Structurally and mechanically tuned macroporous hydrogels for scalable mesenchymal stem cell-extracellular matrix spheroid production.

Mesenchymal stem cells (MSCs) are essential in regenerative medicine. However, conventional expansion and harvesting methods often fail to maintain the essential extracellular matrix (ECM) components, which are crucial for their functionality and efficacy in therapeutic applications. Here, we introduce a bone marrow-inspired macroporous hydrogel designed for the large-scale production of MSC-ECM spheroids. Through a soft-templating approach leveraging liquid-liquid phase separation, we engineer macroporous hydrogels with customizable features, including pore size, stiffness, bioactive ligand distribution, and enzyme-responsive degradability. These tailored environments are conducive to optimal MSC proliferation and ease of harvesting. We find that soft hydrogels enhance mechanotransduction in MSCs, establishing a standard for hydrogel-based 3D cell culture. Within these hydrogels, MSCs exist as both cohesive spheroids, preserving their innate vitality, and as migrating entities that actively secrete functional ECM proteins. Additionally, we also introduce a gentle, enzymatic harvesting method that breaks down the hydrogels, allowing MSCs and secreted ECM to naturally form MSC-ECM spheroids. These spheroids display heightened stemness and differentiation capacity, mirroring the benefits of a native ECM milieu. Our research underscores the significance of sophisticated materials design in nurturing distinct MSC subpopulations, facilitating the generation of MSC-ECM spheroids with enhanced therapeutic potential.

Circular-target-style bifocal zoom metalens.

Optical zoom plays an important role in realizing high-quality image magnification, especially in photography, telescopes, microscopes, etc. Compared to traditional bulky zoom lenses, the high versatility and flexibility of metalens design provide opportunities for modern electronic and photonic systems with demands for miniature and lightweight optical zoom. Here, we propose an ultra-thin, lightweight and compact bifocal zoom metalens, which consists of a conventional circular sub-aperture and a sparse annular sub-aperture with different focal lengths. The imaging resolutions of such single zoom metalens with 164 lp/mm and 117 lp/mm at magnifications of 1× and 2× have been numerically and experimentally demonstrated, respectively. Furthermore, clear zoom images of a dragonfly wing pattern have been also achieved using this zoom metalens, showing its distinctive aspect in biological imaging. Our results provide an approach for potential applications in integrated optical systems, miniaturized imaging devices, and wearable devices.

Governance of Friedrich-Wintgen bound states in the continuum by tuning the internal coupling of meta-atoms.

Bound state in the continuum (BIC) is a phenomenon that describes the perfect confinement of electromagnetic waves despite their resonant frequencies lying in the continuous radiative spectrum. BICs can be realized by introducing a destructive interference between distinct modes, referred to as Friedrich-Wintgen BICs (FW-BICs). Herein, we demonstrate that FW-BICs can be derived from coupled modes of individual split-ring resonators (SRR) in the terahertz band. The eigenmode results manifest that FW-BICs are in the center of the far-field polarization vortices. Quasi-BIC-I keeps an ultrahigh quality factor (Q factor) in a broad momentum range along the Γ-X direction, while the Q factor of the quasi-BIC-II drops rapidly. Our results can facilitate the design of devices with high-Q factors with extreme robustness against the incident angle.

Terahertz inner and outer edge modes in a tetramer of strongly coupled spoof localized surface plasmons.

Photonic edge mode confining light in cavities of surface plasmons is beneficial in image and biosensor applications. In the terahertz band, however, the edge mode in a cavity of spoof localized surface plasmons has not matured sufficiently. Herein, a cost-effective strategy to achieve a terahertz photonic edge mode using a metasurface of strongly coupled fourfold spoof localized surface plasmons in a tetramer layout is demonstrated. The quality factors of edge modes decrease when the tetramer shrinks, as revealed by the terahertz dielectric functions. The edge modes that emerge can be categorized as inner and outer edge modes, as deduced from the simulated electric field distribution. Our results show that the edge modes are due to the interaction of spoof localized surface plasmons in the terahertz band.

GAS1 Promotes Ferroptosis of Liver Cells in Acetaminophen-Induced Acute Liver Failure.

