Selective removal of iron from sulfuric acid leaching solution of aerospace magnetic material scraps by jarosite process.

Aerospace magnetic material scraps are abundant in cobalt and nickel. Sulfuric acid leaching process is an efficient method for extracting them. But it is a non-selective process, a significant amount of iron dissolves in the solution. This study focuses on the selective removal of iron from this solution using the jarosite process. Eh-pH diagram of K-S-Fe-H2O system was established. Based on thermodynamic analysis, H2O2 is used to oxidize Fe2+ into Fe3+, achieving efficient and selective removal of iron from the solution containing cobalt and nickel. The optimal conditions are as follows: temperature 95°C, K2SO4 dosage coefficient 1.5, seed dosage 10 g/L, time 90 min, pH 1.76, and endpoint pH controlled at approximately 3. Under these conditions, the iron removal efficiency is above 99%, while the loss ratios of cobalt and nickel are below 2%. The product is characterized by XRD and SEM-EDS. Results indicate that the product is jarosite ((K,H3O)Fe3(SO4)2(OH)6), exhibiting an ellipsoid structure with the mean particle size in the range of 0.2-5.0 µm. Temperature, pH value and seed dosage significantly affect reaction rate, particle size and crystallinity, and K2SO4 dosage mainly affects reaction rate and the morphology of jarosite. The jarosite crystallization kinetics can be described by the Avrami equation, with an Avrami index (n) of approximately 2.5 and the apparent activation energy of 42.68 kJ/mol.

Signaling pathways activated and regulated by stem cell-derived exosome therapy.

Stem cell-derived exosomes exert comparable therapeutic effects to those of their parental stem cells without causing immunogenic, tumorigenic, and ethical disadvantages. Their therapeutic advantages are manifested in the management of a broad spectrum of diseases, and their dosing versatility are exemplified by systemic administration and local delivery. Furthermore, the activation and regulation of various signaling cascades have provided foundation for the claimed curative effects of exosomal therapy. Unlike other relevant reviews focusing on the upstream aspects (e.g., yield, isolation, modification), and downstream aspects (e.g. phenotypic changes, tissue response, cellular behavior) of stem cell-derived exosome therapy, this unique review endeavors to focus on various affected signaling pathways. After meticulous dissection of relevant literature from the past five years, we present this comprehensive, up-to-date, disease-specific, and pathway-oriented review. Exosomes sourced from various types of stem cells can regulate major signaling pathways (e.g., the PTEN/PI3K/Akt/mTOR, NF-κB, TGF-ß, HIF-1α, Wnt, MAPK, JAK-STAT, Hippo, and Notch signaling cascades) and minor pathways during the treatment of numerous diseases encountered in orthopedic surgery, neurosurgery, cardiothoracic surgery, plastic surgery, general surgery, and other specialties. We provide a novel perspective in future exosome research through bridging the gap between signaling pathways and surgical indications when designing further preclinical studies and clinical trials.

Thiostrepton induces oxidative stress, mitochondrial dysfunction and ferroptosis in HaCaT cells.

TST has been mainly studied for its anti-tumor proliferation and antimicrobial effects, but not widely used in dermatological diseases. The mechanism of cellular damage by TST in response to H2O2-mediated oxidative stress was investigated in human skin immortalized keratinocytes (HaCaT) as an in vitro model. The findings reveal that TST treatment leads to increased oxidative stress in the cells by reducing levels of superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). This effect is further supported by an upsurge in the expression of malondialdehyde (MDA, a pivotal marker of lipid peroxidation). Additionally, dysregulation of FoxM1 at both gene and protein levels corroborates its involvement TST associated effects. Analysis of ferroptosis-related genes confirms dysregulation following TST treatment in HaCaT cells. Furthermore, TST treatment exhibits effects on mitochondrial morphology and function, affirming its induction of apoptosis in the cells through heightened oxidative stress due to mitochondrial damage and dysregulation of mitochondrial membrane potential.

Local Delivery of Dual Stem Cell-Derived Exosomes Using an Electrospun Nanofibrous Platform for the Treatment of Traumatic Brain Injury.

