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Abstract Background Early detection of colorectal cancer (CRC) significantly enhances patient outcomes. Conventional CRC screening tools, like endoscopy and stool-based tests, have constraints due to their invasiveness or suboptimal patient adherence. Recently, liquid biopsy employing plasma cell-free DNA (cfDNA) has emerged as a potential noninvasive screening technique for various malignancies. Methods In this research, we harnessed the Mutation Capsule Plus (MCP) technology to profile an array of genomic characteristics from cfDNA procured from a single blood draw. This profiling encompassed DNA methylation, the 5’ end motif, copy number variation (CNV), and genetic mutations. An integrated model built upon selected multiomics biomarkers was trained using a cohort of 93 CRC patients and 96 healthy controls. Results This model was subsequently validated in another cohort comprising 89 CRC patients and 95 healthy controls. Remarkably, the model achieved an area under the curve (AUC) of 0.981 (95% confidence interval (CI), 0.965–0.998) in the validation set, boasting a sensitivity of 92.1% (95% CI, 84.5%-96.8%) and a specificity of 94.7% (95% CI, 88.1%-98.3%). These numbers surpassed the performance of any single genomic feature. Importantly, the sensitivities reached 80% for stage I, 89.2% for stage II, and were 100% for stages III and IV. Conclusion Our findings underscore the clinical potential of our multiomics liquid biopsy test, indicating its prospective role as a noninvasive method for early-stage CRC detection. This multiomics approach holds promise for further refinement and broader clinical application.

Abstract Neuroticism appears to be a factor that triggers social aggression, but the relationship between neuroticism and social aggression and its underlying mechanisms is unclear. Questionnaire data from 942 college students ranging in age from 17 to 24 (M age = 20.33, SD = 1.03) were analysed to assess whether depression symptoms mediated the relationship between neuroticism and social aggression, and to test a moderating effect of perceived social support. Results showed that neuroticism positively predicted social aggression and this association was mediated by depression symptoms. Moderation was found for the association between neuroticism and depression symptoms, as well as between neuroticism and social aggression, and that neuroticism had a stronger predictive effect on depression symptoms and social aggression under low compared to high perceived social support. These findings may inform prevention and intervention efforts to reduce social aggression.

Background and purposeCurrent studies have substantiated the sparing effect of ultra-high dose rate irradiation (FLASH) in various organs including the brain, lungs, and intestines. Whether this sparing effect extends to esophageal tissue remains unexplored. This study aims to compare the different responses of esophageal tissue in histological and protein expression levels following conventional dose rate irradiation (CONV) and FLASH irradiation to ascertain the presence of a sparing effect.Methods and materialsC57 female mice were randomly divided into three groups: control, CONV, and FLASH groups. The chest region of the mice in the radiation groups was exposed to a prescribed dose of 20 Gy using a modified electron linear accelerator. The CONV group received an average dose rate of 0.1 Gy/s, while the FLASH group received an average dose rate of 125 Gy/s. On the 10th day after irradiation, the mice were euthanized and their esophagi were collected for histopathological analysis. Subsequently, label-free proteomic quantification analysis was performed on esophageal tissue. The validation process involved analyzing transmission electron microscopy images and utilizing the parallel reaction monitoring method.ResultsHistopathology results indicated a significantly lower extent of esophageal tissue damage in the FLASH group compared to the CONV group (p < 0.05). Label-free quantitative proteomic analysis revealed that the sparing effect observed in the FLASH group may be attributed to a reduction in radiation-induced protein damage associated with mitochondrial functions, including proteins involved in the tricarboxylic acid cycle and oxidative phosphorylation, as well as a decrease in acute inflammatory responses.ConclusionsCompared with CONV irradiation, a sparing effect on esophageal tissue can be observed after FLASH irradiation. This sparing effect is associated with alleviated mitochondria damage and acute inflammation.

Summary: Background: The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various cancers, including prostate cancer. This need is particularly significant in prostate cancer. While androgen deprivation therapy (ADT) has demonstrated promising efficacy in prostate cancer, its long-term use can eventually lead to the development of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Notably, p300 has been identified as an important co-activator of the androgen receptor (AR), highlighting its significance in prostate cancer progression. Moreover, recent studies have revealed the involvement of p300 in AR-independent oncogenes associated with NEPC. Therefore, the blockade of p300 may emerge as an effective therapeutic strategy to address the challenges posed by both CRPC and NEPC. Methods: We employed AI-assisted design to develop a peptide-based PROTAC (proteolysis-targeting chimera) drug that targets p300, effectively degrading p300 in vitro and in vivo utilizing nano-selenium as a peptide drug delivery system. Findings: Our p300-targeting peptide PROTAC drug demonstrated effective p300 degradation and cancer cell-killing capabilities in both CRPC, AR-negative, and NEPC cells. This study demonstrated the efficacy of a p300-targeting drug in NEPC cells. In both AR-positive and AR-negative mouse models, the p300 PROTAC drug showed potent p300 degradation and tumor suppression. Interpretation: The design of peptide PROTAC drug targeting p300 is feasible and represents an efficient therapeutic strategy for CRPC, AR-negative prostate cancer, and NEPC. Funding: The funding details can be found in the Acknowledgements section.

Abstract Background Mid‐rectal cancer treatment traditionally involves conventional laparoscopic‐assisted resection (CLAR). This study aimed to assess the clinical and therapeutic advantages of Natural Orifice Specimen Extraction Surgery (NOSES) over CLAR. Aims To compare the clinical outcomes, intraoperative metrics, postoperative recovery, complications, and long‐term prognosis between NOSES and CLAR groups. Materials & Methods A total of 136 patients were analyzed, with 92 undergoing CLAR and 44 undergoing NOSES. Clinical outcomes were evaluated, and propensity score matching (PSM) was employed to control potential biases. Results The NOSES group exhibited significant improvements in postoperative recovery, including lower pain scores on days 1, 3, and 5 (p < .001), reduced need for additional analgesics (p = .02), shorter hospital stays (10.8 ± 2.3 vs. 14.2 ± 5.3 days; p < .001), and decreased intraoperative blood loss (48.1 ± 52.7 mL vs. 71.0 ± 55.0 mL; p = .03). Patients undergoing NOSES also reported enhanced satisfaction with postoperative abdominal appearance and better quality of life. Additionally, the NOSES approach resulted in fewer postoperative complications. Conclusion While long‐term outcomes (overall survival, disease‐free survival, and local recurrence rates) were comparable between the two methods, NOSES demonstrated superior postoperative outcomes compared to CLAR in mid‐rectal cancer treatment, while maintaining similar long‐term oncological safety. These findings suggest that NOSES could serve as an effective alternative to CLAR without compromising long‐term results.

Abstract The recent development of wearable devices is revolutionizing the way of human–machine interaction (HMI). Nowadays, an interactive interface that carries more embedded information is desired to fulfill the increasing demand in era of Internet of Things. However, present approach normally relies on sensor arrays for memory expansion, which inevitably brings the concern of wiring complexity, signal differentiation, power consumption, and miniaturization. Herein, a one‐channel based self‐powered HMI interface, which uses the eigenfrequency of magnetized micropillar (MMP) as identification mechanism, is reported. When manually vibrated, the inherent recovery of the MMP causes a damped oscillation that generates current signals because of Faraday's Law of induction. The time‐to‐frequency conversion explores the MMP‐related eigenfrequency, which provides a specific solution to allocate diverse commands in an interference‐free behavior even with one electric channel. A cylindrical cantilever model is built to regulate the MMP eigenfrequencies via precisely designing the dimensional parameters and material properties. It is shown that using one device and two electrodes, high‐capacity HMI interface can be realized when the magnetic micropillars (MMPs) with different eigenfrequencies have been integrated. This study provides the reference value to design the future HMI system especially for situations that require a more intuitive and intelligent communication experience with high‐memory demand.

