Region-Specific CD16+ Neutrophils Promote Colorectal Cancer Progression by Inhibiting Natural Killer Cells.

The colon is the largest compartment of the immune system, with innate immune cells exposed to antigens in the environment. However, the mechanisms by which the innate immune system is instigated are poorly defined in colorectal cancer (CRC). Here, a population of CD16+ neutrophils that specifically accumulate in CRC tumor tissues by imaging mass cytometry (IMC), immune fluorescence, and flow cytometry, which demonstrated pro-tumor activity by disturbing natural killer (NK) cells are identified. It is found that these CD16+ neutrophils possess abnormal cholesterol accumulation due to activation of the CD16/TAK1/NF-κB axis, which upregulates scavenger receptors for cholesterol intake including CD36 and LRP1. Consequently, these region-specific CD16+ neutrophils not only competitively inhibit cholesterol intake of NK cells, which interrupts NK lipid raft formation and blocks their antitumor signaling but also release neutrophil extracellular traps (NETs) to induce the death of NK cells. Furthermore, CD16-knockout reverses the pro-tumor activity of neutrophils and restored NK cell cytotoxicity. Collectively, the findings suggest that CRC region-specific CD16+ neutrophils can be a diagnostic marker and potential therapeutic target for CRC.

A lava-inspired proteolytic enzyme therapy on cancer with a PEG-based hydrogel enhances tumor distribution and penetration of liposomes.

The enhanced permeability and retention (EPR) effect has become the guiding principle for nanomedicine against cancer for a long time. However, several biological barriers severely resist therapeutic agents' penetration and retention into the deep tumor tissues, resulting in poor EPR effect and high tumor mortality. Inspired by lava, we proposed a proteolytic enzyme therapy to improve the tumor distribution and penetration of nanomedicine. A trypsin-crosslinked hydrogel (Trypsin@PSA Gel) was developed to maintain trypsin's activity. The hydrogel postponed trypsin's self-degradation and sustained the release. Trypsin promoted the cellular uptake of nanoformulations in breast cancer cells, enhanced the penetration through endothelial cells, and degraded total and membrane proteins. Proteomic analysis reveals that trypsin affected ECM components and down-regulated multiple pathways associated with cancer progression. Intratumoral injection of Trypsin@PSA Gel significantly increased the distribution of liposomes in tumors and reduced tumor vasculature. Combination treatment with intravenous injection of gambogic acid-loaded liposomes and intratumoral injection of Trypsin@PSA Gel inhibited tumor growth. The current study provides one of the first investigations into the enhanced tumor distribution of liposomes induced by a novel proteolytic enzyme therapy.

A new therapeutic perspective: Erastin inhibits tumor progression by driving ferroptosis in myelodysplastic syndromes.

Ferroptosis is a recently identified and evolutionarily conserved form of programmed cell death. This process is initiated by an imbalance in iron metabolism, leading to an overload of ferrous ions. These ions promote lipid peroxidation in the cell membrane through the Fenton reaction. As the cell's antioxidant defenses become overwhelmed, a fatal buildup of reactive oxygen species (ROS) occurs, resulting in the rupture of the plasma membrane. Ferroptosis is implicated in conditions such as ischemia-reperfusion injuries and a range of cancers. In our research, we explored ferroptosis in myelodysplastic syndromes (MDS) by measuring iron levels, transferrin receptor expression, and glutathione peroxidase 4 (GPX4) mRNA. Our findings revealed that MDS patients had significantly higher Fe2+ levels in CD33+ cells and increased transferrin receptor mRNA compared to healthy individuals. GPX4 expression was also higher in MDS but not statistically significant. To investigate potential treatments for myeloid hematological diseases through ferroptosis induction, we treated the myelodysplastic syndrome cell line (SKM-1) and two myeloid leukemia cell lines (KG-1 and K562) with erastin, an iron transfer inducer. We observed that erastin treatment led to glutathione depletion, reduced GPX4 activity, and increased ROS, culminating in cell death by ferroptosis. Furthermore, combining erastin with azacitidine demonstrated a synergistic effect on MDS and leukemia cell lines, suggesting a promising approach for treating these hematological conditions with this drug combination. Our experiments confirm erastin's ability to induce ferroptosis in MDS and highlight its potential synergistic use with azacitidine for treatment.

