Formosanin C inhibits pulmonary metastasis by targeting stearyl CoA desaturase-1.

BACKGROUND: Cisplatin (DDP) as the first-line drug has been used in cancer therapy. However, side effects and drug resistance are the challenges of DDP. Disordered lipid metabolism is related to DDP resistance. STUDY DESIGN: In this study, formosanin C (FC) as the main compound of Rhizoma Paridis saponins (RPS) inhibits pulmonary metastasis by targeting stearyl CoA desaturase-1. METHODS AND RESULTS: RPS prolonged the survival period of mice, reduced pulmonary metastases and alleviated colon toxicity caused by DDP. FC as the main compound of RPS enhanced the anti-tumor and anti-metastatic effects of DDP. FC decreased the mRNA level of SCD1 and the content of lipid droplets (LDs) in lung cancer cells. Molecular dynamics and isothermal titration calorimetry verified the binding stability and spontaneously between FC and SCD1. SiSCD1 reduced the content of LDs in cell lines and increased mitochondria (mtROS), which was consistent with the results of FC treatment. The combination group decreased DNA repair associated protein as well as DDP resistance markers such as ERCC1 and 53bp1, and increased DNA damage marker like γH2AX, which indirectly confirmed the occurrence of mtROS. In addition, FC combination with DDP also affected epithelial-mesenchymal transition-related protein like VIM and CDH1 in vivo experiments, and thereby inhibited pulmonary metastasis. CONCLUSION: Our research indicated that the FC as the main compound of RPS targeted the CY2 domain of SCD1, inhibited lipid metabolism in mice, and thereby suppressed cancer metastases. This provided support for use of FC to treat cancer based on lipid metabolism pathway.

Hydralazine loaded nanodroplets combined with ultrasound-targeted microbubble destruction to induce pyroptosis for tumor treatment.

Pyroptosis, a novel type of programmed cell death (PCD), which provides a feasible therapeutic option for the treatment of tumors. However, due to the hypermethylation of the promoter, the critical protein Gasdermin E (GSDME) is lacking in the majority of cancer cells, which cannot start the pyroptosis process and leads to dissatisfactory therapeutic effects. Additionally, the quick clearance, systemic side effects, and low concentration at the tumor site of conventional pyroptosis reagents restrict their use in clinical cancer therapy. Here, we described a combination therapy that induces tumor cell pyroptosis via the use of ultrasound-targeted microbubble destruction (UTMD) in combination with DNA demethylation. The combined application of UTMD and hydralazine-loaded nanodroplets (HYD-NDs) can lead to the rapid release of HYD (a demethylation drug), which can cause the up-regulation of GSDME expression, and produce reactive oxygen species (ROS) by UTMD to cleave up-regulated GSDME, thereby inducing pyroptosis. HYD-NDs combined with ultrasound (US) group had the strongest tumor inhibition effect, and the tumor inhibition rate was 87.15% (HYD-NDs group: 51.41 ± 3.61%, NDs + US group: 32.73%±7.72%), indicating that the strategy had a more significant synergistic anti-tumor effect. In addition, as a new drug delivery carrier, HYD-NDs have great biosafety, tumor targeting, and ultrasound imaging performance. According to the results, the combined therapy reasonably regulated the process of tumor cell pyroptosis, which offered a new strategy for optimizing the therapy of GSDME-silenced solid tumors.

A combination of PD-L1-targeted IL-15 mRNA nanotherapy and ultrasound-targeted microbubble destruction for tumor immunotherapy.

PD-1/PD-L1-based immune checkpoint blockade therapy has shown limited benefits in tumor patients, partially attributed to the inadequate infiltration of immune effector cells within tumors. Here, we established a nanoplatform named DPPA/IL-15 NPs to target PD-L1 for the tumor delivery of IL-15 messenger RNA (mRNA). DPPA/IL-15 NPs were endowed with ultrasound responsiveness and contrast-enhanced ultrasound (CEUS) imaging performance. They effectively protected IL-15 mRNA from degradation and specifically transfected it into tumor cells through the utilization of ultrasound-targeted microbubble destruction (UTMD). This resulted in the activation of IL-15-related immune effector cells while blocking the PD-1/PD-L1 pathway. In addition, UTMD could generate reactive oxygen species (ROS) that induce endoplasmic reticulum (ER) stress-driven immunogenic cell death (ICD), initiating anti-tumor immunity. In vitro and in vivo studies revealed that this combination therapy could induce a robust systemic immune response and enhance anti-tumor efficacy. Thus, this combination therapy has the potential for clinical translation through enhanced immunotherapy and provides real-time ultrasound imaging guidance.

