Metronomic chemotherapy in cancer treatment: new wine in an old bottle.

Over the past two decades, metronomic chemotherapy has gained considerable attention and has demonstrated remarkable success in the treatment of cancer. Through chronic administration and low-dose regimens, metronomic chemotherapy is associated with fewer adverse events but still effectively induces disease control. The identification of its antiangiogenic properties, direct impact on cancer cells, immunomodulatory effects on the tumour microenvironment, and metabolic reprogramming ability has established the intrinsic multitargeted nature of this therapeutic approach. Recently, the utilization of metronomic chemotherapy has evolved from salvage treatment for metastatic disease to adjuvant maintenance therapy for high-risk cancer patients, which has been prompted by the success of several substantial phase III trials. In this review, we delve into the mechanisms underlying the antitumour effects of metronomic chemotherapy and provide insights into potential combinations with other therapies for the treatment of various malignancies. Additionally, we discuss health-economic advantages and candidates for the utilization of this treatment option.

Molecular effects of indoor tanning.

Background: Tanning bed users have a significantly increased risk of melanoma, but it remains unclear how indoor tanning drives melanomagenesis. Tanning bed radiation is often thought of as a substitute for natural UV radiation despite differences in the maximum doses, UV content, body sites exposed, and patterns of melanoma that arise. Methods: To better understand the epidemiologic trends and etiology of melanoma associated with tanning bed use, we described the patterns of melanoma in patients with quantifiable tanning bed usage and performed exome sequencing of 182 melanocytes from normal skin of a subset of these patients. Results: Tanning bed users were more likely than non-users to have melanoma on body sites with low cumulative levels of sun damage and were more likely to have multiple melanomas. The melanocytes in normal appearing skin from tanning bed users had higher mutation burdens, a higher proportion of melanocytes with pathogenic mutations, and distinct mutational signatures. These differences were most prominent over body sites that experience comparatively less exposure to natural sunlight. Conclusions: We conclude that tanning bed radiation induces melanoma by increasing the mutation burden of melanocytes and by mutagenizing a broader field of melanocytes than are typically exposed to natural sunlight. The unique signatures of mutations in skin cells of tanning users may be attributable to the distinct spectra of radiation emitted from solariums.

Clinicopathological characteristics and genomic profiling of pure mucinous breast cancer.

PURPOSE: Pure mucinous breast cancer (PMC) is a rare histological type with a favourable prognosis. However, cases with recurrence have been reported and diagnosed in clinical practice. The mechanisms underlying PMC recurrence remain unknown. In this study, we aimed to identify the prognostic factors associated with PMC. MATERIALS AND METHODS: A total of 166 patients diagnosed with PMC were included. We compared the clinicopathological characteristics between patients with and without recurrence. The 21-gene assay was performed in 10 patients with recurrence and 20 TNM stage-matched patients without recurrence. Whole-exon sequencing was performed in 12 PMC primary tumours and four positive lymph nodes (LNs). RESULTS: Tumour size, lymph node status and TNM staging differed significantly between recurrent group and non-recurrent group. And the 21-gene recurrence scores did not differ significantly between recurrent group and its TNM stage-matched non-recurrent group. The most frequently mutated genes in the primary tumours of regional LN-positive PMCs were ADCY10 (3/6) and SHANK3 (3/6), and they more recurrently harboured gains of 15q23, 17q23.2 and 20p11.21, and loss of 21p11.2. And these alterations were not detected in primary tumours of regional LN-negative PMCs. CONCLUSION: TNM stage is an important prognostic factor in PMC. Although we revealed that regional LN-positive PMCs show increased occurrence of duplication variants at 15q23, 17q23.2 and 20p11.21, and deletion variants at 21p11.2. Further investigation, including multi-omics studies, are needed and may provide additional insights into the nature of PMC.

Precise and automated lung cancer cell classification using deep neural network with multiscale features and model distillation.