Purpose: Acute liver failure (ALF) is a clinically fatal disease that leads to the rapid loss of normal liver function. Acetaminophen (APAP) is a leading cause of drug-induced ALF. Ferroptosis, defined as iron-dependent cell death associated with lipid peroxide accumulation, has been shown to be strongly associated with APAP-induced liver injury. Growth arrest-specific 1 (GAS1) is a growth arrest-specific gene, which is closely related to the inhibition of cell growth and promotion of apoptosis. However, the functional role and underlying mechanism of GAS1 in APAP-induced ferroptosis remain unknown. Methods: We established liver-specific overexpression of GAS1 (GAS1AAV8-OE) mice and the control (GAS1AAV8-vector) mice by tail vein injection of male mice with adeno-associated virus. APAP at 500 mg/kg was intraperitoneally injected into these two groups of mice to induce acute liver failure. The shRNA packaged by the lentivirus inhibits GAS1 gene expression in human hepatoma cell line HepaRG (HepaRG-shNC and HepaRG-shGAS1-2) and primary hepatocytes of mice with liver-specific overexpression of GAS1 were isolated and induced by APAP in vitro to further investigate the regulatory role of GAS1 in APAP-induced acute liver failure. Results: APAP-induced upregulation of ferroptosis, levels of lipid peroxides and reactive oxygen species, and depletion of glutathione were effectively alleviated by the ferroptosis inhibitor, ferrostatin-1, and downregulation of GAS1 expression. GAS1 overexpression promoted ferroptosis-induced lipid peroxide accumulation via p53, inhibiting its downstream target, solute carrier family 7 member 11. Conclusion: Collectively, our findings suggest that GAS1 overexpression plays a key role in aggravating APAP-induced acute liver injury by promoting ferroptosis-induced accumulation of lipid peroxides.

Single-cell RNA sequencing identify SDCBP in ACE2-positive bronchial epithelial cells negatively correlates with COVID-19 severity.

The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in many deaths throughout the world. It is vital to identify the novel prognostic biomarkers and therapeutic targets to assist with the subsequent diagnosis and treatment plan to mitigate the expansion of COVID-19. Since angiotensin-converting enzyme 2 (ACE2)-positive cells are hosts for COVID-19, we focussed on this cell type to explore the underlying mechanisms of COVID-19. In this study, we identified that ACE2-positive cells from the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 belong to bronchial epithelial cells. Comparing with patients of COVID-19 showing severe symptoms, the antigen processing and presentation pathway was increased and 12 typical genes, HLA-DRB5, HLA-DRB1, CD74, HLA-DRA, HLA-DPA1, HLA-DQA1, HSP90AA1, HSP90AB1, HLA-DPB1, HLA-DQB1, HLA-DQA2, and HLA-DMA, particularly HLA-DPB1, were obviously up-regulated in ACE2-positive bronchial epithelial cells of patients with mild disease. We further discovered SDCBP was positively correlated with above 12 genes particularly with HLA-DPB1 in ACE2-positive bronchial epithelial cells of COVID-19 patients. Moreover, SDCBP may increase the immune infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells in different lung carcinoma. Moreover, we found the expression of SDCBP was positively correlated with the expression of antigen processing and presentation genes in post-mortem lung biopsies tissues, which is consistent with previous discoveries. These results suggest that SDCBP has good potential to be further developed as a novel diagnostic and therapeutic target in the treatment of COVID-19.

PRRX1 deficiency induces mesenchymal-epithelial transition through PITX2/miR-200-dependent SLUG/CTNNB1 regulation in hepatocellular carcinoma.

