CanCellVar: A database for single-cell variants map in human cancer.

Numerous variants, including both single-nucleotide variants (SNVs) in DNA and A>G RNA edits in mRNA as essential drivers of cellular proliferation and tumorigenesis, are commonly associated with cancer progression and growth. Thus, mining and summarizing single-cell variants will provide a refined and higher-resolution view of cancer and further contribute to precision medicine. Here, we established a database, CanCellVar, which aims to provide and visualize the comprehensive atlas of single-cell variants in tumor microenvironment. The current CanCellVar identified ∼3 million variants (∼1.4 million SNVs and ∼1.4 million A>G RNA edits) involved in 2,754,531 cells of 5 major cell types across 37 cancer types. CanCellVar provides the basic annotation information as well as cellular and molecular function properties of variants. In addition, the clinical relevance of variants can be obtained including tumor grade, treatment, metastasis, and others. Several flexible tools were also developed to aid retrieval and to analyze cell-cell interactions, gene expression, cell-development trajectories, regulation, and molecular structure affected by variants. Collectively, CanCellVar will serve as a valuable resource for investigating the functions and characteristics of single-cell variations and their roles in human tumor evolution and treatment.

BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study.

BACKGROUND: Antibody-drug conjugates have promising clinical activity in the treatment of solid tumours. BL-B01D1 is a first-in-class EGFR-HER3 bispecific antibody-drug conjugate. We aimed to assess the safety and preliminary antitumour activity of BL-B01D1 in patients with locally advanced or metastatic solid tumours. METHODS: This first-in-human, open-label, multicentre, dose-escalation and dose-expansion phase 1 trial was conducted in seven hospitals in China, enrolling patients aged 18-75 years (dose escalation; phase 1a) or older than 18 years (dose expansion; phase 1b), with a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0-1, and histologically or cytologically confirmed locally advanced or metastatic solid tumours that had progressed on current standard treatment. In the phase 1a i3+3 design, patients received intravenous BL-B01D1 at three different schedules: 0·27 mg/kg, 1·5 mg/kg, and 3·0 mg/kg weekly; 2·5 mg/kg, 3·0 mg/kg, and 3·5 mg/kg on days 1 and 8 of each cycle every 3 weeks; or 5·0 mg/kg and 6·0 mg/kg on day 1 of each cycle every 3 weeks. The primary objectives of phase 1a were to identify the safety, maximum tolerated dose, and dose-limiting toxicity. In phase 1b, patients were treated in two schedules: 2·5 and 3·0 mg/kg on days 1 and 8 every 3 weeks, or 4·5, 5·0, and 6·0 mg/kg on day 1 every 3 weeks. The primary objectives of phase 1b were to assess the safety and recommended phase 2 dose of BL-B01D1, and objective response rate was a key secondary endpoint. Safety was analysed in all patients with safety records who received at least one dose of BL-B01D1. Antitumour activity was assessed in the activity analysis set which included all patients who received at least one dose of BL-B01D1 every 3 weeks. This trial is registered with China Drug Trials, CTR20212923, and ClinicalTrials.gov, NCT05194982, and recruitment is ongoing. FINDINGS: Between Dec 8, 2021, and March 13, 2023, 195 patients (133 [65%] men and 62 [32%] women; 25 in phase 1a and 170 in phase 1b) were consecutively enrolled, including 113 with non-small-cell lung cancer, 42 with nasopharyngeal carcinomas, 13 with small-cell lung cancer, 25 with head and neck squamous cell carcinoma, one with thymic squamous cell carcinoma, and one with submandibular lymphoepithelioma-like carcinoma. In phase 1a, four dose-limiting toxicities were observed (two at 3·0 mg/kg weekly and two at 3·5 mg/kg on days 1 and 8 every 3 weeks; all were febrile neutropenia), thus the maximum tolerated dose was reached at 3·0 mg/kg on days 1 and 8 every 3 weeks and 6·0 mg/kg on day 1 every 3 weeks. Grade 3 or worse treatment-related adverse events occurred in 139 (71%) of 195 patients; the most common of which were neutropenia (91 [47%]), anaemia (76 [39%]), leukopenia (76 [39%]), and thrombocytopenia (63 [32%]). 52 (27%) patients had a dose reduction and five (3%) patients discontinued treatment due to treatment-related adverse events. One patient was reported as having interstitial lung disease. Treatment-related deaths occurred in three (2%) patients (one due to pneumonia, one due to septic shock, and one due to myelosuppression). In 174 patients evaluated for activity, median follow-up was 6·9 months (IQR 4·5-8·9) and 60 (34%; 95% CI 27-42) patients had an objective response. INTERPRETATION: Our results suggest that BL-B01D1 has preliminary antitumour activity in extensively and heavily treated advanced solid tumours with an acceptable safety profile. Based on the safety and antitumour activity data from both phase 1a and 1b, 2·5 mg/kg on days 1 and 8 every 3 weeks was selected as the recommended phase 2 dose in Chinese patients. FUNDING: Sichuan Baili Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

