Single-cell analysis of chemotherapy-resistant microenvironment identifies a chemo-response biomarker for pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal, aggressive cancer due to limited response chemotherapy. The tumor microenvironment (TME) has emerged as a key player in the development of chemoresistance and in malignant progression. In this study, we hypothesized that chemotherapy response is predictable by chemotherapy-related cell types and their differentially expressed genes (DEGs). Methods: DEGs of chemoresistance cell types were identified via single cell analysis and Wilcoxon test. A chemotherapy response signature was established using a random forest model and validated with public datasets. Bulk cell fraction was analyzed using BayesPrism algorithms. Log-rank test was used to analyze survival of PDAC patients. Results: We found that natural killer (NK) cells, myeloid cells, and erythroid cells were highly infiltrated in chemo-resistant TME. A total of 36 chemoresistance-related DEGs of chemo-resistant cells were identified in chemo-resistant PDAC. Functional enrichment analysis showed that chemoresistance upregulated various inflammation-related pathways, including TGF-ß signaling. Based on these features, we constructed a random forest model to predict the response and survival for PDAC patients, which accurately distinguished high-risk and chemoresistant patients with significantly poorer prognosis in both the training and independent validation datasets. Cox regression analysis indicated that predicted labels were an independent prognostic factor in PDAC. Moreover, deconvolution of TME confirmed higher infiltration levels of M2 macrophage and NK cells in predicted chemoresistance. When combined with chemotherapy response related tumor mutations, the model showed excellent ability in predicting chemotherapy response and survival. Conclusions: The TME was closely associated with the chemotherapy response and prognosis of PDAC. Our TME-based random forest model predicted chemotherapy response with complementary knowledge to the response-related genetic mutations.

3D Models of Sarcomas: The Next-generation Tool for Personalized Medicine.

Sarcoma is a complex and heterogeneous cancer that has been difficult to study in vitro. While two-dimensional (2D) cell cultures and mouse models have been the dominant research tools, three-dimensional (3D) culture systems such as organoids have emerged as promising alternatives. In this review, we discuss recent developments in sarcoma organoid culture, with a focus on their potential as tools for drug screening and biobanking. We also highlight the ways in which sarcoma organoids have been used to investigate the mechanisms of gene regulation, drug resistance, metastasis, and immune interactions. Sarcoma organoids have shown to retain characteristics of in vivo biology within an in vitro system, making them a more representative model for sarcoma research. Our review suggests that sarcoma organoids offer a potential path forward for translational research in this field and may provide a platform for developing personalized therapies for sarcoma patients.

Hyaluronated nanohydroxyapatite responsively released from injectable hydrogels for targeted therapy of melanoma.

Nanohydroxyapatite (nHAp) has attracted significant attention for its tumor suppression and tumor microenvironment modulation capabilities. However, a strong tendency to aggregate greatly affects its anti-tumor efficiency. To address this issue, a hydrogel platform consisting of thiolated hyaluronic acid (HA-SH) modified nanohydroxyapatite (nHAp-HA) and HA-SH was developed for sustained delivery of nHAp for melanoma therapy. The hydrophilic and negatively charged HA-SH significantly improved the size dispersion and stability of nHAp in aqueous media while conferring nHAp targeting effects. Covalent sulfhydryl self-cross-linking between HA-SH and nHAp-HA groups ensured homogeneous dispersion of nHAp in the matrix material. Meanwhile, the modification of HA-SH conferred the targeting properties of nHAp and enhanced cellular uptake through the HA/CD44 receptor. The hydrogel platform could effectively reduce the aggregation of nHAp and release nHAp in a sustained and orderly manner. Antitumor experiments showed that the modified nHAp-HA retained the tumor cytotoxicity of nHAp in vitro and inhibited the growth of highly malignant melanomas up to 78.6% while being able to induce the differentiation of macrophages to the M1 pro-inflammatory and antitumor phenotype. This study will broaden the application of nanohydroxyapatite in tumor therapy.

An injectable photocuring silk fibroin-based hydrogel for constructing an antioxidant microenvironment for skin repair.