The combination of multiplex polymerase chain reaction (mPCR) and microfluidic technologies demonstrates great significance in biomedical applications. However, current microfluidics-based molecular diagnostics face challenges in multi-target detection due to their limited fluorescence channels, complicated fabrication process, and high cost. In this research, we proposed a cost-effective sandblasting method for manufacturing silicon microchips and a chip-based microdevice for field mPCR detection. The atomic force microscopy (AFM) images showed a rough surface of the sandblasted microchips, leading to poor biocompatibility. To relieve the inhibitory effect, we dip-coated a layer of bovine serum albumin (BSA) on the irregular substrate. The optimized coating condition was determined by scanning electron microscope (SEM) and energy-dispersive X-ray spectroscopy (EDS) (65 °C for 60 min). After sufficient coating, we performed on-chip PCR tests with 500 copies/mL Coronavirus Disease 2019 (COVID-19) standard sample within 20 min, and the sandblasted microchip displayed a higher amplification rate compared to dry etching chips. Finally, we achieved a 50 min mPCR for screening five resistance genes of the endophthalmitis pathogens on our microdevices, with strong specificity and reliability. Thus, this sandblasted microchip-based platform not only provides a rapid, accessible, and effective solution for multiplex molecular detection but also enables large-scale microfabrication in a low-cost and convenient way.

Abstract Background Although colonoscopy is the standard screening test for colorectal cancer (CRC), its use is limited by a poor compliance rate, the need for extensive bowel preparation, and the risk of complications. As an alternative, an FDA-approved stool-based DNA test, Cologuard, has demonstrated satisfactory detection performance for CRC, but its compliance rate remains suboptimal, primarily attributable to individuals’ reluctance to provide stool samples. Methods We developed a noninvasive blood-based CRC test, ColonSecure, based on cell-free DNA containing cancer-specific CpG island methylation patterns. We initially screened publicly available datasets for differentially methylated CpG sites in CRC with prediction potential. Subsequently, we performed two sequential bisulfite-free methylation sequencing on blood samples obtained from CRC patients and non-cancer controls. Through rigorous evaluation of each marker and machine learning-assisted feature selection, we identified 149 hypermethylated markers from over 193,000 CpG sites. These markers were then utilized to construct the ColonSecure model, enabling accurate CRC detection. Results We validated the efficacy of our cell-free DNA methylation-based blood test for CRC screening with 3493 high-risk individuals identified from 114,136 urban residents. The ColonSecure test identified 89 out of 103 CRC patients diagnosed by the follow-up colonoscopy, outperforming CEA, CRP, and CA19-9 (with a sensitivity of 86.4% compared to 45.6%, 39.8%, and 25.2% for CEA, CRP, and CA19-9 respectively; an AUROC of 0.956 compared to an AUROC of

Abstract Interleukin-2 (IL-2) and its receptor (IL-2R) are essential in orchestrating immune responses. Their function and expression in the tumor microenvironment make them attractive targets for immunotherapy, leading to the development of IL-2/IL-2R-targeted therapeutic strategies. However, the dynamic interplay between IL-2/IL-2R and various immune cells and their dual roles in promoting immune activation and tolerance presents a complex landscape for clinical exploitation. This review discusses the pivotal roles of IL-2 and IL-2R in tumorigenesis, shedding light on their potential as diagnostic and prognostic markers and their therapeutic manipulation in cancer. It underlines the necessity to balance the anti-tumor activity with regulatory T-cell expansion and evaluates strategies such as dose optimization and selective targeting for enhanced therapeutic effectiveness. The article explores recent advancements in the field, including developing genetically engineered IL-2 variants, combining IL-2/IL-2R-targeted therapies with other cancer treatments, and the potential benefits of a multidimensional approach integrating molecular profiling, immunological analyses, and clinical data. The review concludes that a deeper understanding of IL-2/IL-2R interactions within the tumor microenvironment is crucial for realizing the full potential of IL-2-based therapies, heralding the promise of improved outcomes for cancer patients.

Abstracts: It is cost-effective and low-carbon emission using high performance mortar to repair and protect damaged structures. Here, graphene oxide (GO)/steel fiber (SF) reinforced ethylene vinyl acetate (EVA) polymer compound sulfoaluminate cement repair mortar (GOCRM) was directly prepared by water-reducer sonication dispersion and subsequent shear mix method. The workability, mechanical properties, and durability of GOCRM were systematically investigated along with microstructure and micro/nano enhancement mechanism evaluation. The flowability, initial/final setting time, 1 day/28 days flexural, 1 day/28 days compressive, interfacial bonding strength (fb), 90 days drying shrinkage, 3 days water absorption rate, contact angle and migration coefficient of chloride ion of GOCRM at 0.03% GO dosage reach 192.0 mm, 35 min/53 min, 8 MPa/19.9 MPa, 21.3 MPa/79.3 MPa, 4.93 MPa, 1.051×10−4, 0.1%, 80.96° and 2.322×10−13 m2/s, respectively. Microscopic morphology, Fourier transform infrared spectroscopy, and X-ray diffraction spectra of mortars with varied curing ages demonstrate that sulfoaluminate cement, EVA, GO incorporation can improve the microstructure in interiors and at interfaces of mortars by filling micro-pores between products and promoting hydration degree. Accordingly, tighter bonding surface, higher fb and superior bond durability between GOCRM and the old substrate are achieved. These indicate that GOCRM can advantageously serve as high-performance repair mortar with superior fast repair capability, and long-term repair stability.

Abstract Background Checkpoint blockade immunotherapy, represented by PD-1 or PD-L1 antibody treatment, has been of tremendous success in clinical practice. However, the low clinical response rate and lack of biomarkers for prediction of the immune response limit the clinical application of anti-PD-1 immunotherapy. Our recent work showed that a combination of low-dose decitabine and PD-1-ab significantly improved the complete response (CR) rate of cHL patients from 32 to 71%, which indicates that there is a significant correlation between epigenetic regulation and the clinical response to immunotherapy. Methods We recruited two groups of Hodgkin lymphoma patients who were treated with anti-PD-1 and DAC+anti-PD-1. CD8+ T cells were isolated from the patients' peripheral blood, DNA methylation was analyzed by EPIC, the expression profile was analyzed by RNA-seq, and multigroup analysis was performed with IPA and GSEA functional annotations. We explored the effect of DAC on the function of CD8+ T cells in the blood, spleen, tumor and lymph nodes using a mouse model. Furthermore, we explored the function of Tils in the tumor microenvironment. Then, we constructed Runx3-knockout mice to confirm the T-cell-specific function of Runx3 in CD8+ T cells and analyzed various subtypes of T cells and cytokines using mass cytometry (CyTOF). Results Multiomics analysis identified that DNA methylation reprogramming of Runx3 was a crucial mediator of CD8+ T-cell function. Multiomics data showed that reversal of methylation of the Runx3 promoter promoted the infiltration of CD8+ TILs and mitigated the exhaustion of CD8+ T cells. Furthermore, experiments on tissue-specific Runx3-knockout mice showed that Runx3 deficiency reduced CD8+ T infiltration and the differentiation of effector T and memory T cells. Furthermore, Runx3 deficiency significantly decreased CCR3 and CCR5 levels. Immunotherapy experiments in Runx3 conditional knockout mice showed that DAC could not reverse the resistance of anti-PD-1 in the absence of Runx3. Moreover, both our clinical data and data from TISIDB showed that Runx3 could be a potential biomarker for immunotherapy to predict the clinical response rate. Conclusion We demonstrate that the DNA methylation of Runx3 plays a critical role in CD8+ T-cell infiltration and differentiation during decitabine-primed PD-1-ab immunotherapy, which provides a supporting mechanism for the essential role of epiregulation in immunotherapy.