Traumatic brain injury poses serious physical, psychosocial, and economic threats. Although systemic administration of stem cell-derived exosomes has recently been proven to be a promising modality for traumatic brain injury treatment, they come with distinct drawbacks. Luckily, various biomaterials have been developed to assist local delivery of exosomes to improve the targeting of organs, minimize nonspecific accumulation in vital organs, and ensure the protection and release of exosomes. In this study, we developed an electrospun nanofibrous scaffold to provide sustained delivery of dual exosomes derived from mesenchymal stem cells and neural stem cells for traumatic brain injury treatment. The electrospun nanofibrous scaffold employed a functionalized layer of polydopamine on electrospun poly(ε-caprolactone) nanofibers, thereby enhancing the efficient incorporation of exosomes through a synergistic interplay of adhesive forces, hydrogen bonding, and electrostatic interactions. First, the mesenchymal stem cell-derived exosomes and the neural stem cell-derived exosomes were found to modulate microglial polarization toward M2 phenotype, play an important role in the modulation of inflammatory responses, and augment axonal outgrowth and neural repair in PC12 cells. Second, the nanofibrous scaffold loaded with dual stem cell-derived exosomes (Duo-Exo@NF) accelerated functional recovery in a murine traumatic brain injury model, as it mitigated the presence of reactive astrocytes and microglia while elevating the levels of growth associated protein-43 and doublecortin. Additionally, multiomics analysis provided mechanistic insights into how dual stem cell-derived exosomes exerted its therapeutic effects. These findings collectively suggest that our novel Duo-Exo@NF system could function as an effective treatment modality for traumatic brain injury using sustained local delivery of dual exosomes from stem cells.

Immunomodulatory effect of PLGA-encapsulated mesenchymal stem cells-derived exosomes for the treatment of allergic rhinitis.

Introduction: Allergic rhinitis (AR) is an upper airway inflammatory disease of the nasal mucosa. Conventional treatments such as symptomatic pharmacotherapy and allergen-specific immunotherapy have considerable limitations and drawbacks. As an emerging therapy with regenerative potential and immunomodulatory effect, mesenchymal stem cell-derived exosomes (MSC-Exos) have recently been trialed for the treatment of various inflammatory and autoimmune diseases. Methods: In order to achieve sustained and protected release of MSC-Exos for intranasal administration, we fabricated Poly(lactic-co-glycolic acid) (PLGA) micro and nanoparticles-encapsulated MSC-Exos (PLGA-Exos) using mechanical double emulsion for local treatment of AR. Preclinical in vivo imaging, ELISA, qPCR, flow cytometry, immunohistochemical staining, and multiomics sequencing were used for phenotypic and mechanistic evaluation of the therapeutic effect of PLGA-Exos in vitro and in vivo. Results: The results showed that our PLGA platform could efficiently encapsulate and release the exosomes in a sustained manner. At protein level, PLGA-Exos treatment upregulated IL-2, IL-10 and IFN-γ, and downregulated IL-4, IL-17 and antigen-specific IgE in ovalbumin (OVA)-induced AR mice. At cellular level, exosomes treatment reduced Th2 cells, increased Tregs, and reestablished Th1/Th2 balance. At tissue level, PLGA-Exos significantly attenuated the infiltration of immune cells (e.g., eosinophils and goblet cells) in nasal mucosa. Finally, multiomics analysis discovered several signaling cascades, e.g., peroxisome proliferator-activated receptor (PPAR) pathway and glycolysis pathway, that might mechanistically support the immunomodulatory effect of PLGA-Exos. Discussion: For the first time, we present a biomaterial-facilitated local delivery system for stem cell-derived exosomes as a novel and promising strategy for AR treatment.

Temperature-Insensitive Nonpolar Suspensions of Polyoxyethylene Alkyl Ether-Grafted Silica Nanoparticles.