Caffeic acid activates mitochondrial UPR to resist pathogen infection in Caenorhabditis elegans via the transcription factor ATFS-1.

Mitochondria play roles in the resistance of Caenorhabditis elegans against pathogenic bacteria by regulating mitochondrial unfolded protein response (UPRmt). Caffeic acid (CA) (3,4-dihydroxy cinnamic acid) is a major phenolic compound present in several plant species, which exhibits biological activities such as antioxidant, anti-fibrosis, anti-inflammatory, and anti-tumor properties. However, whether caffeic acid influences the innate immune response and the underlying molecular mechanisms remains unknown. In this study, we find that 20 µM caffeic acid enhances innate immunity to resist the Gram-negative pathogen Pseudomonas aeruginosa infection in C. elegans. Meanwhile, caffeic acid also inhibits the growth of pathogenic bacteria. Furthermore, caffeic acid promotes host immune response by reducing the bacterial burden in the intestine. Through genetic screening in C. elegans, we find that caffeic acid promotes innate immunity via the transcription factor ATFS-1. In addition, caffeic acid activates the UPRmt and immune response genes for innate immune response through ATFS-1. Our work suggests that caffeic acid has the potential to protect patients from pathogen infection.

BLVRA exerts its biological effects to induce malignant properties of hepatocellular carcinoma cells via Wnt/ß-catenin pathway.

The function of Biliverdin Reductase A (BLVRA) in hepatocellular carcinoma (HCC) cells proliferation, invasion and migration remains unclear. Therefore, this research intends to explore the effect of BLVRA on HCC cells growth and metastasis. BLVRA expression was analyzed in public dataset and examined by using western blot. The malignant function of BLVRA in HCC cell lines and its effect on Wnt/ß-catenin pathway were measured. Analysis from GEPIA website showed that BLVRA expression was significantly increased in HCC tissues, and high expression of BLVRA resulted in worse prognosis of HCC patients. Results from western blot showed that BLVRA expression was obviously increased in HCC cell lines. Moreover, HepG2 and Hep3B cells in si-BLVRA-1 or si-BLVRA-2 group displayed an obvious reduction in its proliferation, cell cycle, invasion and migration compared to those in the si-control group. Additionally, si-BLVRA-1 or si-BLVRA-2 transfection significantly reduced the protein levels of Vimentin, Snail1 and Snail2, as well as decreased Bcl-2 expression and increased Bax and cleaved-caspase 3 expression. Furthermore, si-BLVRA treatment inhibited the protein levels of c-MYC, ß-catenin, and Cyclin D1. After IWP-4 (Wnt/ß-catenin inhibitor) treatment, the proliferation ability of HCC cells was significantly reduced. BLVRA expression was significantly increased in HCC tissues and cell lines, and knocked down of BLVRA could suppress the proliferation, invasion and migration in HCC cell lines, as well as induce cell apoptosis. Moreover, si-BLVRA transfection blocked the activation of Wnt/ß-catenin pathway.

Erythrocyte membrane n-3 PUFA are inversely associated with breast cancer risk among Chinese women.

