Responsive and traceless assembly of iron nanoparticles and 131I labeled radiopharmaceuticals for ferroptosis enhanced radio-immunotherapy.

Ferroptosis is an iron-dependent form of programmed cell death with the potential to reverse traditional cancer therapy resistance. The combination of ferroptosis with chemotherapy, photodynamic therapy and X-ray therapy has demonstrated remarkably improved therapeutic efficiency. Radiopharmaceutical therapy (RPT) is an emerging approach that achieves precise radiation to diseased tissues via radionuclide delivery. However, insufficient accumulation and retention of therapeutic radiopharmaceuticals in tumor region as well as cancer radioresistance impact treatment efficacy. Here, a nanoassembly of renal clearable ultrasmall iron nanoparticles (USINPs) and 131I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with 131I-aPD-L1. The 150 nm USINAs(131I-aPD-L1) nanoassembly is stable in blood circulation, effectively targets to the tumor and disassembles in the presence of ATP in the tumor microenvironment. Both in vitro and in vivo experiments prove that USINPs-induced ferroptosis boosted the tumor radiosensitization to 131I while 131I-mediated RPT further enhanced ferroptosis. Meanwhile, the immunogenic cell death caused by RPT and ferroptosis combined with PD-L1 immune checkpoint blockade therapy exhibits a strong antitumor immunity. This study provides a novel way to improve the tumor accumulation of ferroptosis inducer and radiopharmaceuticals, insights into the interaction between RPT and ferroptosis and an effective SPECT-guided ferroptosis-enhanced radio-immunotherapy.

Self-Illuminating In Situ Hydrogel with Immune-Adjuvant Amplify Cerenkov Radiation-Induced Photodynamic Therapy.

Cerenkov radiation-induced photodynamic therapy (CR-induced PDT) has shown the potential to overcome the light penetration limitation in conventional PDT. In addition, the tumor-associated antigens (TAAs) produced by PDT can initiate an antitumor immune process but only show a limited immunotherapeutic effect without the use of immunotherapeutic agents. Herein, a CR-induced PDT hydrogel (R837/89Zr-HG-PpIX) has been developed by in situ formation of a hyaluronic acid (HA)-based hydrogel integrated with internal light source 89Zr, photosensitizer protoporphyrin IX (PpIX), and immune adjuvant imiquimod (R837). The obtained R837/89Zr-HG-PpIX hydrogel with long-term tumor retention and low radiation leakage can provide long-lasting photodynamic therapy without phototoxicity in normal tissues. In addition, the loaded R837 improves the immunogenicity of TAAs released after PDT, resulting in considerably enhanced immune responses. At relatively low radioactivity, R837/89Zr-HG-PpIX shows significant inhibition in subcutaneous H22 tumor-bearing BALB/c mice and orthotopic VX2 liver tumor-bearing rabbits. Furthermore, the combination of such a CR-induced PDT hydrogel with anti-PD-L1 exhibits the abscopal effect to inhibit the growth of distant tumors. Therefore, the proposed in situ formed CR-induced PDT hydrogel with long-term photodynamic-immunotherapy provides an effective strategy for deep tumor therapy.

Allelopathic effects of Borreria latifolia on weed germination and identification of allelochemicals.

BACKGROUND: Borreria latifolia (Aubl.) K. Schum (Rubiaceae) is an annual weed with a strong allelopathic inhibitory effect on malignant weeds in orchards in southern China. This study was carried out to investigate its allelopathic potential and to identify allelochemicals present in B. latifolia. RESULTS: Aqueous extracts of B. latifolia inhibited the germination and radicle growth of Eleusine indica and the radicle growth of Bidens alba in a dose-dependent manner. However, only the high-concentration treatment at 50 mg mL-1 delayed the germination of B. alba and Digitaria sanguinalis. Among the root, stem, and leaf aqueous extracts of B. latifolia, the leaf extract had the strongest inhibitory effects on the germination and seedling growth of E. indica, followed by stem extract and then root extract. A total of 47 published allelochemicals, including coumarin, 4-hydroxybenzoate, salicylic acid, 4-hydroxycinnamic acid, and vanillic acid, were identified in the leaf extract. Among the five allelochemicals, coumarin was found to be present in the highest concentration in the leaf extract. Furthermore, coumarin exhibited a significantly greater inhibitory effect on E. indica (EC50 = 36.87 mg L-1) than did the other allelochemicals (EC50 = 100.87-156.30 mg L-1). CONCLUSION: This study indicates that the leaf extracts of B. latifolia and their allelochemicals have excellent potential as bioherbicides and that coumarin is one of the key allelochemicals in B. latifolia. © 2024 Society of Chemical Industry.

