circ_WASF2 regulates ferroptosis by miR-634/ GPX4 signaling in pancreatic cancer.

PURPOSE: Pancreatic cancer (PC) is one of the most lethal malignant gastrointestinal tumors (GI) characterized by a poor prognosis. Ferroptosis is an emerging programmed cell death that plays an essential role in the progression of various cancers. Ferroptosis is driven by iron-dependent phospholipid peroxidation and is regulated by mitochondrial activity, lipid peroxidation, and reactive oxygen species (ROS). The function and mechanism of ferroptosis in PC need more research. METHODS: The levels of circRNAs, miRNAs, and mRNAs were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was used for protein detection. CCK8 assays were used to detect cell proliferation. Cell death, lipid peroxidation, ROS, and Fe2+ were detected by indicted kits. Dual-luciferase reporter and RNA pull-down assays were conducted to confirm the interaction between circRNAs, miRNAs, and mRNAs. RESULTS: In this research, we found that circular RNA hsa_circ_0000003(circ_WASF2) was upregulated in pancreatic cancer cells. The silence of circ_WASF2 inhibited cancer proliferation and increased cell death by increasing ferroptosis accompanied by up-regulation of lipid peroxidation, ROS, and Fe2+. Further studies showed that circ_WASF2 could attenuate ferroptosis by targeting miR-634 and the downstream glutathione peroxidase 4 (GPX4). GPX4 has been well-reported as a central factor in ferroptosis. Our research revealed a new pathway for regulating ferroptosis in PC. CONCLUSION: In summary, we have determined that circ_WASF2/miR-634/GPX4 contributed to ferroptosis-induced cell death, and provided a possible therapeutic target in PC.

Carbon Corrosion Induced by Surface Defects Accelerates Degradation of Platinum/Graphene Catalysts in Oxygen Reduction Reaction.

Graphene supported electrocatalysts have demonstrated remarkable catalytic performance for oxygen reduction reaction (ORR). However, their durability and cycling performance are greatly limited by Oswald ripening of platinum (Pt) and graphene support corrosion. Moreover, comprehensive studies on the mechanisms of catalysts degradation under 0.6-1.6 V versus RHE (Reversible Hydrogen Electrode) is still lacking. Herein, degradation mechanisms triggered by different defects on graphene supports are investigated by two cycling protocols. In the start-up/shutdown cycling (1.0-1.6 V vs. RHE), carbon oxidation reaction (COR) leads to shedding or swarm-like aggregation of Pt nanoparticles (NPs). Theoretical simulation results show that the expansion of vacancy defects promotes reaction kinetics of the decisive step in COR, reducing its reaction overpotential. While under the load cycling (0.6-1.0 V vs. RHE), oxygen containing defects lead to an elevated content of Pt in its oxidation state which intensifies Oswald ripening of Pt. The presence of vacancy defects can enhance the transfer of electrons from graphene to the Pt surface, reducing the d-band center of Pt and making it more difficult for the oxidation state of platinum to form in the cycling. This work will provide comprehensive understanding on Pt/Graphene catalysts degradation mechanisms.

Ubiquitin-specific protease-7 promotes expression of airway mucin MUC5AC via the NF-κB signaling pathway.

Chronic obstructive pulmonary disease (COPD) and other respiratory diseases frequently present with airway mucus hypersecretion, which not only affects the patient's quality of life but also poses a constant threat to their life expectancy. Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, affects cell differentiation, tissue growth, and disease development. However, its role in airway mucus hypersecretion induced by COPD remains elusive. In this study, USP7 expression was significantly upregulated in airway epithelial samples from patients with COPD, and USP7 was also overexpressed in mouse lung and human airway epithelial cells in models of airway mucus hypersecretion. Inhibition of USP7 reduced the expression of nuclear factor kappa B (NF-κB), phosphorylated-NF-κB (p-NF-κB), and phosphonated inhibitor of nuclear factor kappa B (p-IκBα), and alleviated the airway mucus hypersecretion in vivo and in vitro. Further research revealed that USP7 stimulated airway mucus hypersecretion through the activation of NF-κB nuclear translocation. In addition, the expression of mucin 5AC (MUC5AC) was suppressed by the NF-κB inhibitor erdosteine. These findings suggest that USP7 stimulates the NF-κB signaling pathway, which promotes airway mucus hypersecretion. This study identifies one of the mechanisms regulating airway mucus secretion and provides a new potential target for its prevention and treatment.

