57 results about "MMP9" patented technology

The present disclosure provides a combination of oligonucleotides, wherein said combination reduces the expression of the genes COL5A2, COL11A1, MMP9, ITGB1, TGFB1 and BMP1 and use thereof in treating cancer, in particular, metastatic cancer.

The present invention relates to clinical diagnostics including diagnosis, prognosis, prediction, risk assessment and / or risk stratification of preterm birth (PTB) and subsequent treatment in a pregnant subject, and corresponding methods and products. The invention provides decision tools to help clinicians choosing the most appropriate management for the pregnant women. In particular, the present invention relates to a method for the diagnosis, prognosis, prediction, risk assessment and / or risk stratification of preterm birth (PTB) in a pregnant subject, the method comprising determining a level of one or more biomarkers in a sample that has been isolated from said pregnant subject, wherein the one or more biomarkers comprise at least one of matrix metallopeptidase 9 (MMP9) or fragment(s) thereof and Pappalysin-2 (PAPP-A2) or fragment(s) thereof, wherein the level of the one or more biomarkers in the sample is indicative of the presence or absence of a subsequent PTB.

The present invention relates to a macrophage that is genetically engineered to overexpress an interleukin-10 (IL-10) or an IL-10 in combination with a matrix metallopeptidase 9 (MMP9). Such macrophages may be used to treat inflammatory conditions, such as inflammatory organ injury, in a subject. The inflammatory condition may be acute or chronic, and may involve a fibrotic component.

The invention relates to the field of natural medicines, and discloses an alkaloid and a preparation method and application thereof, and the alkaloid has a structure as shown in a formula I and a pharmaceutically acceptable salt thereof. The alkaloid is separated from an n-butyl alcohol extraction part of a dendrobium huoshanense stem ethanol extract through silica gel column chromatography and a preparative thin-layer separation technology, and the structure of the alkaloid is identified through nuclear magnetic resonance and high-resolution mass spectrometry. Cell experiments prove that the alkaloid prepared by the invention can remarkably relieve inflammation induced by LPS, inhibit proliferation of human gastric cancer cells (AGS) and promote apoptosis of the AGS; molecular docking analysis shows that the alkaloid prepared by the invention can be remarkably docked with active sites of inducible iNOS, IL-6, TNF-alpha and MMP9, and the binding energy is 9.5-8.6 kcal / mol.

The invention relates to the technical field of gene therapy and drug development, and provides application of a UCH37 inhibitor in preparation of a drug for treating osteoporosis. The expression level of UCH37 in blood of osteoporosis patients is obviously higher than that of UCH37 in blood of healthy people, and the UCH37 is in positive correlation with osteoclast active markers such as NFATC1 and MMP9. The UCH37 inhibitor is applied to preparation of the medicine for treating osteoporosis and directly targets UCH37, the curative effect does not depend on the expression change of ADRM1, no matter the ADRM1 of osteoporosis patients is in a low or high expression state, an osteoclast activation pathway can be stably blocked, the consistency of treatment effects of different individuals is ensured, the range of applicable people of the medicine is expanded, and the application prospect is broad. The compound has the characteristics of clear action mechanism and wide application range, and provides important theoretical basis and conversion prospect for developing novel and efficient medicines for treating osteoporosis.

The present invention provides a method for detecting the presence of or risk of bladder cancer in a female patient, the method comprising the steps of: detecting the presence of a biomarker panel in a sample isolated from a female patient, the biomarker panel comprising IL-13 and IL-12p70 and one or more biomarkers selected from the group consisting of BTA, midkine, PAI-1 / tPA, 8OHdG, CEA, CK18, Fibrillin, Creatinine, CXCL16, Cystatin B, Cystatin C, d-dimer, EGF, FAS, HAD, IL-1a, IL-1b, IL-4, IL-6, IL-7, IL-8, MCP-1, Microalbumin, MMP9 NGAL, MMP9 TIMP1, NGAL, NSE, Progranulin, TUP, TGFB1, Thrombomodulin, sTNFR1, TPA, VEGF and Triglyceride, and / or the concentration of albumin / microalbumin / protein to creatinine in a sample isolated from a female patient, expressed as an albumin:creatinine ratio; and assessing the result and comparing it to a normal control, wherein an increase in the presence of the biomarkers compared to the normal control indicates the presence or risk of cancer in the patient from which the sample was isolated.

