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Abstract RNA methylation is an important regulatory process to determine immune cell function but how it affects the anti-tumor activity of CD8 T cells is not fully understood. Here we show that the N 6-methyladenosine (m6A) RNA reader YTHDF2 is highly expressed in early effector or effector-like CD8 T cells. We find that YTHDF2 facilitates nascent RNA synthesis, and m6A recognition is fundamental for this distinctively nuclear function of the protein, which also reinforces its autoregulation at the RNA level. Loss of YTHDF2 in T cells exacerbates tumor progression and confers unresponsiveness to PD-1 blockade in mice and in humans. In addition to initiating RNA decay that is necessary for mitochondrial fitness, YTHDF2 orchestrates chromatin changes that promote T cell polyfunctionality. YTHDF2 interacts with IKZF1/3, which is important for sustained transcription of their target genes. Accordingly, immunotherapy-induced efficacy could be largely restored in YTHDF2-deficient T cells through combinational use of IKZF1/3 inhibitor lenalidomide in a mouse model. Thus, YTHDF2 coordinates epi-transcriptional and transcriptional networks to potentiate T cell immunity, which could inform therapeutic intervention.

Abstract Egg white (EW)‐derived hydrogels hold promise as biomaterials for in vitro cell culture due to their ability to mimic the extracellular matrix. However, their highly cross‐linked structures restrict their potential for in vivo applications, as they are unable to integrate dynamically with tissues before degradation. In this study, this limitation is addressed by introducing carbon dots (CDs) as cross‐linking agents for EW in a dilute aqueous solution. The resulting CDs‐crosslinked EW hydrogel (CEWH) exhibits tensile strength comparable to that of skin tissue and features a large pore structure that promotes cell infiltration. Subcutaneous implantation of CEWH demonstrated excellent integration with surrounding tissue and a degradation rate aligned with the hair follicles (HFs) regeneration cycle. This allows the long‐term regeneration and establishment of an M2 macrophage‐dominated immune microenvironment, which in turn promotes the re‐entry of HFs into the anagen phase from the telogen phase. Additionally, CEWH demonstrated potential as a wound dressing material. Overall, this study paves the way for utilizing EW as a versatile biomaterial for tissue engineering.

Abstract Drug screening based on in-vitro primary tumor cell culture has demonstrated potential in personalized cancer diagnosis. However, the limited number of tumor cells, especially from patients with early stage cancer, has hindered the widespread application of this technique. Hence, we developed a digital microfluidic system for drug screening using primary tumor cells and established a working protocol for precision medicine. Smart control logic was developed to increase the throughput of the system and decrease its footprint to parallelly screen three drugs on a 4 × 4 cm2 chip in a device measuring 23 × 16 × 3.5 cm3. We validated this method in an MDA-MB-231 breast cancer xenograft mouse model and liver cancer specimens from patients, demonstrating tumor suppression in mice/patients treated with drugs that were screened to be effective on individual primary tumor cells. Mice treated with drugs screened on-chip as ineffective exhibited similar results to those in the control groups. The effective drug identified through on-chip screening demonstrated consistency with the absence of mutations in their related genes determined via exome sequencing of individual tumors, further validating this protocol. Therefore, this technique and system may promote advances in precision medicine for cancer treatment and, eventually, for any disease.