Nonpolar suspensions of organically modified particles exhibit a strong temperature sensitivity owing to the high-temperature-induced desorption/decomposition and the low-temperature-induced disorder/order conformational transition of the modifiers. This strong temperature sensitivity limits their applications, such as lubricants and oil-based drilling fluids, which require the suspensions to operate over a wide temperature range (e.g., 0-200 °C). We hypothesize that the introduction of a flexible ethylene oxide (EO) chain into the modifiers can disrupt the low-temperature-induced ordered conformation to improve the stability of the nonpolar suspensions. In this article, nonpolar suspensions with temperature insensitivity in the range of 5-160 °C were obtained via the covalent modification of silica NPs and the introduction of EO chains into the modifier molecules. Here, octadecyl-grafted silica NPs (C18-SiO2) and polyoxyethylene alkyl ether-grafted silica NPs (AEOn-SiO2) were synthesized and subsequently dispersed in mineral oil. The rheological properties of each suspension at different temperatures were evaluated, and the thermal stability of AEOn-SiO2 in mineral oil was investigated along with the conformational changes of the grafted chains. In the temperature range of 5-160 °C, the apparent viscosity and gel strength of the C18-SiO2 suspension changed dramatically, whereas the AEOn-SiO2 suspensions exhibited constant rheological properties over this temperature range. This temperature insensitivity of AEOn-SiO2 suspensions is attributed to the excellent thermal stability of AEOn-SiO2 in mineral oil and the disordered conformation of the EO chains upon cooling. This study provides a novel approach to preparing temperature-insensitive nonpolar suspensions, which have potential applications in the petroleum and lubricant industries.

The safety and short-term effect of mixed approach in laparoscopic right hemicolectomy for right colon cancer compared with middle approach: a retrospective study.

PURPOSE: To investigate whether the mixed approach is a safe and advantageous way to operate laparoscopic right hemicolectomy. METHODS: A retrospective study was performed on 316 patients who underwent laparoscopic right hemicolectomy in our center. They were assigned to the middle approach group (n = 158) and the mixed approach group (n = 158) according to the surgical approaches. The baseline data like gender、age and body mass index as well as the intraoperative and postoperative conditions including operation time, blood loss, postoperative hospital stay and complications were analyzed. RESULTS: There were no significant differences in age, sex, BMI, ASA grade and tumor characteristics between the two groups. Compared with the middle approach group, the mixed approach group was significantly lower in terms of operation time (217.61 min vs 154.31 min, p < 0.001), intraoperative blood loss (73.8 ml vs 37.97 ml, p < 0.001) and postoperative drainage volume. There was no significant difference in the postoperative complications like postoperative anastomotic leakage, postoperative infection and postoperative intestinal obstruction. CONCLUSIONS: Compared with the middle approach, the mixed approach is a safe and advantageous way that can significantly shorten the operation time, reduce intraoperative bleeding and postoperative drainage volume, and does not prolong the length of hospital stay or increase the morbidity postoperative complications.

Risk factors and clinical significance of lower perigastric lymph node metastases in Siewert type II and III esophagogastric junction adenocarcinoma: a retrospective cohort study.

BACKGROUND: No consensus has been concluded with regarding to the scope of lymph node (LN) dissection for Siewert type II and III adenocarcinoma of the esophagogastric junction (AEG). This study aimed to explore risk factors for lower perigastric LN (LPLN) metastases (including no. 4d, 5, 6, and 12a LN stations) and analyze the indications for LPLN dissection. METHODS: In total, 302 consecutive patients with Siewert type II and III AEG who underwent total gastrectomy (TG) were enrolled. The logistic regression model was used to perform uni- and multivariate analyses of risk factors for LPLN metastases. Kaplan-Meier curves were used for survival analysis, and log-rank tests were used for group comparisons. Basing on the guidelines of Japanese Gastric Cancer Association, the LN metastases (LNM) as well as the efficiency index (EI) of each LN station was further evaluated. RESULTS: The independent risk factors for LPLN metastases in patients with Siewert type II and III AEG were distance from the esophagogastric junction (EGJ) to the distal end of the tumor (> 4.0 cm), preoperative carcinoembryonic antigen (CEA) ( +), pT4 stage, and HER-2 ( +). LPLN metastases was an independent risk factor for overall survival following TG. The LNM and EI of LPLN were 8.6% and 2.31%, respectively. The LNM of LPLN > 10% under the stratification of the distance from the EGJ to the distal end of the tumor (> 4.0 cm), pT4, preoperative CEA ( +), and HER-2 ( +) exhibited EI values of 3.55%, 2.09%, 2.51%, and 3.64%, respectively. CONCLUSIONS: LPLN metastases was a malignant factor for the prognosis of patients with Siewert type II and III AEG. For patients with preoperative CEA ( +), pT4 stage, HER-2 ( +), and the distance from the EGJ to the distal end of the tumor (> 4.0 cm), TG with LPLN dissection is prioritized for clinical recommendation.