The present disclosure provides a combination of oligonucleotides, wherein said combination reduces the expression of the genes COL5A2, COL11A1, MMP9, ITGB1, TGFB1 and BMP1 and use thereof in treating cancer, in particular, metastatic cancer.

The invention provides application of a bisindole compound XQ-016 in treatment of osteosarcoma, and belongs to the technical field of biological medicines. The bisindole compound XQ-016 can inhibit proliferation, migration and invasion of tumor cells by adjusting an STAT3 / p53 signal channel, inducing G1 phase cell cycle arrest and inhibiting MMP2 / MMP9 expression, shows remarkable anti-tumor activity, is a promising treatment choice in tumor treatment, and can be used as an effective component in anti-tumor drugs.

The invention discloses a plant lactobacillus AR195 strain and application thereof in preparation of a medicine for preventing and / or treating lung cancer, and belongs to the technical field of microorganisms. Through verification, the plant lactobacillus AR195 can inhibit the growth of lung cancer cells, also has certain prevention and treatment effects in a lung cancer mouse model, and can reduce the tumor burden of a BALB / c mouse lung cancer model by reducing MMP9 secretion, so that the plant lactobacillus AR195 can be used for preventing and assisting in treating lung cancer. Meanwhile, the accumulation of the AR195 bacteria in the lung can be improved to the maximum extent through atomization administration, and meanwhile, the adverse side effects of the whole body are reduced. A new drug source is provided for treatment of lung cancer, a novel treatment strategy is provided for treatment of lung cancer by probiotics, and treatment of lung cancer and development of a novel treatment method are facilitated. Meanwhile, the application range of the plant lactobacillus AR195 strain is widened, and a novel treatment strategy is provided for a potential mechanism of treating lung cancer by probiotics.

Provided herein are compositions and methods for modulating MMP9 expression. In some instances, compositions and methods are used to treat a neurodegenerative disorder. In some instances, the compositions comprise antisense oligonucleotides.

The application discloses application of CCL3-AS1 in regulating stability of carotid artery plaque, overexpression of CCL3-AS1 induces inflammatory activity of macrophages and secretion of MMP9, promotes plaque rupture and thrombosis; on the contrary, knockdown of CCL3-AS1 inhibits inflammatory activity of macrophages and secretion of MMP9, reduces plaque rupture and thrombosis; in addition, the application also discloses that CCL3-AS1 enhances MMP9 mRNA stability by combining with hnRNP-K, thereby increasing MMP9 expression and secretion and degrading fibrous cap collagen. The application discloses important role of CCL3-AS1 in stability of carotid artery plaque and a molecular mechanism, provides a new diagnostic marker and a treatment target, not only provides a new direction for research on atherosclerosis related diseases, but also provides a new tool and a means for clinical diagnosis and treatment.

The application discloses application of a GPR146 inhibitor in preparation of a drug for treating wet age-related macular degeneration. The application finds that GPR146 is significantly up-regulated in expression in a mouse model of laser-induced CNV and a mouse model of subretinal fibrosis. In mice, shRNA is used to knock down GPR146, thereby significantly inhibiting CNV, subretinal fibrosis and inflammation. In an in-vitro experiment, siRNA targeting GPR146 can inhibit the in-vitro neovascular function of endothelial cells, such as proliferation, migration and tube formation, and reduce immune cell adhesion and transendothelial cell migration. In addition, targeting GPR146 can also inhibit the expression of TGF-beta, Fibronectin (FN), alpha-SMA, Col1A, MMP9 and other fibrosis-promoting molecules by endothelial cells. Meanwhile, targeting GPR146 can also inhibit the proliferation and migration of smooth muscle cells and reduce the expression of the above fibrosis-promoting molecules. The above results all show that targeting GPR146 can significantly inhibit CNV formation, inflammation and subretinal fibrosis, and has good therapeutic effect.

The application relates to the field of natural medicines, and discloses an alkaloid, a preparation method and application thereof, the alkaloid having a structure shown in formula I and pharmaceutically acceptable salts thereof. The alkaloid is separated from a n-butanol extraction part of an ethanol extract of Dendrobium huoshanense stems through silica gel column chromatography and a preparation thin layer separation technology, and the structure is identified through nuclear magnetic resonance and high-resolution mass spectrometry. Through cell experiments, it is verified that the alkaloid prepared in the application can significantly relieve inflammation induced by LPS, inhibit human gastric cancer cell (AGS) proliferation and promote apoptosis; molecular docking analysis shows that the alkaloid prepared in the application can be significantly docked with active sites of induced iNOS, IL-6, TNF-alpha and MMP9, and the binding energy is-9.5~(-8.6) kcal / mol.

