Clinical treatment patterns, molecular characteristics and survival outcomes of ROS1-rearranged non-small cell lung cancer: A large multicenter retrospective study.

BACKGROUND: Non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements is a molecular subset that exhibits favorable responses to tyrosine kinase inhibitor (TKI) treatment than chemotherapy. This study investigated real-world treatment patterns and survival outcomes among patients with ROS1-rearranged advanced NSCLC. METHODS: We conducted a retrospective analysis of patients with ROS1-rearranged advanced NSCLC treated in four different hospitals in China from August 2018 to March 2022. The study analyzed gene fusion distribution, resistance patterns, and survival outcomes. RESULTS: ROS1 rearrangement occurs in 1.8 % (550/31,225) of our study cohort. CD74 was the most common ROS1 fusion partner, accounting for 45.8 %. Crizotinib was used in 73.9 % of patients in the first-line treatment, and an increased use of chemotherapy, ceritinib, and lorlatinib was seen in the second-line setting. Lung (43.2 %) and brain (27.6 %) were the most common sites of progression in first-line setting, while brain progression (39.2 %) was the most common site of progression in second-line. Median overall survival was 46 months (95 % confidence intervals: 39.6-52.4). First-line crizotinib use yielded significantly superior survival outcomes over chemotherapy in terms of progression-free (18.5 vs. 6.0; p < 0.001) and overall survival (49.8 vs. 37; p = 0.024). The choice of treatment in the latter line also had survival implications, wherein survival outcomes were better when first-line crizotinib was followed by sequential TKI therapy than first-line chemotherapy followed by TKI therapy. CONCLUSIONS: Our study provided insights into the real-world treatment, drug resistance patterns, and survival outcomes among patients with ROS1-rearranged NSCLC. This information serves as a valuable reference for guiding the treatment of this molecular subset of NSCLC.

A Robust Pyrazolate Metal-Organic Framework for Efficient Catalysis of Dehydrogenative C-O Cross Coupling Reaction.

Construction of robust heterogeneous catalysts with atomic precision is a long-sought pursuit in the catalysis field due to its fundamental significance in taming chemical transformations. Herein, we present the synthesis of a single-crystalline pyrazolate metal-organic framework (MOF) named PCN-300, bearing a lamellar structure with two distinct Cu centers and one-dimensional (1D) open channels when stacked. PCN-300 exhibits exceptional stability in aqueous solutions across a broad pH range from 1 to 14. In contrast, its monomeric counterpart assembled through hydrogen bonding displays limited stability, emphasizing the role of Cu-pyrazolate coordination bonds in framework robustness. Remarkably, the synergy of the 1D open channels, excellent stability, and the active Cu-porphyrin sites endows PCN-300 with outstanding catalytic activity in the cross dehydrogenative coupling reaction to form the C-O bond without the "compulsory" ortho-position directing groups (yields up to 96%), outperforming homogeneous Cu-porphyrin catalysts. Moreover, PCN-300 exhibits superior recyclability and compatibility with various phenol substrates. Control experiments reveal the synergy between the Cu-porphyrin center and framework in PCN-300 and computations unveil the free radical pathway of the reaction. This study highlights the power of robust pyrazolate MOFs in directly activating C-H bonds and catalyzing challenging chemical transformations in an environmentally friendly manner.

First-in-human phase I study of BEBT-109 in previously treated EGFR exon 20 insertion-mutated advanced non-small cell lung cancer.