The relationship between erythrocyte membrane n-3 PUFA and breast cancer risk is controversial. We aimed to examine the associations of erythrocyte membrane n-3 PUFA with odds of breast cancer among Chinese women by using a relatively large sample size. A case-control study was conducted including 853 newly diagnosed, histologically confirmed breast cancer cases and 892 frequency-matched controls (5-year interval). Erythrocyte membrane n-3 PUFA were measured by GC. Logistic regression and restricted cubic spline were used to quantify the association between erythrocyte membrane n-3 PUFA and odds of breast cancer. Erythrocyte membrane α-linolenic acid (ALA), docosapentaenoic acid (DPA) and total n-3 PUFA were inversely and non-linearly associated with odds of breast cancer. The OR values (95 % CI), comparing the highest with the lowest quartile (Q), were 0·57 (0·43, 0·76), 0·43 (0·32, 0·58) and 0·36 (0·27, 0·49) for ALA, DPA and total n-3 PUFA, respectively. Erythrocyte membrane EPA and DHA were linearly and inversely associated with odds of breast cancer ((EPA: ORQ4 v. Q1 (95 % CI) = 0·59 (0·45, 0·79); DHA: ORQ4 v. Q1 (95 % CI) = 0·50 (0·37, 0·67)). The inverse associations were observed between ALA and odds of breast cancer in postmenopausal women, and between DHA and oestrogen receptor+ breast cancer. This study showed that erythrocyte membrane total and individual n-3 PUFA were inversely associated with odds of breast cancer. Other factors, such as menopause and hormone receptor status, may warrant further investigation when examining the association between n-3 PUFA and odds of breast cancer.

Phosphate deficiency induced by infection promotes synthesis of anthracnose-resistant anthocyanin-3-O-galactoside phytoalexins in the Camellia sinensis plant.

Tea (Camellia sinensis) is a well-known beverage crop rich in polyphenols with health benefits for humans. Understanding how tea polyphenols participate in plant resistance is beneficial to breeding resistant varieties and uncovering the resistance mechanisms. Here, we report that a Colletotrichum infection-induced 'pink ring' symptom appeared outside the lesion, which is highly likely to occur in resistant cultivars. By identifying morphological feature-specific metabolites in the pink ring and their association with disease resistance, and analysis of the association between metabolite and gene expression, the study revealed that the accumulation of anthocyanin-3-O-galactosides, red phytotoxin compounds resistant to anthracnose, plays a pivotal role in the hypersensitive response surrounding infection sites in tea plants. The results of genetic manipulation showed that the expression of CsF3Ha, CsANSa, CsUGT78A15, CsUGT75L43, and CsMYB113, which are involved in anthocyanin biosynthesis, is positively correlated with anthracnose-resistance and the formation of the pink ring. Further phosphorus quantification and fertilization experiments confirmed that phosphate deficiency caused by anthracnose is involved in the occurrence of the pink ring. Genetic manipulation studies indicated that altering the expression levels of Pi transporter proteins (CsPHT2-1, CsPHT4;4) and phosphate deprivation response transcription factors (CsWRKY75-1, CsWRKY75-2, CsMYB62-1) enhances resistance to anthracnose and the formation of the pink ring symptom in tea plants. This article provides the first evidence that anthocyanin-3-O-galactosides are the anthracnose-resistant phytoalexins among various polyphenols in tea plants, and this presents an approach for identifying resistance genes in tea plants, where genetic transformation is challenging.

Radiomics nomogram for prediction of glypican-3 positive hepatocellular carcinoma based on hepatobiliary phase imaging.

Introduction: The hepatobiliary-specific phase can help in early detection of changes in lesion tissue density, internal structure, and microcirculatory perfusion at the microscopic level and has important clinical value in hepatocellular carcinoma (HCC). Therefore, this study aimed to construct a preoperative nomogram for predicting the positive expression of glypican-3 (GPC3) based on gadoxetic acid-enhanced (Gd-EOB-DTPA) MRI hepatobiliary phase (HBP) radiomics, imaging and clinical feature. Methods: We retrospectively included 137 patients with HCC who underwent Gd-EOB-DTPA-enhanced MRI and subsequent liver resection or puncture biopsy at our hospital from January 2017 to December 2021 as training cohort. Subsequently collected from January 2022 to June 2023 as a validation cohort of 49 patients, Radiomic features were extracted from the entire tumor region during the HBP using 3D Slicer software and screened using a t-test and least absolute shrinkage selection operator algorithm (LASSO). Then, these features were used to construct a radiomics score (Radscore) for each patient, which was combined with clinical factors and imaging features of the HBP to construct a logistic regression model and subsequent nomogram model. The clinicoradiologic, radiomics and nomogram models performance was assessed by the area under the curve (AUC), calibration, and decision curve analysis (DCA). In the validation cohort,the nomogram performance was assessed by the area under the curve (AUC). Results: In the training cohort, a total of 1688 radiomics features were extracted from each patient. Next, radiomics with ICCs<0.75 were excluded, 1587 features were judged as stable using intra- and inter-class correlation coefficients (ICCs), 26 features were subsequently screened using the t-test, and 11 radiomics features were finally screened using LASSO. The nomogram combining Radscore, age, serum alpha-fetoprotein (AFP) >400ng/mL, and non-smooth tumor margin (AUC=0.888, sensitivity 77.7%, specificity 91.2%) was superior to the radiomics (AUC=0.822, sensitivity 81.6%, specificity 70.6%) and clinicoradiologic (AUC=0.746, sensitivity 76.7%, specificity 64.7%) models, with good consistency in calibration curves. DCA also showed that the nomogram had the highest net clinical benefit for predicting GPC3 expression.In the validation cohort, the ROC curve results showed predicted GPC3-positive expression nomogram model AUC, sensitivity, and specificity of 0.800, 58.5%, and 100.0%, respectively. Conclusion: HBP radiomics features are closely associated with GPC3-positive expression, and combined clinicoradiologic factors and radiomics features nomogram may provide an effective way to non-invasively and individually screen patients with GPC3-positive HCC.