The present application relates to a tumor prognosis evaluation gene set and its application, the evaluation gene set is composed of 5 genes, the 5 genes are as follows: MKI67 , PCNA , VEGF-A , MMP9 , TRIM11 , the tumor is selected from any one of colorectal cancer, lung cancer, pancreatic cancer.Compared with the prior art, the present application constructs a multi-type tumor prognosis prediction model MKI67 , PCNA , VEGF-A , MMP9 , TRIM11 Synergistic effect is carried out from four core pathways of tumor proliferation, angiogenesis, invasion and metastasis, abnormal regulation, the detection accuracy of single index is significantly improved, and it is suitable for colorectal cancer, lung cancer and pancreatic cancer.

The present invention discloses a biomarker for diagnosing cardiovascular disease complicated by systemic lupus erythematosus and its application, belonging to the field of biomedical technology. The biomarker includes CD163, IL1B, IL1RN, MMP9 and / or NFKBIA. The present invention uses bioinformatics analysis to determine that the core shared genes involved in the common mechanism of SLE and CVD are CD163, IL1B, IL1RN, MMP9 and NFKBIA. These five genes are used as biomarkers for diagnosing cardiovascular disease complicated by systemic lupus erythematosus, and have good diagnostic efficacy, and can achieve the purpose of early diagnosis of cardiovascular disease complicated by systemic lupus erythematosus. The present invention determines for the first time that these five genes are potential biomarkers for the diagnosis and treatment targets of SLE complicated with CVD, providing an important basis for the improvement of SLE patients, and providing new targets for the clinical diagnosis and treatment of SLE complicated with CVD.

The application discloses application of a petroleum ether extract of a root of a roadside green plant in preparation of a drug for treating colorectal cancer by regulating a PI3K / AKT / MDM2 / p53 pathway. In the application, the petroleum ether extract of the root of the roadside green plant for treating colorectal cancer is obtained by petroleum ether reflux extraction of the root of the roadside green plant. Pharmacological experiments show that the petroleum ether extract of the root of the roadside green plant treats colorectal cancer by regulating the PI3K / AKT / MDM2 / p53 signal pathway through down-regulating p-PI3K / PI3K and p-AKT / AKT ratio, up-regulating p-MDM2 and down-regulating p53 level; the extract has an anti-malignant proliferation effect, induces G1 phase arrest by targeting CDK2, up-regulating p21, down-regulating Cyclin E1-CDK2 and Cyclin D1-CDK4; the extract induces HCT-116 cell apoptosis through a mitochondrial pathway by up-regulating Bax / Bcl-2, reducing ΔΨm, releasing Cyt C, activating Caspase-9 / 3 and cleaving PARP; the extract inhibits migration and invasion of HCT-116 cells by targeting MMP9, down-regulating MMP-2, MMP-9 and N-cadherin expression and up-regulating E-cadherin expression. In addition, the extract inhibits growth of a transplanted tumor in a nude mouse transplanted tumor model by inducing apoptosis of transplanted tumor cells.

The invention belongs to the technical field of protein, and relates to a peptide for preventing collagen loss and a preparation method thereof. The amino acid sequence of the peptide is KSYELPDGQVITIG, and the key active fragment of the peptide is ELPDGQVIT. The peptide is obtained by performing enzymolysis on degreased maggot powder with alkaline protease, trypsin, papain, neutral protease and flavourzyme. The peptide can inhibit the expression of MMP1 and MMP9 in L929 cells after UVA irradiation, and alleviate the loss of collagen.