Near Infrared-II Excited Triplet Fusion Upconversion with Anti-Stokes Shift Approaching the Theoretical Limit.

The anti-Stokes shift represents the capacity of photon upconversion to convert low-energy photons to high-energy photons. Although triplet exciton-mediated photon upconversion presents outstanding performance in solar energy harvesting, photoredox catalysis, stereoscopic 3D printing, and disease therapeutics, the interfacial multistep triplet exciton transfer leads to exciton energy loss to suppress the anti-Stokes shift. Here, we report near infrared-II (NIR-II) excitable triplet exciton-mediated photon upconversion using a hybrid photosensitizer consisting of lead sulfide quantum dots (PbS QDs) and new surface ligands of thiophene-substituted diketopyrrolopyrrole (Th-DPP). Under 1064 nm excitation, this photon upconversion revealed a record-corrected upconversion efficiency of 0.37% (normalized to 100%), with the anti-Stokes shift (1.07 eV) approaching the theoretical limit (1.17 eV). The observation of this unexpected result is due to our discovery of the presence of a weak interaction between the sulfur atom on Th-DPP and Pb2+ on the PbS QDs surface, facilitating electronic coupling between PbS QDs and Th-DPP, such that the realization of triplet exciton transfer efficiency is close to 100% even when the energy gap is as small as 0.04 eV. With this premise, this photon upconversion as a photocatalyst enables the production of standing organic gel via photopolymerization under 1064 nm illumination, displaying NIR-II photon-driven photoredox catalysis. This research not only establishes the foundation for enhancing the performance of NIR-II excitable photonic upconversion but also promotes its development in photonics and photoredox catalysis.

First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

Regulating the Pore Structure of Activated Carbon by Pitch for High-Performance Sodium-Ion Storage.

The pore structure of carbon anodes plays a crucial role in enhancing the sodium storage capacity. Designing more confined pores in carbon anodes is accepted as an effective strategy. However, current design strategies for confined pores in carbon anodes fail to achieve both high capacity and initial Coulombic efficiency (ICE) simultaneously. Herein, we develop a strategy for utilizing the repeated impregnation and precarbonization method of liquid pitch to regulate the pore structure of the activated carbon (AC) material. Driven by capillary coalescence, the pitch is impregnated into the pores of AC, which reduces the specific surface area of the material. During the carbonization process, numerous pores with diameters less than 1 nm are formed, resulting in a high capacity and improved ICE of the carbon anode. Moreover, the ordered carbon layers derived from the liquid pitch also enhance the electrical conductivity, thereby improving the rate capability of as-obtained carbon anodes. This enables the fabricated material (XA-4T-1300) to have a high ICE of 91.1% and a capacity of 383.0 mA h g-1 at 30 mA g-1. The capacity retention is 95.5% after 300 cycles at 1 A g-1. This study proposes a practical approach to adjust the microcrystalline and pore structures to enhance the performance of sodium-ion storage in materials.

Antibiotic heteroresistance in Klebsiella pneumoniae: Definition, detection methods, mechanisms, and combination therapy.

