Regenerative medicine is a technology that uses normal cells and tissues to treat organs and body tissues that have lost their function due to illness and damage. Regenerative medicine can be broadly categorized into the cultivation of epidermal, cartilage, and lamellar cardiomyocytes, cellular reorganization, injection of cells into the human body, and the use of cellular drugs. Currently, there are four types of regenerative medicine products*** that have been approved by Japan's Pharmaceutical and Medical Devices Law (Pharmaceutical and Medical Equipment Law) and are included in insurance treatments. Of these, three products*** utilize tissue engineering techniques such as cell regeneration and recombination: J-TEC (Japan Tissue Engineering)'s "Jace" product, which is used to treat burns by culturing slices of patients' epidermal cells in vitro; and the "Jace" product, which is used to treat burns by culturing patients' cartilage cells and transplanting them into a polymer gel. Jace", a product that cultures chondrocytes from patients, wraps them in polymer gel, and transplants them into joints; and "Heart Sheet", a product that cultures muscle cells from patients with severe heart failure and transplants them onto the surface of the heart, launched by Terumo Corporation.
Terumo Corporation's "Heart Sheet" product slices muscle cells from patients with severe heart failure and transplants them onto the surface of the heart.
In terms of cellular drugs, JCR Pharmaceticals launched the "TEMCELL HS Note" product. Using bone marrow mesenchymal stem cells as the active ingredient, it can effectively control the immune response generated after hematopoietic stem cell transplantation for leukemia.
The technology for developing regenerative medicine products in Japan is growing rapidly, both among venture companies and large pharmaceutical companies.
"Immune checkpoint inhibitors" help immune T-cells to recognize cancer cells that are missed by the body's immune response, and use the T-cells to attack the cancer cells for therapeutic purposes.
The body's immune system recognizes and eliminates foreign substances. One part of the immune system, a type of immune cell called a "cytotoxic T cell," is responsible for recognizing and attacking foreign objects. Of course, the human immune system, in order to avoid excessive immune attack on the body's own cells, has reserved pathways to suppress the immune response, which are called "immune checkpoints".
Immune checkpoint inhibitors are new anti-cancer drugs that block immune checkpoints and stimulate cytotoxic T cells to attack cancer cells. Cancer cells are cunning enough to use the immune checkpoint mechanism to avoid attack by immune T cells.
Representative immune checkpoint inhibitors include "Opdivo" from ONO PHARMACEUTI-CAL, "Keytruda" from MSD of Merck, etc. Opdivo is a new type of anti-cancer drug that blocks immune checkpoints and stimulates cytotoxic T cells to attack cancer cells. "Opdivo and Keytruda bind to the "PD1" immune checkpoint molecule on the surface of cytotoxic T-cells, blocking the binding of PDL1 and PD1 in some cancer cells, and thus lifting the restriction on the immune response.
Drugs such as Opdivo have shown amazing results in the treatment of some cancers, and companies have joined the development of immune checkpoint inhibitors, increasing competition. Similar to Opdivo, in addition to binding to the PD1 molecule, drugs that bind to PDL1, or to other immune checkpoint molecules have been developed.
When cancer cells are infected with an oncolytic virus, the virus rapidly multiplies and eventually lyses the cancer cells. After the cancer cell is lysed and destroyed, the lysogenic virus spreads outside the cell and continues to infect the next cancer cell. This also activates the body's own immune function. When used in conjunction with popular cancer treatment drugs such as Opdivo, the treatment will be twice as effective.
Lysoviruses can alter and rewire the genes of a wide range of viruses, such as adenoviruses, which cause colds, and herpes viruses, which cause herpes simplex infections. These properties prevent cells other than cancer cells from becoming infected with the virus, and even if they do, they have a hard time reproducing.
In 2015, Amgen's IMLYGIC was officially approved. Since then a number of large pharmaceutical companies have made moves to gain access to the technology and marketing rights of drugs developed by the venture.
Japan is also developing related technologies.Oncolys BioPharma has made considerable achievements in lysosomal virus research, developing Telomelysin and enrolling patients with esophageal cancer to begin clinical trials in Japan in 2017.
Chimeric antigen receptor T-cell immunotherapy (CART therapy) is a cell therapy that transforms immune cells into aggressive cells that powerfully destroy cancer cells.