The novel peptide PEP-Z-2 potentially treats renal fibrosis in vivo and in vitro by regulating TGF-ß/Smad/AKT/MAPK signaling.

Renal fibrosis is a process in which excessive deposition of extracellular matrix leads to an increase in tissue hardness and gradual destruction of the renal parenchyma. Chronic kidney disease (CKD) commonly progresses to end-stage renal disease (ESRD), ultimately leading to renal failure. This disease has high incidence and mortality rates, but to date, effective treatment options are lacking. PEP-Z-2 is a collagen peptide isolated from redlip croaker scales and may have potential fibroprotective activity. In this study, PEP-Z-2 was found to alleviate unilateral ureteral obstruction (UUO)- and folic acid (FA)-induced kidney injury in a mouse model, reduce collagen deposition in tissues, normalize renal function, reduce the expression of fibrosis markers, reduce reactive oxygen species (ROS) production, and restore the balance of the oxidant/antioxidant system. In vitro experiments also demonstrated that PEP-Z-2 inhibits the TGF-ß-induced differentiation of fibroblasts and renal tubular epithelial cells into myofibroblasts and reduces the production of extracellular matrix (ECM) proteins such as fibronectin, Col I, and α-SMA, demonstrating notable therapeutic effects on renal fibrosis. This effect is achieved by regulating the TGF-ß/Smad/AKT/MAPK pathway. Our research suggested that PEP-Z-2 is a potential therapeutic drug for renal fibrosis, and peptides from aquatic organisms may constitute a new class of candidate drugs for the treatment of renal fibrosis and even other types of organ fibrosis.

The efficacy and safety of Radiofrequency ablation combined with Lenvatinib plus Sintilimab in Unresectable Hepatocellular Carcinoma: a real-world study.

BACKGROUND: The combination of targeted therapy and immunotherapy has improved the clinical outcomes of unresectable hepatocellular Carcinoma (HCC). However, the overall prognosis remains suboptimal. This study aims to evaluate the efficacy and safety of a novel combination of radiofrequency ablation (RFA) with lenvatinib plus sintilimab in unresectable HCC. METHODS: In this retrospective study, patients diagnosed with unresectable HCC were included and divided into two cohorts: RFA combined with lenvatinib plus sintilimab (R-L-S group) and lenvatinib plus sintilimab (L-S group). The primary efficacy endpoints were objective response rate (ORR) and progression free survival (PFS). Adverse events were analyzed to assess the safety profiles. RESULTS: The median follow-up periods for the entire cohort were 14.0 months. The R-L-S group (n = 60) had a significantly higher ORR than those with L-S alone (n = 62) (40.0% vs. 20.9%; p = 0.022). Moreover, patients in the R-L-S group had improved median PFS (12 vs. 8 months; p = 0.013) and median overall survival (24 vs. 18 months; p = 0.037), as compared with lenvatinib and sintilimab alone. No significant difference in treatment related adverse event (TRAE) of any grade between the two groups. The most common TRAEs of grade ≥ 3 were fatigue 10.0% (6/60) and hand-foot skin reaction 10.0% (6/60) in the R-L-S group and hand-foot skin reaction 11.3% (7/62) in the L-S group. CONCLUSION: In unresectable HCC patients, the incorporation of RFA to lenvatinib plus sintilimab demonstrated improved efficacy without compromising safety compared with lenvatinib plus sintilimab alone.

Multi-omics analysis reveals a feedback loop amplifying immune responses in acute graft-versus-host disease due to imbalanced gut microbiota and bile acid metabolism.

Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving "immune cell-gut microbes-bile acid metabolites" contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD.

Biohybrid Nanorobots Carrying Glycoengineered Extracellular Vesicles Promote Diabetic Wound Repair through Dual-Enhanced Cell and Tissue Penetration.