Klebsiella pneumoniae is a common opportunistic pathogen that presents significant challenges in the treatment of infections due to its resistance to multiple antibiotics. In recent years, K. pneumoniae has been reported for the development of heteroresistance, a phenomenon where subpopulations of the susceptible bacteria exhibit resistance. This heteroresistance has been associated with increased morbidity and mortality rates. Complicating matters further, its definition and detection pose challenges, often leading to its oversight or misdiagnosis. Various mechanisms contribute to the development of heteroresistance in K. pneumoniae, and these mechanisms differ among different antibiotics. Even for the same antibiotic, multiple mechanisms may be involved. However, our current understanding of these mechanisms remains incomplete, and further research is needed to gain a more comprehensive understanding of heteroresistance. While the clinical recommendation is to use combination antibiotic therapy to mitigate heteroresistance, this approach also comes with several drawbacks and potential adverse effects. In this review, we discuss the definition, detection methods, molecular mechanisms, and treatment of heterogenic resistance, aiming to pave the way for more effective treatment and management in the future. However, addressing the problem of heteroresistance in K. pneumoniae represents a long and complex journey that necessitates comprehensive research efforts.

Associations of Frailty with Neuropsychiatric Symptoms of Alzheimer's Disease: A Longitudinal Study.

Background: Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health. Objective: To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD), especially in its different clinical stages. Methods: We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation analyses were conducted to explore the mediation factors between frailty and NPSs. Results: Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%. Conclusions: Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations.

Efficacy and Safety of Type III Collagen Lyophilized Fibers Using Mid-to-Deep Dermal Facial Injections for the Correction of Dynamic Facial Wrinkles.

BACKGROUND: This study aimed to evaluate the therapeutic efficacy and safety of injecting Type III collagen lyophilized fibers into the mid-to-deep layers of the facial dermis to ameliorate dynamic facial wrinkles. METHODS: In this retrospective analysis, clinical data were collected from patients exhibiting dynamic facial wrinkles (encompassing frown lines, forehead lines, and crow's feet) with a wrinkle severity rating scale (WSRS) score of 3 or higher. In the control group, 75 participants received collagen implant injections into the mid-to-deep facial dermal layers, whereas 76 participants in the experimental group received injections of Type III collagen lyophilized fibers in similar layers. The study analyzed and compared clinical efficacy, WSRS score alterations, patient satisfaction, and safety profiles between the groups over the 30-day and 90-day treatment periods. RESULTS: At the 30-day mark, the therapeutic efficacy was not significantly different between the two groups (P > 0.05). However, at 90 days, the treatment efficacy in the experimental group surpassed that in the control group, showing a statistically significant difference (P < 0.05). After 30 days of treatment, the WSRS score improvement in the experimental group was significantly superior to that in the control group (P < 0.05). Conversely, at the 90-day mark, the results revealed no significant variation in WSRS score improvements between the two groups (P > 0.05). Regarding treatment satisfaction among researchers and participants post-30 and 90-day treatment in both groups, no statistically significant differences were observed (P > 0.05). Similarly, the incidence of adverse reactions between the groups was not statistically significant (P > 0.05). CONCLUSIONS: Injections of lyophilized type III collagen fibers into the mid-to-deep layers of the facial dermis have a definitive therapeutic effect on dynamic facial wrinkles. This treatment not only substantially diminishes wrinkle severity but also has a commendable safety profile. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Association of peripheral immunity and cerebral small vessel disease in older adults without dementia: A longitudinal study.

This study explored the associations between peripheral immunity with cerebral small vessel diseases. Older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative were investigated. Peripheral blood was obtained, and magnetic resonance imaging was performed to measure cerebral microbleeds (CMB), lacunar infarctions (LI), and white matter hyperintensities (WMH). Multivariable-adjusted regression models, linear mixed-effects models, and the Spearman correlations were used to evaluate the associations. At baseline, individuals with greater neutrophils (odds ratio [OR] =1.10, 95% confidence interval [CI] 1.00-1.20, p=0.042) and monocytes (OR=1.12, 95% CI 1.02-1.22, p=0.016) had higher WMH volume. On the contrary, a higher lymphocyte-to-monocyte ratio (LMR) was related to lower WMH volume (OR=0.91, 95% CI 0.82-1.00, p=0.041). Longitudinally, higher neutrophils (ρ=0.084, p=0.049) and NLR (ρ=0.111, p=0.009) predicted accelerated progression of WMH volume, while a greater LMR (ρ=-0.101, p=0.018) was linked to slower growth of WMH volume. Nevertheless, associations between peripheral immunity with CMB or LI were not observed at baseline and follow-up. Our study found that peripheral immune indexes could serve as convenient noninvasive biomarkers of WMH.

