88 results about "Gastrointestinal tumor" patented technology

The present invention provides compositions and methods for preventing the development of or reducing the growth of gastrointestinal tumors. The composition comprises polymeric microspheres encapsulating sulindac, IL-12 or both. These polymeric microspheres can be administered orally to individuals to reduce the growth of or prevent the development of gastrointestinal tumors.

The invention discloses a detection method for predicting and diagnosing gastrointestinal tumor as well as a kit and a gene chip thereof. The method comprises the following steps: (1) obtaining a sample to be detected; and (2) detecting whether the following coding mRNA gene is overexpressed in the sample, wherein the gene is a CST1 gene shown in SEQ ID No:39, or a primer of one of mRNA of specificity recognition CST1 gene, CST1 cutter shown in SEQ ID No:43, SEQ ID No:44, cDNA of CST1 gene and cDNA of CST1 cutter, or / and a probe recognized gene, or a gene identified by using an amplicon corresponding to at least one CST1 primer. The method can be applied to diagnosis of gastrointestinal caner, dynamic monitoring and prognosis judgment and has the advantages that a large number of verification samples can be obtained, the result is accurate and reliable result, the sensitivity is high and the like.

The present invention provides preventive approaches and treatments for an inflammatory bowel disorder (e.g., Crohn's disease or ulcerative colitis) or a gastrointestinal tumor (e.g., a colorectal cancer) comprising administering an O-glycan composition (e.g., mucins) to a subject, such as a human patient. In addition, the present invention also provides transgenic mice that fail to synthesize core 1-derived or core 3-derived O-glycans.

The invention relates to a method for extracting and purifying Pinostrobin from medicinal plants, and a pharmaceutical preparation and application thereof. The invention particularly discloses a method for extracting and purifying Pinostrobin from medicinal plants, and a pharmaceutical preparation and application thereof in preparing medicines for treating gastroenteropathy, and belongs to the field of life sciences. The method comprises the following steps: extracting medicinal plants with 70-95% ethanol homogenate; and after the extract is concentrated to a certain volume, standing to precipitate, removing a supernatant, dissolving the obtained precipitate with an organic solvent, separating by gel-resin column chromatography, crystallizing and recrystallizing to obtain the Pinostrobin monomer of which the purity is higher than 90%. The Pinostrobin monomer in which different excipients can be added is prepared into any common pharmaceutical formulation. The pharmaceutical preparation has obvious biological activity on peptic ulcer, gastritis, stomachache, gastric evacuation (gasterectasis), alimentary tract tumors and the like caused by Helicobacter pylori infection, and has thecharacteristic of no toxic or side effect.

The invention belongs to the field of medicines and health products, and concretely relates to an application of Chimonanthus salicifolius total alkaloid extract and monomer compounds thereof in the preparation of medicines or health products for treating gastrointestinal tumor diseases. The Chimonanthus salicifolius total alkaloid extract and chimonanthine monomer compounds (1-4) are extracted and prepared from a Calycanthaceae Chimonanthus plant Chimonanthus salicifolius, and experiments prove that the Chimonanthus salicifolius total alkaloid extract can substantially inhibit proliferation of stomach cancer SGC-7901, colorectal carcinoma SW1116 and colorectal carcinoma HCT116 cells and induce cancer cell apoptosis, and the alkaloid monomer compounds have different inhibition effects on the stomach cancer SGC-7901, colorectal carcinoma SW1116 and colorectal carcinoma HCT116 cells. The Chimonanthus salicifolius extract and the monomer compounds thereof can be applied individually or together or be combined with a suitable excipient, can be processed through a routine method to prepare an oral or non-oral dosage form used for treatment or assisted treatment of gastrointestinal tumor diseases, and is especially suitable for being used to prepare medicines or health products for treating stomach cancer and colorectal carcinoma.

