Identification of an HLA-A*11:01-restricted neoepitope of mutant PIK3CA and its specific T cell receptors for cancer immunotherapy targeting hotspot driver mutations.

Hotspot driver mutations presented by human leukocyte antigens might be recognized by anti-tumor T cells. Based on their advantages of tumor-specificity and immunogenicity, neoantigens derived from hotspot mutations, such as PIK3CAH1047L, may serve as emerging targets for cancer immunotherapies. NetMHCpan V4.1 was utilized for predicting neoepitopes of PIK3CA hotspot mutation. Using in vitro stimulation, antigen-specific T cells targeting the HLA-A*11:01-restricted PIK3CA mutation were isolated from healthy donor-derived peripheral blood mononuclear cells. T cell receptors (TCRs) were cloned using single-cell PCR and sequencing. Their functionality was assessed through T cell activation markers, cytokine production and cytotoxic response to cancer cell lines pulsed with peptides or transduced genes of mutant PIK3CA. Immunogenic mutant antigens from PIK3CA and their corresponding CD8+ T cells were identified. These PIK3CA mutation-specific CD8+ T cells were subsequently enriched, and their TCRs were isolated. The TCR clones exhibited mutation-specific and HLA-restricted reactivity, demonstrating varying degrees of functional avidity. Identified TCR genes were transferred into CD8+ Jurkat cells and primary T cells deficient of endogenous TCRs. TCR-expressing cells demonstrated specific recognition and reactivity against the PIK3CAH1047L peptide presented by HLA-A*11:01-expressing K562 cells. Furthermore, mutation-specific TCR-T cells demonstrated an elevation in cytokine production and profound cytotoxic effects against HLA-A*11:01+ malignant cell lines harboring PIK3CAH1047L. Our data demonstrate the immunogenicity of an HLA-A*11:01-restricted PIK3CA hotspot mutation and its targeting therapeutic potential, together with promising candidates of TCR-T cell therapy.

Endoplasmic reticulum stress potentiates the immunosuppressive microenvironment in hepatocellular carcinoma by promoting the release of SNHG6-enriched small extracellular vesicles.

Endoplasmic reticulum (ER) stress leads to hepatocellular carcinoma (HCC) progression. Small extracellular vesicles (sEVs) play a crucial role in modulating the tumor microenvironment (TME) by influencing cellular communication and immune responses. However, it is unclear whether ER stress modulates the TME through sEVs. In the current study, we investigated the effects and underlying mechanisms of ER stress on the HCC TME. In vivo and in vitro experiments showed that overactivated ER stress was a salient attribute of the immunosuppressive HCC TME. This was caused by the ATF4-promoted release of SNHG6-carrying sEVs, which attenuated T cell-mediated immune responses. Overall, SNHG6 modulated the immunosuppressive TME and aggravated ER stress. Meanwhile, targeting SNHG6 facilitated M1-like macrophage and CD8+ T-cell infiltration and decreased the proportion of M2-like macrophages. In addition, SNHG6 knockdown enhanced anti-PD-1 immunotherapeutic efficacy. Moreover, in HCC patients, overexpression of SNHG6 was associated with a lack of response to anti-PD-1 therapy and poor prognosis, whereas low SNHG6 expression was associated with improved therapeutic efficacy and prognoses. These data indicate that a correlation exists among ER stress, sEVs, an immunosuppressive HCC TME, and immunotherapeutic efficacy. Hence, SNHG6-targeted therapy may represent an effective strategy for patients with HCC.

An emerging strategy: probiotics enhance the effectiveness of tumor immunotherapy via mediating the gut microbiome.