DYNLL1 accelerates cell cycle via ILF2/CDK4 axis to promote hepatocellular carcinoma development and palbociclib sensitivity.

BACKGROUND: Disorder of cell cycle represents as a major driver of hepatocarcinogenesis and constitutes an attractive therapeutic target. However, identifying key genes that respond to cell cycle-dependent treatments still facing critical challenges in hepatocellular carcinoma (HCC). Increasing evidence indicates that dynein light chain 1 (DYNLL1) is closely related to cell cycle progression and plays a critical role in tumorigenesis. In this study, we explored the role of DYNLL1 in the regulation of cell cycle progression in HCC. METHODS: We analysed clinical specimens to assess the expression and predictive value of DYNLL1 in HCC. The oncogenic role of DYNLL1 was determined by gain or loss-of-function experiments in vitro, and xenograft tumour, liver orthotopic, and DEN/CCl4-induced mouse models in vivo. Mass spectrometry analysis, RNA sequencing, co-immunoprecipitation assays, and forward and reverse experiments were performed to clarify the mechanism by which DYNLL1 activates the interleukin-2 enhancer-binding factor 2 (ILF2)/CDK4 signalling axis. Finally, the sensitivity of HCC cells to palbociclib and sorafenib was assessed by apoptosis, cell counting kit-8, and colony formation assays in vitro, and xenograft tumour models and liver orthotopic models in vivo. RESULTS: DYNLL1 was significantly higher in HCC tissues than that in normal liver tissues and closely related to the clinicopathological features and prognosis of patients with HCC. Importantly, DYNLL1 was identified as a novel hepatocarcinogenesis gene from both in vitro and in vivo evidence. Mechanistically, DYNLL1 could interact with ILF2 and facilitate the expression of ILF2, then ILF2 could interact with CDK4 mRNA and delay its degradation, which in turn activates downstream G1/S cell cycle target genes CDK4. Furthermore, palbociclib, a selective CDK4/6 inhibitor, represents as a promising therapeutic strategy for DYNLL1-overexpressed HCC, alone or particularly in combination with sorafenib. CONCLUSIONS: Our work uncovers a novel function of DYNLL1 in orchestrating cell cycle to promote HCC development and suggests a potential synergy of CDK4/6 inhibitor and sorafenib for the treatment of HCC patients, especially those with increased DYNLL1.

Polyphenol-Based Bicontinuous Porous Spheres Via Amine-Mediated Polymerization-Induced Fusion Assembly.

Bicontinuous porous materials, which possess 3D interconnected network and pore channels facilitating the mass diffusion to the interior of materials, have demonstrated their promising potentials in a large variety of research fields. However, facile construction of such complex and delicate structures is still challenging. Here, an amine-mediated polymerization-induced fusion assembly strategy is reported for synthesizing polyphenol-based bicontinuous porous spheres with various pore structures. Specifically, the fusion of pore-generating template observed by TEM promotes the development of bicontinuous porous networks that are confirmed by 3D reconstruction. Furthermore, the resultant bicontinuous porous carbon particles after pyrolysis, with a diameter of ≈600 nm, a high accessible surface area of 359 m2 g-1, and a large pore size of 40-150 nm manifest enhanced performance toward the catalytic degradation of sulfamethazine in water decontamination. The present study expands the toolbox of interfacial tension-solvent-dependent porous spheres while providing new insight into their structure-property relationships.