Skin has a protein microenvironment dominated by functional collagen fibers, while oxidative stress caused by injury can greatly slow down the progress of wound healing. Here, methacrylated dopamine was incorporated into methacrylated silk fibroin molecule chains to develop an injectable hydrogel with photocuring properties for constructing an antioxidant skin protein microenvironment. This silk fibroin-based hydrogel (SF-g-SDA) showed good tensile and adhesion properties for adapting to the wound shape and skin movement, exhibited stable mechanical properties, good biodegradability and cytocompatibility, and promoted cell adhesion and vascularization in vitro. In addition, its phenolic hydroxyl-mediated antioxidant properties effectively protected cells from damage caused by oxidative stress and supported normal cellular life activities. In animal experiments, SF-g-SDA achieved better skin repair effects in comparison to commercial Tegaderm™ in vivo, showing its ability to accelerate wound healing, improve collagen deposition and alignment in newly fabricated tissues, and promote neovascularization and hair follicle formation. These experimental results indicated that the SF-g-SDA hydrogel is a promising wound dressing.

BMSCs alleviate liver cirrhosis by regulating Fstl1/Wnt/ß-Catenin signaling pathway.

Researchers have shown that bone mesenchymal stem cells (BMSCs) can alleviate the progression of liver cirrhosis; however, it is unclear how exactly BMSCs function to cure liver disease. In this study, we used bioinformatics methods to assess differentially expressed genes (DEGs) in liver cirrhosis and found a significantly upregulated gene, Fstl1, in liver cirrhosis. In vivo and in vitro experiments showed that compared with those in the disease model group, the mRNA, and protein expression levels of Fstl1 were significantly reduced after BMSCs treatment, and the ß-Catenin protein level was also significantly reduced after BMSCs treatment. Subsequently, we downregulated Fstl1 in activated hepatic stellate cells (HSCs) and found that Wnt and ß-Catenin protein expression levels also decreased. Finally, we found that in BMSCs-treated activated HSCs, overexpression of Fstl1 reversed the inhibitory effect of BMSCs on the Wnt/ß-Catenin signaling pathway to a certain extent. In summary, our results show that BMSCs can inhibit Wnt/ß-Catenin signaling pathway activation by downregulating the protein expression level of Fstl1, thus alleviating cirrhosis. Therefore, targeted regulation of Fstl1 may provide a new therapeutic strategy for the progression of liver cirrhosis.

From Phenomenon to Essence: A Newly Involved lncRNA Kcnq1ot1 Protective Mechanism of Bone Marrow Mesenchymal Stromal Cells in Liver Cirrhosis.

Bone marrow mesenchymal stromal cells (BMSCs) have a protective effect against liver cirrhosis. Long noncoding RNAs (lncRNAs) play crucial roles in the progression of liver cirrhosis. Therefore, it is aimed to clarify the lncRNA Kcnq1ot1 involved protective mechanism of BMSCs in liver cirrhosis. This study found that BMSCs treatment attenuates CCl4 -induced liver cirrhosis in mice. Additionally, the expression of lncRNA Kcnq1ot1 is upregulated in human and mouse liver cirrhosis tissues, in addition to TGF-ß1-treated LX2 cells and JS1 cells. The expression of Kcnq1ot1 in liver cirrhosis is reversed with BMSCs treatment. The knockdown of Kcnq1ot1 alleviated liver cirrhosis both in vivo and in vitro. Fluorescence in situ hybridization (FISH) confirms that Kcnq1ot1 is mainly distributed in the cytoplasm of JS1 cells. It is predicted that miR-374-3p can directly bind with lncRNA Kcnq1ot1 and Fstl1, which is verified via luciferase activity assay. The inhibition of miR-374-3p or the overexpression of Fstl1 can attenuate the effect of Kcnq1ot1 knockdown. In addition, the transcription factor Creb3l1 is upregulated during JS1 cells activation. Moreover, Creb3l1 can directly bind to the Kcnq1ot1 promoter and positively regulate its transcription. In conclusion, BMSCs alleviate liver cirrhosis by modulating the Creb3l1/lncRNA Kcnq1ot1/miR-374-3p/Fstl1 signaling pathway.

Metal-phenolic self-assembly shielded probiotics in hydrogel reinforced wound healing with antibiotic treatment.