BACKGROUND: BEBT-109 is an oral pan-mutant-selective inhibitor of epidermal growth factor receptor (EGFR) that demonstrated promising antitumor potency in preclinical models. METHODS: This first-in-human study was a single-arm, open-label, two-stage study. Phase Ia dose-escalation study evaluated the safety and pharmacokinetics of BEBT-109 in 11 patients with EGFR T790M-mutated advanced non-small cell lung cancer (aNSCLC). Phase Ib dose-expansion study evaluated the safety and efficacy of BEBT-109 in 18 patients with EGFR exon 20 insertion (ex20ins)-mutated treatment-refractory aNSCLC. The primary outcomes were adverse events and antitumor activity. Clinical trial registration number CTR20192575. FINDINGS: The phase Ia study demonstrated no dose-limiting toxicity, no observation of the maximum tolerated dose, and no new safety signals with BEBT-109 in the dose range of 20-180 mg/d, suggesting that BEBT-109 had an acceptable safety profile among patients with EGFR T790M-mutated aNSCLC. Plasma pharmacokinetics of BEBT-109 showed a dose-proportional increase in the area under the curve and maximal concentration, with no significant drug accumulation. The dose-expansion study demonstrated that BEBT-109 treatment was tolerable across the three dose levels. The three most common treatment-related adverse events were diarrhea (100%; 22.2% ≥Grade 3), rash (66.7%; 5.6% ≥Grade 3), and anemia (61.1%; 0% ≥Grade 3). The objective response rate was 44.4% (8 of 18). Median progression-free survival was 8.0 months (95% confidence intervals, 1.33-14.67). CONCLUSION: Preliminary findings showed that BEBT-109 had an acceptable safety profile and favorable antitumor activity in patients with refractory EGFR ex20ins-mutated aNSCLC. FUNDING: National Natural Science Foundation of China.

Humidity-Induced Self-Oscillating and Self-Healing Hypercrosslinked Metal-Organic Polyhedra Membranes.

Designing autonomously oscillating materials is highly desirable for emerging smart material fields but challenging. Herein, a type of hypercrosslinked metal-organic polyhedra (HCMOPs) membranes formed by covalent crosslinking of boronic acid-modified Zr-based MOPs with polyvinyl alcohol (PVA) are rationally designed. In these membranes, MOPs serve as high-connectivity nodes and provide dynamic borate bonds with PVA in hypercrosslinked networks, which can be broken/formed reversibly upon the stimulus of water vapor. The humidity response characteristic of HCMOPs promotes their self-oscillating and self-healing properties. HCMOP membranes can realize a self-oscillating property above the water surface even after loading a cargo that is 1.5 times the weight of the membrane due to the fast adsorption and desorption kinetics. Finally, the HCMOP actuator can realize energy conversion from mechanical energy into electricity when coupled with a piezoelectric membrane. This work not only paves a new avenue to construct MOP-polymer hybrid materials but also expands the application scopes of MOPs for smart actuation devices.

Study on the Efficacy and Potential Mechanism of Topical Shen Bai Hair Growing Decoction against Androgenetic Alopecia Based on Ultrahigh Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry and RNA-seq.

Androgenetic alopecia (AGA) is a major problem that can happen to people of all ages, leading to psychological problems, such as anxiety and depression. Topical Shen Bai hair growing decoction (TSBHGD) is based on the pathogenesis of AGA, combined with Traditional Chinese Medicine theory, improved by the Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital according to its clinical treatment experience. This study was designed to demonstrate the therapeutic efficacy of TSBHGD against AGA, analyze the chemical components of TSBHGD as well as the skin-retained and blood-retained components in mice after topical administration of TSBHGD, and clarify the mechanism of its therapeutic efficacy. It was demonstrated that TSBHGD could suppress TNF-α and IL-6 levels and improve pathological phenomena such as hair loss, reduced follicle density, and dermal thickness caused by testosterone solution. Totally 35 components were identified in TSBHGD extracts, 12 skin-retained components were identified in drug-containing skin, and 7 blood-retained components were identified in drug-containing plasma, according to ultrahigh performance liquid chromatography quadrupole time-of-flight mass spectrometry. Transcriptomic sequencing revealed that some of the genes in AGA mice had altered expression patterns, which could be reversed by TSBHGD. Through network pharmacology analysis, it was found that TSBHGD mainly regulated eight signaling pathways, among which the apoptosis signaling pathway ranked first with a significance of 0.00149. Finally, both Bcl-2 and Caspase family proteins in the apoptosis signaling pathway were examined by Western blot. It was confirmed that TSBHGD could inhibit the apoptosis level in AGA mice's skin tissue to exert an anti-AGA effect. This will facilitate the development of new-generation herbal compound formulas with precise efficacy and provide novel ideas for AGA therapy.

Clinical evidence for efficacy of pembrolizumab in MSI-H and TMB-H advanced solid tumor: results from three cancer centers in China.

BACKGROUND: Pembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H. METHODS: This retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS). RESULTS: The top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6-21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9-7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events. CONCLUSION: Our study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.

Integrating network pharmacology and experimental verification to explore the mechanism of Tripterygium wilfordii in ankylosing spondylitis.