Dissecting the shared genetic landscape of anxiety, depression, and schizophrenia.

BACKGROUND: Numerous studies highlight the genetic underpinnings of mental disorders comorbidity, particularly in anxiety, depression, and schizophrenia. However, their shared genetic loci are not well understood. Our study employs Mendelian randomization (MR) and colocalization analyses, alongside multi-omics data, to uncover potential genetic targets for these conditions, thereby informing therapeutic and drug development strategies. METHODS: We utilized the Consortium for Linkage Disequilibrium Score Regression (LDSC) and Mendelian Randomization (MR) analysis to investigate genetic correlations among anxiety, depression, and schizophrenia. Utilizing GTEx V8 eQTL and deCODE Genetics pQTL data, we performed a three-step summary-data-based Mendelian randomization (SMR) and protein-protein interaction analysis. This helped assess causal and comorbid loci for these disorders and determine if identified loci share coincidental variations with psychiatric diseases. Additionally, phenome-wide association studies, drug prediction, and molecular docking validated potential drug targets. RESULTS: We found genetic correlations between anxiety, depression, and schizophrenia, and under a meta-analysis of MR from multiple databases, the causal relationships among these disorders are supported. Based on this, three-step SMR and colocalization analyses identified ITIH3 and CCS as being related to the risk of developing depression, while CTSS and DNPH1 are related to the onset of schizophrenia. BTN3A1, PSMB4, and TIMP4 were identified as comorbidity loci for both disorders. Molecules that could not be determined through colocalization analysis were also presented. Drug prediction and molecular docking showed that some drugs and proteins have good binding affinity and available structural data. CONCLUSIONS: Our study indicates genetic correlations and shared risk loci between anxiety, depression, and schizophrenia. These findings offer insights into the underlying mechanisms of their comorbidities and aid in drug development.

Fibroblast growth factor receptor 4 deficiency in macrophages aggravates experimental colitis by promoting M1-polarization.

OBJECTIVE AND DESIGN: Compelling evidence indicates that dysregulated macrophages may play a key role in driving inflammation in inflammatory bowel disease (IBD). Fibroblast growth factor (FGF)-19, which is secreted by ileal enterocytes in response to bile acids, has been found to be significantly lower in IBD patients compared to healthy individuals, and is negatively correlated with the severity of diarrhea. This study aims to explore the potential impact of FGF19 signaling on macrophage polarization and its involvement in the pathogenesis of IBD. METHODS: The dextran sulfate sodium (DSS)-induced mouse colitis model was utilized to replicate the pathology of human IBD. Mice were created with a conditional knockout of FGFR4 (a specific receptor of FGF19) in myeloid cells, as well as mice that overexpressing FGF19 specifically in the liver. The severity of colitis was measured using the disease activity index (DAI) and histopathological staining. Various techniques such as Western Blotting, quantitative PCR, flow cytometry, and ELISA were employed to assess polarization and the expression of inflammatory genes. RESULTS: Myeloid-specific FGFR4 deficiency exacerbated colitis in the DSS mouse model. Deletion or inhibition of FGFR4 in bone marrow-derived macrophages (BMDMs) skewed macrophages towards M1 polarization. Analysis of transcriptome sequencing data revealed that FGFR4 deletion in macrophages significantly increased the activity of the complement pathway, leading to an enhanced inflammatory response triggered by LPS. Mechanistically, FGFR4-knockout in macrophages promoted complement activation and inflammatory response by upregulating the nuclear factor-κB (NF-κB)-pentraxin3 (PTX3) pathway. Additionally, FGF19 suppressed these pathways and reduced inflammatory response by activating FGFR4 in inflammatory macrophages. Liver-specific overexpression of FGF19 also mitigated inflammatory responses induced by DSS in vivo. CONCLUSION: Our study highlights the significance of FGF19-FGFR4 signaling in macrophage polarization and the pathogenesis of IBD, offering a potential new therapeutic target for IBD.

