Cuproptosis: unveiling a new frontier in cancer biology and therapeutics.

Copper plays vital roles in numerous cellular processes and its imbalance can lead to oxidative stress and dysfunction. Recent research has unveiled a unique form of copper-induced cell death, termed cuproptosis, which differs from known cell death mechanisms. This process involves the interaction of copper with lipoylated tricarboxylic acid cycle enzymes, causing protein aggregation and cell death. Recently, a growing number of studies have explored the link between cuproptosis and cancer development. This review comprehensively examines the systemic and cellular metabolism of copper, including tumor-related signaling pathways influenced by copper. It delves into the discovery and mechanisms of cuproptosis and its connection to various cancers. Additionally, the review suggests potential cancer treatments using copper ionophores that induce cuproptosis, in combination with small molecule drugs, for precision therapy in specific cancer types.

Decreased stress shielding with poly-ether-ether-ketone tibial implant for total knee arthroplasty - A preliminary study using finite element analysis.

In total knee arthroplasty (TKA), the mechanical mismatch between cobalt-chromium (CoCr) alloy tibial implant and bone has been implicated in stress shielding and subsequent implant failure and bone resorption. This study investigates the biomechanical advantages of poly-ether-ether-ketone (PEEK) tibial implant, which exhibit properties analogous to those of the surrounding bone. A finite element analysis (FEA) was employed to assess and compare the biomechanical performances of PEEK and CoCr tibial implants in patients with and without osteoporosis. Four FEA models were constructed with PEEK and CoCr alloy implants in normal and osteoporotic tibias. Based on previous literature and our clinical experience, stresses measurements were taken at 16 points on the tibial plateau and 8 points on the two surfaces which were 10 mm and 20 mm apart from the tibial plateau, with specific regions quantified for stress shielding. The results showed significant differences in stress distribution between PEEK and CoCr implants. The PEEK implants exhibited higher equivalent stresses on the tibial plateau in all models (normal bone: 0.22 ± 0.07 MPa vs. 0.13 ± 0.06 MPa, p < 0.01; osteoporotic bone: 0.39 ± 0.06 MPa vs. 0.17 ± 0.07 MPa, p < 0.01). In non-osteoporotic models, the mean equivalent stresses on proximal tibial surfaces were similarly elevated for PEEK implants (0.29 ± 0.13 MPa vs. 0.21 ± 0.08 MPa, p = 0.02). The CoCr implants demonstrated more stress shielding across all measured regions (tibial plateau: 23.47% vs. 2.73%; surface 1: 15.93% vs. 1.37%; surface 2: 10.71% vs. 6.56%). These disparities were even more pronounced in osteoporotic models in the CoCr group (tibial plateau: 32.50% vs. 8.36%). The maximum equivalent stresses on the tibial plateau further supported this trend (normal bone: 1.02 MPa vs. 0.52 MPa; osteoporotic bone: 1.43 MPa vs. 0.67 MPa). These data confirm the hypothesis that a PEEK tibial implant can reduce peri-prosthetic stress shielding, suggesting that PEEK implants have the capability to distribute loads more uniformly and maintain a closer approximation to physiological conditions.

Hypoxic Exosomal circPLEKHM1-Mediated Crosstalk between Tumor Cells and Macrophages Drives Lung Cancer Metastasis.

Intercellular communication often relies on exosomes as messengers and is critical for cancer metastasis in hypoxic tumor microenvironment. Some circular RNAs (circRNAs) are enriched in cancer cell-derived exosomes, but little is known about their ability to regulate intercellular communication and cancer metastasis. Here, by systematically analyzing exosomes secreted by non-small cell lung cancer (NSCLC) cells, a hypoxia-induced exosomal circPLEKHM1 is identified that drives NSCLC metastasis through polarizing macrophages toward to M2 type. Mechanistically, exosomal circPLEKHM1 promoted PABPC1-eIF4G interaction to facilitate the translation of the oncostatin M receptor (OSMR), thereby promoting macrophage polarization for cancer metastasis. Importantly, circPLEKHM1-targeted therapy significantly reduces NSCLC metastasis in vivo. circPLEKHM1 serves as a prognostic biomarker for metastasis and poor survival in NSCLC patients. This study unveils a new circRNA-mediated mechanism underlying how cancer cells crosstalk with macrophages within the hypoxic tumor microenvironment to promote metastasis, highlighting the importance of exosomal circPLEKHM1 as a prognostic biomarker and therapeutic target for lung cancer metastasis.