The occurrence and progression of tumors are often accompanied by disruptions in the gut microbiota. Inversely, the impact of the gut microbiota on the initiation and progression of cancer is becoming increasingly evident, influencing the tumor microenvironment (TME) for both local and distant tumors. Moreover, it is even suggested to play a significant role in the process of tumor immunotherapy, contributing to high specificity in therapeutic outcomes and long-term effectiveness across various cancer types. Probiotics, with their generally positive influence on the gut microbiota, may serve as effective agents in synergizing cancer immunotherapy. They play a crucial role in activating the immune system to inhibit tumor growth. In summary, this comprehensive review aims to provide valuable insights into the dynamic interactions between probiotics, gut microbiota, and cancer. Furthermore, we highlight recent advances and mechanisms in using probiotics to improve the effectiveness of cancer immunotherapy. By understanding these complex relationships, we may unlock innovative approaches for cancer diagnosis and treatment while optimizing the effects of immunotherapy.

Polysaccharide-Based Edible Biopolymer-Based Coatings for Fruit Preservation: A Review.

Over the last decades, a significant rise in fruit consumption has been noticed as they contain numerous nutritional components, which has led to the rise in fruit production globally. However, fruits are highly liable to spoilage in nature and remain vulnerable to losses during the storage and preservation stages. Therefore, it is crucial to enhance the storage life and safeness of fruits for the consumers. To keep up the grade and prolong storage duration, various techniques are employed in the food sector. Among these, biopolymer coatings have gained widespread acceptance due to their improved characteristics and ideal substitution for synthetic polymer coatings. As there is concern regarding the safety of the consumers and sustainability, edible coatings have become a selective substitution for nurturing fruit quality and preventing decay. The application of polysaccharide-based edible coatings offers a versatile solution to prevent the passage of moisture, gases, and pathogens, which are considered major threats to fruit deterioration. Different polysaccharide substances such as chitin, pectin, carrageenan, cellulose, starch, etc., are extensively used for preparing edible coatings for a wide array of fruits. The implementation of coatings provides better preservation of the fruits such as mango, strawberry, pineapple, apple, etc. Furthermore, the inclusion of functional ingredients, including polyphenols, natural antioxidants, antimicrobials, and bio-nanomaterials, into the edible coating solution matrix adds to the nutritional, functional, and sensory attributes of the fruits. The blending of essential oil and active agents in polysaccharide-based coatings prevents the growth of food-borne pathogens and enhances the storage life of the pineapple, also improving the preservation of strawberries and mangoes. This paper aims to provide collective data regarding the utilization of polysaccharide-based edible coatings concerning their characteristics and advancements for fruit preservation.

Lithium prevents glucocorticoid-induced osteonecrosis of the femoral head by regulating autophagy.

Autophagy may play an important role in the occurrence and development of glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH). Lithium is a classical autophagy regulator, and lithium can also activate osteogenic pathways, making it a highly promising therapeutic agent for GC-ONFH. We aimed to evaluate the potential therapeutic effect of lithium on GC-ONFH. For in vitro experiments, primary osteoblasts of rats were used for investigating the underlying mechanism of lithium's protective effect on GC-induced autophagy levels and osteogenic activity dysfunction. For in vivo experiments, a rat model of GC-ONFH was used for evaluating the therapeutic effect of oral lithium on GC-ONFH and underlying mechanism. Findings demonstrated that GC over-activated the autophagy of osteoblasts and reduced their osteogenic activity. Lithium reduced the over-activated autophagy of GC-treated osteoblasts through PI3K/AKT/mTOR signalling pathway and increased their osteogenic activity. Oral lithium reduced the osteonecrosis rates in a rat model of GC-ONFH, and restrained the increased expression of autophagy related proteins in bone tissues through PI3K/AKT/mTOR signalling pathway. In conclusion, lithium can restrain over-activated autophagy by activating PI3K/AKT/mTOR signalling pathway and up-regulate the expression of genes for bone formation both in GC induced osteoblasts and in a rat model of GC-ONFH. Lithium may be a promising therapeutic agent for GC-ONFH. However, the role of autophagy in the pathogenesis of GC-ONFH remains controversial. Studies are still needed to further explore the role of autophagy in the pathogenesis of GC-ONFH, and the efficacy of lithium in the treatment of GC-ONFH and its underlying mechanisms.

