769 results about "Anti neoplastic" patented technology

The invention relates to the field of natural products, in particular to a dimer compound of guaiane type sesquiterpenes and uric acid as well as an extraction and separation method and application of the dimer compound. According to the invention, a new dimer compound of guaiane type sesquiterpene and uric acid is extracted and separated from carpesium abrotanoides in Guizhou, and it is found that the dimer compound has relatively strong anti-tumor activity. The compound has strong inhibitory activity on breast cancer, prostate cancer, nasopharynx cancer, liver cancer, lung cancer, leukemia, pancreatic cancer, glioma, osteosarcoma, skin cancer, cervical cancer, ovarian cancer, kidney cancer and esophageal cancer, and provides an optional scheme for broad-spectrum anti-cancer drugs. Moreover, in human prostate cancer cells PC3, human cervical cancer cells Hela, human liver cancer cells HepG2 and human glioma cells U87 which are resistant to paclitaxel, the compound also shows strong anti-cancer activity, which indicates that the compound has the potential of treating patients resistant to paclitaxel.

The invention relates to an anti-CD3 nano antibody, an anti-CD38 antibody and a bispecific antibody containing the anti-CD3 nano antibody and the anti-CD38 antibody. According to the invention, an anti-CD3 nano antibody and an anti-CD38 monoclonal antibody are excavated and prepared, humanized design is carried out to obtain antibodies with high affinity and specificity, and different configurations of bispecific T cell conjugation antibodies targeting CD3 and CD38 are further designed, so that the CD3 and CD38 dual-specificity T cell conjugation antibodies are obtained. The antigen binding activity, the T cell-mediated tumor cell killing effect and the T cell proliferation and activation function of the antibody are systematically evaluated in vitro, and experimental results show that the T cell conjugation antibody can effectively recruit and activate T cells and has a remarkable killing effect on CD38 positive tumor cells, and it is further verified that the antibody has remarkable in-vivo anti-tumor activity and has a good application prospect. Therefore, the polypeptide has high affinity, good pharmacological characteristics and development potential.

The invention provides an alkaloid compound as well as a preparation method and an application thereof in tumor resistance. The alkaloid compound provided by the invention shows a remarkable cytotoxic effect on human non-small cell lung cancer cells A549, mouse lung adenocarcinoma cells Lewis, human triple negative breast cancer cells MDA-MB-231 and mouse breast cancer cells 4T1, and can be used for preparing medicines for treating breast cancer, lung cancer and the like.

The present application relates to a kind of pH / H2O2 dual-response drug-loaded hydrogel and its preparation method and application, by ε-polylysine derivative as antitumor active ingredient, with oxidized dextran through Schiff base reaction crosslinking rapid gelation. While using 2-formylphenyl boronic acid covalently package CD73 small molecule inhibitor APCP. ε-polylysine derivative has oncolytic activity, can induce ICD and promote the infiltration of immune cells in tumor cells. CD73 small molecule inhibitor APCP can block extracellular CD39-CD73-adenosine pathway, reduce the level of immunosuppressive metabolite adenosine in tumor tissue, so as to activate the infiltrated immune cells, restore its anti-tumor function. The hydrogel of ε-polylysine derivative and APCP co-delivery synergistically inhibits the effect of tumor growth, and its curative effect is greater than the treatment effect of single drug, and is superior to positive control drug oxaliplatin (OXA). The pH / H2O2 dual-response hydrogel is rapidly gelled, and has good biological safety under mild reaction conditions.

The invention belongs to the technical field of pharmaceutical preparation equipment, and particularly discloses a mixing and blending device for preparing an anti-tumor medicament. The bottom of the cylindrical tank body is funnel-shaped and is connected with an outlet of a butterfly valve; a top cover is arranged at the top of the tank body and is provided with a main shaft driven by a servo motor, the upper section of the main shaft is provided with a double-end spiral stirring blade, the screw pitch is gradually reduced from top to bottom, and the lower section is fixed with a shearing stirring blade which is provided with a through hole. A plurality of layers of inclined guide plates are arranged on the inner wall of the tank body to form a layered stirring frame which forms a reverse shear flow field with the spiral blades. An interlayer cavity in the side wall of the tank body is connected with a circulating guide pipe to achieve cooling temperature control, a dynamic sealing ring between the main shaft and the top cover conducts self-adaptive sealing, and the top cover is provided with an inert gas connector and a gas outlet. The supporting base is connected with the fixing ring base through the damping spring. Through the synergistic effect of layered reverse shearing, dynamic sealing and a cooling system, the chemical mixing uniformity is remarkably improved, the oxidation and leakage risks are reduced, and meanwhile vibration and operation complexity are reduced.

