A chest CT-based nomogram for predicting survival in acute myeloid leukemia.

BACKGROUND: The identification of survival predictors is crucial for early intervention to improve outcome in acute myeloid leukemia (AML). This study aim to identify chest computed tomography (CT)-derived features to predict prognosis for acute myeloid leukemia (AML). METHODS: 952 patients with pathologically-confirmed AML were retrospectively enrolled between 2010 and 2020. CT-derived features (including body composition and subcutaneous fat features), were obtained from the initial chest CT images and were used to build models to predict the prognosis. A CT-derived MSF nomogram was constructed using multivariate Cox regression incorporating CT-based features. The performance of the prediction models was assessed with discrimination, calibration, decision curves and improvements. RESULTS: Three CT-derived features, including myosarcopenia, spleen_CTV, and SF_CTV (MSF) were identified as the independent predictors for prognosis in AML (P < 0.01). A CT-MSF nomogram showed a performance with AUCs of 0.717, 0.794, 0.796 and 0.792 for predicting the 1-, 2-, 3-, and 5-year overall survival (OS) probabilities in the validation cohort, which were significantly higher than the ELN risk model. Moreover, a new MSN stratification system (MSF nomogram plus ELN risk model) could stratify patients into new high, intermediate and low risk group. Patients with high MSN risk may benefit from intensive treatment (P = 0.0011). CONCLUSIONS: In summary, the chest CT-MSF nomogram, integrating myosarcopenia, spleen_CTV, and SF_CTV features, could be used to predict prognosis of AML.

The carbon footprint of fast fashion consumption and mitigation strategies-a case study of jeans.

Fast fashion is driving the continued growth of the fashion industry's carbon emissions. Understanding how fast fashion consumption exacerbates carbon emissions is critical to guide mitigation strategies for the fashion industry. Taking jeans, a typical fast fashion product as an example, this study developed an LCA model to assess the carbon footprint of fast fashion consumption at global and national levels, and mitigation potentials of product service systems-related scenarios were then explored. Results show that the carbon footprint of fast fashion consumption is 2.50 kgCO2e/one wear jeans, 11 times higher than that of traditional fashion consumption. Jeans production and cross-broad transportation contributed 91 % of the carbon footprint of fast fashion consumption. Developed countries have a 53 % higher per capita carbon footprint of fast fashion consumption than developing countries. The second-hand trading model has the highest mitigation potential, reducing carbon emissions by 90 %. This study proposed an analytical framework for the carbon footprint of fast fashion consumption, which provides the basis for the environmental footprints of fast fashion products. Our findings provide insights into the carbon footprints of traditional and fast fashion consumption and strategies for the transition to circular fashion.

SHP-1 inhibition targets leukaemia stem cells to restore immunosurveillance and enhance chemosensitivity by metabolic reprogramming.

Leukaemia stem cells (LSCs) in acute myeloid leukaemia present a considerable treatment challenge due to their resistance to chemotherapy and immunosurveillance. The connection between these properties in LSCs remains poorly understood. Here we demonstrate that inhibition of tyrosine phosphatase SHP-1 in LSCs increases their glycolysis and oxidative phosphorylation, enhancing their sensitivity to chemotherapy and vulnerability to immunosurveillance. Mechanistically, SHP-1 inhibition leads to the upregulation of phosphofructokinase platelet (PFKP) through the AKT-ß-catenin pathway. The increase in PFKP elevates energy metabolic activities and, as a consequence, enhances the sensitivity of LSCs to chemotherapeutic agents. Moreover, the upregulation of PFKP promotes MYC degradation and, consequently, reduces the immune evasion abilities of LSCs. Overall, our study demonstrates that targeting SHP-1 disrupts the metabolic balance in LSCs, thereby increasing their vulnerability to chemotherapy and immunosurveillance. This approach offers a promising strategy to overcome LSC resistance in acute myeloid leukaemia.

LncRNA ABHD11-AS1 activates EGFR signaling to promote cervical cancer progression by preventing FUS-mediated degradation of ABHD11 mRNA.