Metastasis is a major obstacle to better prognosis in patients with hepatocellular carcinoma (HCC). Mesenchymal-epithelial transition (MET) is the driving force for metastatic colonization in which E-cadherin re-expression is a critical procedure. It has been reported that the loss of paired-related homeobox transcription factor 1 (PRRX1) is required for cancer cell metastasis. However, the role of PRRX1 in MET and how its downregulation triggers E-cadherin re-expression are unknown. In this study, we performed a systematic, mechanistic study regarding the role of PRRX1 in MET of HCC. We observed PRRX1 downregulation in HCC tissues, which correlated with early metastasis and short overall survival. Overexpression of PRRX1 induced epithelial-mesenchymal transition (EMT), but did not promote metastasis formation, while knockdown of PRRX1 promoted metastasis and colonization of circulating HCC cells as shown in animal model. PRRX1 protein levels reversely correlated with E-cadherin levels in HCC cell lines. PRRX1 knockdown promoted E-cadherin re-expression and cell proliferation and inhibited cell invasion and migration. The microarray results showed that PRRX1 deficiency regulated extracellular matrix (ECM) interaction, focal adhesion, TGF-ß signaling and cancer pathways. PRRX1 knockdown upregulated paired-like homeodomain 2 (PITX2) and inhibited catenin beta 1 (CTNNB1) and SNAIL family zinc finger 2 (SLUG). Silencing of PITX2 reversed CTNNB1 and SLUG inhibition and E-cadherin re-expression. PITX2 upregulation increased miR-200a and miR-200b/429, which further inhibited the transcription of CTNNB1 and SLUG, respectively, thus abrogating the inhibitory effect on E-cadherin. In conclusion, our data showed that the downregulation of PRRX1 induced E-cadherin re-expression through PITX2/miR-200a/CTNNB1 and PITX2/miR-200b/429/SLUG pathway.

Sphingosine kinase 1 knockout alleviates hepatic ischemia/reperfusion injury by attenuating inflammation and oxidative stress in mice.

BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury remains a significant problem in clinical practice. Sphingosine kinase 1 (SphK1) phosphorylates sphingosine to sphingosine-1-phosphate (S1P) which participates in multiple bioactive processes. However, little is known about the role of SphK1 in hepatic I/R injury. This study aimed to investigate the effect of SphK1 knockout on liver I/R injury and to explore underlying mechanisms. METHODS: SphK1 knockout and wild type mice were subjected to 70% partial hepatic I/R. Serum alanine aminotransferase was determined to indicate the degree of liver damage. Hematoxylin-eosin staining and TUNEL assay were used to assess histological changes and hepatocellular apoptosis, respectively. Immunohistochemistry was performed to detect the expression and translocation of phosphorylated p65 and signal transducer and activator of transcription 3 (STAT3). Western blotting was used to determine the expression of S1P receptor 1 (S1PR1), phosphorylated p65 and STAT3. Real-time PCR was used to demonstrate the changes of proinflammatory cytokines. Oxidative stress markers were also determined through biochemical assays. RESULTS: SphK1 knockout significantly ameliorated I/R-induced liver damage, mitigated liver tissue necrosis and apoptosis compared with wild type control. I/R associated inflammation was alleviated in SphK1 knockout mice as demonstrated by attenuated expression of S1PR1 and reduced phosphorylation of nuclear factor kappa B p65 and STAT3. The proinflammatory cytokines interleukin-1ß, interleukin-6 and tumor necrosis factor-α were also inhibited by SphK1 genetic deletion. The oxidative stress markers were lower in SphK1 knockout mice after I/R injury than wild type mice. CONCLUSIONS: Knockout of SphK1 significantly alleviated damage after hepatic I/R injury, possibly through inhibiting inflammation and oxidative stress. SphK1 may be a novel and potent target in clinical practice in I/R-related liver injury.

Epidemiology and clinical characteristics of acute respiratory tract infections among hospitalized infants and young children in Chengdu, West China, 2009-2014.

BACKGROUND: Acute respiratory infection (ARI) is the leading cause of morbidity and mortality in pediatric patients worldwide and imposes an intense pressure on health care facilities. Data on the epidemiology profiles of ARIs are scarce in the western and rural areas of China. The purpose of the current study is to provide data on the presence of potential pathogens of ARIs in hospitalized children in Chengdu, west China. METHODS: Respiratory specimens were obtained from hospitalized patients (under 6 years old) with ARIs in a local hospital in Chengdu. Eight respiratory viruses were identified by PCR and 6 respiratory bacteria by biochemical reactions and Analytical Profile Index (API). Pathogens profiles, clinical characteristics and seasonality were analyzed. RESULTS: Fifty-one percent of patients were identified with at least one respiratory pathogen. Human rhinovirus (HRV) (23%), Respiratory syncytial virus (RSV) (22.7%) was the most commonly identified viruses, with Klebsiella pneumoniae (11.5%) the most commonly identified bacterium in the study. The presences of more than one pathogen were found, and multiple viral, bacterial, viral/bacterial combinations were identified in 14.9, 3.3 and 13.9% of patients respectively. Respiratory viruses were identified throughout the year with a seasonal peak in December-February. Pathogens profiles and clinical associations were different between infants (< 1 year of age) and older children (> 1 year of age). Infants with ARIs were more likely to have one or more viruses than older children. Infants identified with multiple pathogens had significantly higher proportions of tachypnea than infants that were not. CONCLUSIONS: This study demonstrated that viral agents were frequently found in hospitalized children with ARI in Chengdu during the study period. This study gives us better information on the pathogen profiles, clinical associations, co-infection combinations and seasonal features of ARIs in hospitalized children, which is important for diagnoses and treatment of ARIs, as well as implementation of vaccines in this area. Moreover, future efforts in reducing the impact of ARIs will depend on programs in which available vaccines, especially vaccines on RSV, HRV and S. pneumoniae could be employed in this region and new vaccines could be developed against common pathogens.