Living probiotics secrete bioactive substances to accelerate wound healing, but the clinical application of antibiotics inhibits the survival of probiotics. Inspired by the chelation of tannic acid and ferric ions, we developed a metal-phenolic self-assembly shielded probiotic (Lactobacillus reuteri, L. reuteri@FeTA) to prevent interference from antibiotics. Here, a superimposing layer was formed on the surface of L. reuteri to adsorb and inactivate antibiotics. These shielded probiotics were loaded into an injectable hydrogel (Gel/L@FeTA) formed by carboxylated chitosan and oxidized hyaluronan. The Gel/L@FeTA aided the survival of probiotics and supported the continuous secretion of lactic acid to perform biological functions in an environment containing gentamicin. Furthermore, the Gel/L@FeTA hydrogels presented a better performance than the Gel/L in inflammatory regulation, angiogenesis, and tissue regeneration both in vitro and in vivo in the presence of antibiotics. Hence, a new method for designing probiotic-based biomaterials for clinical wound management is provided.

Comparison between traditional and new obesity measurement index for screening metabolic associated fatty liver disease.

Objectives: Obesity measurement indexes have certain screening value for metabolic diseases. To investigate associations between metabolic associated fatty liver disease (MAFLD) and obesity measurement indexes, including traditional indexes (BMI, WC, WHtR) and new indexes (ABSI, BRI, VAI, LAP), and assess their screening ability. Methods: 12,658 subjects aged 18-75 at the Health Center of a Class III Grade A Hospital were included, who were divided into MAFLD and non-MAFLD groups. Spearman's rank correlation was used to study the correlation between MAFLD and obesity measurement indexes. Receiver operating characteristic (ROC) curves were used to calculate the area under the curve (AUC) to evaluate their screening accuracy. Results: MAFLD had strong correlation with traditional BMI and new index LAP. ROC analysis showed that BMI had the highest AUC (0.89), followed by LAP (0.87). Stratification by BMI, LAP had the highest AUC (0.90) for MAFLD in population without obesity (BMI< 23kg/m2), and its optimal cutoff value was 20.75, with a sensitivity and specificity of 85.9% and 79.0%, respectively. Conclusions: We proposed a two-step screening strategy for MAFLD, combining BMI and LAP, and defined a high-risk population for MAFLD as follows: 1) BMI ≥ 23 kg/m2; and 2) BMI< 23 kg/m2 and LAP ≥ 20.75.

Electrospun Hyaluronan Nanofiber Membrane Immobilizing Aromatic Doxorubicin as Therapeutic and Regenerative Biomaterial.

Lesioned tissue requires synchronous control of disease and regeneration progression after surgery. It is necessary to develop therapeutic and regenerative scaffolds. Here, hyaluronic acid (HA) was esterified with benzyl groups to prepare hyaluronic acid derivative (HA-Bn) nanofibers via electrospinning. Electrospun membranes with average fiber diameters of 407.64 ± 124.8 nm (H400), 642.3 ± 228.76 nm (H600), and 841.09 ± 236.86 nm (H800) were obtained by adjusting the spinning parameters. These fibrous membranes had good biocompatibility, among which the H400 group could promote the proliferation and spread of L929 cells. Using the postoperative treatment of malignant skin melanoma as an example, the anticancer drug doxorubicin (DOX) was encapsulated in nanofibers via hybrid electrospinning. The UV spectroscopy of DOX-loaded nanofibers (HA-DOX) revealed that DOX was successfully encapsulated, and there was a π-π interaction between aromatic DOX and HA-Bn. The drug release profile confirmed the sustained release of about 90%, achieved within 7 days. In vitro cell experiments proved that the HA-DOX nanofiber had a considerable inhibitory effect on B16F10 cells. Therefore, the HA-Bn electrospun membrane could facilitate the potential regeneration of injured skin tissues and be incorporated with drugs to achieve therapeutic effects, offering a powerful approach to developing therapeutic and regenerative biomaterial.

Effect of a reused insulin needle remaining in a patient's body.