68Ga-FAPI PET imaging monitors response to combined TGF-ßR inhibition and immunotherapy in metastatic colorectal cancer.

BACKGROUNDImproving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor-ß receptor (TGF-ßR) inhibitor that targets cancer-associated fibroblasts (CAFs) is promising for the enhancement of efficacy of immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy.METHODSWe measured CAFs in vivo using the 68Ga-labeled fibroblast activation protein inhibitor-04 (68Ga-FAPI-04) for PET/CT imaging to guide the combination of TGF-ß inhibition and immunotherapy. One hundred thirty-one patients with metastatic colorectal cancer (CRC) underwent 68Ga-FAPI and 18F-fluorodeoxyglucose (18F-FDG) PET/CT imaging. The relationship between uptake of 68Ga-FAPI and tumor immunity was analyzed in patients. Mouse cohorts of metastatic CRC were treated with the TGF-ßR inhibitor combined with KN046, which blocks programmed death ligand 1 (PD-L1) and CTLA-4, followed by 68Ga-FAPI and 18F-FDG micro-PET/CT imaging to assess tumor responses.RESULTSPatients with metastatic CRC demonstrated high uptake rates of 68Ga-FAPI, along with suppressive tumor immunity and poor prognosis. The TGF-ßR inhibitor enhanced tumor-infiltrating T cells and significantly sensitized metastatic CRC to KN046. 68Ga-FAPI PET/CT imaging accurately monitored the dynamic changes of CAFs and tumor response to combined the TGF-ßR inhibitor with immunotherapy.CONCLUSION68Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and the response to immunotherapy in metastatic CRC. This study supports future clinical application of 68Ga-FAPI PET/CT to guide precise TGF-ß inhibition plus immunotherapy in CRC patients, recommending 68Ga-FAPI and 18F-FDG dual PET/CT for CRC management.TRIAL REGISTRATIONCFFSTS Trial, ChiCTR2100053984, Chinese Clinical Trial Registry.FUNDINGNational Natural Science Foundation of China (82072695, 32270767, 82272035, 81972260).

Arterial chemotherapy for hepatocellular carcinoma in China: consensus recommendations.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer-related deaths globally. Hepatic arterial infusion chemotherapy (HAIC) treatment is widely accepted as one of the alternative therapeutic modalities for HCC owing to its local control effect and low systemic toxicity. Nevertheless, although accumulating high-quality evidence has displayed the superior survival advantages of HAIC of oxaliplatin, fluorouracil, and leucovorin (HAIC-FOLFOX) compared with standard first-line treatment in different scenarios, the lack of standardization for HAIC procedure and remained controversy limited the proper and safe performance of HAIC treatment in HCC. Therefore, an expert consensus conference was held on March 2023 in Guangzhou, China to review current practices regarding HAIC treatment in patients with HCC and develop widely accepted statements and recommendations. In this article, the latest evidence of HAIC was systematically summarized and the final 22 expert recommendations were proposed, which incorporate the assessment of candidates for HAIC treatment, procedural technique details, therapeutic outcomes, the HAIC-related complications and corresponding treatments, and therapeutic scheme management.

CAR-T cell therapy for hematological malignancies: History, status and promise.

For many years, the methods of cancer treatment are usually surgery, chemotherapy and radiation therapy. Although these methods help to improve the condition, most tumors still have a poor prognosis. In recent years, immunotherapy has great potential in tumor treatment. Chimeric antigen receptor T-cell immunotherapy (CAR-T) uses the patient's own T cells to express chimeric antigen receptors. Chimeric antigen receptor (CAR) recognizes tumor-associated antigens and kills tumor cells. CAR-T has achieved good results in the treatment of hematological tumors. In 2017, the FDA approved the first CAR-T for the treatment of B-cell acute lymphoblastic leukemia (ALL). In October of the same year, the FDA approved CAR-T to treat B-cell lymphoma. In order to improve and enhance the therapeutic effect, CAR-T has become a research focus in recent years. The structure of CAR, the targets of CAR-T treatment, adverse reactions and improvement measures during the treatment process are summarized. This review is an attempt to highlight recent and possibly forgotten findings of advances in chimeric antigen receptor T cell for treatment of hematological tumors.

