targetscan. Furthermore, GO and KEGG pathway enrichment analysis and GSEA were performed. The Kaplan-Meier plotter was used to analyze the prognosis of key DEmiRNAs and DEmRNAs on PC patients. The relationship between the key DEmRNAs and tumor-infiltrating immune cells in PC was investigated using CIBERSORT method using the LM22 signature as reference. Key infiltrating immune cells were further analyzed for the associations with prognosis of TCGA PAAD patients., Results: Four DEmiRNAs, including hsa-miR-3178, hsa-miR-485-3p, hsa-miR-574-5p, and hsa-miR-584-5p, were identified to target seven DEmRNAs, including MSI2, TEAD1, GNPDA1, RND3, PRKACB, TRIM68, and YKT6, individually, in gemcitabine-resistant PC cells versus parental cells. Gemcitabine-resistant PC cells were enriched in proteasome-related, immune-related, and memory CD4 + T cell-related pathways, indicating a gemcitabine therapeutic effect on PC cells. All four DEmiRNAs and almost all DEmRNAs had an impact on the prognosis of PC patients. All seven DEmRNAs had remarkable effects on CD4 + memory T cells, which were affected by the gemcitabine therapeutic effect. Effector memory CD4 + T cells rather than central memory CD4 + T cells predicted a good prognosis according to the TCGA PAAD dataset., Conclusions: Gemcitabine resistance can alter the fraction of memory CD4 + T cells via hsa-miR-3178, hsa-miR-485-3p, hsa-miR-574-5p and hsa-miR-584-5p targeted MSI2, TEAD1, GNPDA1, RND3, PRKACB, TRIM68, and YKT6 network in PC., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Background: Our objective was to evaluate the prevalence and different diagnostic methods of breastmilk (BM)-acquired cytomegalovirus (CMV) infection in a pathologically jaundiced cohort., Methods: A total of 400 infants confirmed with pathological jaundice at The People's Hospital of Qingyang City were screened for BM-acquired CMV infection between February 2018 and February 2019. A total of 300 infants were finally enrolled in our study. CMV infection was confirmed by detecting both CMV-DNA in various samples using FQ-PCR and CMV-IgM with chemiluminescence. Clinical and other laboratory data were collected from these infants during their hospitalization or regular visits., Results: Ninety-eight (32.67%) subjects were confirmed to be BM CMV-DNA-positive, and 18 (18.37%) were diagnosed with a BM-acquired CMV infection. All 18 (100%) infants with a BM-acquired CMV infection were CMV-DNA-positive in urine, while 5 (27.78%) cases and 11 (61.11%) cases were confirmed in plasma and peripheral blood mononuclear cells (PBMCs), respectively. Only 6 (33.33%) infants were CMV-IgM-positive. Birthweight, direct bilirubin, aspartate aminotransferase, and the viral load in BM of the BM-acquired CMV group were higher than those in the non-infected group (P < .05). Low birthweight and viral load in BM were risk factors for BM-acquired CMV infection. Detecting CMV-DNA in urine samples exhibited better performance than the other methods for screening BM-acquired CMV infections., Conclusions: Our study found a high prevalence of BM-acquired CMV infection in jaundiced infants, and detecting CMV-DNA in a urine sample was the most sensitive method for disease screening., (© 2020 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Pancreatic ductal adenocarcinoma (PDAC) is associated with several genetic syndromes. However, the molecular mechanism underlying PDAC progression is still unknown. In this study, we showed that Laminin Subunit Beta 3 (LAMB3) was aberrantly overexpressed in PDAC and was closely associated with the overall survival rate of patients with PDAC. Functional studies demonstrated that LAMB3 played important roles in cell proliferation, the cell cycle, and invasion capacity. Using bioinformatics analysis, we determined that miR-24-3p was an upstream miRNA of LAMB3, and further experiments verified that miR-24-3p regulated LAMB3 expression in PDAC cells. A dual-luciferase reporter system demonstrated that miR-24-3p directly targeted the LAMB3 3'UTR, and FISH assay confirmed that miR-24-3p and LAMB3 mRNA mostly resided in cytoplasm, accounting for their post-translational regulation. Rescue assay demonstrated that miR-24-3p exerted its anti-cancer role by suppressing LAMB3 expression. Finally, by using a subcutaneous xenotransplanted tumor model, we demonstrated that miR-24-3p overexpression inhibited the proliferation of PDAC by suppressing LAMB3 expression in vivo . Collectively, our results provide evidence that the miR-24-3p/LAMB3 axis plays a vital role in the progression of PDAC and indicate that the miR-24-3p/LAMB3 axis may represent a novel therapeutic target for PDAC., (Copyright © 2020 Huang, Gu, Tao, Zhang, Wang and Fan.)