The mainstay of CART therapy utilizes a cancer patient's own T cells. Specifically, an immune cell called a "T-cell" (the blue cell in the figure) is first isolated from the blood of a cancer patient, and the T-cell is embedded with a "chimeric antigen receptor" (the orange part on Figure 3-4) gene. The embedded T cell reacts only to cancer cells and has the function of an immune cell that attacks cancer cells. The number of "super-aggressive" T cells is increased and reintroduced into the patient. The super-aggressive T-cells returned to the patient's body now fully utilize the attacking effect of cancer cells, and at the same time, increase cell activity and multiply to ensure a high level of attacking ability in the long term.
In late August 2017, "tisagenlecleucel" chimeric antigen receptor T-cell therapy (CART therapy) developed by Novartis was recognized for the first time in the United States.
The majority of patients treated with CART therapy had their disease under control. Novartis experimented with a life-threatening form of leukemia, targeting cancer cells **** through the markers, using CART therapy, and found that after 3 months of medication, 83% of patients had almost all of their cancer cells disappear from their bodies.
In addition, malignant lymphoma treatment, Kite Pharmaceuticals (Kite Pharma) venture has submitted an application for recognition of CART therapy to the United States. Domestically, Novartis Japan Incorporated, Novartis Pharmaceuticals, and Bao Nippon Physical Technology and Daiichi Sankyo Company (Daiichi Sankyo Company)*** are working together to develop the application of CART therapies in the area of severe leukemia and malignant lymphoma. The side effects of CART therapy are accompanied by a superb attack effect. Once applied in the clinic, the issue of how to quickly detect and respond to side effects has also become a problem that needs to be addressed. In addition, all CART therapies at this stage are "customized" and cost a lot of money to produce and distribute. In the future, the relevant parties should not only consider how to reduce the cost, but also from the social level to study the problem of payment of medical fees.
A spray on a possible cancerous area, and within a few minutes, only the cancerous area will glow, this is the "Cancer Fluorescent Spray". In the near future, the cancer fluorescent spray may appear in the medical field as a powerful tool to assist endoscopy and surgery.
In order to apply this spray to the "intraoperative rapid pathology diagnosis" technology for breast cancer, the drug approval was obtained in 2018, and the performance evaluation of the cancer fluorescent spray is now in full swing. Endoscopy and surgical safety testing for esophageal cancer is also underway.
The scientific name for the spray is "fluorescent probe," and it was developed by Prof. Yasutaka Urano of the Graduate School of Pharmaceutical Sciences, Faculty of Medicine, University of Tokyo, in collaboration with Chief Researcher Hisataka Kobayashi of the National Institutes of Health (NIH) in the U.S.A.**** The reagent reacts with certain proteolytic enzymes. The reagent fluoresces when it reacts with certain proteolytic enzymes, and its main components are small organic molecules.
A fluorescent probe is a reagent that combines amino acids and wakadamycin-like fluorescent molecules and is colorless and non-fluorescent in its normal state. After the reagent encounters the proteolytic enzymes on the surface of the cancer cells, the fluorescent molecules decomposed with water are immediately freed from the amino acids, enter the interior of the cancer cells and emit fluorescence. If less than 1 milligram of spray is applied to a suspected cancerous area, the cancerous area will light up within a few minutes.
An important area of clinical research for this reagent is breast cancer. In order to avoid residual lesions, breast cancer surgery requires the production of a biopsy (excision section) specimen on-site to detect the complete removal of cancer cells, which is known as "intraoperative rapid pathology diagnosis". Fluorescent probe technology can quickly make a diagnosis, which is an important means to reduce the burden on surgeons and pathologists.
So far, fluorescent probe technology has achieved over 90% accuracy in validation and can clearly identify breast cancer. Clinical studies on breast cancer are being conducted at several institutions, centering on the Saiseikai Fukuoka General Hospital (Fukuoka City), and data is being collected for a full year. It is required to submit the data when applying to the Pharmaceuticals and Medical Devices Agency (PMDA) for drug clinical trials. Soon the fluorescent probe will be filed for drug access in FY2018.
