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BACKGROUND: In China, both percutaneous microwave/radiofrequency ablation liver partition plus portal vein embolization (PALPP) and transarterial chemoembolization (TACE) plus portal vein embolization (PVE) have been utilized in planned hepatectomy. However, there is a lack of comparative studies on the effectiveness of these two techniques for cases with insufficient future liver remnant (FLR). METHODS: Patients were categorized into either the PALPP group or the TACE + PVE group. Clinical data, including FLR growth rate, complications, secondary resection rate, and overall survival rate, were compared and analyzed for both groups retrospectively. RESULTS: Between December 2014 and October 2021, a total of 29 patients underwent TACE + PVE (n = 12) and PALPP (n = 17). In the TACE + PVE group, 7 patients successfully underwent two-stage hepatectomy, while in the PALPP group, 13 patients underwent the procedure (two-stage resection rate: 58.3% vs. 76.5%, P = 0.42). There were no significant differences in postoperative complications of one-stage procedures (11.8% vs. 8.3%, P > 0.05) and second-stage resection complication (0% vs. 46.2%, P = 0.05) between the TACE + PVE and PALPP groups. However, the PALPP group demonstrated a shorter time to FLR volume growth for second-stage resection (18.5 days vs. 66 days, P = 0.001) and KGR (58.5 ml/week vs. 7.7 ml/week, P = 0.001). CONCLUSIONS: Compared with TACE + PVE, PALPP results in a more significant increase in FLR volume and a higher rate of two-stage resection without increasing postoperative complications.
Subject(s)
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Hepatectomy , Liver Neoplasms , Microwaves , Portal Vein , Radiofrequency Ablation , Humans , Hepatectomy/methods , Male , Female , Middle Aged , Liver Neoplasms/therapy , Liver Neoplasms/surgery , Chemoembolization, Therapeutic/methods , Radiofrequency Ablation/methods , Microwaves/therapeutic use , Retrospective Studies , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/surgery , Aged , Adult , Liver/surgery , Liver/blood supply , Embolization, Therapeutic/methods , Treatment Outcome , Postoperative Complications/etiology , Postoperative Complications/epidemiology , Survival Rate , China/epidemiology , Combined Modality TherapyABSTRACT
Surfactant-enhanced aquifer remediation (SEAR) has effectively removed dense nonaqueous phase liquids (DNAPLs) from the contaminated aquifers. However, restricted by structural defects, typical monomeric surfactants undergo precipitation, high adsorption loss, and poor solubilization in aquifers, resulting in low remediation efficiency. In this study, a novel sugar-based anionic and non-ionic Gemini surfactant (SANG) was designed and synthesized for SEAR. Glucose was introduced into SANG as a non-ionic group to overcome the interference of low temperature and ions in groundwater. Sodium sulfonate was introduced as an anionic group to overcome aquifer adsorption loss. Two long-straight carbon chains were introduced as hydrophobic groups to provide high surface activity and solubilizing capacity. Even with low temperature or high salt content, its solution did not precipitate in aquifer conditions. The adsorption loss was as low as 0.54 and 0.90 mg/g in medium and fine sand, respectively. Compared with typical surfactants used for SEAR, SANG had the highest solubilization and desorption abilities for perchloroethylene (PCE) without emulsification, a crucial negative that Tween80 and other non-ionic surfactants exhibit. After flushing the contaminated aquifer using SANG, > 99 % of PCE was removed. Thus, with low potential environmental risk, SANG is effectively applicable in subsurface remediation, making it a better surfactant choice for SEAR.