Considerable progress has been made in the development of drug delivery systems for diabetic wounds. However, underlying drawbacks, such as low delivery efficiency and poor tissue permeability, have rarely been addressed. In this study, a multifunctional biohybrid nanorobot platform comprising an artificial unit and several biological components is constructed. The artificial unit is a magnetically driven nanorobot surface modified with antibacterial 2-hydroxypropyltrimethyl ammonium chloride chitosan, which enables the entire platform to move and has excellent tissue penetration capacity. The biological components are two-step engineered extracellular vesicles that are first loaded with mangiferin, a natural polyphenolic compound with antioxidant properties, and then glycoengineered on the surface to enhance cellular uptake efficiency. As expected, the platform is more easily absorbed by endothelial cells and fibroblasts and exhibits outstanding dermal penetration performance and antioxidant properties. Encouraging results are also observed in infected diabetic wound models, showing improved wound re-epithelialization, collagen deposition, angiogenesis, and accelerated wound healing. Collectively, a biohybrid nanorobot platform that possesses the functionalities of both artificial units and biological components serves as an efficient delivery system to promote diabetic wound repair through dual-enhanced cell and tissue penetration and multistep interventions.

Robust Transparent Photothermal Omniphobic Coating for Efficient Anti/Deicing and Antifogging.

Icing and fogging on optical material surfaces bring various problems in daily life. Recently, some photothermal coatings have been reported to prevent the condensation or freeze of water droplets by increasing the surface temperature. However, it is a great challenge to apply them in practical conditions due to their opaqueness and poor mechanical wear-resistant property. In this work, we constructed a robust transparent photothermal omniphobic coating with a simple dip-coating technique. In the coating system, photothermal polypyrrole nanoparticles are introduced into inorganic silica networks, and then polydimethylsiloxane (PDMS) brushes were grafted on the inorganic silica layer to endow the surface with omniphobicity and stain resistance. The transparency and photothermal capacity of the coating can be regulated by the deposition times of the coating. In addition, the coating has an excellent anti/deicing property and reduces ice adhesion obviously due to the existence of "liquid-like" PDMS brushes. More importantly, the coating presents outstanding mechanical wear-resistant and self-lubricating properties that can endure several thousand friction cycles without performance loss. The mechanically robust photothermal omniphobic coating gives a feasible approach to anti-icing and antifogging of transparent substrates under sunlight irradiation.

Identification of the function of a key gene NnHCT1 in lignin synthesis in petioles of Nelumbo nucifera.

Leaf petiole or stem strength is an important agronomic trait affecting the growth of underground organs as a channel for material exchange and plays a vital role in the quality and yield of crops and vegetables. There are two different types of petioles in lotus, floating leaf petioles and vertical leaf petioles; however, the internal difference mechanism between these petioles is unclear. In this study, we investigated the differences between the initial vertical leaf petioles and the initial floating leaf petioles based on RNA sequencing (RNA-seq), and >2858 differentially expressed genes were annotated. These genes were chiefly enriched in phenylpropanoid biosynthesis, which is the source of the lignin and cellulose in petioles and stems. Lignin biology-related gene NnHCT1 was identified, and subsequent biological function validation demonstrated that the transient overexpression of NnHCT1 significantly increased the lignin and cellulose contents in lotus petioles and tobacco leaves. In contrast, silencing NnHCT1 through virus-induced gene silencing significantly reduced petiole lignin synthesis. Additionally, differentially up-regulated MYB family transcription factors were identified using RNA-seq. Yeast-one-hybrid and dual-luciferase reporter assays demonstrated that MYB4 could bind to the NnHCT1 promoter and up-regulate NnHCT1 expression. These findings demonstrate the significant potential of NnHCT1 to enhance lignin synthesis, thereby improving stem or petiole resistance to stunting and explaining the need for the study of differential petiole relationships in plants.

Energetic utilization of corn stalk and elimination of methyl orange in ECMO-like integrated reactor: Co-occurrence of anaerobic digestion and aerobic treatment.