The invention provides a disposable stool screening and collecting detection suit for gastrointestinal tumors, solving the technical problem that an existing stool screening and collecting detection suit for gastrointestinal tumors is tedious in flow and time- and labor-wasting, the environment is easily polluted and the effectiveness of a sample is easily affected as a reagent and the sample are in an open interflowing state with the environmental air all the way in the preparation and operation processes of the sample, and moreover, the detection is only performed in a special medical mechanism and is hard to popularize and apply in a large scope. The suit is provided with an inspection tube part and a feces sampling part. The feces sampling part comprises a feces sampling sleeve, a puncture needle is arranged in the middle of the feces sampling sleeve, a pressing end is arranged at the upper end of the puncture needle, a feces sampling sleeve connecting end is arranged in a part, close to the upper end surface, of the feces sampling sleeve, and the front end of the inspection tube part is connected to the connecting end of the feces sampling sleeve. The suit provided by the invention can be widely applied to collecting and detecting feces in screening gastrointestinal tumors in common families and quickly and accurately judging the detection result.

The present invention belongs to the field of medicine technology, and is especially one kind of medicine composition for regulating apparent genetic modification to prevent and treat gastrointestinal tumor. The medicine composition consists of effective components folic acid and sodium butyrate, medicine carrier and excipient. Experiments show that the medicine composition of the present invention can affect the methylation and acetylation of apparent genetic modification DNA, and further affect the gene expression of cell line of gastric cancer and / or large intestinal cancer or even change the cell period and inhibit tumor growth. The present invention has obvious tumor preventing and treating effect, no obvious toxic side effect and low cost.

The invention relates to the field of traditional Chinese medicines, in particular to a traditional Chinese medicine for treating gastrointestinal tumors and provides a novel method for treating the tumors on account of defects of traditional Chinese medicine for treating the tumors in the prior art. Growth of the tumors can be effectively controlled. According to a technical scheme for solving the problem, the traditional Chinese medicine is prepared from the following raw materials in parts by weight: 0.01-0.03 parts of venenum bufonis, 5-6 parts of scorpions, 9-15 parts of rhizoma pinelliae, 3-5 parts of trogopterus dung (ground into powder with liquor), 8-10 parts of rhizoma atractylodis macrocephalae, 2-3 parts of pericarpium citri reticulatae, 2-3 parts of fructus amomi, 2-3 parts of radix aucklandiae, 8-10 parts of rhizoma cyperi, 5-7 parts of Szechwan Chinaberry fruits, 6-8 parts of pollen typhae (fried), 12-15 parts of bulbus fritillariae thunbergii, 6-8 parts of radix glehniae, 10-12 parts of radix angelicae sinensis, 10-12 parts of radix rehmanniae recens and 4-5 parts of radix liquiritiae. The traditional Chinese medicine has the advantages that toxic and side effects are small, treatment is convenient, treatment cost is low, and the treatment cost is only one-fifth to one-tenth of the cost of the chemotherapy and surgery when the same curative effect is achieved.

The invention discloses a detection reagent for a PIEZO2 gene in a human gastrointestinal tumor. The detection reagent comprises a pair of specific primers, wherein the nucleotide sequence of the upstream primer is GGAGTTAGGC GGGAGTATAG TAC, and the nucleotides of the downstream primer is TTCTTCAAAA ATAACTAATA CCGAA. The detection reagent is specific to the PIEZO2 gene in the human gastrointestinal tumor, the relation of the PIEZO2 gene and the tumor is not clear currently, but the fact that in the gastrointestinal tumor, the PIEZO2 gene methylation degree of the PIEZO2 gene of cancer tissue and the PIEZO2 gene methylation degree of the PIEZO2 gene of para-carcinoma tissue, in fluorescent quantitative methylation detection, are different, and the PIEZO2 gene methylation degree of the cancer tissue is apparently higher than that of the para-carcinoma tissue, is discovered. The detection reagent has the advantages of being flexible and quick in detection, simple and convenient, highly targeted, accurate and reliable, high in efficiency and economical, and is beneficial to early detection and immediate treatment of the colorectal cancer and the stomach cancer.

The invention provides a pharmaceutical composition of a quinoline derivative and a PD-1 monoclonal antibody. The pharmaceutical composition comprises a tyrosine kinase inhibitor and an immune checkpoint inhibitor. The tyrosine kinase inhibitor is a compound as shown in formula I or a pharmaceutically acceptable salt thereof. The pharmaceutical composition has good anti-tumor activity against gastrointestinal tumors, urologic neoplasms or neuroendocrine carcinomas.