The invention relates to the field of antitumor drugs, in particular to a thiophene acetyl tetrahydro-beta-carboline compound and application thereof. The thiophene acetyl tetrahydro-beta-carboline compound or the pharmaceutically acceptable salt thereof, and the pharmaceutical composition containing the compound can be used for preparing medicines for preventing and / or treating various cancers. The cancer is at least one of breast cancer, lung cancer, osteosarcoma, melanoma, gastric cancer, pancreatic cancer, kidney cancer, glioma and ovarian cancer. Activity screening is carried out on various compounds, it is found for the first time that the 12 compounds provided by the invention have remarkable broad-spectrum inhibitory activity on various human cancer cell lines, and key candidate compounds are provided for developing novel anti-cancer drugs.

The invention discloses application of a tripterygium wilfordii exosome in preparation of an anti-cervical cancer medicine and a tumor angiogenesis inhibiting medicine, and relates to the field of biological medicine. The medicinal plant exosome derived from tripterygium wilfordii is successfully separated, and it is proved that the medicinal plant exosome can regulate related pathways through delivery of functional nucleic acid molecules to inhibit proliferation and migration of cervical cancer cells and promote active oxygen related apoptosis so as to be used for tumor treatment. The tripterygium wilfordii exosome can further act on vascular endothelial cells in a tumor microenvironment, the migration function of Hela cells is inhibited, and then the effect of resisting cell proliferation in the tumor microenvironment is achieved. The tripterygium wilfordii exosome has the advantages of being simple in preparation method, remarkable in tumor growth resistance and tumor cell migration inhibition effect, good in biocompatibility, high in delivery efficiency and the like, and can be used as a novel nano-drug for tumor treatment.

The invention discloses a platinum (IV)-pirfenidone compound prodrug, a preparation method and microenvironment remodeling anti-tumor application, and belongs to the field of medical technology and drug synthesis. A series of molecules are characterized by being platinum prodrugs modified by pirfenidone derivatives. The synthesis method sequentially comprises the following steps: oxidizing platinum drugs, modifying hydroxyl groups, and introducing pirfenidone derivatives through esterification reaction. A series of molecules are reduced into Pt (II) drugs at the focus to kill cancer cells, and meanwhile, the released pirfenidone derivative can remodel the tumor microenvironment. The platinum prodrug disclosed by the invention not only has excellent cancer cell killing ability, but also is relatively low in drug resistance and excellent in safety, can trigger immunogenic cell death, and is a brand new chemotherapy-immunotherapy method. A series of molecules are convenient to synthesize, the preparation process is simple, and the amphipathicity is excellent, the anti-cancer capability is excellent, the drug resistance and toxicity are low, and the clinical application prospect is good.

This invention belongs to the field of organic synthesis and relates to a nitrogen-containing [3,2-b]indole derivative, its preparation method, and its application. The nitrogen-containing [3,2-b]indole derivative is a compound, optical isomer, or pharmaceutically acceptable salt thereof, as shown in the following structure: ; wherein R1, R2, R3, and R4 are independently selected from hydrogen atoms, halogens, cyano groups, C1-C8 alkyl groups, and C1-C8 alkoxy groups; R5, R6, R7, and R8 are independently selected from hydrogen atoms, halogens, and C1-C8 alkyl groups; R9 is selected from C1-C8 alkyl groups; when R1, R2, R3, R4, R5, R6, R7, and R8 are all hydrogen atoms, R9 is selected from C1-C2 alkyl groups. The compound exhibits antitumor activity, particularly against HeLa cervical cancer, showing a significant inhibitory effect on its proliferation.