Peptide Transporter 1-Mediated Dipeptide Transport Promotes Hepatocellular Carcinoma Metastasis by Activating MAP4K4/G3BP2 Signaling Axis.

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.

Integrated multi-omics analysis and machine learning developed a prognostic model based on mitochondrial function in a large multicenter cohort for Gastric Cancer.

BACKGROUND: Gastric cancer (GC) is a common and aggressive type of cancer worldwide. Despite recent advancements in its treatment, the prognosis for patients with GC remains poor. Understanding the mechanisms of cell death in GC, particularly those related to mitochondrial function, is crucial for its development and progression. However, more research is needed to investigate the significance of the interaction between mitochondrial function and GC cell death. METHODS: We employed a robust computational framework to investigate the role of mitochondria-associated proteins in the progression of GC in a cohort of 1,199 GC patients. Ten machine learning algorithms were utilized and combined into 101 unique combinations. Ultimately, we developed a Mitochondrial-related-Score (MitoScore) using the machine learning model that exhibited the best performance. We observed the upregulation of LEMT2 and further explored its function in tumor progression. Mitochondrial functions were assessed by measuring mitochondrial ATP, mitochondrial membrane potential, and levels of lactate, pyruvate, and glucose. RESULTS: MitoScore showed significant correlations with GC immune and metabolic functions. The higher MitoScore subgroup exhibited enriched metabolic pathways and higher immune activity. Overexpression of LETM2 (leucine zipper and EF-hand containing transmembrane protein 2) significantly enhanced tumor proliferation and metastasis. LETM2 plays a role in promoting GC cell proliferation by activating the mTOR pathway, maintaining mitochondrial homeostasis, and promoting glycolysis. CONCLUSION: The powerful machine learning framework highlights the significant potential of MitoScore in providing valuable insights and accurate assessments for individuals with GC. This study also enhances our understanding of LETM2 as an oncogene signature in GC. LETM2 may promote tumor progression by maintaining mitochondrial health and activating glycolysis, offering potential targets for diagnosis, treatment, and prognosis of GC.

Hypobaric hypoxia aggravates osteoarthritis via the alteration of the oxygen environment and bone remodeling in the subchondral zone.

A high prevalence of osteoarthritis (OA) has been observed among individuals living at high altitudes, and hypobaric hypoxia (HH) can cause bone mass and strength deterioration. However, the effect of HH on OA remains unclear. In this study, we aimed to explore the impact of HH on OA and its potential mechanisms. A rat knee OA model was established by surgery, and the rats were bred in an HH chamber simulating a high-altitude environment. Micro-computed tomography (Micro-CT), histological analysis, and RNA sequencing were performed to evaluate the effects of HH on OA in vivo. A hypoxic co-culture model of osteoclasts and osteoblasts was also established to determine their effects on chondrogenesis in vitro. Cartilage degeneration significantly worsened in the HH-OA group compared to that in the normoxia-OA (N-OA) group, 4 weeks after surgery. Micro-CT analysis revealed more deteriorated bone mass in the HH-OA group than in the N-OA group. Decreased hypoxia levels in the cartilage and enhanced hypoxia levels in the subchondral bone were observed in the HH-OA group. Furthermore, chondrocytes cultured in a conditioned medium from the hypoxic co-culture model showed decreased anabolism and extracellular matrix compared to those in the normoxic model. RNA sequencing analysis of the subchondral bone indicated that the glycolytic signaling pathway was highly activated in the HH-OA group. HH-related OA progression was associated with alterations in the oxygen environment and bone remodeling in the subchondral zone, which provided new insights into the pathogenesis of OA.

Targeting DEP domain containing 1 in anaplastic thyroid carcinoma: Implications for stemness regulation and malignant phenotype suppression.