The invention discloses a novel application of gastrin in inhibiting gastrointestinal tumor tumors. Gastric cancer target gene anion exchange protein 1 is interacted with tumor suppressor protein p16 so as to induce gastric cancer, however, 17 peptide gastrin (H-pGlu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) can effectively inhibit expression of gastric cancer target gene AE1 and p16 and breaks through the traditional view that gastrin induces tumors, and clinical pathologies show that the gastrin has obvious negative correlation with AE1 and p16. The invention alsodiscloses that the gastrin with the concentration of 10-10mol / L-10-70mol / L has obvious inhibition effect on gastric cancer cell activity after a certain time, thus prompting that the gastrin has curing effect on gastric antrum cancer and providing a new direction for curing gastric cancer based on the test results.

The invention relates to a three-dimensional porous graphene assembled drug temperature controlled chemotherapy and thermotherapy gastrointestinal tumor device, which comprises a three-dimensional porous graphene assembled drug multi-temperature-controlled chemotherapy and thermotherapy tumor instrument, wherein the tumor instrument comprises a three-dimensional porous graphene assembled drug multi-temperature-controlled therapeutic apparatus, a telescopic multi-beam optical fiber rod and a dimming chamber; the three-dimensional porous graphene assembled drug multi-temperature-controlled therapeutic apparatus, the dimming chamber and the telescopic multi-beam optical fiber rod form an integrated controllable telescopic structure together which can generate actions such as linkage extensionand retraction in the whole device; the three-dimensional porous graphene assembled drug multi-temperature-controlled therapeutic apparatus comprises a three-dimensional porous graphene assembled multi-temperature-controlled drug releasing chamber; the three-dimensional porous graphene assembled multi-temperature-controlled drug releasing chamber comprises three-dimensional porous graphene and assembled drugs; and different types of drugs can be released for multiple times under different temperature control conditions. The device in the embodiment of the invention can also be applicable to chemotherapy and thermotherapy for tumors at the throat and tumors in the skin of the human body.

The invention provides novel application of proanthocyanidin oligomer F2 and a polymer F3 in preparing anti-tumor health care food and medicine, in particular novel application in preparing health care food and medicine for treating glioma. The application researches inhibiting function of F2 on brain tumor, blood system tumor, alimentary canal tumor, respiratory system tumor and urinary genital system tumor. Firstly, F2 and F3 are discovered to have the inhibiting functions on glioma cell strains U-87 and U251, humanized leukemia HL-60 cell strains, humanized liver cancer Hep3B cell strains, humanized colon cancer Colon-205 cell strains, humanized prostate cancer Du-145 cell strains and humanized A549 lung cancer cell strains, and the inhibiting function is improved along with progressive increase of dosage. In addition, the F2 can also remarkably inhibit chemotaxis of human malignant glioma U-87 cells induced by formyl peptide and expression of formyl peptide receptor (FPR) in the cells. The receptor has important function on mediating migration, survival, growth and vasculogenesis of the human malignant glioma cells.

The invention provides a tumor microsatellite instability detection kit based on a second-generation sequencing probe capture technology. The detection kit adopts the second-generation sequencing probe capture technology, and reagents of the detection kit comprise a quality control product, a library building reagent and an RNA probe; the quality control products comprise a negative quality control product and a positive quality control product; the negative quality control product is a negative sample dissolved in TE, and the positive quality control product is a plasmid containing an MSI site dissolved in TE; an NGS technology is selected on the basis of an MSI experimental method; the kit has the advantages that detection sites are many, up to 40 microsatellite sites are covered after screening, the microsatellite coverage area is wide, the uniformity is good after RNA probe adjustment, good medication guidance can be provided for patients, and the kit is suitable for multiple tumors such as colorectal cancer, endometrial cancer and gastrointestinal tumor.

The invention discloses a novel application of a Xianglian (coptidis rhizoma and radix aucklandiae) pill product in preventing or treating helicobacter pylori, gastrointestinal tumors, atrophic gastritis, cardiovascular and cerebrovascular diseases and the like. The invention solves the problems that the treatment effect of Xianglian pills is always limited to dysentery caused by damp-heat of large intestines, and the symptoms are purulent and bloody stool, tenesmus, fever and abdominal pain, enteritis and bacillary dysentery, and the new treatment effect is not developed all the time. The Xianglian pill product has the effect of resisting helicobacter pylori Hp, and the safety of the Xianglian pill product is higher than that of coptidis rhizoma and coptidis rhizoma extract; the Xianglian pill product can also be used for treating gastrointestinal tumors; and in addition, the Xianglian pill product also has the effect of preventing cardiovascular and cerebrovascular diseases including atherosclerosis.