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Studies have shown that vascular dysfunction is closely related to the pathogenesis of Alzheimer's disease. The middle temporal gyrus region of the brain is susceptible to pronounced impairment in Alzheimer's disease. Identification of the molecules involved in vascular aberrance of the middle temporal gyrus would support elucidation of the mechanisms underlying Alzheimer's disease and discovery of novel targets for intervention. We carried out single-cell transcriptomic analysis of the middle temporal gyrus in the brains of patients with Alzheimer's disease and healthy controls, revealing obvious changes in vascular function. CellChat analysis of intercellular communication in the middle temporal gyrus showed that the number of cell interactions in this region was decreased in Alzheimer's disease patients, with altered intercellular communication of endothelial cells and pericytes being the most prominent. Differentially expressed genes were also identified. Using the CellChat results, AUCell evaluation of the pathway activity of specific cells showed that the obvious changes in vascular function in the middle temporal gyrus in Alzheimer's disease were directly related to changes in the vascular endothelial growth factor (VEGF)A-VEGF receptor (VEGFR) 2 pathway. AUCell analysis identified subtypes of endothelial cells and pericytes directly related to VEGFA-VEGFR2 pathway activity. Two subtypes of middle temporal gyrus cells showed significant alteration in AD: endothelial cells with high expression of Erb-B2 receptor tyrosine kinase 4 (ERBB4high) and pericytes with high expression of angiopoietin-like 4 (ANGPTL4high). Finally, combining bulk RNA sequencing data and two machine learning algorithms (least absolute shrinkage and selection operator and random forest), four characteristic Alzheimer's disease feature genes were identified: somatostatin (SST), protein tyrosine phosphatase non-receptor type 3 (PTPN3), glutinase (GL3), and tropomyosin 3 (PTM3). These genes were downregulated in the middle temporal gyrus of patients with Alzheimer's disease and may be used to target the VEGF pathway. Alzheimer's disease mouse models demonstrated consistent altered expression of these genes in the middle temporal gyrus. In conclusion, this study detected changes in intercellular communication between endothelial cells and pericytes in the middle temporal gyrus and identified four novel feature genes related to middle temporal gyrus and vascular functioning in patients with Alzheimer's disease. These findings contribute to a deeper understanding of the molecular mechanisms underlying Alzheimer's disease and present novel treatment targets.
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Background: Challenges such as poor drug selectivity, non-target reactivity, and the development of drug resistance continue to pose significant obstacles in the clinical application of cancer therapeutic drugs. To overcome the limitations of drug resistance in chemotherapy, a viable treatment strategy involves designing multifunctional nano-platforms that exploit the unique physicochemical properties of tumor microenvironment (TME). Methods: Herein, layer-by-layer nanoparticles with polyporous CuS as delivery vehicles, loaded with a sonosensitizer (tetra-(4-aminophenyl) porphyrin, TAPP) and sequentially functionalized with pH-responsive CaCO3, targeting group hyaluronic acid (HA) were designed and synthesized for synergistic treatment involving chemodynamic therapy (CDT), sonodynamic therapy (SDT), photothermal therapy (PTT), and calcium overload. Upon cleavage in an acidic environment, CaCO3 nanoparticles released TAPP and Ca2+, with TAPP generating 1O2 under ultrasound trigger. Exposed CuS produced highly cytotoxic ·OH in response to H2O2 and also exhibited a strong PTT effect. Results: CuS@TAPP-CaCO3/HA (CTCH) delivered an enhanced ability to release more Ca2+ under acidic conditions with a pH value of 6.5, which in situ causes damage to HeLa mitochondria. In vitro and in vivo experiments both demonstrated that mitochondrial dysfunction greatly amplified the damage caused by reactive oxygen species (ROS) to tumor, which strongly confirms the synergistic effect between calcium overload and reactive oxygen therapy. Conclusion: Collectively, the development of CTCH presents a novel therapeutic strategy for tumor treatment by effectively responding to the acidic TME, thus holding significant clinical implications.
Subject(s)
Calcium Carbonate , Calcium , Nanoparticles , Tumor Microenvironment , Humans , Animals , Nanoparticles/chemistry , Calcium/chemistry , Calcium Carbonate/chemistry , Calcium Carbonate/pharmacology , Tumor Microenvironment/drug effects , HeLa Cells , Reactive Oxygen Species/metabolism , Mice , Hyaluronic Acid/chemistry , Porphyrins/chemistry , Porphyrins/pharmacology , Porphyrins/pharmacokinetics , Porphyrins/administration & dosage , Photothermal Therapy/methods , Hydrogen-Ion Concentration , Ultrasonic Therapy/methods , Neoplasms/therapy , Neoplasms/drug therapy , Mitochondria/drug effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Mice, Inbred BALB C , Mice, Nude , Layer-by-Layer NanoparticlesABSTRACT
Nitric oxide (NO) and reactive oxygen species (ROS) embody excellent potential in cancer therapy. However, as a small molecule, their targeted delivery and precise, controllable release are urgently needed to achieve accurate cancer therapy. In this paper, a novel US-responsive bifunctional molecule (SD) and hyaluronic acid-modified MnO2 nanocarrier was developed, and a US-responsive NO and ROS controlled released nanoplatform was constructed. US can trigger SD to release ROS and NO simultaneously at the tumor site. Thus, SD served as acoustic sensitizer for sonodynamic therapy and NO donor for gas therapy. In the tumor microenvironment, the MnO2 nanocarrier can effectively deplete the highly expressed GSH, and the released Mn2+ can make H2O2 to produce .OH by Fenton-like reaction, which exhibited a strong chemodynamic effect. The high concentration of ROS and NO in cancer cell can induce cancer cell apoptosis ultimately. In addition, toxic ONOO-, which was generated by the reaction of NO and ROS, can effectively cause mitochondrial dysfunction, which induced the apoptosis of tumor cells. The 131I was labeled on the nanoplatform, which exhibited internal radiation therapy for tumor therapy. In -vitro and -vivo experiments showed that the nanoplatform has enhanced biocompatibility, and efficient anti-tumor potential, and it achieves synergistic sonodynamic/NO/chemodynamic/radionuclide therapy for cancer.