Cervical cancer is one of the most common gynecological cancers with high metastasis, poor prognosis and conventional chemotherapy. The long non-coding RNA (lncRNA) ABHD11 antisense RNA 1 (ABHD11-AS1) plays a vital role in tumorigenesis and is involved in cell proliferation, differentiation, and apoptosis. Especially for cervical cancer, the functions and mechanisms of ABHD11-AS1 are still undetermined. In this study, we explored the role and underlying mechanism of ABHD11-AS1 in cervical cancer. We found that ABHD11-AS1 is highly expressed in cervical cancer tissue. The roles of ABHD11-AS1 and EGFR have investigated the loss of function analysis and cell movability in SiHa and Hela cells. Knockdown of ABHD11-AS1 and EGFR significantly inhibited the proliferation, migration, and invasion and promoted apoptosis of SiHa and Hela cells by up-regulating p21 and Bax and down-regulating cyclin D1, Bcl2, MMP9, and Vimentin. ABHD11-AS1 knockdown could decrease the expression of EGFR. In addition, ABHD11-AS1 could regulate the EGFR signaling pathway, including p-EGFR, p-AKT, and p-ERK. Spearman's correlation analysis and cell experiments demonstrated that ABHD11 was highly expressed in tumor tissue and partially offset the effect of shABHD11-AS1 on the proliferation, migration, and invasion of SiHa and Hela cells. Then, RNA pulldown was used to ascertain the mechanisms of ABHD11-AS1 and FUS. ABHD11-AS1 inhibited ABHD11 mRNA degradation by bounding to FUS. A subcutaneous xenograft of SiHa cells was established to investigate the effect of ABHD11-AS1 in tumor tissue. Knockdown of ABDH11-AS1 inhibited tumor growth and decreased the tumor volume. ABHD11-AS1 knockdown inhibited the expression of Ki67 and Vimentin and up-regulated the expression of Tunel. Our data indicated that ABHD11-AS1 promoted cervical cancer progression by activating EGFR signaling, preventing FUS-mediated degradation of ABHD11 mRNA. Our findings provide novel insights into the potential role of lncRNA in cervical cancer therapy.

Super-enhancer-associated gene CAPG promotes AML progression.

Acute myeloid leukemia is the most common acute leukemia in adults, the barrier of refractory and drug resistance has yet to be conquered in the clinical. Abnormal gene expression and epigenetic changes play an important role in pathogenesis and treatment. A super-enhancer is an epigenetic modifier that promotes pro-tumor genes and drug resistance by activating oncogene transcription. Multi-omics integrative analysis identifies the super-enhancer-associated gene CAPG and its high expression level was correlated with poor prognosis in AML. CAPG is a cytoskeleton protein but has an unclear function in AML. Here we show the molecular function of CAPG in regulating NF-κB signaling pathway by proteomic and epigenomic analysis. Knockdown of Capg in the AML murine model resulted in exhausted AML cells and prolonged survival of AML mice. In conclusion, SEs-associated gene CAPG can contributes to AML progression through NF-κB.

A Ferroptosis-Inducing and Leukemic Cell-Targeting Drug Nanocarrier Formed by Redox-Responsive Cysteine Polymer for Acute Myeloid Leukemia Therapy.

Ferroptosis is an alternative strategy to overcome chemoresistance, but effective therapeutic approaches to induce ferroptosis for acute myeloid leukemia (AML) treatment are limited. Here, we developed glutathione (GSH)-responsive cysteine polymer-based ferroptosis-inducing nanomedicine (GCFN) as an efficient ferroptosis inducer and chemotherapeutic drug nanocarrier for AML treatment. GCFN depleted intracellular GSH and inhibited glutathione peroxidase 4, a GSH-dependent hydroperoxidase, to cause lipid peroxidation and ferroptosis in AML cells. Furthermore, GCFN-loaded paclitaxel (PTX@GCFN) targeted AML cells and spared normal hematopoietic cells to limit the myeloablation side effects caused by paclitaxel. PTX@GCFN treatment extended the survival of AML mice by specifically releasing paclitaxel and simultaneously inducing ferroptosis in AML cells with restricted myeloablation and tissue damage side effects. Overall, the dual-functional GCFN acts as an effective ferroptosis inducer and a chemotherapeutic drug carrier for AML treatment.

PD-1 signalling defines and protects leukaemic stem cells from T cell receptor-induced cell death in T cell acute lymphoblastic leukaemia.