Asymmetric Synthesis of Tertiary α-Hydroxylation-Cyclopentanones via Synergetic Catalysis of Chiral-at-Metal Rhodium(III) Complexes/Pyrrolidine.

Catalytic and asymmetric domino Michael/aldol reaction of 1,2-dicarbonyl compounds with α,ß-unsaturated ketones under the synergetic catalysis of chiral-at-metal rhodium complexes and pyrrolidine to deliver tertiary α-hydroxylation-cyclopentanones (45-89% yields with 81-99% ee and up to >20:1 dr) bearing three contiguous stereogenic centers had been established. Moreover, the scalability and practical utility of this protocol were well demonstrated by employing a gram-scale reaction and some representative transformations.

[Advances in the Treatment of Osteochondral Lesions of the Talus]. / è·éª¨éª¨è½¯éª¨æŸä¼¤æ²»ç–—çš„ç ”ç©¶è¿›å±•.

Osteochondral lesion of the talus (OLT) is a localized cartilage and subchondral bone injury of the talus trochlea. OLT is caused by trauma and other reasons, including osteochondritis dissecans of the talus (OCD) and talus osteochondral tangential fracture. OLT can develop from being asymptomatic to subchondral bone cysts accompanied by deep ankle pain. OLT tends to occur on the medial and lateral sides of the talar vault. OLT seriously affects the patients' life and work and may even lead to disability. Herein, we reviewed advances in the treatment of OLT and the strengths and weaknesses of various treatments. Different treatment methods, including conservative treatments and surgical treatments, can be adopted according to the different subtypes or clinical symptoms of OLT. Conservative treatments mostly relieve symptoms in the short term and only slow down the disease. In recent years, it has been discovered that platelet-rich plasma injection, microfracture, periosteal bone grafting, talar cartilage transplantation, allograft bone transplantation, reverse drilling under robotic navigation, and other methods can achieve considerable benefits when each of these treatment methods is applied. Furthermore, microfracture combined with platelet-rich plasma injections, microfracture combined with cartilage transplantation, and various other treatment methods combined with anterior talofibular ligament repair have all led to good treatment outcomes.

Leap-Type Response of Redox/Photo-Active Lanthanide-Based Metal-Organic Frameworks for Early and Accurate Screening of Prostate Cancer.

The development of high-accuracy technologies to distinguish the quite tiny concentration change of tumor markers between negative and positive is of vital significance for early screening and diagnosis of cancers, but is still a great challenge for the conventional biosensors because of their "gradual" detection mode. Herein, a unique "leap-type" responsive lanthanide MOF-based biosensor (designated as Tb-CeMOF-X) with defect-mediated redox-/photo-activities is developed for precisely identifying acid phosphatase (ACP), an early pathological marker of prostate cancer (PCa) in serum. The engineered Tb-CeMOF-X probe achieves a bursting switch-on luminescence at the critical concentration of ACP (9 U·L-1), while keeping silent below this threshold, undergoing a qualitative signal change from "zero" to "one" between negative and positive indicators and thus significantly improving the identification precision. Significantly, such "leap-type" response performance can be further edited and amplified by rational defect engineering in the crystal structure to improve the accessibility of active centers, consequently maximizing the detection sensitivity toward ACP in the complex biological media. This study proposes the first paradigm for the development of "leap-type" biosensors with ultra-sensitive differentiation capability between negative and positive, and provides a potentially valuable tool for early and accurate screening of PCa.

Protein S-palmitoylation modification: implications in tumor and tumor immune microenvironment.