Carbon nanotubes (CNTs) reinforced cementitious composite (CNRC) with excellent electrical and self-sensing properties, which enables it to serve as an intrinsic sensor for structural health monitoring (SHM). However, the requirements of modern industry for accurate calculation and performance design of engineering materials are not met by traditional experimental studies alone. The finite element method (FEM) has the advantages of simplicity of operation, accuracy, and cost-effectiveness, and it has been widely used in the property verification and prediction of various composite materials. In this article, the constitutive model, FEM modeling method, and simulation process of CNRC along with existing model types, innate relations, and model parameters are reviewed, and the corresponding mechanical, electrical, and electromechanical coupling properties of CNRC under different parameters are systematically analyzed by FEM method. By combining different uncertainty parameters and model types, the advantages and disadvantages of FEM for mechanical, electromechanical coupling, and SHM applications of CNRC modeling are explored. The results are in good agreement with those in the existing CNRC experiment, which effectively proves the reliability of the FEM method in CNRC research. This work is important to develop a sound theoretical model verification and performance prediction for early applications in SHM of CNRC.

We summarize the most important advances in RNA delivery and nanomedicine. We describe lipid nanoparticle-based RNA therapeutics and the impacts on the development of novel drugs. The fundamental properties of the key RNA members are described. We introduced recent advances in the nanoparticles to deliver RNA to defined targets, with a focus on lipid nanoparticles (LNPs). We review recent advances in biomedical therapy based on RNA drug delivery and state-of-the-art RNA application platforms, including the treatment of different types of cancer. This review presents an overview of current LNPs based RNA therapies in cancer treatment and provides deep insight into the development of future nanomedicines sophisticatedly combining the unparalleled functions of RNA therapeutics and nanotechnology.

Abstract Cuproptosis was a copper-dependent and unique kind of cell death that was separate from existing other forms of cell death. The last decade has witnessed a considerable increase in investigations of programmed cell death, and whether copper induced cell death was an independent form of cell death has long been argued until mechanism of cuproptosis has been revealed. After that, increasing number of researchers attempted to identify the relationship between cuproptosis and the process of cancer. Thus, in this review, we systematically detailed the systemic and cellular metabolic processes of copper and the copper-related tumor signaling pathways. Moreover, we not only focus on the discovery process of cuproptosis and its mechanism, but also outline the association between cuproptosis and cancers. Finally, we further highlight the possible therapeutic direction of employing copper ion ionophores with cuproptosis-inducing functions in combination with small molecule drugs for targeted therapy to treat specific cancers.

Abstract Objectives This study aims to characterize the specific organ metastatic rates in lung adenocarcinoma (LUAD) patients and identify the prognosis‐associated factors. Methods Using the Surveillance, Epidemiology and End Results database, 40 117 patients diagnosed with positive histology as the only primary LUAD were included. We stratified patients by diagnosed year, age, sex, race/ethnicity, marital status, insurance, location, TNM stage, organ‐specific metastases, surgery, chemotherapy, and radiation therapy. We performed multivariable logistic and Cox regression to identify the factors associated with the presence of specific organ metastases and prognosis predictors. Results For the 40 117 LUAD patients, 43.69%, 26.25%, 19.66%, 10.60%, and 17.89% had specific organ, bone, brain, liver, and lung metastases, respectively. The average survival in patients with organ metastases was 12.19 months, compared to 36.40 months in patients without metastases. In different kinds of metastatic organ cohorts, the longest average survival was 12.60 months in the lung metastases cohort, and the shortest was 8.43 months in liver metastases cohort. In total, 571 patients with metastases received surgery, which was significantly associated with decreased mortality (hazard ratio 1.82, 95% confidence interval 1.65–2.01, p

Abstract Background Lung adenocarcinoma (LUAD) is a major cause of cancer-related death worldwide, and the roles of complement-related genes in it have not been thoroughly investigated yet. In the study, we aimed to systemically examine the prognostic performance of complement-related genes, classify the patients into two different clusters and stratify the patients into different risk groups using a complement-related gene signature. Methods To achieve this, clustering analyses, Kaplan–Meier survival analyses, immune infiltration analyses were performed. LUAD patients from The Cancer Genome Atlas (TCGA) were classified into two subtypes (C1 and C2). A prognostic signature, consisting of four complement-related genes, was established using TCGA-LUAD cohort and validated in six Gene Expression Omnibus datasets and an independent cohort from our center. Results The prognosis of C2 patients is better than that of C1 patients and the prognosis of low risk patients is significantly better than high risk patients across the public datasets. In our cohort, the OS of patients in low risk group is better than that in high risk group but the difference is not significant. Patients with a lower risk score were characterized by a higher immune score, a higher level of BTLA, higher infiltration levels of T cells, B lineage, myeloid dendritic cells, neutrophils, endothelial cells, and a lower infiltration level of fibroblast. Conclusions In summary, our study has established a new classification method and developed a prognostic signature for LUAD, while future studies are needed for further exploration of the underlying mechanism.

Abstract With the development and introduction of immune checkpoint inhibitors (ICIs) in cancer patients, immune‐related side effects have increasingly attracted attention. However, the risks of immune‐related renal toxicity are poorly characterized. In this study, we performed a network meta‐analysis (NMA) of ICI‐related randomized clinical trials (RCTs) to elucidate the comparative risk of acute kidney injury (AKI) in cancer patients receiving different ICIs. We also sought to identify other factors potentially affecting the risk of AKI. PubMed and EMBASE were searched for peer‐reviewed trial reports published between January 2000 and May 2021. Eligible studies were RCTs studying ICIs in cancer patients and reporting AKI data. We performed a frequentist NMA to evaluate the risk ratios for grade 1‐5 and grade 3‐5 AKI between the treatment groups. We also assessed the absolute incidence of AKI in the ICI‐containing arm using traditional direct meta‐analysis. Once significant heterogeneity was detected in a traditional direct meta‐analysis, multivariable meta‐regression analysis was applied to identify factors that significantly affected the absolute incidence of AKI. A total of 85 RCTs were included in this study. In the NMA for the risk of grade 1‐5 and 3‐5 AKI, ipilimumab showed a significantly higher risk than avelumab and durvalumab, whereas 1 mg/kg nivolumab plus 3 mg/kg ipilimumab (N1I3) showed a significantly higher risk than other groups. In terms of treatment ranking, durvalumab ± low‐dose tremelimumab and avelumab were consistently among the top three safest treatments for grade 1‐5 or 3‐5 AKI, whereas N1I3, ipilimumab and tremelimumab were consistently among the top three treatments with the highest risk for grade 1‐5 or 3‐5 AKI. Compared with other cancers, renal cell carcinoma and urothelial carcinoma showed a significantly higher risk of AKI. The incidence of AKI was significantly higher with ICI+chemotherapy than with ICI monotherapy. In this NMA involving large‐scale up‐to‐date ICI trials, we demonstrated the comparative safety of existing ICI drugs for grade 1‐5 and grade 3‐5 AKI. Based on data from the ICI arms of these trials, we also revealed several potential risk factors for immune‐related AKI, including tumor type and treatment paradigm.

Squalene epoxidase (SQLE) is a key enzyme in the mevalonate–cholesterol pathway that plays a critical role in cellular physiological processes. It converts squalene to 2,3-epoxysqualene and catalyzes the first oxygenation step in the pathway. Recently, intensive efforts have been made to extend the current knowledge of SQLE in cancers through functional and mechanistic studies. However, the underlying mechanisms and the role of SQLE in cancers have not been fully elucidated yet. In this review, we retrospected current knowledge of SQLE as a rate-limiting enzyme in the mevalonate–cholesterol pathway, while shedding light on its potential as a diagnostic and prognostic marker, and revealed its therapeutic values in cancers. We showed that SQLE is regulated at different levels and is involved in the crosstalk with iron-dependent cell death. Particularly, we systemically reviewed the research findings on the role of SQLE in different cancers. Finally, we discussed the therapeutic implications of SQLE inhibitors and summarized their potential clinical values. Overall, this review discussed the multifaceted mechanisms that involve SQLE to present a vivid panorama of SQLE in cancers.