T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy with poor prognosis, but a decisive marker and effective treatment for leukaemia stem cells (LSCs) remain unclear. Here, using lineage tracing, limiting dilution assays and in vivo live imaging approaches, we identify rare inhibitory receptor programmed cell death 1 (PD-1)-expressing cells that reside at the apex of leukaemia hierarchy for initiation and relapse in T-ALL. Ablation of PD-1-expressing cells, deletion of PD-1 in T-ALL cells or blockade of PD-1 or PD-1 ligand 1 significantly eradicated LSCs and suppressed disease progression. Combination therapy using PD-1 blockade and chemotherapy substantially extended the survival of mice engrafted with mouse or human T-ALL cells. Mechanistically, PD-1+ LSCs had high NOTCH1-MYC activity for disease initiation. Furthermore, PD-1 signalling maintained quiescence and protected LSCs against T cell receptor-signal-induced apoptosis. Overall, our data highlight the hierarchy of leukaemia by identifying PD-1+ LSCs and provide a therapeutic approach for the elimination of LSCs through PD-1 blockade in T-ALL.

FAM83A has a pro-tumor function in ovarian cancer by affecting the Akt/Wnt/ß-catenin pathway.

Family with sequence similarity 83, member A (FAM83A) is a tumor-exclusive gene that has a vital role in numerous tumors. However, its role in tumorigenesis remains controversial. This work is dedicated to the study of the role of FAM83A in ovarian cancer. We observed elevated levels of FAM83A in ovarian cancer specimens and cells. Kaplan-Meier survival curves revealed that elevated FAM83A levels predicted a worse overall survival in ovarian cancer patients. The inhibition of FAM83A caused remarkable suppressive effects on the proliferation and invasion of ovarian cancer cells, and enhanced their chemosensitivity. On the contrary, the upregulation of FAM83A had opposite effects. Mechanistically, FAM83A had an effect on the Akt and Wnt/ß-catenin pathways in ovarian cancer cells. The repression of Akt could cancel the regulatory effect of FAM83A overexpression on the Wnt/ß-catenin pathway. Moreover, reactivation of the Wnt/ß-catenin pathway abolished FAM83A-inhibition-evoked antitumor effects. Additionally, FAM83A inhibition weakened the tumorigenic potential of ovarian cancer in vivo. Taken together, this work shows that FAM83A exerts a pro-tumor function in ovarian cancer by affecting the Akt/Wnt/ß-catenin pathway and proposes FAM83A as an effective and possible treatment target for ovarian cancer.

Runt-Related Transcription Factor 3 Promotes Acute Myeloid Leukemia Progression.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with high relapse/refractory rate. Genetic and epigenetic abnormalities are driving factors for leukemogenesis. RUNX1 and RUNX2 from the Runt-related transcription factor (RUNX) family played important roles in AML pathogenesis. However, the relationship between RUNX3 and AML remains unclear. Here, we found that RUNX3 was a super-enhancer-associated gene and highly expressed in AML cells. The Cancer Genome Atlas (TCGA) database showed high expression of RUNX3 correlated with poor prognosis of AML patients. We observed that Runx3 knockdown significantly inhibited leukemia progression by inducing DNA damage to enhance apoptosis in murine AML cells. By chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we discovered that RUNX3 in AML cells mainly bound more genes involved in DNA-damage repair and antiapoptosis pathways compared to that in normal bone marrow cells. Runx3 knockdown obviously inhibited the expression of these genes in AML cells. Overall, we identified RUNX3 as an oncogene overexpressed in AML cells, and Runx3 knockdown suppressed AML progression by inducing DNA damage and apoptosis.

Expression and prognosis analyses of CASP1 in acute myeloid leukemia.