Natural compound library screening to identify berberine as a treatment for rheumatoid arthritis.

OBJECTIVE: Fibroblast-like synoviocytes (FLS) play a critical role on the exacerbation and deterioration of rheumatoid arthritis (RA). Aberrant activation of FLS pyroptosis signaling is responsible for the hyperplasia of synovium and destruction of cartilage of RA. This study investigated the screened traditional Chinese medicine berberine (BBR), an active alkaloid extracted from the Coptis chinensis plant, that regulates the pyroptosis of FLS and secretion of inflammatory factors in rheumatoid arthritis. METHODS: First, BBR was screened using a high-throughput drug screening strategy, and its inhibitory effect on RA-FLS was verified by in vivo and in vitro experiments. Second, BBR was intraperitoneally administrated into the collagen-induced arthritis rat model, and the clinical scores, arthritis index, and joint HE staining were evaluated. Third, synovial tissues of CIA mice were collected, and the expression of NLRP3, cleaved-caspase-1, GSDMD-N, Mst1, and YAP was detected by Western blot. RESULTS: The administration of BBR dramatically alleviated the severity of collagen-induced arthritis rat model with a decreased clinical score and inflammation reduction. In addition, BBR intervention significantly attenuates several pro-inflammatory cytokines (interleukin-1ß, interleukin-6, interleukin-17, and interleukin-18). Moreover, BBR can reduce the pyroptosis response (caspase-1, NLR family pyrin domain containing 3, and gasdermin D) of the RA-FLS in vitro, activating the Hippo signaling pathway (Mammalian sterile 20-like kinase 1, yes-associated protein, and transcriptional enhanced associate domains) so as to inhibit the pro-inflammatory effect of RA-FLS. CONCLUSION: These results support the role of BBR in RA and may have therapeutic implications by directly repressing the activation, migration of RA-FLS, which contributing to the attenuation of the progress of CIA. Therefore, targeting PU.1 might be a potential therapeutic approach for RA. Besides, BBR inhibited RA-FLS pyroptosis by downregulating of NLRP3 inflammasomes (NLRP3, caspase-1) and eased the pro-inflammatory activities via activating the Hippo signaling pathway, thereby improving the symptom of CIA.

Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.

Augmented CD4+ T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4+ T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4+ T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4+ T cell subsets in vitro, and mice with KAT6A-deficient CD4+ T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4+ T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity.

Clinical Experience of External Application of Clearing Heat and Removing Dampness in Relieving Grade 2 to 3 Rash Caused by Programed Cell Death Protein 1 (PD-1)/Programed Cell Death Ligand 1 (PD-L1) Inhibitors: A Single-Center Retrospective Study.