Iron is a nutrient metal, but excess iron promotes tissue damage. Since iron chelation therapies exhibit multiple off-target toxicities, there is a substantial demand for more specific approaches to decrease iron burden in iron overload. While the divalent metal transporter 1 (DMT1) plays a well-established role in the absorption of dietary iron, up-regulation of intestinal DMT1 is associated with iron overload in both humans and rodents. Hence, we developed a novel pH-sensitive multi-compartmental particulate (MCP) oral delivery system that encapsulates DMT1 siRNA and validated its efficacy in mice. Using the gelatin NPs coated with Eudragit® L100-55, we demonstrated that DMT1 siRNA-loaded MCPs down-regulated DMT1 mRNA levels in the duodenum, which was consistent with decreased intestinal absorption of orally-administered 59 Fe. Together, the Eudragit® L100-55-based oral siRNA delivery system could provide an effective strategy to specifically down-regulate duodenal DMT1 and mitigate iron absorption., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Compared to pure hyaluronic acid filler, cross-linked hyaluronic acid (HAc) exhibits superior biocompatibility and longevity as a dermal filler. We previously developed composite HAc-hydroxyapatite (HAp) fillers. Herein, we systematically compared the protein-level increase and gene expression between HAc-micro-HAp and HAc-nano-HAp in mice and determined the mechanisms underlying the biological responses to HAc and HAp. Five-week-old female BALB/c-nude mice were classified into five groups: normal skin, Radiesse, Restylane, HAc-nano-HAp, and HAc-micro-HAp. Fillers (200 μl) were injected to evenly fill the back of mice. Skin biopsies were performed to investigate collagen and elastic fiber synthesis after filler injections. Western blot analysis, real-time polymerase chain reaction analysis, and immunohistochemistry were performed to investigate protein and gene expression changes. Organ (liver, lung, spleen, and kidney) toxicity of HAc-nano-HAp was determined by hematoxylin and eosin staining after 12 weeks. Protein and gene expression analyses indicated that, compared with pure fillers, HAc-nano-HAp and HAc-micro-HAp hydrogels preferentially promoted collagen and elastic fiber formation through the TGF-β pathway. The composite fillers also exhibited no evidence of organ toxicity. HAc-HAp filler might play an important role in collagen and elastic fiber regeneration. HAc filler stimulates collagen type 1 and elastic fiber synthesis through the TGF-β/Smad pathway. The role of HAc-HAp composite fillers in photoaging in animal models and their effects on skin, including elasticity and tensile strength, should be investigated., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 play important roles in necroptosis that are closely linked to the inflammatory response. Although the activation of necroptosis is well characterized, the mechanism that tunes down necroptosis is largely unknown. Here we find that Parkin (also known as PARK2), an E3 ubiquitin ligase implicated in Parkinson's disease and as a tumour suppressor, regulates necroptosis and inflammation by regulating necrosome formation. Parkin prevents the formation of the RIPK1-RIPK3 complex by promoting polyubiquitination of RIPK3. Parkin is phosphorylated and activated by the cellular energy sensor AMP-activated protein kinase (AMPK). Parkin deficiency potentiates the RIPK1-RIPK3 interaction, RIPK3 phosphorylation and necroptosis. Parkin deficiency enhances inflammation and inflammation-associated tumorigenesis. These findings demonstrate that the AMPK-Parkin axis negatively regulates necroptosis by inhibiting RIPK1-RIPK3 complex formation; this regulation may serve as an important mechanism to fine-tune necroptosis and inflammation.

