The neutrophil–osteogenic cell axis promotes bone destruction in periodontitis

The immune-stromal cell interactions play a key role in health and diseases. In periodontitis, the most prevalent infectious disease in humans, immune cells accumulate in the oral mucosa and promote bone destruction by inducing receptor activator of nuclear factor-κB ligand (RANKL) expression in osteogenic cells such as osteoblasts and periodontal ligament cells. However, the detailed mechanism underlying immune–bone cell interactions in periodontitis is not fully understood. Here, we performed single-cell RNAsequencing analysis on mouse periodontal lesions and showed that neutrophil–osteogenic cell crosstalk is involved in periodontitis-induced bone loss. The periodontal lesions displayed marked infiltration of neutrophils, and in silico analyses suggested that the neutrophils interacted with osteogenic cells through cytokine production. Among the cytokines expressed in the periodontal neutrophils, oncostatin M (OSM) potently induced RANKL expression in the primary osteoblasts, and deletion of the OSM receptor in osteogenic cells significantly ameliorated periodontitis-induced bone loss. Epigenomic data analyses identified the OSM-regulated RANKL enhancer region in osteogenic cells, and mice lacking this enhancer showed decreased periodontal bone loss while maintaining physiological bone metabolism. These findings shed light on the role of neutrophils in bone regulation during bacterial infection, highlighting the novel mechanism underlying osteoimmune crosstalk.

Bone destruction of orbital wall in idiopathic orbital inflammatory pseudotumor:does it always imply malignancy?

AIM:To assess the clinical presentations and outcomes of idiopathic orbital inflammatory pseudotumor(IOIP)patients with orbital wall bone destruction(OWBD)and to propose an expanded classification system that includes bone destruction.METHODS:The study retrospectively reviewed clinical presentations,imaging findings,treatment modalities,and outcomes of six patients diagnosed histopathologically with IOIP and OWBD at the Beijing Tongren Hospital,Capital Medical University between October 2018 and June 2021.RESULTS:Over two years,6(10%)of 60 IOIP patients at our hospital exhibited OWBD,but this may overrepresent severe cases.The cohort consisted of three men and three women,aged 17 to 60y(mean 35.5±16.1y).Presenting symptoms included proptosis,eyelid swelling,decreased visual acuity with pain,and palpable mass.Imaging revealed multiple anatomical structures involved with the medial wall being the most common site of bone destruction.Histopathological examination showed classic type in five patients and sclerosing type in one patient.All patients underwent surgical resection followed by methylprednisolone treatment.Follow-up(mean 30.3±3.1mo)indicated three patients had no recurrence,while others had varying degrees of symptom persistence or recurrence.CONCLUSION:IOIP with bone destruction is a rare but significant subtype that mimics malignancy,leading to potential diagnostic and therapeutic challenges.Our findings suggest that complete surgical resection combined with adjunctive glucocorticoid therapy can yield favorable outcomes.However,larger-scale studies are needed to further optimize therapeutic approaches.

Gold mineralization in Jiaodong Peninsula and destruction of North China Craton:Insights from Mesozoic granite

Large-scale tectonic magmatism and extensive gold mineralization have occurred in the eastern North China Craton(NCC)(Jiaodong and Liaodong peninsulas)since Mesozoic,which indicated that the region experienced decratonization process.The genesis type of granites evolved from S-type to I-type and A-type during Late Jurassic to Early Cretaceous,and thus reflects the evolution of geodynamics in the Late Mesozoic,indicating the varied subduction process of the Paleo-Pacific Plate(PPP)and the craton destruction.The evolution of geochemical features shows that the mantle beneath the Jiaodong Peninsula evolved from EM-II in Jurassic to EM-I in Early Cretaceous,demonstrating that the mantle switched from enriched to depleted.The gold of decratonic gold deposits in Jiaodong Peninsula mainly comes from the lithospheric mantle domains metasomatized by fluids derived from the metamorphism and dehydration of the subducted slab in the mantle transition zone.The rapid decomposition of minerals leads to the concentrated release of ore-forming fluids,and this process leads to the explosive gold mineralization during the craton destruction.Extensive magmatic uplift and extensional structures,triggered by the craton destruction in Early Cretaceous formed the extensional tectonic system,providing space for the decratonic gold deposits in Jiaodong Peninsula.