OBJECTIVE: In China, grade 2 to 3 immune-related rash will probably lead to the interruption of immunotherapy. Corticosteroid (CS) is the main treatment, but not always effective. The external application of clearing heat and removing dampness, which is represented by Qing-Re-Li-Shi Formula (QRLSF), has been used in our hospital to treat immune-related cutaneous adverse events (ircAEs) for the last 5 years. The purpose of this study was to discuss its efficacy and safety in the treatment of grade 2 to 3 rash. METHODS: A retrospective study of patients with grade 2 to 3 immune-related rash in our hospital from December 2019 to December 2022 was conducted. These patients received QRLSF treatment. Clinical characteristics, treatment outcome, and health-related quality of life (HrQoL) were analyzed. RESULTS: Thirty patients with grade 2 to 3 rash (median onset time: 64.5 days) were included. The skin lesions of 24 cases (80%) returned to grade 1 with a median time of 8 days. The accompanying symptoms were also improved with median time of 3 to 4 days. The addition of antihistamine (AH) drug didn't increase the efficacy of QRLSF (AH + QRLSF: 75.00% vs QRLSF: 83.33%, P = .66). No significant difference was observed in the efficacy of QRLSF treatment regardless of whether patients had previously received CS therapy (untreated population: 88.24% vs treated population: 69.23%, P = .36). During 1-month follow-up, 2 cases (8.33%) underwent relapses. In terms of HrQoL, QRLSF treatment could significantly reduce the median scores of all domains of Skindex-16, including symptoms (39.58 vs 8.33, P < .0001), emotions (58.33 vs 15.48, P < .0001), functioning (46.67 vs 13.33, P < .0001) and composite (52.60 vs 14.06, P < .0001). CONCLUSION: External application of clearing heat and removing dampness was proven to be an effective and safe treatment for such patients. In the future, high-quality trials are required to determine its clinical application in the field of ircAEs.

Associations of cerebrospinal fluid complement proteins with Alzheimer's pathology, cognition, and brain structure in non-dementia elderly.

BACKGROUND: Cerebrospinal fluid (CSF) complement activation is a key part of neuroinflammation that occurs in the early stages of Alzheimer's disease (AD). However, the associations of CSF complement proteins with AD pathology, cognition, and structural neuroimaging biomarkers for AD have been rarely investigated. METHODS: A total of 210 participants (125 mild cognitive impairment [MCI] patients and 85 normal controls) were included from Alzheimer's Disease Neuroimaging Initiative (ADNI) database who measured AD pathology, cognition, and neuroimaging at baseline and every 12 months. The mixed-effect linear models were utilized to investigate longitudinal associations of CSF complement proteins with AD pathology, cognition, and neuroimaging in cognitively normal (CN) and mild cognitive impairment (MCI) subjects. Causal mediation analyses were conducted to explore the potential mediators between CSF complement proteins and cognitive changes. RESULTS: We found that the subjects with low CSF complement protein levels at baseline had worse outcomes in AD pathology, indicated by their lowest concentrations observed in A + and A + T + individuals. The reduced CSF complement proteins were associated with faster accumulation of tau among CN subjects and with cognitive decline and greater brain atrophy of specific regions among MCI subjects. Furthermore, mediation analyses showed that the effects of CSF complement proteins on cognitive performance were partially mediated by regional brain structures (mediation proportions range from 19.78 to 94.92%; p < 0.05). CONCLUSIONS: This study demonstrated that CSF complement proteins were involved in the early progression of AD. Our results indicated that regional brain atrophy might be a plausible way to connect CSF complement protein levels and cognition.

Evaluation of bevacizumab biosimilar on wound healing complications in patients with colorectal cancer undergoing endoscopic mucosal resection: A systematic review and meta-analysis in anorectal medicine.