Clinical applications of stem cell-derived exosomes.

Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared to stem cells, stem cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic potential and ethical issues. Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency. After a thorough search and meticulous dissection of relevant literature from the last five years, we present this comprehensive, up-to-date, specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes. Exosomes derived from stem cells (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, and endothelial stem cells) are capable of treating numerous diseases encountered in orthopedic surgery, neurosurgery, plastic surgery, general surgery, cardiothoracic surgery, urology, head and neck surgery, ophthalmology, and obstetrics and gynecology. The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses, and cell-specific molecular signaling pathways. In this review, we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions. We recommend that future research combines wisdoms from surgeons, nanomedicine practitioners, and stem cell researchers in this relevant and intriguing research area.

CT-Based Radiomics for the Preoperative Prediction of Occult Peritoneal Metastasis in Epithelial Ovarian Cancers.

RATIONALE AND OBJECTIVES: The objective of this study was to develop a comprehensive combined model for predicting occult peritoneal metastasis (OPM) in epithelial ovarian cancers (EOCs) using radiomics features derived from computed tomography (CT) and clinical-radiological predictors. MATERIALS AND METHODS: A total of 224 patients with EOCs were randomly divided into training dataset (N = 156) and test dataset (N = 86). Five clinical factors and seven radiological features were collected. The radiomics features were extracted from CT images of each patient. Multivariate logistic regression was employed to construct clinical and radiological models. The correlation analysis and least absolute shrinkage and selection operator algorithm were used to select radiomics features and build radiomics model. The important clinical, radiological factors, and radiomics features were integrated into a combined model by multivariate logistic regression. Receiver operating characteristics curve with area under the curve (AUC) were used to evaluate and compare predictive performance. RESULTS: Carbohydrate antigen 125 (CA-125) and human epididymal protein 4 (HE-4) were independent clinical predictors. Laterality, thickened septa and margin were independent radiological predictors. In the training dataset, the AUCs for the clinical, radiological and radiomics models in evaluating OPM were 0.759, 0.819, and 0.830, respectively. In the test dataset, the AUCs for these models were 0.846, 0.835, and 0.779, respectively. The combined model outperformed other models in both the training and the test datasets with AUCs of 0.901 and 0.912, respectively. Decision curve analysis indicated that the combined model yielded a higher net benefit compared to the other models. CONCLUSION: The combined model, integrating radiomics features with clinical and radiological predictors exhibited improved accuracy in predicting OPM in EOCs.

Validation and Comparison of Four Mortality Prediction Models in a Geriatric Ward in China.

Purpose: The efficacy of mortality risk prediction models among older patients in China remains uncertain. We aimed to validate and compare the performances of the Walter Index, Geriatric Prognostic Index (GPI), Charlson Comorbidity Index (CCI), and FRAIL Scale in predicting 1-year all-cause mortality post-discharge in geriatric inpatients in China. Patients and Methods: This study was conducted at a geriatric ward of a tertiary Hospital in Beijing, including patients aged 70 years or older with a documented comprehensive geriatric assessment, discharged between January 1, 2016, and December 31, 2021. Patients with a hospital stay ≤24 h or >60 days were excluded. All-cause mortality data within one year of discharge were collected from medical files and telephone interviews between August 2022 and February 2023. Multiple imputation, Logistic regression analysis, Brier scores, C-statistics, Hosmer-Lemeshow goodness-of-fit-test, and calibration plots were employed for statistical analysis. Results: We included 832 patients with a median (interquartile range) age of 77 (74-82) years. One-hundred patients (12.0%) died within one year. After adjusting for covariates-marital status, social support, cigarette use, length of stay, number of medications, hemoglobin levels, handgrip strength, and Short Physical Performance Battery-CCI scores of 3-4 and >4, and increased Walter Index, GPI, and FRAIL Scale scores were significantly associated with 1-year mortality risk. The Brier scores varied from 0.07 (Walter Index) to 0.10 (FRAIL Scale). The C-statistic ranged from 0.74 (95% confidence interval, 0.69-0.78) for FRAIL Scale to 0.88 (95% confidence interval, 0.84-0.91) for the Walter Index. Calibration curves showed that the Walter Index, GPI, and FRAIL Scale were well calibrated, while the CCI was poor. Conclusion: Combining the Brier score, discrimination and calibration, the Walter Index was confirmed for the first time to be the best model to predict the 1-year mortality risk of geriatric inpatients in China among the four models.