The invention discloses gastrointestinal tumor postoperative auxiliary rehabilitation equipment. The equipment comprises a bed body, wherein supporting legs are mounted on one side of the bottom of the bed body; a medicated bath assembly is mounted in the center of the top of the bed body; a left-right displacement assembly is fixed to the center of the outer wall of the bed body; a vertical plateis fixed to the left-right displacement assembly; a control panel is mounted on the outer wall of the vertical plate; a microwave nursing assembly is installed at the top of the vertical plate; the control panel is electrically connected with the left-right displacement assembly, the microwave nursing assembly and the medicated bath assembly; the microwave nursing assembly comprises a connectingframe, a rotating motor, a speed reducer, a nursing box, a microwave generator, a microwave transmitting probe, a rotating disc and a bearing; and the nursing box is fixed to the top of the vertical plate. The equipment is novel in structure and ingenious in conception, can help a patient to carry out nursing after a tumor treatment operation, relieves the pain of the patient, improves the rehabilitation effect, and relieves the workload of medical staff.

The invention discloses a gastrointestinal tumor biopsy sampling device and belongs to the technical field of medical instrument equipment. The device comprises a lifting assembly, a rotating assembly, a sampling assembly, an expansion assembly, a dirt sucking assembly and a moving assembly, wherein the moving assembly is vertically arranged; the rotating assembly is arranged on the moving assembly and is rotationally connected with the moving assembly; the lifting assembly is arranged at the top of the rotating assembly; the sampling assembly is arranged at the lifting end of the lifting assembly; the sampling assembly comprises a sliding part and two sampling parts; the lifting part is arranged at the lifting end of the lifting assembly; the two sampling parts are symmetrically arrangedat the moving end of the sliding part; the expansion assembly is arranged at the lifting end of the lifting assembly; and the dirt sucking assembly is arranged at the lifting end of the lifting assembly and is positioned at the other end of the sampling assembly. By adopting the device, scraping and sampling operation on a tumor part of a patient is implemented in all direction in multiple anglesthrough swinging of a sampling blade, so that samples of different parts of a tumor of the patient can be obtained.

The invention discloses an intestinal tumor microscopic hyperspectral image processing method based on a convolutional neural network, and particularly relates to the technical field of gastrointestinal tumor detection, and the hyperspectral image processing method comprises the following steps: 1, obtaining a hyperspectral initial image, and irradiating the gastrointestinal tumor position of a patient by using related equipment. According to the invention, the hyperspectral initial image is segmented; a second sub-image is obtained by using the first sub-image, the feature points in each section of the second sub-image is extracted in a convolutional neural network manner; a third sub-image is constructed, and the feature points are integrated in each group of third sub-images; therefore, the hyperspectral target image formed by combining the feature points is obtained, the hyperspectral initial image can be effectively processed, the hyperspectral initial image is more visual and concise, the processing efficiency of a large amount of data in the hyperspectral initial image is improved, and meanwhile the disease diagnosis accuracy of people is improved.

The invention discloses a butt joint device for installation of a gastric tube after operation of gastrointestinal tumor, wherein the butt joint device includes a hoop, and a first gastric tube body and a second gastric tube body which are in butt joint. The butt joint ends of the first gastric tube body and the second gastric tube body are respectively fixedly connected with a first butt joint end and a second butt joint end, and at least two first installation grooves are symmetrically arranged on the end surface, close to the outer edge, of the first butt joint end, and a second installation groove is arranged close to the inner edge; semicircle clamping grooves are arranged at the upper and lower opposite positions of the middle, in a length direction, of each first installation groove; the end face of the first butt joint end is fixedly connected with a rubber seal gasket, and the end face of the second butt joint end is fixedly connected with a first installation strip and a second installation strip; grooves are arranged at the upper and lower opposite positions of the middle of the first installation strip; the grooves are each internally provided with a semicircle clamp block matched with the semicircle clamp groove, and a spring is connected between each semicircle clamp block and the groove bottom of each groove. The device can improve firm butt joint of the two gastric tubes.