A predictive model of immune infiltration and prognosis of head and neck squamous cell carcinoma based on cell adhesion-related genes: including molecular biological validation.

Background: Focal adhesion serves as a bridge between tumour cells and the extracellular matrix (ECM) and has multiple roles in tumour invasion, migration, and therapeutic resistance. However, studies on focal adhesion-related genes (FARGs) in head and neck squamous cell carcinoma (HNSCC) are limited. Methods: Data on HNSCC samples were obtained from The Cancer Genome Atlas and GSE41613 datasets, and 199 FARGs were obtained from the Molecular Signatures database. The integrated datasets' dimensions were reduced by the use of cluster analysis, which was also used to classify patients with HNSCC into subclusters. A FARG signature model was developed and utilized to calculate each patient's risk score using least extreme shrinkage and selection operator regression analysis. The risk score was done to quantify the subgroups of all patients. We evaluated the model's value for prognostic prediction, immune infiltration status, and therapeutic response in HNSCC. Preliminary molecular and biological experiments were performed to verify these results. Results: Two different HNSCC molecular subtypes were identified according to FARGs, and patients with C2 had a shorter overall survival (OS) than those with C1. We constructed an FARG signature comprising nine genes. We constructed a FARG signature consisting of nine genes. Patients with higher risk scores calculated from the FARG signature had a lower OS, and the FARG signature was considered an independent prognostic factor for HNSCC in univariate and multivariate analyses. FARGs are associated with immune cell invasion, gene mutation status, and chemosensitivity. Finally, we observed an abnormal overexpression of MAPK9 in HNSCC tissues, and MAPK9 knockdown greatly impeded the proliferation, migration, and invasion of HNSCC cells. Conclusion: The FARG signature can provide reliable prognostic prediction for patients with HNSCC. Apart from that, the genes in this model were related to immune invasion, gene mutation status, and chemosensitivity, which may provide new ideas for targeted therapies for HNSCC.

Effect of lorecivivint on osteoarthritis: A systematic review and meta-analysis.

Objective: To comprehensively evaluate the effectiveness and safety of lorecivivint inhibitors in the treatment of osteoarthritis through meta-analysis. Methods: A comprehensive literature search on lorecivivint inhibitors in osteoarthritis was performed using electronic databases such as PubMed, Embase, Web of Science, and CochraneLibrary up to July 30, 2022. Two reviewers independently screened, evaluated, and reviewed the eligible studies. Data analysis and processing were carried out using RevMan 5.4 software. Results: A total of six studies involving 3056 participants were included. Meta-analysis showed that compared with the control group, lorecivivint significantly increased WOMAC discomfort (0.03 mg Week 12) (MD = -0.21, 95% CI [-1.94 - 1.53]; P = 0.81), WOMAC function (0.07 mg Week 24) (MD = -1.81, 95% CI [-4.74 - 1.12]; P = 0.23) and Joint space width (0.23 mg Week 24) (MD = -1.16, 95% CI [-3.69 - 1.38]; P = 0.37). Conclusion: A new treatment method combining Wnt pathway modulators with intra-articular CLK2/DYRK1A inhibitors could be a promising therapy for treating osteoarthritis. Lorecivivint was found to significantly improve WOMAC discomfort, WOMAC function, and joint space width in osteoarthritis patients. It is anticipated to be a reliable, safe, and effective treatment option for osteoarthritis with significant therapeutic utility and potential applications.

CD73 mitigates hepatic damage in alcoholic steatohepatitis by regulating PI3K/AKT-mediated hepatocyte pyroptosis.