p300 and C/EBPß-regulated IKKß expression are involved in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells.

Asthma and chronic obstructive pulmonary disease (COPD) are common chronic lung inflammatory diseases. Thrombin and interleukin (IL)-8/C-X-C chemokine ligand 8 (CXCL8) play critical roles in lung inflammation. Our previous study showed that c-Src-dependent IκB kinase (IKK)/IκBα/nuclear factor (NF)-κB and mitogen-activated protein kinase kinase kinase 1 (MEKK1)/extracellular signal-regulated kinase (ERK)/ribosomal S6 protein kinase (RSK)-dependent CAAT/enhancer-binding protein ß (C/EBPß) activation are involved in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells. In this study, we aimed to investigate the roles of p300 and C/EBPß-reliant IKKß expression in thrombin-induced IL-8/CXCL8 expression. Thrombin-induced increases in IL-8/CXCL8-luciferase activity and IL-8/CXCL8 release were inhibited by p300 small interfering (siRNA). Thrombin-caused histone H3 acetylation was attenuated by p300 siRNA. Stimulation of cells with thrombin for 12h resulted in increases in IKKß expression and phosphorylation in human lung epithelial cells. However, thrombin did not affect p65 expression. Moreover, 12h of thrombin stimulation produced increases in IKKß expression and phosphorylation, and IκBα phosphorylation, which were inhibited by C/EBPß siRNA. Finally, treatment of cells with thrombin caused increases in p300 and C/EBPß complex formation, p65 and C/EBPß complex formation, and recruitment of p300, p65, and C/EBPß to the IL-8/CXCL8 promoter. These results imply that p300-dependent histone H3 acetylation and C/EBPß-regulated IKKß expression contribute to thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells. Results of this study will help clarify C/EBPß signaling pathways involved in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells.

Formation of Mn-Co-Ni-O Nanoceramic Microspheres Using In Situ Ink-Jet Printing: Sintering Process Effect on the Microstructure and Electrical Properties.

Mn-Co-Ni-O nanoceramic microspheres with high density, uniformity, and size tunability are successfully fabricated using in situ ink-jet printing and two step sintering (TSS) techniques. The microspheres, synthesized by an effective and facile reverse microemulsion method, consist of uncalcined Mn-Co-Ni-O nanocrystallines that show a well formed single tetragonal spinel phase and an average particle size distribution of ≈20 nm. The sintering behavior, microstructure, and electrical properties of the Mn-Co-Ni-O nanoceramic microspheres are systematically investigated and characterized. The results indicate that the sintered Mn-Co-Ni-O nanoceramic microspheres show high density and improved electrical properties. The highest R25 , B25/50 , Ea , and α25 values achieved at sintering temperature of 1150 °C are 4846.7 KΩ, 4320 K, 0.401 eV, and -5.24% K-1 , respectively for these Mn-Co-Ni-O nanoceramic microspheres. Furthermore, the formation mechanism of uncalcined Mn-Co-Ni-O nanocrystallines and an analysis of the TSS procedure of the nanoceramic microspheres are discussed.