CAFs targeted ultrasound-responsive nanodroplets loaded V9302 and GLULsiRNA to inhibit melanoma growth via glutamine metabolic reprogramming and tumor microenvironment remodeling.

Despite rapid advances in metabolic therapies over the past decade, their efficacy in melanoma has been modest, largely due to the interaction between cancer-associated fibroblasts (CAFs) and cancer cells to promote cancer growth. Altering the tumor microenvironment (TME) is challenging and elusive. CAFs is critical for glutamine deprivation survival in melanoma. In this research, we assembled a CAFs-targeted, controlled-release nanodroplets for the combined delivery of the amino acid transporter ASCT2 (SLC1A5) inhibitor V9302 and GLULsiRNA (siGLUL). The application of ultrasound-targeted microbubble disruption (UTMD) allows for rapid release of V9302 and siGLUL, jointly breaking the glutamine metabolism interaction between CAFs and cancer cells on one hand, on the other hand, blocking activated CAFs and reducing the expression of extracellular matrix (ECM) to facilitate drug penetration. In addition, ultrasound stimulation made siGLUL more accessible to tumor cells and CAFs, downregulating GLUL expression in both cell types. FH-V9302-siGLUL-NDs also serve as contrast-enhanced ultrasound imaging agents for tumor imaging. Our study developed and reported FH-NDs as nanocarriers for V9302 and siGLUL, demonstrating that FH-V9302-siGLUL-NDs have potential bright future applications for integrated diagnostic therapy. Graphical Abstract.

Prevalence trend and burden of neglected parasitic diseases in China from 1990 to 2019: findings from global burden of disease study.

Objective: This study sought to investigate the parasitic diseases of neglected tropical diseases defined by the World Health Organization based on the Global Burden of Disease Study (GBD) database. Importantly, we analyzed the prevalence and burden of these diseases in China from 1990 to 2019 to provide valuable information to formulate more effective measures for their management and prevention. Methods: Data on the prevalence and burden of neglected parasitic diseases in China from 1990 to 2019 were extracted from the global health data exchange (GHDx) database, including the absolute number of prevalence, age-standardized prevalence rate, disability-adjusted life year (DALY) and age-standardized DALY rate. Descriptive analysis was used to analyze the prevalence and burden changes, sex and age distribution of various parasitic diseases from 1990 to 2019. A time series model [Auto-Regressive Integrated Moving Average (ARIMA)] was used to predict the DALYs of neglected parasitic diseases in China from 2020 to 2030. Results: In 2019, the number of neglected parasitic diseases in China was 152518062, the age-standardized prevalence was 11614.1 (95% uncertainty interval (UI) 8758.5-15244.5), the DALYs were 955722, and the age-standardized DALY rate was 54.9 (95% UI 26.0-101.8). Among these, the age-standardized prevalence of soil-derived helminthiasis was the highest (9370.2/100,000), followed by food-borne trematodiases (1502.3/100,000) and schistosomiasis (707.1/100,000). The highest age-standardized DALY rate was for food-borne trematodiases (36.0/100,000), followed by cysticercosis (7.9/100,000) and soil-derived helminthiasis (5.6/100,000). Higher prevalence and disease burden were observed in men and the upper age group. From 1990 to 2019, the number of neglected parasitic diseases in China decreased by 30.4%, resulting in a decline in DALYs of 27.3%. The age-standardized DALY rates of most diseases were decreased, especially for soil-derived helminthiasis, schistosomiasis and food-borne trematodiases. The ARIMA prediction model showed that the disease burden of echinococcosis and cysticercosis exhibited an increasing trend, highlighting the need for further prevention and control. Conclusion: Although the prevalence and disease burden of neglected parasitic diseases in China have decreased, many issues remain to be addressed. More efforts should be undertaken to improve the prevention and control strategies for different parasitic diseases. The government should prioritize multisectoral integrated control and surveillance measures to prioritize the prevention and control of diseases with a high burden of disease. In addition, the older adult population and men need to pay more attention.