For the simultaneous energetic utilization of corn stalk and azo-dye contaminated wastewater, an ECMO-like integrated reactor was come up to achieve the biogas production and azo-dye degradation during anaerobic digestion (AD). Methyl orange (MO) was selected as the model compound for azo-dye. The ECMO-like reactor included AD main reactor with a spray device and solid-liquid separation components, integrated with an aeration reactor for biogas slurry. Methane yields of corn stalks (100.82 mL/g VS) were highest in the ECMO-like reactor, compared with reactors without aeration. As a stable metabolite, 4-aminobenzenesulfonic acid (4-ABA) was detected in AD, while it was assumed that the metabolites can be further transformed in the ECMO-like reactor (R3), due to the 4-ABA removal efficiency as 92.87 % after 35 days' digestion. Class Alphaproteobacteria and Clostridia were assumed as functional microbes responding to aeration. Overall, this ECMO-like integrated reactor provided a novel biotechnology strategy for agricultural and azo dye waste treatment.

SORBS1 inhibits epithelial to mesenchymal transition (EMT) of breast cancer cells by regulating PI3K/AKT signaling and macrophage phenotypic polarization.

This study aimed to explore the regulatory role of SORBS1 in macrophage polarization and the PI3K/AKT signaling pathway, as well as analyze its mechanism in epithelial-mesenchymal transition (EMT) of breast cancer cells. We established SORBS1-overexpressing and knockout cell lines and verified the effects of SORBS1 on cell viability, invasion, and migration by phenotyping experiments and assaying the expression of associated proteins. Furthermore, we established a breast cancer cell and macrophage co-culture system to validate the effect of SORBS1 expression on macrophage polarization and killing of breast cancer cells. Bioinformatics analysis showed that SORBS1 was lowly expressed in breast cancer (BRCA) samples and highly expressed in healthy tissues. Decreased SORBS1 expression was associated with poor prognosis, and the PI3K/AKT signaling pathway was the most significantly enriched pathway. In vitro experiments showed that high expression of SORBS1 inhibited the migration of breast cancer cells, as well as the PI3K/AKT signaling pathway, and blocked EMT of these cells. In addition, SORBS1 induced macrophage polarization to the M1-type and enhanced the killing effect on breast cancer cells in the co-culture system. In conclusion, we successfully verified that SORBS1 inhibits the invasion and migration of breast cancer cells, induces macrophage M1-type polarization, and blocks EMT of breast cancer cells, and it may act by regulating the PI3K/AKT signaling pathway.

A photoelectrochemical aptasensor based on double Z-scheme α-Fe2O3/MoS2/Bi2S3 ternary heterojunction for sensitive detection of circulating tumor cells.

A novel photoelectrochemical (PEC) aptasensor based on a dual Z-scheme α-Fe2O3/MoS2/Bi2S3 ternary heterojunction for the ultrasensitive detection of circulating tumor cells (CTCs) was developed. The α-Fe2O3/MoS2/Bi2S3 nanocomposite was prepared via a step-by-step route, and the photoproduced electron/hole transfer path was speculated by conducting trapping experiments of reactive species. α-Fe2O3/MoS2/Bi2S3-modified electrodes exhibited greatly enhanced photocurrent under visible light due to the double Z-scheme charge transfer process, which met the requirement of the PEC sensor for detecting larger targets. After the aptamer was conjugated on the photoelectrode through chitosan (CS) and glutaraldehyde (GA), when MCF-7 cells were presented and captured, the photocurrent of the PEC biosensing system decreased due to steric hindrance. The current intensity had a linear relationship with the logarithm of MCF-7 cell concentration ranging from 10 to 1×105 cells mL-1, with a low detection limit of 3 cell mL-1 (S/N = 3). The dual Z-scheme α-Fe2O3/MoS2/Bi2S3 ternary heterojunction-modified PEC aptasensor exhibited high sensitivity and excellent specificity and stability. Additionally, MCF-7 cells in human serum were determined by this PEC aptasensor, exhibiting great potential as a promising tool for clinical detection.

A versatile engineered extracellular vesicle platform simultaneously targeting and eliminating senescent stromal cells and tumor cells to promote tumor regression.

