As reflected in the name of TIM-3, current research on it is mainly focused on T cells. TIM-3 is regarded as a marker molecule of T cell exhaustion in chronic viral infection and cancer models[2].

Although multiple drugs targeting TIM-3 have entered clinical trials[1], but The mechanism of blocking TIM-3’s anti-tumor activity is still a bit vague Because TIM-3 is also expressed on many other immune cells, do immune cells other than T cells participate in its anti-cancer effect, or even play a more important role?

On June 9, 2021, the Vijay K. Kuchroo team from Harvard Medical School published important research results in the journal Nature. They found Blocking TIM-3 on dendritic cells (DCs) may play a more critical role in enhancing anti-tumor immunity [3]!

Screenshot of the paper’s homepage

In order to understand the specific functional mechanism of TIM-3, the researchers used a large number of conditional knockout mouse models.They found that in After knocking out TIM-3 in CD4 and CD8+ T cells at the same time, tumor growth was inhibited to a certain extent, but not very significant ;and Specific knockout of TIM-3 in CD8+ T cells, regulatory T cells or NK cells does not affect tumor growth .

This result is a bit surprising, but the researchers quickly thought, would TIM-3 on myeloid cells have a more important function?

The researchers found through single-cell sequencing combined with flow cytometry that High expression of TIM-3 in DC1s and migDCs (migDCs) in tumors .in After specifically knocking out TIM-3 in DCs, tumor growth was significantly inhibited, and This effect is stronger than TIM-3 knocking out T cells .

Knock out TIM-3 in dendritic cells (gene name is Havcr2), the tumor is significantly suppressed

So, how does TIM-3 on DCs affect the anti-tumor immune response?

With the help of single-cell sequencing results, the researchers found that after knocking out TIM-3 in DCs, the number of CD8+ T cells infiltrated in the tumor increased. A more detailed analysis found that Early activation, effect, memory, memory precursor T cells increased , These T cells play a key role in the anti-tumor immune response[4].

Streaming analysis also confirmed that in After conditionally knocking out the TIM-3 of DCs, the memory precursor CD8+ T cells and effector T cells infiltrated in the tumor increased significantly .

After knocking out TIM-3 of DCs, memory precursor CD8+ T cells (TCF1) and effector T cells (CX3CR1, T-bet, Ki67) increased

One of the main functions of DCs is to promote the anti-tumor immune function of antigen-specific CD8+ T cells through antigen presentation[5].Further analyzing the myeloid cells in single-cell sequencing, the researchers found Some genes related to MHC class I antigen presentation are significantly elevated .

Mouse experiments also confirmed that after knocking out the TIM-3 of DCs, the proportion of antigen-specific CD8+ T cells in the tumor was significantly increased, and it had a stronger killing potential.Description Inhibition of TIM-3 can enhance antigen-specific immune response .

After knocking out the TIM-3 of DCs, the proportion of antigen-specific CD8+ T cells increases and has a stronger killing potential

After studying the mechanism at the cellular level, the researchers began to further explore more detailed molecular mechanisms.

The researchers first analyzed the interaction between CD8+ T cells and DCs based on single-cell sequencing technology. The results showed that after knocking out the TIM-3 of DCs, the ligand-receptor interaction scores of Il18–Il18r1 and Il18–Il18rap increased significantly.Analysis of cytokines in tumor homogenate also found Significantly increased levels of IL-1β and IL-18 .

Friends who are familiar with inflammasomes must be able to think that inflammasomes mediate the activation and release of IL-1β and IL-18. Does knocking out TIM-3 activate the inflammasomes?

Pattern diagram of inflammasome activation[6]

Sure enough, analyzing single-cell sequencing data, the researchers found that in the TIM-3 knockout DCs, inflammasome-related gene characteristics were significantly enriched.

Inflammasomes can be activated by pathogen-related molecular patterns (PAMP) and damage-related molecular patterns (DAMP)[7]Since the research here did not involve pathogens, researchers naturally wondered whether endogenous DAMP (such as reactive oxygen species, oxidized lipids, and oxidized DNA) activated the inflammasomes?