Background: Anaplastic thyroid carcinoma (ATC), a rare but highly aggressive endocrine malignancy, is characterized by a significant presence of cancer stem-like cells (CSCs). These CSCs, known for their self-renewal and differentiation capacities, contribute to various aggressive tumor properties, including recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. Despite their critical role, the regulatory mechanisms of CSCs in ATC remain poorly elucidated, posing challenges in effectively targeting these cells for treatment. Methods: To delve into this, we employed the single sample gene set enrichment analysis (ssGSEA) algorithm to evaluate the stemness of samples in combined datasets. Samples were then classified into high and low stemness subgroups based on their average stemness scores. Differential gene expression between these subgroups was analyzed. We further explored the association of candidate genes with patient prognosis. Additionally, we conducted gene set enrichment analysis (GSEA) and a series of cell biology experiments to validate the role of DEP domain-containing protein 1 (DEPDC1) in fostering CSC-like traits and regulating the malignant phenotypes of ATC. Results: Our investigation demonstrated that DEPDC1 was significantly upregulated in CSCs and is abundantly expressed in ATC tissues. In vitro assays revealed that knockdown of DEPDC1 markedly inhibited tumor sphere formation and attenuated the proliferation, invasion, and migration of ATC cells. This silencing also resulted in reduced expression of stemness markers associated with CSCs. Furthermore, our GSEA findings linked high DEPDC1 expression to cell cycle progression and the maintenance of tumor cell stemness, with DEPDC1 knockdown disrupting these signaling pathways. Collectively, our results position DEPDC1 as a pivotal regulator of CSC-like characteristics in ATC, where aberrant DEPDC1 expression amplifies stemness properties and fuels the cancer's aggressive behavior. Consequently, DEPDC1 emerges as a promising therapeutic target for ATC management. In summary, this study underscores the pivotal role of DEPDC1 in modulating CSC-like features in ATC, offering new avenues for targeted therapy in this challenging malignancy.

Multiparametric MR-based feature fusion radiomics combined with ADC maps-based tumor proliferative burden in distinguishing TNBC versus non-TNBC.

Objective.To investigate the incremental value of quantitative stratified apparent diffusion coefficient (ADC) defined tumor habitats for differentiating triple negative breast cancer (TNBC) from non-TNBC on multiparametric MRI (mpMRI) based feature-fusion radiomics (RFF) model.Approach.466 breast cancer patients (54 TNBC, 412 non-TNBC) who underwent routine breast MRIs in our hospital were retrospectively analyzed. Radiomics features were extracted from whole tumor on T2WI, diffusion-weighted imaging, ADC maps and the 2nd phase of dynamic contrast-enhanced MRI. Four models including the RFFmodel (fused features from all MRI sequences), RADCmodel (ADC radiomics feature), StratifiedADCmodel (tumor habitas defined on stratified ADC parameters) and combinational RFF-StratifiedADCmodel were constructed to distinguish TNBC versus non-TNBC. All cases were randomly divided into a training (n= 337) and test set (n= 129). The four competing models were validated using the area under the curve (AUC), sensitivity, specificity and accuracy.Main results.Both the RFFand StratifiedADCmodels demonstrated good performance in distinguishing TNBC from non-TNBC, with best AUCs of 0.818 and 0.773 in the training and test sets. StratifiedADCmodel revealed significant different tumor habitats (necrosis/cysts habitat, chaotic habitat or proliferative tumor core) between TNBC and non-TNBC with its top three discriminative parameters (p <0.05). The integrated RFF-StratifiedADCmodel demonstrated superior accuracy over the other three models, with higher AUCs of 0.832 and 0.784 in the training and test set, respectively (p <0.05).Significance.The RFF-StratifiedADCmodel through integrating various tumor habitats' information from whole-tumor ADC maps-based StratifiedADCmodel and radiomics information from mpMRI-based RFFmodel, exhibits tremendous promise for identifying TNBC.

A subregion-based RadioFusionOmics model discriminates between grade 4 astrocytoma and glioblastoma on multisequence MRI.

