High comprehensive properties of colorless transparent polyimide films derived from fluorine-containing and ether-containing dianhydride.

Fluorinated colorless transparent polyimide (CPI) films are crucial for flexible displays and wearable devices, but their development is limited by high costs and relatively low mechanical properties. In this study, a series of colorless transparent polyimide films was synthesized by incorporating the cost-effective ether-containing diamine, 4,4'-isopropylidenediphenoxy bis(phthalic anhydride) (BPADA), into commercially available 4,4'-(hexafluoroisopropyl)diphthalic anhydride (6FDA) and 2,2'-bis(trifluoromethyl)benzidine (TFMB). The comprehensive properties of the films were systematically investigated using a combination of experimental and numerical methods, including molecular dynamics (MD) simulations and density functional theory (DFT). This study focuses on exploring the influence of varying dianhydride ratios on the aforementioned properties. The incorporation of BPADA in the dianhydride significantly enhances the mechanical properties and flexibility of the film. When the ratio of ether anhydride to fluorine anhydride is 4 : 6 (CPI-4), the tensile strength is 135.3 MPa, and the elongation at break is 8.3%, which is 109.6% and 118.45% higher than that of the original film without ether anhydride. This research provides valuable insights for the future application of new polyimide materials in flexible display devices.

Nanotechnology in Advancing Chimeric Antigen Receptor T Cell Therapy for Cancer Treatment.

Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking treatment for hematological cancers, yet it faces significant hurdles, particularly regarding its efficacy in solid tumors and concerning associated adverse effects. This review provides a comprehensive analysis of the advancements and ongoing challenges in CAR-T therapy. We highlight the transformative potential of nanotechnology in enhancing CAR-T therapy by improving targeting precision, modulating the immune-suppressive tumor microenvironment, and overcoming physical barriers. Nanotechnology facilitates efficient CAR gene delivery into T cells, boosting transfection efficiency and potentially reducing therapy costs. Moreover, nanotechnology offers innovative solutions to mitigate cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cutting-edge nanotechnology platforms for real-time monitoring of CAR-T cell activity and cytokine release are also discussed. By integrating these advancements, we aim to provide valuable insights and pave the way for the next generation of CAR-T cell therapies to overcome current limitations and enhance therapeutic outcomes.

Abietane diterpenoids from Isodon amethystoides and their biological activities.

Seven undescribed abietane diterpenoids [abietamethinols A-G (1-7)] were isolated from the twigs and leaves of Isodon amethystoides. Their structures were elucidated on the basis of spectroscopic methods including 2D NMR, and they were further confirmed by X-ray crystallographic data. Lophanic acid was considered as the precursor of 1-7 in the biosynthesis pathway hypothesis. These compounds were evaluated for their cytotoxic, anti-bacterial and anti-AIV (avian influenza virus) activities. Compound 5 showed 42.9% inhibitory activity against the cancer cell line SMMC-7721 at the concentration of 40 µM, 3 and 4 could inhibit the bacterial growth of Streptococcus sobrinus by 55.3% and 63.2% at the concentrations of 148.6 and 141.9 µM, respectively, and 4 was demonstrated with antiviral activity against AIV with the inhibitory effect of 68.4% at 25 µM.

Outcomes of patients aged ≥26 years with relapsed or refractory B-cell acute lymphoblastic leukemia in ZUMA-3 and historical trials.

Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 CAR T-cell therapy approved in the USA and European Union (EU) for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL; aged ≥26 years in EU). Here, outcomes for patients with R/R B-ALL aged ≥26 years in ZUMA-3 treated with brexu-cel were compared with historical standard-of-care (SOC) therapy. After median follow-up of 26.8 months, the overall complete remission (CR) rate among patients treated with brexu-cel in Phase 2 (N = 43) was 72% and median overall survival (OS) was 25.4 months (95% CI, 15.9-NE). Median OS was improved in Phase 2 patients versus matched historical SOC-treated patients. Compared with aggregate historical trial data, Phase 1 and 2 patients had improved OS versus blinatumomab, inotuzumab, and chemotherapy in a matching-adjusted indirect comparison (MAIC) study. These data demonstrate clinical benefit of brexu-cel relative to SOC in patients ≥26 years with R/R B-ALL.