BACKGROUND: Alcohol use is a major risk factor for death and disability, resulting in a significant global disease burden. Alcoholic steatohepatitis (ASH) reflects an acute exacerbation of alcoholic liver disease (ALD) and is a growing health care and economic burden worldwide. Pyroptosis plays a central role in the pathogenesis of ASH. Nt5e (CD73) is a cell surface ecto-5'-nucleotidase, which is a key enzyme that converts the proinflammatory signal ATP to the anti-inflammatory mediator adenosine (ADO). Studies have found that CD73 is involved in multiple diseases and can alleviate gasdermin D (GSDMD)-mediated pyroptosis; however, its role and mechanism in ASH are not explicit. AIM: To investigate the role and mechanisms of CD73-mediated hepatocyte pyroptosis in alcohol-induced liver injury through in vivo and in vitro experiments. METHODS: CD73 knockout (CD73-/-) mice, wild-type (WT) mice, and AML-12 cells were used to evaluate the effect of CD73 on hepatocyte pyroptosis in vivo and in vitro. A combination of molecular and histological methods was performed to assess pyroptosis and investigate the mechanism both in vivo and in vitro. RESULTS: The protein expression of CD73 and pyroptosis pathway-associated genes was increased significantly in hepatocyte injury model both in vivo and in vitro. In vivo, CD73 knockout dramatically aggravated inflammatory damage, lipid accumulation, and hepatocyte pyroptosis in the liver. In vitro, overexpression of CD73 by pEGFP-C1/CD73 can decrease NLRP3 inflammasome activation and pyroptosis in hepatocytes. Further analysis revealed that the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is a possible mechanism of CD73 regulation. Meanwhile, this pathological process was inhibited after the use of PI3K inhibitors. CONCLUSION: Our results show a novel function of CD73 regulates hepatocytes pyroptosis and highlights the therapeutic opportunity for reducing the disease process in ALD.

Qualitative analysis of a reaction-diffusion SIRS epidemic model with nonlinear incidence rate and partial immunity.

In this paper, a reaction-diffusion SIRS epidemic model with nonlinear incidence rate and partial immunity in a spatially heterogeneous environment is proposed. The well-posedness of the solution is firstly established. Then the basic reproduction number R0 is defined and a threshold dynamics is obtained. That is, when R0 < 1, the disease-free steady state is locally stable, which implies that the disease is extinct, when R0 > 1, the disease is permanent, and there exists at least one positive steady state solution. Finally, the asymptotic profiles of the positive steady state solution as individuals disperse at small and large rates are investigated. Furthermore, as an application of theoretical analysis, a numerical example involving the spread of influenza is discussed. Based on the numerical simulations, we find that the increase of transmission rate and spatial heterogeneity can enhance the risk of influenza propagation, and the increase of diffusion rate, saturation incidence for susceptible and recovery rate can reduce the risk of influenza propagation. Therefore, we propose to reduce the flow of people to lower the effect of spatial heterogeneity, increase the transfer of infected individuals to hospitals in surrounding areas to increase the diffusion rate, and increase the construction of public medical resources to increase the recovery rate for controlling influenza propagation.

Consequences of using poly-ether-ether-ketone versus traditional implant on tibial cement penetration and short-term clinical outcomes during total knee arthroplasty: a randomized controlled trial.

BACKGROUND: The use of poly-ether-ether-ketone (PEEK) prosthesis during total knee arthroplasty (TKA) is a relatively new concept. Several studies have suggested that the thickness of cement penetration during TKA may affect the stability of the implants. The present study aimed to compare the cement penetration and clinical performance between PEEK and traditional cobalt chromium molybdenum (CoCrMo) prosthesis during TKA. METHODS: This study was a randomized controlled trial with level I of evidence. A total of 48 patients were randomly assigned to either the PEEK group (n = 24) or the CoCrMo group (n = 24). Mean bone cement penetration under the tibial baseplate was assessed radiographically in four zones in the anteroposterior view and two zones in the lateral view, in accordance with the Knee Society Scoring System. Furthermore, parameters such as the Knee Society Score (KSS), visual analogue scale (VAS) scores, complications and survivorship at 1 year postoperatively were also compared. RESULTS: According to the results of this study, the mean bone cement penetration exhibited no significant difference between PEEK and CoCrMo groups (2.49 ± 0.61 mm vs. 2.53 ± 0.68 mm, p = 0.85). Additionally, there were no remarkable differences in the KSS clinical score, functional score, and VAS score between the two groups. Moreover, complications and survivorship were also statistically compared between the groups and presented no significant differences. CONCLUSIONS: Based on the current findings, it can be concluded that PEEK implant present similar bone cement penetration, short-term clinical outcomes, and survivorship with traditional CoCrMo implant in TKA without added complications. Trial registration Chinese Clinical Trial Registry (ChiCTR2100047563).

Effectiveness of the recurrent laryngeal nerve monitoring during endoscopic thyroid surgery: systematic review and meta-analysis.