Researchers found that in TIM-3 knock-out DCs, the enrichment level of oxidative stress-related gene characteristics was significantly increased, and flow analysis also confirmed Increased ROS levels in DC1s and mDCs .Furthermore, the researchers treated mice with tumors with antioxidants (N-acetylcysteine) and found that The tumor suppressor effect brought by knocking out TIM-3 is completely eliminated, and the increase in IL-1β levels in the tumor is also completely eliminated .

After knocking out TIM-3, the level of ROS in DC1s and migDCs increased

So, is the activation of the inflammasome pathway the reason for the enhanced anti-tumor immune response?

Researchers used three ways to inhibit the inflammasome pathway (inhibition of caspase1, inhibition of NLRP3 inflammasome, inhibition of IL-1β/IL-18, friends can check the above schematic diagram), and found The anti-tumor effect enhanced by knocking out TIM-3 completely disappears, and the function-enhancing effect of CD8+ T cells is also eliminated .

Inhibition of the inflammasome pathway can eliminate the immune enhancement effect of blocking TIM-3

Overall, this study found that compared to T cells, TIM-3 on DCs may play a more critical role in tumor immunity , This discovery has a certain subversive significance to people’s previous cognition.

The author analyzes the mechanism from the perspectives of cell function changes in the tumor microenvironment and changes in molecular pathways in DCs, but this article still leaves many unanswered questions.

For example, how does knocking out TIM-3 lead to increased levels of oxidative stress in DCs? In addition, the experimental evidence of the relationship between oxidative stress and inflammasome activation in this article is still weak. In this model, is it possible that the inflammasome may be activated by other factors?

How does the activation of inflammasome affect the function of DCs and T cells? Is it possible that TIM-3 may affect the function of DCs through other mechanisms?For example, in the latest issue of Immunity, Brian Ruffell and others believe that Blocking TIM-3 contributes to the activation of the cGAS-STING pathway in DCs, thereby promoting the anti-tumor immune response [8].

Although TIM-3 still has a lot to be studied, it is worth looking forward to that many TIM-3 antibodies have entered clinical trials, including some domestic drugs. It is hoped that these drugs can be marketed as soon as possible and benefit more patients.

references

1. Siddiqui I, Schaeuble K, Chennupati V, et al. Intratumoral Tcf1(+)PD-1(+)CD8(+) T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy. Immunity. Jan 15 2019;50(1):195-211 e10. doi:10.1016/j.immuni.2018.12.021

2. Roberts EW, Broz ML, Binnewies M, et al. Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma. Cancer Cell. Aug 8 2016; 30(2):324-336. doi:10.1016/j.ccell.2016.06.003

3. Terlizzi M, Casolaro V, Pinto A, Sorrentino R. Inflammasome: cancer’s friend or foe? Pharmacol Ther. Jul 2014;143(1):24-33. doi:10.1016/j.pharmthera.2014.02.002

4. de Mingo Pulido A, Hanggi K, Celias DP, et al. The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake. Immunity. Jun 8 2021;54( 6):1154-1167 e7. doi:10.1016/j.immuni.2021.04.019

Vice Chairman of the Provincial People’s Committee Doan Tan Buu, leaders of the Department of Health, CDC Dong Thap visited the testing process at CDC Dong Thap. (Photo: dongthap.gov.vn) Accordingly, the Director of the Pasteur Institute in Ho Chi Minh City under the Ministry of Health issued a decision to recognize the ability to confirm the SARS-CoV-2 virus by Realtime PCR (RT-PCR) for the Center for Disease Control and Prevention. Disease Control Department (Dong Thap CDC) and Dong Thap General Hospital. The laboratory for diagnosing SARS-CoV-2 by RT-PCR at these 2 units meets the biosafety standards level 2, facilities, equipment and human resources meet the standards prescribed by the Ministry of Health. Medical. To increase reliability, Dong Thap CDC and Dong Thap General Hospital performed a PCR test to diagnose COVID-19 (62 samples from Dong Thap CDC, 20 samples from Dong Thap General Hospital). As a result, 100% of the samples tested by the two units gave similar results to the Pasteur Institute in Ho Chi Minh City. In terms of testing capacity, on average, Dong Thap CDC and Dong Thap General Hospital are capable of testing from 250-300 samples/machine per day. In urgent conditions, the demand for testing is high, can be equipped with an automatic extractor to increase testing capacity. Previously, CDC Dong Thap only performed a screening test for SARS-CoV-2, if a positive case was suspected, the sample had to be transferred to the Pasteur Institute in Ho Chi Minh City for confirmatory testing. Comrade Doan Tan Buu – Vice Chairman of the Provincial People’s Committee emphasized that being recognized as having sufficient testing capacity to confirm the SARS-CoV-2 virus not only affirms the professional capacity of the 2 units, and meets the time schedule. time to identify COVID-19 cases, reducing dependence on upline. This is very important in helping Dong Thap proactively implement measures to trace, monitor, isolate as well as implement synchronous measures to prevent the COVID-19 epidemic.