Diabetes is one of the most common chronic diseases at present, and insulin pen injection therapy plays an important role in the treatment of diabetes. However, the majority of patients might reuse disposable insulin pen needles for various reasons, which leads to related complications. As far as we know, this article is the first to describe a patient whose needle remained in the right upper limb while reusing a disposable insulin injection needle for subcutaneous insulin injection with the non-dominant hand. The patient went to the doctor 1 week later. The needle moved from the lateral area of the proximal upper arm (the injection site) to the posterolateral area of the distal upper arm. The needle was then successfully removed by surgery. The reuse of disposable insulin pen needles might lead to serious complications. It is suggested to strengthen the education of people living with diabetes to help them use insulin pen needles safely.

Bioabsorbable nano-micelle hybridized hydrogel scaffold prevents postoperative melanoma recurrence.

The residual and scattered small tumor tissue or cells after surgery are the main reason for tumor recurrence. Chemotherapy has a powerful ability to eradicate tumors but always accompanied by serious side effects. In this work, tissue-affinity mercapto gelatin (GelS) and dopamine-modified hyaluronic acid (HAD) were employed to fabricate a hybridized cross-linked hydrogel scaffold (HG) by multiple chemical reactions, which could integrate the doxorubicin (DOX) loaded reduction-responsive nano-micelle (PP/DOX) into this scaffold via click reaction to obtain the bioabsorbable nano-micelle hybridized hydrogel scaffold (HGMP). With the degradation of HGMP, PP/DOX was slowly released and formed targeted PP/DOX with degraded gelatin fragments as target molecules, which increased the intracellular accumulation, and inhibited the aggregation of B16F10 cells in vitro. In mouse models, HGMP absorbed the scattered B16F10 cells and released targeted PP/DOX to suppress tumorigenesis. For another, implantation of HGMP at the surgical site reduced the recurrence rate of postoperative melanoma and inhibited the growth of recurrent tumors. Meanwhile, HGMP significantly relieved the damage of free DOX to hair follicle tissue. This bioabsorbable nano-micelle hybridized hydrogel scaffold provided a valuable strategy for adjuvant therapy after tumor surgery.

The emerging applications and advancements of Raman spectroscopy in pediatric cancers.

Although the survival rate of pediatric cancer has significantly improved, it is still an important cause of death among children. New technologies have been developed to improve the diagnosis, treatment, and prognosis of pediatric cancers. Raman spectroscopy (RS) is a non-destructive analytical technique that uses different frequencies of scattering light to characterize biological specimens. It can provide information on biological components, activities, and molecular structures. This review summarizes studies on the potential of RS in pediatric cancers. Currently, studies on the application of RS in pediatric cancers mainly focus on early diagnosis, prognosis prediction, and treatment improvement. The results of these studies showed high accuracy and specificity. In addition, the combination of RS and deep learning is discussed as a future application of RS in pediatric cancer. Studies applying RS in pediatric cancer illustrated good prospects. This review collected and analyzed the potential clinical applications of RS in pediatric cancers.

The role of the probiotic Akkermansia muciniphila in brain functions: insights underpinning therapeutic potential.

The role of Akkermansia muciniphila, one of the most abundant microorganisms of the intestinal microbiota, has been studied extensively in metabolic diseases, such as obesity and diabetes. It is considered a next-generation probiotic microorganism. Although its mechanism of action has not been fully elucidated, accumulating evidence indicates the important role of A. muciniphila in brain functions via the gut-brain axis and its potential as a therapeutic target in various neuropsychiatric disorders. However, only a limited number of studies, particularly clinical studies, have directly assessed the therapeutic effects of A. muciniphila interventions in these disorders. This is the first review to discuss the comprehensive mechanism of A. muciniphila in the gut-brain axis via the protection of the intestinal mucosal barrier and modulation of the immune system and metabolites, such as short-chain fatty acids, amino acids, and amino acid derivatives. Additionally, the role of A. muciniphila and its therapeutic potential in various neuropsychiatric disorders, including Alzheimer's disease and cognitive deficit, amyotrophic lateral sclerosis, Parkinson's disease, and multiple sclerosis, have been discussed. The review suggests the potential role of A. muciniphila in healthy brain functions.