Caspase1 (CASP1) is a gene that encodes multiple proteins related to cell death. Nevertheless, the function of CASP1 in the pathogenesis of AML is still unclear. In the present study, a detailed analysis of cancer versus normal samples was performed to explore the relationship between CASP1 and leukemia. We used sequencing data from multiple cancer gene databases to analyze the gene expression and regulatory network of CASP1 in leukemia. We discovered that mRNA expression levels of CASP1 are increased in leukemia cell lines, especially in acute myelocytic leukemia (AML). Then, we verified the mRNA expression of CASP1 in AML clinical samples and observed significantly higher expression of CASP1 in relapsed AML patients. High CASP1 expression was associated with poor prognosis and CASP1 inhibition could impair the proliferation of AML cells. Related functional network identification suggests that CASP1 regulates apoptosis, immune and inflammatory response via pathways involving LYN, LCK, and the E2F family. These findings suggest that CASP1 probably contributes to the pathogenesis, and identify CASP1 as a factor for predicting the prognosis and as a therapeutic target of AML patients.

In Vivo Visualization of the Pericardium Meridian with Fluorescent Dyes.

The anatomical basis of acupuncture meridians continues to be enigmatic. Although much attention has been placed on potential correlations with inter/intramuscular fascia or lower electrical impedance, animal studies performed in the past 40 years have shown that tracer dyes-specifically Tc-99m pertechnetate-injected at strategic skin points generate linear migrations closely aligning with acupuncture meridians. To evaluate whether this phenomenon is also observable in humans, we injected two fluorescent dyes-fluorescein sodium and indocyanine green (ICG)-into the dermal layer both at acupuncture points (PC5, PC6, and PC7) and a nonacupoint control. Fifteen healthy volunteers were enrolled in this study. Of the 19 trials of fluorescein injected at PC6, 15 (79%) were associated with slow diffusion of the dye proximally along a path matching closely with the pericardium meridian. Furthermore, the dye emerged and coalesced proximally at exactly acupoint PC3. Injections of ICG at the acupoints PC5, PC6, or PC7 showed a similar trajectory close to the injection site but diverged when migrating proximally, failing converge on acupoint PC3. Injections of either dye at an adjacent PC6-control did not generate any notable linear pathway. Both ultrasound imaging and vein-locating device did not reveal any corresponding vessels (arterial or venous) at the visualized tracer pathway but did demonstrate correlations with intermuscular fascia.

Retinoic Acid Inhibits Tumor-Associated Mesenchymal Stromal Cell Transformation in Melanoma.

Bone marrow mesenchymal stem/stromal cells (BMSCs) can be transformed into tumor-associated MSCs (TA-MSCs) within the tumor microenvironment to facilitate tumor progression. However, the underline mechanism and potential therapeutic strategy remain unclear. Here, we explored that interleukin 17 (IL-17) cooperating with IFNγ transforms BMSCs into TA-MSCs, which promotes tumor progression by recruiting macrophages/monocytes and myeloid-derived suppressor cells (MDSCs) in murine melanoma. IL-17 and IFNγ transformed TA-MSCs have high expression levels of myelocyte-recruiting chemokines (CCL2, CCL5, CCL7, and CCL20) mediated by activated NF-κB signaling pathway. Furthermore, retinoic acid inhibits NF-κB signaling, decreases chemokine expression, and suppresses the tumor-promoting function of transformed TA-MSCs by prohibiting the recruitment of macrophages/monocytes and MDSCs in the tumor microenvironment. Overall, our findings demonstrate that IL-17 collaborating with IFNγ to induce TA-MSC transformation, which can be targeted by RA for melanoma treatment.

SUV39H1-Mediated DNMT1 is Involved in the Epigenetic Regulation of Smad3 in Cervical Cancer.