The invention discloses a biological marker, a therapeutic drug and an action target spot for traumatic brain injury, and belongs to the technical field of biological medicine. The miRNA is selected from one or more of rno-miR-382-3p, rno-miR-21-5p, rno-miR-370-3p and the like, and the miRNA is one or more of the following components: the rno-miR-382-3p and the like. The invention also provides an application of the ginsenoside Rg1 in preparing a medicine for regulating and controlling the expression quantity of the miRNA in the claim 1 and an action target of the ginsenoside Rg1 for treating TBI by regulating and controlling the expression quantity of the miRNA in the claim 1, wherein the action target mainly comprises AKT1, EGFR, MMP9, SRC, STAT3 and CASP3. The method has the beneficial effects that the miRNAs expression change of exosomes in plasma after traumatic brain injury is evaluated through a high-throughput RNA sequencing technology, and 14 miRNAs are screened and proposed and can be used as biomarkers for diagnosing traumatic brain injury; and the influence of the Rg1 on the expression of the miRNAs in the plasma after trauma is further researched so as to determine the effectiveness and the targeting action way of treating the trauma by the Rg1.

An umbilical cord mesenchymal stem cell and application thereof in treating osteoarthritis. The application discloses a dual-response hydrogel drug delivery system for osteoarthritis treatment and application thereof, and relates to a synergistic design of a bifunctional fusion protein BFP, an epigenetic regulator TSA and a temperature-sensitive-enzyme response hydrogel. The bifunctional protein BFP contains a cartilage induction domain CIP-2 and an anti-inflammatory domain AIP-3, which are connected in series through a rigid connection peptide EAKAK, and can specifically activate the TGF-beta pathway and respond to MMP9 to release the anti-inflammatory fragment. The temperature-sensitive-enzyme dual-response hydrogel is composed of thiolated hyaluronic acid and poloxamer 407, and can rapidly gelate within 3.5±0.5 minutes at 37 DEG C, the gel transition point is 29.2±0.3 DEG C, and the synergistic release of BFP / TSA can be realized in the presence of MMP9, and the 72-hour release rate reaches 86.7%. Experiments prove that the system can make the SOX9 / COL2A1 gene expression of UC-MSCs increase by 6.77 times and 5.9 times respectively, the GAG deposition amount reaches 0.81 OD630, the ICRS score in the rat OA model increases by 267%, and the serum MMP-13 level decreases by 78.3%. Therefore, the technology of the application provides a new direction for the precise treatment of osteoarthritis.

The present application provides a derivative with a repaglinide tetravalent platinum structure and a preparation method and use thereof, the compound with the repaglinide tetravalent platinum structure is shown as general formula (I), wherein, selected from cisplatin or oxaliplatin; L is hydroxyl or a series of repaglinide platinum (IV) compounds targeting p53 pathway described in the present application, which shows good anti-proliferation and anti-metastasis activity in vitro and in vivo. The severe DNA damage caused by platinum core can up-regulate the expression of p53, and repaglinide (RPG) can also effectively promote the secretion of p53 through the lumican / p53 / p21 pathway. The present application designs and synthesizes a series of repaglinide tetravalent platinum derivatives, which can start mitochondrial-mediated apoptosis through the Bcl-2 / Bax / caspase-3 pathway. Subsequently, with the up-regulation of p53, the compound can effectively activate pro-apoptotic autophagy, inhibit the epithelial-mesenchymal transition (EMT) process, and then inhibit tumor angiogenesis by inhibiting COX-2, MMP9 and VEGFA. The compound can also increase the number of CD3 + And CD8 + T cells in tumors by blocking immune checkpoint PD-L1, and stimulate anti-tumor immunity. The above multiple anti-tumor mechanisms synergistically inhibit the proliferation and metastasis of tumor cells.

The invention belongs to the technical field of microorganisms, and finds that trans-cinnamic acid is a key metabolite of microorganism staphylococcus epidermidis H62-3 for the first time, so that a new method is provided for preparation of the trans-cinnamic acid, and meanwhile, the problem of environmental pollution caused by chemical synthesis of the trans-cinnamic acid is also avoided. In addition, the invention also relates to an application of trans-cinnamic acid in preparation of a product for resisting skin photoaging. The trans-cinnamic acid provided by the invention has the effect of resisting skin photoaging, can effectively relieve the transcriptional level of senescence-related genes p53, p21 and p16 and inflammatory factors IL-1beta, IL-6 and TNF-alpha induced by UVB irradiation, reduces the level of reactive oxygen species (ROS), inhibits the expression of matrix metalloproteinases MMP9, MMP3 and MMP1, promotes the synthesis of I-type collagen (COL1), and can be used for preparing anti-aging drugs for treating skin aging. And the activity of beta-galactosidase (SA-beta-gal) related to aging is reduced.