PURPOSE: To explore a subregion-based RadioFusionOmics (RFO) model for discrimination between adult-type grade 4 astrocytoma and glioblastoma according to the 2021 WHO CNS5 classification. METHODS: 329 patients (40 grade 4 astrocytomas and 289 glioblastomas) with histologic diagnosis was retrospectively collected from our local institution and The Cancer Imaging Archive (TCIA). The volumes of interests (VOIs) were obtained from four multiparametric MRI sequences (T1WI, T1WI + C, T2WI, T2-FLAIR) using (1) manual segmentation of the non-enhanced tumor (nET), enhanced tumor (ET), and peritumoral edema (pTE), and (2) K-means clustering of four habitats (H1: high T1WI + C, high T2-FLAIR; (2) H2: high T1WI + C, low T2-FLAIR; (3) H3: low T1WI + C, high T2-FLAIR; and (4) H4: low T1WI + C, low T2-FLAIR). The optimal VOI and best MRI sequence combination were determined. The performance of the RFO model was evaluated using the area under the precision-recall curve (AUPRC) and the best signatures were identified. RESULTS: The two best VOIs were manual VOI3 (putative peritumoral edema) and clustering H34 (low T1WI + C, high T2-FLAIR (H3) combined with low T1WI + C and low T2-FLAIR (H4)). Features fused from four MRI sequences ([Formula: see text]) outperformed those from either a single sequence or other sequence combinations. The RFO model that was trained using fused features [Formula: see text] achieved the AUPRC of 0.972 (VOI3) and 0.976 (H34) in the primary cohort (p = 0.905), and 0.971 (VOI3) and 0.974 (H34) in the testing cohort (p = 0.402). CONCLUSION: The performance of subregions defined by clustering was comparable to that of subregions that were manually defined. Fusion of features from the edematous subregions of multiple MRI sequences by the RFO model resulted in differentiation between grade 4 astrocytoma and glioblastoma.

Role of sodium taurocholate cotransporting polypeptide (NTCP) in HBV-induced hepatitis: Opportunities for developing novel therapeutics.

Hepatitis B is an infectious disease caused by the HBV virus. It presents a significant challenge for treatment due to its chronic nature and the potential for developing severe complications, including hepatocirrhosis and hepatocellular carcinoma. These complications not only cause physical and psychological distress to patients but also impose substantial economic and social burdens on both individuals and society as a whole. The internalization of HBV relies on endocytosis and necessitates the involvement of various proteins, including heparin sulfate proteoglycans, epidermal growth factor receptors, and NTCP. Among these proteins, NTCP is pivotal in HBV internalization and is primarily located in the liver's basement membrane. As a transporter of bile acids, NTCP also serves as a receptor facilitating HBV entry into cells. Numerous molecules have been identified to thwart HBV infection by stifling NTCP activity, although only a handful exhibit low IC50 values. In this systematic review, our primary focus dwells on the structure and regulation of NTCP, as well as the mechanism involved in HBV internalization. We underscore recent drug breakthroughs that specifically target NTCP to combat HBV infection. By shedding light on these advances, this review contributes novel insights into developing effective anti-HBV medications.

ε-Poly-l-lysine-hydroxyphenyl propionic acid/IL-4 composite hydrogels with inflammation regulation and antibacterial activity for improving integration stability of soft tissues and orthopedic implants.

The failure of orthopedic implants is usually caused by inflammation, poor tissue integration, and infection, which can lead to pain, limited mobility, dysfunction of patients. This may require additional surgical interventions, such as removal, replacement, or repair of implants, as well as related treatment measures such as antibiotic therapy, physical therapy. Here, an injectable hydrogel carrier was developed for the steady release of inflammatory regulators to reduce the surface tissue inflammatory response of orthopedic implants and induce soft tissue regeneration, ultimately achieving the promotion of implants stability. The hydrogels carrier was prepared by hydroxyphenyl propionic acid-modified ε-Poly-l-lysine (EPA), hydrogen peroxide and horseradish peroxidase, which showed antibacterial bioactive and stable factor release ability. Due to the introduction of IL-4, EPA@IL-4 hydrogels showed good inflammatory regulation. EPA@IL-4 hydrogels regulated the differentiation of macrophages into M2 in inflammatory environment in vitro, and promoted endothelial cells to show a more obvious trend of tube formation. The composite hydrogels reduced the inflammation on the surface of the implants in vivo, induced local endothelial cell angiogenesis, and had more collagen deposition and new granulation tissue. Therefore, EPA hydrogels based on IL-4 release are promising candidates for promoting of implants surface anti-inflammatory, soft tissue regeneration, and anti-infection.