Identification of a marine-derived sesquiterpenoid, Compound-8, that inhibits tumour necrosis factor-induced cell death by blocking complex II assembly.

BACKGROUND AND PURPOSE: Tumour necrosis factor (TNF) is a pleiotropic inflammatory cytokine that not only directly induces inflammatory gene expression but also triggers apoptotic and necroptotic cell death, which leads to tissue damage and indirectly exacerbates inflammation. Thus, identification of inhibitors for TNF-induced cell death has broad therapeutic relevance for TNF-related inflammatory diseases. In the present study, we isolated and identified a marine fungus-derived sesquiterpenoid, 9α,14-dihydroxy-6ß-p-nitrobenzoylcinnamolide (named as Cpd-8), that inhibits TNF receptor superfamily-induced cell death by preventing the formation of cytosolic death complex II. EXPERIMENTAL APPROACH: Marine sponge-associated fungi were cultured and the secondary metabolites were extracted to yield pure compounds. Cell viability was measured by ATP-Glo cell viability assay. The effects of Cpd-8 on TNF signalling pathway were investigated by western blotting, immunoprecipitation, and immunofluorescence assays. A mouse model of acute liver injury (ALI) was employed to explore the protection effect of Cpd-8, in vivo. KEY RESULTS: Cpd-8 selectively inhibits TNF receptor superfamily-induced apoptosis and necroptosis. Cpd-8 prevents the formation of cytosolic death complex II and subsequent RIPK1-RIPK3 necrosome, while it has no effect on TNF receptor I (TNFR1) internalization and the formation of complex I in TNF signalling pathway. In vivo, Cpd-8 protects mice against TNF-α/D-GalN-induced ALI. CONCLUSION AND IMPLICATIONS: A marine fungus-derived sesquiterpenoid, Cpd-8, inhibits TNF receptor superfamily-induced cell death, both in vitro and in vivo. This study not only provides a useful research tool to investigate the regulatory mechanisms of TNF-induced cell death but also identifies a promising lead compound for future drug development.

Oroxylin A suppress LL-37 generated rosacea-like skin inflammation through the modulation of SIRT3-SOD2-NF-κB signaling pathway.

Rosacea is a long-term inflammatory skin disease associated with the dysfunction of vascular and immunological systems. Treatment options for rosacea are difficult to implement. Oroxylin A(OA), a traditional Chinese medicine, has anti-inflammation effects in a variety of inflammatory diseases. However, it is not known that whether OA exerts protective effects against LL-37-induced rosacea. In this study, bioinformatics analyses showed that the mechanisms of rosacea and the pharmacological targets of OA were highly overlapped. Subsequently, it was shown that the administration of OA resulted in a notable amelioration of rosacea-like skin lesions, as evidenced by a reduction in immune cell infiltration, modulation of cytokine production, and inhibition of angiogenesis. Plus, it was shown that OA effectively suppressed the generation of ROS generated by LL-37, as well as the subsequent activation of NF-κB signaling pathway. To explore further, we found that OA inhibited LL-37-induced ROS production via SIRT3-SOD2 signaling pathway in keratinocytes. Based on the aforementioned evidence, it can be inferred that OA exhibits a mitigating effect on the inflammatory response in rosacea by modulating the SIRT3-SOD2-NF-κB signaling pathway.

Amrubicin encapsulated PLGA NPs inhibits the PI3K/AKT signaling pathway by activating PTEN and inducing apoptosis in TMZ-resistant Glioma.