OBJECTIVE: This study aimed to validate the mechanism of triptolide in treating ankylosing spondylitis (AS) through network pharmacology, molecular docking, and in vitro experiments. METHODS: We gathered AS-related genes using databases including DrugBank, OMIM, GeneCards, TTD and DisGeNET. TCMSP database was used to collect Tripterygium wilfordii (TWHF)-related data. Additionally, the potential targets of TWHF in treating AS were predicted by consulting databases such as Venny, String, Cytoscape, and Cytohubba. Subsequently, a protein-protein interaction network was created and the gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed by metascape database. After selecting the most active ingredient of TWHF, molecular docking was performed to confirm the predicted results. Furthermore, we explore the potential mechanism of the most active ingredient of TWHF in the treatment of AS in vitro. RESULT: By integrating the results of network pharmacological analysis, 62 genes were found to be strongly associated with AS, such as STAT3, TNF, MMP9, VEGFA, CXCL8, PTGS2, etc. Triptolide (TP) is one of the most active ingredients in TWHF. The enrichment analysis indicated that 292 biological processes and 132 signaling pathways were involved, with the T helper 17 cells cell differentiation pathway as the key pathway. TP was selected for molecular docking and in vitro experiments. The molecular docking results indicated that TP had excellent affinity with 6 key targets. Further, flow cytometry, cell counting assay, and ELISA demonstrated that the serum level of IL-17 was higher in AS patients compared to XXX, and 25 µg/mL TP was the optimal intervention concentration. RT-qPCR and Western blotting further verified that TP could inhibit the activation of RORγt and the JAK2/STAT3 signaling pathway. CONCLUSION: In conclusion, based on network pharmacology, molecular docking, and experimental verification in vitro, we proposed that the TP can inhibit the activation of RORγt and the JAK2/STAT3 signaling pathway and inhibit the differentiation of T helper 17 cells cells. The article provide a theoretical basis for further development and utilization of TWHF in AS management.

B cells intervention in inflammatory mechanism of ankylosing spondylitis: A visualization analysis for the past 20 years.

Ankylosing spondylitis (AS) is an autoimmune disease with complex inflammatory mechanism. The aim of this study is to apply the methods of bibliometrics and knowledge mapping to analyze the research trends and hot spots of B cells intervention in inflammatory mechanism of AS. Global published articles on B-cells intervention in inflammatory mechanism of AS were retrieved from the Web of Science (WOS) database from 2004 to 2023. CiteSpace 6.1.R6 software was used to conduct the visualization analysis of countries, authors, institutions, references and keywords in this field. A total of 359 related articles were collected. Since 2004, the number of articles published in the field of B cells intervention in inflammatory mechanism of AS has shown a fluctuating upward trend. The 29 core authors are part of a research group centered on Bowness, Paul and Breban, Maxime. The main research institutions are Anhui Med Univ and Charite. Co-citation analysis reveals that research in this field is currently focused on "intergenic region" and "bone mineral density." Keyword analysis shows that the current research hotspots and trends in this field mainly focus on the cellular immune mechanism, humoral immune mechanism and clinical application value of B cells intervention in inflammatory mechanism of AS. In the past 20 years, the research on the mechanism of B cells intervention in AS inflammation has focused on B cells intervention in AS inflammation through humoral and cellular immune mechanisms. The future research focus may tend to use B cells as a new therapeutic target for AS.

Mesenchymal Stem Cells in Heterotopic Ossification in Ankylosing Spondylitis: A Bibliometric Study Based on CiteSpace and VOSViewer.

Background: Heterotopic ossification is a complication in the late stage of ankylosing spondylitis (AS), and involves abnormal osteogenesis by mesenchymal stem cells (MSC). Research activity in this area has been rapidly expanding, but there is a lack of bibliometric studies that summarize the progresses. Methods: We searched the Web of Science (WoS) for articles pertaining to the role of MSCs in heterotopic ossification in AS from the database inception to December 2022 and visualized the countries, authors, institutions, references, and keywords using CiteSpace 6.1.R6 and VOSViewer. Results: A total of 127 publications from 188 institutions were identified, with a trend for increasing number of articles per year. China published the largest number of literature, followed by the United States and France. There were 47 core authors. The most recent research in this area mainly focused on "osteogenic differentiation", "gene expression", "inflammation", "TNF-α" and "bone formation". Current research can be broadly summarized into two topics: abnormalities in the inflammatory microenvironment and abnormalities in the MSCs. Aberrant expression of a variety of surface proteins in MSCs predisposes these cells to undergo osteogenic differentiation, and pro-inflammatory cytokines in the inflammatory milieu stimulate osteogenic differentiation of MSCs. Conclusion: MSCs in heterotopic ossification in AS is a relatively new area of research. Research activities primarily consist abnormalities in the inflammatory microenvironment and abnormalities in the MSCs.