Sarcomas are heterogeneous connective tissue malignancies that have been historically categorized into soft tissue and bone cancers. Although multimodal therapies are implemented, many sarcoma subtypes are still difficult to treat. Lipids play vital roles in cellular activities; however, ectopic levels of lipid metabolites have an impact on tumor recurrence, metastasis, and drug resistance. Thus, precision therapies targeting lipid metabolism in sarcoma need to be explored. In this study, we performed a comprehensive analysis of molecular stratification based on lipid metabolism-associated genes (LMAGs) using both public datasets and the data of patients in our cohort and constructed a novel prognostic model consisting of squalene epoxidase (SQLE) and tumor necrosis factor (TNF). We first integrated information on gene expression profile and survival outcomes to divide TCGA sarcoma patients into high- and low-risk subgroups and further revealed the prognosis value of the metabolic signature and immune infiltration of patients in both groups, thus proposing various therapeutic recommendations for sarcoma. We observed that the low-risk sarcoma patients in the TCGA-SARC cohort were characterized by high proportions of immune cells and increased expression of immune checkpoint genes. Subsequently, this lipid metabolic signature was validated in four external independent sarcoma datasets including the CHCAMS cohort. Notably, SQLE, a rate-limiting enzyme in cholesterol biosynthesis, was identified as a potential therapeutic target for sarcoma. Knockdown of SQLE substantially inhibited cell proliferation and colony formation while promoting the apoptosis of sarcoma cells. Terbinafine, an inhibitor of SQLE, displayed similar tumor suppression capacity in vitro. The prognostic predictive model and the potential drug target SQLE might serve as valuable hints for further in-depth biological, diagnostic, and therapeutic exploration of sarcoma.

Abstract Background Combination of chemotherapy and immune checkpoint inhibitor therapy has greatly improved the anticancer effect on multiple malignancies. However, the efficiency on triple-negative breast cancer (TNBC) is limited, since most patients bear “cold” tumors with low tumor immunogenicity. Doxorubicin (DOX), one of the most effective chemotherapy agents, can induce immunogenic cell death (ICD) and thus initiating immune response. Methods In this study, to maximize the ICD effect induced by DOX, chitosan and cell-penetrating peptide (R6F3)-modified nanoparticles (PNPs) loaded with ginsenoside Rg3 (Rg3) were fabricated using the self-assembly technique, followed by co-encapsulation with DOX based on thermo-sensitive hydrogel. Orthotopic tumor model and contralateral tumor model were established to observe the antitumor efficacy of the thermo-sensitive hydrogel combined with anti-PD-L1 immunotherapy, besides, the biocompatibility was also evaluated by histopathological. Results Rg3-PNPs strengthened the immunogenic cell death (ICD) effect induced by DOX. Moreover, the hydrogel co-loading Rg3-PNPs and DOX provoked stronger immune response in originally nonimmunogenic 4T1 tumors than DOX monotherapy. Following combination with PD-L1 blocking, substantial antitumor effect was achieved due to the recruitment of memory T cells and the decline of adaptive PD-L1 enrichment. Conclusion The hydrogel encapsulating DOX and highly permeable Rg3-PNPs provided an efficient strategy for remodeling immunosuppressive tumor microenvironment and converting immune “cold” 4T1 into “hot” tumors.

Abstract Background Maintenance of cancer stem‐like cell (CSC) stemness supported by aberrantly regulated cancer cell metabolism is critical for CSC self‐renewal and tumor progression. As a key glycolytic enzyme, hexokinase 2 (HK2) plays an instrumental role in aerobic glycolysis and tumor progression. However, whether HK2 directly contribute to CSC stemness maintenance in small cell lung cancer (SCLC) is largely unclear. In this study, we aimed to investgate whether HK2 independent of its glycolytic activity is directly involved in stemness maintenance of CSC in SCLC. Methods Immunoblotting analyses were conducted to determine the expression of HK2 in SCLC CSCs and their differentiated counterparts. CSC‐like properties and tumorigenesis of SCLC cells with or without HK2 depletion or overexpression were examined by sphere formation assay and xenograft mouse model. Immunoprecipitation and mass spectrometry analyses were performed to identify the binding proteins of CD133. The expression levels of CD133‐associated and CSC‐relevant proteins were evaluated by immunoblotting, immunoprecipitation, immunofluorescence, and immunohistochemistry assay. RNA expression levels of Nanog, POU5F1, Lin28, HK2, Prominin‐1 were analyzed through quantitative reverse transcription PCR. Polyubiquitination of CD133 was examined by in vitro or in vivo ubiquitination assay. CD133+ cells were sorted by flow cytometry using an anti‐CD133 antibody. Results We demonstrated that HK2 expression was much higher in CSCs of SCLC than in their differentiated counterparts. HK2 depletion inhibited CSC stemness and promoted CSC differentiation. Mechanistically, non‐mitochondrial HK2 directly interacted with CD133 and enhanced CD133 expression without affecting CD133 mRNA levels. The interaction of HK2 and CD133 promoted the binding of the deubiquitinase ubiquitin‐specific protease 11 (USP11) to CD133, thereby inhibiting CD133 polyubiquitylation and degradation. HK2‐mediated upregulation of CD133 expression enhanced the expression of cell renewal regulators, SCLC cell stemness, and tumor growth in mice. In addition, HK2 expression was positively correlated with CD133 expression in human SCLC specimens, and their expression levels were associated with poor prognosis of SCLC patients. Conclusions These results revealed a critical non‐metabolic function of HK2 in promotion of cancer cell stemness. Our findings provided new insights into the multifaceted roles of HK2 in tumor development.

Abstract Background Growth differentiation factor-11 (GDF-11), also known as bone morphogenetic protein-11, belongs to the transforming growth factor-beta superfamily. GDF-11 was first identified as an important regulator during embryonic development. Increasing evidence has demonstrated that GDF-11 regulates the development of various organs and its aberrant expressions are associated with the risk of cardiovascular diseases and cancers. Extravillous trophoblast (EVT) cells invasion is a critical event for placenta development and needs to be finely regulated. However, to date, the biological function of GDF-11 in the human EVT cells remains unknown. Methods HTR-8/SVneo, a human EVT cell line, and primary cultures of human EVT cells were used to examine the effect of GDF-11 on matrix metalloproteinase 2 (MMP2) expression. Matrigel-coated transwell invasion assay was used to examine cell invasiveness. A series of in vitro experiments were applied to explore the underlying mechanisms that mediate the effect of GDF-11 on MMP2 expression and cell invasion. Results Treatment with GDF-11 stimulates MMP2 expression, in the HTR-8/SVneo and primary human EVT cells. Using a pharmacological inhibitor and siRNA-mediated knockdown approaches, our results demonstrated that the stimulatory effect of GDF-11 on MMP2 expression was mediated by the ALK4/5-SMAD2/3 signaling pathways. In addition, the expression of inhibitor of DNA-binding protein 2 (ID2) was upregulated by GDF-11 and that was required for the GDF-11-stimulated MMP2 expression and EVT cell invasion. Conclusions These findings discover a new biological function and underlying molecular mechanisms of GDF-11 in the regulation of human EVT cell invasion. Video Abstract

Abstract Anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy has dramatically changed the therapeutic landscape of inoperable non-small cell lung cancer (NSCLC), and has been included in first-line treatments. Sintilimab is a domestic anti-PD-1 monoclonal antibody in China that has received approvals from the National Medical Products Administration to treat classical Hodgkin’s lymphoma, hepatocellular carcinoma, and squamous and non-squamous NSCLC. In a prospective clinical study we led, neoadjuvant sintilimab has led to major and complete pathologic responses, which are recommended as surrogate endpoints for neoadjuvant immunotherapy; however, its effect remains inconclusive in pulmonary ground glass nodules. Meanwhile, combination plans seem more likely to be satisfying therapeutic options. Specifically, sintilimab plus platinum-based chemotherapy plans conferred better anti-tumor efficacy and clinical benefits compared to chemotherapy alone, which led to their approval in China and the acceptance of a biological license application in the US. Besides, the combination with other plans, such as docetaxel, cytokine-induced killer cell immunotherapy, radiation therapy, and anlotinib have also shown promising anti-tumor efficacy, with acceptable toxicities, and are therefore worth further exploration. In addition, several clinical trials on NSCLC at our center are ongoing. In general, sintilimab and its combinatorial plans were effective and well tolerated, but the treatment requires appropriate timing; pathologic responses can be surrogate endpoints for neoadjuvant immunotherapy, while more effective biomarkers are warranted. This study provides an overview of sintilimab-based clinical trials on NSCLC, and may support further investigation of sintilimab in future clinical trials.