Chemotherapy is an important therapeutic approach for malignant tumors for it triggers apoptosis of cancer cells. However, chemotherapy also induces senescence of stromal cells in the tumor microenvironment to promote tumor progression. Strategies aimed at killing tumor cells while simultaneously eliminating senescent stromal cells represent an effective approach to cancer treatment. Here, we developed an engineered Src-siRNA delivery system based on small extracellular vesicles (sEVs) to simultaneously eliminate senescent stromal cells and tumor cells for cancer therapy. The DSPE-PEG-modified urokinase plasminogen activator (uPA) peptide was anchored to the membranes of induced mesenchymal stem cell-derived sEVs (uPA-sEVs), and Src siRNA was loaded into the uPA-sEVs by electroporation (uPA-sEVs-siSrc). The engineered uPA-sEVs-siSrc retained the basic sEVs properties and protected against siSrc degradation. uPA peptide modification enhanced the sEVs with the ability to simultaneously target doxorubicin-induced senescent stromal cells and tumor cells. Src silencing by uPA-sEVs-siSrc induced apoptosis of both senescent stromal cells and tumor cells. The uPA-sEVs-siSrc displayed preferential tumor accumulation and effectively inhibited tumor growth in a tumor xenograft model. Furthermore, uPA-sEVs-siSrc in combination with doxorubicin significantly reduced the senescence burden and enhanced the therapeutic efficacy of chemotherapy. Taken together, uPA-sEVs-siSrc may serve as a promising therapy to kill two birds with one stone, not only killing tumor cells to achieve remarkable antitumor effect, but also eliminating senescent cells to enhance the efficacy of chemotherapeutic agent in tumor regression.

Clinical efficacy analysis of surgical treatment for spinal metastasis under the multidisciplinary team using the NOMS decision system combined with the revised Tokuhashi scoring system: a randomized controlled study.

OBJECTIVE: Despite advancements in spinal metastasis surgery techniques and the rapid development of multidisciplinary treatment models, we aimed to explore the clinical efficacy of spinal metastasis surgery performed by a combined NOMS decision system-utilizing multidisciplinary team and Revised Tokuhashi scoring system, compared with the Revised Tokuhashi scoring system. METHODS: Clinical data from 102 patients with spinal metastases who underwent surgery at three affiliated hospitals of Zunyi Medical University from December 2017 to June 2022 were analysed. The patients were randomly assigned to two groups: 52 patients in the treatment group involving the combined NOMS decision system-utilizing multidisciplinary team and Revised Tokuhashi scoring system (i.e., the combined group), and 50 patients in the treatment group involving the Revised Tokuhashi scoring system only (i.e., the revised TSS-only group). Moreover, there were no statistically significant differences in preoperative general data or indicators between the two groups. Intraoperative and postoperative complications, average hospital stay, mortality rate, and follow-up observation indicators, including the visual analogue scale (VAS) score for pain, Eastern Cooperative Oncology Group (ECOG) performance status, Karnofsky Performance Status (KPS) score, negative psychological assessment score (using the Self-Rating Anxiety Scale, [SAS]), and neurological function recovery score (Frankel functional classification) were compared between the two groups. RESULTS: All 102 patients successfully completed surgery and were discharged. The follow-up period ranged from 12 to 24 months, with an average of (13.2 ± 2.4) months. The patients in the combined group experienced fewer complications such as surgical wound infections 3 patients(5.77%), intraoperative massive haemorrhage 2 patients(3.85%), cerebrospinal fluid leakage 2 patients(3.85%), deep vein thrombosis 4 patients(7.69%),and neurological damage 1 patient(1.92%), than patients in the revised TSS-only group (wound infections,11 patients(22%); intraoperative massive haemorrhage, 8 patients(16%);cerebrospinal fluid leakage,5 patients(10%);deep vein thrombosis,13 patients (26%); neurological damage,2 patients (4%). Significant differences were found between the two groups in terms of surgical wound infections, intraoperative massive haemorrhage, and deep vein thrombosis (P < 0.05). The average postoperative hospital stay in the combined group (7.94 ± 0.28 days) was significantly shorter than that in the revised TSS-only group (10.33 ± 0.30 days) (P < 0.05). Long-term follow-up (1 month, 3 months, 6 months, and 1 year postoperatively) revealed better clinical outcomes in the combined group than in the revised TSS-only group in terms of VAS scores, overall KPS%, neurological function status Frankel classification, ECOG performance status, and SAS scores.(P < 0.05). CONCLUSION: A multidisciplinary team using the NOMS combined with the Revised Tokuhashi scoring system for spinal metastasis surgery showed better clinical efficacy than the sole use of the Revised Tokuhashi scoring system. This personalized, precise, and rational treatment significantly improves patient quality of life, shortens hospital stay, reduces intraoperative and postoperative complications, and lowers mortality rates.