The application discloses a kind of 2-substituted benzylhydrazine-4-indole pyrimidine-5-carbonitrile derivatives and preparation method and application thereof.The derivative has general formula (I) structure: wherein R is hydroxyl or C1-C4 alkoxy, n=1~3.Preferred compound is 2-hydroxy, 4-hydroxy-3-methoxy, 2,3-dihydroxy or 2,4-dihydroxy substituted benzylhydrazine derivative.The application also provides key intermediate 2-hydrazine-4-(1H-indole-3-carbonyl) pyrimidine-5-carbonitrile and preparation method thereof.In vitro antitumor activity shows that the derivative has excellent inhibitory activity on human gastric cancer cell MGC-803, and the inhibition rate is up to 96.3% at 10 μmol / L, which is better than positive control doxorubicin.In vivo combination test shows synergistic effect with 5-fluorouracil or anti-PD-1 antibody.The compound of the application has mild synthesis route, high yield, various preparation forms, good safety, and can be applied in the preparation of anti-gastric cancer drugs.

The application discloses an 8-hydroxyquinoline anticancer zinc (II) complex and a synthesis method and application thereof. The 8-hydroxyquinoline anticancer zinc (II) complex is synthesized by taking 5,7-diiodo-8-hydroxyquinoline, 5,7-dichloro-8-hydroxyquinoline, 5-chloro-7-iodo-8-hydroxyquinoline, 5,7-dibromo-8-hydroxyquinoline and 5-chloro-8-hydroxyquinoline as a first ligand and taking 4,4'-dimethoxy-2,2'-bipyridine, 4,4-di-tert-butyl-2,2-bipyridine, 5,5'-dimethyl-2,2-bipyridine, 2,2-bipyridine and 4,4'-dimethyl-2,2'-bipyridine as auxiliary ligands. The 8-hydroxyquinoline anticancer zinc (II) complex has good inhibiting effect on SK-OV-3CR cells of an ovarian cancer drug-resistant strain, is higher than that of cisplatin drugs, overcomes drug resistance of clinical drugs, has potential medicinal value and can be used for preparation of various antitumor drugs.

The present invention relates to a novel antibody targeting B7-H3 or an antigen-binding fragment thereof, a chimeric antigen receptor (CAR) comprising same, an immune cell comprising the CAR, and uses thereof. The CAR-T cells according to the present invention have low toxicity and excellent antitumor activity, and thus can be effectively used in immune cell treatment for cancer treatment.

The present invention discloses an antitumor pharmaceutical composition based on immune checkpoint blockade and its application, which comprises paroxetine hydrochloride and a T cell enhancer, which is at least one of vitamin E and thymosin. Through a series of in vitro and in vivo experiments, the present invention has first discovered that cannabidiol and paroxetine hydrochloride can effectively reduce the expression of PD-L1 on the surface of tumor cells, block the PD-1 / PD-L1 signaling pathway, and enhance the tumor cell killing effect of T cells. Based on this, the addition of a T cell enhancer can further increase the number and activity of T cells, significantly enhancing the killing ability of T cells after immunosuppression is released, thereby significantly enhancing the antitumor effect of the drug. The components of the pharmaceutical composition of the present invention, cannabidiol, paroxetine hydrochloride, vitamin E, and thymosin, exert a synergistic effect, improving the antitumor effect.

The application discloses a 3-(5-(aminomethyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione derivative and a synthesis method and application thereof, and relates to a 3-(5-(aminomethyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione derivative which is a compound with the following general formula (I): wherein R1 is selected from,,,,,,,,, and R2 is selected from,,, and. The compound can significantly inhibit the proliferation of leukemia, multiple myeloma, lymphoma, breast cancer, liver cancer and the like at a low dose (nanomole), can effectively degrade IKZF1, IKZF3, BRD4, GSPT1 and CK1 alpha, and has the prospect of being developed into an anti-tumor drug. The application solves the problem that the existing malignant hematological disease treatment drugs have a high safety risk.

The invention relates to the technical field of anti-cancer chemical drugs, in particular to a thiadiazole tetranuclear copper complex with anti-tumor and antibacterial activity and a preparation method and application of the thiadiazole tetranuclear copper complex. The chemical formula of the complex is [Cu4 (C3H3S2N2) 2 (C3H4S2N2) 4], the complex is synthesized from ligand thiadiazole and CuX, X is I or Br, and copper in the obtained complex is + 1 valence. The complex shows a good cytotoxic effect on breast cancer cells MCF-7, is likely to play a toxic effect by inducing apoptosis, ferroptosis, copper death and other ways, has a good antibacterial effect, has potential medicinal value, and is expected to be developed into a new generation of anti-tumor drugs with antibacterial properties.