ObjectivesThis study aimed to evaluate the prognostic significance of the eighth edition TNM stage criteria in patients with combined small-cell lung cancer (C-SCLC) on a population level.MethodsUsing the Surveillance, Epidemiology, and End Results (SEER) database, patients diagnosed with C-SCLC (histology code 8245) between the years 2004 and 2015 were identified. We performed a Kaplan–Meier analysis and used the multivariable cox regression proportional hazards model to obtain prognostic overall survival estimates for each group of patients.ResultsA total of 477 patients diagnosed with C-SCLC were identified. The T, N, M, TNM, and combined TNM stage status of the eighth edition were all significant prognostic factors for patients’ overall survivals, with the best discrimination identified in the combined stages. Surgery was also found to be a prognostic factor (HR =1.95, 95%CI =1.49-2.56, p

Abstract The recent pandemic of variants of concern (VOC) of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) highlights the need for innovative anti‐SARS‐CoV‐2 approaches in addition to vaccines and antiviral therapeutics. Here, we demonstrate that a CRISPR‐Cas13‐based strategy against SARS‐CoV‐2 can effectively degrade viral RNA. First, we conducted a cytological infection experiment, screened CRISPR‐associated RNAs (crRNAs) targeting conserved regions of viruses, and used an in vitro system to validate functional crRNAs. Reprogrammed Cas13d effectors targeting NSP13, NSP14, and nucleocapsid transcripts achieved >99% silencing efficiency in human cells which are infected with coronavirus 2, including the emerging variants in the last 2 years, B.1, B.1.1.7 (Alpha), D614G B.1.351 (Beta), and B.1.617 (Delta). Furthermore, we conducted bioinformatics data analysis. We collected the sequence information of COVID‐19 and its variants from China, and phylogenetic analysis revealed that these crRNA oligos could target almost 100% of the SARS‐CoV family, including the emerging new variant, Omicron. The reprogrammed Cas13d exhibited high specificity, efficiency, and rapid deployment properties; therefore, it is promising for antiviral drug development. This system could possibly be used to protect against unexpected SARS‐CoV‐2 variants carrying multiple mutations.

Abstract Background Tightly regulation of extravillous cytotrophoblast (EVT) cell invasion is critical for the placentation and establishment of a successful pregnancy. Insufficient EVT cell invasion leads to the development of preeclampsia (PE) which is a leading cause of maternal and perinatal mortality and morbidity. Transforming growth factor-beta1 (TGF-β1) and kisspeptin are expressed in the human placenta and have been shown to inhibit EVT cell invasion. Kisspeptin is a downstream target of TGF-β1 in human breast cancer cells. However, whether kisspeptin is regulated by TGF-β1 and mediates TGF-β1-suppressed human EVT cell invasion remains unclear. Methods The effect of TGF-β1 on kisspeptin expression and the underlying mechanisms were explored by a series of in vitro experiments in a human EVT cell line, HTR-8/SVneo, and primary cultures of human EVT cells. Serum levels of TGF-β1 and kisspeptin in patients with or without PE were measured by ELISA. Results TGF-β1 upregulates kisspeptin expression in HTR-8/SVneo cells and primary cultures of human EVT cells. Using pharmacological inhibitor and siRNA, we demonstrate that the stimulatory effect of TGF-β1 on kisspeptin expression is mediated via the ALK5 receptor. Treatment with TGF-β1 activates SMAD2/3 canonical pathways as well as ERK1/2 and PI3K/AKT non-canonical pathways. However, only inhibition of ERK1/2 activation attenuates the stimulatory effect of TGF-β1 on kisspeptin expression. In addition, siRNA-mediated knockdown of kisspeptin attenuated TGF-β1-suppressed EVT cell invasion. Moreover, we report that serum levels of TGF-β1 and kisspeptin are significantly upregulated in patients with PE. Conclusions By illustrating the potential physiological role of TGF-β1 in the regulation of kisspeptin expression, our results may serve to improve current strategies used to treat placental diseases.

Abstract Background Aging and senescence can alter immune cell fitness and influence the efficacy of lung cancer treatments, especially immunotherapy. However, the correlations between cellular senescence and tumor microenvironment are still not clearly clarified and the value of cellular senescence-related genes in evaluating the immune infiltration and clinical outcomes of lung adenocarcinoma (LUAD) need further investigated. Methods We identified three cellular senescence clusters by NMF algorithm and correlated the cellular senescence clusters with the immune landscape in LUAD patients. A prognostic scoring system was established using random survival forest algorithm and validated in 4 external cohorts. Multivariate Cox regression analysis was performed to evaluate the prognostic value of the scoring system. Expression of LYPD3 was evaluated by immunohistochemistry in LUAD samples. Results Based on the mRNA expression profiles of 278 cellular senescence-related genes, three cellular senescence clusters with distinct prognosis were identified. We characterized three cellular senescence clusters by differences in biological processes, EMT score, expression of immunomodulatory genes, extent of intratumor heterogeneity and response to immunotherapy. Meanwhile, a cellular senescence-related scoring system (CSS) was established and validated as an independent prognostic factor and immunotherapy predictor of LUAD. Patients with low CSS was characterized by prolonged survival time. In response to anti-cancer drugs, patients with low CSS exhibited higher sensitivities to molecular drugs, such as Roscovitine (CDKs inhibitor), Lenaidornide (TNF-α inhibitor), MK2206 (Akt 1/2/3 inhibitor), and especially increased response to anti-PD-1/L1 immunotherapy. Conclusions This study demonstrated the correlations between cellular senescence patterns and tumor immune landscape in LUAD, which enhanced our understanding of the tumor immune microenvironment and provided new insights for improving the outcome of immunotherapy for LUAD patients.

Cheng, Fan, Li et al. identified ANGPTL4 as a G1-induced target gene of GPER/YAP in HRT8 cells using RNA-seq and highlighted its importance in regulating trophoblast cell invasion. The authors also reported GPER downregulation in the placenta and lower estradiol levels in patients who developed preeclampsia.