Influence of vacuoles with gas–liquid inclusions on the thermobaric destruction conditions of natural quartz under dynamic heating in an RF-TICP torch system

In the present work,the turbulent mixing process of a polydisperse quartz particle flow with a plasma stream generated by a radio-frequency(RF)inductively coupled plasma torch was numerically studied.The thermobaric stress in the quartz particles under dynamic heating in a heterogeneous plasma flow was determined by a two-stage approximation approach.The effect of the presence of vacuoles in natural quartz on the particle thermobaric destruction conditions was studied.It was found that the equivalent thermal and baric stresses in quartz particles may significantly increase in the presence of vacuoles within a small gas volume fraction.The influence of the regime and energetic working conditions of an RF inductively coupled plasma torch system on the particle thermobaric destruction conditions was examined,and a recommendation was given to promote the degree of thermobaric destruction of quartz particles,which is of substantial importance for improving the overall enrichment efficiency of quartz concentrates.

Theoretical Study on Destruction Mechanism of 2,3,7,8-TCDD by O3 and NO3

In order to improve the destruction efficiency of dioxins and also for developing new dioxin control technology, the destruction mechanisms of 2,3,7,8-tetrachlorodihenzo-p-dioxin （2,3,7,8-TCDD） by O3 and NO3, were investigated employing quantum chemical calculations. For involved reactions, the microcosmic reaction processes were analyzed and depicted in detail based on geometry optimizations made by the B3LYP/6-31G（d） method. At the same time, the reaction activation energies were also calculated at the MP2/6- 311G（d,p）//B3LYP/6-31G（d） level. Configuration analysis indicated that 2,3,7,8-TCDD could be destroyed by 03 and NO3 in two different ways. The destruction of 2,3,7,8-TCDD by 03 proceeded via the addition of 03 and the cleavage of C=C while the destruction of 2,3,7,8-TCDD by NO3 proceeded via the substitution of chlorine by NO3. Calculated results show that, the activation energy of the destruction reaction of 2,3,7,8-TCDD by NO3 （267.48 kJ/mol） is much larger than that of the destruction reaction of 2,3,7,8-TCDD by O3 （51.20 kJ/mol）. This indicated that the destruction of 2,3,7,8-TCDD by 03 is much more efficient than that of 2,3,7,8-TCDD by NO3. The reason why the activation energy for the destruction reaction of 2,3,7,8-TCDD by NO3 is so large, is also discussed.

Determination of Optimum Conditions for Cell-wall Destruction of Auricularia auricula Mycelia under the Synergistic Effect of Ultrasonic Waves and Repeated Freeze-thaw Cycles

We aimed to investigate the synergistic effects of ultrasonic waves and repeated freeze-thaw cycles on cel-wal destruction of Auricularia auric-ula mycelia, and determine the best combination of conditions for cel-wal destruc-tion of Auricularia auricula mycelia. [Method] The effects of destruction time, added water, destruction times, freeze time and number of freeze-thaw cycles during ultra-sonic treatment on polysaccharide yield were investigated by single-factor test in our research. The optimum conditions for cel-wal destruction of Auricularia auricula mycelia by the synergistic effect of ultrasonic waves and repeated freeze-thaw cycles were ascertained by orthogonal test. [Result] The results of single test indicated the best combination of conditions was as fol ows： freeze time, 30 min; destruction time, 20 min; added water, 15 times; destruction times, 2 times; number of freeze-thaw cycles, 3 cycles. The results of orthogonal test indicated the influencing factors ranked as destruction time 〉 destruction times 〉 freeze time. The best combination of conditions was as fol ows： freeze time, 30 min; destruction time, 25 min; destruc-tion times, 2 times. Under above conditions, the polysaccharide yield reached 57.76 mg/g. [Conclusion] This research would provide a basis and reference for practical production.