This invention relates to a pharmaceutical composition for tumor treatment and its application. Specifically, this invention relates to a composition containing a fluorouracil drug and pyrimidine nucleosides and their derivatives. Fluorouracil drugs and pyrimidine nucleotides and their derivatives have a synergistic antitumor effect; combined use can reduce the concentration of single drugs and achieve better antitumor efficacy, while reducing toxic side effects.

The application discloses a LYTAG-Gem compound for enhancing the anti-tumor effect of gemcitabine and application thereof, relates to the technical field of biological medicine, and particularly relates to a gemcitabine (Gem) targeted delivery system based on a lysosome targeting chimera (LYTAC) and application thereof in enhancing the anti-tumor process. 2+ The system is assembled from heavy chain ferritin, Ni 2+ , NTA-PEG5000-DBCO and a targeting ligand TPP-1-N3 in a specific mass percentage, can efficiently load Gem and form a nano compound with a particle size of about 59-79 nm, the system targets tumor cells through heavy chain ferritin, and realizes site-specific release of Gem in cells by means of an endocytosis-lysosome pathway mediated by the LYTAC structure, in-vivo pharmacodynamic experiments show that the LYTAC-Gem compound can significantly inhibit the tumor growth of a KPC pancreatic cancer mouse model, molecular mechanism research further reveals that the LYTAC-Gem compound can down-regulate the expression of PD-L1 protein in tumor tissues, and it is indicated that the LYTAC-Gem compound has the potential to activate an anti-tumor immune response, and the application provides a novel targeted delivery strategy for overcoming the toxic side effects and tumor drug resistance of gemcitabine.

The disclosure relates to the combination of inhibitors of phosphodiesterase 1 (PDE1) useful for the treatment of certain cancers or tumors, such as colon cancer. In another embodiment, the disclosure relates to the use of inhibitors of PDE1 and an optional antitumor agent for the treatment of certain cancers or tumors.

The invention relates to the technical field of biological medicine, in particular to an anti-tumor stapharia rugosoannulata water-soluble protein compound preparation and a preparation method thereof. The compound preparation is prepared from the following raw material components in parts by weight: 2 to 3 parts of stapharia rugosoannulata water-soluble protein, 0.8 to 1.2 parts of fermentation preparation and 0.1 to 0.2 part of rosmarinic acid.

The application belongs to the technical field of antitumor drugs, and particularly relates to an AuNRs@L / D-Ag2S QDs complex, a preparation method and application thereof. Sodium polystyrene sulfonate is electrostatically adsorbed on AuNRs to obtain 1-PSS-AuNRs; polyallylamine hydrochloride is electrostatically adsorbed on 1-PSS-AuNRs to obtain 2-PAH-AuNRs; polyallylamine hydrochloride is electrostatically adsorbed on 2-PAH-AuNRs to obtain a non-chiral nanomaterial; and the non-chiral nanomaterial is covalently crosslinked with L / D-Ag2S QDs to obtain the AuNRs@L / D-Ag2S QDs complex. The application combines the efficient photo-thermal conversion characteristics of AuNRs with the chiral-dependent targeting and potential fluorescence imaging ability of chiral Ag2S quantum dots by constructing a complex structure, so that a novel nanodiagnostic and therapeutic agent with efficient photo-thermal performance and chiral selectivity is obtained.

This invention discloses the application of Uncaria rhynchophylla neutral polysaccharide URP-W in the preparation of anti-glioma drugs, belonging to the field of anti-tumor technology of medicinal plant polysaccharides. The invention obtains a crude polysaccharide extract from Uncaria rhynchophylla through hot water extraction and ethanol precipitation, followed by purification using a DEAE cellulose column and G200 dextran gel to obtain Uncaria rhynchophylla neutral polysaccharide URP-W. The monosaccharide composition of URP-W includes arabinose, rhamnose, galactose, glucose, xylose, mannose, galacturonic acid, and mannuronic acid in a molar ratio of 17.99:6.32:21.71:27.17:2.56:7.57:16.20:0.49. Experiments have shown that URP-W can inhibit the proliferation of gliomas and induce apoptosis, exhibiting significant anti-tumor activity against glioma cells, providing a new drug raw material and treatment method for the clinical treatment of gliomas.