Quantitative Measurement on Contrast-Enhanced CT Distinguishes Small Clear Cell Renal Cell Carcinoma From Benign Renal Tumors: A Multicenter Study.

RATIONALE AND OBJECTIVES: To evaluate the potential of quantitative measurements on contrast-enhanced CT (CECT) in differentiating small (≤4 cm) clear cell renal cell carcinoma (ccRCC) from benign renal tumors, including fat-poor angiomyolipoma (fpAML) and renal oncocytoma (RO). MATERIALS AND METHODS: 244 patients with pathologically confirmed ccRCC (n = 184) and benign renal tumors (fpAML, n = 50; RO, n = 10) were randomly assigned into training cohort (n = 193) and test cohort 1 (n = 51), while external test cohort 2 (n = 50) was from another hospital. Quantitative parameters were obtained from CECT (unenhanced phase, UP; corticomedullary phase, CMP; nephrographic phase, NP; excretory phase, EP) by measuring attenuation of renal mass and cortex and subsequently calculated. Univariable and multivariable logistic regression analyses were performed to evaluate the association between these parameters and ccRCC. Finally, the constructed models were compared with radiologists' diagnoses. RESULTS: In univariable analysis, UP-related parameters, particularly UPC-T (cortex minus tumor attenuation on UP), demonstrated AUC of 0.766 in training cohort, 0.901 in test cohort 1, 0.805 in test cohort 2. The heterogeneity-related parameter SD (standard deviation) showed AUC of 0.781, 0.834, and 0.875 respectively. In multivariable analysis, model 1 incorporating UPC-T, NPC-T (cortex minus tumor attenuation on NP), CMPT-UPT (tumor attenuation on CMP minus UP), and SD yielded AUC of 0.866, 0.923, and 0.949 respectively. When compared with radiologists, multivariate models demonstrated higher accuracy (0.800-0.860) and sensitivity (0.794-0.971) than radiologists' assessments (accuracy: 0.700-0.720, sensitivity: 0.588-0.706). CONCLUSION: Quantitative measurements on CECT, particularly UP- and heterogeneity-related parameters, have potential to discriminate ccRCC and benign renal tumors (fpAML, RO).

Antibacterial and DNA-Based Hydrogels In Situ Block TNF-α to Promote Diabetic Alveolar Bone Rebuilding.

Alveolar bone injury under diabetic conditions can severely impede many oral disease treatments. Rebuilding diabetic alveolar bone in clinics is currently challenging due to persistent infection and inflammatory response. Here, an antibacterial DNA-based hydrogel named Agantigel is developed by integrating silver nanoclusters (AgNCs) and tumor necrosis factor-alpha (TNF-α) antibody into DNA hydrogel to promote diabetic alveolar bone regeneration. Agantigel can effectively inhibit bacterial growth through AgNCs while exhibiting negligible cytotoxicity in vitro. The sustained release of TNF-α antibody from Agantigel effectively blocks TNF-α and promotes M2 polarization of macrophages, ultimately accelerating diabetic alveolar bone regeneration in vivo. After 21 days of treatment, Agantigel significantly accelerates the defect healing rate of diabetic alveolar bone up to 82.58 ± 8.58% and improves trabecular architectures compared to free TNF-α (42.52 ± 15.85%). The results imply that DNA hydrogels are potential bio-scaffolds helping the sustained release of multidrug for treating DABI or other oral diseases.

Dual-Modality Imaging-Guided Manganese-Based Nanotransformer for Enhanced Gas-Photothermal Therapy Combined Immunotherapeutic Strategy Against Triple-Negative Breast Cancer.

