Devastating the Supply Wagons: Multifaceted Liposomes Capable of Exhausting Tumor to Death via Triple Energy Depletion.

The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.

TC2N inhibits distant metastasis and stemness of breast cancer via blocking fatty acid synthesis.

BACKGROUND: Tandem C2 domains, nuclear (TC2N) is a C2 domain-containing protein that belongs to the carboxyl-terminal type (C-type) tandem C2 protein family, and acts as an oncogenic driver in several cancers. Previously, we preliminarily reported that TC2N mediates the PI3K-Akt signaling pathway to inhibit tumor growth of breast cancer (BC) cells. Beyond that, its precise biological functions and detailed molecular mechanisms in BC development and progression are not fully understood. METHODS: Tumor tissues of 212 BC patients were subjected to tissue microarray and further assessed the associations of TC2N expression with pathological parameters and FASN expression. The protein levels of TC2N and FASN in cell lines and tumor specimens were monitored by qRT-PCR, WB, immunofluorescence and immunohistochemistry. In vitro cell assays, in vivo nude mice model was used to assess the effect of TC2N ectopic expression on tumor metastasis and stemness of breast cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics, proteomics and lipidomics, and the underlying mechanism was explored by WB and co-IP assays. RESULTS: Here, we found that the expression of TC2N remarkedly silenced in metastatic and poorly differentiated tumors. Function-wide, TC2N strongly inhibits tumor metastasis and stem-like properties of BC via inhibition of fatty acid synthesis. Mechanism-wise, TC2N blocks neddylated PTEN-mediated FASN stabilization by a dual mechanism. The C2B domain is crucial for nuclear localization of TC2N, further consolidating the TRIM21-mediated ubiquitylation and degradation of FASN by competing with neddylated PTEN for binding to FASN in nucleus. On the other hand, cytoplasmic TC2N interacts with import proteins, thereby restraining nuclear import of PTEN to decrease neddylated PTEN level. CONCLUSIONS: Altogether, we demonstrate a previously unidentified role and mechanism of TC2N in regulation of lipid metabolism and PTEN neddylation, providing a potential therapeutic target for anti-cancer.

Turning Polysaccharides into Injectable and Rapid Self-Healing Antibacterial Hydrogels for Antibacterial Treatment and Bacterial-Infected Wound Healing.

Great efforts have been devoted to the development of novel and multifunctional wound dressing materials to meet the different needs of wound healing. Herein, we covalently grafted quaternary ammonium groups (QAGs) containing 12-carbon straight-chain alkanes to the dextran polymer skeleton. We then oxidized the resulting product into oxidized quaternized dextran (OQD). The obtained OQD polymer is rich in antibacterial QAGs and aldehyde groups. It can react with glycol chitosan (GC) via the Schiff-base reaction to form a multifunctional GC@OQD hydrogel with good self-healing behavior, hemostasis, injectability, inherent superior antibacterial activity, biocompatibility, and excellent promotion of healing of methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds. The biosafe and nontoxic GC@OQD hydrogel with a three-dimensional porous network structure possesses an excellent swelling rate and water retention capacity. It can be used for hemostasis and treating irregular wounds. The designed GC@OQD hydrogel with inherent antibacterial activity possesses good antibacterial efficacy on both S. aureus (Gram-positive bacteria) and Escherichia coli (Gram-negative bacteria), as well as MRSA bacteria, with antibacterial activity greater than 99%. It can be used for the treatment of wounds infected by MRSA and significantly promotes the healing of wounds. Thus, the multifunctional antibacterial GC@OQD hydrogel has the potential to be applied in clinical practice as a wound dressing.

Evaluation of Low-Cost CO2 Sensors Using Reference Instruments and Standard Gases for Indoor Use.

CO2 monitoring is important for carbon emission evaluation. Low-cost and medium-precision sensors (LCSs) have become an exploratory direction for CO2 observation under complex emission conditions in cities. Here, we used a calibration method that improved the accuracy of SenseAir K30 CO2 sensors from ±30 ppm to 0.7-4.0 ppm for a CO2-monitoring instrument named the SENSE-IAP, which has been used in several cities, such as in Beijing, Jinan, Fuzhou, Hangzhou, and Wuhan, in China since 2017. We conducted monthly to yearly synchronous observations using the SENSE-IAP along with reference instruments (Picarro) and standard gas to evaluate the performance of the LCSs for indoor use with relatively stable environments. The results show that the precision and accuracy of the SENSE-IAP compared to the standard gases were rather good in relatively stable indoor environments, with the short-term (daily scale) biases ranging from -0.9 to 0.2 ppm, the root mean square errors (RMSE) ranging from 0.7 to 1.6 ppm, the long-term (monthly scale) bias ranging from -1.6 to 0.5 ppm, and the RMSE ranging from 1.3 to 3.2 ppm. The accuracy of the synchronous observations with Picarro was in the same magnitude, with an RMSE of 2.0-3.0 ppm. According to our evaluation, standard instruments or reliable standard gases can be used as a reference to improve the accuracy of the SENSE-IAP. If calibrated daily using standard gases, the bias of the SENSE-IAP can be maintained within 1.0 ppm. If the standard gases are hard to access frequently, we recommend a calibration frequency of at least three months to maintain an accuracy within 3 ppm.