The invention relates to a pharmaceutical composition for preventing recurrence and metastasis of gastrointestinal tumors. The pharmaceutical composition is prepared from the following bulk drugs in parts by weight: 1 to 6 parts of American ginseng, 6 to 12 parts of pseudo-ginseng root, 6 to 30 parts of pinellia tuber, 9 to 30 parts of baikal skullcap root, 6 to 30 parts of coptis root, 1 to 6 parts of ginseng, 6 to 9 parts of dried ginger, 6 to 12 parts of liquoric root, 5 to 12 parts of Chinese date, 10 to 30 parts of Indian strawberry and 10 to 30 parts of Chinese actinidia root. The invention also provides a preparation method and application of the pharmaceutical composition. According to the pharmaceutical composition, the recurrence and the metastasis of the gastrointestinal tumors can be effectively prevented, and the health quality of a patient is improved.

The invention relates to the technical field of medical equipment, in particular to a gastrointestinal tumor target tracking device and method. The gastrointestinal tumor target tracking device comprises a capsule main body, a first electric push rod, a pressure sensor, a motor, a second electric push rod and a third electric push rod, an adjusting mechanism is arranged at the upper end of the capsule body and comprises a motor, a rotating block, a first clamping block and a second clamping groove, and the motor is fixedly installed in the middle of the upper end of the capsule body. The target tracking device is provided with the fixing mechanism, the medicament injection mechanism and the clamping mechanism, and a medicament is directly injected into a tumor in the stomach, so that the problem that a large amount of time is consumed to transfer a medicament part into the tumor through oral administration of the medicament, absorption of the medicament by the stomach and cells in the traditional tumor target tracking is solved; the problems that the stomach absorbs the medicine and the medicine is transferred into the tumor to cause the medicine loss, so that the time and the medicine are wasted are solved.

The invention relates to the field of traditional Chinese medicine applications and in particular discloses a traditional Chinese medicine for treating gastrointestinal tumors. The traditional Chinesemedicine for treating gastrointestinal tumors is prepared by mixing the following raw materials: dendrobe, tortoise shells, the seed of Chinese dodder, Codonopsis pilosula, acanthopanax, rhizoma panacis majoris, asparagus fern, radix polygonati officinalis, turmeric, polygala fallax hemsl, fruits of camptotheca acuminate, curcuma zedoary, leonurus, the root of red-rooted salvia and Herba Rabdosiae as raw materials in a certain weight ratio. The traditional Chinese medicine for treating gastrointestinal tumors is simple to prepare, good in absorption effect, long in efficacy duration, remarkable in curative effect, free of side effects, high in safety and low in production cost, and symptoms of patients are immediately alleviated.

The invention relates to a traditional Chinese medicine composition for treating anemia caused by gastrointestinal tumors and a preparation method thereof. According to the traditional Chinese medicine composition, traditional Chinese medicines such as prepared rhizome of rehmannia, radix paeoniae alba, ligusticum wallichii, ginseng, angelica sinensis, astragalus membranaceus, radix actinidiae chinensis, colla corii asini, bletilla striata and carbonized hair are used as raw materials, wherein prepared rhizome of rehmannia and radix paeoniae alba are feminine and soft blood replenishing products, angelica sinensis and ligusticum wallichii are qi-in-blood medicines, ginseng and astragalus membranaceus are added for consolidating and controlling blood, bletilla striata and carbonized hair are added for healing sores and stopping bleeding, colla corii asini adheres to stop bleeding and generate blood and enhance the functions of stopping bleeding and nourishing blood, and radix actinidiaechinensis is added for resisting tumors and ulcer and promoting wound healing. A whole-body internal application method and a local surgical ointment external application method are applied. The traditional Chinese medicine composition disclosed by the invention can be used for treating anemia caused by gastrointestinal tumors by taking the traditional Chinese medicine composition in two ways. The internal administration method can tonify qi, enrich blood, support the healthy energy and consolidate the basis. The ointment is externally applied, is adhered to a local part of a tumor, is adhered to a tumor blood vessel, and is used for treating local ulcers and ulcers of the tumor, healing ulcers and promoting tissue regeneration, controlling blood circulation and stopping bleeding, and specially treating bleeding, so as to treat the symptoms of the tumor.