In breast cancer surgery, many patients opt for partial excision to protect the integrity of the breast form, but the partial excision method also increases the risk of cancer residue. In order to check whether there is any residual cancer, it is necessary to carry out "intraoperative rapid pathology diagnosis" during the operation, but many medical institutions are facing problems such as insufficient pathologists and high business volume, which makes it difficult to implement completely.
Goryo Chemical and Hamamatsu Photonics have joined the research camp. Under license from Professor Urano at the University of Tokyo, Goryo Chemical is responsible for manufacturing the fluorescent probes, while Hamamatsu Photonics has set out to develop a device to quantitatively measure fluorescence intensity.
An "in vivo hospital" is a technology in which the human body itself carries out diagnosis and treatment on the necessary occasions and at the necessary times.
Nanomolecules called "intelligent nanomachines" travel through the body to diagnose and treat diseases such as cancer on the spot. The Innovation Center of Nano Medicine, which has been selected as a stronghold of Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) Innovation Output Program, COINS Program, and is directed by Kazunori Kataoka, has as its main goal an "in vivo hospital".
To realize intelligent nanomachine technology, Kataoka et al. have developed a drug delivery system that targets cancer. Using hydrophilic and hydrophobic polymers as tissues, the medicine is wrapped in nanocapsules (polymer micelles) and delivered directly to the affected area for treatment.
The development of polymer micelles to encapsulate anticancer drugs has been a labor of love, requiring the polymer micelles to be designed with virus-sized diameters of 30 and 100 nanometers, which is the only way to ensure that they do not enter the vascular gaps of normal tissues, but can enter the widely spaced crevices characteristic of the blood vessels of cancerous tissues. Only in this way can we ensure the effect of targeted medication on cancer.
The PH (hydrogen ion index) value of the cancer tissue is lower than that of the normal tissue, and when the reaction occurs, the polymer micelles break down and the internal anti-cancer drugs are released. The polymer micelles enter the cancer tissue like a "Trojan horse" and launch a fierce attack. Many companies are developing polymer micelle technology for wrapping anti-cancer drugs, and clinical trials are underway.
The polymer micelles that encapsulate anti-cancer drugs are the first step in realizing smart nanomachine technology. In the second step, Kataoka et al. are working on the development of pharmaceuticals with both diagnostic and therapeutic effects. One of the results is a "nano-machine contrast agent" that facilitates the visualization of malignant, hard-to-treat parts of cancer by MRI (magnetic resonance imaging). Nanoparticles encapsulated with a manganese contrast agent release the contrast agent in the presence of stomach acid, reacting only to the cancer-specific environment.
Kataoka sees the ultimate goal of nanomachine technology as collecting all the biological information from a patient's body, feeding it back to a chip built into the body, and thus accomplishing disease diagnosis. Arguably this vision resembles the construction of an asteroid probe, and perhaps one day in the future, the world depicted in the half-century-old sci-fi movie Fantastic Voyage will actually become a reality.
The "virtual colonoscopy" utilizes a multilayer spiral CT (computed tomography) to photograph the large intestine, and computer processing to create a three-dimensional image of the large intestine, which helps doctors to find polyps, cancerous lesions, and is also known as a "CT colonoscopy".
Virtual colonoscopy, which uses more than 16 rows of multilayer CT to accurately photograph the peristalsis of the large intestine in a short period of time, is already in clinical use. The combination of countless thin cross-sectional images from multilayer CT into a three-dimensional image is almost identical to that of an endoscope, which is why this technique is also known as "virtual endoscopy".
After clinical observation and research, the virtual colonoscopy technology in the identification of lesions in the sensitivity, specificity and endoscopy, many depth of physical examination organizations have also begun to introduce virtual colonoscopy. The large intestine has many folds and curved shapes, and with virtual colonoscopy, even lesions hidden inside the folds can be accurately detected.
A small amount of radiation exposure is unavoidable during CT examinations. According to the National Cancer Research Center of Japan, after simulating the entire virtual colonoscopy process, the radiation exposure in the diathesis position*** is 2-3mSv, which is about 1/5 of the radiation exposure from enema X-ray detection (10-12mSv).
In the current colorectal cancer examination, the first thing that needs to be done is to perform a fecal occult blood test, which is determined to be positive before colorectal endoscopy is performed. Considering many factors such as taking laxatives, the complexity of the pre-treatment process and shame, women tend to shy away from endoscopic testing. Moreover, only about 30% of the population actually needs the test. Not only that, when the endoscope is inserted from the anus and then pulled out during the examination, the hidden lesions hidden in the inner folds of the large intestine are difficult to be discovered.