Protein S-palmitoylation is a reversible post-translational lipid modification that involves the addition of a 16-carbon palmitoyl group to a protein cysteine residue via a thioester linkage. This modification plays a crucial role in the regulation protein localization, accumulation, secretion, stability, and function. Dysregulation of protein S-palmitoylation can disrupt cellular pathways and contribute to the development of various diseases, particularly cancers. Aberrant S-palmitoylation has been extensively studied and proven to be involved in tumor initiation and growth, metastasis, and apoptosis. In addition, emerging evidence suggests that protein S-palmitoylation may also have a potential role in immune modulation. Therefore, a comprehensive understanding of the regulatory mechanisms of S-palmitoylation in tumor cells and the tumor immune microenvironment is essential to improve our understanding of this process. In this review, we summarize the recent progress of S-palmitoylation in tumors and the tumor immune microenvironment, focusing on the S-palmitoylation modification of various proteins. Furthermore, we propose new ideas for immunotherapeutic strategies through S-palmitoylation intervention.

Pleiotropic Regulation of PGC-1α in Tumor Initiation and Progression.

Significance: Mitochondria are recognized as a central metabolic hub with bioenergetic, biosynthetic, and signaling functions that tightly control key cellular processes. As a crucial component of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is involved in regulating various metabolic pathways, including energy metabolism and reactive oxygen species homeostasis. Recent Advances: Recent studies have highlighted the significant role of PGC-1α in tumorigenesis, cancer progression, and treatment resistance. However, PGC-1α exhibits pleiotropic effects in different cancer types, necessitating a more comprehensive and thorough understanding. Critical Issues:In this review, we discuss the structure and regulatory mechanisms of PGC-1α, analyze its cellular and metabolic functions, explore its impact on tumorigenesis, and propose potential strategies for targeting PGC-1α. Future Directions: The targeted adjustment of PGC-1α based on the metabolic preferences of different cancer types could offer a hopeful therapeutic approach for both preventing and treating tumors.

FGL1 and FGL2: emerging regulators of liver health and disease.

Liver disease is a complex group of diseases with high morbidity and mortality rates, emerging as a major global health concern. Recent studies have highlighted the involvement of fibrinogen-like proteins, specifically fibrinogen-like protein 1 (FGL1) and fibrinogen-like protein 2 (FGL2), in the regulation of various liver diseases. FGL1 plays a crucial role in promoting hepatocyte growth, regulating lipid metabolism, and influencing the tumor microenvironment (TME), contributing significantly to liver repair, non-alcoholic fatty liver disease (NAFLD), and liver cancer. On the other hand, FGL2 is a multifunctional protein known for its role in modulating prothrombin activity and inducing immune tolerance, impacting viral hepatitis, liver fibrosis, hepatocellular carcinoma (HCC), and liver transplantation. Understanding the functions and mechanisms of fibrinogen-like proteins is essential for the development of effective therapeutic approaches for liver diseases. Additionally, FGL1 has demonstrated potential as a disease biomarker in radiation and drug-induced liver injury as well as HCC, while FGL2 shows promise as a biomarker in viral hepatitis and liver transplantation. The expression levels of these molecules offer exciting prospects for disease assessment. This review provides an overview of the structure and roles of FGL1 and FGL2 in different liver conditions, emphasizing the intricate molecular regulatory processes and advancements in targeted therapies. Furthermore, it explores the potential benefits and challenges of targeting FGL1 and FGL2 for liver disease treatment and the prospects of fibrinogen-like proteins as biomarkers for liver disease, offering insights for future research in this field.

Fibroblast growth factor signaling in macrophage polarization: impact on health and diseases.

Fibroblast growth factors (FGFs) are a versatile family of peptide growth factors that are involved in various biological functions, including cell growth and differentiation, embryonic development, angiogenesis, and metabolism. Abnormal FGF/FGF receptor (FGFR) signaling has been implicated in the pathogenesis of multiple diseases such as cancer, metabolic diseases, and inflammatory diseases. It is worth noting that macrophage polarization, which involves distinct functional phenotypes, plays a crucial role in tissue repair, homeostasis maintenance, and immune responses. Recent evidence suggests that FGF/FGFR signaling closely participates in the polarization of macrophages, indicating that they could be potential targets for therapeutic manipulation of diseases associated with dysfunctional macrophages. In this article, we provide an overview of the structure, function, and downstream regulatory pathways of FGFs, as well as crosstalk between FGF signaling and macrophage polarization. Additionally, we summarize the potential application of harnessing FGF signaling to modulate macrophage polarization.