Development of a fibroblast activation protein-targeted PET/NIR dual-modality probe and its application in head and neck cancer.

Purpose: The combination of near-infrared (NIR) and positron emission tomography (PET) imaging presents an opportunity to utilize the benefits of dual-modality imaging for tumor visualization. Based on the observation that fibroblast activation protein (FAP) is upregulated in cancer-associated fibroblasts (CAFs) infiltrating all solid tumors, including head and neck squamous cell carcinoma (HNSCC), we developed the novel PET/NIR probe [68Ga]Ga-FAP-2286-ICG. Preclinically, the specificity, biodistribution and diagnostic properties were evaluated. Methods: Cell uptake assays were completed with the U87MG cell to evaluate the specificity of the [68Ga]Ga-FAP-2286-ICG. The tumor-targeting efficiency, biodistribution and optimal imaging time window of the [68Ga]Ga-FAP-2286-ICG were studied in mice bearing U87MG xenografts. HNSCC tumor-bearing mice were used to evaluate the feasibility of [68Ga]Ga-FAP-2286-ICG for tumor localization and guided surgical resection of HNSCC tumors. Results: The in vitro experiments confirmed that [68Ga]Ga-FAP-2286-ICG showed good stability, specific targeting of the probe to FAP, and the durable retention effect in high-expressing FAP tumors U87MG cell. Good imaging properties such as good tumor uptake, high tumor-to-background ratios (5.44 ± 0.74) and specificity, and tumor contouring were confirmed in studies with mice bearing the U87MG xenograft. PET/CT imaging of the probe in head and neck cancer-bearing mice demonstrated specific uptake of the probe in the tumor with a clear background. Fluorescence imaging further validated the value of the probe in guiding surgical resection and achieving precise removal of the tumor and residual lesions. Conclusion: In a preclinical model, these attractive [68Ga]Ga-FAP-2286-ICG PET/NIR imaging acquired in head and neck cancer make it a promising FAP-targeted multimodal probe for clinical translation.

Upregulation of S100A6 and its relation with CD34+ cells apoptosis in high-risk myelodysplastic syndromes patients.

Objectives: Myelodysplastic syndromes (MDS) are a group of myeloid malignancies characterized by peripheral blood cytopenia and hematopoietic dysplasia that often progress to acute myeloid leukemia (AML). Increased apoptosis of normal hematopoietic cells and decreased apoptosis of malignant clonal hematopoietic cells in patients with MDS is some of the mechanisms leading to ineffective hematopoietic cells in the bone marrow. S100 calcium-binding protein A6 (S100A6) is upregulated in many malignancies. The overexpression of S100A6 in these malignancies has been associated with proliferation, migration, and invasion phenotypes in cancer cells, and we aimed to investigate the expression of S100A6 in CD34+ cells and the relationship between S100A6 expression and apoptosis of CD34+ cells in high-risk patients with MDS. Methods: We measured S100A6 mRNA expression in bone marrow (BM) CD34+ cells from high-risk patients with MDS using RT-PCR. Next, we examined S100A6 expression in CD34+ cells using flow cytometry. We also analyzed the correlation between CD34+ cell apoptosis and S100A6 expression in high-risk patients with MDS. Results: Our data showed increased S100A6 mRNA expression in CD34+ cells in patients with MDS (1.05 ± 0.69 vs. 0.17 ± 0.12; P＜0.01). The expression of S100A6 in BM CD34+ cells also increased (58.40 ± 13.18 vs. 45.83 ± 15.01). The expression of S100A6 in CD34+ cells and apoptosis of CD34+ cells were negatively correlated in patients (r = -0.75; P < 0.01). Conclusions: Collectively, S100A6 may be a potential marker of CD34+ cells in high-risk patients with MDS and may participate in the pathological behaviors of CD34+ cells, such as evasion of apoptosis. Thus, S100A6 may be a potential target for eliminating minimal residual disease.