Baicalein alleviates cisplatin-induced acute kidney injury by inhibiting ALOX12-dependent ferroptosis.

BACKGROUND: In acute kidney injury (AKI), ferroptosis is the main mechanism of cell death in the renal tubular epithelium. Baicalein, a traditional Chinese medicine monomer, plays a protective role in various kidney diseases; however, the effect of baicalein on ferroptosis in AKI still needs further exploration. PURPOSE: In this study, we explored the role of baicalein and its specific mechanism in mediating ferroptosis in cisplatin-induced AKI. METHODS: We used a cisplatin-induced AKI model to study the effects of baicalein on renal tissue and tubular epithelial cell injury. The effects of baicalein on tubular epithelial cell ferroptosis were detected in cisplatin-induced AKI and further verified by folic acid-induced AKI. The Swiss Target Prediction online database was used to predict the possible mechanism by which baicalein regulates ferroptosis, and the specific target proteins were further verified. Molecular docking and SPR were used to further determine the binding potential of baicalein to the target protein. Finally, RNA interference (RNAi) technology and enzymatic inhibition were used to determine whether baicalein regulates ferroptosis through target proteins. RESULTS: Baicalein alleviated cisplatin- and folic acid-induced renal dysfunction and pathological damage and improved cisplatin-induced HK2 cell injury. Mechanistically, baicalein reduced the expression of 12-lipoxygenase (ALOX12), which inhibits phospholipid peroxidation and ferroptosis in AKI. Molecular docking and SPR demonstrated direct binding between baicalein and ALOX12. Finally, we found that silencing ALOX12 had a regulatory effect similar to that of baicalein. Comparable results were also obtained with the ALOX12 inhibitor ML355. CONCLUSION: This was the first study to confirm that baicalein regulates ferroptosis both in vitro and in vivo in cisplatin-induced AKI and to verify the regulatory effect of baicalein in folic acid-induced AKI. Our results reveal the critical role of ALOX12 in kidney damage and ferroptosis caused by cisplatin and emphasize the regulatory effect of baicalein on renal tubular epithelial cell ferroptosis mediated by ALOX12. Baicalein is an effective drug for treating AKI, and ALOX12 is a potential drug target.

Behind the Indolent Facade: Uncovering the Molecular Features and Malignancy Potential in Lung Minimally Invasive Adenocarcinoma by Single-Cell Transcriptomics.

The increased use of low-dose computed tomography screening has led to more frequent detection of early stage lung tumors, including minimally invasive adenocarcinoma (MIA). To unravel the intricacies of tumor cells and the immune microenvironment in MIA, this study performs a comprehensive single-cell transcriptomic analysis and profiles the transcriptomes of 156,447 cells from fresh paired MIA and invasive adenocarcinoma (IA) tumor samples, peripheral blood mononuclear cells, and adjacent normal tissue samples from three patients with synchronous multiple primary lung adenocarcinoma. This study highlights a connection and heterogeneity between the tumor ecosystem of MIA and IA. MIA tumor cells exhibited high expression of aquaporin-1 and angiotensin II receptor type 2 and a basal-like molecular character. Furthermore, it identifies that cathepsin B+ tumor-associated macrophages may over-activate CD8+ T cells in MIA, leading to an enrichment of granzyme K+ senescent CD8+ T cells, indicating the possibility of malignant progression behind the indolent appearance of MIA. These findings are further validated in 34 MIA and 35 IA samples by multiplexed immunofluorescence. These findings provide valuable insights into the mechanisms that maintain the indolent nature and prompt tumor progression of MIA and can be used to develop more effective therapeutic targets and strategies for MIA patients.

Study on Matrix Damage and Control Methods of Fracturing Fluid on Tight Sandstone Gas Reservoirs.