Preoperative inflammation-based markers predict early and late recurrence of hepatocellular carcinoma after curative hepatectomy.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after curative resection remains a major cause of treatment failure and tumor-related death. Patterns of HCC recurrence can be categorized into early recurrence and late recurrence which have different underlying mechanisms. In this study, we investigated if simple inflammation-based clinical markers can distinguish patterns of recurrence after curative resection of HCC. METHODS: A retrospective analysis of 223 patients who underwent curative hepatectomy for HCC was performed. Preoperative inflammation-based factors including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio, gamma-glutamyl transferase/alanine aminotransferase ratio, aspartate aminotransferase/platelet ratio index (APRI) and prognostic nutritional index together with other clinicopathologic parameters were evaluated by univariate analysis and multivariate analysis to identify independent prognostic factors. By combining risk factors, predictive models were established to distinguish populations at high risk of early or late recurrence. RESULTS: Age ≤50 years, resection margin ≤1 cm, TNM stage III-IV, NLR>2.75, APRI>0.23 and positive alpha-fetoprotein were independent adverse prognostic factors for early recurrence. Patients with three or more risk factors were at significant higher risk of early recurrence. APRI>0.23 and positive hepatitis B e antigen (HBeAg) were independent risk factors of late recurrence, the coexistence of high APRI and positive HBeAg increased the risk of late recurrence. CONCLUSIONS: Preoperative inflammation-based prognostic factors predict early and late recurrence of HCC after curative resection. Different prognostic factor combinations distinguish high-risk populations of early or late HCC recurrence.

Preoperative serum liver enzyme markers for predicting early recurrence after curative resection of hepatocellular carcinoma.

BACKGROUND: Early recurrence of hepatocellular carcinoma (HCC) is associated with worse prognosis after liver resection. This study aimed to investigate the prognostic value of common liver enzyme markers in HCC early recurrence after curative hepatectomy and to establish a simple predictive model for HCC early recurrence. METHODS: A total of 200 patients who had undergone curative resection for HCC were retrospectively analyzed. The patients were divided into early recurrence (within 2 years) and non-early recurrence groups. Demographical characteristics, preoperative liver function parameters, surgical factors and tumor related factors of the patients were assessed by univariate analysis to identify potential significant predictors for early recurrence after resection of HCC. Parameters with statistical significance were entered into a Cox proportional hazard model to find independent risk factors. Receiver operating characteristic analysis was done to determine optimal cut-off values and the number of combined factors in multi-factor predictive model. RESULTS: Of 13 potential risk factors for early recurrence identified by univariate analysis, high lactate dehydrogenase (LDH>206 U/L, HR=1.711, P=0.006), high aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AST/ALT>0.96, HR=1.769, P=0.006), elevated alpha-fetoprotein (AFP<8.6 ng/mL, HR=2.079, P=0.007), small resection margin (≤1 cm, HR=2.354, P<0.001) and advanced TNM stage (TNM III-IV, HR=2.164, P<0.001) were independent risk factors for early recurrence of HCC shown by multivariate analysis. Patients with three or more concurrent independent risk factors had significantly higher risk for early recurrence than those with low risk factors. The sensitivity and specificity of this predictive model are 53.6% and 80.7%, respectively (area under curve=0.741, 95% CI 0.674-0.800, P<0.0001). CONCLUSIONS: Preoperative common liver enzyme markers, LDH and AST/ALT ratio, were independently associated with early recurrence of HCC. The combination of serum liver enzyme markers with AFP, resection margin and TNM stage better predicted early recurrence of HCC after curative resection in a simple multi-factor model.

Inferior right hepatic vein-preserving major right hepatectomy for hepatocellular carcinoma in patients with significant fibrosis or cirrhosis.