A Prognostic Model of Head and Neck Cancer Based on Amino Acid Metabolism-Related Signature and Its Implication for Immunosuppressive Microenvironment.

Amino acid metabolism has been implicated in tumorigenesis and tumor progression. Alterations in intracellular and extracellular metabolites associated with metabolic reprogramming in cancer have profound effects on gene expression, cell differentiation, and tumor immune microenvironment. However, the prognostic significance of amino acid metabolism in head and neck cancer remains to be further investigated. In this study, we identified 98 differentially expressed genes related to amino acid metabolism in head and neck cancer in The Cancer Genome Atlas. Using batch univariate Cox regression and Lasso regression, we extracted nine amino acid metabolism-related genes. Based on that, we developed the amino acid metabolism index. The prognostic value of this index was validated in two Gene Expression Omnibus cohorts. The results show that this model can help predict tumor recurrence and prognosis. The infiltration of immune cells in the tumor microenvironment was analyzed, and it was discovered that the high index is associated with an immunosuppressive microenvironment. In addition, this study demonstrated the impact of the amino acid metabolism index on clinical indicators, survival of patients with head and neck cancer, and the prediction of treatment response to immune checkpoint inhibitors. We conducted several cell experiments and demonstrated that epigenetic drugs could affect the index and enhance tumor immunity. In conclusion, our study demonstrates that the index not only has important prognostic value in head and neck cancer patients but also facilitates patient stratification for immunotherapy.

Is robotic assistance more eye-catching than computer navigation in joint arthroplasty? A Google trends analysis from the point of public interest.

Computer-assisted navigation system (CAS) and robotic assisted surgery (RAS) have been widely used in joint arthroplasty, but few studies focused on public interest. We aimed to evaluate current trend and seasonality of public interest in CAS and RAS arthroplasty over the past 10 years, and forecast the future development. All data related to CAS or RAS arthroplasty from January 2012 to December 2021 were collected through Google Trends. Public interest was described by relative search volume (RSV). Pre-existing trend was evaluated by linear and exponential models. Time series analysis and ARIMA model were utilized to analyze the seasonality and future trend. R software 3.5.0 was for statistics analysis. Public interest in RAS arthroplasty has been continuously increasing (P < 0.001) and exponential model (R2 = 0.83, MAE = 7.35, MAPE = 34%, RSME = 9.58) fitted better than linear one (R2 = 0.78, MAE = 8.44, MAPE = 42%, RSME = 10.67). CAS arthroplasty showed a downtrend (P < 0.01) with equivalent R2 (0.04) and accuracy measures (MAE = 3.92, MAPE = 31%, RSME = 4.95). The greatest popularity of RAS was observed in July and October, while the lowest was in March and December. For CAS, a rise of public interest was in May and October, but lower values were observed in January and November. Based on ARIMA models, the popularity of RAS might continuously increase and nearly double in 2030, along with a stability with slight downtrend for CAS. Public interest in RAS arthroplasty has been continuously increasing and seems to maintain this uptrend in the next 10 years, whereas popularity of CAS arthroplasty will likely remain stable.