The invention provides a marker combination for predicting the treatment effect of a gastrointestinal tumor immune checkpoint inhibitor and application of the marker combination. The marker combination comprises at least one of HLA-B62 supertypes. According to the marker combination provided by the embodiment of the invention, the treatment effect of the gastrointestinal tumor immune checkpoint inhibitor of an object can be accurately predicted, for example, a PD-1 / PD-L1 inhibitor is singly used or combined with a CTLA-4 inhibitor, so that the response rate of treatment of the gastrointestinal tumor immune checkpoint inhibitor is improved.

The invention relates to the field of medicines and particularly relates to a relapse drug-resistant gastrointestinal tumor Decitabine comprehensive treatment scheme and a composition of relapse drug-resistant gastrointestinal tumor Decitabine.

The invention belongs to the technical field of molecular biology, and specifically relates to a tumor blood vessel and M1 type macrophage targeting peptide and its application. Aiming at the problem of lack of small molecule targeting peptides used for preparing drugs for diagnosis or treatment of tumors, the present invention provides a tumor vessel and M1 type macrophage targeting peptide TCP‑2 and its carrier. The small-molecule targeting peptide has the amino acid sequence shown in Seq ID NO: 1, can specifically target tumor blood vessels and M1 macrophages, and can be used to prepare targeted drugs for diagnosis or treatment of tumors, especially for use in For the treatment of gastrointestinal tumors, it provides a new option for targeted therapy of tumors.

The invention relates to a laryngeal precancerous lesion animal model and a construction method and application thereof. The construction method comprises the steps that a dichloromethane solution dissolved with 4-nitro quinoline-1-oxide is smeared on the laryngeal mucosa of an animal, and the laryngeal precancerous lesion animal model is obtained. 4NQO and dichloromethane are combined to achievea synergistic carcinogenic effect, so that the time required for successfully making the model by single drugs can be obviously shortened; the model is similar to a human patient, the laryngeal mucosaof the model turns white, spinous protrusions appear on the surface, or plaques and superficial ulcer appear on the surface of the laryngeal mucosa, and the model is highly similar to the patient inperformance and has good clinical symptom simulation; secondly, the 4NQO can be directly dissolved in the dichloromethane, so that the solubility and the stability of the 4NQO are improved; and a prepared mixed solution has certain viscosity and can be in better contact with and attached to the laryngeal mucosa when smeared on the laryngeal mucosa, and the stimulation time of cancerogen to the laryngeal mucosa is obviously prolonged. The construction method does not induce gastrointestinal tumors and reduces interference factors.

The invention discloses a medicinal composition for treating gastrointestinal tumors. The composition is prepared from the following raw materials in parts by weight: 20-30 parts of walnut leaves, 15-25 parts of goose blood, 15-25 parts of goat blood, 50-60 parts of acanthopanax roots, 10-20 parts of gecko, 30-45 parts of duchesnea, 30-40 parts of kelp, 15-25 parts of mole crickets, 30-50 parts ofschisandra chinensis, 20-30 parts of rabdosia lophanthide and 20-30 parts of abutilon seeds. The medicinal composition has good effects of remarkably reducing markers of gastrointestinal tumors, treating gastrointestinal tumors, preventing relapse and metastasis of gastrointestinal tumors and the like since the raw materials are synergized to furthest achieve the medicinal efficacy, is safe, doesnot have toxic or side effect, and can effectively improve the compliance and accumulated life expectancy of patients with gastrointestinal tumors.

The invention discloses a detection method for predicting and diagnosing gastrointestinal tumor as well as a kit and a gene chip thereof. The method comprises the following steps: (1) obtaining a sample to be detected; and (2) detecting whether the following coding mRNA gene is overexpressed in the sample, wherein the gene is a CST1 gene shown in SEQ ID No:39, or a primer of one of mRNA of specificity recognition CST1 gene, CST1 cutter shown in SEQ ID No:43, SEQ ID No:44, cDNA of CST1 gene and cDNA of CST1 cutter, or / and a probe recognized gene, or a gene identified by using an amplicon corresponding to at least one CST1 primer. The method can be applied to diagnosis of gastrointestinal caner, dynamic monitoring and prognosis judgment and has the advantages that a large number of verification samples can be obtained, the result is accurate and reliable result, the sensitivity is high and the like.