BACKGROUND: Liver resection represents a most effective treatment for hepatocellular carcinoma (HCC). The extent of hepatectomy for HCC involves maintaining a tricky balance between radical resection of tumors and preservation of sufficient liver parenchyma. Generally, removal of the right hepatic vein often involves resection of the whole posterior right lobe, which may prevent patients with impaired liver function from maintaining a functional reserve and could also limit the future liver remnant from curative hepatectomy. As a common anatomic variation, preservation of the inferior right hepatic vein (IRHV) may enable preservation of liver segment 6, even when the right hepatic vein has to be removed. In the present study, we report our experience with IRHV-preserving major right hepatectomy. METHODS: From February 2009 to December 2011, eight trisegmentectomies 5-7-8 and two segmentectomies 4-5-7-8 were performed with the IRHV-sparing technique on patients with HCC and significant fibrosis or cirrhosis. Data including demographic information, preoperative evaluations, postoperative outcomes, and follow-up results were collected and evaluated. RESULTS: All patients survived and recovered from hepatectomy. The incidence of complications was higher in cirrhotic patients. The 1-year overall survival rate was 80 %, and the 1-year disease free survival rate was 60 %. CONCLUSIONS: IRHV-preserving major right hepatectomy increases the resectability of HCC. Intraoperative ultrasonography is recommended to facilitate protection of the IRHV. This technique is safe with careful preoperative evaluation and meticulous perioperative care. The short-term outcome of IRHV-preserving liver resections is satisfactory.

Emerging roles of MRG15 in liver metabolic diseases.

MORF4 (mortality factor on chromosome 4)-related gene 15 (MRG15) is a chromodomain protein that exists in various multiprotein complexes involved in transcription, DNA repair, and development. Here we summarize the recent advances involving MRG15 in modulating liver metabolism, both through its chromatin-binding capability and independently of it, highlighting MRG15 as a potential therapeutic target for liver metabolic diseases.

MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells by binding ITGB4/LAMB3 to activate the AKT signaling pathway.

Colorectal cancer (CRC) is one of the most lethal cancers. Single-cell RNA sequencing (scRNA-seq) and protein-protein interactions (PPIs) have enabled the systematic study of CRC. In our research, the activation of the AKT pathway in CRC was analyzed by KEGG using single-cell sequencing data from the GSE144735 dataset. The correlation and PPIs of MDFI and ITGB4/LAMB3 were examined. The results were verified in the TCGA and CCLE and further tested by coimmunoprecipitation experiments. The effect of MDFI on the AKT pathway via ITGB4/LAMB3 was validated by knockdown and lentiviral overexpression experiments. The effect of MDFI on oxaliplatin/fluorouracil sensitivity was probed by colony formation assay and CCK8 assay. We discovered that MDFI was positively associated with ITGB4/LAMB3. In addition, MDFI was negatively associated with oxaliplatin/fluorouracil sensitivity. MDFI upregulated the AKT pathway by directly interacting with LAMB3 and ITGB4 in CRC cells, and enhanced the proliferation of CRC cells via the AKT pathway. Finally, MDFI reduced the sensitivity of CRC cells to oxaliplatin and fluorouracil. In conclusion, MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells, partially through the activation of the AKT signaling pathway by the binding to ITGB4/LAMB3. Our findings provide a possible molecular target for CRC therapy.

Toward Practical Applications of Engineered Living Materials with Advanced Fabrication Techniques.

Engineered Living Materials (ELMs) are materials composed of or incorporating living cells as essential functional units. These materials can be created using bottom-up approaches, where engineered cells spontaneously form well-defined aggregates. Alternatively, top-down methods employ advanced materials science techniques to integrate cells with various kinds of materials, creating hybrids where cells and materials are intricately combined. ELMs blend synthetic biology with materials science, allowing for dynamic responses to environmental stimuli such as stress, pH, humidity, temperature, and light. These materials exhibit unique "living" properties, including self-healing, self-replication, and environmental adaptability, making them highly suitable for a wide range of applications in medicine, environmental conservation, and manufacturing. Their inherent biocompatibility and ability to undergo genetic modifications allow for customized functionalities and prolonged sustainability. This review highlights the transformative impact of ELMs over recent decades, particularly in healthcare and environmental protection. We discuss current preparation methods, including the use of endogenous and exogenous scaffolds, living assembly, 3D bioprinting, and electrospinning. Emphasis is placed on ongoing research and technological advancements necessary to enhance the safety, functionality, and practical applicability of ELMs in real-world contexts.

"Find Me" and "Eat Me" signals: tools to drive phagocytic processes for modulating antitumor immunity.