BACKGROUND: SMAD3 is a pivotal intracellular mediator for participating in the activation of multiple immune signal pathways. OBJECTIVE: The epigenetic regulation mechanism of the positive immune factor SMAD3 in cervical cancer remains unknown. Therefore, the epigenetic regulation on SMAD3 is investigated in this study. METHODS: The methylation status of SMAD3 was detected by Methylation-Specific PCR (MS-PCR) and Quantitative Methylation-Specific PCR (MS-qPCR) in cervical cancer tissues and cell lines. The underlying molecular mechanisms of SUV39H1-DNMT1-SMAD3 regulation were elucidated using cervical cancer cell lines containing siRNA or/and over-expression systems. The regulation of DNMT1 by SUV39H1 was confirmed using Chromatin Immunoprecipitation-qPCR (ChIP-qPCR). The statistical methods used for comparing samples between groups were paired t-tests and one-way ANOVAs. RESULTS: H3K9me3 protein regulated by SUV39H1 directly interacts with the DNMT1 promoter region to regulate its expression in cervical cancer cells, resulting in the reduced expression of the downstream target gene DNMT1. In addition, DNMT1 mediates the epigenetic modulation of the SMAD3 gene by directly binding to its promoter region. The depletion of DNMT1 effectively restores the expression of SMAD3 in vitro. Moreover, in an in vivo assay, the expression profile of SUV39H1-DNMT1 was found to correlate with SMAD3 expression in accordance with the expression at the cellular level. Notably, the promoter region of SMAD3 was hypermethylated in cervical cancer tissues, and this hypermethylation inhibited the subsequent gene expression. CONCLUSION: These results indicate that SUV39H1-DNMT1 is a crucial SMAD3 regulatory axis in cervical cancer. SUV39H1-DNMT1 axis may provide a potential therapeutic target for the treatment of cervical cancer.

SUV39H1-DNMT3A-mediated epigenetic regulation of Tim-3 and galectin-9 in the cervical cancer.

BACKGROUND: Methylation of histone 3 at lysine 9 (H3K9) and DNA methylation are epigenetic marks correlated with genes silencing. The tumor microenvironment significantly influences therapeutic responses and clinical outcomes. The epigenetic-regulation mechanism of the costimulatory factors Tim-3 and galectin-9 in cervical cancer remains unknown. METHODS: The methylation status of HAVCR2 and LGALS9 were detected by MS-PCR in cervical cancer tissues and cell lines. The underlying molecular mechanism of SUV39H1-DNMT3A-Tim-3/galectin-9 regulation was elucidated using cervical cancer cell lines containing siRNA or/and over-expression system. Confirmation of the regulation of DNMT3A by SUV39H1 used ChIP-qPCR. RESULTS: SUV39H1 up-regulates H3K9me3 expression at the DNMT3A promoter region, which in turn induced expression of DNMT3A in cervical cancer. In addition, the mechanistic studies indicate that DNMT3A mediates the epigenetic modulation of the HAVCR2 and LGALS9 genes by directly binding to their promoter regions in vitro. Moreover, in an in vivo assay, the expression profile of SUV39H1 up-regulates the level of H3K9me3 at the DNMT3A promoter region was found to correlate with Tim-3 and galectin-9 cellular expression level. CONCLUSION: These results indicate that SUV39H1-DNMT3A is a crucial Tim-3 and galectin-9 regulatory axis in cervical cancer.

Evaluation of the Efficacy and Safety of PARP Inhibitors in Advanced-Stage Epithelial Ovarian Cancer.

Purpose: PARP inhibitors are a novel targeted anti-cancer drug and a large number of clinical studies on PARP inhibitors have been accomplished. This updated meta-analysis was conducted to evaluate the efficacy and safety of PARP inhibitors in advanced-stage epithelial ovarian cancer. Methods: Medline (PubMed), Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus were searched to identify the eligible trials up to April 2020. ClinicalTrials.gov was also screened for additional unpublished trials. Data extraction and risk of bias assessment were performed by two independent investigators, respectively. The hazard ratios (HRs) and its 95% confidence intervals (CI) for time-to-event data of progression-free survival (PFS) and overall survival (OS), and the risk ratios (RRs) with 95% CI for dichotomous data of overall response rate (ORR) and occurrence of adverse events (AEs) were calculated by Review Manager 5.3 and Stata 12.0 software. Results: A total of 12 trials with 5,347 patients were included in this meta-analysis. Compared with the control group, PARP inhibitors significantly improved PFS (HR, 0.51; 95% CI, 0.40-0.65; P < 0.00001) and ORR (RR, 1.26; 95% CI, 1.11-1.43; P = 0.0003). Specifically, PFS was improved regardless of BRCA genes mutations and homologous-recombination status. However, no difference was observed in OS between the PARP inhibitors group and the control group (95% CI, 0.73-1.01; P = 0.06). PARP inhibitors were associated with a statistically significant higher risk of hematologic events and different PARP inhibitors had different toxicities profiles. Conclusion: PARP inhibitors are an effective and well-tolerated treatment for patients with advanced-stage epithelial ovarian cancer.