Activating the stimulator of the interferon gene (STING) is a promising immunotherapeutic strategy for converting "cold" tumor microenvironment into "hot" one to achieve better immunotherapy for malignant tumors. Herein, a manganese-based nanotransformer is presented, consisting of manganese carbonyl and cyanine dye, for MRI/NIR-II dual-modality imaging-guided multifunctional carbon monoxide (CO) gas treatment and photothermal therapy, along with triggering cGAS-STING immune pathway against triple-negative breast cancer. This nanosystem is able to transfer its amorphous morphology into a crystallographic-like formation in response to the tumor microenvironment, achieved by breaking metal-carbon bonds and forming coordination bonds, which enhances the sensitivity of magnetic resonance imaging. Moreover, the generated CO and photothermal effect under irradiation of this nanotransformer induce immunogenic death of tumor cells and release damage-associated molecular patterns. Simultaneously, the Mn acts as an immunoactivator, potentially stimulating the cGAS-STING pathway to augment adaptive immunity, resulting in promoting the secretion of type I interferon, the proliferation of cytotoxic T lymphocytes and M2-macrophages repolarization. This nanosystem-based gas-photothermal treatment and immunoactivating therapy synergistic effect exhibit excellent antitumor efficacy both in vitro and in vivo, reducing the risk of triple-negative breast cancer recurrence and metastasis; thus, this strategy presents great potential as multifunctional immunotherapeutic agents for cancer treatment.

Improved sustained-release properties of ginger essential oil in a Pickering emulsion system incorporated in sodium alginate film and delayed postharvest senescence of mango fruits.

The insufficient water vapor barrier and mechanical capacity of sodium alginate (SA) film limited its application in fruit preservation. Herein, cellulose nanocrystals (CNCs) were used to stabilize Pickering emulsion. Then, we prepared SA composite films. Ginger essential oil (GEO) was loaded as antimicrobials and antioxidants. Finally, the application on mangos were investigated. Compared to coarse emulsion, Pickering emulsion and its film-formation-solution showed more stable system and larger droplet size. The emulsion significantly changed the properties of SA film. Specifically, CNCs improved the thermal, tensile, and barrier properties of the film and GEO enhanced the ultraviolet-visible light barrier capacity. Additionally, the SA/CNC film possessed a homogeneous micromorphology which had a sustained-release effect on GEO, thus maintaining high postharvest quality and long-term bioavailability for mangos. In conclusion, the film prepared via Pickering emulsion showed satisfactory properties which had great potential in fruit preservation.

Evaluation of molecular receptors status in breast cancer using an mpMRI-based feature fusion radiomics model: mimicking radiologists' diagnosis.

Objective: To investigate the performance of a novel feature fusion radiomics (RFF) model that incorporates features from multiparametric MRIs (mpMRI) in distinguishing different statuses of molecular receptors in breast cancer (BC) preoperatively. Methods: 460 patients with 466 pathology-confirmed BCs who underwent breast mpMRI at 1.5T in our center were retrospectively included hormone receptor (HR) positive (HR+) (n=336) and HR negative (HR-) (n=130). The HR- patients were further categorized into human epidermal growth factor receptor 2 (HER-2) enriched BC (HEBC) (n=76) and triple negative BC (TNBC) (n=54). All lesions were divided into a training/validation cohort (n=337) and a test cohort (n=129). Volumes of interest (VOIs) delineation, followed by radiomics feature extraction, was performed on T2WI, DWI600 (b=600 s/mm2), DWI800 (b=800 s/mm2), ADC map, and DCE1-6 (six continuous DCE-MRI) images of each lesion. Simulating a radiologist's work pattern, 150 classification base models were constructed and analyzed to determine the top four optimum sequences for classifying HR+ vs. HR-, TNBC vs. HEBC, TNBC vs. non-TNBC in a random selected training cohort (n=337). Building upon these findings, the optimal single sequence models (Rss) and combined sequences models (RFF) were developed. The AUC, sensitivity, accuracy and specificity of each model for subtype differentiation were evaluated. The paired samples Wilcoxon signed rank test was used for performance comparison. Results: During the three classification tasks, the optimal single sequence for classifying HR+ vs. HR- was DWI600, while the ADC map, derived from DWI800 performed the best in distinguishing TNBC vs. HEBC, as well as identifying TNBC vs. non-TNBC, with corresponding training AUC values of 0.787, 0.788, and 0.809, respectively. Furthermore, the integration of the top four sequences in RFF models yielded improved performance, achieving AUC values of 0.809, 0.805 and 0.847, respectively. Consistent results was observed in both the training/validation and testing cohorts, with AUC values of 0.778, 0.787, 0.818 and 0.726, 0.773, 0.773, respectively (all p < 0.05 except HR+ vs. HR-). Conclusion: The RFF model, integrating mpMRI radiomics features, demonstrated promising ability to mimic radiologists' diagnosis for preoperative identification of molecular receptors of BC.