Identification and classification of glioma subtypes based on RNA-binding proteins.

BACKGROUND: Glioma is a common and aggressive primary malignant cancer known for its high morbidity, mortality, and recurrence rates. Despite this, treatment options for glioma are currently restricted. The dysregulation of RBPs has been linked to the advancement of several types of cancer, but their precise role in glioma evolution is still not fully understood. This study sought to investigate how RBPs may impact the development and prognosis of glioma, with potential implications for prognosis and therapy. METHODS: RNA-seq profiles of glioma and corresponding clinical data from the CGGA database were initially collected for analysis. Unsupervised clustering was utilized to identify crucial tumor subtypes in glioma development. Subsequent time-series analysis and MS model were employed to track the progression of these identified subtypes. RBPs playing a significant role in glioma progression were then pinpointed using WGCNA and Lasso Cox regression models. Functional analysis of these key RBP-related genes was conducted through GSEA. Additionally, the CIBERSORT algorithm was utilized to estimate immune infiltrating cells, while the STRING database was consulted to uncover potential mechanisms of the identified biomarkers. RESULTS: Six tumor subgroups were identified and found to be highly homogeneous within each subgroup. The progression stages of these tumor subgroups were determined using time-series analysis and a MS model. Through WGCNA, Lasso Cox, and multivariate Cox regression analysis, it was confirmed that BCLAF1 is correlated with survival in glioma patients and is closely linked to glioma progression. Functional annotation suggests that BCLAF1 may impact glioma progression by influencing RNA splicing, which in turn affects the cell cycle, Wnt signaling pathway, and other cancer development pathways. CONCLUSIONS: The study initially identified six subtypes of glioma progression and assessed their malignancy ranking. Furthermore, it was determined that BCLAF1 could serve as an RBP-related prognostic marker, offering significant implications for the clinical diagnosis and personalized treatment of glioma.

Different anatomical variations in the anterior segment of the right upper lung.

During a routine physical examination three years ago, a 47-year-old woman received a diagnosis of a nodule in her right upper lung. Since then, she has been regularly attending outpatient clinic appointments for follow-up. Over time, the nodule has shown gradual growth, leading to a suspicion of lung cancer. Through the use of enhanced CT imaging, a three-dimensional reconstruction was performed to examine the bronchi and blood vessels in the patient's chest. This reconstruction revealed several variations in the anatomy of the anterior segment of the right upper lobe. Specifically, the anterior segmental bronchus (B3) was found to have originated from the right middle lung bronchus. Additionally, the medial subsegmental artery of the anterior segmental artery (A3b) and the medial segmental artery (A5) were observed to share a common trunk. As for the lateral subsegmental artery of the anterior segmental artery (A3a), it was found to have originated from the right inferior pulmonary trunk. Furthermore, the apical subsegmental artery of the apical segmental artery (A1a) and the posterior segmental artery (A2) were found to have a shared trunk.

Successful Treatment of Switching EGFR-TKIs for Advanced Lung Adenocarcinoma Due to Interstitial Lung Disease: A Case Report.

INTRODUCTION: Icotinib and almonertinib are efficacious for non-small cell lung cancer (NSCLC) factor patients with epidermal growth receptor (EGFR)-mutation. Patients who previously used EGFR tyrosine kinase inhibitor (EGFR TKI) may switch to another one due to the adverse events. CASE PRESENTATION: Here, we report a case of a 73-year-old male patient with advanced lung adenocarcinoma in which an EGFR (exon 21 L858R substitution) was found. Icotinib (125mg three times daily) was administered initially. He achieved partial response two months later but developed acute interstitial lung disease (grade 2) with dry cough and chest tightness five months later. Icotinib was discontinued, and treatment with methylprednisolone improved the interstitial lung disease. Chemotherapy with pemetrexed, carboplatin, and bevacizumab was initiated as subsequent therapy. Considering the effectiveness of EGFR-TKIs, we decided cautiously to rechallenge the third-generation TKI almonertinib administration. The patient successfully received almonertinib for almost one year without the recurrence of interstitial lung disease and tumor progression. ILD was an infrequent but often life-threatening reaction associated with icotinib. CONCLUSION: This is the first reported case of successful switching from icotinib to another EGFR TKI because of interstitial lung disease associated with icotinib, suggesting that EGFR-TKIs rechallenge because of adverse events rather than progression might provide a significant benefit in patients with EGFR driver positive NSCLC.

Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma.

BACKGROUND: While anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in patients with lung adenocarcinoma may hinder the efficacy of anti-PD-1 monotherapy. METHODS: Here, we delved into the patterns of lipid metabolism in patients with The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and their correlation with the immune microenvironment's cellular infiltration characteristics of the tumor. Furthermore, the lipid metabolism score (LMS) system was constructed, and based on the LMS system, we further performed screening for potential agents targeting lipid metabolism. The mechanism of MK1775 was further validated using RNA sequencing, co-culture technology, and in vivo experiments. RESULTS: We developed an LSM system and identified a potential sensitizing agent, MK1775, which targets lipid metabolism and enhances the effects of anti-PD-1 treatment. Our results demonstrate that MK1775 inhibits tumor progression by influencing lipid crosstalk between tumor cells and tumor-associated macrophages and CD8+T cells, thereby increasing the effectiveness of anti-PD-1 treatment. Further, we found that MK1775 inhibited the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, which on one hand downregulated FASN-mediated synthesis of fatty acids (FAs) to inhibit fatty acid oxidation of tumor-associated macrophages, and on the other hand, promoted IRF-mediated secretion of CXCL10 and CXCL11 to facilitate the infiltration of CD8+ T cells. CONCLUSIONS: These findings emphasize the important role of lipid metabolism in shaping the complex tumor microenvironment. By manipulating the intricate intricacies of lipid metabolism within the tumor microenvironment, we can uncover and develop promising strategies to sensitize immunotherapy, potentially revolutionizing cancer treatment approaches.

Antibody-drug conjugates in cancer therapy: mechanisms and clinical studies.

Antibody-drug conjugates (ADCs) consist of monoclonal antibodies that target tumor cells and cytotoxic drugs linked through linkers. By leveraging antibodies' targeting properties, ADCs deliver cytotoxic drugs into tumor cells via endocytosis after identifying the tumor antigen. This precise method aims to kill tumor cells selectively while minimizing harm to normal cells, offering safe and effective therapeutic benefits. Recent years have seen significant progress in antitumor treatment with ADC development, providing patients with new and potent treatment options. With over 300 ADCs explored for various tumor indications and some already approved for clinical use, challenges such as resistance due to factors like antigen expression, ADC processing, and payload have emerged. This review aims to outline the history of ADC development, their structure, mechanism of action, recent composition advancements, target selection, completed and ongoing clinical trials, resistance mechanisms, and intervention strategies. Additionally, it will delve into the potential of ADCs with novel markers, linkers, payloads, and innovative action mechanisms to enhance cancer treatment options. The evolution of ADCs has also led to the emergence of combination therapy as a new therapeutic approach to improve drug efficacy.

Application of cord blood-derived platelet-rich plasma in the treatment of diseases.

Platelet-rich plasma (PRP), a blood product containing high concentrations of platelets, has been increasingly used for the treatment of a number of diseases because of its anti-inflammatory and regenerative properties. PRP is generally obtained from the patient's own peripheral blood when used in clinical applications, but allogeneic PRP extracted from umbilical cord blood has also attracted attention due to its unique advantages. The main purpose of this narrative review was to summarize the research and clinical application of cord blood-derived PRP (CB-PRP) in the treatment of diseases up to April 2024. This review also discusses the differences between CB-PRP and autologous PRP (A-PRP). A thorough search of PubMed® and Clinicaltrials.gov identified 13 articles and four clinical trials. To date, CB-PRP has been primarily studied in the fields of orthopaedics, dermatology, neurology, obstetrics/gynaecology and ophthalmology. This is likely to be because this research is relatively novel. Considering the differences between the characteristics of A-PRP and CB-PRP, it is thought that CB-PRP might hold more promise for broader applications in the future.