The application relates to the technical field of natural medicinal chemistry, and specifically discloses a triterpenoid compound and application, and a preparation method of the compound. The preparation method comprises the following steps: drying and crushing schisandra chinensis roots to obtain dried and crushed schisandra chinensis roots, extracting the dried and crushed schisandra chinensis roots by using 70% ethanol water solution under negative pressure cavitation, combining and concentrating the extract to obtain a crude extract, separating the crude extract by using a D101 macroporous adsorption resin, eluting the crude extract by using water, 30% ethanol, 70% ethanol and 90% ethanol in sequence, collecting a 70% ethanol elution part, performing MCI column chromatography on the 70% ethanol elution part, performing gradient elution on the 70% ethanol elution part by using methanol-water, collecting a depigmentation sample, performing ODS column chromatography on the depigmentation sample, performing gradient elution on the depigmentation sample by using water-methanol, collecting a target component, and purifying the target component by using a preparative high performance liquid chromatograph to obtain the target compound. The application separates a novel triterpenoid compound from schisandra chinensis roots for the first time, expands the development range of medicinal resources of schisandra chinensis plants, simultaneously provides a novel structure mother nucleus and a candidate active molecule for anticancer drug research and development, and enriches the research and development reserves of antitumor natural medicines.

The application provides a combination drug of a PLA2G7 inhibitor and a chemotherapeutic drug and its use in resisting triple-negative breast cancer, and belongs to the technical field of medicines. The combination drug is a PLA2G7 inhibitor and a chemotherapeutic drug in the same or different specifications of unit preparations for simultaneous or separate administration, and a pharmaceutically acceptable carrier. The application first discovers and proves that the PLA2G7 inhibitor Darapladib can significantly enhance the anti-tumor activity of paclitaxel, 5-fluorouracil or cisplatin on triple-negative breast cancer, and meanwhile, the combination of the PLA2G7 inhibitor and paclitaxel has a synergistic effect in down-regulating the phosphorylation level of STAT3 protein in cancer cells and inhibiting the growth and proliferation of cancer cells; the combination of the PLA2G7 inhibitor and 5-fluorouracil also shows a synergistic effect in inhibiting the growth and proliferation of cancer cells. The application provides a new and effective combination drug strategy for improving the treatment effect of the chemotherapeutic drug on triple-negative breast cancer.

This application belongs to the field of biomedicine, specifically relating to a method for preparing an antitumor composition for pets, aiming to solve the technical problems of low bioavailability, poor stability, and poor drug administration compliance of poorly soluble active ingredients in antitumor drugs for pets. The method includes: a raw material pretreatment step, in which curcumin, resveratrol, quercetin, green tea polyphenols, and astragalus polysaccharides are pulverized and sieved separately; an organic phase preparation step, in which egg yolk lecithin and solid lipids are dissolved in an ethanol-acetone mixed solvent, and curcumin and resveratrol are added and dissolved by stirring in a water bath; an aqueous phase preparation step, in which poloxamer F68 is dissolved in purified water and dissolved in a water bath; a high-pressure homogenization step, in which a nanoemulsion containing a solid lipid core is prepared; a moderately polar component encapsulation step, in which quercetin and green tea polyphenols are ultrasonically dispersed and then added dropwise to the nanoemulsion; a freeze-drying step, in which a nano-lyophilized powder is obtained; and an outer hydrophilic component coating step, in which astragalus polysaccharides are sprayed or adsorbed onto the surface of the freeze-dried powder. The composition obtained by this method is a core-shell multilayer nanoparticle with a core consisting of curcumin and resveratrol encapsulated by solid lipids, a middle shell adsorbing quercetin and green tea polyphenols, and an outer shell coated with astragalus polysaccharides. This application utilizes the above-mentioned layered encapsulation technology to achieve stable co-encapsulation of multiple antitumor active ingredients, improve the bioavailability of poorly soluble components, optimize drug stability, and enhance antitumor effects through multi-target synergistic effects. Simultaneously, it endows the composition with immunomodulatory functions and sustained-release properties. The composition can be formulated into a nano-lyophilized powder form, making it easy to add to pet food or formulate into a paste for administration, improving pet drug compliance. Figure 2 is a schematic diagram of the three-layer core-shell nanoparticle structure of the composition of this invention.