Immunoglobulin A Vasculitis With Intussusception in Children.

BACKGROUND: Immunoglobulin A (IgA) vasculitis with intussusception is acute and severe vasculitis combined with acute abdomen in children. The diagnosis of the disease depends on the results of imaging examinations, and its treatment mainly includes enema and surgery. The literature summarized the detailed diagnosis and treatment data in previous literature reports. METHODS: We described the clinical manifestations, ultrasonic features, and treatment of patients admitted to a single center and reviewed previous literature regarding cases with detailed clinical data in the PubMed database within the past 20 years. RESULTS: The review included 36 patients, including 22 boys and 14 girls. A total of 32 patients were diagnosed using ultrasound (88.9%). The main sites of intussusception were the ileum and ileocolon in 16 (44.4%) and 11 (30.6%) cases, respectively. Thirteen patients (36.1%) were treated with enema, with 6 responding to the treatment. 26 patients (72.2%) underwent surgical treatment. Patients with ileal intussusception were more likely to be treated with surgery than those with colonic intussusception (P < .05). The single-center clinical data of 23 patients showed that there was no significant difference in laboratory test findings between patients with and without surgical treatment (P > .05). Patients with long insertion lengths were more likely to require surgery and resection (P < .05). CONCLUSIONS: Ultrasonography is the first-line investigation for diagnosis. The main sites of intussusception were ileum and ileocolon. The length of intubation was related to surgery; treatment is according to the intussusception site. Air enema is not suitable for intussusception of the small intestine.

Tensile Stress-Activated and Exosome-Transferred YAP/TAZ-Notch Circuit Specifies Type H Endothelial Cell for Segmental Bone Regeneration.

The Ilizarov technique has been continuously innovated to utilize tensile stress (TS) for inducing a bone development-like regenerative process, aiming to achieve skeletal elongation and reconstruction. However, it remains uncertain whether this distraction osteogenesis (DO) process induced by TS involves the pivotal coupling of angiogenesis and osteogenesis mediated by type H endothelial cells (THECs). In this study, it is demonstrated that the Ilizarov technique induces the formation of a metaphysis-like architecture composed of THECs, leading to segmental bone regeneration during the DO process. Mechanistically, cell-matrix interactions-mediated activation of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcriptionally upregulates the expression of Notch1 and Delta-like ligand 4, which act as direct positive regulators of THECs phenotype, in bone marrow endothelial cells (BMECs) upon TS stimulation. Simultaneously, the Notch intracellular domain enhances YAP/TAZ activity by transcriptionally upregulating YAP expression and stabilizing TAZ protein, thus establishing the YAP/TAZ-Notch circuit. Additionally, TS-stimulated BMECs secrete exosomes enriched with vital molecules in this positive feedback pathway, which can be utilized to promote segmental bone defect healing, mimicking the therapeutic effects of Ilizarov technique. The findings advance the understanding of TS-induced segmental bone regeneration and establish the foundation for innovative biological therapeutic strategies aimed at activating THECs.

Patterns of Gene Expression Profiles Associated with Colorectal Cancer in Colorectal Mucosa by Using Machine Learning Methods.

BACKGROUND: Colorectal cancer (CRC) has a very high incidence and lethality rate and is one of the most dangerous cancer types. Timely diagnosis can effectively reduce the incidence of colorectal cancer. Changes in para-cancerous tissues may serve as an early signal for tumorigenesis. Comparison of the differences in gene expression between para-cancerous and normal mucosa can help in the diagnosis of CRC and understanding the mechanisms of development. OBJECTIVES: This study aimed to identify specific genes at the level of gene expression, which are expressed in normal mucosa and may be predictive of CRC risk. METHODS: A machine learning approach was used to analyze transcriptomic data in 459 samples of normal colonic mucosal tissue from 322 CRC cases and 137 non-CRC, in which each sample contained 28,706 gene expression levels. The genes were ranked using four ranking methods based on importance estimation (LASSO, LightGBM, MCFS, mRMR, and RF) and four classification algorithms (decision tree [DT], K-nearest neighbor [KNN], random forest [RF], and support vector machine [SVM]) were combined with incremental feature selection [IFS] methods to construct a prediction model with excellent performance. RESULT: The top-ranked genes, namely, HOXD12, CDH1, and S100A12, were associated with tumorigenesis based on previous studies. CONCLUSION: This study summarized four sets of quantitative classification rules based on the DT algorithm, providing clues for understanding the microenvironmental changes caused by CRC. According to the rules, the effect of CRC on normal mucosa can be determined.