Ultrasonic interventional analgesia in pancreatic carcinoma with chemical destruction of celiac ganglion

AIM： To detect the therapeutic effects of chemical destruction of celiac ganglion in patients with pancreatic carcinoma with intractable pain. METHODS： Ninety-seven cases with advanced pancreatic carcinoma received chemical destruction of celiac ganglion-5 mL pure alcohol injection around celiac artery under ultrasonic guidance. The changes of visual analogue scale （VAS）, serum substance P （Sub P）, β-endopeptide （β-EP） and T-lymphocyte subtypes level were compared between pre- and post-therapy. RESULTS： Successful rate of puncture was 98.7%, with one failure. No serious complications such as traumatic pancreatitis, pancreatic fistula, abdominal cavity hemorrhage or peritoneal infection occurred. VAS, serum Sub P and β-EP level significantly changed after treatment （8.0 ± 2.3 vs 4.6 ± 2.1, 254.1 ± 96.7 vs 182.4 ± 77.6, 3.2 ± 0.8 vs 8.8 ± 2.1, P 〈 0.01, P 〈 0.05, P 〈 0.01） with complete relief rate 54.2%, partial relief rate 21.9%, ineffective rate 12.5% and recurrent rate 10.7%. The T-lymphocyte subtypes level remarkably increased when compared with that of pre-therapy （46.7 ± 3.7 vs 62.5 ± 5.5, P 〈 0.01）. CONCLUSION： Our study suggests that chemical destruction of celiac ganglion under ultrasonic guidance is highly safe, and can evidently relieve cancer pain and improve the cellular immunity in patients with advanced pancreatic carcinoma.

Destruction of PCDD/Fs by gliding arc discharges

PCDD/Fs have been become a serious issue because of their toxicological effects and associated adverse health implications. In this study, the gliding arc plasma was tested for treatment of polychlorinated dibenzo-p-dioxins （PCDDs） and polychlorinated dibenzofurans （PCDFs）, which was synthesized from pentachlorophenol in atmospheric condition at 350℃ with or without the catalysis of CuCl2. From the experiment, we found that the destruction efficiency of PCDD/F homologues after gliding was discharge ranged from 25% to 79%. This result demonstrates that gliding arc plasma is an effective technology to decompose PCDDs/Fs in flue gas. A plausible degradation mechanism for PCDD/Fs by gliding arc was discussed. Finally, a multistage reactor structure of gliding arc was proposed to upgrade removal efficiency for PCDD/Fs.

Kinetics study and analysis of zeolite Y destruction

A series of zeolites,including USY zeolites without sodium,Na-USY at different Na contents,La-USY with different rare earth（RE） contents and La-Na-USY with RE and Na were prepared by an ion exchange method.They were investigated to understand the activation barriers for the destruction of Y zeolite structure under hydrothermal treatment and the effect of V using the solid-state kinetic model.The results showed that the pathways for Y zeolite destruction were dealumination,desiliconization and the disappearance of La-O bonds.Zeolites were destroyed by steam through acid hydrolysis,which was accelerated by V.In addition,Na and V exerted a synergistic effect on the framework destruction,and the formation of NaOH was the rate-determining step.The presence of RE elements decreased hydrolysis and stabilized the structure of the zeolites.The interaction between V and RE destroyed zeolite structure by eliminating the stabilizing La-O[RE-OH-RE]^（5＋）bridges in the sodalite cages.

Ultrasound-triggered microbubble destruction enhances the radiosensitivity of glioblastoma by inhibiting PGRMC1-mediated autophagy in vitro and in vivo

Background:Ultrasound-triggered microbubble destruction(UTMD) is a widely used noninvasive technology in both military and civilian medicine,which could enhance radiosensitivity of various tumors.However,little information is available regarding the effects of UTMD on radiotherapy for glioblastoma or the underlying mechanism.This study aimed to delineate the effect of UTMD on the radiosensitivity of glioblastoma and the potential involvement of autophagy.Methods:GL261,U251 cells and orthotopic glioblastoma-bearing mice were treated with ionizing radiation(IR) or IR plus UTMD.Autophagy was observed by confocal microscopy and transmission electron microscopy.Western blotting and immunofluorescence analysis were used to detect progesterone receptor membrane component 1(PGRMC1),light chain 3 beta 2(LC3B2) and sequestosome 1(SQSTM1/p62) levels.Lentiviral vectors or siRNAs transfection,and fluorescent probes staining were used to explore the underlying mechanism.Results:UTMD enhanced the radiosensitivity of glioblastoma in vitro and in vivo(P<0.01).UTMD inhibited autophagic flux by disrupting autophagosome-lysosome fusion without impairing lysosomal function or autophagosome synthesis in IR-treated glioblastoma cells.Suppression of autophagy by 3-methyladenine,bafilomycin A1 or ATG5 siRNA had no significant effect on UTMD-induced radiosensitization in glioblastoma cells(P<0.05).Similar results were found when autophagy was induced by rapamycin or ATG5 overexpression(P>0.05).Furthermore,UTMD inhibited PGRMC1expression and binding with LC3B2 in IR-exposed glioblastoma cells(P<0.01).PGRMC1 inhibitor AG-205 or PGRMC1siRNA pretreatment enhanced UTMD-induced LC3B2 and p62 accumulation in IR-exposed glioblastoma cells,thereby promoting UTMD-mediated radiosensitization(P<0.05).Moreover,PGRMC1 overexpression abolished UTMD-caused blockade of autophagic degradation,subsequently inhibiting UTMD-induced radiosensitization of glioblastoma cells.Finally,compared with IR plus UTMD group,PGRMC1 overexpression significantly increased tumor size [(3.8±1.1) mm^(2)vs.(8.0±1.9) mm^(2),P<0.05] and decreased survival time [(67.2±2.6) d vs.(40.0±1.2) d,P=0.0026] in glioblastoma-bearing mice.Conclusions:UTMD enhanced the radiosensitivity of glioblastoma partially by disrupting PGRMC1-mediated autophagy.