Phagocytosis, a vital defense mechanism, involves the recognition and elimination of foreign substances by cells. Phagocytes, such as neutrophils and macrophages, rapidly respond to invaders; macrophages are especially important in later stages of the immune response. They detect "find me" signals to locate apoptotic cells and migrate toward them. Apoptotic cells then send "eat me" signals that are recognized by phagocytes via specific receptors. "Find me" and "eat me" signals can be strategically harnessed to modulate antitumor immunity in support of cancer therapy. These signals, such as calreticulin and phosphatidylserine, mediate potent pro-phagocytic effects, thereby promoting the engulfment of dying cells or their remnants by macrophages, neutrophils, and dendritic cells and inducing tumor cell death. This review summarizes the phagocytic "find me" and "eat me" signals, including their concepts, signaling mechanisms, involved ligands, and functions. Furthermore, we delineate the relationships between "find me" and "eat me" signaling molecules and tumors, especially the roles of these molecules in tumor initiation, progression, diagnosis, and patient prognosis. The interplay of these signals with tumor biology is elucidated, and specific approaches to modulate "find me" and "eat me" signals and enhance antitumor immunity are explored. Additionally, novel therapeutic strategies that combine "find me" and "eat me" signals to better bridge innate and adaptive immunity in the treatment of cancer patients are discussed.

Ezetimibe inhibits the migration and invasion of triple-negative breast cancer cells by targeting TGFß2 and EMT.

The important role of cholesterol in tumor metastasis has been widely studied in recent years. Ezetimibe is currently the only selective cholesterol uptake inhibitor on the market. Here, we explored the effect of ezetimibe on breast cancer metastasis by studying its impact on breast cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT). Differential gene expression analysis and validation were also carried out to compare ezetimibe-treated and untreated breast cancer cells. Finally, breast cancer cells overexpressing TGFß2 were constructed, and the effect of TGFß2 on the migration and invasion of ezetimibe-treated breast cancer cells was examined. Our results show that ezetimibe treatment of breast cancer cells inhibited cell migration, invasion, and EMT, and it significantly suppressed the expression of TGFß2. Overexpression of TGFß2 reversed the inhibitory effect of ezetimibe on the migration and invasion of breast cancer cells. Taken together, our results suggest that ezetimibe might be a potential candidate for the treatment of breast cancer metastasis.

CuET overcomes regorafenib resistance by inhibiting epithelial-mesenchymal transition through suppression of the ERK pathway in hepatocellular carcinoma.

BACKGROUND AND PURPOSE: Regorafenib was approved by the US Food and Drug Administration (FDA) for hepatocellular carcinoma (HCC) patients showing progress on sorafenib treatment. However, there is an inevitably high rate of drug resistance associated with regorafenib, which reduces its effectiveness in clinical treatment. Thus, there is an urgent need to find a potential way to solve the problem of regorafenib resistance. The metabolite of disulfiram complexed with copper, the Diethyldithiocarbamate-copper complex (CuET), has been found to be an effective anticancer drug candidate. In the present study, we aimed to evaluate the effect of CuET on regorafenib resistance in HCC and uncover the associated mechanism. EXPERIMENTAL APPROACH: Regorafenib-resistant HCC strains were constructed by applying an increasing concentration gradient. This study employed a comprehensive range of methodologies, including the cell counting kit-8 (CCK-8) assay, colony formation assay, cell cycle analysis, wound healing assay, Transwell assay, tumor xenograft model, and immunohistochemical analysis. These methods were utilized to investigate the antitumor activity of CuET, assess the combined effect of regorafenib and CuET, and elucidate the molecular mechanism underlying CuET-mediated regorafenib resistance. KEY RESULTS: The inhibitory effect of regorafenib on cell survival, proliferation and migration was decreased in regorafenib-resistant MHCC-97H (MHCC-97H/REGO) cells compared with parental cells. CuET demonstrated significant inhibitory effects on cell survival, proliferation, and migration of various HCC cell lines. CuET restored the sensitivity of MHCC-97H/REGO HCC cells to regorafenib in vitro and in vivo. Mechanistically, CuET reverses regorafenib resistance in HCC by suppressing epithelial-mesenchymal transition (EMT) through inhibition of the ERK signaling pathway. CONCLUSION AND IMPLICATIONS: Taken together, the results of this study demonstrated that CuET inhibited the activation of the ERK signaling pathway, leading to the suppression of the epithelial-mesenchymal transition (EMT) and subsequently reversing regorafenib resistance in HCC both in vivo and in vitro. This study provides a new idea and potential strategy to improve the treatment of regorafenib-resistant HCC.