Integrated analysis of tumor microenvironment features to establish a diagnostic model for papillary thyroid cancer using bulk and single-cell RNA sequencing technology.

BACKGROUND: Characterizing tumor microenvironment using single-cell RNA sequencing has been a promising strategy for cancer diagnosis and treatment. However, a few studies have focused on diagnosing papillary thyroid cancer (PTC) through this technology. Therefore, our study explored tumor microenvironment (TME) features and identified potential biomarkers to establish a diagnostic model for papillary thyroid cancer. METHODS: The cell types were identified using the markers from the CellMarker database and published research. The CellChat package was conducted to analyze the cell-cell interaction. The SCEVAN package was used to identify malignant thyroid cells. The SCP package was used to perform multiple single-cell downstream analyses, such as GSEA analysis, enrichment analysis, pseudotime trajectory analysis, and differential expression analysis. The diagnostic model of PTC was estimated using the calibration curves, receiver operating characteristic curves, and decision curve analysis. RT-qPCR was performed to validate the expression of candidate genes in human papillary thyroid samples. RESULTS: Eight cell types were identified in the scRNA-seq dataset by published cell markers. Extensive cell-cell interactions like FN1/ITGB1 existed in PTC tissues. We identified 26 critical genes related to PTC progression. Further, eight subgroups of PTC tumor cells were identified and exhibited high heterogeneity. The MDK/LRP1, MDK/ALK, GAS6/MERTK, and GAS6/AXL were identified as potential ligand-receptor pairs involved in the interactions between fibroblasts/endothelial cells and tumor cells. Eventually, the diagnostic model constructed by TRPC5, TENM1, NELL2, DMD, SLC35F3, and AUTS2 showed a good efficiency for distinguishing the PTC and normal tissues. CONCLUSIONS: Our study comprehensively characterized the tumor microenvironment in papillary thyroid cancer. Through combined analysis with bulk RNA-seq, six potential diagnostic biomarkers were identified and validated. The diagnostic model we constructed was a promising tool for PTC diagnosis. Our findings provide new insights into the heterogeneity of thyroid cancer and the theoretical basis for diagnosing thyroid cancer.

Reducing Interface Defects and Porosity of Adhesive Bonded Aluminum Alloy Joints via Ultrasonic Vibration.

The surface microstructure formed by physical or chemical modification is essential for the desired joint strength. However, defects in the bonding interface and adhesive can be found. Such defects decrease shear strength and durability. In this study, ultrasonic vibration was applied to liquid adhesive on the sandblasted aluminum alloy plates. With ultrasonic treatment, the joints obtained the compact bonding interfaces and lower porosity of the adhesive layer. The treatment improved the shear strength by 9.1%. After two weeks of hydrothermal aging, the shear strength of joints only sandblasted decreased drastically by 48.9%, while it was 14% for the joints with ultrasonic vibration. The cavitation effect in the adhesive was detected by the aluminum foil erosion method. The result showed that a great number of micro-jets generated by the cavitation effect have intensive impact on the bonding interface which provide the adhesive with powerful force to fill the micro-grooves. Another finding in this work is that bubbles were gathered in the adhesive away from the vibration area. This mechanism was successfully used to reduce the porosity of the adhesive layer of joints.

Efficacy of Immune Checkpoint Inhibitor Plus Chemotherapy in Patients With ROS1-Rearranged Advanced Lung Adenocarcinoma: A Multicenter, Retrospective Cohort Study.