Lung diseases globally impose a significant pathological burden and mortality rate, particularly the differential diagnosis between adenocarcinoma, squamous cell carcinoma, and small cell lung carcinoma, which is paramount in determining optimal treatment strategies and improving clinical prognoses. Faced with the challenge of improving diagnostic precision and stability, this study has developed an innovative deep learning-based model. This model employs a Feature Pyramid Network (FPN) and Squeeze-and-Excitation (SE) modules combined with a Residual Network (ResNet18), to enhance the processing capabilities for complex images and conduct multi-scale analysis of each channel's importance in classifying lung cancer. Moreover, the performance of the model is further enhanced by employing knowledge distillation from larger teacher models to more compact student models. Subjected to rigorous five-fold cross-validation, our model outperforms existing models on all performance metrics, exhibiting exceptional diagnostic accuracy. Ablation studies on various model components have verified that each addition effectively improves model performance, achieving an average accuracy of 98.84% and a Matthews Correlation Coefficient (MCC) of 98.83%. Collectively, the results indicate that our model significantly improves the accuracy of disease diagnosis, providing physicians with more precise clinical decision-making support.

PLAU, transcriptionally negatively regulated by GATA6, promotes lung squamous carcinoma cell proliferation and migration.

BACKGROUND: Lung squamous cell carcinoma (LUSC) is associated with high mortality and has limited therapeutic treatment options. Plasminogen activator urokinase (PLAU) plays important roles in tumor cell malignancy. However, the oncogenic role of PLAU in the progression of LUSC remains unknown. GATA-binding factor 6 (GATA6), a key regulator of lung development, inhibits LUSC cell proliferation and migration, but the underlying regulatory mechanism remains to be further explored. Moreover, the regulatory effect of GATA6 on PLAU expression has not been reported. The aim of this study was to identify the role of PLAU and the transcriptional inhibition mechanism of GATA6 on PLAU expression in LUSC. METHODS: To identify the potential target genes regulated by GATA6, differentially expressed genes (DEGs) obtained from GEO datasets analysis and RNA-seq experiment were subjected to Venn analysis and correlation heatmap analysis. The transcriptional regulatory effects of GATA6 on PLAU expression were detected by real-time PCR, immunoblotting, and dual-luciferase reporter assays. The oncogenic effects of PLAU on LUSC cell proliferation and migration were evaluated by EdU incorporation, Matrigel 3D culture and Transwell assays. PLAU expression was detected in tissue microarray of LUSC via immunohistochemistry (IHC) assay. To determine prognostic factors for prognosis of LUSC patients, the clinicopathological characteristics and PLAU expression were subjected to univariate Cox regression analysis. RESULTS: PLAU overexpression promoted LUSC cell proliferation and migration. PLAU is overexpressed in LUSC tissues compared with normal tissues. Consistently, high PLAU expression, which acts as an independent risk factor, is associated with poor prognosis of LUSC patients. Furthermore, the expression of PLAU is transcriptionally regulated by GATA6. CONCLUSION: In this work, it was revealed that PLAU is a novel oncogene for LUSC and a new molecular regulatory mechanism of GATA6 in LUSC was unveiled. Targeting the GATA6/PLAU pathway might help in the development of novel therapeutic treatment strategies for LUSC.

Bortezomib restrains M2 polarization and reduces CXCL16-associated CXCR6+CD4 T cell chemotaxis in bleomycin-induced pulmonary fibrosis.

BACKGROUND: The development of pulmonary fibrosis involves a cascade of events, in which inflammation mediated by immune cells plays a pivotal role. Chemotherapeutic drugs have been shown to have dual effects on fibrosis, with bleomycin exacerbating pulmonary fibrosis and bortezomib alleviating tissue fibrotic processes. Understanding the intricate interplay between chemotherapeutic drugs, immune responses, and pulmonary fibrosis is likely to serve as the foundation for crafting tailored therapeutic strategies. METHODS: A model of bleomycin-induced pulmonary fibrosis was established, followed by treatment with bortezomib. Tissue samples were collected for analysis of immune cell subsets and functional assessment by flow cytometry and in vitro cell experiments. Additionally, multi-omics analysis was conducted to further elucidate the expression of chemokines and chemokine receptors, as well as the characteristics of cell populations. RESULTS: Here, we observed that the expression of CXCL16 and CXCR6 was elevated in the lung tissue of a pulmonary fibrosis model. In the context of pulmonary fibrosis or TGF-ß1 stimulation in vitro, macrophages exhibited an M2-polarized phenotype and secreted more CXCL16 than those of the control group. Moreover, flow cytometry revealed increased expression levels of CD69 and CXCR6 in pulmonary CD4 T cells during fibrosis progression. The administration of bortezomib alleviated bleomycin-induced pulmonary fibrosis, accompanied by reduced ratio of M2-polarized macrophages and decreased accumulation of CD4 T cells expressing CXCR6. CONCLUSIONS: Our findings provide insights into the key immune players involved in bleomycin-induced pulmonary fibrosis and offer preclinical evidence supporting the repurposing strategy and combination approaches to reduce lung fibrosis.