Abstract Background During pregnancy, trophoblast cell invasion needs to be finely controlled. Aberrant trophoblast cell invasion is associated with placental diseases. Epidermal growth factor (EGF) and its receptor, EGFR, are expressed in trophoblast cells. Although the pro-invasive effect of EGF on trophoblast cells has been reported, the underlying mechanism remains largely unknown. Results In the present study, we conducted an RNA sequencing (RNA-seq) to HTR-8/SVneo human trophoblast cells in response to EGF and identified KISS1 as a target gene of EGF. The human KISS1 gene encodes kisspeptin, also known as metastin, which can suppress tumor metastasis. Our results showed that EGF treatment downregulated KISS1 expression and secretion by activating the EGFR-mediated PI3K/AKT signaling pathway. In addition, the expression of inhibitor of DNA-binding protein 3 (ID3) was downregulated by EGF and that was required for the EGF-suppressed KISS1 expression. Functionally, transwell invasion assays demonstrated that EGF stimulated human trophoblast cell invasion by downregulating KISS1 expression. Preeclampsia (PE) is a placental disease characterized by insufficient trophoblast cell invasion. Our clinical results revealed that serum levels of EGF were downregulated while serum and placental levels of KISS1 were upregulated in PE patients. Conclusions This study demonstrates that downregulation of EGF can lead to poor trophoblast cell invasion by increasing KISS1 expression which subsequently contributes to the pathogenesis of PE. Video Abstract

Objective To evaluate the feasibility, safety, and short-term outcomes of middle rectal resection followed by transanal specimen extraction. Methods Forty-four patients with small mid-rectal tumors underwent laparoscopic rectal resection followed by transanal specimen extraction. Results The procedure was successful in all patients without intraoperative conversion or additional access. The mean operation time was 182.7 minutes (range, 130–255 minutes), the mean blood loss was 26.5 mL (range, 5–120 mL), the mean postoperative exhaust time was 31.3 hours (range, 16–60 hours), and the mean length of hospital stay was 9.5 days (range, 8–19 days). One patient developed anastomotic leakage, which was treated by intravenous antibiotics and daily pelvic cavity flushes through the abdominal drainage tube. No infection-related complications or anal incontinence were observed. The mean tumor size was 2.1 cm (range, 1.6–3.2 cm), the mean number of harvested lymph nodes was 16.5 (range, 6–31), and the mean follow-up time was 8.5 months (range, 2–16 months). By the last follow-up, no signs of recurrence had been found in any patient. Conclusion The combination of standard laparoscopic proctectomy and transanal specimen extraction could become a well-established strategy for selected patients.

Background: The type 2 mannose receptor C (MRC2) is involved in tumor biological processes and plays a new role in the remodeling of the extracellular matrix turnover. Previous studies have demonstrated MRC2 expression profiling and prognostic relevance in some tumor types. However, the clinical and immunotherapeutic value of MRC2 in pan-cancers remains controversial. Our study aimed to evaluate MRC2 expression pattern, clinical characteristics and prognostic significance in 33 cancers, explore the relationship between MRC2 and immune-related characteristics, and assess the prediction of MRC2 for the immunotherapeutic response.Methods: Transcriptional and clinical data of 33 cancers were downloaded from The Cancer Genome Atlas database (TCGA) database and two independent immunotherapeutic cohorts were obtained from GSE67501 and the IMvigor210 study. Next, patients stratified by MRC2 expression levels were displayed by Kaplan-Meier plot to compare prognosis-related indexes. Meanwhile, immune infiltrates of different cancers were estimated by tumor immune estimation resources (TIMER) and CIBERSORT. The ESTIMATE algorithm was used to estimate the immune and stromal scores in tumor tissues. MRC2 expression and immunological modulators, including immune inhibitors, immune stimulators, and MHC molecules, were screened through the TISIDB portal. Gene-set enrichment analysis analyses were performed to explore the underlying biological process of MRC2 across different cancers. The immunotherapeutic response prediction was performed in two independent cohorts (GSE78220: metastatic melanoma with pembrolizumab treatment and IMvigor210: advanced urothelial cancer with atezolizumab intervention).Results: MRC2 is expressed differently in many cancers and has been shown to have potential prognostic predicting significance. MRC2 was significantly associated with immune cell infiltration, immune modulators, and immunotherapeutic markers. Notably, the immunotherapeutic response group was associated with lower MRC2 expression in metastatic melanoma and advanced urothelial carcinoma cohort.Conclusion: This study demonstrated that MRC2 could be a prognostic indicator for certain cancer and is critical for tumor immune microenvironments. MRC2 expression level may influence and predict immune checkpoint blockade response as a potential indicator.

Abstract Background Cancer cell–specific variation and circulating tumour DNA (ctDNA) methylation are promising biomarkers for non‐invasive cancer detection and molecular classification. Nevertheless, the applications of ctDNA to the early detection and screening of cancer remain highly challenging due to the scarcity of cancer cell–specific ctDNA, the low signal‐to‐noise ratio of DNA variation, and the lack of non‐locus‐specific DNA methylation technologies. Methods We enrolled three cohorts of breast cancer (BC) patients from two hospitals in China (BC: n = 123; healthy controls: n = 40). We developed a ctDNA whole‐genome bisulfite sequencing technology employing robust trace ctDNA capture from up to 200 μL plasma, mini‐input (1 ng) library preparation, unbiased genome‐wide coverage and comprehensive computational methods. Results A diagnostic signature comprising 15 ctDNA methylation markers exhibited high accuracy in the early (area under the curve [AUC] of 0.967) and advanced (AUC of 0.971) BC stages in multicentre patient cohorts. Furthermore, we revealed a ctDNA methylation signature that discriminates estrogen receptor status (Training set: AUC of 0.984 and Test set: AUC of 0.780). Different cancer types, including hepatocellular carcinoma and lung cancer, could also be well distinguished. Conclusions Our study provides a toolset to generate unbiased whole‐genome ctDNA methylomes with a minimal amount of plasma to develop highly specific and sensitive biomarkers for the early diagnosis and molecular subtyping of cancer.

USP13 is significantly amplified in over 20% of lung cancer patients and critical for tumor progression. However, the functional role of USP13 in small cell lung cancer (SCLC) remains largely unclear. In this study, we found that the deubiquitinase USP13 is highly expressed in SCLC tumor samples and positively associated with poor prognosis in multiple cohorts. In vitro and in vivo depletion of USP13 inhibited SCLC cancer stem cells (CSCs) properties and tumorigenesis, and this inhibitory effect was rescued by reconstituted expression of wide type (WT) USP13 but not the enzyme-inactive USP13 mutant. Mechanistically, USP13 interacts with fatty acid synthase (FASN) and enhances FASN protein stability. FASN downregulation suppresses USP13-enhanced cell renewal regulator expression, sphere formation ability, and de novo fatty acids biogenesis. Accordingly, we found FASN expression is upregulated in surgical resected SCLC specimens, positively correlated with USP13, and associated with poor prognosis of SCLC patients. More importantly, the small molecule inhibitor of FASN, TVB-2640, significantly inhibits lipogenic phenotype and attenuates self-renewal ability, chemotherapy resistance and USP13-mediated tumorigenesis in SCLC. Thus, our study highlights a critical role of the USP13-FASN-lipogenesis axis in SCLC cancer stemness maintenance and tumor growth, and reveals a potential combination therapy for SCLC patients.

Pancreatic cancer (PC) is a deadly malignant digestive tumor with poor prognoses and a lack of effective treatment options. Cuproptosis, a recently identified copper-dependent programmed cell death type, has been implicated in multiple cancers. Long non-coding RNAs (lncRNAs) are also linked to the progression of PC. However, the role and prognostic values of cuproptosis-related lncRNAs in pancreatic adenocarcinoma (PAAD) remain unclear. In this study, we systemically analyzed the differential expressions and prognostic values of 672 cuproptosis-related lncRNAs in PAAD. Based on this, a prognostic signature including four lncRNAs (LINC00853, AC099850.3, AC010719.1, and AC006504.7) was constructed and was able to divide PAAD patients into high- and low-risk groups with significantly different prognoses. Next, we focused on lncRNA LINC00853. The differential expressions of LINC00853 between normal tissue and PAAD samples were validated by qRT-PCR. LINC00853 was knocked down by siRNA in PC cell lines BxPC-3 and PANC-1 and the oncogenic role of LINC00853 was validated by CCK8, colony formation, and EdU assays. Subsequently, LINC00853 knockdown cells were subjected to tumor xenograft tests and exhibited decreased tumor growth in nude mice. Mechanistically, knockdown of LINC00853 significantly reduced cellular glycolysis and enhanced cellular mitochondrial respiration levels in PC cells. Moreover, knockdown of LINC00853 decreased the protein level of a glycolytic kinase PFKFB3. Finally, glycolysis tests and functional tests using LINC00853 and HA-PFKFB3 indicated that the effects of LINC00853 on glycolysis and cell proliferation were mediated by PFKFB3. In conclusion, our systemic analyses have highlighted the important roles of cuproptosis-related lncRNAs in PAAD while the prognostic signature based on them showed excellent performance in PAAD patients and is expected to provide clinical guidance for individualized treatment. In addition, our findings provide a novel mechanism by which the LINC00853-PFKFB3 axis critically regulates aerobic glycolysis and cell proliferation in PC cells.