Background: The authors investigated the synergistic effects of adipose-derived stem cells and fat graft on skin wrinkles in a nude mouse model of chronologic aging., Methods: After 50 weeks of chronologic aging, 44 female BALB/c nude mice were classified into four groups: (1) negative control, (2) mice injected subcutaneously with fat on the back skin (0.5 cm), (3) mice injected with adipose-derived stem cells (1 × 10 cells in 0.5 cm Hanks balanced salt solution), and (4) mice injected with both fat (0.5 cm) and adipose-derived stem cells (1 × 10 cells in 0.5 cm Hanks balanced salt solution). The degree of wrinkling was evaluated using replica analysis, and skin biopsies were performed after 4 weeks. The dermal thickness and density of collagen were determined. Type I procollagen and matrix metalloproteinase levels were determined using real-time polymerase chain reaction and Western blot analysis. Tropoelastin, fibrillin-1, and CD31 levels were evaluated using immunohistochemistry., Results: Based on the total wrinkle area, there was significant wrinkle reduction in the fat-treated and adipose-derived stem cell with fat-treated groups. Type I procollagen mRNA and collagen levels were significantly higher in the adipose-derived stem cell with fat-treated group than in the adipose-derived stem cell-treated and the fat-treated groups. In addition, the adipose-derived stem cells with fat graft group exhibited significantly higher CD31 expression level than the adipose-derived stem cell-treated and the fat-treated groups., Conclusion: Both adipose-derived stem cells and fat graft have a wrinkle-reducing effect and synergistically affect collagen synthesis and neovascularization.

Pancreatic ductal adenocarcinoma (PDAC) is a genetic disease and a leading cause of cancer-related mortality. However, the molecular mechanism underlying PDAC progression remains unclear. In this study, we first confirmed that ECM1 is significantly upregulated in PDAC tissues and that its high levels of expression are closely associated with an advanced histologic grade and a poor prognosis using The Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) database. We then found that miR-23a-5p binds directly to the ECM1 3'-untranslated region (3'-UTR), thereby inhibiting ECM1 expression. Functional studies revealed that the induced expression of ECM1 promoted oncogenic abilities and reversed the suppressive effects induced by miR-23a-5p. Collectively, our findings indicate that ECM1 is a proto-oncogene and show that targeting the miR-23a-5p/ECM1 axis may represent a promising therapeutic strategy for PDAC., Competing Interests: None.

Previously, we reported that Y 6 , a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin (DOX)--mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y 6 in reversing drug resistance both in vitro and in vivo by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter (ABCB1 or P-glycoprotein, P-gp). Our results showed that Y 6 significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y 6 significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y 6 exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mouse tumor xenograft model, Y 6 (110 mg/kg, intragastric administration), in combination with doxorubicin (2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y 6 significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.