Se-methylselenocysteine inhibits the progression of non-small cell lung cancer via ROS-mediated NF-κB signaling pathway.

Se-methylselenocysteine (MSC) is recognized for its potential in cancer prevention, yet the specific effects and underlying processes it initiates within non-small cell lung cancer (NSCLC) remain to be fully delineated. Employing a comprehensive array of assays, including CCK-8, colony formation, flow cytometry, MitoSOX Red staining, wound healing, transwell, and TUNEL staining, we evaluated MSC's effects on A549 and 95D cell lines. Our investigation extended to the ROS-mediated NF-κB signaling pathway, utilizing Western blot analysis, P65 overexpression, and the application of IκB-α inhibitor (BAY11-7082) or N-acetyl-cysteine (NAC) to elucidate MSC's mechanism of action. In vivo studies involving subcutaneous xenografts in mice further confirmed MSC's inhibitory effect on tumor growth. Our findings indicated that MSC inhibited the proliferation of A549 and 95D cells, arresting cell cycle G0/G1 phase and reducing migration and invasion, while also inducing apoptosis and increasing intracellular ROS levels. This was accompanied by modulation of key proteins, including the upregulation of p21, p53, E-cadherin, Bax, cleaved caspase-3, cleaved-PARP, and downregulation of CDK4, SOD2, GPX-1. MSC was found to inhibit the NF-κB pathway, as evidenced by decreased levels of P-P65 and P-IκBα. Notably, overexpression of P65 and modulation of ROS levels with NAC could attenuate MSC's effects on cellular proliferation and metastasis. Moreover, MSC significantly curtailed tumor growth in vivo and disrupted the NF-κB signaling pathway. In conclusion, our research demonstrates that MSC exhibits anticancer effects against NSCLC by modulating the ROS/NF-κB signaling pathway, suggesting its potential as a therapeutic agent in NSCLC treatment.

Autophagy-related protein 5 (ATG5) interacts with bone marrow stromal cell antigen 2 (BST2) to stimulate HBV replication through antagonizing the antiviral activity of BST2.

Hepatitis B virus (HBV) infection is a major global health burden with 820 000 deaths per year. In our previous study, we found that the knockdown of autophagy-related protein 5 (ATG5) significantly upregulated the interferon-stimulated genes (ISGs) expression to exert the anti-HCV effect. However, the regulation of ATG5 on HBV replication and its underlying mechanism remains unclear. In this study, we screened the altered expression of type I interferon (IFN-I) pathway genes using RT² Profiler™ PCR array following ATG5 knock-down and we found the bone marrow stromal cell antigen 2 (BST2) expression was significantly increased. We then verified the upregulation of BST2 by ATG5 knockdown using RT-qPCR and found that the knockdown of ATG5 activated the Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway. ATG5 knockdown or BST2 overexpression decreased Hepatitis B core Antigen (HBcAg) protein, HBV DNA levels in cells and supernatants of HepAD38 and HBV-infected NTCP-HepG2. Knockdown of BST2 abrogated the anti-HBV effect of ATG5 knockdown. Furthermore, we found that ATG5 interacted with BST2, and further formed a ternary complex together with HBV-X (HBx). In conclusion, our finding indicates that ATG5 promotes HBV replication through decreasing BST2 expression and interacting with it directly to antagonize its antiviral function.

A retrospective study of combination therapy with glucocorticoids and pirfenidone for PD-1 inhibitor-related immune pneumonitis.

