Roflumilast ameliorates GAN diet-induced non-alcoholic fatty liver disease by reducing hepatic steatosis and fibrosis in ob/ob mice.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent progressive liver disease. Currently, there is only one drug for NAFLD treatment, and the options are limited. Phosphodiesterase-4 (PDE-4) inhibitors have potential in treating NAFLD. Therefore, this study aims to investigate the effect of roflumilast on NAFLD. Here, we fed ob/ob mice to induce the NAFLD model by GAN diet. Roflumilast (1 mg/kg) was administered orally once daily. Semaglutide (20 nmol/kg), used as a positive control, was injected subcutaneously once daily. Our findings showed that roflumilast has beneficial effects on NAFLD. Roflumilast prevented body weight gain and improved lipid metabolism in ob/ob-GAN NAFLD mice. In addition, roflumilast decreased hepatic steatosis by down-regulating the expression of hepatic fatty acid synthesis genes (SREBP1c, FASN, and CD36) and improving oxidative stress. Roflumilast not only reduced liver injury by decreasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, but also ameliorated hepatic inflammation by reducing the gene expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6). Roflumilast lessened liver fibrosis by inhibiting the expression of fibrosis mRNA (TGFß1, α-SMA, COL1a1, and TIMP-1). Collectively, roflumilast could ameliorate NAFLD, especially in reducing hepatic steatosis and fibrosis. Our findings suggested a PDE-4 inhibitor roflumilast could be a potential drug for NAFLD.

Molten Guest-Mediated Metal-Organic Frameworks Featuring Multi-Modal Supramolecular Interaction Sites for Flame-Retardant Superionic Conductor in All-Solid-State Batteries.

The development of solid-state electrolytes (SSEs) with outstanding comprehensive performance is currently a critical challenge for achieving high energy density and safer solid-state batteries (SSBs). In this study, a strategy of nano-confined in situ solidification is proposed to create a novel category of molten guest-mediated metal-organic frameworks, named MGM-MOFs. By embedding the newly developed molten crystalline organic electrolyte (ML20) into the nanocages of anionic MOF-OH, MGM-MOF-OH, characterized by multi-modal supramolecular interaction sites and continuous negative electrostatic environments within nano-channels, is achieved. These nanochannels promote ion transport through the successive hopping of Li+ between neighbored negative electrostatic environments and suppress anion movement through the chemical constraint of the hydroxyl-functionalized pore wall. This results in remarkable Li+ conductivity of 7.1 × 10-4 S cm-1 and high Li+ transference number of 0.81. Leveraging these advantages, the SSBs assembled with MGM-MOF-OH exhibit impressive cycle stability and a high specific energy density of 410.5 Wh kganode + cathode + electrolyte -1 under constrained conditions and various working temperatures. Unlike flammable traditional MOFs, MGM-MOF-OH demonstrates high robustness under various harsh conditions, including ignition, high voltage, and extended to humidity.

Self-sufficient nanoparticles with dual-enzyme activity trigger radical storms and activate cascade-amplified antitumor immunologic responses.

Radiotherapy (RT) can potentially induce systemic immune responses by initiating immunogenic cell death (ICD) of tumor cells. However, RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases. Herein, we construct multifunctional self-sufficient nanoparticles (MARS) with dual-enzyme activity (GOx and peroxidase-like) to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse. In addition to limiting the Warburg effect to actualize starvation therapy, MARS catalyzes glucose to produce hydrogen peroxide (H2O2), which is then used in the Cu+-mediated Fenton-like reaction and RT sensitization. RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms, which have a robust ICD impact on mobilizing the immune system. Thus, when MARS is combined with RT, potent systemic antitumor immunity can be generated by activating antigen-presenting cells, promoting dendritic cells maturation, increasing the infiltration of cytotoxic T lymphocytes, and reprogramming the immunosuppressive tumor microenvironment. Furthermore, the synergistic therapy of RT and MARS effectively suppresses local tumor growth, increases mouse longevity, and results in a 90% reduction in lung metastasis and postoperative recurrence. Overall, we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.

Association between time from diagnosis to treatment and survival of patients with nasopharyngeal carcinoma: A population-based cohort study.