The invention relates to the technical field of biological medicine and tissue engineering, in particular to a tissue engineering blood vessel and a preparation method and application thereof. The tissue engineering blood vessel is obtained by modifying interleukin 24 (IL-24) on the surface of an acellular blood vessel, after the tissue engineering blood vessel is transplanted into a body, the number of CD31 + and CD34 + cells can be remarkably increased, and infiltration of M2 type macrophages (CD163 +) on the surface of the blood vessel is remarkably increased; the expression of HIF-1 alpha (hypoxia marker) and MMP9 is obviously reduced; the expression of the nerve specific protein S-100 is obviously increased, thrombosis and intimal hyperplasia are effectively inhibited, and the patency rate of transplanted blood vessels is obviously increased.

The invention relates to a fusion polypeptide for diabetes wound repair and a pharmaceutical composition thereof, and discloses a sequence design and a preparation method of the fusion polypeptide FP-DW01-Chol, and a temperature-sensitive hydrogel composition containing the polypeptide and MitoQ. The fusion polypeptide contains a TREM2 agonist domain, an AGE-RAGE blocking domain, an MMP9 recognition cleavage site, an Angiopoietin-2 mimic peptide fragment and a cholesterol modification terminal, and can activate anti-inflammatory polarization of macrophages, block a chronic inflammation pathway and respond to a wound enzyme environment to release an angiogenesis promoting fragment. The pharmaceutical composition takes poloxamer 407 / 188 as a temperature-sensitive carrier, realizes cooperative delivery of polypeptide and MitoQ, and has the advantages of slow release, skin retention and stability. In-vitro and db / db mouse model experiments prove that the composition can remarkably promote high-glucose damaged cell activity recovery, inhibit inflammatory factor release, accelerate wound closure, promote angiogenesis and tissue remodeling, provides a multi-mechanism synergistic and local long-acting treatment scheme for diabetic refractory wounds, and has important clinical transformation value.

The invention provides a derivative with a repaglinide tetravalent platinum structure and a preparation method and application of the derivative, the compound with the repaglinide tetravalent platinum structure is shown in the general formula (I), # imgabs0 #, # imgabs1 # is selected from cis-platinum or oxaliplatin, # imgabs2 # is selected from iso-platinum or oxaliplatin, and # imgabs2 # is selected from iso-platinum or oxaliplatin. L is hydroxyl or # imgabs2. A series of repaglinide platinum (IV) compounds taking the p53 pathway as the target spot disclosed by the invention show good anti-proliferation and anti-metastasis activity in vitro and in vivo. The expression of p53 can be up-regulated due to serious DNA damage caused by platinum nucleus, and repaglinide (RPG) can also effectively promote the secretion of p53 through a lumican / p53 / p21 pathway. According to the invention, a series of repaglinide tetravalent platinum derivatives are designed and synthesized, and the compounds start mitochondrial mediated apoptosis through a Bcl-2 / Bax / caspase-3 pathway. Afterwards, along with up-regulation of p53, the compound can effectively activate apoptosis-promoting autophagy and inhibit an epithelial-mesenchymal transition (EMT) process, and further inhibit angiogenesis of tumors by inhibiting COX-2, MMP9 and VEGFA (vascular endothelial growth factor A). The compound can also increase the number of CD3 + and CD8 + T cells in tumors by blocking an immune checkpoint PD-L1 and stimulate anti-tumor immunity. The multiple anti-tumor mechanisms synergistically inhibit proliferation and metastasis of tumor cells.

The invention discloses an application of CCL3-AS1 in regulating and controlling the stability of carotid plaques, which is characterized in that the CCL3-AS1 is overexpressed to induce the inflammatory activity of macrophages and MMP9 secretion and promote plaque rupture and thrombosis; on the contrary, the CCL3-AS1 is knocked down to inhibit the inflammatory activity of macrophages and MMP9 secretion, and plaque rupture and thrombosis are reduced; in addition, the invention also discloses that CCL3-AS1 is combined with hnRNP-K to enhance the mRNA stability of MMP9, so that the expression and secretion of MMP9 are increased, and the fibrocap collagen is degraded. The invention discloses an important function of CCL3-AS1 in carotid plaque stability and a molecular mechanism of CCL3-AS1, provides a novel diagnostic marker and a novel therapeutic target, not only provides a novel direction for research of atherosclerosis related diseases, but also provides a novel tool and means for clinical diagnosis and treatment.