Significant contribution of carbonyls to atmospheric oxidation capacity (AOC) during the winter haze pollution over North China Plain.

Atmospheric carbonyl compounds play significant roles in the cycling of radicals and have exhibited surprisingly high levels in winter that were well correlated to particulate matter, for which the reason have not been clearly elucidated. Here we measured carbonyl compounds and other trace gasses together with PM2.5 over urban Jinan in North China Plain during the winter. Markedly higher carbonyl concentrations (average: 14.63 ± 4.21 ppbv) were found during wintertime haze pollution, about one to three-times relative to those on non-haze days, with slight difference in chemical composition except formaldehyde (HCHO). HCHO (3.68 ppbv), acetone (3.17 ppbv), and acetaldehyde (CH3CHO) (2.83 ppbv) were the three most abundant species, accounting for ∼75% of the total carbonylson both haze and non-haze days. Results from observational-based model (OBM) with atmospheric oxidation capacity (AOC) indicated that AOC significantly increased with the increasing carbonyls during the winter haze events. Carbonyl photolysis have supplied key oxidants such as RO2 and HO2, and thereby enhancing the formation of fine particles and secondary organic aerosols, elucidating the observed haze-carbonyls inter-correlation. Diurnal variation with carbonyls exhibiting peak values at early-noon and night highlighted the combined contribution of both secondary formation and primary diesel-fuel sources. 1-butene was further confirmed to be the major precursor for HCHO. This study confirms the great contribution of carbonyls to AOC, and also suggests that reducing the emissions of carbonyls would be an effective way to mitigate haze pollution in urban area of the NCP region.

Antioxidant and antibacterial hydrogel formed by protocatechualdehyde-ferric iron complex and aminopolysaccharide for infected wound healing.

To better treat bacteria-infected wounds and promote healing, new wound dressings must be developed. In this study, we obtained PA@Fe by chelating iron trivalent ions (Fe3+) with protocatechualdehyde (PA), which has a catechol structure. Subsequently, we reacted it with ethylene glycol chitosan (GC) via a Schiff base reaction and loaded vancomycin to obtain an antibacterial Gel@Van hydrogel with a photothermal response. The as-prepared Gel@Van hydrogel exhibited good injectability, self-healing, hemostasis, photothermal stability, biocompatibility, and antioxidant and antibacterial properties. Moreover, Gel@Van hydrogel achieved highly synergistic antibacterial efficacy through photothermal and antibiotic sterilization. In a mouse skin-damaged infection model, Gel@Van hydrogel had a strong ability to promote the healing of methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds, indicating the great potential application value of Gel@Van hydrogel in the field of treating and promoting the healing of infected wounds.

Prognostic value of lymph node-to-primary tumor ratio of PET standardized uptake value for nasopharyngeal carcinoma: a recursive partitioning risk stratification analysis.

Background: Induction chemotherapy (IC) combined with concurrent chemoradiotherapy has become the standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Data on the prognostic value of the lymph node-to-primary tumor ratio (NTR) of positron emission tomography (PET) standardized uptake value (SUV) for patients treated with IC were limited. Objectives: To evaluate the prognostic value of the SUV NTR for patients with LA-NPC treated with IC. Design: In all, 467 patients with pretreatment 18F-fluorodeoxyglucose PET/computed tomography (CT) scans between September 2017 and November 2020 were retrospectively reviewed. Methods: The receiver operating characteristic (ROC) analysis was used to determine the optimal cut-off value of SUV NTR. Kaplan-Meier method was used to evaluate survival rates. The recursive partitioning analysis (RPA) was performed to construct a risk stratification model. Results: The optimal cutoff value of SUV NTR was 0.74. Multivariate analyses showed that SUV NTR and overall stage were independent predictors for distant metastasis-free survival (DMFS) and regional recurrent-free survival (RRFS). Therefore, an RPA model based on the endpoint of DMFS was generated and categorized the patients into three distinct risk groups: RPA I (low risk: SUV NTR < 0.74 and stage III), RPA II (medium risk: SUV NTR < 0.74 and stage IVa, or SUV NTR ⩾ 0.74 and stage III), and RPA III (high risk: SUV NTR ⩾ 0.74 and stage IVa), with a 3-year DMFS of 98.9%, 93.4%, and 84.2%, respectively. ROC analysis showed that the RPA model had superior predictive efficacy than the SUV NTR or overall stage alone. Conclusion: SUV NTR was an independent prognosticator for distant metastasis and regional recurrence in locoregionally advanced NPC. The RPA risk stratification model based on SUV NTR provides improved DMFS and RRFS prediction over the eighth edition of the TNM (Tumor Node Metastasis) staging system.