Integrated Analysis of TME and Hypoxia Identifies a Classifier to Predict Prognosis and Therapeutic Biomarkers in Soft Tissue Sarcomas.

Soft tissue sarcoma (STS) is one of the rarest but most aggressive cancer. It is important to note that intratumoral hypoxia and tumor microenvironment (TME) infiltration play a significant role in the growth and therapeutic resistance of STS. The goal of this study was therefore to determine whether linking hypoxia-related parameters to TME cells could provide a more accurate prediction of prognosis and therapeutic response. An analysis of 109 hypoxia-related genes and 64 TME cells was conducted in STS. Hypoxia-TME classifier was constructed based on 6 hypoxia prognostic genes and 8 TME cells. As a result, we evaluated the prognosis, tumor, and immune characteristics, as well as the effectiveness of therapies in Hypoxia-TME-defined subgroups. The Lowplus group showed a better prognosis and therapeutic response than any other subgroup. It is possible to unravel these differences based on immune-related molecules and somatic mutations in tumors. Further validation of Hypoxia-TME was done in an additional cohort of 225 STS patients. Additionally, we identified five key genes through differential analysis and RT-qPCR, namely, ACSM5, WNT7B, CA9, MMP13, and RAC3, which could be targeted for therapy. As a whole, the Hypoxia-TME classifier demonstrated a pretreatment predictive value for prognosis and therapeutic outcome, providing new approaches to therapy strategizing for patients.

Hair follicle-MSC-derived small extracellular vesicles as a novel remedy for acute pancreatitis.

BACKGROUND: Hair follicle-derived mesenchymal stem cell (HF-MSC)-based therapies protect against acute pancreatitis (AP). However, accumulating evidence suggests that MSC-based therapy mainly involves the secretion of MSC-derived small extracellular vesicles (MSC-sEVs) through paracrine effects. Thus, the present research investigated the therapeutic effect of HF-MSC-sEVs in AP and the underlying mechanisms. METHODS: SEVs were purified from cultured HF-MSC supernatant. The effects of sEVs in vitro were analyzed on caerulein-simulated pancreatic acinar cells (PACs). The therapeutic potential of sEVs in vivo was examined in a caerulein-induced AP model. The organ distribution of sEVs in mice was determined by near-infrared fluorescence (NIRF) imaging. Serum specimens and pancreatic tissues were collected to analyze the inhibition of inflammation and pyroptosis in vivo, as well as the appropriate infusion route: intraperitoneal (i.p.) or intravenous (i.v.) injection. RESULTS: HF-MSC-sEVs were taken up by PACs and improved cell viability in vitro. In vivo, sEVs were abundant in the pancreas, and the indicators of pancreatitis, including amylase, lipase, the inflammatory response, myeloperoxidase (MPO) expression and histopathology scores, in sEV-treated mice were markedly improved compared with those in the AP group, especially via tail vein injection. Furthermore, we revealed that sEVs observably downregulated the levels of crucial pyroptosis proteins in both PACs and AP tissue. CONCLUSIONS: We innovatively demonstrated that HF-MSC-sEVs could alleviate inflammation and pyroptosis in PACs in AP, suggesting a refreshing cell-free remedy for AP.

Nanohydroxyapatite Stimulates PD-L1 Expression to Boost Melanoma Combination Immunotherapy.

Although checkpoint-inhibitor immunotherapy held tremendous advances, improving immune response during treatment has always been an urgent clinical issue. With the help of mRNA microarray technology, it was found that short rod-like nanohydroxyapatite (nHA) promoted the upregulation of CD274 and PD-L1 related gene transcription, which was confirmed by the significantly enhanced PD-L1 expression level in B16, B16F10, and 4T1 cells in vitro. Hence, an injectable in situ responsive hydrogel reservoir embed with nHA and PD-1/PD-L1 inhibitor was engineered for a combination immunotherapy by peritumoral administration. The results confirmed that the combinational strategy effectively suppressed tumorigenesis and tumor growth, recovered the abnormal lactate dehydrogenase, aspartate transaminase, and alanine aminotransferase indicators, and significantly elongated the life span of a tumor-bearing mouse. The substantive progress mainly derived from nHA-induced T cell infiltration reinforcement in a tumor site and CD8+ T cell polarization in spleen, implying that nHA might function as an immunomodulator for melanoma immunotherapy.