Subject(s)
Iodine Radioisotopes , Manganese Compounds , Nitric Oxide , Oxides , Reactive Oxygen Species , Nitric Oxide/chemistry , Nitric Oxide/metabolism , Reactive Oxygen Species/metabolism , Humans , Animals , Manganese Compounds/chemistry , Manganese Compounds/pharmacology , Oxides/chemistry , Oxides/pharmacology , Iodine Radioisotopes/chemistry , Apoptosis/drug effects , Nanoparticles/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Mice , Drug Screening Assays, Antitumor , Cell Proliferation/drug effects , Molecular Structure , Mice, Inbred BALB C , Ultrasonic Therapy , Cell Survival/drug effects , Dose-Response Relationship, Drug , Ultrasonic Waves , Cell Line, TumorABSTRACT
BACKGROUND: Postoperative complications are vital factors affecting the prognosis of patients with hepatocellular carcinoma (HCC), especially for complex hepatectomy. The present study aimed to compare perioperative complications between laparoscopic and robotic complex hepatectomy (LCH vs. RCH). METHODS: Patients with solitary HCC after complex hepatectomy were collected from a multicenter database. Propensity score-matched (PSM) analysis was adopted to control confounding bias. Multivariable analysis was performed to determine the prognostic factors. RESULTS: 436 patients were included. After PSM, 43 patients were included in both the LCH and RCH groups. The results showed that compared to LCH, RCH had lower rates of blood loss and transfusion, and lower postoperative 30-day and major morbidity, and post-hepatectomy liver failure (PHLF) (all P < 0.05). Additionally, the length of hospital stay was shorter in the RCH group (P = 0.026). Multivariable analysis showed RCH is an independent protective factor for reducing the 30-day morbidity, major morbidity and PHLF. CONCLUSION: RCH has advantages over LCH in the minimally invasive treatment of complex HCC, as it can reduce the incidence of postoperative morbidity. Therefore, RCH should be considered for patients with HCC who require complex hepatectomy.