PURPOSE: Immune checkpoint inhibitors (ICIs) exert robust antitumor activity in non-small-cell lung cancer (NSCLC) without actionable mutations. Apart from isolated case reports, the efficacy of PD-1 blockade in ROS1-rearranged NSCLC is currently unknown. METHODS: This retrospective cohort study included 23 patients with ROS1-rearranged advanced lung adenocarcinoma who received ICI plus chemotherapy regardless of the treatment setting. ICI plus chemotherapy was received as a later-line regimen by 14 patients, as the first-line regimen by six patients, and after chemoradiotherapy by three patients. RESULTS: All three patients who received chemoradiotherapy followed by ICI plus chemotherapy achieved partial response (PR) and had a progression-free survival (PFS) of >17.9 months. Of the six patients who received first-line ICI plus chemotherapy, five patients achieved PR and one had stable disease (SD), with a median PFS of 24.3 months (95% CI, 4.9 to 43.7). Of the 14 previously treated patients who received later-line ICI plus chemotherapy, the Objective Response Rate (ORR) was 28.6%, the Disease Control Rate (DCR) was 92.9%, and the median PFS was 5.8 months (95% CI, 0.2 to 9.4). The median time on ICI therapy was 10.0 months (95% CI, 1.5 to 32.5). The duration of response was 24.3 months (95% CI, 5.4 to 43.2) and 4.8 months (95% CI, 2.3 to 12.7) for first-line (n = 5) and subsequent-line (n = 4) ICI plus chemotherapy, respectively. Of the 10 patients with brain metastasis before receiving ICI plus chemotherapy, four patients achieved intracranial PR and five patients achieved intracranial SD, achieving an intracranial ORR of 40.0% and an intracranial DCR of 90.0%. CONCLUSION: Our retrospective study provides real-world clinical evidence that ROS1-rearranged NSCLCs benefit from ICI plus chemotherapy in any treatment setting, including patients who present with brain metastasis.

Theoretical modeling and simulation of fiber Bragg grating sensor interrogator based on linear variable filter.

With the increasing frequency of aviation accidents in recent years, aircraft safety has received increasing attention. Aircraft operating condition detection is an important part of aviation safety. Fiber Bragg grating (FBG) sensors, with their excellent characteristics, enable online monitoring of aircraft operating conditions. However, the application of FBG sensors in aviation is currently limited because it is difficult for FBG sensor interrogators to meet the requirements of small size, light weight, and good vibration resistance in the aviation field. Therefore, this paper proposes a linear variable filter (LVF)-based FBG sensor interrogator to meet the requirements. An optical model of the interrogator is established. The parameters which determine the performances of the interrogator are analyzed and the design criteria are discussed. According to the requirements in the aviation field, the optical system of the interrogator is designed. The simulation results show that the LVF-based FBG sensor interrogation system has a bandwidth range of 90 nm (1505 nm-1595 nm), a resolution of 2 pm, and a capacity of 15 FBG sensors.

Engineering Covalent Organic Frameworks with Polyethylene Glycol as Self-Sustained Humidity-Responsive Actuators.

Regarding the global energy crisis, it is of profound significance to develop spontaneous power generators that harvest natural energy. Fabricating humidity-responsive actuators that can conduct such energy transduction is of paramount importance. Herein, we incorporate covalent organic frameworks with flexible polyethylene glycol to fabricate rigid-flexible coupled membrane actuators. This strategy significantly improves the mechanical properties and humidity-responsive performance of the actuators, meanwhile, the existence of ordered structures enables us to unveil the actuation mechanism. These high-performance actuators can achieve various actuation applications and exhibit interesting self-oscillation behavior above a water surface. Finally, after being coupled with a piezoelectric film, the bilayer device can spontaneously output electricity over 2 days. This work paves a new avenue to fabricate rigid-flexible coupled actuators for self-sustained energy transduction.

Identification and validation of an immune-related lncRNAs signature to predict the overall survival of ovarian cancer.