Immune checkpoint inhibitor pneumonitis (ICIP) is thought to be a self-limiting disease; however, an effective treatment option does not currently exist. This study aimed to determine the clinical efficacy of combination therapy with glucocorticoids and pirfenidone for ICIP related to programmed cell death protein-1 (PD-1) inhibitors. We conducted a retrospective analysis of 45 patients with advanced non-small cell lung cancer who developed ICIP following PD-1 inhibitor and albumin-bound paclitaxel or carboplatin treatment at our hospital. The PD-1 inhibitor was discontinued, and glucocorticoids were used alone or in combination with pirfenidone to treat ICIP. The relevant clinical data of these patients were collected and analyzed. Compared with the glucocorticoid alone group, the glucocorticoid-pirfenidone group showed significant improvement in forced vital capacity (FVC), carbon monoxide diffusing capacity [%], peripheral capillary oxygen saturation, and 6-minute walk distance (P < .05). There were benefits with respect to the St. George's Respiratory Questionnaire score and the recurrence rate of ICIP, but there was no significant difference between the 2 groups (P > .05). Adding pirfenidone to glucocorticoid treatment was shown to be safe and may be more beneficial than glucocorticoids alone for improving pulmonary interstitial lesions, reversing ICIP, and preventing its recurrence.

Construction of a prognostic model based on memory CD4+ T cell-associated genes for lung adenocarcinoma and its applications in immunotherapy.

The association between memory CD4+ T cells and cancer prognosis is increasingly recognized, but their impact on lung adenocarcinoma (LUAD) prognosis remains unclear. In this study, using the cell-type identification by estimating relative subsets of RNA transcripts algorithm, we analyzed immune cell composition and patient survival in LUAD. Weighted gene coexpression network analysis helped identify memory CD4+ T cell-associated gene modules. Combined with module genes, a five-gene LUAD prognostic risk model (HOXB7, MELTF, ABCC2, GNPNAT1, and LDHA) was constructed by regression analysis. The model was validated using the GSE31210 data set. The validation results demonstrated excellent predictive performance of the risk scoring model. Correlation analysis was conducted between the clinical information and risk scores of LUAD samples, revealing that LUAD patients with disease progression exhibited higher risk scores. Furthermore, univariate and multivariate regression analyses demonstrated the model independent prognostic capability. The constructed nomogram results demonstrated that the predictive performance of the nomogram was superior to the prognostic model and outperformed individual clinical factors. Immune landscape assessment was performed to compare different risk score groups. The results revealed a better prognosis in the low-risk group with higher immune infiltration. The low-risk group also showed potential benefits from immunotherapy. Our study proposes a memory CD4+ T cell-associated gene risk model as a reliable prognostic biomarker for personalized treatment in LUAD patients.

Phenylspirodrimane with Moderate Reversal Effect of Multidrug Resistance Isolated from the Deep-Sea Fungus Stachybotrys sp. 3A00409.

Two new phenylspirodrimanes, stachybotrins K and L (1 and 2), together with eight known analogues (3-10), were isolated from deep-sea-derived Stachybotrys sp. MCCC 3A00409. Their structures were determined by extensive NMR data and mass spectroscopic analysis. Absolute configurations of new compounds were determined through a comparison of their circular dichroism (CD) spectra with other reported compounds. The possible reversal effects of all compounds were assayed in the resistant cancer cell lines. Stachybotrysin B (8) can reverse multidrug resistance (MDR) in ABCB1-overexpression cells (KBv200, Hela/VCR) at the non-cytotoxic concentration. Doxorubicin accumulation assay and molecular-docking analysis reveal that the mechanism of its reversal MDR effect may be related to the increase in the intracellular concentration of substrate anticancer drugs.

Investigation of catalytic methane oxidation over Ag/Co2MOx (M = Co, Ni, Cu) catalysts with varying interfacial electron transfer.

Atom-doped Co3O4 catalysts loaded with Ag were examined as cost-effective catalysts for methane oxidation. The synthesized Ag/Co2NiOx catalysts exhibited distinctive surface characteristics in contrast with Ag/Co3O4 and Ag/Co2CuOx catalysts prepared using a similar method. Characterization results unveiled that Ag/Co2NiOx featured a higher presence of active surface oxygen species, lattice defects, a larger surface area, and enhanced reducibility. A methane oxidation catalytic performance followed the sequence: Ag/Co2NiOx > Ag/Co3O4 > Ag/Co2CuOx. The investigation delved into methane degradation pathways on the surfaces of three catalysts, examining their behavior under both aerobic and anaerobic atmospheres through in-situ DRIFTS analysis. Furthermore, introducing Ag showed a marked positive effect on Co-Ni mixed oxide, inducing electron transfer and a more active electron system, whereas it exhibited an inverse impact within the surface of Co-Cu mixed oxide. This work provides innovative perspectives on the development of forthcoming environmental catalysts.