Complications related to wound healing pose substantial obstacle in the management of colorectal cancer (CRC), specifically in the field of anorectal medicine. Biosimilars of bevacizumab have emerged as crucial therapeutic agents in the management of these complications. With the particular emphasis on effects of Bevacizumab Biosimilar Plus on wound healing among patients diagnosed with CRC, this review underscores the potential of this anorectal medication to improve patient outcomes and was aimed to assess the safety and efficacy of Bevacizumab Biosimilar Plus in relation to complications associated with wound healing in patients with CRC. The assessment centers on its therapeutic potential and safety profile within the domain of anorectal medicine. In accordance with the PRISMA guidelines, a comprehensive literature search was performed, resulting in the identification of 19 pertinent studies out of an initial 918. Priority was given to assessing the safety and adverse effects of Bevacizumab Biosimilar Plus in conjunction with its effectiveness in wound healing. The extracted data comprised the following: study design, patient demographics, comprehensive treatment regimens, wound healing-specific outcomes and adverse effects. The evaluation of study quality was conducted utilizing the instruments provided by the Cochrane Collaboration and the Newcastle-Ottawa Scale (NOS). Bevacizumab Biosimilar Plus demonstrates efficacy in the management of wound healing complications among patients with CRC, with a safety and efficacy profile similar to that of the original Bevacizumab, according to the analysis. Notably, several studies reported improved rates of wound healing in relation to the biosimilar. The safety profiles exhibited similarities to the anticipated anti-VEGF agent effects. In wound management, the biosimilar also demonstrated advantages in terms of prolonged efficacy. In addition, analyses of cost-effectiveness suggested that the use of biosimilars could result in cost reductions. Bevacizumab Biosimilar Plus exhibited potential as an anorectal medication for the effective management of wound healing complications in patients with CRC. This has substantial ramifications for improving the quality of patient care, encompassing the affordability and effectiveness of treatments.

SPOP promotes CREB5 ubiquitination to inhibit MET signaling in liver cancer.

Liver cancer is ranked as the sixth most prevalent from of malignancy globally and stands as the third primary contributor to cancer-related mortality. Metastasis is the main reason for liver cancer treatment failure and patient deaths. Speckle-type POZ protein (SPOP) serves as a crucial substrate junction protein within the cullin-RING E3 ligase complex, acting as a significant tumor suppressor in liver cancer. Nevertheless, the precise molecular mechanism underlying the role of SPOP in liver cancer metastasis remain elusive. In the current study, we identified cAMP response element binding 5 (CREB5) as a novel SPOP substrate in liver cancer. SPOP facilitates non-degradative K63-polyubiquitination of CREB5 on K432 site, consequently hindering its capacity to activate receptor tyrosine kinase MET. Moreover, liver cancer-associated SPOP mutant S119N disrupts the SPOP-CREB5 interactions and impairs the ubiquitination of CREB5.This disruption ultimately leads to the activation of the MET signaling pathway and enhances metastatic properties of hepatoma cells both in vitro and in vivo. In conclusion, our findings highlight the functional significance of the SPOP-CREB5-MET axis in liver cancer metastasis.

Diagnosis and treatment of the portal vein complications for children undergoing spilt liver transplantation / 器官移植

Objective To investigate the diagnosis and treatment strategy of the portal vein complications in children undergoing split liver transplantation. Methods The clinical data of 88 pediatric recipients who underwent split liver transplantation were retrospectively analyzed. Intraoperative anastomosis at the bifurcating site of the portal vein or donor iliac vein bypass anastomosis was performed depending on the internal diameter and development of the recipient's portal vein. A normalized portal venous blood stream monitoring was performed during the perioperative stage. After operation, heparin sodium was used to bridge warfarin for anticoagulation therapy. After portal vein stenosis or thrombosis was identified with enhanced CT or portography, managements including embolectomy, systemic anticoagulation, interventional thrombus removal, balloon dilatation and/or stenting were performed. Results Among the 88 recipients, a total of 10 children were diagnosed with portal vein complications, of which 4 cases were diagnosed with portal vein stenosis at 1 d, 2 months, 8 months, and 11 months after surgery, and 6 cases were diagnosed with portal vein thrombosis at intraoperative, 2 d, 3 d (n=2), 6 d, and 11 months after surgery, respectively. One patient with portal vein stenosis and one patient with portal vein thrombosis died perioperatively. The fatality related to portal vein complications was 2% (2/88). Of the remaining 8 patients, 1 underwent systemic anticoagulation, 2 underwent portal venous embolectomy, 1 underwent interventional balloon dilatation, and 4 underwent interventional balloon dilatation plus stenting. No portal venous related symptoms were detected during postoperative long term follow up, and the retested portal venous blood stream parameters were normal. Conclusions The normalized intra- and post-operative portal venous blood stream monitoring is a useful tool for the early detection of portal vein complications, the early utilization of useful managements such as intraoperative portal venous embolectomy, interventional balloon dilatation and stenting may effectively treat the portal vein complications, thus minimizing the portal vein complication related graft loss and recipient death.