Hydraulic fracturing is a highly effective method for stimulating the development of gas reservoirs. However, the process of pumping fracturing fluid (FF) into the reservoir unavoidably causes damage to the surrounding matrix, leading to a decrease in the overall stimulation effect. To assess the extent of matrix permeability damage caused by the intrusion of FF, as well as its impact on the pore throat structure, and to propose appropriate measures to control this damage, we conducted a series of experimental studies on tight gas reservoirs. These studies included mercury intrusion, core flow, nitrogen adsorption, linear expansion, and contact angle measurements. The findings revealed that the damage inflicted on matrix permeability by FF was significantly greater than that caused by its gel-breaking counterpart. Surprisingly, the damage rate of the rejecting fluid to the matrix was found to be comparable to that of its gel-breaking counterpart. The fractal dimension (D2) was observed to have a strong correlation with surface area, pore volume, and mean pore size, making it an effective means of characterizing pore structure characteristics. After the rock samples were displaced by the formation water, the D2 value decreased, leading to a decrease in the complexity of the pore throat structure and an increase in matrix permeability. Conversely, the displacement of the FF increased the D2 value, indicating a gradual complication of the pore throat structure and a more uneven distribution of pore sizes. The inclusion of polyamide in antiexpansion FF, as well as its gel-breaking counterpart, proved to be effective in inhibiting the hydration and expansion of clay minerals, thereby reducing water-sensitive damage. Additionally, the use of surfactants with low surface tension enhanced the flowback rate of FF by increasing the contact angle and reducing the work of adhesion. This, in turn, helped to decrease the apparent water film thickness and expand gas flow channels, ultimately improving gas permeability.

Matching-Adjusted Indirect Comparisons of Brexucabtagene Autoleucel with Alternative Standard Therapies for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients.

INTRODUCTION: Brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, is approved for relapsed/refractory B-cell precursor acute lymphoblastic leukemia in adults aged 18+/26+ years in the US/European Union (EU), based on efficacy results from the single-arm ZUMA-3 trial. This study aimed to estimate the relative treatment effects of brexu-cel versus inotuzumab ozogamicin (InO), blinatumomab (blina), and chemotherapies using unanchored matching-adjusted indirect comparison (MAIC) methods. METHODS: Individual patient data from ZUMA-3 and published aggregate level data from two randomized controlled trials, INO-VATE (InO versus chemotherapy) and TOWER (blina versus chemotherapy), were used. Patient-level data from ZUMA-3 were weighted to match the mean of the following prognostic variables at baseline, which were pre-specified based on clinical input, for each comparator population: primary refractory disease, duration of first remission < 12 months, prior stem-cell transplantation, age, performance status, salvage status, bone marrow blast, complex karyotype, and Philadelphia chromosome status. The base case analysis was conducted using the modified intention-to-treat population (i.e., received brexu-cel) from ZUMA-3. Relative treatment effects for overall survival (OS) and event-free survival (EFS) were expressed as hazard ratios (HR) and differences in restricted mean survival time (RMST) with 95% confidence intervals (CI). RESULTS: The base case MAIC results suggested brexu-cel improved OS and EFS compared to blina (OS HR 0.46 [95% CI 0.28, 0.75]; EFS HR 0.37 [95% CI 0.25, 0.56]) and pooled INO-VATE/TOWER chemotherapy (OS HR 0.32 [95% CI 0.18, 0.56]; EFS HR 0.27 [0.18, 0.40]). Brexu-cel also improved OS compared to InO (HR 0.45 [95% CI 0.24, 0.85]). The point estimate for EFS favored brexu-cel over Ino but the difference was not statistically significant (HR 0.67 [95% CI 0.41, 1.10]). Findings were consistent between the HR and RMST analyses. CONCLUSION: Despite limitations, these MAIC results suggest that brexu-cel may improve OS and EFS versus currently used therapies in this population.

Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3.

BACKGROUND: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported. METHODS: Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×106 CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided. RESULTS: Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7-58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups.Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22). CONCLUSIONS: In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.