Ovarian cancer (OC) is the most lethal gynecological cancer in women. Studies had reported that immune-related lncRNAs signatures were valuable in predicting the survival and prognosis of patients with various cancers. In our study, the prognostic value of immune-related lncRNAs was investigated in OC patients from TCGA-RNA-seq cohort (n=378) and HG-U133_Plus_2 cohort (n=590), respectively. Pearson correlation analysis was implemented to screen the immune-related lncRNA and then univariate Cox regression analysis was performed to explore their prognostic value in OC patients. Five prognostic immune-related lncRNAs were identified as prognostic lncRNAs. Besides, they were inputted into a LASSO Cox regression to establish and validate an immune-related lncRNA prognostic signature in TCGA-RNA-Seq cohort and HG-U133_Plus_2 cohort, respectively. Based on the best cut-off value of risk score, patients were divided into high- and low-risk groups. Survival analysis suggested that patients in the high-risk group had a worse overall survival (OS) than those in the low-risk group in both cohorts. The association between clinicopathological feathers and risk score was then evaluated by using stratification analysis. Moreover, we constructed a nomogram based on risk score, age and stage, which had a strong ability to forecast the OS of the OC patients. The influence of risk score on immune infiltration and immunotherapy response were assessed and the results suggested that patients with high-risk score might recruit multiple immune cells and stromal cells, leading to facilitating immune surveillance evasive. Ultimately, we demonstrated that the risk model was associated with chemotherapy response of multiple antitumor drugs, especially for paclitaxel, metformin and veliparib, which are commonly used in treating OC patients. In conclusion, we constructed a novel immune-related lncRNA signature, which had a potential prognostic value for OC patients and might facilitate personalized counselling for immunotherapy and chemotherapy.

Effect of ultrasonic vibration on adhesive enhancement of plasma-modified nickel surface.

Poor adhesion of nickel surface limits its further application in the aerospace field. In this study, plasma modification was conducted on the surface of the nickel plate pretreated by sandblasting, and then ultrasonic vibration was applied during the adhesively bonding process of the CFRP(Carbon fibre-reinforced polymer)/Ni joints. The bonding strength of the joints was increased by 65%. The adherend surface and the bonding interface were analyzed from microstructure, element distribution and chemical bonding to study the strengthening mechanism. By the sandblasting, irregular pits were formed on the nickel surface, effectively increasing the surface roughness. The plasma modification could introduce active functional groups including hydroxyl, amino and carbonyl on the nickel surface, which improved the surface wettability macroscopically. However, at a microscopic level, the adhesive with high viscosity and poor fluidity did not form a compact interface with the nickel. The ultrasonic application could promote the filling of the adhesive in irregular micro-scale pits on the surface, thereby strengthening the mechanical anchoring effect. Furthermore, the ultrasonic application produced dynamic impingement at the interface, enhancing the contact between the adhesive and the nickel plate. The adhesive molecules could fully collide and react with the active functional groups introduced on the nickel surface to form more chemical bonds, thus effectively improving the bonding strength of the CFRP/Ni joints.

Successful multimodality treatment of metastatic gallbladder cancer: A case report and review of literature.

BACKGROUND: Gallbladder cancer is the most common malignant tumor in the biliary system, and it is characterized by high aggressiveness and an extremely poor prognosis. Current treatment for advanced gallbladder cancer remains unsatisfactory. Here, we report a patient with advanced gallbladder cancer who was cured by multidisciplinary treatment. CASE SUMMARY: A 73-year-old male presented to our hospital with right abdominal pain for 3 d and was diagnosed with stage IVB gallbladder cancer with multiple liver metastases, peritoneum metastasis, diaphragm metastasis and lymph node metastases. The patient initially received chemotherapy, targeted therapy, 125I seed implantation and immunotherapy, as there were no specific indications for radical surgery. During these palliative therapies, the level of tumor markers gradually decreased but remained higher than the normal level, lymph node metastases gradually disappeared, and liver metastasis was gradually limited to the left liver. Finally, the patient received radical surgery with left hepatectomy, radical lymphadenectomy and partial diaphragmatic resection. To date, the patient has survived for more than six years posttreatment, the levels of tumor markers are normal, and imaging examinations show no signs of tumor recurrence. CONCLUSION: Currently, the prognosis of advanced gallbladder cancer remains unsatisfactory. A single treatment method is not sufficient for patients with advanced gallbladder cancer. Multidisciplinary individualized treatment is essential and should be utilized for advanced gallbladder cancer patients to further improve prognosis.

Cynarin suppresses gouty arthritis induced by monosodium urate crystals.