BACKGROUND: Thyroid disease is a common endocrine disorder, and thyroid surgeries and postoperative complications have increased recently. This study aimed to explore the effectiveness of intraoperative nerve monitoring (IONM) in endoscopic thyroid surgery using subgroup analysis and determine confounding factors. MATERIALS AND METHODS: Two researchers individually searched for relevant studies published till November 2022 in the PubMed, Embase, Web of Science and Cochrane Library databases. Eventually, eight studies met the inclusion criteria. Heterogeneity was assessed using the Cochran's Q test, and a funnel plot was implemented to evaluate publication bias. The odds ratio or risk difference were calculated using fixed-effects models. The weighted mean difference of continuous variables was calculated. Subgroup analysis was performed according to the disease type. RESULTS: Eight eligible papers included 915 patients and 1242 exposed nerves. The frequencies of transient, permanent and total recurrent laryngeal nerve (RLN) palsy were 2.64, 0.19 and 2.83%, respectively, in the IONM group and 6.15, 0.75 and 6.90%, respectively, in the conventional exposure group. In addition, analysis of the secondary outcome indicators for the average total length of surgery, localisation time of the RLN, recognition rate of the superior laryngeal nerve and length of incision revealed that IONM reduced the localisation time of the RLN and increased the identification rate of the superior laryngeal nerve. Subgroup analysis showed that IONM significantly reduced the incidence of RLN palsy in patients with malignancies. CONCLUSIONS: The use of IONM significantly reduced the incidence of transient RLN palsy during endoscopic thyroid surgery, but it did not significantly reduce the incidence of permanent RLN palsy. However, the reduction in the total RLN palsy was statistically significant. In addition, IONM can effectively reduce the location time of the RLN and increase the recognition rate of the superior laryngeal nerve. Therefore, the application of IONM for malignant tumours is recommended.

Plantar Pressure Distribution and Posture Balance During Walking in Individuals with Unilateral Chronic Ankle Instability: An Observational Study.

BACKGROUND Patients with chronic ankle instability (CAI) can present with abnormal gait. The purpose of this study was to evaluate plantar pressure distributions and posture balance during walking in unilateral CAI patients. MATERIAL AND METHODS We recruited 24 unilateral CAI patients and 24 healthy individuals; plantar pressure analysis was conducted using the Footscan® 3D pressure system. The following parameters were assessed and recorded: peak force/weight (PF/W), time to peak force (TPF), time to boundary (TTB), and COP velocity. The differences between the affected and unaffected side of the CAI group and control group were determined. Pearson correlation analysis and univariate analysis was used to investigate the correlation between plantar pressure parameters and related factors. RESULTS The comparison of PF/W showed that the plantar pressure of both sides in the CAI group were laterally distributed. The comparison of TPF, TTB, and COP velocity in different groups showed that the posture balance on the affected side of CAI patient was more impaired than the unaffected side and the control group. Male patients with CAI tend to have better posture balance than females, and a low CAIT score is correlated with poor posture balance. CONCLUSIONS The plantar pressure on both sides in unilateral CAI patients was laterally distributed and their balance function was impaired. It is necessary for CAI patients to receive functional training of both sides during rehabilitation, and plantar pressure analysis is promising for diagnosis and evaluation of CAI.

Eupatilin alleviates inflammatory response after subarachnoid hemorrhage by inhibition of TLR4/MyD88/NF-κB axis.