Efficient destruction of sodium cyanide by thermal decomposition with addition of ferric oxide

Efficient destruction of cyanide by thermal decomposition with ferric oxide addition was proposed. The mechanism of destruction of sodium cyanide with or without ferric oxide addition under various conditions was examined by XRD, DSC-TG, and chemical analysis technologies. In the absence of ferric oxide, sodium cyanide decomposes at 587.4 ℃ in air and 879.2 ℃ in argon atmosphere. In the presence of ferric oxide, about 60% of sodium cyanide decomposes at 350 ℃ for 30 min in argon, while almost all sodium cyanide decomposes within 30 min in air or O2 with mass ratio of ferric oxide to sodium cyanide of 1:1. The increase of ferric oxide addition, temperature, and heating time facilitates the destruction of sodium cyanide. It is believed that with ferric oxide addition, NaCN reacts with Fe2O3 to form Na4Fe(CN)6, Na2CO3, NaNO2 and Fe3O4 in argon. NaCN decomposes into NaCNO, Na4Fe(CN)6, minor NaNO2, and the formed NaCNO and Na4Fe(CN)6 further decompose into Na2CO3, CO2, N2, FeOx, and minor NOx in air or O2.

Simulation of the relationship between roadway dynamic destruction and hypocenter parameters

Many factors can induce rock burst. Shock energy and shock distance are two key factors affecting rock burst. The 32101 roadway of the Xingcun coal mine, which has a tendency for rock burst, was used as an example. The dynamic module of Itasca’s FLAC (Fast Lagrangian Analysis of Continua) 2D explicit finite-difference software was used to simulate the roadway’s destruction. The vibration velocity and displacements of the rock surrounding the roadway were modeled for different shock energies and hypocenter distances. The simulation results indicate that the vibration velocity and displacement of rock surrounding the roadway have a quadratic relationship to the shock energy and a power law relationship to the distance of the hypocenter from the roadway. A dynamic view of the process was obtained from a series of "snap-shots" collected at 100 different time steps. This shows an isolating "river" is first formed at the hypocenter. The region above the "river" is a low stress zone while below the "river" a high stress zone exists. This high stress zone surrounds the ribs of the roadway in a "double ear" pattern. Continuous and repeated action of the high stress in the "double ear" shaped zone destroys the roadway.

Overexpression of the neuroglobin gene delivered by ultrasound-targeted microbubble destruction protects SH-SY5Y cells against cobalt chloride induced hypoxia

In this study, we examined the effects of neuroglobin gene （Ngb） transfection into SH-SY5Y cells, using ultrasound-targeted microbubble destruction （UTMD）, on cobalt chloride-induced hypoxia. With an ultrasound intensity of 0.8 W/cm2, a 60-second exposure duration, 50% duty cycle, and 20% microbubble concentration, pAcGFP1-C1-Ngb-transfected cells exhibited the highest cell viability and transfection efficiency. The efficiency of plasmid delivery was significantly higher with UTMD than transfection with plasmid alone, transfection with plasmid using microbubbles, or transfection of plasmid by ultrasound. In addition, during cobalt chloride-induced hypoxia, caspase-3 activity in pAcGFP1-C1-Ngb-transfected cells was significantly lower than in untransfected cells. Ngb protein and mRNA expression were significantly higher in cells transfected by UTMD than in cells transfected with the other methods. These results demonstrate that UTMD can very efficiently mediate exogenous gene delivery, and that Ngb overexpression protects cells against cobalt chloride-induced hypoxia.