Subject(s)
Carcinoma, Hepatocellular , Hepatectomy , Laparoscopy , Liver Neoplasms , Postoperative Complications , Propensity Score , Robotic Surgical Procedures , Humans , Carcinoma, Hepatocellular/surgery , Hepatectomy/adverse effects , Hepatectomy/methods , Liver Neoplasms/surgery , Male , Laparoscopy/adverse effects , Female , Robotic Surgical Procedures/adverse effects , Middle Aged , Postoperative Complications/etiology , Postoperative Complications/epidemiology , Retrospective Studies , Treatment Outcome , Aged , Databases, Factual , Length of Stay , Risk Factors , Time Factors , Risk Assessment , AdultABSTRACT
BACKGROUND: The Naples Prognostic Score (NPS), integrating inflammatory and nutritional biomarkers, has been reported to be associated with the prognosis of various malignancies, but there is no report on intrahepatic cholangiocarcinoma (ICC). This study aimed to explore the prognostic value of NPS in patients with ICC. METHODS: Patients with ICC after hepatectomy were collected, and divided into three groups. The prognosis factors were determined by Cox regression analysis. Predictive efficacy was evaluated by the time-dependent receiver operating characteristic (ROC) curves. RESULTS: A total of 174 patients were included (Group 1: 33 (19.0%) patients; Group 2: 83 (47.7%) patients; and Group 3: 58 (33.3%) patients). The baseline characteristics showed the higher the NPS, the higher the proportion of patients with cirrhosis and Child-Pugh B, and more advanced tumors. The Kaplan-Meier curves reflect higher NPS were associated with poor survival. Multivariable analysis showed NPS was an independent risk factor of overall survival (NPS group 2 vs. 1: HR = 1.671, 95% CI: 1.022-3.027, p = 0.009; NPS group 3 vs. 1: HR = 2.208, 95% CI: 1.259-4.780, p = 0.007) and recurrence-free survival (NPS group 2 vs. 1: HR = 1.506, 95% CI: 1.184-3.498, p = 0.010; NPS group 3 vs. 1: HR = 2.141, 95% CI: 2.519-4.087, P = 0.001). The time ROC indicated NPS was superior to other models in predicting prognosis. CONCLUSIONS: NPS is a simple and effective tool for predicting the long-term survival of patients with ICC after hepatectomy. Patients with high NPS require close follow-up, and improving NPS may prolong the survival time.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Hepatectomy , Humans , Cholangiocarcinoma/surgery , Cholangiocarcinoma/mortality , Cholangiocarcinoma/pathology , Male , Female , Middle Aged , Prognosis , Bile Duct Neoplasms/surgery , Bile Duct Neoplasms/mortality , Bile Duct Neoplasms/pathology , Aged , ROC Curve , Retrospective Studies , Kaplan-Meier Estimate , Adult , Risk FactorsABSTRACT
Although robotic radical resection for hilar cholangiocarcinoma (HCCA) has been reported in some large hepatobiliary centers, biliary-enteric reconstruction (BER) remains a critical step that hampers the operation's success. This study aimed to evaluate the feasibility and quality of BER in robotic radical resection of HCCA and propose technical recommendations. A retrospective study was conducted on patients with HCCA who underwent minimally invasive radical resection at Zhejiang Provincial People's Hospital between January 2016 and July 2023. A 1:2 propensity score matching (PSM), widely used to reduce selection bias, was performed to evaluate the outcomes, especially BER-related data, between the robotic and laparoscopic surgery. Forty-six patients with HCCA were enrolled; ten underwent robotic-assisted resection, while the others underwent laparoscopic surgery. After PSM at a ratio of 1:2, 10 and 20 patients were assigned to the robot-assisted and laparoscopic groups, respectively. The baseline characteristics of both groups were generally well-balanced. The average liver resection time was longer in the robotic group than in the laparoscopic group (139.5 ± 38.8 vs 108.1 ± 35.8 min, P = 0.036). However, the former had less intraoperative blood loss [200 (50-500) vs 310 (100-850) ml], despite no statistical difference (P = 0.109). The number of residual bile ducts was 2.6 ± 1.3 and 2.7 ± 1.2 (P = 0.795), and anastomoses were both 1.6 ± 0.7 in the two groups (P = 0.965). The time of BER was 38.4 ± 13.6 and 59.1 ± 25.5 min (P = 0.024), accounting for 9.9 ± 2.8% and 15.4 ± 4.8% of the total operation time (P = 0.001). Although postoperative bile leakage incidence in laparoscopic group (40%) was higher than that in robotic group (10%), there was no significant difference between the two groups (P = 0.204); 6.7 ± 4.4 and 12.1 ± 11.7 days were observed for tube drawing (P = 0.019); anastomosis stenosis and calculus rate was 10% and 30% (P = 0.372), 0% and 15% (P = 0.532), respectively. Neither group had hemorrhage- or bile leakage-related deaths. Robotic radical resection for HCCA may offer perioperative outcomes comparable to conventional laparoscopic procedures and tends to be advantageous in terms of anastomosis time and quality. We are optimistic about its wide application in the future with the improvement of surgical techniques and experience.