Reversal of epithelial-mesenchymal transition and inhibition of tumor stemness of breast cancer cells through advanced combined chemotherapy.

The abnormal activation of the Wnt/ß-catenin signaling pathway and epithelial-mesenchymal transition (EMT) in drug-resistant tumor cells and cancer stem cells (CSCs) stimulate tumor metastasis and recurrence. Here, a promising combined chemotherapeutic strategy of salinomycin (SL) and doxorubicin (DOX) with specific inhibition of tumor stemness by a targeted co-delivery nanosystem was developed to overcome this abnormal progression. This strategy could be benefit drugs to effectively penetrate and infiltrate into spheres of 3D-cultured breast cancer stem cells (BCSCs). The expression of the Wnt/ß-catenin signaling pathway-related genes (ß-catenin, LRP6, LEF1, and TCF12) and target genes (Cyclin D1, Cmyc, and Fibronectin) as well as CSC stemness-related genes (Oct4, Nanog, and Hes1) was downregulated by redox-sensitive co-delivery micelles decorated with oligohyaluronic acid as the active targeting moiety. The changes in EMT-associated gene expression (E-cadherin and Vimentin) in vitro showed that the EMT process was also effectively inverted. This strategy achieved a strong inhibitory effect on solid tumor growth and an effective reduction in the risk of tumor metastasis in 4T1 tumor-bearing mice in vivo and effectively alleviated splenomegaly caused by the malignant tumor. Immunohistochemical staining analysis of E-cadherin, Vimentin, and ß-catenin confirmed that the inversion of the EMT was also achieved in solid tumors. These results highlight the potential of SL and DOX combined chemotherapeutic strategy for eliminating breast carcinoma. STATEMENT OF SIGNIFICANCE: Cancer stem cells (CSCs), as an important part of tumor heterogeneity, can survive against conventional chemotherapy and initiate tumorigenesis, recurrence, and metastasis. Moreover, non-CSCs can convert into the CSC state through the abnormal Wnt/ß-catenin pathway, which is closely related to the epithelial-mesenchymal transition (EMT) process. Here, redox-degradable binary drug-loaded micelles (PPH/DOX+SL) were designed to target CSCs and overcome drug resistance of breast cancer cells. The combined chemotherapy of salinomycin (SL) and doxorubicin (DOX) reversed drug resistance, while the PPH/DOX+SL micelles enhanced the intracellular accumulation and drug penetration of BCSC spheres. The introduction of SL downregulated the expression of tumor stemness genes and the Wnt/ß-catenin pathway-related genes and inverted the EMT process. PPH/DOX+SL continuously inhibited tumor growth and invasion in vivo.

Cross-Talk of Multiple Types of RNA Modification Regulators Uncovers the Tumor Microenvironment and Immune Infiltrates in Soft Tissue Sarcoma.

Background: Soft-tissue sarcoma (STS) represents a rare and diverse cohort of solid tumors, and encompasses over 100 various histologic and molecular subtypes. In recent years, RNA modifications including m6A, m5C, m1A, and m7G have been demonstrated to regulate immune response and tumorigenesis. Nevertheless, the cross-talk among these RNA modification regulators and related effects upon the tumor microenvironment (TME), immune infiltrates, and immunotherapy in STS remain poorly understood. Methods: In this study, we comprehensively investigated transcriptional and genetic alterations of 32 RNA modification regulators in STS patients from The Cancer Genome Atlas (TCGA) cohort and validated them in the Gene Expression Omnibus (GEO) cohort. Single-cell transcriptomes were introduced to identify regulators within specific cell types, with own sequencing data and RT-qPCR conducted for biological validation. Distinct regulator clusters and regulator gene subtypes were identified by using unsupervised consensus clustering analysis. We further built the regulator score model based on the prognostic regulator-related differentially expressed genes (DEGs), which could be used to quantitatively assess the risk for individual STS patients. The clinical and biological characteristics of different regulator score groups were further examined. Results: A total of 455 patients with STS were included in this analysis. The network of 32 RNA modification regulators demonstrated significant correlations within multiple different RNA modification types. Distinct regulator clusters and regulator gene subtypes were characterized by markedly different prognoses and TME landscapes. The low regulator score group in the TCGA-SARC cohort was characterized by poor prognosis. The robustness of the scoring model was further confirmed by the external validation in GSE30929 and GSE17674. The regulator score was negatively correlated with CD4+ T cell, Th2 cell, and Treg cell recruitment and most immunotherapy-predicted pathways, and was also associated with immunotherapy efficacy. Conclusions: Overall, our study is the first to demonstrate the cross-talk of RNA modification regulators and the potential roles in TME and immune infiltrates in STS. The individualized assessment based on the regulator score model could facilitate and optimize personalized treatment.