Glioblastoma (GBM) remains a challenging malignancy due to its aggressive nature and the lack of efficacious therapeutic interventions. Nanotechnology-based approaches exhibit promise in GBM treatment; however, the successful translation of these strategies from preclinical models to clinical settings is hindered by inefficient nanoparticle clearance from vital organs. Addressing this concern, we investigated the therapeutic potential of amrubicin (AMR) encapsulated within poly (lactic-co-glycolic acid) nanoparticles (AMR-PLGA-NPs) in combating temozolomide (TMZ) resistant GBM. The study demonstrated that AMR-PLGA-NPs exerted a pronounced inhibitory effect on the cellular viability and migratory capacity of TMZ-resistant GBM cells. Furthermore, these nanoparticles exhibited considerable efficacy in downregulating the PI3K/AKT signaling pathway, thereby inducing apoptosis specifically in TMZ-resistant glioma cells and glioma stem-like cells through the activation of PTEN. Notably,in vivoexperimentation revealed the ability of AMR-PLGA-NPs to traverse biological barriers within murine models. Collectively, these findings underscore the potential therapeutic utility of AMR-PLGA-NPs as a versatile nanoplatform for addressing the formidable challenges posed by GBM, particularly in mitigating drug resistance mechanisms. The study substantiates the stability and safety profile of AMR-PLGA-NPs, positioning them as a promising avenue for combating drug resistance in GBM therapeutics.

Clinical applications of stem cell-derived exosomes.

Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared to stem cells, stem cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic potential and ethical issues. Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency. After a thorough search and meticulous dissection of relevant literature from the last five years, we present this comprehensive, up-to-date, specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes. Exosomes derived from stem cells (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, and endothelial stem cells) are capable of treating numerous diseases encountered in orthopedic surgery, neurosurgery, plastic surgery, general surgery, cardiothoracic surgery, urology, head and neck surgery, ophthalmology, and obstetrics and gynecology. The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses, and cell-specific molecular signaling pathways. In this review, we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions. We recommend that future research combines wisdoms from surgeons, nanomedicine practitioners, and stem cell researchers in this relevant and intriguing research area.

Cold atmospheric plasma sensitizes head and neck cancer to chemotherapy and immune checkpoint blockade therapy.

Head and neck cancer (HNC) is the seventh most prevalent cancer globally, often characterized by chemo-resistance and immunosuppression, which significantly hampers treatment efficacy. Cold atmospheric plasma (CAP) has recently emerged as a promising adjuvant oncotherapy with substantial potential and advantages. In this study, Piezobrush® PZ2, a handheld CAP unit based on the piezoelectric direct discharge technology, was used to generate and deliver non-thermal plasma. We aimed to investigate the effects of CAPPZ2 on various types of HNC cells and elucidate the underlying mechanisms. In addition, we endeavored to examine the efficacy of combining CAPPZ2 with chemotherapy drugs (i.e., cisplatin) or immune checkpoint blockade (ICB, i.e., PD1 antibody) in HNC treatment. Firstly, the results demonstrated that CAPPZ2 exerted anti-neoplastic functions through inhibiting cell proliferation, migration and invasion, and promoting apoptosis and autophagy. Secondly, using transcriptomic sequencing, Western blotting, and quantitative real-time PCR, the mechanisms underlying CAPPZ2 treatment in vitro was presumed to be a multitargeted blockade of major cancer survival pathways, such as redox balance, glycolysis, and PI3K/AKT/mTOR/HIF-1α signaling. Lastly, combinatorial thearpy containing CAPPZ2 and cisplatin or PD-1 antibody significantly suppressed tumor growth and prolonged recipient survival in vivo. Collectively, the synergistic effects of CAPPZ2 and cisplatin or PD-1 antibody could serve as a promising solution to enhance head and neck tumor elimination.

Biologics targeting IL-17 and IL-23 maintain stability in patients with psoriasis during COVID-19 infection: a case-control study.