Abstract Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy among primary liver cancers, with an increasing overall incidence and poor prognosis. The intertumoral and intratumoral heterogeneity of ICC makes it difficult to find efficient drug therapies. Therefore, it is essential to identify tumor suppressor genes and oncogenes that induce ICC formation and progression. Here, we performed CRISPR/Cas9-mediated genome-wide screening in a liver-specific Smad4/Pten knockout mouse model (Smad4 co/co ;Pten co/co ;Alb-Cre, abbreviated as SPC), which normally generates ICC after 6 months, and detected that mutations in Trp53, Fbxw7, Inppl1, Tgfbr2, or Cul3 markedly accelerated ICC formation. To illustrate the potential mechanisms, we conducted transcriptome sequencing and found that multiple receptor tyrosine kinases were activated, which mainly upregulated the PI3K pathway to induce cell proliferation. Remarkably, the Cul3 mutation stimulated cancer progression mainly by altering the immune microenvironment, whereas other mutations promoted the cell cycle. Moreover, Fbxw7, Inppl1, Tgfbr2, and Trp53 also affect inflammatory responses, apelin signaling, mitotic spindles, ribosome biogenesis, and nucleocytoplasmic transport pathways, respectively. We further examined FDA-approved drugs for the treatment of liver cancer and performed high-throughput drug screening of the gene-mutant organoids. Different drug responses and promising drug therapies, including chemotherapy and targeted drugs, have been discovered for ICC.

Abstract Circulating tumor cells (CTCs) shed from primary tumors must overcome the cytotoxicity of immune cells, particularly natural killer (NK) cells, to cause metastasis. The tumor microenvironment (TME) protects tumor cells from the cytotoxicity of immune cells, which is partially executed by cancer‐associated mesenchymal stromal cells (MSCs). However, the mechanisms by which MSCs influence the NK resistance of CTCs remain poorly understood. This study demonstrates that MSCs enhance the NK resistance of cancer cells in a gap junction‐dependent manner, thereby promoting the survival and metastatic seeding of CTCs in immunocompromised mice. Tumor cells crosstalk with MSCs through an intercellular cGAS‐cGAMP‐STING signaling loop, leading to increased production of interferon‐β (IFNβ) by MSCs. IFNβ reversely enhances the type I IFN (IFN‐I) signaling in tumor cells and hence the expression of human leukocyte antigen class I (HLA‐I) on the cell surface, protecting the tumor cells from NK cytotoxicity. Disruption of this loop reverses NK sensitivity in tumor cells and decreases tumor metastasis. Moreover, there are positive correlations between IFN‐I signaling, HLA‐I expression, and NK tolerance in human tumor samples. Thus, the NK‐resistant signaling loop between tumor cells and MSCs may serve as a novel therapeutic target.

Abstract Intestinal cancer is one of the most frequent and lethal types of cancer. Modeling intestinal cancer using organoids has emerged in the last decade. Human intestinal cancer organoids are physiologically relevant in vitro models, which provides an unprecedented opportunity for fundamental and applied research in colorectal cancer. “Human intestinal cancer organoids” is the first set of guidelines on human intestinal organoids in China, jointly drafted and agreed by the experts from the Chinese Society for Cell Biology and its branch society: the Chinese Society for Stem Cell Research. This standard specifies terms and definitions, technical requirements, test methods for human intestinal cancer organoids, which apply to the production and quality control during the process of manufacturing and testing of human intestinal cancer organoids. It was released by the Chinese Society for Cell Biology on 24 September 2022. We hope that the publication of this standard will guide institutional establishment, acceptance and execution of proper practocal protocols, and accelerate the international standardization of human intestinal cancer organoids for clinical development and therapeutic applications.

Abstract Organoids have attracted great interest for disease modelling, drug discovery and development, and tissue growth and homeostasis investigations. However, lack of standards for quality control has become a prominent obstacle to limit their translation into clinic and other applications. “Human intestinal organoids” is the first guideline on human intestinal organoids in China, jointly drafted and agreed by the experts from the Chinese Society for Cell Biology and its branch society: the Chinese Society for Stem Cell Research. This standard specifies terms and definitions, technical requirements, test methods, inspection rules for human intestinal organoids, which is applicable to quality control during the process of manufacturing and testing of human intestinal organoids. It was originally released by the Chinese Society for Cell Biology on 24 September 2022. We hope that the publication of this standard will guide institutional establishment, acceptance and execution of proper practical protocols and accelerate the international standardization of human intestinal organoids for applications.