Tumor Cell Targeting and Responsive Nanoplatform for Multimodal-Imaging Guided Chemodynamic/Photodynamic/Photothermal Therapy toward Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with ineffective treatment and poor prognosis. It is in great demand to develop a novel theranostic strategy for accurate diagnosis and targeted treatment of TNBC. In the present study, one nanoplatform (HA-ICG-Fe-PDA), endowed with multimodal imaging-guided chemodynamic/photodynamic/photothermal (CDT/PDT/PTT) synergistic therapy capacity toward TNBC, was innovatively constructed. The nanoplatform was prepared by covalently conjugating ICG-decorated hyaluronic acid (HA) on Fe3+-chelated polydopamine (PDA). HA facilitated the targeting and accumulating of the nanoplatform in tumor tissue and cells of TNBC, thus producing enhanced magnetic resonance signal. Upon entering into TNBC cells, the intracellular hyaluronidase-catalyzed cleavage of HA-ICG-Fe-PDA activated the prequenched near-infrared (NIR) fluorescence signal, allowing for the activatable NIR fluorescence imaging. On the other hand, Fe3+ in the nanoplatform could be reduced to reactive Fe2+ in tumor microenvironment, guaranteeing efficient Fenton reaction-mediated CDT. The combination of ICG with Fe-PDA enhanced the NIR absorption of the nanoplatform so that considerable PTT/PDT and photothermal imaging were achieved under 808 nm laser irradiation. In vitro and in vivo experiments have verified that the proposed nanoplatform integrates the potential of TNBC-targeting, precise NIR fluorescence/magnetic resonance/photothermal trimodal imaging, efficient treatment via synergistic CDT/PDT/PTT, as well as excellent biocompatibility. Therefore, this multifunctional nanoplatform provides a simple and versatile strategy for imaging-guided theranostics of TNBC.

Preference of musculoskeletal pain treatment in middle-aged and elderly chinese people: a machine learning analysis of the China health and retirement longitudinal study.

BACKGROUND: Musculoskeletal pain is a major cause of physical disability, associated with huge socioeconomic burden. Patient preference for treatment is an important factor contributing to the choice of treatment strategies. However, effective measurements for evaluating the ongoing management of musculoskeletal pain are lacking. To help improve clinical decision making, it's important to estimate the current state of musculoskeletal pain management and analyze the contribution of patient treatment preference. METHODS: A nationally representative sample for the Chinese population was derived from the China Health and Retirement Longitudinal Study (CHARLS). Information on the patients' demographic characteristics, socioeconomic status, other health-related behavior, as well as history on musculoskeletal pain and treatment data were obtained. The data was used to estimate the status of musculoskeletal pain treatment in China in the year 2018. Univariate analysis and multivariate analysis were used to find the effect factors of treatment preference. XGBoost model and Shapley Additive exPlanations (SHAP) method were performed to analyze the contribution of each variable to different treatment preferences. RESULTS: Among 18,814 respondents, 10,346 respondents suffered from musculoskeletal pain. Approximately 50% of musculoskeletal pain patients preferred modern medicine, while about 20% chose traditional Chinese medicine and another 15% chose acupuncture or massage therapy. Differing preferences for musculoskeletal pain treatment was related to the respondents' gender, age, place of residence, education level, insurance status, and health-related behavior such as smoking and drinking. Compared with upper or lower limb pain, neck pain and lower back pain were more likely to make respondents choose massage therapy (P < 0.05). A greater number of pain sites was associated with an increasing preference for respondents to seek medical care for musculoskeletal pain (P < 0.05), while different pain sites did not affect treatment preference. CONCLUSION: Factors including gender, age, socioeconomic status, and health-related behavior may have potential effects on people' s choice of treatment for musculoskeletal pain. The information derived from this study may be useful for helping to inform clinical decisions for orthopedic surgeons when devising treatment strategies for musculoskeletal pain.

CD301b+ macrophage: the new booster for activating bone regeneration in periodontitis treatment.