Enterobacterial therapy is a treatment that injects intestinal flora into the large intestine to adjust the intestinal environment and treat and prevent diseases. Some studies have reported that disruption of the normal flora in the intestinal flora is the main cause of diarrhea, constipation, and obesity. Recently, there are also research results to prove that the intestinal flora will not only lead to ulcerative colitis, allergic enteritis and other difficult diseases, but will also induce neurological disorders, coronary artery disease and many other diseases.
The injection of intestinal bacteria is categorized as follows: intestinal transplantation of feces, capsule transplantation of intestinal bacteria lacking in the intestines, and drug delivery for the treatment of intestinal flora diseases.
A number of medical institutions in Japan are conducting clinical trials and research on fecal transplantation therapy for elderly hospitalized patients who are susceptible to difficult intestinal infectious diseases and ulcerative colitis. Among them, Juntendo University's research group mainly conducted research on the combination of fecal transplantation and antimicrobial drug therapy for patients with ulcerative colitis. After taking antimicrobial drugs, the number of intestinal flora was drastically reduced, and after transplanting feces, the intestinal flora was greatly improved.
During the treatment, after the antimicrobials were taken, about 200 grams of saline was added to the patient's feces collected on the same day to make about 400 milliliters of solution, and the solution was injected into the appendix. This is confirmed by colonoscopy within 6 hours of completion of transplantation.
In clinical studies to date, about 80% of the patients who completed the treatment showed significant improvement in their symptoms, and an analysis of the intestinal flora showed a significant increase in the proportion of "Mycobacterium avium", the main bacterium that makes up the effective flora, compared to the ineffective flora, suggesting that the patients' intestinal flora had increased significantly. This indicates that the patient's intestinal flora is gradually stabilizing.
The Juntendo University research team plans to develop fecal transplantation and antimicrobial combination therapy for Crohn's disease in the future. The intestinal flora of patients with Crohn's disease is very disturbed.
The "Non-Invasive Continuous Blood Glucose Test" is a test that directly measures changes in blood glucose without taking blood (non-invasive). The method installs sensors in the subcutaneous tissue of the patient's abdomen and wrist, and simulates the up and down movement of blood glucose values by measuring the glucose current conversion in the interstitial fluid of the tissue.
In January 2017, the "FreeStyle Libre" product, which allows patients to measure their own blood glucose at any time, was launched, and in September, it was added to Japan's insurance coverage. The product is sold by Abbott Japan. The FreeStyle Libre allows you to measure your blood glucose in real time for 14 days without collecting blood. "The FreeStyle Libre product is characterized by the fact that the patient manages the machine without the need for a doctor. Once the sensor is installed in the human body, the patient simply touches the sensor with a reader and immediately learns the current blood glucose data, as well as the rise and fall of the blood glucose level. This product is conducive to the prevention of hypoglycemia, rational control of diet, control of blood glucose rise, but also to remind the user of the exercise randomization, and may even change the traditional diabetes treatment.
Prior to the launch of FreeStyle Libre, in December 2016, Abbott launched FreeStyle Libre Pro. This is a doctor-specific product with a maximum measurement time of 14 days. According to one expert, "With two weeks of monitoring, the amount and type of medication can be adjusted weekly, and the blood glucose results can be analyzed to give the patient the most appropriate prescription." This product has many advantages, both in terms of continuously recording the patient's blood glucose changes and helping to detect nighttime hypoglycemia in patients.
Both products are designed with minimal current fluctuations, eliminating the need to prick your finger to correct values. In contrast, most previous products require piercing the fingertip to collect blood, which is an invasive method of testing.
"Endovascular imaging" is mainly used for the diagnosis of cardiovascular diseases such as angina pectoris, and can measure the amount of atherosclerosis, its distribution, its shape, and whether there are any tears in the lining of the blood vessels, etc.
In recent years, the use of endovascular imaging has become more and more popular.
In recent years, the development of endovascular endoscopy has been particularly rapid, and there is also the technique of intravascular ultrasound (IVUS), which utilizes ultrasound to observe tomographic images of blood vessels in real time. Both techniques do not require X-rays, so patients do not need to worry about the effects of radiation, and they are easy for doctors to observe. The technology began to be used in clinical practice in the 1990s, and technological innovations continue to advance.