Abstract Clinical updates suggest conserving metastatic sentinel lymph nodes (SLNs) of breast cancer (BC) patients during surgery; however, the immunoadjuvant potential of this strategy is unknown. Here we leverage an immune-fueling flex-patch to animate metastatic SLNs with personalized antitumor immunity. The flex-patch is implanted on the postoperative wound and spatiotemporally releases immunotherapeutic anti-PD-1 antibodies (aPD-1) and adjuvants (magnesium iron-layered double hydroxide, LDH) into the SLN. Genes associated with citric acid cycle and oxidative phosphorylation are enriched in activated CD8+ T cells (CTLs) from metastatic SLNs. Delivered aPD-1 and LDH confer CTLs with upregulated glycolytic activity, promoting CTL activation and cytotoxic killing via metal cation-mediated shaping. Ultimately, CTLs in patch-driven metastatic SLNs could long-termly maintain tumor antigen-specific memory, protecting against high-incidence BC recurrence in female mice. This study indicates a clinical value of metastatic SLN in immunoadjuvant therapy.

Abstract Background Left-behind adolescents (LBAs) are adolescents aged 11–18 years who are separated from their parents and left behind in local cities by one or both parents for a period of more than 6 months. LBAs in rural areas are likely to engage in aggressive behavior, which can affect interpersonal relationships, reduce academic performance, and even lead to anxiety and depression. To our knowledge, no studies have examined the mediating effect of resilience and self-esteem on the relationship between negative life events and aggression among Chinese rural LBAs. Therefore, this study aimed to explore the relationship between negative life events and aggression among Chinese rural LBAs and how self-esteem and resilience mediate the association. Methods Using a stratified random sampling method, 1344 LBAs in Hunan Province of China were investigated. Information was collected by a self-designed sociodemographic questionnaire, Adolescent Self-Rating Life Events Checklist, Resilience Scale Chinese Adolescent, Rosenberg Self-Esteem Scale and Aggression Scales to assess the psychology of LBAs. Data analysis was conducted using descriptive statistics, Pearson correlation, and regression analysis to estimate direct and indirect effects using bootstrap analysis. Results Negative life events were significantly related to self-esteem (r = − 0.338), resilience (r = − 0.359), and aggression (r = 0.441). Aggression was directly affected by self-esteem (β = − 0.44) and resilience (β = − 0.34). Negative life events were not only directly related to aggression (β = 0.34, 95% CI: 0.275 ~ 0.398) but also showed an indirect effect on aggression through self-esteem and resilience. The direct effect, total effect and indirect effect of negative life events on aggression through self-esteem and resilience were 0.3364, 0.4344 and 0.0980, respectively. The mediating effect of self-esteem and resilience accounted for 22.56% of the relationship between negative life events and aggression. Conclusions We found that self-esteem and resilience mediated most negative life events on aggression. It is imperative for educators and families to improve LBAs’ self-esteem and resilience to reduce the occurrence of aggression. Future intervention studies should be designed to strengthen self-esteem and resilience.

Drug combination therapy is a highly effective approach for enhancing the therapeutic efficacy of anti-cancer drugs and overcoming drug resistance. However, the innumerable possible drug combinations make it impractical to screen all synergistic drug pairs. Moreover, biological insights into synergistic drug pairs are still lacking. To address this challenge, we systematically analyzed drug combination datasets curated from multiple databases to identify drug pairs more likely to show synergy. We classified drug pairs based on their MoA and discovered that 110 MoA pairs were significantly enriched in synergy in at least one type of cancer. To improve the accuracy of predicting synergistic effects of drug pairs, we developed a suite of machine learning models that achieve better predictive performance. Unlike most previous methods that were rarely validated by wet-lab experiments, our models were validated using two-dimensional cell lines and three-dimensional tumor slice culture (3D-TSC) models, implying their practical utility. Our prediction and validation results indicated that the combination of the RTK inhibitors Lapatinib and Pazopanib exhibited a strong therapeutic effect in breast cancer by blocking the downstream PI3K/AKT/mTOR signaling pathway. Furthermore, we incorporated molecular features to identify potential biomarkers for synergistic drug pairs, and almost all potential biomarkers found connections between drug targets and corresponding molecular features using protein-protein interaction network. Overall, this study provides valuable insights to complement and guide rational efforts to develop drug combination treatments.