Periodontal bone regeneration is a major challenge in the treatment of periodontitis. Currently the main obstacle is the difficulty of restoring the regenerative vitality of periodontal osteoblast lineages suppressed by inflammation, via conventional treatment. CD301b+ macrophages were recently identified as a subpopulation that is characteristic of a regenerative environment, but their role in periodontal bone repair has not been reported. The current study indicates that CD301b+ macrophages may be a constituent component of periodontal bone repair, and that they are devoted to bone formation in the resolving phase of periodontitis. Transcriptome sequencing suggested that CD301b+ macrophages could positively regulate osteogenesis-related processes. In vitro, CD301b+ macrophages could be induced by interleukin 4 (IL-4) unless proinflammatory cytokines such as interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α) were present. Mechanistically, CD301b+ macrophages promoted osteoblast differentiation via insulin-like growth factor 1 (IGF-1)/thymoma viral proto-oncogene 1 (Akt)/mammalian target of rapamycin (mTOR) signaling. An osteogenic inducible nano-capsule (OINC) consisting of a gold nanocage loaded with IL-4 as the "core" and mouse neutrophil membrane as the "shell" was designed. When injected into periodontal tissue, OINCs first absorbed proinflammatory cytokines in inflamed periodontal tissue, then released IL-4 controlled by far-red irradiation. These events collectively promoted CD301b+ macrophage enrichment, which further boosted periodontal bone regeneration. The current study highlights the osteoinductive role of CD301b+ macrophages, and suggests a CD301b+ macrophage-targeted induction strategy based on biomimetic nano-capsules for improved therapeutic efficacy, which may also provide a potential therapeutic target and strategy for other inflammatory bone diseases.

Arsenic-Containing Medicine Treatment Disturbed the Human Intestinal Microbial Flora.

Human intestinal microbiome plays vital role in maintaining intestinal homeostasis and interacting with xenobiotics. Few investigations have been conducted to understand the effect of arsenic-containing medicine exposure on gut microbiome. Most animal experiments are onerous in terms of time and resources and not in line with the international effort to reduce animal experiments. We explored the overall microbial flora by 16S rRNA genes analysis in fecal samples from acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA). Gut microbiomes were found to be overwhelmingly dominated by Firmicutes and Bacteroidetes after taking medicines containing arsenic in APL patients. The fecal microbiota composition of APL patients after treatment showed lower diversity and uniformity shown by the alpha diversity indices of Chao, Shannon, and Simpson. Gut microbiome operational taxonomic unit (OTU) numbers were associated with arsenic in the feces. We evaluated Bifidobacterium adolescentis and Lactobacillus mucosae to be a keystone in APL patients after treatment. Bacteroides at phylum or genus taxonomic levels were consistently affected after treatment. In the most common gut bacteria Bacteroides fragilis, arsenic resistance genes were significantly induced by arsenic exposure in anaerobic pure culture experiments. Without an animal model, without taking arsenicals passively, the results evidence that arsenic exposure by drug treatment is not only associated with alterations in intestinal microbiome development at the abundance and diversity level, but also induced arsenic biotransformation genes (ABGs) at the function levels which may even extend to arsenic-related health outcomes in APL.

Postsurgical wound management and prevention of triple-negative breast cancer recurrence with a pryoptosis-inducing, photopolymerizable hydrogel.

Surgical removal remains the predominant treatment strategy for triple-negative breast cancer (TNBC). However, risks that include high locoregional recurrence and remote metastasis threaten patient survival and quality of life after surgery. In this study, a hydrogel based on poly (ethylene glycol) dimethacrylate and sericin methacryloyl was fabricated by photopolymerization to fill the resection cavity and prevent recurrence. The obtained hydrogel exhibited mechanical properties compatible with breast tissue and facilitated postsurgical wound management by promoting tissue regeneration. The DNA methylation inhibitor decitabine (DEC) and poly (lactic-co-glycolic acid)-encapsulated phytochemical gambogic acid (GA) were loaded into the hydrogel. The as-prepared hydrogel promoted fast release of DEC and sustained release of GA, leading to gasdermin E-mediated tumor cell pyroptosis and activating antitumor immune responses. Inducing postsurgical tumor cell pyroptosis inhibited local tumor recurrence and lung metastasis. While the dual-drug-loaded hydrogel system cured less than half of tumor-bearing mice, the cured mice survived for over half a year. These findings indicate that our hydrogel system is an excellent biocompatible platform for postsurgical TNBC therapy.

Phytosphingosine inhibits cell proliferation by damaging DNA in human cell lines.