LncRNA BBOX1-AS1 Contributes to the Development of Nasopharyngeal Carcinoma via miR-204-5p/MUC4 Axis.

OBJECTIVE: Dysregulation of long non-coding RNAs (lncRNAs) is common in nasopharyngeal carcinoma (NPC) progression, and it is important to have an in-depth understanding of their functions in NPC. This study is the first to explore the role of the lncRNA BBOX1-AS1 in NPC development. METHODS: The expression of lncRNA BBOX1-AS1, MUC4, or miR-204-5p was measured in NPC cell lines or tissues via RT-qPCR and western blotting. Wound healing assays and CCK-8 were used to identify cell migration and cell viability, respectively. The protein expression of Bax and Bcl-2 was measured by western blotting. The tumorigenic effect of NPC cells in vivo was verified using xenograft tumors in nude mice. Luciferase reporter and RIP assays were conducted to clarify the association between miR-204-5p and lncRNA BBOX1-AS1 or MUC4. RESULTS: lncRNA BBOX1-AS1 upregulation was observed in NPC cells and tissues. Silencing lncRNA BBOX1-AS1 suppressed the migration and viability of C666-1 and TW03 cells while promoting cell apoptosis. Knockdown of the lncRNA BBOX1-AS1 repressed tumor growth in vivo. Moreover, the tumor suppression effect of silenced lncRNA BBOX1-AS1 might be reversed with the help of the miR-204-5p inhibitor. lncRNA BBOX1-AS1 targets miR-204-5p and regulates MUC4 expression in NPC. MUC4 is a miR-204-5p target and exerts a function similar to that of lncRNA BBOX1-AS1. CONCLUSION: These observations highlight that lncRNA BBOX1-AS1 is an essential NPC progression promoter and suggest that the lncRNA BBOX1-AS1/miR-204-5p/MUC4 axis is a potential therapeutic target in NPC.

Survival and Disease Burden Analysis of Occupational Pneumoconiosis From 1956 to 2021 in Jiangsu Province.

OBJECTIVES: The aims of the study are to investigate the survival status and its influencing factors of pneumoconiosis patients and to analyze the disease burden and its trend in Jiangsu Province. METHODS: We used the life table and Cox model to analyze the survival status. The disease burden and its temporal trend were examined using the disability-adjusted life years (DALY). RESULTS: The average survival time was 16.22 ± 10.11 years. First diagnosis age, first diagnosis stage, and upgrade of stages were crucial risk factors for the survival. The cumulative DALY was 154,500.83 person-years. The DALY attributed to silicosis, coal worker pneumoconiosis, and welder's pneumoconiosis were 99,806.72 (64.60%), 35,483.21 (22.97%), and 37,85.83 (2.45%) person-years, respectively. CONCLUSIONS: Although the disease burden of pneumoconiosis is decreasing because of the implementation of relevant health policies and improved medical standards, the prevention and control of pneumoconiosis still need greater attention.

Spatiotemporal dissection of tumor microenvironment via in situ sensing and monitoring in tumor-on-a-chip.

Real-time monitoring in the tumor microenvironment provides critical insights of cancer progression and mechanistic understanding of responses to cancer treatments. However, clinical challenges and significant questions remain regarding assessment of limited clinical tissue samples, establishment of validated, controllable pre-clinical cancer models, monitoring of static versus dynamic markers, and the translation of insights gained from in vitro tumor microenvironments to systematic investigation and understanding in clinical practice. State-of-art tumor-on-a-chip strategies will be reviewed herein, and emerging real-time sensing and monitoring platforms for on-chip analysis of tumor microenvironment will also be examined. The integration of the sensors with tumor-on-a-chip platforms to provide spatiotemporal information of the tumor microenvironment and the associated challenges will be further evaluated. Though optimal integrated systems for in situ monitoring are still in evolution, great promises lie ahead that will open new paradigm for rapid, comprehensive analysis of cancer development and assist clinicians with powerful tools to guide the diagnosis, prognosis and treatment course in cancer.