Subject(s)
Bile Duct Neoplasms , Laparoscopy , Propensity Score , Robotic Surgical Procedures , Humans , Male , Female , Middle Aged , Robotic Surgical Procedures/methods , Retrospective Studies , Laparoscopy/methods , Aged , Bile Duct Neoplasms/surgery , Bile Duct Neoplasms/pathology , Klatskin Tumor/surgery , Klatskin Tumor/pathology , Treatment Outcome , Plastic Surgery Procedures/methods , Postoperative Complications/epidemiologyABSTRACT
Seipin is a key regulator of lipid metabolism, the deficiency of which leads to severe lipodystrophy. Hypothalamus is the pivotal center of brain that modulates appetite and energy homeostasis, where Seipin is abundantly expressed. Whether and how Seipin deficiency leads to systemic metabolic disorders via hypothalamus-involved energy metabolism dysregulation remains to be elucidated. In the present study, we demonstrated that Seipin-deficiency induced hypothalamic inflammation, reduction of anorexigenic pro-opiomelanocortin (POMC), and elevation of orexigenic agonist-related peptide (AgRP). Importantly, administration of rosiglitazone, a thiazolidinedione antidiabetic agent, rescued POMC and AgRP expression, suppressed hypothalamic inflammation, and restored energy homeostasis in Seipin knockout mice. Our findings offer crucial insights into the mechanism of Seipin deficiency-associated energy imbalance and indicates that rosiglitazone could serve as potential intervening agent towards metabolic disorders linked to Seipin.
Subject(s)
Agouti-Related Protein , Energy Metabolism , GTP-Binding Protein gamma Subunits , Homeostasis , Hypothalamus , Mice, Knockout , Pro-Opiomelanocortin , Rosiglitazone , Animals , Mice , Hypothalamus/metabolism , Energy Metabolism/drug effects , Pro-Opiomelanocortin/genetics , Pro-Opiomelanocortin/biosynthesis , Agouti-Related Protein/genetics , GTP-Binding Protein gamma Subunits/genetics , Rosiglitazone/pharmacology , Male , Neuroinflammatory Diseases/etiology , Mice, Inbred C57BL , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Neuropeptides/genetics , Neuropeptides/deficiency , Gene Expression Regulation/drug effectsABSTRACT
BACKGROUND AND AIMS: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing hepatectomy is unsatisfactory, especially for those with microvascular invasion (MVI). This study aimed to determine the impact of adjuvant transcatheter arterial chemoembolization (TACE) and Lenvatinib on the prognosis of patients with HCC and MVI after hepatectomy. METHODS: Patients diagnosed with HCC and MVI were reviewed, and stratified into four groups according to adjuvant TACE and/or Lenvatinib. Multivariate Cox regression analyses are used to determine independent risk factors. RESULTS: 346 patients were included, and divided into four groups (Group I, TACE+ Lenvatinib; Group II, Lenvatinib; Group III, TACE; Group IV, without adjuvant therapy). Multivariable analysis showed that compared to Group IV, Group I had the best effect on improving the overall survival (OS, HR 0.321, 95%CI 0.099-0.406, P = 0.001) and recurrence-free survival (RFS, HR 0.319, 95%CI 0.129-0.372, P = 0.001). Additionally, compared with Group II or Group III, Group I also can significantly improve the OS and RFS. There is no significant difference between Group II and Group III in OS and RFS. CONCLUSION: The combination of TACE and Lenvatinib should be considered for anti-recurrence therapy for patients with HCC and MVI after hepatectomy.
ABSTRACT
BACKGROUND & AIMS: Complications after laparoscopic liver resection (LLR) are important factors affecting the prognosis of patients, especially for complex hepatobiliary diseases. The present study aimed to evaluate the value of a three-dimensional (3D) printed dry-laboratory model in the precise planning of LLR for complex hepatobiliary diseases. METHODS: Patients with complex hepatobiliary diseases who underwent LLR were preoperatively enrolled, and divided into two groups according to whether using a 3D-printed dry-laboratory model (3D vs. control group). Clinical variables were assessed and complications were graded by the Clavien-Dindo classification. The Comprehensive Complication Index (CCI) scores were calculated and compared for each patient. Multivariable analysis was performed to determine the risk factors of postoperative complications. RESULTS: Sixty-two patients with complex hepatobiliary diseases underwent the precise planning of LLR. Among them, thirty-one patients acquired the guidance of a 3D-printed dry-laboratory model, and others were only guided by traditional enhanced CT or MRI. The results showed no significant differences between the two groups in baseline characters. However, compared to the control group, the 3D group had a lower incidence of intraoperative blood loss, as well as postoperative 30-day and major complications, especially bile leakage (all P < 0.05). The median score on the CCI was 20.9 (range 8.7-51.8) in the control group and 8.7 (range 8.7-43.4) in the 3D group (mean difference, -12.2, P = 0.004). Multivariable analysis showed the 3D model was an independent protective factor in decreasing postoperative complications. Subgroup analysis also showed that a 3D model could decrease postoperative complications, especially for bile leakage in patients with intrahepatic cholelithiasis. CONCLUSION: The 3D-printed models can help reduce postoperative complications. The 3D-printed models should be recommended for patients with complex hepatobiliary diseases undergoing precise planning LLR.