Early brain injury (EBI) is associated with the adverse prognosis of subarachnoid hemorrhage (SAH) patients. The key bioactive component of the Chinese herbal medicine Artemisia asiatica Nakai (Asteraceae) is eupatilin. Recent research reports that eupatilin suppresses inflammatory responses induced by intracranial hemorrhage. This work is performed to validate whether eupatilin can attenuate EBI and deciphers its mechanism. A SAH rat model was established by intravascular perforation in vivo. At 6 h after SAH in rats, 10 mg/kg eupatilin was injected into the rats via the caudal vein. A Sham group was set as the control. In vitro, BV2 microglia was treated with 10 µM Oxyhemoglobin (OxyHb) for 24 h, followed by 50 µM eupatilin treatment for 24 h. The SAH grade, brain water content, neurological score, and blood-brain barrier (BBB) permeability of the rats were measured 24 h later. The content of proinflammatory factors was detected via enzyme-linked immunosorbent assay. Western blot analysis was conducted to analyze the expression levels of TLR4/MyD88/NF-κB pathway-associated proteins. In vivo, eupatilin administration alleviated neurological injury, and decreased brain edema and BBB injury after SAH in rats. Eupatilin markedly reduced the levels of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α), and suppressed the expression levels of MyD88, TLR4, and p-NF-κB p65 in the SAH rats' cerebral tissues. Eupatilin treatment also reduced the levels of IL-1ß, IL-6, and TNF-α, and repressed the expression levels of MyD88, TLR4, and p-NF-κB p65 in OxyHb-induced BV2 microglia. Additionally, pyrrolidine dithiocarbamate or resatorvid enhanced the suppressive effects of eupatilin on OxyHb-induced inflammatory responses in BV2 microglia. Eupatilin ameliorates SAH-induced EBI via modulating the TLR4/MyD88/NF-κB pathway in rat model.

The optimal size of screw for using cement-screw technique to repair tibial defect in total knee arthroplasty: A finite element analysis.

Cement can be reinforced with cancellous screws for repairing tibial defect in total knee arthroplasty (TKA). However, it is still unknown which size (diameter, length) of screws is better, and the purpose of this study was to perform a finite element analysis (FEA) to determine it. Twelve FEA models were set to represent the cement-screw technique with different diameters (3.5 mm, 5 mm and 6.5 mm) and lengths (20 mm, 25 mm, 30 mm and 35 mm). Contact stresses on the surface of cancellous bone in different areas were calculated. Compared to screws with diameter of 3.5 mm, stresses on the surface of bone defect reduced 5.75% of 5 mm and 10.68% of 6.5 mm for the screw length of 20 mm, 4.23% of 5 mm and 9.16% of 6.5 mm for 25 mm, 6.65% of 5 mm and 12.30% of 6.5 mm for 30 mm, and 5.05% of 5 mm and 12.16% of 6.5 mm for 35 mm. Compared to screws with diameter of 5 mm, stresses on the surface of defect reduced 5.24%, 5.15%, 6.05%, and 7.49% of 6.5 mm for the screw length of 20, 25, 30, and 35 mm. However, it did not show any significant difference in other comparisons. For the treatment of tibial defect in TKA with cement-screw technique, longer screw may not achieve better stability, but the thicker screw can reduce more stresses on the surface of tibial defect and achieve better stability. However, the depth of bone defect must be considered when making a choice.

Flexible integrated sensor with asymmetric structure for simultaneously 3D tactile and thermal sensing.

The human body detects tactile stimuli through a combination of pressure force and temperature signals via various cutaneous receptors. The development of a multifunctional artificial tactile perception system has potential benefits for future robotic technologies, human-machine interfaces, artificial intelligence, and health monitoring devices. However, constructing systems beyond simple pressure sensing capabilities remains challenging. Here, we propose an artificial flexible and ultra-thin (50 µ m) skin system to simultaneously capture 3D tactile and thermal signals, which mimics the human tactile recognition process using customized sensor pairs and compact peripheral signal-converting circuits. The 3D tactile sensors have a flower-like asymmetric structure with 5-ports and 4 capacitive elements in pairs. Differential and average signals would reveal the curl and amplitude values of the fore field with a resolution of 0.18/mm. The resistive thermal sensors are fabricated with serpentine lines and possess stable heat-sensing performance (165 mV/°C) under shape deformation conditions. Real-time monitoring of the skin stimuli is displayed on the user interface and stored on mobile clients. This work offers broad capabilities relevant to practical applications ranging from assistant prosthetics to artificial electronic skins.

P38γ modulates the lipid metabolism in non-alcoholic fatty liver disease by regulating the JAK-STAT signaling pathway.