FGF19-Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer.

Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver-metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer-associated fibroblasts (iCAFs) by activating the autocrine effect of IL-1α via the FGFR4-JAK2-STAT3 pathway. FGF19-induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL-1ß, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19-induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.

Ultrasound-Targeted Microbubble Disruption with Key Nanodroplets for Effective Ferroptosis in Triple-Negative Breast Cancer Using Animal Model.

Introduction: Triple-negative breast cancer (TNBC) is known to be the most aggressive form of breast cancer. Due to its high recurrence and mortality rates, the treatment of TNBC is a significant challenge for the medical community. Besides, ferroptosis is an emerging regulatory cell death that may provide new insights into the treatment of TNBC. As a central inhibitor of the ferroptosis process, the selenoenzyme glutathione peroxidase 4 (GPX4) is its classical therapeutic target. However, inhibition of GPX4 expression is quite detrimental to normal tissues. Ultrasound contrast agents, as an emerging visualization precision treatment, may provide a solution to the existing problem. Methods: In this study, nanodroplets (NDs) carrying simvastatin (SIM) were constructed using the homogeneous/emulsification method. Then, the characterization of SIM-NDs was systematically evaluated. Meanwhile, in this study, the ability of SIM-NDs combined with ultrasound-targeted microbubble disruption (UTMD) to initiate ferroptosis and its respective mechanisms of ferroptosis induction were verified. Finally, the antitumor activity of SIM-NDs was investigated in vitro and in vivo using MDA-MB-231 cells and TNBC animal models. Results: SIM-NDs exhibited excellent pH- and ultrasound-responsive drug release and noticeable ultrasonographic imaging ability, also showing good biocompatibility and biosafety. UTMD could promote increased intracellular reactive oxygen species and consume intracellular glutathione. However, SIM-NDs were efficiently internalized into cells under ultrasound irradiation, followed by the rapid release of SIM, which inhibited intracellular mevalonate production, and synergistically downregulated GPX4 expression, thereby promoting ferroptosis. Moreover, this combined treatment demonstrated strong antitumor ability in vitro and in vivo. Conclusion: The combination of UTMD and SIM-NDs presents a promising avenue for harnessing ferroptosis in the treatment of malignant tumors.

Inhibition of interleukin-6 trans-signaling improves survival and prevents cognitive impairment in a mouse model of sepsis.

Sepsis-associated encephalopathy (SAE) manifests clinically as acute and chronic cognitive impairments, which is associated with increased morbidity and mortality. Interleukin-6 (IL-6), a pro-inflammatory cytokine, is consistently up-regulated in sepsis. IL-6 initiates proinflammatory effects after binding to soluble IL-6 receptor (IL-6R) through trans-signalling, which requires the transducer gp130. In this study, we investigated whether inhibition of IL-6 trans-signalling is a putative therapeutic target for sepsis and SAE. Twenty-five patients (12 septic and 13 non-septic patients) were recruited for the study. A significant increase of IL-6, IL-1ß, IL-10, and IL-8 was observed in the septic patients 24 h after ICU admission. In animal study, cecal ligation and puncture (CLP) was used to induce sepsis in male C57BL/6J mice. One hour before or after inducing sepsis, mice were treated with sgp130, a selective IL-6 trans-signaling inhibitor, respectively. Survival rate, cognition, levels of inflammatory cytokines, integrity of blood-brain barrier (BBB), and oxidative stress were assessed. In addition, immune cells activation and transmigration were evaluated in peripheral blood and brains. Sgp130 improved survival rate and cognitive functions, reduced levels of inflammatory cytokines, including IL-6, TNF-α, IL-10, and MCP-1, in plasma and hippocampus (hipp), mitigated BBB disruption, and ameliorated sepsis-induced oxidative stress. Sgp130 also affected monocytes/macrophages and lymphocytes transmigration and activation in septic mice. Our results indicate that selective inhibition of IL-6 trans-signaling by sgp130 exerts protective effects against SAE in a mouse model of sepsis, suggesting a potential therapeutic strategy.