BACKGROUND: Treatment delays have frequently been observed in cancer patients. Whether the treatment delays would impair the survival of patients with nasopharyngeal carcinoma (NPC) is still unclear. METHODS: The data were derived from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. Patients were divided into groups of timely treatment (<1 month), intermediate delay (1 and 2 months), and long delay (3-6 months). The influence of different treatment delay intervals on long-term survival was evaluated by multivariate Cox regression analysis. RESULTS: In total, 2,048 patients with NPC were included in our study. There were 551 patients in the early stage (I, II stage: 26.9 %) and 1,497 patients in the advanced stage (III, IV stage: 73.1 %). No significant difference in overall survival (OS) or cancer-specific survival (CSS) was observed among the groups with various treatment delay intervals (p = 0.48 in OS and p = 0.43 in CSS, respectively). However, upon adjusting for covariates, a significantly improved OS probability emerged in patients with intermediate treatment delays compared to those who received timely interventions in both the entire study population (adjustedHazard Ratio (aHR)=0.86, 95 % CI: 0.74-0.99, p = 0.043) and the subgroup with advanced stage (aHR=0.85, 95 % CI: 0.72-1.00, p = 0.049). Regarding the CSS probability, similar associations were also observed in the entire study population (aHR=0.84, 95 % CI: 0.71-0.98, p = 0.030) as well as the advanced-stage patients (aHR=0.83, 95 % CI: 0.70-0.99, p =  0.038). CONCLUSIONS: Our results revealed that treatment delays are not associated with worse survival of NPC patients. Tumor-specific characteristics and subsequent treatment modalities play more pivotal roles in the prognosis of NPC.

Preparation of Cationic Polyacrylamide Suspension and Its Application in Oilfield Wastewater Treatment.

Cationic polyacrylamide (CPAM) solid particle is one of the most commonly used organic polymer flocculants in oilfield wastewater treatment, but it poses some problems, such as a slow dissolution rate and an easy formation into a "fish-eye" in the process of diluting into aqueous solution. However, the current liquid CPAM products also have some problems, such as low effective content, poor storage stability, degradation in a short time, and high preparation costs. In this paper, a CPAM suspension was successfully prepared with 50.00% CPAM fine powder, 46.87% oil phase solvent, 0.63% separating agent, 1.56% emulsifying and dispersing agent, and 0.94% rheology modifier. This suspension has an effective content of 50.00%. It also showed no separation in 7 days of storage at room temperature, no separation in 30 min of centrifugation at a speed of 2000 rpm, and diluted to a 0.40% solution in just 16.00 min. For 1000 NTU of diatomite-simulated wastewater, the optimal turbidity removal rate of the suspension was 99.50%, which was higher than the optimal turbidity removal rate of 98.40% for the inorganic flocculant polymeric aluminum chloride (PAC). For oilfield wastewater, the optimal turbidity removal rate of the CPAM suspension was 35.60%, which was higher than the optimal turbidity removal rate of 28.40% for solid particle CPAM. In a scale-up test, the CPAM suspension achieved a good application effect.

Alkaline Hydrolysis of Waste Acrylic Fibers Using the Micro-Water Method and Its Application in Drilling Fluid Gel Systems.

Filtrate reducer is a drilling fluid additive that can effectively control the filtration loss of drilling fluid to ensure the safe and efficient exploitation of oilfields. It is the most widely used treatment agent in oilfields. Due to its moderate conditions and controllable procedure, alkaline hydrolysis of high-purity waste polyacrylonitrile has been utilized for decades to produce filtrate reducer on a large scale in oilfields. However, the issues of long hydrolysis time, high viscosity of semi-finished products, high drying cost, and tail gas pollution have constrained the development of the industry. In this study, low-purity waste acrylic fiber was first separated and purified using high-temperature hydroplastization, and the hydrolyzed product was obtained using alkaline hydrolysis with the micro-water method, which was called MW-HPAN. The hydrolysis reaction was characterized using X-ray diffraction, scanning electron microscopy, infrared spectroscopy, and thermogravimetric analysis, and the elemental analysis showed a hydrolysis degree of 73.21%. The experimental results showed that after aging at 180 °C for 16 h, the filtration volume of the freshwater base slurry with 0.30% dosage and 4% brine base slurry with 1.20% dosage was 12.7 mL and 18.5 mL, respectively. The microstructure and particle size analysis of the drilling fluid gel system showed that MW-HPAN could prevent the agglomeration of clay and maintain a reasonable particle size distribution even under the combined deteriorating effect of high temperature and inorganic cations, thus forming a dense filter cake and achieving a low filtrate volume of the drilling fluid gel system. Compared with similar commercially available products, MW-HPAN has better resistance to temperature and salt in drilling fluid gel systems, and the novel preparation method is promising to be extended to practical production.