Double-edged role of mechanical stimuli and underlying mechanisms in cartilage tissue engineering.

Mechanical stimuli regulate the chondrogenic differentiation of mesenchymal stem cells and the homeostasis of chondrocytes, thus affecting implant success in cartilage tissue engineering. The mechanical microenvironment plays fundamental roles in the maturation and maintenance of natural articular cartilage, and the progression of osteoarthritis Hence, cartilage tissue engineering attempts to mimic this environment in vivo to obtain implants that enable a superior regeneration process. However, the specific type of mechanical loading, its optimal regime, and the underlying molecular mechanisms are still under investigation. First, this review delineates the composition and structure of articular cartilage, indicating that the morphology of chondrocytes and components of the extracellular matrix differ from each other to resist forces in three top-to-bottom overlapping zones. Moreover, results from research experiments and clinical trials focusing on the effect of compression, fluid shear stress, hydrostatic pressure, and osmotic pressure are presented and critically evaluated. As a key direction, the latest advances in mechanisms involved in the transduction of external mechanical signals into biological signals are discussed. These mechanical signals are sensed by receptors in the cell membrane, such as primary cilia, integrins, and ion channels, which next activate downstream pathways. Finally, biomaterials with various modifications to mimic the mechanical properties of natural cartilage and the self-designed bioreactors for experiment in vitro are outlined. An improved understanding of biomechanically driven cartilage tissue engineering and the underlying mechanisms is expected to lead to efficient articular cartilage repair for cartilage degeneration and disease.

[Optimization of extraction process for classic prescription Yihuang Decoction based on Box-Behnken design-response surface methodology, standard relation, and analytic hierarchy process combined with entropy weight method].

Based on the concept of quality by design(QbD), the Box-Behnken design-response surface methodology combined with standard relation(SR) and analytic hierarchy process(AHP)-entropy weight method(EWM) was applied to optimize the extraction process of the classic prescription Yihuang Decoction. The content of geniposidic acid, phellodendrine hydrochloride, and berberine hydrochloride in Yihuang Decoction, the extract yield, and fingerprint similarity were used as the critical quality attributes(CQAs) of the extraction process. The extraction time, water addition, and extraction times were used as the critical process parameters(CPPs). After determining the levels of each factor and level through single-factor experiments, response surface experiments were designed according to the Box-Behnken principle, and the experimental results were analyzed. The SR between each sample and the reference sample under various evaluation indicators of different extraction parameters was calculated. The weights of the five evaluation indicators were determined using AHP-EWM, followed by comprehensive evaluation. A function model between CPPs and CQAs characterized by comprehensive scores was established to predict the optimal extraction process parameters. In the final comprehensive weight coefficients, the yield rate accounted for 43.1%, and the content of berberine hydrochloride, phellodendrine hydrochloride, and geniposidic acid accounted for 35.1%, 6.3%, and 15.5%, respectively. After comprehensive score analysis with SR, the established second-order polynomial model was statistically significant(P<0.01, and the lack of fit was not significant). The predicted optimal extraction conditions for Yihuang Decoction were determined as follows: 8-fold volume of water, extraction time of 1.5 h, and extraction once. The mean comprehensive score of the validation experiment was 85.77, with an RSD of 0.99%, and it met the quality control stan-dards for the reference sample of Yihuang Decoction. The results indicate that the optimized extraction process for Yihuang Decoction is stable and reliable, and the water extract is close in quality attributes to the reference sample. This can serve as a foundation for the research and development of granules in the future. Box-Behnken design-response surface methodology combined with SR and AHP-EWM can provide references for the modern extraction process research of other classic prescriptions.