Background: Psoriasis is a chronic and refractory skin disease. The emergence of biologics provides more options for the treatment of psoriasis, but the COVID-19 pandemic poses challenges for the management of psoriasis. Objectives: The purpose of this study was to investigate the effect of different biologics on the stabilization of psoriasis during COVID-19 infection in China. Methods: This is a single-center, observational, retrospective, case-control study. Using our database, we conducted a remote dermatologic study by means of questionnaire follow-up or telephone follow-up to collect general information of patients, information related to COVID-19 infection and conditions of psoriasis for comparison and further analysis between groups. Results: Our study ultimately included 274 patients for analysis. We found that the patients in this collection had mild symptoms of COVID-19 infection, and only 13 of them needed to go to the hospital for medical treatment. Further studies found that in biologics, relative to tumor necrosis factor-α inhibitors (TNF-αi), interleukin-17 inhibitors (IL-17i) and interleukin-23 inhibitors (IL-23i) are both protective factors in flare-up of psoriasis [IL-17i: OR (95% CI) = 0.412 (0.189-0.901); IL-23i: OR (95% CI) = 0.291 (0.097-0.876)]. In addition, we also found that the proportion of people with increased psoriasis developing long COVID-19 increased, and we speculated that increased psoriasis may be a potential risk factor for long COVID-19. Conclusion: Our study showed that the use of IL-17i and IL-23i was a protective factor for psoriasis compared with TNF-αi, and could keep the psoriasis stable.

Development of a fibroblast activation protein-targeted PET/NIR dual-modality probe and its application in head and neck cancer.

Purpose: The combination of near-infrared (NIR) and positron emission tomography (PET) imaging presents an opportunity to utilize the benefits of dual-modality imaging for tumor visualization. Based on the observation that fibroblast activation protein (FAP) is upregulated in cancer-associated fibroblasts (CAFs) infiltrating all solid tumors, including head and neck squamous cell carcinoma (HNSCC), we developed the novel PET/NIR probe [68Ga]Ga-FAP-2286-ICG. Preclinically, the specificity, biodistribution and diagnostic properties were evaluated. Methods: Cell uptake assays were completed with the U87MG cell to evaluate the specificity of the [68Ga]Ga-FAP-2286-ICG. The tumor-targeting efficiency, biodistribution and optimal imaging time window of the [68Ga]Ga-FAP-2286-ICG were studied in mice bearing U87MG xenografts. HNSCC tumor-bearing mice were used to evaluate the feasibility of [68Ga]Ga-FAP-2286-ICG for tumor localization and guided surgical resection of HNSCC tumors. Results: The in vitro experiments confirmed that [68Ga]Ga-FAP-2286-ICG showed good stability, specific targeting of the probe to FAP, and the durable retention effect in high-expressing FAP tumors U87MG cell. Good imaging properties such as good tumor uptake, high tumor-to-background ratios (5.44 ± 0.74) and specificity, and tumor contouring were confirmed in studies with mice bearing the U87MG xenograft. PET/CT imaging of the probe in head and neck cancer-bearing mice demonstrated specific uptake of the probe in the tumor with a clear background. Fluorescence imaging further validated the value of the probe in guiding surgical resection and achieving precise removal of the tumor and residual lesions. Conclusion: In a preclinical model, these attractive [68Ga]Ga-FAP-2286-ICG PET/NIR imaging acquired in head and neck cancer make it a promising FAP-targeted multimodal probe for clinical translation.

Piezoeletric cold atmospheric plasma induces apoptosis and autophagy in human hepatocellular carcinoma cells through blocking glycolysis and AKT/mTOR/HIF-1α pathway.

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the fourth leading cause of cancer-related death worldwide. Advanced or metastatic HCC is currently managed using systemic drug therapy with unsatisfactory patient survival. Cold atmospheric plasma has emerged as a promising, physicochemical, and broad-spectrum oncotherapy. In this preclinical study, we investigated the anti-neoplastic functions and mechanism of piezoelectric direct discharge technology-based CAP, Piezo-CAP, on HCC in vitro and in vivo. Various HCC cells lines, such as SMMC7721, HepG2 and LM3, were used as in vitro cancer model for the phenotypic and mechanistic studies. Specifically, the cell counting Kit-8 and colony formation assay, flow cytometry, Transwell assay, Western blot, reactive oxygen species (ROS) assay, and glutathione to oxidized glutathione ratio (GSH/GSSG) assay were used to demonstrate plasma-induced changes in HCC cell proliferation, cell cycle progression, migration and invasion, epithelial-to-mesenchymal transition, intracellular ROS, and antioxidant capacity, respectively. In addition, the Acridine orange and ethidium bromide (AO/EB) staining and transmission electron microscopy were performed for cellular and subcellular assessment of HCC cell apoptosis. The Ad-mCherry-RFP-LC3B fluorescent double-labeled lentiviral system was used to detect autophagic flux. On the other hand, RNA-sequencing, quantitative real-time PCR, and Western blot were used to demonstrate plasma-induced metabolic and molecular disruption of tumor glycolysis and oncogenic proliferation, respectively. In vivo experiments using a human cell-line-derived xenograft model and immunohistochemistry (IHC) were utilized to investigate the mechanism. Piezo-CAP exerted anti-neoplastic functions through inhibiting cell proliferation, migration and invasion, and promote cell apoptosis and autophagy. Treatment of Piezo-CAP could suppress proliferation and induce autophagy of HCC cells through simultaneously disrupts cancer survival pathways of redox deregulation, glycolytic pathway, and PI3K/AKT/mTOR/HIF1α pathway signaling. Moreover, upon translation of these in vitro results into the tissue level, Piezo-CAP significantly suppressed in situ tumor growth. These findings collectively suggest that Piezo-CAP-induced apoptosis and autophagy of HCC cells though a multitargeted blockade of major cancer survival pathways of deregulated redox balance, glycolysis, and PI3K/AKT/mTOR/HIF-1α signaling.