Background: Computational tools are becoming more and more powerful and comprehensive as compared to past decades in facilitating pharmaceutical, pharmacological and clinical practice. Anticancer agents are used either as monotherapy or in combination therapy to treat malignant conditions of the body. A single antineoplastic agent may be used in different types of malignancies at different doses according to the stage of the disease., Objective: To study the behavior of CPT-11 (Irinotecan) and its metabolite SN-38 in tumor tissue compartment through the Whole Body-Physiologically Pharmacokinetics (WB-PBPK) and to determine the activity of metabolic enzymes and transporters participating in the disposition of CPT-11 and SN-38 working in their physiological environment inside the human body., Methods: Whole body PBPK approach is used to determine the activity of different metabolic enzymes and transporters involved in the disposition of CPT-11 and its active metabolite, SN-38. The concentrations and pharmacokinetic parameters of the parent compound and its metabolite administered at clinically applicable dose via the intravenous route in the tumor tissue are predicted using this approach., Results: The activity rate constants of metabolic enzymes and transporters of CPT-11 are derived at their natural anatomic locations. Concentration-time curves of CPT-11 and SN-38 with their 5th to 95th percentage range are achieved at the tumor tissue level. Mean tumor tissue pharmacokinetics of both compounds are determined in a population of 100 individuals., Conclusion: Tumor tissue concentration-time curves of CPT-11 and SN-38 can be determined via PBPK modeling. Rate constants of enzymes and transporters can be shown for healthy and tumor bearing individuals. The results will throw light on the effective concentration of active compound at its target tissue at the clinically applied IV dose., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Here, we present a novel strategy to fabricate hyaluronic acid (HA) hydrogels with excellent physical and biological properties. The cross-linking of HA hydrogel by butanediol diglycidyle ether (BDDE) was characterized under different reaction temperatures, and the resulting physical properties (i.e., the storage modulus and swelling ratio) were measured. The ratio between the cross-linking rate (a strengthening effect) and the hydrolysis rate (a weakening effect) was much greater with lower cross-linking temperatures after sufficient cross-linking time, resulting in a noticeably higher storage modulus. As the cross-linking temperature decreased, the formed HA hydrogel structure became denser with smaller pores. Moreover, the introduction of low-temperature HA cross-linking strategy also resulted in an enhanced several important characteristics of HA hydrogels including its enzymatic resistivity and its ability to elicit a cellular response. These results indicate the performance of HA hydrogels can be markedly enhanced without further additives or modifications, which is expected to contribute to the advancement of applications of HA hydrogels in all industrial fields., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The potential of Fiber Reinforced Polymer (FRP) in the reinforcement of concrete structures has been shown in many studies and practical applications. However, few works have focused systematically on the development of quantitative criteria to measure surface roughness and relate this parameter to the bonding mechanical property. Moreover, some researchers have declared that, if the concrete interface is rougher, the bond performance between FRP and concrete will be increase, However, there is no answer to how rough the surface is. There are limited application standards for engineers to conduct in FRP reinforcement projects. This work evaluated several concrete specimens with three different strengths and six types of interface roughness. A single shear test was conducted to study the influence of surface roughness on the interfacial bonding performance of a carbon fiber-reinforced composite (CFRP)-concrete beam. The results show that, among the six interfaces, a concrete interface with the roughness of 0.44 has the best interfacial bonding performance. An interfacial appearance with the cement mortar almost cleaned away, and almost one fifth of the single coarse aggregate bared will get the best bond performance. Roughness parameters significantly influenced the effective bond length. The effective bond length of the six interfaces experienced an overall decreasing trend as the roughness increased. The bond⁻slip curves of concrete interfaces with roughness of 0.25⁻0.44 did not significantly change the rigidity within the brittle region. The rougher the interface was, the shorter the brittle region was. After entering a plasticity stage, the bond⁻slip curves for the six types of interfaces all declined with different slopes, and the max slip values were 0.04⁻0.35 mm when debonding failure occurred.

A hyaluronic acid (HAc)-hydroxyapatite (HAp) nanocomposite (HAc-nanoHAp) hydrogel was fabricated through an in situ precipitation process for mechanical and biological enhancement as a soft tissue augmentation product. In this study, these composite hydrogel fillers were analyzed from three different perspectives and compared with pure HAc hydrogel for soft tissue augmentation application: (1) rheological behaviors, (2) in vivo lateral diffusion under mouse skin, and (3) wrinkle improvement in a photo-aged mouse model. HAc-nanoHAp provided great improvement to wrinkles because of its higher stiffness and gel cohesiveness in comparison with that of pure HAc. HAc-nanoHAp also presented great enhancement in strengthening the dermal matrix by stimulating the synthesis of collagen and elastin. Thus, HAc-nanoHAp filler has great potential as a soft tissue augmentation product, improving the biophysical and biological performance in skin tissue. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3315-3325, 2017., (© 2017 Wiley Periodicals, Inc.)

We performed a first-principles study on Fe-, Co-, and Ni-terminated zigzag phosphorene nanoribbons (ZPNRs) with different widths. Magnetic edges were observed for Fe- and Co-terminated ZPNRs, whereas Ni-terminated ZPNRs were nonmagnetic. Interestingly, magnetism could be induced in Ni-ZPNRs by external electric fields, and the distribution of the magnetic moments could be tuned by the direction of the electric fields. Furthermore, Fe-ZPNRs and Co-ZPNRs exhibit semi-metallic and metallic characteristics, respectively, whereas Ni-ZPNRs are mainly semiconductors with band gaps generally increasing monotonously with the increase in nanoribbon width. These fascinating properties of iron-group atom terminated ZPNRs indicate their great potential applications in future spintronics, optoelectronics, and information technologies.

Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Treatment of colorectal cancer remains a challenge to clinicians as well as drug developers. Irinotecan, a Camptothecin derivative, is successfully used for the treatment of this rapidly progressing malignancy and finds its place in the first line of therapeutic agents. Irinotecan is also effective in treating SCLC, malignant glioma and pancreatic adenocarcinoma. However, its adverse effects limit its clinical application. Mainly metabolized by hepatic route, and excreted through biliary tract, this dug has been found to possess high variation in patients in its pharmacokinetic (PK) profile. Physiologically based pharmacokinetic (PBPK) models using compartmental approach have attained their position to foresee the possible PK behavior of different drugs before their administration to patients and such models have been proposed for several anticancer agents. In this work, we used WB-PBPK technology to develop a model in a population of tumor patients who used IV irinotecan therapy. This model depicted the concentration of drug and its pharmacologically active metabolite in human body over a specific period of time. Knowledge about pharmacokinetic parameters is extracted from this profile and the model is evaluated by the observed results of clinical study presented in literature. The predicted behavior of the drug by this approach is in good agreement with the observed results and can aid in further exploration of PK of irinotecan in cancer patients, especially in those concomitantly suffer from other morbidity.

Background: Liver cancer is the second most common cause of cancer death worldwide. The hepatectomy is the most effective and the only potentially curative treatment for patients with resectable neoplasm. Precisely preoperative assessment of remnant liver volume is essential in preventing postoperative liver failure. The aim of our study is to report our experience of using a medical image three dimensional (3D) visualization system (MI-3DVS), which was developed by our team, in assisting hepatectomy for patients with liver cancer., Methods: Between January 2010 and June 2016, 69 patients with liver cancer underwent hepatic resection based on the MI-3DVS were enrolled in this study. All patients underwent CT scan 5 days before the surgery and within 5 days after resection. CT images were reconstructed with the MI-3DVS to assist to perform hepatectomy. Simple linear regression, intra-class correlation coefficient (ICC) and Bland-Altman analysis were used to evaluate the relationship and agreement between actual excisional liver volume (AELV) and predicted excisional liver volume (PELV)., Results: Among 69 patients in this study, 62(89.85%) of them were diagnosed with hepatocellular carcinoma by histopathologic examination, and 41(59.42%) underwent major hepatectomy. The average AELV was 330.13 cm 3 and the average PELV was 287.67 cm 3 . The simple regression equation is AELV = 1.016 × PELV+30.39(r = 0.966; p < 0.0003). PELV (ICC = 0.964) achieved an excellent agreement with AELV with statistical significance (p < 0.001). 65 of 69 dots are in the range of 95% confidence interval in Bland-Altman analyses., Conclusions: The MI-3DVS has advantages of simple usage and convenient hold. It is accurate in assessment of postoperative liver volume and improve safety in liver resection., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Recently, photothermal therapy (PTT) has become viewed as an ideal auxiliary therapeutic treatment for cancers. However, the development of safe, convenient, and highly effective photothermal agents remains a great challenge. In this study, we prepared single-walled carbon nanotubes (SWNTs) for PTT against breast tumors under the guidance of infrared fluorescent cyanines. Tumors were accurately located using near-infrared imaging (NIR) and then exposed to laser irradiation. Both the in vivo and in vitro results showed that the SWNTs have high stability and low cytotoxicity. Introducing polyethylene glycol into our nanoparticles increased the blood-circulation time. Our in vivo results further showed that Cy5.5-conjugated SWNTs mediated PTT, resulting in efficient tumor suppression in mice under the guidance of near-infrared imaging. Due to the small amount of absorption at 808-nm, Cy5.5 increased the efficiency of PTT. Breast tumors significantly shrunk after irradiation under the 808-nm near-infrared laser. The treated mice developed scabs, but otherwise recovered after 15 days, and their physical conditions restored gradually. These data indicate that our unique photothermal-responsive SWNT-Cy5.5-based theranostic agent can serve as a promising candidate for PTT., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