The study is aimed to determine the effects of cynarin (Cyn) on mice with gouty arthritis (GA) induced by monosodium urate (MSU). We measured swelling in the hind paws of mice in vivo using Vernier calipers and ultrasound. The liver, kidney, and hind paws were stained with hematoxylin-eosin, and M1 type macrophages were detected in the hind paws using anti-F4/80 and anti-iNOS antibodies. The mRNA expression of inflammatory factors in bone marrow-derived macrophages (BMDMs) and in the hind paws was detected via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes and the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were analyzed via western blotting. Cyn was detected in vitro using Cell Counting Kit-8 (CCK-8). Cyn treatment reduced hind paw swelling and M1 macrophage infiltration, suppressed the mRNA expression of inflammatory factors, and inhibited NLRP3 inflammasome activation in vivo, in addition to inhibiting the phosphorylation of IKKa/ß, p65, and c-Jun NH 2-terminal kinase (JNK). Furthermore, Cyn exerted anti-inflammatory and anti-swelling effects in mice with GA by regulating the NF-κB and JNK pathways and NLRP3 inflammasomes.

TRPM7 silencing modulates glucose metabolic reprogramming to inhibit the growth of ovarian cancer by enhancing AMPK activation to promote HIF-1α degradation.

BACKGROUND: Tumor cell metabolic reprogramming is crucial for the malignant behavior of cancer cells by promoting their proliferation. However, little is known on how transient receptor potential 7 (TRPM7) modulates metabolic reprogramming in ovarian cancer. METHODS: The effects of TRPM7 silencing on transcriptome profile, glucose uptake, lactic acid production, extracellular acidification rate (ECAR), oxygen consumption rate (OCR), intracellular ROS and ATP levels, and NAD+/NADH ratios in ovarian cancer cells were examined. The impacts of TRPM7 silencing on the levels of glycolysis-related HK2, PDK1 and oxidative phosphorylation (OXPHOS)-related IDH3B and UQCRC1, HIF-1α expression and AMPK phosphorylation were determined in ovarian cancer. The effect of AMPK activity on HIF-1α ubiquitination degradation was investigated in ovarian cancer cells. RESULTS: Compared with the control, TRPM7 silencing suppressed the proliferation of ovarian cancer cells by shifting preferable glycolysis to OXPHOS. In parallel, TRPM7 silencing decreased the glucose uptake of tumor-bearing mice and TRPM7 levels were negatively correlated with IDH3B and UQCRC1, but positively with HK2 and PDK1 expression in ovarian cancer tissues. Mechanistically, TRPM7 silencing significantly increased AMPK phosphorylation and decreased HIF-1α protein levels in ovarian cancer, particularly in HIF-1α silencing cells. The shifting from glycolysis to OXPHOS by TRPM7 silencing was abrogated by HIF-1α over-expression and impaired by inhibiting AMPK activity in ovarian cancer cells. Moreover, enhanced AMPK activation inhibited glycolysis, which was abrogated by HIF-1α over-expression in ovarian cancer cells. Moreover, the enhanced AMPK activation promoted HIF-1α ubiquitination degradation. CONCLUSIONS: TRPM7 silencing enhanced AMPK activation to shift glycolysis to oxidative phosphorylation by promoting HIF-1α ubiquitination degradation in ovarian cancer. Hence, TRPM7 may be a therapeutic target for intervention of ovarian cancer.

Study on Curing Kinetics and the Mechanism of Ultrasonic Curing of an Epoxy Adhesive.

Ultrasonic curing is an effective way to enhance the curing extent of composite material bonding in the aerospace industry. The non-thermal effect of ultrasonic has been revealed to improve curing efficiency. However, the mechanism of the ultrasonic non-thermal effect is still not clear. In this work, a variable activation energy model of ultrasonic curing was established by utilizing the iso-conversional method, including the activation energy of the thermal effect and activation energy of the non-thermal effect. The thermal effect caused by ultrasonic was accurately peeled off. An obvious decrease in activation energy was found from 54 kJ/mol in thermal curing to 38 kJ/mol in ultrasonic curing. The activation energy of the reaction system in ultrasonic curing was substituted into the modified Kamal autocatalytic equation, and the parameters of the ultrasonic curing kinetic model were estimated by means of an ALO algorithm. Further discussion based on in situ FTIR showed that the non-thermal effect of ultrasonic can affect the vibration strength, stability, and chemical bond energy of internal groups, but cannot cause the fracture of chemical bonds. Moreover, frontier molecular orbital analysis showed that the chemical reactivity of epoxy/amine molecules increased and the HOMO-LUMO energy gap decreased from 6.511 eV to 5.617 eV under the effect of ultrasonic.