Polydimethylsiloxane (PDMS) has been widely used to make lab-on-a-chip devices, such as reactors and sensors, for biological research. Real-time nucleic acid testing is one of the main applications of PDMS microfluidic chips due to their high biocompatibility and transparency. However, the inherent hydrophobicity and excessive gas permeability of PDMS hinder its applications in many fields. This study developed a silicon-based polydimethylsiloxane-polyethylene-glycol (PDMS-PEG) copolymer microfluidic chip, the PDMS-PEG copolymer silicon chip (PPc-Si chip), for biomolecular diagnosis. By adjusting the modifier formula for PDMS, the hydrophilic switch occurred within 15 s after contact with water, resulting in only a 0.8% reduction in transmittance after modification. In addition, we evaluated the transmittance at a wide range of wavelengths from 200 nm to 1000 nm to provide a reference for its optical property study and application in optical-related devices. The improved hydrophilicity was achieved by introducing a large number of hydroxyl groups, which also resulted in excellent bonding strength of PPc-Si chips. The bonding condition was easy to achieve and time-saving. Real-time PCR tests were successfully conducted with higher efficiency and lower non-specific absorption. This chip has a high potential for a wide range of applications in point-of-care tests (POCT) and rapid disease diagnosis.

The epitranscriptomic regulation of adenomatous polyposis coli (APC) tumour suppressor gene in cancers is unclear. Here the authors show that N6-methyladenosine methylation writer METTL3 downregulates APC by recruiting YTHDF2 for APC mRNA degradation, and that this promotes glycolysis and tumour growth in oesophageal cancers.

Primary small cell carcinoma of the oesophagus has a poor prognosis, and has not been fully characterised molecularly. Here, the authors study the disease using multi-omics technology and find frequent RB1 disruptions and similarities to small cell lung cancer, opening potential therapeutic avenues.

Abstract FTO removes the N6-methyladenosine (m6A) modification from genes and plays a critical role in cancer development. However, the mechanisms underlying the regulation of FTO and its subsequent impact on the regulation of the epitranscriptome remain to be further elucidated. Here, we demonstrate that FTO expression is downregulated and inversely correlated with poor survival of lung adenocarcinoma patients. Mechanistically, Wnt signaling induces the binding of EZH2 to β-catenin. This protein complex binds to the LEF/TCF-binding elements at the promoter region of FTO, where EZH2 enhances H3K27me3 and inhibits FTO expression. Downregulated FTO expression substantially enhances the m6A levels in the mRNAs of a large number of genes in critical pathways, particularly metabolic pathway genes, such as MYC. Enhanced m6A levels on MYC mRNA recruit YTHDF1 binding, which promotes MYC mRNA translation and a subsequent increase in glycolysis and proliferation of tumor cells and tumorigenesis. Our findings uncovered a critical mechanism of epitranscriptome regulation by Wnt/β-catenin-mediated FTO downregulation and underscored the role of m6A modifications of MYC mRNA in regulating tumor cell glycolysis and growth.

There is no cost-effective, accurate, and non-invasive method for the detection of esophageal squamous cell carcinoma (ESCC) in clinical practice. We aimed to investigate the diagnostic potential of tumor-educated platelets in ESCC. In this study, seventy-one ESCC patients and eighty healthy individuals were enrolled and divided into a training cohort (23 patients and 27 healthy individuals) and a validation cohort (48 patients and 53 healthy individuals). Next-generation RNA sequencing was performed on platelets isolated from peripheral blood of all participants, and a support vector machine/leave-one-out cross validation (SVM/LOOCV) approach was used for binary classification. A diagnostic signature composed of ARID1A, GTF2H2, and PRKRIR discriminated ESCC patients from healthy individuals with 91.3% sensitivity and 85.2% specificity in the training cohort and 87.5% sensitivity and 81.1% specificity in the validation cohort. The AUC was 0.924 (95% CI, 0.845–0.956) and 0.893 (95% CI, 0.821–0.966), respectively, in the training cohort and validation cohort. This 3-gene platelet RNA signature could effectively discriminate ESCC from healthy control. Our data highlighted the potential of tumor-educated platelets for the noninvasive diagnosis of ESCC. Moreover, we found that keratin and collagen protein families and ECM-related pathways might be involved in tumor progression and metastasis of ESCC, which might provide insights to understand ESCC pathobiology and advance novel therapeutics.

The immune cell infiltration in TME has been reported to be associated with prognosis and immunotherapy efficiency of lung cancers. However, to date, the immune infiltrative landscape of lung adenocarcinoma (LUAD) has not been elucidated yet. Therefore, this study aimed to identify a new transcriptomic-based TME classification and develop a risk scoring system to predict the clinical outcomes of patients with LUAD. We applied “CIBERSORT” algorithm to analyze the transcriptomic data of LUAD samples and classified LUAD into four discrete subtypes according to the distinct immune cell infiltration patterns. Furthermore, we established a novel predictive tool (TMEscore) to quantify the immune infiltration patterns for each LUAD patient by principal component analysis. The TMEscore displayed as a reliable and independent prognostic biomarker for LUAD, with worse survival in TMEscrore-high patients and better survival in TMEscrore-low patients in both TCGA and other five GEO cohorts. In addition, enriched pathways and genomic alterations were also analyzed and compared in different TMEscore subgroups, and we observed that high TMEscore was significantly correlated with more aggressive molecular changes, while the low TMEscore subgroup enriched in immune active-related pathways. The TMEscore-low subtype showed overexpression of PD-1, CTLA4, and associations of other markers of sensitivity to immunotherapy, including TMB, immunophenoscore (IPS) analysis, and tumor immune dysfunction and exclusion (TIDE) algorithm. Conclusively, TMEscore is a promising and reliable biomarker to distinguish the prognosis, the molecular and immune characteristics, and the benefit from ICIs treatments in LUAD.

The prognoses of sarcomas are poor and the responses of them to systemic therapies are limited and controversial. Thus, there is an urgent need to stratify the risk factors and identify the patients who may benefit from systemic therapies. Here, we developed a reliable, complement-based gene signature to predict the prognosis of sarcoma patients. Survival-related complement genes were identified by univariate Cox analyses and were used to build a gene signature, which was further selected using the least absolute shrinkage and selection operator model, and determined using a stepwise Cox proportional hazards regression model. The whole sarcoma cohort of TCGA was randomly divided into a training set and a test set. The signature was constructed using the training set and validated subsequently in the test set, the whole TCGA sarcoma cohort, and another two independent cohorts from the TARGET and GEO databases, respectively. Furthermore, the prognostic value of the signature was also validated in an independent cohort from our center. This model effectively predicted prognoses across the training set, different validation cohorts, and different clinical subgroups. Next, immune cell infiltration analysis, GO and KEGG analysis, and gene set enrichment analysis were performed to explore possible underlying mechanisms of this signature. Moreover, this signature may predict the response to immunotherapy. Collectively, the current complement-related gene signature can predict overall survival and possible immunotherapy response of sarcoma patients; it may serve as a powerful prognostic tool to further optimize clinical treatment and prognosis management for sarcoma patients.