Serum Saturated Fatty Acids including Very Long-Chain Saturated Fatty Acids and Colorectal Cancer Risk among Chinese Population.

The association between circulating saturated fatty acids (SFAs) including very long-chain SFAs (VLCSFAs) and colorectal cancer (CRC) risk has not been clearly established. To investigate the association between serum SFAs and CRC risk in Chinese population, 680 CRC cases and 680 sex and age-matched (5-year interval) controls were recruited in our study. Serum levels of SFAs were detected by gas chromatography. Unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between serum SFAs and CRC risk. Results showed that total SFAs were positively associated with the risk of CRC (adjusted OR quartile 4 vs. 1 = 2.64, 95%CI: 1.47-4.74). However, VLCSFAs were inversely associated with CRC risk (adjusted OR quartile 4 vs. 1 = 0.51, 95%CI: 0.36-0.72). Specifically, lauric acid, myristic acid, palmitic acid, heptadecanoic acid, and arachidic acid were positively associated with CRC risk, while behenic acid and lignoceric acid were inversely associated with CRC risk. This study indicates that higher levels of total serum SFAs and lower levels of serum VLCSFAs were associated with an increased risk of CRC in Chinese population. To reduce the risk of CRC, we recommend reducing the intake of foods containing palmitic acid and heptadecanoic acid such as animal products and dairy products, and moderately increasing the intake of foods containing VLCSFAs such as peanuts and canola oil.

pH-/Redox-Responsive Nanodroplet Combined with Ultrasound-Targeted Microbubble Destruction for the Targeted Treatment of Drug-Resistant Triple Negative Breast Cancer.

Multiple drug resistance (MDR) exists in divergent cancers including triple negative breast cancer (TNBC) and partly results in the resistance to many first-line anti-cancer agents, bringing a big challenge to TNBC management. To develop novel TNBC therapeutics, in our study, a hyaluronic acid (HA)-carboxymethyl chitosan (CMC) conjugate linked via a disulfide-bond (HA-SS-CMC, HSC) was synthesized to fabricate nanodroplets (NDs). The NDs encapsulating doxorubicin (DOX) and perfluorohexane (DOX-HSC-NDs) were prepared via a homogenization/emulsification strategy and exhibited not only high biocompatibility but also noticeable tumor cell targeting ability and dual pH/redox responsiveness. Besides, DOX-HSC-NDs can be used as a contrast-enhanced ultrasound imaging agent for specific tumor imaging. DOX-HSC-NDs in combination with ultrasound targeted microbubble destruction could improve intracellular drug aggregation and retention of MDR cells and work against multiple mechanisms of drug resistance through synergistic strategies, including up-regulating the reactive oxygen species (ROS) level, promoting apoptosis, and scavenging glutathione, while reducing the expression levels of P-glycoprotein and inhibiting the epithelial-mesenchymal transition. This combination strategy showed protective effects against TNBC in both MDA-MB-231/ADR cells and tumor-bearing mice. Our study for the first time developed and reported the ultrasound-augmented HSC-NDs as the DOX nanocarrier and provided scientific evidence to support the future application of DOX-HSC-NDs as a potential TNBC therapy.

Serum levels of n-3 PUFA and colorectal cancer risk in Chinese population.