Reduced EGFR signaling enhances cartilage destruction in a mouse osteoarthritis model

Osteoarthritis （OA） is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor （EGFR） signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus （DMM） to induce OA in two mouse models with reduced EGFR activity, one with genetic modification （, was/＋ mice） and the other one with pharmacological inhibition （gefitinib treatment）. Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 （MMP13）, the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2α （HIF2α）, a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation.

Destruction of the Northern Margin of the North China Craton in Mid-Late Triassic: Evidence from Asthenosphere-derived Mafic Enclaves in the Jiefangyingzi Granitic Pluton from the Chifeng Area, Southern Inner Mongolia

The petrology, geochronology and geochemistry of the mafic enclaves in the Mid-Late Triassic Jiefangyingzi pluton from Chifeng area, southern Inner Mongolia, in China are studied to reveal their petrogenetic relationship with the host pluton. Furthermore, the coeval magmatic assemblage and its petrogenesis on the northern margin of the North China craton(NCC) are studied synthetically to elucidate their tectonic setting and the implications for the destruction of the NCC. Zircon U-Pb dating reveals that the mafic enclaves formed at 230.4 ± 2.2 Ma, which is similar to the age of the host pluton. The most basic mafic enclaves belong to weak alkaline rocks, and they display rare earth element(REE) and trace element normalized patterns and trace element compositions similar to those of ocean island basalt(OIB). In addition, they have positive εNd(t) values(+3.84 to +4.94) similar to those of the Cenozoic basalts on the northern margin of the NCC. All of these geochemical characteristics suggest that the basic mafic rocks originated from the asthenosphere. Petrological and geochemical studies suggest that the Jiefangyingzi pluton and the intermediate mafic enclaves were formed by the mixing of the asthenosphere-derived and crust-derived magmas in different degrees. The Mid-Late Triassic magmatic rocks on the northern margin of the NCC could be classified into three assemblages according to their geochemical compositions: alkaline series, weak alkaline–sub-alkaline series and sub-alkaline series rocks. Petrogenetic analyses suggest that the upwelling of the asthenosphere played an important role in the formation of these Mid-Late Triassic magmatic rocks. Basing on an analysis of regional geological data, we suggest that the northern margin of the NCC underwent destruction due to the upwelling of the asthenosphere during the Mid-Late Triassic, which was induced by the delamination of the root of the collisional orogeny between Sino-Korean and Siberian paleoplates in Late Permian.

Modeling of organic pollutant destruction in a stirred tank reactor by ozonation

Destruction of organic contaminants in water by ozonation is a gas-liquid process which involves ozone mass transfer and fast irreversible chemical reactions. Ozonation reactor design and process optimizing require the modeling of the gas-liquid interactions within the reactor. In this paper a theoretical model combining the fluid dynamic and reaction kinetic parameters is proposed for predicting the destruction rates of organic pollutants in a semi-batch stirred-tank reactor by ozonation. A simple expression for the enhancement factor as our previous work has been applied to evaluate the chemical mass transfer coefficient in ozone absorption. 2,4-dichlorophenol (2,4-DCP) and 2,6-DCP or their mixture are chosen as the model compounds for simulating, and the predicted DCP concentrations are compared with some measured data.

The research on the thermal destruction of environment and controlling techniques of the No.4 outcrops fire in Haibaoqing

The coal fire is one of very serious disasters in natural, not only amount of coal resources was burned and some ecological environment problems such as ground subsidence, acid rain, pollution and vegetation died were caused serious. The No.4 coal seam outcrops fire in Haibaoqing was take as research object, based on the existing theory of mechanism and characteristics of coal outcrop fires, a new fire-fighting composite gel is applicated which fits in with extinguishment of outcrop coal fires well. The technology has many advantages in extinguishing coal fires including isolating the coal from oxygen and lowering the temperature of the high-temperature coal and rock. The structure and chemical composition as well as fires-fighting properties of the composite gel is analyzed profoundly, as a result, reduce and stop the environment destruction caused by the coal fire.