Subject(s)
Laparoscopy , Liver Diseases , Postoperative Complications , Printing, Three-Dimensional , Humans , Female , Male , Middle Aged , Laparoscopy/methods , Laparoscopy/adverse effects , Postoperative Complications/prevention & control , Postoperative Complications/etiology , Liver Diseases/surgery , Aged , Biliary Tract Diseases/prevention & control , Biliary Tract Diseases/surgery , Biliary Tract Diseases/etiology , Hepatectomy/methods , Hepatectomy/adverse effects , Adult , Retrospective Studies , Cohort StudiesABSTRACT
The identification of key points in the human body is vital for sports rehabilitation, medical diagnosis, human-computer interaction, and related fields. Currently, depth cameras provide more precise depth information on these crucial points. However, human motion can lead to variations in the positions of these key points. While the Mediapipe algorithm demonstrates effective anti-shake capabilities for these points, its accuracy can be easily affected by changes in lighting conditions. To address these challenges, this study proposes an illumination-adaptive algorithm for detecting human key points through the fusion of multi-source information. By integrating key point data from the depth camera and Mediapipe, an illumination change model is established to simulate environmental lighting variations. Subsequently, the fitting function of the relationship between lighting conditions and adaptive weights is solved to achieve lighting adaptation for human key point detection. Experimental verification and similarity analysis with benchmark data yielded R2 results of 0.96 and 0.93, and cosine similarity results of 0.92 and 0.90. With a threshold range of 8, the joint accuracy rates for the two rehabilitation actions were found to be 89% and 88%. The experimental results demonstrate the stability of the proposed method in detecting key points in the human body under changing illumination conditions, its anti-shake ability for human movement, and its high detection accuracy. This method shows promise for applications in human-computer interaction, sports rehabilitation, and virtual reality.
Subject(s)
Algorithms , Lighting , Humans , Lighting/methods , Human Body , Movement/physiology , Image Processing, Computer-Assisted/methods , LightABSTRACT
Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a promising treatment approach for multidrug resistant infections. PDT/PTT combination therapy can more efficiently eliminate pathogens without drug resistance. The key to improve the efficacy of photochemotherapy is the utilization efficiency of non-radiation energy of phototherapy agents. Herein, a facile phototherapy molecule (SCy-Le) with the enhancement of non-radiative energy transfer is designed by an acid stimulation under a single laser. Introduction of the protonated receptor into SCy-Le results in a distorted intramolecular charge in the infected acidic microenvironment, pH ≈ 5.5, which in turn, enhances light capture, reduces the singlet-triplet transition energies (ΔES1-T1), promotes electron system crossing, enhances capacity of reactive oxygen species generation, and causes a significant increase in temperature by improving vibrational relaxation. SCy-Le shows more than 99% bacterial killing rate against both methicillin-resistant Staphylococcus aureus and its biofilms in vitro and causes bacteria-induced wound healing in mice. This work will provide a new perspective for the design of phototherapy agents, and the emerging photochemotherapy will be a promising approach to combat the problem of antibiotic resistance.
ABSTRACT
Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe lipid metabolic disorders but also cognitive impairments and motor disabilities. Myelin, composed mainly of lipids, facilitates nerve transmission and is important for motor coordination and learning. Whether Seipin deficiency-leaded defects in learning and motor coordination is underlined by lipid dysregulation and its consequent myelin abnormalities remains to be elucidated. In the present study, we verified the expression of Seipin in oligodendrocytes (OLs) and their precursors, oligodendrocyte precursor cells (OPCs), and demonstrated that Seipin deficiency compromised OPC differentiation, which led to decreased OL numbers, myelin protein, myelinated fiber proportion and thickness of myelin. Deficiency of Seipin resulted in impaired spatial cognition and motor coordination in mice. Mechanistically, Seipin deficiency suppressed sphingolipid metabolism-related genes in OPCs and caused morphological abnormalities in lipid droplets (LDs), which markedly impeded OPC differentiation. Importantly, rosiglitazone, one agonist of PPAR-gamma, substantially restored phenotypes resulting from Seipin deficiency, such as aberrant LDs, reduced sphingolipids, obstructed OPC differentiation, and neurobehavioral defects. Collectively, the present study elucidated how Seipin deficiency-induced lipid dysregulation leads to neurobehavioral deficits via impairing myelination, which may pave the way for developing novel intervention strategy for treating metabolism-involved neurological disorders.