Immunological characteristics of immunogenic cell death genes and malignant progression driving roles of TLR4 in anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) was a rare malignancy featured with the weak immunotherapeutic response. So far, disorders of immunogenic cell death genes (ICDGs) were identified as the driving factors in cancer progression, while their roles in ATC remained poorly clear. Datasets analysis identified that most ICDGs were high expressed in ATC, while DE-ICDGs were located in module c1_112, which was mainly enriched in Toll-like receptor signalings. Subsequently, the ICD score was established to classify ATC samples into the high and low ICD score groups, and function analysis indicated that high ICD score was associated with the immune characteristics. The high ICD score group had higher proportions of specific immune and stromal cells, as well as increased expression of immune checkpoints. Additionally, TLR4, ENTPD1, LY96, CASP1 and PDIA3 were identified as the dynamic signature in the malignant progression of ATC. Notably, TLR4 was significantly upregulated in ATC tissues, associated with poor prognosis. Silence of TLR4 inhibited the proliferation, metastasis and clone formation of ATC cells. Eventually, silence of TLR4 synergistically enhanced paclitaxel-induced proliferation inhibition, apoptosis, CALR exposure and release of ATP. Our findings highlighted that the aberrant expression of TLR4 drove the malignant progression of ATC, which contributed to our understanding of the roles of ICDGs in ATC.

Longitudinal change of six common inflammatory cytokines and their relationship to anxiety, depression, and cognitive impairment in acute ischemic stroke patients.

Inflammatory cytokines are known to be involved in acute ischemic stroke (AIS), while the relationship of multiple inflammatory cytokines with mental disorders in AIS is less reported. This research intended to explore the longitudinal variation of common inflammatory cytokines and their correlation with anxiety, depression, and cognitive impairment in AIS patients. Six inflammatory cytokines were detected by enzyme-linked immunosorbent assay among 175 AIS patients at admission (baseline) and on the day (D)1, D3, and D7 after admission. Anxiety, depression, and cognition were evaluated using the Hospital Anxiety and Depression Scale and Mini-Mental State Examination at discharge, respectively. Anxiety, depression, and cognitive impairment rates were 32.6, 39.4, and 19.4%, respectively. Tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, and IL-17A increased from baseline to D1, then decreased from D1 to D7 (all P<0.001), while IL-10 presented an opposite trend (P<0.001). Interestingly, TNF-α on D1 and D3, IL-6 on D3, IL-8 on D3 and D7, and IL-17A on D1, D3, and D7 correlated with higher anxiety rate (all P<0.05). TNF-α on D1, D3, and D7, IL-8 at baseline, D1, D3, and D7, IL-17A on D1 and D7 correlated with increased depression rate (all P<0.05). In addition, IL-1ß on D1 and IL-17 at baseline, D1, D3, and D7 correlated with elevated cognitive-impairment rate (all P<0.05). Inflammatory cytokines were dysregulated after disease onset, and their longitudinal change correlated with psychological issues in AIS patients.