Two-Hour Nicotine Withdrawal Improves Inhibitory Control Dysfunction in Male Smokers: Evidence from a Smoking-Cued Go/No-Go Task ERP Study.

Purpose: Nicotine withdrawal is a multifaceted physiological and psychological process that can induce a spectrum of mood disturbances. Gaining a more nuanced understanding of how pure nicotine withdrawal influences cognitive control functions may provide valuable insights for the enhancement of smoking cessation programs. This study investigated changes in inhibitory control function in smokers after 2-hour nicotine withdrawal using the event-related potential (ERP) technique. Participants and Methods: 28 nicotine dependence (ND) patients and 28 health controls (HCs) completed a smoking-cued Go/No-go task containing two different types of picture stimuli, smoking-cued and neutral picture stimuli. We analyzed the behavioral and ERP data using a mixed model Repeated Measure Analysis of Variance (ANOVA). Results: No-go trials accuracy rate (ACC) at baseline (time 1) was lower in the ND group compared to HCs with smoking-cued stimuli, and No-go trials ACC after 2-hour nicotine withdrawal (time 2) was not lower in the ND group compared to HCs. When confronted with smoking-cued stimuli, the No-go trials ACC was higher in time 2 than in time 1 in the ND group. For the ERP component, the No-go N2 amplitudes in the ND group with smoking-cued stimuli were lower than that of HCs, whereas after 2-hour nicotine withdrawal, the ND group's No-go N2 amplitudes higher than that at time 1, and did not differ from that of HCs. No-go P3 amplitudes were not significantly different between the two groups. Conclusion: Evidenced from ERP data, ND patients have an inhibitory control dysfunction in the face of smoking cues, which is mainly manifested in the early stage of response inhibition rather than in the late stage. Two-hour nicotine withdrawal improves inhibitory control dysfunction in ND patients. The No-go N2 component is an important and sensitive neuroelectrophysiological indicator of inhibitory control function in ND patients.

CircDCBLD2 alleviates liver fibrosis by regulating ferroptosis via facilitating STUB1-mediated PARK7 ubiquitination degradation.

BACKGROUND: Liver fibrosis can progress to cirrhosis and hepatic carcinoma without treatment. CircDCBLD2 was found to be downregulated in liver fibrosis. However, the precise underlying mechanism requires further investigation. METHODS: qRT-PCR, Western blot, and immunohistochemistry assays were used to detect the related molecule levels. HE, Masson's trichrome, and Sirius Red staining were used to assess the pathological changes in mice's liver tissues. Flow cytometric analysis and commercial kit were used to assess the levels of lipid reactive oxygen species (ROS), malonaldehyde (MDA), glutathione (GSH), and iron. Cell viability was assessed by MTT. Immunoprecipitation was used to study the ubiquitination of PARK7. Mitophagy was determined by immunostaining and confocal imaging. RIP and Co-IP assays were used to assess the interactions of circDCBLD2/HuR, HuR/STUB1, and STUB1/PARK7. Fluorescence in situ hybridization and immunofluorescence staining were used to assess the co-localization of circDCBLD2 and HuR. RESULTS: CircDCBLD2 was downregulated, whereas PARK7 was upregulated in liver fibrosis. Ferroptosis activators increased circDCBLD2 while decreasing PARK7 in hepatic stellate cells (HSCs) and mice with liver fibrosis. CircDCBLD2 overexpression reduced cell viability and GSH, PARK7, and GPX4 expression in erastin-treated HSCs while increasing MDA and iron levels, whereas circDCBLD2 knockdown had the opposite effect. CircDCBLD2 overexpression increased STUB1-mediated PARK7 ubiquitination by promoting HuR-STUB1 binding and thus increasing STUB1 mRNA stability. PARK7 overexpression or HuR knockdown reversed the effects of circDCBLD2 overexpression on HSC activation and ferroptosis. CircDCBLD2 reduced liver fibrosis in mice by inhibiting PARK7. CONCLUSION: CircDCBLD2 overexpression increased PARK7 ubiquitination degradation by upregulating STUB1 through its interaction with HuR, inhibiting HSC activation and promoting HSC ferroptosis, ultimately enhancing liver fibrosis.