This study was to evaluate the accuracy, consistency, and efficiency of three liver volumetry methods- one interactive method, an in-house-developed 3D medical Image Analysis (3DMIA) system, one automatic active shape model (ASM)-based segmentation, and one automatic probabilistic atlas (PA)-guided segmentation method on clinical contrast-enhanced CT images. Forty-two datasets, including 27 normal liver and 15 space-occupying liver lesion patients, were retrospectively included in this study. The three methods - one semiautomatic 3DMIA, one automatic ASM-based, and one automatic PA-based liver volumetry - achieved an accuracy with VD (volume difference) of -1.69%, -2.75%, and 3.06% in the normal group, respectively, and with VD of -3.20%, -3.35%, and 4.14% in the space-occupying lesion group, respectively. However, the three methods achieved an efficiency of 27.63 mins, 1.26 mins, 1.18 mins on average, respectively, compared with the manual volumetry, which took 43.98 mins. The high intraclass correlation coefficient between the three methods and the manual method indicated an excel-lent agreement on liver volumetry. Significant differences in segmentation time were observed between the three methods (3DMIA, ASM, and PA) and the manual volumetry (p < 0.001), as well as between the automatic volumetries (ASM and PA) and the semiautomatic volumetry (3DMIA) (p < 0.001). The semiautomatic interactive 3DMIA, automatic ASM-based, and automatic PA-based liver volum-etry agreed well with manual gold standard in both the normal liver group and the space-occupying lesion group. The ASM- and PA-based automatic segmentation have better efficiency in clinical use., (© 2016 The Authors.)

Percutaneous abdominal puncture is a popular interventional method for the management of abdominal tumors. Image-guided puncture can help interventional radiologists improve targeting accuracy. The second generation of Kinect(™) was released recently, we developed an optical navigation system to investigate its feasibility for guiding percutaneous abdominal puncture, and compare its performance on needle insertion guidance with that of the first-generation Kinect(™). For physical-to-image registration in this system, two surfaces extracted from preoperative CT and intraoperative Kinect(™) depth images were matched using an iterative closest point (ICP) algorithm. A 2D shape image-based correspondence searching algorithm was proposed for generating a close initial position before ICP matching. Evaluation experiments were conducted on an abdominal phantom and six beagles in vivo. For phantom study, a two-factor experiment was designed to evaluate the effect of the operator's skill and trajectory on target positioning error (TPE). A total of 36 needle punctures were tested on a Kinect(™) for Windows version 2 (Kinect(™) V2). The target registration error (TRE), user error, and TPE are 4.26  ±  1.94 mm, 2.92  ±  1.67 mm, and 5.23  ±  2.29 mm, respectively. No statistically significant differences in TPE regarding operator's skill and trajectory are observed. Additionally, a Kinect(™) for Windows version 1 (Kinect(™) V1) was tested with 12 insertions, and the TRE evaluated with the Kinect(™) V1 is statistically significantly larger than that with the Kinect(™) V2. For the animal experiment, fifteen artificial liver tumors were inserted guided by the navigation system. The TPE was evaluated as 6.40  ±  2.72 mm, and its lateral and longitudinal component were 4.30  ±  2.51 mm and 3.80  ±  3.11 mm, respectively. This study demonstrates that the navigation accuracy of the proposed system is acceptable, and that the second generation Kinect(™)-based navigation is superior to the first-generation Kinect(™), and has potential of clinical application in percutaneous abdominal puncture.

Purpose: A robust, automatic, and rapid method for liver delineation is urgently needed for the diagnosis and treatment of liver disorders. Until now, the high variability in liver shape, local image artifacts, and the presence of tumors have complicated the development of automatic 3D liver segmentation. In this study, an automatic three-level AdaBoost-guided active shape model (ASM) is proposed for the segmentation of the liver based on enhanced computed tomography images in a robust and fast manner, with an emphasis on the detection of tumors., Methods: The AdaBoost voxel classifier and AdaBoost profile classifier were used to automatically guide three-level active shape modeling. In the first level of model initialization, fast automatic liver segmentation by an AdaBoost voxel classifier method is proposed. A shape model is then initialized by registration with the resulting rough segmentation. In the second level of active shape model fitting, a prior model based on the two-class AdaBoost profile classifier is proposed to identify the optimal surface. In the third level, a deformable simplex mesh with profile probability and curvature constraint as the external force is used to refine the shape fitting result. In total, three registration methods-3D similarity registration, probability atlas B-spline, and their proposed deformable closest point registration-are used to establish shape correspondence., Results: The proposed method was evaluated using three public challenge datasets: 3Dircadb1, SLIVER07, and Visceral Anatomy3. The results showed that our approach performs with promising efficiency, with an average of 35 s, and accuracy, with an average Dice similarity coefficient (DSC) of 0.94 ± 0.02, 0.96 ± 0.01, and 0.94 ± 0.02 for the 3Dircadb1, SLIVER07, and Anatomy3 training datasets, respectively. The DSC of the SLIVER07 testing and Anatomy3 unseen testing datasets were 0.964 and 0.933, respectively., Conclusions: The proposed automatic approach achieves robust, accurate, and fast liver segmentation for 3D CTce datasets. The AdaBoost voxel classifier can detect liver area quickly without errors and provides sufficient liver shape information for model initialization. The AdaBoost profile classifier achieves sufficient accuracy and greatly decreases segmentation time. These results show that the proposed segmentation method achieves a level of accuracy comparable to that of state-of-the-art automatic methods based on ASM.