Individualized 3D-printed bolus promotes precise postmastectomy radiotherapy in patients receiving breast reconstruction.

Purpose: To evaluate the efficacy and safety of 3D-printed tissue compensations in breast cancer patients receiving breast reconstruction and postmastectomy radiotherapy (PMRT). Methods and materials: We enrolled patients with breast cancer receiving breast reconstruction and PMRT. The dose distribution of target and skin, conformability, and dose limit of organs at risk (OARs) were collected to evaluate the efficacy of the 3D-printed bolus. Radiation Therapy Oncology Group (RTOG) radiation injury classification was used to evaluated the skin toxicities. Results: A total of 30 patients diagnosed between October 2019 to July 2021 were included for analysis. Among all the patients, the 3D-printed bolus could ensure the dose coverage of planning target volume (PTV) [homogeneity index (HI) 0.12 (range: 0.08-0.18)], and the mean doses of D99%, D98%, D95%, D50%, D2% and Dmean were 4606.29cGy, 4797.04cGy, 4943.32cGy, 5216.07cGy, 5236.10cGy, 5440.28cGy and 5462.10cGy, respectively. The bolus demonstrated an excellent conformability, and the mean air gaps between the bolus and the chest wall in five quadrants were 0.04cm, 0.18cm, 0.04cm, 0.04cm and 0.07cm, respectively. In addition, the bolus had acceptable dosage limit of OARs [ipsilateral lung: Dmean 1198.68 cGy, V5 46.10%, V20 21.66%, V30 16.31%); heart: Dmean 395.40 cGy, V30 1.02%, V40 0.22%; spinal cord planning risk volume (PRV): Dmax 1634 cGy] and skin toxicity (grade 1, 76.0%; grade 2, 21.0%; grade 3, 3.3%). Conclusion: The 3D-printed bolus offers advantages in terms of dose uniformity and controllable skin toxicities in patients receiving breast reconstruction and PMRT. Further research is needed to comprehensively evaluate the effectiveness of the 3Dprinted bolus in this patient subset.

The disparities in prognostic prediction and annualized hazard function in different molecular subtypes between young Chinese and White American women with breast cancer.

Background and objectives: The prognostic disparities in different molecular subtypes between young Chinese and White American breast cancer patients remain unclear. The goal of this study was to explore the prognostic differences in different molecular subtypes between Chinese and White American patients aged ≤ 40 years. Methods: We included Chinese and White female breast cancer patients at or under the age of 40 from the Surveillance, Epidemiology, and End Results database (SEER) and the West China Hospital of Sichuan University. The chi-square test, log-rank test, and Cox proportional hazards model were employed to evaluate the distribution and survival disparities in the two racial/ethnic cohorts and different molecular subtypes. An annualized hazard function was used to calculate the annual failure rate among different molecular subtypes. Results: This study included 20,859 female breast cancer patients at or under the age of 40, of whom 18,400 were White women and 2,459 were Chinese women. With a median follow-up time of 47 months, the 5-year breast cancer-specific survival (BCSS) rates for young Chinese and White women were 93.9% and 90.0%, respectively (P< 0.001). Molecular subtype was found to be a significant predictor in both young Chinese and White patients (P< 0.001), but different trends were observed in the two racial/ethnic cohorts when exploring the association between BCSS and molecular subtypes. Among young White patients, the hormone receptor (HoR) (+)/epidermal growth factor receptor 2 (HER2) (+) subtype had the best 5-year BCSS rate, while in young Chinese patients, the HoR (+)/HER2 (+) and HoR (+)/HER2 (-) showed comparable survival curves and both showed superior 5-year BCSS than other subtypes. Stratification by molecular subtypes, young Chinese patients demonstrated a superior 5-year BCSS in HoR (+)/HER2 (-) (96.3% vs 92.9%, P< 0.001) and triple-negative subtypes (88% vs 81.7%, P= 0.006) compared to young White American patients, while no significant differences were found in HoR (+)/HER2 (+) and HER2 enriched tumors. The annual hazard function for BCSS showed that there were significantly different trends in the HoR (+)/HER2 (-) and HoR (+)/HER2 (+) subtypes between young Chinese and White patients. Conclusions: There are disparities in prognosis and annualized hazard function between young Chinese and White females with breast cancer in different molecular subtypes.

Survival and Trends in Annualized Hazard Function by Age at Diagnosis Among Chinese Breast Cancer Patients Aged ≤40 Years: Case Analysis Study.