BackgroundRapid tumor growth inevitably results in energy stress, including deficiency of glutamine, a critical amino acid for tumor cell proliferation. However, whether glutamine deficiency allows tumor cells to use lipid droplets as an energy resource and the mechanism underlying this potential regulation remain unclear.MethodsWe purified lipid droplets from H322 and H358 human non-small-cell lung cancer (NSCLC) cells under glutamine deprivation conditions and performed immunoblotting to determine the binding of choline kinase (CHK) α2 to lipid droplets. Immunofluorescence was used to quantify lipid droplet numbers and sizes. Immunoprecipitation and immunoblotting were performed to examine AMPK activation and CHKα2 phosphorylation. Cellular fatty acid levels, mitochondrial acetyl coenzyme A and ATP production, and cell apoptosis and proliferation were measured. Immunohistochemical analyses were performed to determine the expression levels of ACC pS79 and CHKα2 pS279 in tumor specimens from NSCLC patients. The prognostic value of ACC pS79 and CHKα2 pS279 was assessed using the Kaplan-Meier method and Cox regression models.ResultsGlutamine deficiency induces AMPK-mediated CHKα2 S279 phosphorylation, which promotes the binding of CHKα2 to lipid droplets, resulting in recruitment of cytosolic lipase ATGL and autophagosomes and subsequent lipolysis of lipid droplets to sustain tumor cell survival and proliferation. In addition, the levels of ACC pS79 and CHKα S279 were much higher in human NSCLC specimens than in their adjacent normal tissues and positively correlated with each other. Notably, ACC pS79 and CHKα pS279 expression levels alone were associated with poor prognosis of NSCLC patients, and combined values of both phosphorylation levels were correlated with worse prognosis of the patients.ConclusionCHKα2 plays a critical role in lipolysis of lipid droplets in NSCLC. ACC pS79 and CHKα2 pS279 alone or in combination can be used as prognostic markers in NSCLC.

The Three-North Shelter Forest (TNSF) program is a significant ecological safety barrier in northern China, where both climate change and anthropogenic activity contribute to the increase in vegetation coverage observed. However, comprehensive effects of these factors on vegetation have not been accurately quantified yet. This study utilized the Global Land Surface Satellite (GLASS) Advanced Very-High-Resolution Radiometer (AVHRR) Fractional Vegetation Cover (FVC) data, meteorological data, and spatial distribution of ecological engineering to analyze spatiotemporal variation of FVC and climate in the TNSF program region in China during the period 1982–2018. A partial correlation analysis and residual analysis were performed to determine the relative contribution of climate change and anthropogenic activity to the FVC and the overall effect of ecological governance. Results showed that since 1982, the average FVC in the TNSF program region was 0.201–0.253, with an average growth rate of 0.01·(10a)−1. The FVC showed a significant increase in 66.45% of the TNSF region, and will continue to increase, while only 7.02% showed a significant decrease. The coefficient of variation showed a large spatial variation, with 30.86% being in very low stability regions, mainly distributed in Inner Mongolia and the Loess Plateau. A warm and wet climate is more conducive to increasing the FVC than the warm and dry climate, and ecological engineering has the largest impact on areas with an annual accumulated precipitation greater than 300 mm. A quantitative analysis revealed that climate change and anthropogenic activity contributed to the significant increase in the FVC in 15.58% and 46.81% of the TNSF region, respectively. Therefore, ecological governance projects, such as the TNSF program, play a crucial role in enhancing the FVC in this region.

Soccer participation among children and adolescents is low in China. To achieve a coordinated development of soccer in all regions and to promote the physical health of children and adolescents, this study aims to identify the influencing factors regarding the participation of children and adolescents in soccer programs through a cross-sectional analysis of the “soccer population” of children and adolescents. A total of 38,258 children and adolescents aged 7–18 years were included in this study. In addition, the analysis was conducted by dividing the regions where the children and adolescents live into three parts according to socioeconomic status, and by incorporating five dimensions, including environment, family, school, community, and individual levels to find the influencing factors of children and adolescents’ participation in soccer. Chi-square test, Pearson’s correlation, and one-way logistic regression analyses were used. The results showed that the area (r = 0.487) and the average annual precipitation (r = −0.367) were associated with the participation of children and adolescents in soccer programs. Moreover, the percentage of children and adolescents who participated in soccer programs (24.5%) was higher than those who liked soccer or were proficient in it (14.4%). Meanwhile, parental encouragement and support (OR = 0.627; 95% CI, 1.102–3.179), as well as the accessibility (OR = 0.558; 95% CI, 1.418–2.155), availability (OR = 1.419; 95% CI, 1.179–1.707), and safety of sports facilities (OR = 0.316; 95% CI, 0.614–0.865), influence children and adolescents’ participation in soccer programs.

Real-time polymerase chain reaction (real-time PCR) tests were successfully conducted in an aluminum-based microfluidic chip developed in this work. The reaction chamber was coated with silicone-modified epoxy resin to isolate the reaction system from metal surfaces, preventing the metal ions from interfering with the reaction process. The patterned aluminum substrate was bonded with a hydroxylated glass mask using silicone sealant at room temperature. The effect of thermal expansion was counteracted by the elasticity of cured silicone. With the heating process closely monitored, real-time PCR testing in reaction chambers proceeded smoothly, and the results show similar quantification cycle values to those of traditional test sets. Scanning electron microscope (SEM) and atomic force microscopy (AFM) images showed that the surface of the reaction chamber was smoothly coated, illustrating the promising coating and isolating properties. Energy-dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), and inductively coupled plasma-optical emission spectrometer (ICP-OES) showed that no metal ions escaped from the metal to the chip surface. Fourier-transform infrared spectroscopy (FTIR) was used to check the surface chemical state before and after tests, and the unchanged infrared absorption peaks indicated the unreacted, antifouling surface. The limit of detection (LOD) of at least two copies can be obtained in this chip.

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer with poor prognosis. Here the authors performed multi-omics analysis of human samples to investigate the mutational landscape of PSC and show three subgroups of PSC with distinct biology, prognosis and potential therapeutic strategies.

Abstract Background Lung adenocarcinomas (LUAD) is the most common histological subtype of lung cancers. Tumor immune microenvironment (TIME) is involved in tumorigeneses, progressions, and metastases. This study is aimed to develop a robust immune‐related signature of LUAD. Methods A total of 1774 LUAD cases sourced from public databases were included in this study. Immune scores were calculated through ESTIMATE algorithm and weighted gene co‐expression network analysis (WGCNA) was applied to identify immune‐related genes. Stability selections and Lasso COX regressions were implemented to construct prognostic signatures. Validations and comparisons with other immune‐related signatures were conducted in independent Gene Expression Omnibus (GEO) cohorts. Abundant infiltrated immune cells and pathway enrichment analyses were carried out, respectively, through ImmuCellAI and gene set enrichment analysis (GSEA). Results In Cancer Genome Atlas (TCGA) LUAD cohorts, immune scores of higher levels were significantly associated with better prognoses (P

As the concept of variable stiffness and variable damping (VSVD) has increasingly drawn attention, suspensions applied with magnetorheological (MR) dampers to achieve varying stiffness and damping have been an attractive method to improve vehicle performance and driver comfort further. As highly nonlinearity of MR damper dynamics and coupled interconnections in the case of multi-output control, to build a direct control system for VSVD suspension based on multiple MR dampers is difficult. Applying Takagi-Sugeno (T-S) fuzzy model on the VSVD system enables the linear control theory to be directly utilized to build the multi-output controller for multi-MR dampers. In this paper, a T-S fuzzy model is established to describe an MR VSVD suspension model, and then an H∞ controller that considers the multi-input/multi-output (MIMO) coupled interconnections characteristic and multi-object optimization is designed. To estimate state information for the T-S fuzzy model in real-time, a state observer is designed and integrated in the controller. Then, the performance of the VSVD control algorithm was evaluated by numerical simulation. The results demonstrate that the T-S fuzzy model-based H∞ controller outperforms the independent control method for a VSVD suspension system with multi-MR dampers.