Circulating n-3 PUFA, which integrate endogenous and exogenous n-3 PUFA, can be better used to investigate the relationship between n-3 PUFA and disease. However, studies examining the associations between circulating n-3 PUFA and colorectal cancer (CRC) risk were limited, and the results remained inconclusive. This case­control study aimed to examine the association between serum n-3 PUFA and CRC risk in Chinese population. A total of 680 CRC cases and 680 sex- and age-matched (5-year interval) controls were included. Fatty acids were assayed by GC. OR and 95 % CI were calculated using multivariable logistic regression after adjustment for potential confounders. Higher level of serum α-linolenic acid (ALA), docosapentaenoic acid (DPA), DHA, long-chain n-3 PUFA and total n-3 PUFA were associated with lower odds of CRC. The adjusted OR and 95 % CI were 0·34 (0·24, 0·49, Pfor trend < 0·001) for ALA, 0·57 (0·40, 0·80, Pfor trend < 0·001) for DPA, 0·48 (0·34, 0·68, Pfor trend < 0·001) for DHA, 0·39 (0·27, 0·56, Pfor trend < 0·001) for long-chain n-3 PUFA and 0·31 (0·22, 0·45, Pfor trend < 0·001) for total n-3 PUFA comparing the highest with the lowest quartile. However, there was no statistically significant association between EPA and odds of CRC. Analysis stratified by sex showed that ALA, DHA, long-chain n-3 PUFA and total n-3 PUFA were inversely associated with odds of CRC in both sexes. This study indicated that serum ALA, DPA, DHA, long-chain n-3 PUFA and total n-3 PUFA were inversely associated with odds of having CRC in Chinese population.

Predictive models and early postoperative recurrence evaluation for hepatocellular carcinoma based on gadoxetic acid-enhanced MR imaging.

BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) is still poor largely due to the high incidence of recurrence. We aimed to develop and validate predictive models of early postoperative recurrence for HCC using clinical and gadoxetic acid-enhanced magnetic resonance (MR) imaging-based findings. METHODS: In this retrospective case-control study, 209 HCC patients, who underwent gadoxetic acid-enhanced MR imaging before curative-intent resection, were enrolled. Boruta algorithm and backward stepwise selection with Akaike information criterion (AIC) were used for variables selection Random forest, Gradient-Boosted decision tree and logistic regression model analysis were used for model development. The area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis were used to evaluate model's performance. RESULTS: One random forest model with Boruta algorithm (RF-Boruta) was developed consisting of preoperative serum ALT and AFP levels and six MRI findings, while preoperative serum AST and AFP levels and four MRI findings were included in one logistic regression model with backward stepwise selection method (Logistic-AIC).The two predictive models demonstrated good discrimination performance in both the training set (RF-Boruta: AUC, 0.820; Logistic-AIC: AUC, 0.853), internal validation set (RF-Boruta: AUC, 0.857, Logistic-AIC: AUC, 0.812) and external validation set(RF-Boruta: AUC, 0.805, Logistic-AIC: AUC, 0.789). Besides, in both the internal validation and external validation sets, the RF-Boruta model outperformed Barcelona Clinic Liver Cancer (BCLC) stage (p < 0.05). CONCLUSIONS: The RF-Boruta and Logistic-AIC models with good prediction performance for early postoperative recurrence may lead to optimal and comprehensive treatment approaches, and further improve the prognosis of HCC after resection.

Ultrasound targeted microbubble destruction-triggered nitric oxide release via nanoscale ultrasound contrast agent for sensitizing chemoimmunotherapy.

Immunotherapy had demonstrated inspiring effects in tumor treatment, but only a minority of people could benefit owing to the hypoxic and immune-suppressed tumor microenvironment (TME). Therefore, there was an urgent need for a strategy that could relieve hypoxia and increase infiltration of tumor lymphocytes simultaneously. In this study, a novel acidity-responsive nanoscale ultrasound contrast agent (L-Arg@PTX nanodroplets) was constructed to co-deliver paclitaxel (PTX) and L-arginine (L-Arg) using the homogenization/emulsification method. The L-Arg@PTX nanodroplets with uniform size of about 300 nm and high drug loading efficiency displayed good ultrasound diagnostic imaging capability, improved tumor aggregation and achieved ultrasound-triggered drug release, which could prevent the premature leakage of drugs and thus improve biosafety. More critically, L-Arg@PTX nanodroplets in combination with ultrasound targeted microbubble destruction (UTMD) could increase cellular reactive oxygen species (ROS), which exerted an oxidizing effect that converted L-Arg into nitric oxide (NO), thus alleviating hypoxia, sensitizing chemotherapy and increasing the CD8 + cytotoxic T lymphocytes (CTLs) infiltration. Combined with the chemotherapeutic drug PTX-induced immunogenic cell death (ICD), this promising strategy could enhance immunotherapy synergistically and realize powerful tumor treatment effect. Taken together, L-Arg@PTX nanodroplets was a very hopeful vehicle that integrated drug delivery, diagnostic imaging, and chemoimmunotherapy.