Potential antiplatelet aggregation metabolites from the discarded sorghum (Sorghum bicolor L.) root.

Sorghum (Sorghum bicolor L.) is the fifth largest crop in the world and has potential health benefits, but vast quantities of sorghum roots are discarded after harvest. Based on the previous antiplatelet aggregation for this species, two new multi-substituted 3H-indole alkaloids sorghumine A (1) and sorghumine B (2), together with 14 known compounds (3-16), were found from the water extract of sorghum roots. Compounds 1-2 were identified by analyzing their spectroscopic data and physic and chemical properties, and the absolute configuration was further determined by electronic circular dichroism (ECD) analysis and calculations. 1-2, 4, 6-8 and 13-15 showed significant inhibition of platelet aggregation induced by adenosine diphosphate. 2-4, 6-9 and 11 showed significant inhibition of platelet aggregation induced by collagen. 4-6, 8, 10-11 and 16 showed significant inhibition on platelet aggregation induced by thrombin. Furthermore, molecular docking showed that active compounds can bind to P2Y12 and COX-1 receptors in platelet.

Three-year results from phase I of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia.

Here we present the 3-year results of ZUMA-4, a phase I/II multicenter study evaluating the safety and efficacy of KTEX19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Phase I explored two dose levels and formulations. The primary endpoint was the incidence of dose-limiting toxicities. Thirty-one patients were enrolled; KTE-X19 was administered to 24 patients (median age 13.5 years, range 3-20; median follow-up 36.1 months). No dose-limiting toxicities were observed. All treated patients had grade ≥3 adverse events, commonly hypotension (50%) and anemia (42%). Grade 3 cytokine release syndrome rates were 33% in all treated patients, 75% in patients given the dose of 2×106 CAR T cells/kg, 27% in patients given the dose of 1×106 cells/kg in the 68 mL formulation, and 22% in patients given the dose of 1×106 cells/kg in the 40 mL formulation; the percentages of patients experiencing grade ≥3 neurologic events were 21%, 25%, 27%, and 11% respectively. Overall complete remission rates (including complete remission with incomplete hematologic recovery) were 67% in all treated patients, 75% in patients given 2×106 CAR T cells/kg, 64% in patients given 1×106 cells/kg in the 68 mL formulation, and 67% in patients given 1×106 cells/kg in the 40 mL formulation. Overall minimal residual diseasenegativity rates were 100% among responders; 88% of responders underwent subsequent allogeneic stem-cell transplantation. In the 1×106 (40 mL) group (recommended phase II dose), the median duration of remission censored at allogeneic stem-cell transplantation and median overall survival were not reached. Pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia achieved high minimal residual disease-negative remission rates with a manageable safety profile after a single dose of KTE-X19. Phase II of the study is ongoing at the dose of 1×106 CAR T cells/kg in the 40 mL formulation. ClinicalTrials.gov: NCT02625480.

Synthesis and Characterization of a Resin/Acrylamide-2-acrylamide-2-methylpropane Sulfonate-Diallyl Dimethyl Ammonium Chloride-N-vinyl-2-pyrrolidinone Polymer Microcapsule Gelling Agent for Oil and Gas Field Transformation.

Deep carbonate rock oil and gas reservoir is an important support for increasing oil and gas storage and production at present. The environment of ultradeep and ultrahigh-temperature reservoirs has put forward higher technical requirements for reservoir modification acid technology. Moreover, gelling acid is the main acid solution for high-temperature reservoir acidizing transformation, with a temperature resistance of no more than 180 °C, and the gelling agent is one of the key factors restricting its high-temperature resistance performance. In this paper, AM, AMPS, DMDAAC, and NVP were used as monomers, oxidants, and reducing agents to prepare a high-temperature-resistant polymer gel through polymerization. At the same time, microcapsules were prepared by in situ polymerization using epoxy resin as the wall material. The indoor performance evaluation results indicate that the gelling agent is easily soluble in high-concentration acid solution and has good viscosity increasing effect. At 180 °C and 170 s-1 shear rate, 0.8% mass fraction of the gelling agent was dissolved in 20% mass fraction of hydrochloric acid. After shearing for 60 min, the viscosity remained at about 22.45 mPa·s, demonstrating good temperature resistance and shear resistance, and its performance was superior to existing commonly used gelling agent products.

Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study.

BACKGROUND: Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care. METHODS: Adults with R/R B-ALL received a single infusion of KTE-X19 (1 × 106 CAR T cells/kg). Long-term post hoc subgroup assessments of ZUMA-3 were conducted. Outcomes from matched patients between historical clinical trials and ZUMA-3 patients were assessed in the retrospective historical control study SCHOLAR-3. RESULTS: After 26.8-months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients (N = 55) in phase 2 was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients (N = 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 (N = 49) and matched historical controls (N = 40) was 25.4 and 5.5 months, respectively. CONCLUSIONS: These data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult R/R B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population. TRIAL REGISTRATION: NCT02614066.

Integrated radiomics, dose-volume histogram criteria and clinical features for early prediction of saliva amount reduction after radiotherapy in nasopharyngeal cancer patients.

PURPOSE: Previously, the evaluation of xerostomia depended on subjective grading systems, rather than the accurate saliva amount reduction. Our aim was to quantify acute xerostomia with reduced saliva amount, and apply radiomics, dose-volume histogram (DVH) criteria and clinical features to predict saliva amount reduction by machine learning techniques. MATERIAL AND METHODS: Computed tomography (CT) of parotid glands, DVH, and clinical data of 52 patients were collected to extract radiomics, DVH criteria and clinical features, respectively. Firstly, radiomics, DVH criteria and clinical features were divided into 3 groups for feature selection, in order to alleviate the masking effect of the number of features in different groups. Secondly, the top features in the 3 groups composed integrated features, and features selection was performed again for integrated features. In this study, feature selection was used as a combination of eXtreme Gradient Boosting (XGBoost) and SHapley Additive exPlanations (SHAP) to alleviate multicollinearity. Finally, 6 machine learning techniques were used for predicting saliva amount reduction. Meanwhile, top radiomics features were modeled using the same machine learning techniques for comparison. RESULT: 17 integrated features (10 radiomics, 4 clinical, 3 DVH criteria) were selected to predict saliva amount reduction, with a mean square error (MSE) of 0.6994 and a R2 score of 0.9815. Top 17 and 10 selected radiomics features predicted saliva amount reduction, with MSE of 0.7376, 0.7519, and R2 score of 0.9805, 0.9801, respectively. CONCLUSION: With the same number of features, integrated features (radiomics + DVH criteria + clinical) performed better than radiomics features alone. The important DVH criteria and clinical features mainly included, white blood cells (WBC), parotid_glands_Dmax, Age, parotid_glands_V15, hemoglobin (Hb), BMI and parotid_glands_V45.

Bioactive isopimarane and 3,4-seco isopimarane diterpenoids from Isodon amethystoides.

Isodon amethystoides (Lamiaceae) is a popular plant in folk medicine in the southern provinces of China. Our phytochemical investigation of the twigs and leaves of this plant led to the discovery of five new diterpenoids with isopimarane and 3,4-seco isopimarane scaffolds [isoamethinols A-E (1-5)], along with the known compound 3,4-seco isopimara-4(18),7,15-triene-3-oic acid methylester (6). The chemical structures of these compounds, including the absolute configurations of the new diterpenoids, were determined by comprehensive spectroscopic analyses and single crystal X-ray diffraction measurements. These compounds were evaluated for their biological activities against a panel of human cancer cell lines, gram-positive bacterial strains and HIV. Notably, the 3,4-seco-isopimarane isoamethinol D (4) showed toxicity to the cervical Hela cancer (Hela) cells with an IC50 value of 27.21 µM and the lung (A549) cancer cells with an IC50 value of 21.47 µM. Compound 4 also exhibited mild antimicrobial activity against the oral bacterial strain Streptococcus mutans. These findings suggested that the diterpenoids with a 3,4-seco-isopimarane diterpenoids isolated from I. amethystoides could provide a novel structure scaffold for the discovery of anticancer and antimicrobial compounds.