Multigene testing panels reveal pathogenic variants in sporadic breast cancer patients in northern China.

Background: Breast cancer, the most prevalent malignancy in women worldwide, presents diverse onset patterns and genetic backgrounds. This study aims to examine the genetic landscape and clinical implications of rare mutations in Chinese breast cancer patients. Methods: Clinical data from 253 patients, including sporadic and familial cases, were analyzed. Comprehensive genomic profiling was performed, categorizing identified rare variants according to the American College of Medical Genetics (ACMG) guidelines. In silico protein modeling was used to analyze potentially pathogenic variants' impact on protein structure and function. Results: We detected 421 rare variants across patients. The most frequently mutated genes were ALK (22.2%), BARD1 (15.6%), and BRCA2 (15.0%). ACMG classification identified 7% of patients harboring Pathogenic/Likely Pathogenic (P/LP) variants, with one case displaying a pathogenic BRCA1 mutation linked to triple-negative breast cancer (TNBC). Also identified were two pathogenic MUTYH variants, previously associated with colon cancer but increasingly implicated in breast cancer. Variants of uncertain significance (VUS) were identified in 112 patients, with PTEN c.C804A showing the highest frequency. The role of these variants in sporadic breast cancer oncogenesis was suggested. In-depth exploration of previously unreported variants led to the identification of three potential pathogenic variants: ATM c.C8573T, MSH3 c.A2723T, and CDKN1C c.C221T. Their predicted impact on protein structure and stability suggests a functional role in cancer development. Conclusion: This study reveals a comprehensive overview of the genetic variants landscape in Chinese breast cancer patients, highlighting the prevalence and potential implications of rare variants. We emphasize the value of comprehensive genomic profiling in breast cancer management and the necessity of continuous research into understanding the functional impacts of these variants.

Construction and experimental validation of a necroptosis-related lncRNA signature as a prognostic model and immune-landscape predictor for lung adenocarcinoma.

Necroptosis is a new form of cell death. Since the discovery that long non-coding RNAs can affect the proliferation of lung adenocarcinoma, much has been learned about it, yet those of necroptosis-related long non-coding RNAs (NRlncRNAs) in lung adenocarcinoma (LUAD) remain enigmatic. This study aims to explore novel biomarkers and therapeutic targets for LUAD. The LUAD data was downloaded from The Cancer Genome Atlas, and necroptosis-related genes were retrieved from published literature. Co-expression analysis, univariate Cox analysis, least absolute shrinkage and selection operator regression analysis were used to identify necroptosis-related prognostic long non-coding RNAs. A comprehensive evaluation of tumor immunity for necrosis-related features was performed, and we identified a 9-NRlncRNA signature. Kaplan-Meier and Cox regression analyses confirmed that the signature was an independent predictor of LUAD outcome in the test and train sets (all P < 0.05). The areas of 1-, 2-, and 3-year overall survival under the time-dependent receiver operating characteristics (ROC) curve (AUC) were 0.754, 0.746, and 0.720, respectively. The GSEA results showed that 9 NRlncRNAs were associated with multiple malignancy-associated and immunoregulatory pathways. Based on this model, we found that the immune status and level of response to chemotherapy and targeted therapy were significantly different in the low-risk group compared with the high-risk group. qRT-PCR assay revealed that 9 NRlncRNAs were involved in the regulation of tumor cell proliferation and may affect the expression of programmed cell death 1 (PD1) and CD28 at human immune checkpoints. Our results indicated that the novel signature involving 9 NRlncRNAs (AL031600.2, LINC01281, AP001178.1, AL157823.2, LINC01290, MED4-AS1, AC026355.2, AL606489.1, FAM83A-AS1) can predict the prognosis of LUAD and are associated with the immune response. This will provide new insights into the pathogenesis and development of therapies for LUAD.