One of the major technological innovations in vascular endoscopy comes from JIMRO, a subsidiary of Otsuka Holdings. In May 2017, the company launched a new vascular endoscope, the "angiography IJS 2.2," which utilizes a 3 MOS camera and an LED light source to produce high-definition, perfect output images.
Another technological innovation in vascular endoscopy is the "dualinfusion", which makes the coronary arteries, and even the aorta, where a lot of blood flows, clearly visible. The new technology allows doctors to see subtle damage to the aorta, such as the precursor to aortic coarctation, which has been difficult to diagnose until now.
As for IVUS, the catheter is inserted directly over the vascular lesion, and the tip of the catheter is equipped with an ultrasound transceiver to slowly take images of the lesion. The frequency of ultrasound has been increased to 60MHz from 40MHz in the past, and new products have been introduced that dramatically increase the resolution and shorten the examination time.
The high-resolution technology helps to visualize the separation of atherosclerosis in the inner wall of the blood vessel, and also makes it easy to evaluate the neoplastic condition of the lining of an implanted stent that improves arterial stenosis. The examination time is short, coronary artery insertion time is reduced, and the risk of ischemia is greatly reduced.
Previously, when diagnosing ischemic cardiovascular diseases such as angina pectoris and myocardial infarction, it was necessary to fill the inner lumen of the blood vessel with a contrast medium and perform catheterized coronary arteriography using X-ray irradiation, which not only irradiated the patient, but also did not always detect the shape and development of atherosclerosis.
The use of proteins (nuclease) that function like scissors to cut off the genes (DNA) of various organisms, and the process of gene repair, which modifies the genetic factors of a cell by altering the DNA sequence or replacing similar DNA sequences, and implanting DNA sequences from the breaks that have been removed from other organisms, is gene editing technology. With gene editing technology, human beings are free to change the genes of species and develop new foods and drugs, and its applications in the biological field are expanding.
So far, gene editing technology has gone through three generations: the first generation is "Zinc-Finger Nucleases (ZFN)" technology, the second generation is "Transcription Activator-Like Effector Nucleases (TALE)" technology, and the second generation is "Transcription Activator-Like Effector Nucleases (TALE)" technology. Zinc-Finger Nucleases (ZFN), Transcription Activator-Like Effector Nucleases (TALEN), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISP). Palindromic Repeats (CRISPR/Cas 9). Among them, CRISPR/Cas 9 technology can complete gene editing in a short time and is inexpensive, so it quickly became popular all over the world. With CRISPR/Cas 9, humans can alter the genes of plants, fish, nematodes, mice, pigs, monkeys, humans, and other species, and the universal applicability of the technology has accelerated its popularity.
Many countries use CRISPR/Cas 9 technology to cultivate genetically modified animals and conduct experiments such as recombinant cells. The technology has not only been used in real life to breed a number of excellent breeds, and to conduct gene therapy through the collection of highly small cells produced by substances, etc., but has also blossomed fully in the fields of agriculture, forestry, fisheries, chemistry, and medicine.
For example, using CRISPR/Cas 9 technology, it is possible to change genes that inhibit muscle growth, and breed pigs and snappers that are well-fed and have much more edible parts. Research is also underway to remove the gene for congenital amaurosis (LCA), an abnormal gene for a difficult eye disease.
Previous transgenic technology generally involved irradiating multiple individuals with radiation to change the genetic characteristics of the individuals, selecting the individuals that had accidentally changed after irradiation and met the requirements (mutants), and extracting similar DNA sequences for homologous recombination and embedding the genetic fragments that needed to be imported.
In cases such as breeding transgenic knockout mice, homologous recombination costs 3-5 million yen and takes 1-2 years. With the advent of CRISPR/Cas 9 technology, the cost is only a few thousand yen and the time is reduced to about a month.
"Next-generation compact sequencing technology" is a small device that reads genetic factors and sequences genomic bases at high speed.