The application discloses a kind of nanoparticles for tumor sonodynamic combined individualized immunotherapy and its preparation method and application, belong to the field of biological medicine.The nanoparticles for tumor sonodynamic combined individualized immunotherapy are double-shell core structure nanoparticles formed by inner core and shell, and the inner core is formed by self-assembly of TLR3 agonist Poly (I:C), L-arginine and polylysine, and the shell is hyaluronic acid layer HA-Ce6 conjugated with photosensitizer Ce6.It is found through experiment verification that the nanoparticles can target tumor, generate reactive oxygen species to kill tumor cells under the action of ultrasound, promote M1 macrophage polarization and produce NO release at the same time, play the role of antitumor and immune effect, and realize the combined application of sonodynamic and NO gas therapy.The nanoparticles for tumor sonodynamic combined individualized immunotherapy can trigger systemic immune response, inhibit primary tumor, produce immune memory effect, and prevent tumor metastasis and recurrence.

Disclosed are new anti-HER2 ADCs conjugated to camptothecin derivatives as toxins for therapeutic use. The antitumor effects of the ADCs of Formula (PL-A) (e.g., compounds MB-2a and MB-3a (trastuzumab meditecan)) render these compounds useful for treating cell proliferative diseases such as cancers.

This application discloses a purino[1,2-a]carbazolin derivative, its preparation method, and its application. Specifically, it discloses a compound having the structure shown in Formula I, or its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, cocrystals, or prodrugs: ; wherein R1 and R2 are each independently selected from hydrogen, hydroxyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, -CONH-R3, and -COO-R4; wherein R3 is a substituted or unsubstituted C1-C5 alkyl, and the substituent can be any of cyano, halogen, alkylC1-C5 alkoxy, C1-C5 alkylsulfonyl, di(C1-C5 alkyl)amino, nitrogen-containing heterocyclic, aryl, and C1-C5 heteroaryl; R4 is selected from any of substituted or unsubstituted aryl C1-C5 alkyl and nitrogen-containing saturated heterocyclic C1-C5 alkyl. This compound can be used as a TDP1 inhibitor for antitumor therapy.

Disclosed are new anti-HER2 ADCs conjugated to camptothecin derivatives as toxins for therapeutic use. The antitumor effects of the ADCs of Formula (PL-A) (e.g., compounds MB-2a and MB-3a (trastuzumab meditecan)) render these compounds useful for treating cell proliferative diseases such as cancers.

The application discloses a 4-(1H-benzo[d]imidazol-2-yl)-N,N-bis(2-chloroethyl) aniline derivative and a preparation method and application thereof, and belongs to the technical field of biological medicines. A structural formula is shown in the following formula I: wherein the R substituent is selected from any one of hydrogen, halogen, a carboxyl group, a cyano group, a nitro group and an alkoxy group. The application takes 4-position substituted o-phenylenediamine and 4-[bis(beta-chloroethyl)amino]benzaldehyde as raw materials, and obtains a target molecule through a condensation reaction. At present, similar nitrogen mustard or benzimidazole drug synthesis needs multiple steps of reaction, and separation and purification is complicated. The application has only one step of synthesis, a simple separation method and low requirement on equipment. In vitro anti-tumor experiments show that the target compounds synthesized by the application all have obvious anti-tumor effects, exhibit strong pharmacological activities in inhibiting tumor cell proliferation, and have wide research and development value in the field of anti-tumor drugs.

This invention relates to the field of pharmaceutical technology, and discloses a stress particle targeted degrader, its preparation method, and its applications. The compounds provided by this invention include ternary complexes composed of stress particle protein, a linker group, and an E3 ubiquitin ligand, or ternary complexes composed of stress particle protein, a linker group, and a ribonuclease L ligand. Compounds with different ligands exhibit good targeting and degradation effects on stress particles and can be used as stress particle targeted degraders in the preparation of antitumor drugs and anti-neurodegenerative disease drugs, showing promising application prospects in treating stress particle-induced tumor drug resistance and neurodegenerative diseases.