Harmful cyanobacterial blooms have caused numerous biosecurity incidents owing to the production of hazardous secondary metabolites such as microcystin. Additionally, cyanobacteria also release many other components that have not been explored. We identified compounds of a toxic mixture exudated from a dominant, blooming species, Microcystis aeruginosa, and found that phytosphingosine (PHS) was one of the bioactive components. Since PHS exhibited toxicity and is deemed a hazardous substance by the European Chemicals Agency, we hypothesized that PHS is a potentially toxic compound in M. aeruginosa exudates. However, the mechanisms of PHS ecotoxicity remain unclear. We assessed the cytotoxicity of PHS using an in vitro cell model in eight human cell lines and observed that the nasopharyngeal carcinoma cell line CNE2 was the most sensitive. We exposed CNE2 cells to 0-25 µmol/L PHS for 24 hr to explore its toxicity and mechanism. PHS exposure resulted in abnormal nuclear morphology, micronuclei, and DNA damage. Moreover, PHS significantly inhibited cell proliferation and arrested cell cycle at S phase. The results of Western blot suggested that PHS increased the expression of DNA damage-related proteins (ATM, p-P53 and P21) and decreased the expression of S phase-related proteins (CDK2, CyclinA2 and CyclinE1), indicating the toxicological mechanism of PHS on CNE2 cells. These data provide evidence that PHS has genetic toxicity and inhibits cell proliferation by damaging DNA. Our study provides evidence that PHS inhibits cell proliferation by damaging DNA. While additional work is required, we propose that PHS been considered as a potentially toxic component in MaE in addition to other well-characterized secondary compounds.

CSTF2T up-regulates IGHG1 by binding to ZEB1 to promote melanoma cell proliferation, migration, and invasion.

OBJECTIVES: Melanoma progression involves multiple molecular pathways. In this study, we explored the effect of immunoglobulin heavy constant gamma 1 (IGHG1) on melanoma progression. METHODS: IGHG1, zinc finger E-box binding homeobox 1 (ZEB1), and cleavage stimulation factor subunit 2 tau variant (CSTF2T) expression levels were measured by quantitative reverse-transcription polymerase chain reaction and western blot. BALB/c nude mice were subcutaneously injected with A375 cells to develop a transplantation tumor model, 4 weeks after which the tumor tissues were collected. Cell proliferation, cell invasion, and cell migration of A375 and SK-MEL-28 cells were measured after gain- and loss-of-function of IGHG1, ZEB1, and CSTF2T. Binding of ZEB1 to the IGHG1 promoter was assayed by chromatin immunoprecipitation and dual-luciferase reporter gene assays, while binding of CSTF2T to ZEB1 mRNA was investigated by RNA immunoprecipitation and RNA pull-down assays. RESULTS: IGHG1, ZEB1, and CSTF2T were all highly expressed in human melanoma cell lines. In A375 and SK-MEL-28 cells, ZEB1 binds directly to the IGHG1 promoter. ZEB1 silencing reduced IGHG1 expression and melanoma cell proliferative, invasive, and migratory properties, and these cellular effects were nullified by overexpression of IGHG1. CSTF2T binds directly to ZEB1 mRNA. Silencing of CSTF2T diminished ZEB1 expression and restrained melanoma cell proliferative, invasive, and migratory capabilities. The impacts of CSTF2T silencing on melanoma cells were counteracted by concomitant overexpression of ZEB1. CSTF2T knockdown reduced tumor volume and weight in nude mice. CONCLUSIONS: The CSTF2T-ZEB1-IGHG1 axis promotes melanoma cell proliferation and invasion.

Myeloid-derived suppressor cells inhibit natural killer cells in myelodysplastic syndromes through the TIGIT/CD155 pathway.