Comprehensive Profiling Reveals Prognostic and Immunogenic Characteristics of Necroptosis in Soft Tissue Sarcomas.

Soft tissue sarcomas (STSs) are heterogeneous malignancies derived from mesenchymal cells. Due to its rarity, heterogeneity, and limited overall response to chemotherapy, STSs represent a therapeutic challenge. Necroptosis is a novel therapeutic strategy for enhancing immunotherapy of cancer. Nevertheless, no research has explored the relationship between necroptosis-related genes (NRGs) and STSs. In this study, differentially expressed NRGs were identified using The Cancer Genome Atlas (TCGA) and The Cancer Genotype-Tissue Expression (GTEx) project. The expression levels of 34 NRGs were significantly different. Several key NRGs were validated using RT-qPCR and our own sequencing data. Patients with STSs were divided into two clusters using consensus cluster analysis, and significant differences were observed in their survival (p=0.002). We found the differentially expressed genes (DEGs) between the two clusters and carried out subsequent analysis. The necroptosis-related gene signatures with 10 key DEGs were identified with a risk score constructed. The prognosis of TCGA-SARC cohort with low necroptosis-related risk score was better (p<0.001). Meanwhile, the low-risk group had a significantly increased immune infiltration. Using the data of GSE17118 and another immunotherapy cohort as external validations, we observed significant survival differences between the two risk groups (p=0.019). The necroptosis-related risk score proved to be an independent prognostic factor, and a nomogram was further established and integrated with other clinical features. Notably, the necroptosis-related gene signature could also act as the prognostic indicator in other malignancies based on pan-cancer analysis. In summary, the study outlines NRGs in STSs and their potential role in prognosis and will be one of the important directions for future research.

Incidence and Predictors of Synchronous Bone Metastasis in Newly Diagnosed Differentiated Thyroid Cancer: A Real-World Population-Based Study.

BACKGROUND: Clinical and sociodemographic characteristics of differentiated thyroid cancer (DTC) patients with synchronous bone metastasis (SBM) remain unclear. This real-world study aimed to elucidate the incidence and prognosis of DTC patients with SBM using population-based data. METHODS: Data of patients with newly diagnosed DTC from 2010 to 2016 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariable logistic regression analysis was utilized to identify predictors of developing SBM in patients with DTC and was further evaluated by receiver operator characteristics (ROC) analysis. Multivariable Cox regression was applied to identify prognostic factors associated with overall survival (OS) and cancer-specific survival (CSS). RESULTS: A total of 67,176 patients with DTC were screened from the database, with 0.36% (244/67,176) developed SBM. The age-adjusted incidence of SBM in patients with DTC was relatively stable during the study period with an average annual percentage change (AAPC) of 2.52. Multivariable logistic regression analysis recognized seven factors (older age, male gender, black race, other races, follicular histology, the American Joint Committee on Cancer (AJCC) T2, T3, T4 staging, and N1 staging) as predictors of developing SBM among the entire cohort, with the value of area under the curve (AUC) of 0.931 (95% CI: 0.915-0.947). The median survival time of DTC patients with SBM was 22 months (interquartile range, 7-47 months). The multivariable Cox regression analysis indicated multiple metastatic sites, surgical procedures, and chemotherapy as predictors for the survival of patients. CONCLUSIONS: Predictors and prognostic factors of SBM in patients with DTC were identified in this study. Patients with risk factors should be given more attention in clinical practice.