Construction of a tumor microenvironment pH-responsive cleavable PEGylated hyaluronic acid nano-drug delivery system for colorectal cancer treatment.

In order to improve active tumor targeting, tumor cell uptake efficiency and circulation time of doxorubicin (DOX) in vivo, we constructed a cleavable PEGylated hyaluronic acid nano-drug delivery system (HA-mPEG2k-DOX) based on a tumor microenvironment pH-responsive imine bond. In this study, HA-mPEG2k-DOX can self-assemble into stable nanoparticles (HA-mPEG2k-DOX NPs) with a particle size of 50 nm. And the NPs can efficiently target CD44 positive CT26 cells and the pH-responsive cleavable PEG shell can be detached under weakly acidic environments and effectively promote the cellular uptake of HA-DOX NPs. Compared with DOX·HCl, the HA-mPEG2k-DOX NPs can significantly increase the DOX circulation time by 12.5 times, efficiently target the tumor tissues of CT26 tumor-bearing mice and remain for 72 hours. Therefore, the antitumor results in vivo indicated that the HA-mPEG2k-DOX NPs have the best anti-tumor effect while reducing the toxicity of the DOX. Overall, the cleavable PEGylated HA-mPEG2k-DOX NPs responding to pH-sensitive imine bonds, while actively targeting CD44-positive tumor cells, improve the dilemma of cellular uptake and delivery by the PEGylated nano delivery system.

Ethyl pyruvate confers protection against endotoxemia and sepsis by inhibiting caspase-11-dependent cell pyroptosis.

Ethyl pyruvate exertsa special protectiveeffecton endotoxin-induced endotoxemia and experimental sepsis, but the underlying mechanism remains elusive. Werecently demonstrated that ethyl pyruvate inhibited caspase-11-mediated macrophage pyroptotic cell death. GasderminDis akeymolecule incaspase-11 mediated non-canonical inflammasome-inducedpyroptosis. We proved that ethyl pyruvate significantly decreased caspase-11 and gasdermin D-mediated pyroptosis induced by cytoplasmic lipopolysaccharide (LPS) and bacterial outer membrane vesicles (OMVs). Ethyl pyruvate treatment offered effective protection against lethal endotoxemia and reduced the release of IL-1α and IL-1ß. Similarresults were observed in the mousececal ligation and puncture (CLP)peritonitissepsismodel. These findings identified ethyl pyruvate as an inhibitor against LPS-mediated activation of cytoplasmic caspase-11 and gasdermin D. This mechanism is believed to contribute tothe further explanation of theprotectiveactionof ethyl pyruvate in experimental sepsis and endotoxemia and the potential application of ethyl pyruvate for rescuing sepsis.

Evaluation of Risk Factors for Venous Thromboembolism in Patients Who Underwent Gynecological Surgery and Validation of a Fast-Rating Assessment Table.

BACKGROUND The aim of this study was to retrospectively analyze the risk factors for venous thromboembolism (VTE) in gynecological patients and verify the validity of a fast-rating assessment table. MATERIAL AND METHODS From October 2015 to October 2017, 53 patients complicated with VTE after gynecological operations were analyzed, and a total of 106 patients with 2 adjacent operations were selected as the control group. Factors such as age, body mass index (BMI), and tumor type were analyzed by univariate and multivariate analysis. A fast-rating assessment table of VTE risk factors was constructed. This fast-rating assessment table and the Caprini score table were used to compare the scores of all patients. RESULTS In the univariate analysis, there were significant differences in BMI, tumor type, operation duration, blood loss, blood transfusion, bed rest time, and thrombus-related history between the 2 groups. In the multiple factor analysis, age >60 years old, BMI >28 kg/m², malignant tumors, operation duration ≥3 hours, laparoscopic surgery and thrombus-related history were independent risk factors for VTE in patients. Both the fast-rating assessment table and the Caprini score table identified 90% of VTE patients as high-risk and very high-risk, and there was no significant difference between the tables. CONCLUSIONS Patients with older age, high BMI, malignant tumors, longer operation duration, laparoscopic surgery, or history of thrombosis may be more prone to VTE after gynecologic surgery. The fast-rating assessment table is easy to operate and has a high recognition level for VTE. It can be applied widely.