Abstract Efficient red emissive carbon dots (CDs) in aqueous solutions are very scarce for high performance bioimaging applications. In this work, we report a one-step solvothermal treatment to synthesize pure red emissive CDs (FA-CDs) from citric acid and urea in formic acid without complicated purification procedures. Photoluminescence quantum yield (PLQY) of 43.4% was observed in their dimethyl sulfoxide solutions. High PLQY up to 21.9% in aqueous solutions was achieved in their bovine serum albumin (BSA) composites (FA-CDs@BSA) with significantly enhanced multi-photon fluorescence. The strong surface electron-withdrawing structure of FA-CDs caused by the high content of C = O groups contributes for their pure red emission. Owing to the significantly enhanced single and multi-photon red fluorescence and enlarged particle sizes after composing with BSA, in vivo tumor imaging and two-photon fluorescence imaging of blood vessels in mouse ear have been realized via intravenous injection of FA-CDs@BSA aqueous solutions.

Egg white (EW)‐derived hydrogels hold promise as biomaterials for in vitro cell culture due to their ability to mimic the extracellular matrix. However, their highly cross‐linked structures restrict their potential for in vivo applications, as they are unable to integrate dynamically with tissues before degradation. In this study, this limitation is addressed by introducing carbon dots (CDs) as cross‐linking agents for EW in a dilute aqueous solution. The resulting CDs‐crosslinked EW hydrogel (CEWH) exhibits tensile strength comparable to that of skin tissue and features a large pore structure that promotes cell infiltration. Subcutaneous implantation of CEWH demonstrated excellent integration with surrounding tissue and a degradation rate aligned with the hair follicles (HFs) regeneration cycle. This allows the long‐term regeneration and establishment of an M2 macrophage‐dominated immune microenvironment, which in turn promotes the re‐entry of HFs into the anagen phase from the telogen phase. Additionally, CEWH demonstrated potential as a wound dressing material. Overall, this study paves the way for utilizing EW as a versatile biomaterial for tissue engineering. [ABSTRACT FROM AUTHOR]

Fragile X mental retardation protein (FMRP), an RNA binding protein (RBP), is aberrantly hyper‐expressed in human tumors and plays an essential role in tumor invasion, metastasis and immune evasion. However, there is no small‐molecule inhibitor for FMRP so far. In this study, we developed the first FMRP‐targeting degrader based on PROteolysis TArgeting Chimera (PROTAC) technology and constructed a heterobifunctional PROTAC through linking a FMRP‐targeting G‐quadruplex RNA (sc1) to a von Hippel‐Lindau (VHL)‐targeting ligand peptide (named as sc1‐VHLL). Sc1‐VHLL specifically degraded endogenous FMRP via ubiquitination pathway in both mouse and human cancer cells. The FMRP degradation significantly changed the secretion pattern of cancer cells, resulting in higher expression of pro‐inflammatory cytokine and smaller amounts of immunomodulatory contents. Furthermore, sc1‐VHLL, when encapsulated into ionizable liposome nanoparticles (LNP), efficiently targeted tumor site and degraded FMRP in cancer cells. In CT26 tumor‐bearing mouse model, FMRP degradation within tumors substantially promoted the infiltration of lymphocytes and CD8 T cells and reduced the proportion of Treg cells, reshaping the proinflammatory tumor microenvironment and accordingly transforming cold tumor into hot tumor. When combined with immune checkpoint blockade (ICB) therapy, sc1‐VHLL based treatment remarkably inhibited the tumor growth. [ABSTRACT FROM AUTHOR]