Subject(s)
Cell Differentiation , Cognitive Dysfunction , GTP-Binding Protein gamma Subunits , Myelin Sheath , Oligodendrocyte Precursor Cells , Animals , GTP-Binding Protein gamma Subunits/metabolism , GTP-Binding Protein gamma Subunits/genetics , Mice , Oligodendrocyte Precursor Cells/metabolism , Myelin Sheath/metabolism , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/pathology , Cognitive Dysfunction/genetics , Lipid Metabolism , Oligodendroglia/metabolism , Oligodendroglia/pathology , Mice, Inbred C57BL , PPAR gamma/metabolism , PPAR gamma/genetics , Mice, Knockout , Male , Rosiglitazone/pharmacologyABSTRACT
Cancer metastasis is the leading cause of mortality in patients with hepatocellular carcinoma (HCC). To meet the rapid malignant growth and transformation, tumor cells dramatically increase the consumption of nutrients, such as amino acids. Peptide transporter 1 (PEPT1), a key transporter for small peptides, has been found to be an effective and energy-saving intracellular source of amino acids that are required for the growth of tumor cells. Here, the role of PEPT1 in HCC metastasis and its underlying mechanisms is explored. PEPT1 is upregulated in HCC cells and tissues, and high PEPT1 expression is associated with poor prognosis in patients with HCC. PEPT1 overexpression dramatically promoted HCC cell migration, invasion, and lung metastasis, whereas its knockdown abolished these effects both in vitro and in vivo. Mechanistic analysis revealed that high PEPT1 expression increased cellular dipeptides in HCC cells that are responsible for activating the MAP4K4/G3BP2 signaling pathway, ultimately facilitating the phosphorylation of G3BP2 at Thr227 and enhancing HCC metastasis. Taken together, these findings suggest that PEPT1 acts as an oncogene in promoting HCC metastasis through dipeptide-induced MAP4K4/G3BP2 signaling and that the PEPT1/MAP4K4/G3BP2 axis can serve as a promising therapeutic target for metastatic HCC.
Subject(s)
Carcinoma, Hepatocellular , Dipeptides , Liver Neoplasms , Peptide Transporter 1 , Signal Transduction , Animals , Humans , Male , Mice , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Movement , Dipeptides/metabolism , Dipeptides/pharmacology , Disease Models, Animal , Liver Neoplasms/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Mice, Nude , Neoplasm Metastasis , Peptide Transporter 1/metabolism , Peptide Transporter 1/genetics , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/geneticsABSTRACT
BACKGROUND: Post-hepatectomy liver failure (PHLF) is a serious complication after hepatectomy and a major cause of death. The current criteria for PHLF diagnosis (ISGLS consensus) require laboratory data of elevated INR level and hyperbilirubinemia on or after postoperative day 5. This study aims to propose a new indicator for the early clinical prediction of PHLF. METHODS: The peri-operative arterial lactate concentration level ratios were derived from time points within the 3 days before surgery and within POD1, the patients were divided into two groups: high lactate ratio group (≥ 1) and low lactate ratio group (< 1). We compared the differences in morbidity rates between the two groups. Utilized logistic regression analysis to identify the risk factors associated with PHLF development and ROC curves to compare the predictive value of lactate ratio and other liver function indicators for PHLF. RESULTS: A total of 203 patients were enrolled in the study. Overall morbidity and severe morbidity occurred in 64.5 and 12.8 per cent of patients respectively. 39 patients (19.2%) met the criteria for PHLF, including 15 patients (7.4%) with clinically relevant Post-hepatectomy liver failure (CR-PHLF). With a significantly higher incidence of PHLF observed in the lactate ratio ≥ 1 group compared to the lactate ratio < 1 group (n = 34, 26.8% vs. n = 5, 6.6%, P < 0.001). Multivariable logistic regression analysis revealed that a lactate ratio ≥ 1 was an independent predictor for PHLF (OR: 3.239, 95% CI 1.097-9.565, P = 0.033). Additionally, lactate ratio demonstrated good predictive efficacy for PHLF (AUC = 0.792). CONCLUSIONS: Early assessment of peri-operative arterial lactate concentration level ratios may provide experience in early intervention of complications in patients with hepatocellular carcinoma, which can reduce the likelihood of PHLF occurrence and improve patient prognosis.