This invention belongs to the field of protein technology and relates to a peptide that prevents collagen loss and its preparation method. The amino acid sequence of the peptide is KSYELPDGQVITIG, with the key active fragment being ELPDGQVIT. The peptide is obtained by enzymatic hydrolysis of defatted grain insect powder using alkaline protease, trypsin, papain, neutral protease, and flavor protease. This peptide can inhibit the expression of MMP1 and MMP9 in L929 cells after UVA irradiation, thus alleviating collagen loss.

The present invention relates to a method of detecting liver cancer in a mammalian subject by detecting an antibody in a test sample comprising a bodily fluid from the mammalian subject, wherein the antibody is an autoantibody immunologically specific for a tumour marker protein selected from the group consisting of MMP9, AIF1, EpCAM and CDKN1B, which method comprises contacting the test sample with a tumour marker antigen selected from the group consisting of MMP9, AIF1, EpCAM and CDKN1B and determining the presence or absence of complexes of the tumour marker antigen bound to autoantibodies present in the test sample where the presence of said complexes is indicative of the presence of liver cancer. Also included within the invention are corresponding methods of diagnosing and treating liver cancer in a mammalian subject, corresponding methods of predicting response to an anti-liver cancer treatment, a corresponding method of detecting an antibody in a test sample comprising a bodily fluid from a mammalian subject and kits suitable for performing methods of the invention.

The invention relates to application of an Arteridin gene as a biomarker in preparation of a product for auxiliary diagnosis of abdominal aortic aneurysm, clinical specimens and animal experiments find that the expression of Arteridin in occurrence of abdominal aortic aneurysm is remarkably increased, which indicates that Arteridin can be used as the biomarker for auxiliary diagnosis of abdominal aortic aneurysm; the invention also relates to a product for down-regulating the expression of Arterin and an application of the product in preparation of drugs for treating abdominal aortic aneurysm, the product comprises siRNA and shRNA of a targeted Arterin gene and AAV for coding the sequence of the shRNA, and after specific knockdown of Arterin by smooth muscle cells is realized, in an Elatase-induced abdominal aortic mouse model, the expression of Arterin is reduced, and the expression of Arterin is reduced. The diameter of the aneurysm is reduced, the occurrence rate is reduced, the elastin destruction degree is reduced, the expression quantity of vascular remodeling genes MMP2 and MMP9 is reduced, and the difference is obvious compared with that of a control group; the result shows that Arteridin is expected to become a target spot for treating abdominal aortic aneurysm.

Disclosed is an in vitro method for assessing whether a human patient suffering from periodontitis has mild periodontitis or advanced periodontitis. The method is based on the insight to determine a selection of two biomarker proteins. Accordingly, in a sample of saliva a patient suffering from periodontitis, the concentrations are measured of the proteins Pyruvate Kinase (PK) and at least one of Matrix metalloproteinase-9 (MMP9), S100 calcium-binding protein A8 (S100A8), and Hemoglobin subunit beta (Hb-beta); or of the proteins Matrix metalloproteinase-9 (MMP9) and at least one of S 100 calcium-binding protein A8 (S100A8) and S100 calcium-binding protein A9 (S100A9). Based on the concentrations as measured, a value is determined reflecting the joint concentrations for said proteins. This value is compared with a threshold value reflecting in the same manner the joint concentrations associated with advanced periodontitis. The comparison allows assessing whether the testing value is indicative of the presence of advanced periodontitis or of mild periodontitis in said patient. Thereby, typically, a testing value reflecting a joint concentration below the joint concentration reflected by the threshold value is indicative for mild periodontitis in said patient, and a testing value reflecting a joint concentration at or above the joint concentration reflected by the threshold value, is indicative for advanced periodontitis in said patient.

The present invention relates to a macrophage genetically engineered to overexpress interleukin-10 (IL-10) or IL-10 in combination with matrix metallopeptidase 9 (MMP9). Such macrophages are useful for treating cirrhosis in a subject. In particular, the subject can be treated after having experienced a first liver decompensation event requiring hospitalization of the subject. The subject can have experienced a subsequent decompensation event prior to treatment.