Background: Co-exposure to multiple volatile organic compounds (VOCs) is common in daily life. However, few studies have evaluated the associations between the patterns of simultaneous exposure to multiple VOCs and the risk of hyperuricemia. Methods: This study included 7490 adults from the National Health and Nutrition Examination Survey conducted between 2003 and 2012. The K-means clustering method was applied to cluster eight kinds of VOCs in the blood into various co-exposure patterns, including benzene, bromodichloromethane, chloroform, dibromochloromethane, 1,4-dichlorobenzene, ethylbenzene, methyl tertiary-butyl ether (MTBE), and o-xylene. Binary logistic regression analysis was utilized to assess the association between single VOCs, the co-exposure patterns of multiple VOCs, and the hyperuricemia risk. Restricted cubic spline functions were utilized to investigate the non-linear relationships. Results: Based on eight VOCs, four characteristic co-exposure patterns were generated. Compared with the low-level exposure group, the levels of volatile organic compound (VOC) co-exposure in cluster 2, characterized by relatively high levels of MTBE and moderate levels of bromodichloromethane, chloroform, and dibromochloromethane, were associated with increased hyperuricemia risk, with an odds ratio of 1.32 (1.02, 1.71). Increasing levels of bromodichloromethane and chloroform were significantly associated with an increased risk of hyperuricemia. A strong J-shaped relationship was found between MTBE and hyperuricemia. Conclusions: This study indicated that blood bromodichloromethane and chloroform were positively associated with hyperuricemia risk. Blood MTBE had a J-shaped association with hyperuricemia. In addition, the significant association of the co-exposure patterns of multiple VOCs in the blood with hyperuricemia risk was observed. Changing VOC co-exposure patterns may play a crucial role in the occurrence of hyperuricemia. [ABSTRACT FROM AUTHOR]

Conventional techniques for in vitro cancer drug screening require labor-intensive formalin fixation, paraffin embedding, and dye staining of tumor tissues at fixed endpoints. This way of assessment discards the valuable pharmacodynamic information in live cells over time. Here, we found endogenous lipofuscin-like autofluorescence acutely accumulated in the cell death process. Its unique red autofluorescence could report the apoptosis without labeling and continuously monitor the treatment responses in 3D tumor-culture models. Lifetime imaging of lipofuscin-like red autofluorescence could further distinguish necrosis from apoptosis of cells. Moreover, this endogenous fluorescent marker could visualize the apoptosis in live zebrafish embryos during development. Overall, this study validates that lipofuscin-like autofluorophore is a generic cell death marker. Its characteristic autofluorescence could label-free predict the efficacy of anti-cancer drugs in organoids or animal models.

Abstract Rapid, efficient, and precise cancer therapy is highly desired. Here, this work reports solvothermally synthesized photoactivatable Pt(IV)‐coordinated carbon dots (Pt‐CDs) and their bovine serum albumin (BSA) complex (Pt‐CDs@BSA) as a novel orange light‐triggered anti‐tumor therapeutic agent. The homogeneously distributed Pt(IV) in the Pt‐CDs (Pt: 17.2 wt%) and their carbon cores with significant visible absorption exhibit excellent photocatalytic properties, which not only efficiently releases cytotoxic Pt(II) species but also promotes hydroxy radical generation from water under orange light. When triggered with a 589 nm laser, Pt‐CDs@BSA possesses the ultrastrong cancer cell killing capacities of intracellular Pt(II) species release, hydroxyl radical generation, and acidification, which induce powerful immunogenic cell death. Activation of Pt‐CDs@BSA by a single treatment with a 589 nm laser effectively eliminated the primary tumor and inhibited distant tumor growth and lung metastasis. This study thus presents a new concept for building photoactivatable Pt(IV)‐enriched nanodrug‐based CDs for precision cancer therapy.