Soluble ST2 is a biomarker associated with left ventricular hypertrophy and concentric hypertrophy in patients with essential hypertension.

BACKGROUND: Elevated soluble stimulating factor 2 (sST2) level is observed in cardiovascular diseases, such as heart failure and acute coronary syndrome, which reflects myocardial fibrosis and hypertrophy, indicating adverse clinical outcomes. However, the association between sST2 and hypertensive heart disease are less understood. This study aimed to determine the relationship of sST2 with left ventricular hypertrophy (LVH) and geometric remodeling in essential hypertension (EH). METHODS: We enrolled 483 patients (aged 18-80 years; 51.35% female). sST2 measurements and echocardiographic analyses were performed. RESULTS: Stepwise multiple linear regression analysis showed significant associations between sST2, left ventricular (LV) mass, and LV mass index. The prevalence of LVH and concentric hypertrophy (CH) increased with higher sST2 grade levels (p for trend<0.05). Logistic regression analysis suggested that the highest tertile of sST2 was significantly associated with increased LVH risk, compared with the lowest tertile (multivariate-adjusted odds ratio [OR] of highest group: 6.61; p<0.001). Similar results were observed in the left ventricular geometric remodeling; the highest tertile of sST2 was significantly associated with increased CH risk (multivariate-adjusted OR of highest group: 5.80; p<0.001). The receiver operating characteristic analysis results revealed that sST2 had potential predictive value for LVH (area under the curve [AUC]: 0.752, 95% confidence interval [CI]: 0.704-0.800) and CH (AUC: 0.750, 95% CI: 0.699-0.802) in patients with EH. CONCLUSIONS: High sST2 level is strongly related to LVH and CH in patients with EH and can be used as a biomarker for the diagnosis and risk assessment of hypertensive heart disease.

Nomogram-based risk assessment model for left ventricular hypertrophy in patients with essential hypertension: Incorporating clinical characteristics and biomarkers.

Left ventricular hypertrophy (LVH) is a hypertensive heart disease that significantly escalates the risk of clinical cardiovascular events. Its etiology potentially incorporates various clinical attributes such as gender, age, and renal function. From mechanistic perspective, the remodeling process of LVH can trigger increment in certain biomarkers, notably sST2 and NT-proBNP. This multicenter, retrospective study aimed to construct an LVH risk assessment model and identify the risk factors. A total of 417 patients with essential hypertension (EH), including 214 males and 203 females aged 31-80 years, were enrolled in this study; of these, 161 (38.6%) were diagnosed with LVH. Based on variables demonstrating significant disparities between the LVH and Non-LVH groups, three multivariate stepwise logistic regression models were constructed for risk assessment: the "Clinical characteristics" model, the "Biomarkers" model (each based on their respective variables), and the "Clinical characteristics + Biomarkers" model, which amalgamated both sets of variables. The results revealed that the "Clinical characteristics + Biomarkers" model surpassed the baseline models in performance (AUC values of the "Clinical characteristics + Biomarkers" model, the "Biomarkers" model, and the "Clinical characteristics" model were .83, .75, and .74, respectively; P < .0001 for both comparisons). The optimized model suggested that being female (OR: 4.26, P <.001), being overweight (OR: 1.88, p = .02) or obese (OR: 2.36, p = .02), duration of hypertension (OR: 1.04, P = .04), grade III hypertension (OR: 2.12, P < .001), and sST2 (log-transformed, OR: 1.14, P < .001) were risk factors, while eGFR acted as a protective factor (OR: .98, P = .01). These findings suggest that the integration of clinical characteristics and biomarkers can enhance the performance of LVH risk assessment.