A Prognostic Model of Head and Neck Cancer Based on Amino Acid Metabolism-Related Signature and Its Implication for Immunosuppressive Microenvironment.

Amino acid metabolism has been implicated in tumorigenesis and tumor progression. Alterations in intracellular and extracellular metabolites associated with metabolic reprogramming in cancer have profound effects on gene expression, cell differentiation, and tumor immune microenvironment. However, the prognostic significance of amino acid metabolism in head and neck cancer remains to be further investigated. In this study, we identified 98 differentially expressed genes related to amino acid metabolism in head and neck cancer in The Cancer Genome Atlas. Using batch univariate Cox regression and Lasso regression, we extracted nine amino acid metabolism-related genes. Based on that, we developed the amino acid metabolism index. The prognostic value of this index was validated in two Gene Expression Omnibus cohorts. The results show that this model can help predict tumor recurrence and prognosis. The infiltration of immune cells in the tumor microenvironment was analyzed, and it was discovered that the high index is associated with an immunosuppressive microenvironment. In addition, this study demonstrated the impact of the amino acid metabolism index on clinical indicators, survival of patients with head and neck cancer, and the prediction of treatment response to immune checkpoint inhibitors. We conducted several cell experiments and demonstrated that epigenetic drugs could affect the index and enhance tumor immunity. In conclusion, our study demonstrates that the index not only has important prognostic value in head and neck cancer patients but also facilitates patient stratification for immunotherapy.

Luteolin-Loaded Nanoparticles for the Treatment of Melanoma.

Background and Purpose: Luteolin (LUT), a flavonoid found in various plants, has been reported to have potential therapeutic effects in melanoma. However, poor water solubility and low bioactivity have severely restricted the clinical application of LUT. Based on the high reactive oxygen species (ROS) levels in melanoma cells, we developed nanoparticles encapsulating LUT with the ROS-responsive material poly(propylene sulfide)-poly(ethylene glycol) (PPS-PEG) to enhance the water solubility of LUT, accelerate the release of LUT in melanoma cells, and further enhance its anti-melanoma effect, providing a viable solution for the application of LUT nano-delivery systems in melanoma therapy. Methods: In this study, LUT-loaded nanoparticles were prepared with PPS-PEG and named as LUT-PPS-NPs. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) were applied to determine the size and morphology of LUT-PPS-NPs. In vitro studies were carried out to determine the uptake and mechanism of LUT-PPS-NPs by SK-MEL-28 melanoma cells. According to the CCK-8 assay, the cytotoxic effects of LUT-PPS-NPs on human skin fibroblasts (HSF) and SK-MEL-28 cells were assessed. Apoptosis assays, cell migration and invasion assays, and proliferation inhibition assays with low and normal density plating were also applied to test the in vitro anti-melanoma effect. Additionally, melanoma models were established utilizing BALB/c nude mice and initially evaluated the growth inhibitory impact following intratumoral injection of LUT-PPS-NPs. Results: The size of LUT-PPS-NPs was 169.77 ± 7.33 nm with high drug loading (15.05 ± 0.07%). In vitro, cellular assays confirmed that LUT-PPS-NPs were efficiently internalized by SK-MEL-28 cells and showed low cytotoxicity against HSF. Moreover, LUT released from LUT-PPS-NPs significantly inhibited tumor cell proliferation, migration and invasion. Animal experiments showed that LUT-PPS-NPs inhibited tumor growth more than 2-fold compared with the LUT group. Conclusion: In conclusion, the LUT-PPS-NPs developed in our study enhanced the anti-melanoma effect of LUT.