Photo: India Express It is known that on May 15, China confirmed that Tiawen-1 had successfully dropped the Zurong rover to the surface of Mars. This is a historic milestone that makes China the second country to successfully launch a probe on the Red Planet. In the past, only NASA has succeeded in landing and operating probes on the red planet. (The Soviet Mars 3 spacecraft landed on Mars in 1971 and remained in contact for only about 20 seconds.) The landing took place at Utopia Planitia, a flat land on Mars and the same area where NASA’s Viking 2 rover landed in 1976. After landing, the lander dropped the Zhurong rover – Powered six-wheeled robot named after the god of fire in ancient Chinese mythology. The spacecraft carries an integrated toolkit, including two cameras, a Mars subsurface probe radar, a Mars magnetic field detector and a Martian meteorological tracker. “This is the hardest place to land in the solar system,” said Emily Lakdawalla, author of “The Design and Engineering of Curiosity.” China’s success in its first attempt indicates that it is one of the most capable space agencies.” The European Space Agency also tried to land on Mars in 2003, but its Beagle 2 probe had problems. The ExoMars Schiaparelli spacecraft – another ESA (European Space Agency) effort also crashed in 2016 after software mis-estimated its altitude during a landing attempt. Photo: The Verge The Tianwen-1 spacecraft launched from Wenchang Launch Site in Hainan Province, China last July, embarking on a seven-month trip to Mars. China said that “Tianwen-1 has been operating normally since it entered the orbit of the Red Planet,” the China National Space Administration (CNSA) said in a statement on the morning of May 15. CNSA revealed that Tianwen-1 has collected a large amount of data and photos taken from the orbit of Mars. Andrew Jones, a journalist covering China’s activities in space, said that Tiawen-1 has been exploring the Utopia Planitia landing site for more than three months while orbiting Mars. Now, after a successful landing, the Zhurong rover will embark on a mission that will last at least three months to study Mars’ climate and geology. “The main mission of the Tiawen-1 mission is to conduct a comprehensive and extensive survey of the entire planet using orbiters and to bring the probes to surface locations of great scientific interest. focused to conduct detailed investigations with precision and high resolution,” the leading scientists wrote in Nature Astronomy last year. It is known that this expedition vehicle weighs about 240kg, nearly double the weight of China’s previous Yuto Moon. The CNSA said last month: “The Mars rover Zhurong is hoped to ignite the fire of China’s interplanetary exploration and guide humanity into the vast unknowns of outer space.” Photo: The Verge Before Tiawen-1 successfully landed on Mars, the United States also successfully landed 5 rovers on the surface of the Red Planet. More recently, on February 20, 2021, NASA’s Perseverance probe passed through the atmosphere of Mars and landed on the planet on a historic mission to recover rocks to help answer the question. whether life ever existed on Mars. Although this CNSA project is more than four decades behind NASA, this success of China shows that its space engineers are rapidly closing the gap with the US. Tiawen-1 marked a big step for China in the field of space exploration. Previously, China also became the first country to successfully land and operate a probe in the dark side of the Moon in 2019. Recently, China also successfully launched its first core module. Chinese space station. In the future, this will be inhabited by groups of astronauts in space. Earlier this year, China, in partnership with Russia, announced plans to build a space station on the surface of the Moon.