In 2015, the UK-based Oxford Nanopore Technologies made a world premiere of a product called MinION, which is the size of the palm of your hand and connects to a personal computer. The company provides the host computer for free, and users only need to buy a disposable sensor that costs 1,000 dollars a piece. Because of its small size, it can be used outdoors for a change. In order to realize the reuse of water in the space, NASA (NASA) introduced MinION to determine the status of water pollution.
Oxford Nanopore Technologies will release smaller, cheaper products after the end of 2017. Due to the reduction of the number of sensors to read genome (DNA), ribonucleic acid (RNA), its disposable part of the cost is reduced by 1/3-1/5. Looking around the world, not only Oxford Nanopore Technologies has a new generation of small sequencing technology, Japan Quantum Biosystems (Quantum Biosystems) is also working on the development of related technology, we look forward to the future! We expect the market to become more active in the future.
Genetic factors carry protein information for various functions of an organism, and there are countless genetic factors in the genome, the totality of biological genetic information. The causes of difficult diseases and the development of new drugs are inseparable from the analysis of genetic factors and genomes.
The total amount of information in the genome varies with the type of organism. The human genome has about 3 billion base pairs, and the detection of such a large genome has to rely on high-speed reading technology and "next-generation mini-sequencing technology" support. By reading the bases from a large number of genome fragments, and searching the network for the information of the read fragments, the genome sequence of the original organism can be obtained.
The technology for analyzing data at high speed and in large quantities is spreading rapidly, but the cost of introducing it ranges from tens of millions of yen to hundreds of millions of yen, which is prohibitively expensive. However, in order to increase the information of gene fragments and perform optical detection of fluorescent markers, a large-scale device is essential. MinION utilizes a special protein sensor to measure the electric current that passes through a unit of DNA and RNA, and then completes the gene analysis. Because the CCD camera and laser technology for reading genes have been simplified, the device is also more compact.
"Cryo-electron microscopy" is a technique in which a measurement object, such as a biomolecule, is placed in an ultra-low-temperature environment at about minus 200 degrees Celsius, an image is captured using an electron beam, and the image is analyzed by a computer to ultimately obtain a tiny three-dimensional structure of the measurement object. Cryo-electron microscopy in the English name Cryo-Electron Microscopy "cryo" is the meaning of ultra-low temperature, it is since the end of 2013 quickly gained the attention of all walks of life.
Cryo-electron microscopy has a resolution of 1 ?m (0.1 nanometers), which is close to the size of a single atom, and can accurately analyze the three-dimensional structure of proteins and other biomolecules. Unraveling the biomolecular structure of biomolecules, the "culprits" of infectious diseases, will be of great benefit to the development of medicines and other drugs. If we can unravel the molecular structure of plant photosynthesis, we can even artificially complete photosynthesis and synthesize organic matter from sunlight.
The steps for using cryoEM are as follows: first interrupt the particle structure of the object of analysis - a biomolecule, such as a protein - to make a frozen sample embedded in the limiting particles. Each protein molecule is about 10 nanometers in size, and the frozen sample can hold multiple particles. The samples are placed into a frozen ice realm for observation, and over the course of a single night, the device can automatically take hundreds of high-resolution electron microscope images. With hundreds of particles photographed on a single image, the total number of protein particles photographed in one night's time would be more than 100,000. From these, tens of thousands of complete and good data are selected and analyzed by computer, and ultimately more detailed information about the three-dimensional structure can be obtained.
If the sample is of good quality, the electron microscope can even observe the atoms that make up the molecule, and images with 5-? resolution can be obtained in about 1 week of observation, and atomic models can be obtained in about a month.
1 cryo-electron microscope requires 100-200 million yen investment package, many research institutions, universities, pharmaceutical and chemical companies have been introduced. Some of the more famous companies in the cryo-electron microscope industry include Japan's Japan Electronics (JEOL) and others.
Before the advent of cryo-electron microscopy, scientists mainly analyzed the structure of biomolecules by crystalline X-ray diffraction analysis. After using X-rays to irradiate a crystalline body, the X-rays diffract as the density inside the crystal varies, using physical principles to analyze the three-dimensional structure of the crystal. The more regular and larger the crystals are, the more detailed the information on the three-dimensional structure will be. However, high-quality crystals of biomolecules are hard to come by, so there are still many proteins whose three-dimensional structures have yet to be solved, and the industry is looking forward to more protein structures that can be analyzed by cryo-electron microscopy, which does not require crystals.
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