Serum Metabonomics of Articular Cartilage Destruction Induced by T-2 Toxin in Wistar Rats

The molecular pathogenesis of T-2 toxin-induced cartilage destruction has not been fully unraveled yet. The aim of this study was to detect changes in serum metabolites in a rat anomaly model with articular cartilage destruction. Thirty healthy male Wistar rats were fed a diet containing T-2 toxin （300 ng/kg chow） for 3 months. Histopathological changes in femorotibial cartilage were characterized in terms of chondrocyte degeneration/necrosis and superficial cartilage defect, and the endogenous metabolite profile of serum was determined by UPLC/Q-TOF MS. Treated rats showed extensive areas of chondrocyte necrosis and superficial cartilage defect in the articular cartilage. In addition, 8 metabolites were found to change significantly in these rats compared to the control group, including lyso PE （18：0/0：0）, lyso PC（14：0）, lyso PC[18：4 （6Z,9Z,12Z,15Z）], lyso PC[（16：1（9Z）], lyso PC（16：0）, L-valine, hippuric acid, and asparaginyl-glycine. These 8 metabolites associated with cartilage injury are mainly involved in phospholipid and amino acid metabolic pathways.

Coordination and evolution mechanism of fractal crack network in mining rock mass destruction

Based on the natural characters of stratum, complicated geological mining conditions and the essence of mining rock mass destruction, the complexity of rock mass destruction caused by miningw as analyzed. The inner link between rock mass destruction phenomena caused by mining and nonlinear science was revealed. There are numerous cracks in natural rock mass. The cracks’ distribution is irregular and is of statistical fractal structure. Self-organizational nonlinear evolution of the inner structure flaws leads to the rock mass destruction with external force. The evolution includes single fault’s fractal development, formation and evolution of fractal crack network and coordination of fractal crack network, etc. The law of fractal crack network’s evolution was introduced, at the same time, the coordination of fractal crack network was analyzed. Finally, based on coordination the principal equation of mining-caused subsidence of structural rock mass was established and its steady-state solution and unsteady-state solution were found.

Antitumor effect of VEGFR2-targeted microbubble destruction with gemcitabine using an endoscopic ultrasound probe:In vivo mouse pancreatic ductal adenocarcinoma model

Background:Ultrasound-targeted microbubble destruction(UTMD)induces cellular inflow of drugs at low intensity,while high intensity eradicates tumor vessels.Since vascular endothelial growth factor receptor 2(VEGFR2)is highly expressed in pancreatic ductal adenocarcinoma(PDAC),VEGFR2-targeted microbubble(MB)might additionally increase the tissue specificity of drugs and thus improve antitumor effects.In addition,fixing the dual pulse intensity could maximize MB properties.This study evaluated the one-off(experiment 1)and cumulative(experiment 2)treatment effect of UTMD by regulating the dual pulse output applied to PDAC using VEGFR2-targeted MB.Methods:C57BL/6 mice inoculated with Pan-02 cells were allocated to five groups:VEGFR2-targeted MB+gemcitabine(GEM),VEGFR2-targeted MB,non-targeted MB+GEM,GEM,and control groups.After injection of GEM or GEM and either VEGFR2-targeted or non-targeted MB,UTMD was applied for several minutes at low intensity followed by high intensity application.In experiment 1,mice were treated by the protocol described above and then euthanized immediately or at the tumor diameter doubling time(TDT).In experiment 2,the same protocol was repeated weekly and mice were euthanized at TDT regardless of protocol completion.Histological analysis by CD31 and VEGFR2 staining provided microvascular density(MVD)and VEGFR2 expression along vessels(VEGFR2v)or intra/peripheral cells(VEGFR2c).Results:In experiment 1,TDT was significantly longer in the VEGFR2-targeted MB+GEM group compared to the non-targeted MB+GEM,GEM,and control groups,while the VEGFR2-targeted MB group showed no statistical significance.MVD and VEGFR2v in the immediate euthanasia was significantly lower in the VEGFR2-targeted MB+GEM and VEGFR2-targeted MB groups than other conditions.In experiment 2,the VEGFR2-targeted MB+GEM group produced significantly longer TDT than the GEM or control groups,whereas the VEGFR2-targeted MB group showed no significant difference.Histology revealed significantly reduced VEGFR2v and VEGFR2c in the VEGFR2-targeted and non-targeted MB+GEM groups,while only VEGFR2v was significantly less in the VEGFR2-targeted MB group.Conclusions:UTMD-mediated GEM therapy with the dual pulse application using VEGFR2-targeted MB substantially suppresses PDCA growth.