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Ulcerative colitis (UC) is a chronic, recurrent inflammatory bowel disease. UC confronts with severe challenges including the unclear pathogenesis and lack of specific diagnostic markers, demanding for identifying predictive biomarkers for UC diagnosis and treatment. We perform immune infiltration and weighted gene co-expression network analysis on gene expression profiles of active UC, inactive UC, and normal controls to identify UC related immune cell and hub genes. Neutrophils, M1 macrophages, activated dendritic cells, and activated mast cells are significantly enriched in active UC. MMP-9, CHI3L1, CXCL9, CXCL10, CXCR2 and S100A9 are identified as hub genes in active UC. Specifically, S100A9 is significantly overexpressed in mice with colitis. The receiver operating characteristic curve demonstrates the excellent performance of S100A9 expression in diagnosing active UC. Inhibition of S100A9 expression reduces DSS-induced colonic inflammation. These identified biomarkers associated with activity in UC patients enlighten the new insights of UC diagnosis and treatment.
Subject(s)
Colitis, Ulcerative , Colitis , Inflammatory Bowel Diseases , Humans , Animals , Mice , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/genetics , Colitis, Ulcerative/therapy , Calgranulin B/genetics , Computational Biology , BiomarkersABSTRACT
Background: Xanthogranulomatous cholecystitis (XGC) and gallbladder carcinoma (GBC) share similar imaging and serological profiles, posing significant challenges in accurate preoperative diagnosis. This study aimed to identify reliable indicators and develop a predictive model to differentiate between XGC and GBC. Methods: This retrospective study involved 436 patients from Zhejiang Provincial People's Hospital and The Affiliated Lihuili Hospital of Ningbo University. Comprehensive preoperative imaging, including ultrasound, Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and blood tests, were analyzed. Machine learning (Random Forest method) was employed for variable selection, and a multivariate logistic regression analysis was used to construct a nomogram for predicting GBC. Statistical analyses were performed using SPSS and RStudio software. Results: The study identified gender, Murphy's sign, absolute neutrophil count, glutamyl transpeptidase level, carcinoembryonic antigen level, and comprehensive imaging diagnosis as potential risk factors for GBC. A nomogram incorporating these factors demonstrated high predictive accuracy for GBC, outperforming individual or combined traditional diagnostic methods. External validation of the nomogram showed consistent results. Conclusion: The study successfully developed a predictive nomogram for distinguishing GBC from XGC with high accuracy. This model, integrating multiple clinical and imaging indicators, offers a valuable tool for clinicians in making informed diagnostic decisions. The findings advocate for the use of comprehensive preoperative evaluations combined with advanced analytical tools to improve diagnostic accuracy in complex medical conditions.
ABSTRACT
Sonodynamic therapy (SDT), a tumor treatment modality with high tissue penetration and low side effects, is able to selectively kill tumor cells by producing cytotoxic reactive oxygen species (ROS) with ultrasound-triggered sonosensitizers. N-type inorganic semiconductor TiO2 has low ROS quantum yields under ultrasound irradiation and inadequate anti-tumor activity. Herein, by using atomic layer deposition (ALD) to create a heterojunction between porous TiO2 and CoOx, the sonodynamic therapy efficiency of TiO2 can be improved. Compared to conventional techniques, the high controllability of ALD allows for the delicate loading of CoOx nanoparticles into TiO2 pores, resulting in the precise tuning of the interfaces and energy band structures and ultimately optimal SDT properties. In addition, CoOx exhibits a cascade of H2O2âO2â·O2 - in response to the tumor microenvironment, which not only mitigates hypoxia during the SDT process, but also contributes to the effect of chemodynamic therapy (CDT). Correspondingly, the synergistic CDT/SDT treatment is successful in inhibiting tumor growth. Thus, ALD provides new avenues for catalytic tumor therapy and other pharmaceutical applications.