Comprehensive Characterization of the C3HC4 RING Finger Gene Family in Potato (Solanum tuberosum L.): Insights into Their Involvement in Anthocyanin Biosynthesis.

The C3HC4 RING finger gene (RING-HC) family is a zinc finger protein crucial to plant growth. However, there have been no studies on the RING-HC gene family in potato. In this study, 77 putative StRING-HCs were identified in the potato genome and grouped into three clusters based on phylogenetic relationships, the chromosome distribution, gene structure, conserved motif, gene duplication events, and synteny relationships, and cis-acting elements were systematically analyzed. By analyzing RNA-seq data of potato cultivars, the candidate StRING-HC genes that might participate in tissue development, abiotic stress, especially drought stress, and anthocyanin biosynthesis were further determined. Finally, a StRING-HC gene (Soltu.DM.09G017280 annotated as StRNF4-like), which was highly expressed in pigmented potato tubers was focused on. StRNF4-like localized in the nucleus, and Y2H assays showed that it could interact with the anthocyanin-regulating transcription factors (TFs) StbHLH1 of potato tubers, which is localized in the nucleus and membrane. Transient assays showed that StRNF4-like repressed anthocyanin accumulation in the leaves of Nicotiana tabacum and Nicotiana benthamiana by directly suppressing the activity of the dihydroflavonol reductase (DFR) promoter activated by StAN1 and StbHLH1. The results suggest that StRNF4-like might repress anthocyanin accumulation in potato tubers by interacting with StbHLH1. Our comprehensive analysis of the potato StRING-HCs family contributes valuable knowledge to the understanding of their functions in potato development, abiotic stress, hormone signaling, and anthocyanin biosynthesis.

Role of Exosomal Modulation of Macrophages in Liver Fibrosis.

Exosomes are 60-120 nm diameter double-membrane lipid organelles discharged by cells. Various studies have shown that exosomes exert multiple functions in both physical and diseased processes, such as intercellular information exchange, immune response, and disease progression. Repeated chronic injury to the liver often leads to inflammation and liver fibrosis (LF), a disorder that, if unchecked, may progress to cirrhosis, liver failure, portal hypertension, and even hepatocellular carcinoma. As an essential component of host innate immunity against pathogen invasion, macrophages play an important role in modulating inflammation homeostasis by finely tuning the polarization process of macrophages into either M1 or M2 subtypes in response to different microenvironments. As a critical contributor to the inflammation process, macrophages also play a complex and instrumental function in the progression of LF. This review focuses on recent advancements in the role of macrophage-associated exosomes implicated in LF, including macrophage-released exosomes and macrophage-targeted exosomes. In addition, the progress made in exosome-based antifibrotic therapy by in vivo and in vitro studies is also highlighted.

Enantiomer-Dependent Supramolecular Immunosuppressive Modulation for Tissue Reconstruction.

Modulating the properties of biomaterials in terms of the host immune response is critical for tissue repair and regeneration. However, it is unclear how the preference for the cellular microenvironment manipulates the chiral immune responses under physiological or pathological conditions. Here, we reported that in vivo and in vitro oligopeptide immunosuppressive modulation was achieved by manipulation of macrophage polarization using chiral tetrapeptide (Ac-FFFK-OH, marked as FFFK) supramolecular polymers. The results suggested that chiral FFFK nanofibers can serve as a defense mechanism in the restoration of tissue homeostasis by upregulating macrophage M2 polarization via the Src-STAT6 axis. More importantly, transiently acting STAT6, insufficient to induce a sustained polarization program, then passes the baton to EGR2, thereby continuously maintaining the M2 polarization program. It is worth noting that the L-chirality exhibits a more potent effect in inducing macrophage M2 polarization than does the D-chirality, leading to enhanced tissue reconstruction. These findings elucidate the crucial molecular signals that mediate chirality-dependent supramolecular immunosuppression in damaged tissues while also providing an effective chiral supramolecular strategy for regulating macrophage M2 polarization and promoting tissue injury repair based on the self-assembling chiral peptide design.