BACKGROUND: Young breast cancer patients are more likely to develop aggressive tumor characteristics and a worse prognosis than older women, and different races and ethnicities have distinct epidemiologies and prognoses. However, few studies have evaluated the clinical biological features and relapse patterns in different age strata of young women in Asia. OBJECTIVE: We aimed to explore survival differences and the hazard function in young Chinese patients with breast cancer (BC) by age. METHODS: The patients were enrolled from West China Hospital, Sichuan University. The chi-squared test, a Kaplan-Meier analysis, a log-rank test, a Cox multivariate hazards regression model, and a hazard function were applied for data analysis. Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), breast cancer-specific survival (BCSS), and overall survival (OS) were defined as end points. RESULTS: We included 1928 young BC patients diagnosed between 2008 and 2019. Patients aged 18 to 25, 26 to 30, 31 to 35, and 36 to 40 years accounted for 2.7% (n=53), 11.8% (n=228), 27.7% (n=535), and 57.7% (n=1112) of the patients, respectively. The diagnosis of young BC significantly increased from 2008 to 2019. Five-year LRFS, DMFS, BCSS, and OS for the entire population were 98.3%, 93.4%, 94.4%, and 94%, respectively. Patients aged 18 to 25 years had significantly poorer 5-year LRFS (P<.001), 5-year DMFS (P<.001), 5-year BCSS (P=.04), and 5-year OS (P=.04) than those aged 31 to 35, 26 to 30, and 36 to 40 years. The hazard curves for recurrence and metastasis for the whole cohort continuously increased over the years, while the BC mortality risk peaked at 2 to 3 years and then slowly decreased. When stratified by age, the annualized hazard function for recurrence, metastasis, and BC mortality in different age strata showed significantly different trends, especially for BC mortality. CONCLUSIONS: The annual diagnosis of young BC seemed to increase in Chinese patients, and the distinct age strata of young BC patients did not differ in survival outcome or failure pattern. Our results might provide strategies for personalized management of young BC.

The prognostic differences and the effect of postmastectomy radiotherapy between post-chemotherapy ypT1-2ypN1 and de novo pT1-2N1 breast cancer.

BACKGROUND: The prognosis and the value of postmastectomy radiotherapy (PMRT) between post-chemotherapy ypT1-2ypN1 and de novo pT1-2N1 breast cancer (BC) remain controversial. We aimed to evaluate the prognostic differences and the effect of PMRT between the two patient subsets. METHODS: Patients diagnosed with pT1-2N1M0 BC were identified between 2010 and 2018. The study endpoints were overall survival (OS), breast cancer-specific survival (BCSS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and disease-free survival (DFS). The chi-square test, Kaplan-Meier method and Cox regression analysis were used for data analysis. RESULTS: Total number of 2103 pT1-2N1M0 BC patients were included in the study, including 270 post-chemotherapy (97 without PMRT, 173 with PMRT) and 1833 de novo cases (993 without PMRT, 840 with PMRT). No significant differences were found between post-chemotherapy ypT1-2ypN1 and de novo pT1-2N1 BC patients in 5-year OS (p = 0.068), BCSS (p = 0.054), LRFS (p = 0.241), DMFS (p = 0.104) or DFS (p = 0.08). PMRT did not improve any survival outcome in patients receiving neoadjuvant chemotherapy; however, the PMRT group had a better 5-year BCSS (97.0% vs. 95.8%, p = 0.033) in de novo pT1-2N1 BC. Cox multivariate analysis demonstrated that PMRT was a significant independent predictor of BCSS (HR 0.628; 95% CI, 0.403-0.978; p = 0.04) in de novo pT1-2N1 patients. CONCLUSIONS: There seemed no survival difference in post-chemotherapy ypT1-2ypN1 and de novo pT1-2N1 BC patients with contemporary systemic therapy. In addition, PMRT might be exempted in patients with post-chemotherapy ypT1-2ypN1 BC, while not in patients with de novo pT1-2N1 BC.

Epstein-Barr virus DNA change level combined with tumor volume reduction ratio after inductive chemotherapy as a better prognostic predictor in locally advanced nasopharyngeal carcinoma.