Non-alcoholic fatty liver disease (NAFLD) is a major health problem in Western countries and has become the most common cause of chronic liver disease. Although NAFLD is closely associated with obesity, inflammation, and insulin resistance, its pathogenesis remains unclear. The disease begins with excessive accumulation of triglycerides in the liver, which in turn leads to liver cell damage, steatosis, inflammation, and so on. P38γ is one of the four isoforms of P38 mitogen-activated protein kinases (P38 MAPKs) that contributes to inflammation in different diseases. In this research, we investigated the role of P38γ in NAFLD. In vivo, a NAFLD model was established by feeding C57BL/6J mice with a methionine- and choline-deficient (MCD) diet and adeno-associated virus (AAV9-shRNA-P38γ) was injected into C57BL/6J mice by tail vein for knockdown P38γ. The results indicated that the expression level of P38γ was upregulated in MCD-fed mice. Furthermore, the downregulation of P38γ significantly attenuated liver injury and lipid accumulation in mice. In vitro, mouse hepatocytes AML-12 were treated with free fatty acid (FFA). We found that P38γ was obviously increased in FFA-treated AML-12 cells, whereas knockdown of P38γ significantly suppressed lipid accumulation in FFA-treated AML-12 cells. Furthermore, P38γ regulated the Janus Kinase-Signal transducers and activators of transcription (JAK-STAT) signaling pathway. Inhibition of P38γ can inhibit the JAK-STAT signaling pathway, thereby inhibiting lipid accumulation in FFA-treated AML-12 cells. In conclusion, our results suggest that targeting P38γ contributes to the suppression of lipid accumulation in fatty liver disease.

Microsurgical Management of Fourth Ventricle Lesions Via the Median Suboccipital Keyhole Telovelar Approach.

In this 2-year retrospective analysis, 13 patients with fourth ventricle lesions who underwent microsurgical resection via the midline suboccipital keyhole telovelar approach were analyzed. This is the first study to investigate the surgical outcome and complications of using this approach to resect various types of lesions in the fourth ventricle. We aimed to clarify whether this approach has met its promise of lesion dissection. Three patients (23.1%) had intraoperative extraventricular drains. There were no immediate postoperative deaths. Gross total resection was achieved in 84.6% of the cases. The Fisher exact test showed there was no statistically significant correlation between lesion location, lesion size, brainstem invasion, and extent of resection. About two third (69.2%) of the cases were free of complications. New or worsening gait/focal motor disturbance (15.4%) was the most common neurological deficit in the immediate postoperative period. One patient (7.7%) had worse gait disturbance/motor deficit following surgical intervention. Two patients (15.4%) developed meningitis. Two patients (15.4%) required postoperative cerebrospinal fluid diversion after tumor resection, of these 2 patients, 1 (7.7%) eventually needed a permanent shunt. There were no cases of cerebellar mutism and bulbar paralysis. The median suboccipital keyhole telovelar approach provides relative wide access to resect most fourth ventricle tumors completely and with satisfactory results. In contrast, this requires the appropriate patient selection and skilled surgeons.

Fabrication of Polymethyl Methacrylate (PMMA) Hydrophilic Surfaces Using Combined Offset-Tool-Servo Flycutting and Hot Embossing Methods.

Polymethyl methacrylate (PMMA) is a material with good surface wettability and has unique and widespread applications in industrial fields. However, fabricating this material in an environmentally friendly way while maintaining its mechanical robustness remains a challenging task. One effective way is through the rational design of microstructure surfaces. The current study fabricated a pyramid microstructure array on a mold surface using offset-tool-servo flycutting, which was then combined with hot embossing to replicate an inverted pyramid microstructure array on a PMMA surface. Firstly, a toolpath compensation algorithm was developed to linearize the arc toolpath and reduce the cost of ultra-precision lathe. Then, the algorithm was further developed to achieve automatic linear toolpath intersection, aiming to ensure the machining accuracy and improve machining efficiency. An experiment testing the linear toolpath intersecting at 90° was conducted, fabricating a pyramid microstructure array with nanoscale roughness on the mold surface. This surface was then employed for replicating an inverted pyramid microstructure array on the PMMA surface using hot embossing. Furthermore, the accuracy of replication was evaluated, and the experimental results demonstrated excellent replication fidelity, exceeding 98%. The microstructural surface of the PMMA exhibited a change in surface wettability. The wettability test showed a water-droplet contact angle reduction from 84.8° ± 0.1° to 56.2° ± 0.1°, demonstrating a good hydrophilic effect. This study introduces a novel, environmentally friendly and high-precision method to fabricate a functional PMMA surface with an inverted pyramid microstructure array. The results of this study also provide strong technical support and theoretical guidance for micro-nanostructure functional surface machining and replicating.