Laboratory – Center for high-tech medical diagnosis Thien Nhan Danang has enough capacity to confirm positive for Sars-CoV-2. Today, April 26, Dr. Do Thai Hung, Director of Nha Trang Pasteur Institute signed Decision No. 905 / QD-IPN on recognition of the laboratory – Center for high-tech medical diagnosis Thien Nhan Da Nang. confirmation of SARS-CoV-2 virus positive cases. This laboratory is responsible for confirming cases of positive for SARS-CoV-2 virus in Da Nang, to confirm for other localities upon request and report test data according to regulations. . Earlier on April 24, Nha Trang Pasteur Institute conducted an inspection and assessment of the testing capacity for SARS-CoV-2 virus of Thien Nhan Laboratory – Thien Nhan, Thien Nhan High-tech Medical Diagnostic Center in Da Nang. . Thien Nhan Da Nang High-Tech Medical Diagnostic Center has built a molecular biology laboratory according to international association standards, ensuring accuracy and safety in the process of receiving and manipulating tests. Sample / Solution Transport … Nha Trang Pasteur Institute has verified and recognized all the operating documents / procedures, equipment management, initial waste treatment in medical waste treatment, general testing procedures. test; fully equipped with chemicals, biologicals and materials for the SARS-CoV-2 confirmation test. In particular, people who test positive cases for SARS-CoV-2 virus meet the prescribed requirements, are well trained in screening testing techniques trained by Nha Trang Pasteur Institute. According to Mr. Ngo Duc Hai, Director of Thien Nhan High-tech Medical Diagnostic Center, is the first private medical unit in Da Nang to be licensed by the Department of Health of Da Nang City to coordinate the City Disease Control Center. Da Nang (CDC) tested for SARS-CoV-2 from August 2020. Over the past time, Thien Nhan laboratory has tested SARS-CoV-2 for more than 8,000 people, actively serving the Covid-19 epidemic prevention and control of Da Nang city and central provinces. Especially during the peak epidemic in Da Nang 8-2020, to meet the needs of safety in production, travel, exit … in accordance with regulations on prevention and control of Covid-19 epidemic. Thien Nhan hopes to contribute more to the proactively coping with the increasingly complicated Covid-19 epidemic in the world, serving the safety of production, travel, study and work of the people. local at home and abroad.

This is also the first private medical facility licensed by the Department of Health of Da Nang City to coordinate with CDC Da Nang to test for SARS-CoV-2 in August 2020. Up to now, the center has tested for more than 8,000 people, actively serving the epidemic prevention work of Da Nang City and neighboring provinces. “We want to contribute more to proactively deal with the increasingly complex COVID-19 epidemic in the world. Serve the safety of production, travel, study and work of local people at home and abroad “- said the representative of the establishment. Laboratory of SARS-CoV-2 at Thien Nhan High-tech Medical Diagnostic Center. Photo: T.AN Previously, to serve the SARS-CoV-2 virus testing, the center has invested in advanced equipment systems such as Realtime PCR machine, grade II biosafety cabinet, sound refrigerator 80 degrees Celsius to store positive / suspected patient samples. In particular, building a negative pressure room with suction and disinfection system at the speed of 1,500m3 / hour, ensuring maximum safe and sterile ventilation for the laboratory. The Japanese microbiological liquid waste treatment system ensures absolute safety before going to the environment with the regular monitoring inspection by the General Department of Meteorology and Hydrology – Central Hydrometeorology Station. The set. In addition, the center’s laboratory is also fully equipped with chemicals, biologicals and materials for the SARS-CoV-2 confirmation test. Personnel for SARS-CoV-2 testing, meeting the prescribed requirements, are well trained in SARS-CoV-2 screening techniques trained by Nha Trang Pasteur Institute.

Screenshots As of now, Apple has not confirmed the release date of iOS 14.5. However, with 8 beta versions released, iOS 14.5 is definitely nearing the time to reach users. Not excluding the possibility that iOS 14.5 will be announced by Apple tonight. Photo: MacRumors This isn’t the first time rumors about Apple incubating a podcast listening service have surfaced. Earlier, a report by analysts Loup Ventures said that Apple’s new service could be called “Podcasts +.” According to this report, “Podcasts +” will stay within existing Podcasts app and allow users to listen to premium content. Photo: HT Tech Before that, Apple is said to have been in talks with a lot of content producers to prepare for the above podcast service. Apple negotiated to acquire podcast network Wondery before it went to Amazon and took over podcast app Scout FM in September 2020. Photo: Ars Technica If the above information is authentic, Podcast + will be a new service included in Apple’s Apple One service pack. MacRumors says that Podcast + will be available to Apple One users at no additional charge. This way, Apple can attract more users for Apple One in general and Apple Music in particular.