BACKGROUND: To explore the prognosis predicting ability of the combined factors, Epstein-Barr virus DNA change level (EBVCL) and tumor volume reduction ratio (TVRR) after inductive chemotherapy (IC), in locally advanced nasopharyngeal carcinoma (LANPC). METHODS: From 2010 to 2018, 299 LANPC patients were included in this retrospective study. Receiver operating characteristic (ROC) curve analysis was performed to acquire the best critical values. According to the best critical values of EBVCL and TVRR, patients were stratified into low- and high-risk groups. Kaplan-Meier and ROC curve analyses were utilized to verify the prognostic ability of the new predictor (EBVCL+TVRR). The prognostic values among EBVCL+TVRR, EBVCL, TVRR, TNM stage, and the RECIST 1.1 criteria were compared by ROC curve. The primary end points were overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional failure-free survival (LRFFS). RESULTS: ROC curve analyses of TVRR on three-year survival showed the best critical values of TVRR was 32.72% for OS, 30.21% for PFS and LRFFS, 29.87% for DMFS. The best critical value of EBVCL was 127 copies/ml for OS, and 87.7 copies/ml for PFS, DMFS, and LRFFS. The three-year OS, PFS, DMFS, and LRFFS for low- and high-risk groups were 97.7% versus 78.3% (hazard ratio [HR] = 0.2398; 95% confidence interval [CI]: 0.1277-0.4502; p < 0.0001), 91.1% versus 60.9% (HR = 0.3294; 95% CI: 0.2050-0.5292; p < 0.0001), 94.2% versus 68.7% (HR = 0.2413; 95% CI: 0.1284-0.4535; p < 0.0001) and 97.8% versus 77.9% (HR = 0.3078; 95% CI: 0.1700-0.5573; p = 0.0001), respectively. The maximal area under ROC curve of EBVCL+TVRR, EBVCL, TVRR, TNM stage, and RECIST 1.1 criteria for three-year OS was 0.829, 0.750, 0.711, 0.555, and 0.605, respectively. CONCLUSION: The new-developed indicator (EBVCL+TVRR) could better predict the LANPC patient's survival after IC compared with TNM stage system or RECIST 1.1 criteria.

Effective Combinations of Immunotherapy and Radiotherapy for Cancer Treatment.

Though single tumor immunotherapy and radiotherapy have significantly improved the survival rate of tumor patients, there are certain limitations in overcoming tumor metastasis, recurrence, and reducing side effects. Therefore, it is urgent to explore new tumor treatment methods. The new combination of radiotherapy and immunotherapy shows promise in improving therapeutic efficacy and reducing recurrence by enhancing the ability of the immune system to recognize and eradicate tumor cells, to overcome tumor immune tolerance mechanisms. Nanomaterials, as new drug-delivery-system materials of the 21st century, can maintain the activity of drugs, improve drug targeting, and reduce side effects in tumor immunotherapy. Additionally, nanomaterials, as radiosensitizers, have shown great potential in tumor radiotherapy due to their unique properties, such as light, heat, electromagnetic effects. Here, we review the mechanisms of tumor immunotherapy and radiotherapy and the synergy of radiotherapy with multiple types of immunotherapies, including immune checkpoint inhibitors (ICIs), tumor vaccines, adoptive cell therapy, and cytokine therapy. Finally, we propose the potential for nanomaterials in tumor radiotherapy and immunotherapy.

The Clinical Application of 3D-Printed Boluses in Superficial Tumor Radiotherapy.

During the procedure of radiotherapy for superficial tumors, the key to treatment is to ensure that the skin surface receives an adequate radiation dose. However, due to the presence of the built-up effect of high-energy rays, equivalent tissue compensators (boluses) with appropriate thickness should be placed on the skin surface to increase the target radiation dose. Traditional boluses do not usually fit the skin perfectly. Wet gauze is variable in thickness day to day which results in air gaps between the skin and the bolus. These unwanted but avoidable air gaps lead to a decrease of the radiation dose in the target area and can have a poor effect on the outcome. Three-dimensional (3D) printing, a new rising technology named "additive manufacturing" (AM), could create physical models with specific shapes from digital information by using special materials. It has been favored in many fields because of its advantages, including less waste, low-cost, and individualized design. It is not an exception in the field of radiotherapy, personalized boluses made through 3D printing technology also make up for a number of shortcomings of the traditional commercial bolus. Therefore, an increasing number of researchers have tried to use 3D-printed boluses for clinical applications rather than commercial boluses. Here, we review the 3D-printed bolus's material selection and production process, its clinical applications, and potential radioactive dermatitis. Finally, we discuss some of the challenges that still need to be addressed with the 3D-printed boluses.