Enhanced Label-Free Nanoplasmonic Cytokine Detection in SARS-CoV-2 Induced Inflammation Using Rationally Designed Peptide Aptamer.

Rapid and precise serum cytokine quantification provides immense clinical significance in monitoring the immune status of patients in rapidly evolving infectious/inflammatory disorders, examplified by the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. However, real-time information on predictive cytokine biomarkers to guide targetable immune pathways in pathogenic inflammation is critically lacking, because of the insufficient detection range and detection limit in current label-free cytokine immunoassays. In this work, we report a highly sensitive localized surface plasmon resonance imaging (LSPRi) immunoassay for label-free Interleukin 6 (IL-6) detection utilizing rationally designed peptide aptamers as the capture interface. Benefiting from its characteristically smaller dimension and direct functionalization on the sensing surface via Au-S bonding, the peptide-aptamer-based LSPRi immunoassay achieved enhanced label-free serum IL-6 detection with a record-breaking limit of detection down to 4.6 pg/mL, and a wide dynamic range of ∼6 orders of magnitude (values from 4.6 to 1 × 106 pg/mL were observed). The immunoassay was validated in vitro for label-free analysis of SARS-CoV-2 induced inflammation, and further applied in rapid quantification of serum IL-6 profiles in COVID-19 patients. Our peptide aptamer LSPRi immunoassay demonstrates great potency in label-free cytokine detection with unprecedented sensing capability to provide accurate and timely interpretation of the inflammatory status and disease progression, and determination of prognosis.

Stemness Analysis Uncovers That The Peroxisome Proliferator-Activated Receptor Signaling Pathway Can Mediate Fatty Acid Homeostasis In Sorafenib-Resistant Hepatocellular Carcinoma Cells.

Hepatocellular carcinoma (HCC) stem cells are regarded as an important part of individualized HCC treatment and sorafenib resistance. However, there is lacking systematic assessment of stem-like indices and associations with a response of sorafenib in HCC. Our study thus aimed to evaluate the status of tumor dedifferentiation for HCC and further identify the regulatory mechanisms under the condition of resistance to sorafenib. Datasets of HCC, including messenger RNAs (mRNAs) expression, somatic mutation, and clinical information were collected. The mRNA expression-based stemness index (mRNAsi), which can represent degrees of dedifferentiation of HCC samples, was calculated to predict drug response of sorafenib therapy and prognosis. Next, unsupervised cluster analysis was conducted to distinguish mRNAsi-based subgroups, and gene/geneset functional enrichment analysis was employed to identify key sorafenib resistance-related pathways. In addition, we analyzed and confirmed the regulation of key genes discovered in this study by combining other omics data. Finally, Luciferase reporter assays were performed to validate their regulation. Our study demonstrated that the stemness index obtained from transcriptomic is a promising biomarker to predict the response of sorafenib therapy and the prognosis in HCC. We revealed the peroxisome proliferator-activated receptor signaling pathway (the PPAR signaling pathway), related to fatty acid biosynthesis, that was a potential sorafenib resistance pathway that had not been reported before. By analyzing the core regulatory genes of the PPAR signaling pathway, we identified four candidate target genes, retinoid X receptor beta (RXRB), nuclear receptor subfamily 1 group H member 3 (NR1H3), cytochrome P450 family 8 subfamily B member 1 (CYP8B1) and stearoyl-CoA desaturase (SCD), as a signature to distinguish the response of sorafenib. We proposed and validated that the RXRB and NR1H3 could directly regulate NR1H3 and SCD, respectively. Our results suggest that the combined use of SCD inhibitors and sorafenib may be a promising therapeutic approach.