How to manage isolated tension non-surgical pneumoperitonium during bronchoscopy? A case report.

BACKGROUND: Tension pneumoperitonium is a rare complication during bronchoscopy that can cause acute respiratory and hemodynamic failure, with fatal consequences. Isolated pneumoperitonium during bronchoscopy usually results from ruptures of the abdominal viscera that need surgical repair. Non-surgical pneumoperitoneum (NSP) refers to some pneumoperitoneum that could be relieved without surgery and only by conservative therapy. However, the clinical experience of managing tension pneumoperitonium during bronchoscopy is limited and controversial. CASE SUMMARY: A 51-year-old female was admitted to our hospital for cough with bloody sputum of seven days. On the 8th day of her admission, a bronchoscopy was arranged for bronchial-alveolar lavage to detect possible pathogens in the lower respiratory tract, as oxygen was delivered via a 12 F nasopharyngeal cannula, approximately 5-6 cm from the tip of the catheter, with a flow rate of 5-10 L/min. After four minutes of bronchoscopy, the patient suddenly vomited 20 mL of water, followed by severe abdominal pain, while physical examination revealed obvious abdominal distension, as well as hardness and tenderness of the whole abdomen, which was considered pneumoperitonium, and the bronchoscopy was terminated immediately. A computer tomography scan indicated isolated tension pneumoperitonium, and abdominal decompression was performed with a drainage tube, after which her symptoms were relieved. A multidisciplinary expert consultation discussed her situation and a laparotomy was suggested, but finally refused by her family. She had no signs of peritonitis and was finally discharged 5 d after bronchoscopy with a good recovery. CONCLUSION: The possibility of tension pneumoperitonium during bronchoscopy should be guarded against, and given its serious clinical consequences, cardiopulmonary instability should be treated immediately. Varied strategies could be adopted according to whether it is complicated with pneumothorax or pneumomediastinum, and the presence of peritonitis. When considering NSP, conservative therapy maybe a reasonable option with good recovery. An algorithm for the management of pneumoperitonium during bronchoscopy is proposed, based on the features of the case series reviewed and our case reported.

Improving Reporter Gene Assay Methodology for Evaluating the Ability of Compounds to Restore P53 Activity.

Tumor suppressor protein P53 induces cycle arrest and apoptosis by mediating the transcriptional expression of its target genes. Mutations causing conformational abnormalities and post-translational modifications that promote degradation are the main reasons for the loss of P53 function in tumor cells. Reporter gene assays that can scientifically reflect the biological function can help discover the mechanism and therapeutic strategies that restore P53 function. In the reporter gene system of this work, tetracycline-inducible expression of wild-type P53 was used to provide a fully activated state as a 100% activity reference for the objective measurement of biological function. It was confirmed by RT-qPCR, cell viability assay, immunofluorescence, and Western blot analysis that the above-mentioned reporter gene system could correctly reflect the differences in biological activity between the wild-type and mutants. After that, the system was tentatively used for related mechanism research and compound activity evaluation. Through the tetracycline-induced co-expression of wild-type P53 and mutant P53 in exact proportion, it was observed that the response modes of typical transcriptional response elements (TREs) to dominant negative P53 mutation effect were not exactly the same. Compared to the relative multiple-to-solvent control, the activity percentage relative to the 100% activity reference of wild-type P53 can better reflect the actual influence of the so-called P53 mutant reactivator. Similarly, relative to the 100% activity reference, it can objectively reflect the biological effects caused by the inhibitor of P53 negative factors, such as MDM2. In conclusion, this study provides a 100% activity reference and a reliable calculation model for relevant basic research and drug development.