Delta magnetic resonance imaging radiomics features­based nomogram predicts long­term efficacy after induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: To establish and validate a delta-radiomics-based model for predicting progression-free survival (PFS) in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) following induction chemotherapy (IC). METHODS AND MATERIALS: A total of 250 LA-NPC patients (training cohort: n = 145; validation cohort: n = 105) were enrolled. Radiomic features were extracted from MRI scans taken before and after IC, and changes in these features were calculated. Following feature selection, a delta-radiomics signature was constructed using LASSO-Cox regression analysis. A prognostic nomogram incorporating independent clinical indicators and the delta-radiomics signature was developed and assessed for calibration and discrimination. Risk stratification by the nomogram was evaluated using Kaplan-Meier methods. RESULTS: The delta-radiomics signature, consisting of 12 features, was independently associated with prognosis. The nomogram, integrating the delta-radiomics signature and clinical factors demonstrated excellent calibration and discrimination. The model achieved a Harrell's concordance index (C-index) of 0.848 in the training cohort and 0.820 in the validation cohort. Risk stratification identified two groups with significantly different PFS rates. The three-year PFS for high-risk patients who received concurrent chemoradiotherapy (CCRT) or radiotherapy plus adjuvant chemotherapy (RT+AC) after IC was significantly higher than for those who received RT alone, reaching statistical significance. In contrast, for low-risk patients, the three-year PFS after IC was slightly higher for those who received CCRT or RT+AC compared to those who received RT alone; however, this difference did not reach statistical significance. CONCLUSIONS: Our delta MRI-based radiomics model could be useful for predicting PFS and may guide subsequent treatment decisions after IC in LA-NPC.

The lncRNA-MALAT1/miR-330-3p Axis Promotes Growth and Metastasis of Gastric Cancer Through Regulation of Vascular Endothelial Growth Factor A: A Genetic and Cell Evaluation Study

SUMMARY: Overexpression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in various tumor tissues and cell lines was found to promote tumor cell proliferation, migration, and invasion. However, the role of MALAT1 in gastric cancer (GC) is still unclear. We aimed to investigate the correlation between long-chain non-coding RNAs (lncRNAs), MALAT1, MicroRNAs (miRNA) and vascular endothelial growth factor A (VEGFA) in gastric cancer and to disclose underlying mechanism. The correlation between MALAT1 levels and clinical features was analyzed by bioinformatics data and human samples. The expression of MALAT1 was down regulated in AGS cells to detect the cell proliferation, migration, and invasion characteristics, as well as the effects on signal pathways. Furthermore, we validated the role of MALAT1/miR-330-3p axis in GC by dual luciferase reporter gene assays. Expression of MALAT1 was higher in cancer tissues than in para-cancerous tissues. The high MALAT1 level predicted malignancy and worse prognosis. Down-regulation of MALAT1 expression in AGS cells inhibited cell proliferation, migration, and invasion by targeting VEGFA. By dual luciferase reporter gene assay and miR-330-3p inhibitor treatment, we demonstrate that MALAT1 sponged miR-330-3p in GC, leading to VEGFA upregulation and activation of the mTOR signaling pathway. The MALAT1/miR-330-3p axis regulates VEGFA through the mTOR signaling pathway and promotes the growth and metastasis of gastric cancer.

Se descubrió que la sobreexpresión del transcrito 1 de adenocarcinoma de pulmón asociado a metástasis (MALAT1) en varios tejidos tumorales y líneas celulares promueve la proliferación, migración e invasión de células tumorales. Sin embargo, el papel de MALAT1 en el cáncer gástrico (CG) aún no está claro. Nuestro objetivo fue investigar la correlación entre los ARN no codificantes de cadena larga (lncRNA), MALAT1, los microARN (miARN) y el factor de crecimiento endotelial vascular A (VEGFA) en el cáncer gástrico y revelar el mecanismo subyacente. La correlación entre los niveles de MALAT1 y las características clínicas se analizó mediante datos bioinformáticos y muestras humanas. La expresión de MALAT1 se reguló negativamente en las células AGS para detectar las características de proliferación, migración e invasión celular, así como los efectos sobre las vías de señales. Además, validamos el papel del eje MALAT1/miR- 330-3p en GC mediante ensayos de genes indicadores de luciferasa dual. La expresión de MALAT1 fue mayor en tejidos cancerosos que en tejidos paracancerosos. El alto nivel de MALAT1 predijo malignidad y peor pronóstico. La regulación negativa de la expresión de MALAT1 en células AGS inhibió la proliferación, migración e invasión celular al apuntar a VEGFA. Mediante un ensayo de gen indicador de luciferasa dual y un tratamiento con inhibidor de miR-330-3p, demostramos que MALAT1 esponjaba miR-330-3p en GC, lo que lleva a la regulación positiva de VEGFA y la activación de la vía de señalización mTOR. El eje MALAT1/miR-330-3p regula VEGFA a través de la vía de señalización mTOR y promueve el crecimiento y la metástasis del cáncer gástrico.