A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma.

To better understand intrinsic resistance to immune checkpoint blockade (ICB), we established a comprehensive view of the cellular architecture of the treatment-naive melanoma ecosystem and studied its evolution under ICB. Using single-cell, spatial multi-omics, we showed that the tumor microenvironment promotes the emergence of a complex melanoma transcriptomic landscape. Melanoma cells harboring a mesenchymal-like (MES) state, a population known to confer resistance to targeted therapy, were significantly enriched in early on-treatment biopsies from non-responders to ICB. TCF4 serves as the hub of this landscape by being a master regulator of the MES signature and a suppressor of the melanocytic and antigen presentation transcriptional programs. Targeting TCF4 genetically or pharmacologically, using a bromodomain inhibitor, increased immunogenicity and sensitivity of MES cells to ICB and targeted therapy. We thereby uncovered a TCF4-dependent regulatory network that orchestrates multiple transcriptional programs and contributes to resistance to both targeted therapy and ICB in melanoma.

Cobalt catalyzed ethane dehydrogenation to ethylene with CO2: Relationships between cobalt species and reaction pathways.

TiO2, ZrO2 and a series of TiO2-ZrO2 (TxZ1, x means the atomic ratio of Ti/Zr = 10, 5, 1, 0.2 and 0.1) composite oxide supports were prepared through co-precipitation, and then 3 wt% Co was loaded through wetness impregnation methods. The obtained 3 wt% Co/TiO2 (3CT), 3 wt% Co/ZrO2 (3CZ) and 3 wt% Co/TxZ1 (3CTxZ1) catalysts were evaluated for the oxidative ethane dehydrogenation reaction with CO2 (CO2-ODHE) as a soft oxidant. 3CT1Z1 catalyst exhibits excellent catalytic properties, with C2H4 yield, C2H6 conversion and CO2 conversion about 24.5 %, 33.8 % and 18.0 % at 650 °C, respectively. X-Ray Diffraction (XRD), in-situ Raman, UV-vis diffuse reflectance spectra (UV-vis DRS), H2 temperature-programmed reduction (H2-TPR), Electron paramagnetic resonance (EPR) and quasi in-situ X-ray Photoelectron Spectroscopy (XPS) have been utilized to thoroughly characterize the investigated catalysts. The results revealed that 3CT1Z1 produced TiZrO4 solid solution with more metal defect sites and oxygen vacancies (Ov), promoting the formation of Co2+-TiZrO4 structure. Furthermore, the presence of Ov and Ti3+can facilitate the high dispersion and stabilization of Co2+, as well as suppressing the severe reduction of Co2+, leading to superior ethane oxidative dehydrogenation activity. Besides, less Co0 is beneficial to ODHE reaction, because of its promotion effects for reverse water gas shift reaction; however, more Co0 results in dry reforming reaction (DRE). This work will shed new lights for the design and preparation of highly efficient catalysts for ethylene production.

Thymopentin plays a key role in restoring the function of macrophages to alleviate the sepsis process.

Immune dysfunction is one of the leading causes of death of sepsis. How to regulate host immune functions to improve prognoses of septic patients has always been a clinical focus. Here we elaborate on the efficacy and potential mechanism of a classical drug, thymopentin (TP5). TP5 could decrease peritoneal bacterial load, and reduce inflammatory cytokine levels both in the peritoneal lavage fluid (PLF) and serum, alleviate pathological injuries in tissue and organ, coaxed by cecal ligation and perforation (CLP) in mice, ultimately improve the prognosis of septic mice. Regarding the mechanism, using RNA-seq and flow cytometry, we found that TP5 induced peptidoglycan recognition protein 1 (PGLYRP1) expression, increased phagocytosis and restored TNF-α expression of small peritoneal macrophage (SPM) in the septic mice. This may be increased SPM's ability to clear peritoneal bacteria, thereby attenuates the inflammatory response both in the peritoneal cavity and the serum. It was shown that TP5 plays a key role in restoring the function of peritoneal macrophages to alleviate the sepsis process. We reckon that this is closely relevant to SPM phagocytosis, which might involve increased PGLYRP1 expression and restored TNF-α secretion.