OBJECTIVE: This experiment will explore the role of TIGIT/PVR signaling pathway in the pathogenesis of MDS immune tolerance through in vitro co-culture of NK cells and MDSC cells. METHODS: Flow cytometry was used to detect the expression percentage of MDSCs and CD155 on MDSCs in the bone marrow of MDS patients and controls. The expression of NK cell surface receptors (NKG2D, NKp30, NKp46), secreted cytokines (perforin, granzyme B, CD107a, IFN-γ) and NK cell apoptosis rate were detected by flow cytometry to evaluate the effect of MDSCs on NK cell function. RESULTS: The number of MDSCs in bone marrow of MDS patients was notably higher than that of the control group (8.39 ± 7.01 vs 2.31 ± 1.65, P = 0.0001). Compared with the control group, the expression of CD155 on MDSCs in MDS group was increased (31.81 ± 21.33 vs. 10.49 ± 6.53, P < 0.0001). After NK cells were co-cultured with MDSCs, NKG2D, NKp30, NKp46, CD107a, IFN-γ, perforin and granzyme B were decreased, and the NK function partially recovered after the addition of inhibitors. CONCLUSION: Compared with the normal control, MDSCs and CD155 on MDSCs were highly expressed in MDS patients. After co-culture with MDSCs, the expression of NK cells' surface receptors decreased, the secretion of cytokines decreased and the apoptosis rate increased. After blocking TIGIT/CD155 pathway, NK cell function was reversed, but NK cell apoptosis was not reduced.

Computed tomography-based radiomics machine learning classifiers to differentiate type I and type II epithelial ovarian cancers.

OBJECTIVES: To compare computed tomography (CT)-based radiomics for preoperatively differentiating type I and II epithelial ovarian cancers (EOCs) using different machine learning classifiers and to construct and validate the best diagnostic model. METHODS: A total of 470 patients with EOCs were included retrospectively. Patients were divided into a training dataset (N = 329) and a test dataset (N = 141). A total of 1316 radiomics features were extracted from the portal venous phase of contrast-enhanced CT images for each patient, followed by dimension reduction of the features. The support vector machine (SVM), k-nearest neighbor (KNN), random forest (RF), naïve Bayes (NB), logistic regression (LR), and eXtreme Gradient Boosting (XGBoost) classifiers were trained to obtain the radiomics signatures. The performance of each radiomics signature was evaluated and compared by the area under the receiver operating characteristic curve (AUC) and relative standard deviation (RSD). The best radiomics signature was selected and combined with clinical and radiological features to establish a combined model. The diagnostic value of the combined model was assessed. RESULTS: The LR-based radiomics signature performed well in the test dataset, with an AUC of 0.879 and an accuracy of 0.773. The combined model performed best in both the training and test datasets, with AUCs of 0.900 and 0.934 and accuracies of 0.848 and 0.823, respectively. CONCLUSION: The combined model showed the best diagnostic performance for distinguishing between type I and II EOCs preoperatively. Therefore, it can be a useful tool for clinical individualized EOC classification. KEY POINTS: • Radiomics features extracted from computed tomography (CT) could be used to differentiate type I and II epithelial ovarian cancers (EOCs). • Machine learning can improve the performance of differentiating type I and II EOCs. • The combined model exhibited the best diagnostic capability over the other models in both the training and test datasets.

Clusterbody Enables Flow Sorting-Assisted Single-Cell Mass Spectrometry Analysis for Identifying Reversal Agent of Chemoresistance.

Identifying effective reversal agents overcoming multidrug resistance with causal mechanisms from an efflux pump protein is of vital importance for enhanced tumor chemotherapy in clinic. To achieve this end, we construct a metal cluster-based probe, named clusterbody, to develop flow sorting-assisted single-cell mass spectrometry analysis. This clusterbody synthesized by biomimetic mineralization possesses an antibody-like property to selectively recognize an efflux pump protein. The intrinsic red fluorescence emission of the clusterbody facilitates fluorescence-activated high-throughput cell sorting of subpopulations with different multidrug resistance levels. Furthermore, based on the accurate formula of the clusterbody, the corresponding protein abundance at the single-cell level is determined through detecting gold content via precise signal amplification by laser ablation inductively coupled plasma mass spectrometry. Therefore, the effect of reversal agent treatment overcoming multidrug resistance is evaluated in a quantitative manner. This work opens a new avenue to identify reversal agents, shedding light on developing combined or synergetic tumor therapy.