Lung cancer is a leading cause of cancer deaths worldwide, chemotherapy has improved overall survival but remains limited at <12 months median overall survival. Cabazitaxel is hopeful to do the same in advanced lung cancer as well as in metastatic prostate cancer. However, its clinical application was restricted due to its high hydrophobicity and severe side effects. To overcome these problems, we developed self-assembled micelle loading cabazitaxel (CBZ-PM) for therapy of lung cancer. The CBZ-PM has high drug loading (10.52%) and encapsulation efficiency (99.30%) with particle size of 28.77 ± 0.52 nm and polydisperse index of 0.114 ± 0.012. The transmission electron microscope image presented its spherical and homogeneous appearance. In vitro release profile showed CBZ-PM has a sustained-release behavior. Furthermore, the result of cell proliferation assays proved that CBZ-PM could induce the Lewis lung carcinoma (LLC) cells death through G2/M arrest more effectively than free CBZ. In vivo anti-tumor activity of CBZ-PM was further studied in mice model of LLC. The tumor inhibitory rate of CBZ-PM was more than 50% and the survival time of LLC bearing mice was efficiently prolonged following administration of CBZ-PM. In addition, the immunohistochemical study showed that more apoptosis cells were detected in the tumor tissue of CBZ-PM group than that of the positive control group. All these indicated that CBZ-PM served as a potential anti-lung cancer agent., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: A detailed evaluation of blood supply anatomy, especially the biliary anatomy at the hepatic hilus, is essential to ensure a complete and curative resection for Bismuth and Corlette type III hilar cholangiocarcinoma. The study aimed to investigate the impact of individualized preoperative planning using 3D modeling on surgical treatment for type III hilar cholangiocarcinoma., Methods: This was a retrospective study of patients with type III hilar cholangiocarcinoma (n=47) who underwent surgery at the Hepatobiliary Surgery Department of Zhujiang Hospital between March 2007 and January 2015. All patients had undergone preoperative computed tomography (CT) examination, and 3D images were reconstructed. Preoperative surgery simulation was performed, and the simulation was applied in the subsequent surgery. Clinical, surgical, and pathological characteristics were compared between patients undergoing preoperative planning (n=25) and those who did not (n=22). Complications were examined., Results: Surgical time and blood loss were significantly smaller in patients with 3D reconstruction compared to those without. The number of bile duct orifices was correctly estimated in 14/25 (56.0%) patients with preoperative planning. The width of the hepatic surgical margin could be measured for 18 hepatic ducts, and 17 (68.0%) of them were pathologically diagnosed as margin-negative., Conclusions: This technique has the advantages of precise visualization of the anatomic structures and 3D assessment of biliary branches and vessels, allowing improved operative planning for the treatment of hilar cholangiocarcinoma.

Tissue necrosis commonly accompanies the development of a wide range of serious diseases. Therefore, highly sensitive detection and precise boundary delineation of necrotic tissue via effective imaging techniques are crucial for clinical treatments; however, no imaging modalities have achieved satisfactory results to date. Although fluorescence molecular imaging (FMI) shows potential in this regard, no effective necrosis-avid fluorescent probe has been developed for clinical applications. Here, we demonstrate that indocyanine green (ICG) can achieve high avidity of necrotic tissue owing to its interaction with lipoprotein (LP) and phospholipids. The mechanism was explored at the cellular and molecular levels through a series of in vitro studies. Detection of necrotic tissue and real-time image-guided surgery were successfully achieved in different organs of different animal models with the help of FMI using in house-designed imaging devices. The results indicated that necrotic tissue with a 0.6 mm diameter could be effectively detected with precise boundary definition. We believe that the new discovery and the associated imaging techniques will improve personalized and precise surgery in the near future.