Clinicopathological characteristics and treatment outcome of resectable gastric cancer patients with small para-aortic lymph node.

Background: Resectable gastric cancer (GC) patients with small para-aortic lymph node (smaller than 10mm in diameter, sPAN) were seldom reported, and existing guidelines did not provide definite treatment recommendation for them. Methods: A total of 667 consecutive resectable GC patients were enrolled. 98 patients were in the sPAN group, and 569 patients without enlarged para-aortic lymph node were in the nPAN group. Standard D2 lymphadenectomy was performed. Neoadjuvant and adjuvant chemotherapy were administrated according to the cTNM and pTNM stage, respectively. Clinicopathological features and prognosis were compared between these two groups. Results: The median size of sPAN was 6 (range, 2-9) mm and the distribution was prevalent in No. 16b1. cN stage (p=0.001) was significantly related to the presence of sPAN. sPAN was both independent risk factor for OS (p=0.031) and RFS (p=0.046) of all patients. The prognosis of patients with sPAN was significantly worse than that of patients with nPAN (OS: p=0.008; RFS: p=0.007). Preoperative CEA and CA19-9 were independent risk factors for prognosis of patients with sPAN. Furthermore, patients in the sPAN group with normal CEA and CA19-9 exhibited acceptable prognosis (5-year OS: 67%; RFS: 64%), while those with elevated CEA or CA19-9 suffered significantly poorer prognosis (5-year OS: 17%; RFS: 17%) than patients in the nPAN group (5-year OS: 64%; RFS 62%) (both p < 0.05). Conclusions: Standard D2 lymphadenectomy should be considered a valid approach for GC patients with sPAN associate to normal preoperative CEA and CA19-9 levels. Patients with sPAN associated to elevated CEA or CA19-9 levels could benefit from a multimodal approach: neoadjuvant chemotherapy; radical surgery with D2 plus lymph nodal dissection extended to No. 16 station.

Serum and peritoneal biomarkers for the early prediction of symptomatic anastomotic leakage in patients following laparoscopic low anterior resection: A single-center prospective cohort study.

BACKGROUND: Anastomotic leakage (AL) is one of the common complications after rectal cancer surgery. This study aimed to evaluate the combination of biomarkers for the early prediction of symptomatic AL after surgery. METHODS: A prospective cohort study evaluated the serum and peritoneal biomarkers of patients who underwent laparoscopic low anterior resection (Lap LAR) from November 1, 2021, to May 1, 2022. Multivariate-penalized logistic regression was performed to explore the independent biomarker with a P-value <.1, and receiver operating characteristic (ROC) curve was used to analyze the area under the curve (AUC), sensitivity, and specificity of the independent biomarkers. A predictive model for symptomatic AL was built based on the independent biomarkers and was visualized with a nomogram. The calibration curve with the concordance index (c-index) was further applied to evaluate the efficacy of the predictive model. RESULTS: A total of 157 patients were included in this study, and 7 (4.5%) were diagnosed with symptomatic AL. C-reactive protein/album ratio (CAR) on postoperative day 1 and systemic immune-inflammation index (SII) and peritoneal interleukin-6 (IL-6) on postoperative day 3 were proven to be independent predictors for the early prediction of symptomatic AL. The optimal cutoff values of CAR, SII, and peritoneal IL-6 were 1.04, 916.99, and 26430.09 pg/ml, respectively. Finally, the nomogram, including these predictors, was established, and the c-index of this nomogram was 0.812, indicating that the nomogram could be used for potential clinical reference. CONCLUSION: The combination of CAR, SII, and peritoneal IL-6 might contribute to the early prediction of symptomatic AL in patients following Lap LAR. Given the limitations of this study and the emergence of other novel biomarkers, multicenter prospective studies are worthy of further exploration.