However, when they expanded their study to animals, they discovered some early forms of B117 in dogs, including a sample taken in the US in July 2020. Artwork: AP “These initial variants included most or all of the B117 mutations in the Canidae breed and they could have infected humans after a rapid mutation,” Professor Chen Luonan and colleagues at the State Cell Biology Key Laboratory said in a report posted on biorxiv on April 16. The arrival of the B117 variant has puzzled researchers. After being isolated from two patients in Kent in southeast England and London in September 2020, the new variant of the SARS-CoV-2 virus quickly became the dominant strain in the UK and many other countries. the ability to spread more strongly than the original virus strain. Some experts believe that the variant may have emerged from the local community due to the selective pressures of antiviral drugs used during the pandemic. According to a popular theory, this variant suddenly appeared in England and then spread to many other parts of the world. However, this variant had nine mutations that were rarely found on previous human variants, said Chan and colleagues. These mutations do not appear in adjacent genes, but spread across the entire genome of the virus. The likelihood of these mutations occurring at the same time is very low. The Shanghai team of researchers believes that these nine mutations created one mutation after another. Their model also suggests that variations may have appeared outside the UK and spawned mutations that were present on non-human hosts. The dogs are the most likely animal in this case, followed by the weasels and the cats. Qu Liandong, a virology professor at the Harbin Veterinary Research Institute who was not involved in the study, said that more clear evidence is needed to support the hypothesis. The variations found in dogs do not quite resemble the first confirmed variant in a British patient, although the number of genetic sequences the researchers gathered from hundreds of thousands of patients was still overwhelming. small compared to the total number of patients in the world. Some of the early forms of the B117 variant were missed in the sample collection program, he said. However, if pets like dogs become hosts, “we will have a big problem,” said Professor Qu. “Nearly all of our measures to deal with disease so far have only considered humans. If the animals are also sick, it will completely change the situation,” he said. . When bird flu outbreaks occur in a chicken farm, all chickens are destroyed, even healthy ones, to prevent the risk of infection. Dogs are close friends of man. If they are able to carry or create variant SARS-CoV-2, they could suffer a similar fate, Qu said. Another solution is to inject animals with vaccines. “However, we cannot inject dogs with human vaccines. We need to develop completely new vaccines. Right now, we are still struggling in the campaign to vaccinate humans. Can the vaccination program be extended to both dogs and other animals? “asks Qu. There is growing concern that the B117 could make the dogs weaker. Veterinarians near London discovered a spike in pets, including dogs and cats, with myocarditis, and many of these were positive for the new variant of the SARS-CoV- virus. 2. Humans and animals have different immune systems and it is often difficult for viruses to be transmitted from one species to another. The SARS-CoV-2 virus is thought to have originated in bats and it takes decades to adapt in humans. When and where this virus spreads from animals to humans remains a mystery. The B117 variant has a special evolutionary process to increase infectivity, so it can be spread more easily from one host to another, says Chen’s team. Whether this process helps the variant of SARS-CoV-2 cross the species gap is still in need of further study, the experts said./.

Like previous times, Apple did not reveal any information on the announcement line for the upcoming event other than the stylized image of its logo and the headline “Spring Loaded”. The doodle image printed on the notice reminds many of the stylus drawings, coinciding with the information that Apple may launch an Apple Pencil, a pen that can be controlled by the button. .

The new event timeline also coincides with the new iPad Pro tablet launches from Apple. Although the new 11 and 12.9-inch iPad versions are expected to have similar designs to last year’s models, the difference is that the 12.9-inch iPad will be the first Apple device to use a screen. Mini Led.

In addition, many speculations about Apple will upgrade the processor on the iPad to be more powerful, equivalent to the M1 chip used on the new MacBook with improvements in USB-C ports and cameras. Most likely, a new iPad mini, with a size of about 8.5-9 inches (the old 7.9 inch) will be released in the first half of this year.

Apple AirTags, a product used to find devices that can be lost by attaching to them, is also a product with a high chance of appearing at the upcoming event. Although information about AirTags has been around since early 2019 and is believed to have been in mass production in 2020, they have yet to be officially announced.

Besides the long rumored products, maybe Apple can still surprise its fans with a few other products in the upcoming event.