Zhongxin. com, Guangzhou, June 6 (Fang Weibin, Jiang Xiaobo, Wang Xisong) Guangdong Marine Police Bureau reported on the 6 th that recently, it seized a batch of suspected smuggled frozen products in the waters of Zhanjiang Port, Guangdong Province, seized an iron-clad transport ship on the spot, and arrested three suspects. The frozen products were about 485 tons, and the case value was about 40 million yuan.

　　According to the report, at 0: 20 on May 30, the Guangdong Marine Police received a report from the masses that there were smuggling activities in the waters near Zhanjiang Port in Zhanjiang City. The bureau immediately assigned the law enforcement boat of Zhanjiang Marine Police Bureau of Guangdong Province to the target sea area for investigation.

　　At about 1 o’clock, the law enforcement boat arrived at the target sea area. After searching the sea, it was found that a ship was very suspicious. Law enforcement officers quickly locked the suspected ship, shouted a warning to it and stopped the ship for inspection. However, the suspected ship refused to cooperate with the inspection in an attempt to speed up the escape. Law enforcement officers immediately pursued it and intercepted the suspected ship in the waters off Zhanjiang Seaside Shipyard, and controlled three suspects on the spot.

　　After investigation, it was found that the suspected ship was an iron transport ship, with a cargo hold behind the bridge. The cargo hold was filled with white and black plastic woven bags, which contained about 485 tons of frozen products such as beef, brisket, tripe, beef tendon and donkey offal of unknown origin, with a case value of about 40 million yuan. The crew on board failed to provide proof of the relevant legal origin of the goods loaded on board, and law enforcement officers detained the ship and frozen products according to law.

　　At present, the case is under further investigation.

foreword　 　

At present, tumor immunotherapy is in the ascendant, and one of the most effective treatment strategies is adoptive cell transfer therapy (ACT). Chimeric antigen receptor (CAR) and engineered T cell receptor (TCR) are the main adoptive T cell immunotherapy in recent years. TCR engineering T cells express tumor antigen-specific receptors, and their α chains and β chains are produced by high-quality and high-affinity antigen-specific T cell clones.

TCR molecule belongs to a superfamily of immunoglobulin, which consists of two covalently bound polymorphic subunits, each of which is antigen-specific, and they are related to at least four different types of signal transduction chains. In order to activate T cells, there must be interaction between TCR and MHC.

The interaction between TCRs and pMHC(peptide-MHC) determines the fate of immature thymocytes, which is very important for the survival of naive T cells. Therefore, TCR-T immunotherapy technology activates the host’s immune system through effective interaction with MHC, especially class II molecules, which are specifically recognized by TCR-T cells and CAR-T cells. TCR-T cells can recognize tumor-specific antigens in cells, while CAR-T cells mainly recognize tumor-specific antigens on the surface. This makes TCR-T cells more effective in tumor treatment.

At present, some new technologies and tools are being applied to TCR-T, which is helpful to improve the efficacy and safety of TCR-T therapy. TCR-T cell therapy is showing great potential for anti-tumor therapy.

　 Comparison between CAR-T and TCR-T

In ACT therapy, TCR-T and CAR-T cells have been successfully used in the clinical treatment of solid tumors.

CAR contains single chain antibody targeting tumor antigen, transmembrane domain and intracellular activation domain of CD3ζ. In this way, the engineered CAR can recognize specific tumor-associated antigens, and CAR can bind untreated tumor surface antigens without MHC treatment.

The first generation of CAR-T cells showed limited expansion and relatively short persistence, and the "second generation" CAR-T added costimulatory receptors CD28, 4-1BB/CD137 and OX40. These costimulatory receptors are added to the CD3ζ domain of CAR-T cells, thus promoting a more powerful and lasting T cell response. The third generation CARs combines two co-stimulatory signals (CD28 and 4-1BB) at the same time, which has better amplification and longer persistence than the second generation CARs.

On the contrary, TCR is an α/β heterodimer that binds to MHC antigen complex. Compared with TCR, CARs has some disadvantages in identifying tumor antigens, such as extratumoral toxicity. Compared with CARs, TCRs has some structural advantages in T cell-based therapy, such as more subunits (10: 1) in its receptor structure, more tyrosine-based activation motifs (ITAMs) in immune receptors (10: 3), less dependence on antigens (1: 100), and more costimulatory receptors (CD3, CD4, CD28, etc.). TCR with a low MHC affinity range (104-106M-1) can effectively activate T cells, whereas CARs needs a higher affinity range (106-109M-1).

Therefore, CAR-mediated cytotoxicity depends on higher density of cell surface antigens. In addition, T-cell/antigen interaction IS initiated in the structure of immune synapse (IS), in which TCR presents an annular region with peripheral LFA-1 adhesion, while CAR presents a diffuse LFA-1 distribution without annular region. Therefore, TCR-IS is slower but lasts longer than CAR-IS. At the same time, CAR-T cells show faster killing function and migrate to the next tumor target (serial killing), which is in sharp contrast to TCR-T cells’ prolonged signal transduction and killing time.

Recombination TCRs 　

TCR is one of the most complex receptors in human body. It contains six different receptor subunits, which have a very wide range of functions in T cells. The change of TCR of tumor infiltrating lymphocytes (TILs) significantly affects tumor-specific T cells. Among them, the change of TCR is helpful to the proliferation of T cells, and the diversity of TCR is related to the anti-tumor effect.

TCR engineering of TIL is one of the best treatment methods for tumors. TCR consists of α chain and β chain bound to peptide -MHC ligand, signal subunits (,γ and δ) of CD3 complex and CD3ζ homodimer. Except CD3ζ, all subunits have extracellular immunoglobulin (Ig) domain. Based on these structures, new technologies using engineering TCR include ImmTAC, TRuCs and TAC.

Immune mobilization monoclonal t cell receptor (ImmTAC)

ImmTACs is designed using engineered, soluble and affinity-enhanced monoclonal TCRs(mTCRs). ImmTACs is basically a fusion protein, which combines the engineering TCR targeting system and single chain antibody fragment (scFv) effector function. In the construction of ImmTACs, TCR can recognize peptides from intracellular targets presented by human leukocyte antigen (HLA).

ImmTAC specifically targets HLA- peptide complexes on the surface of tumor cells, and promotes T cell-mediated effector function through the interaction between scFv antibody fragments and CD3. ImmTAC also activates CD8+T cells in a dose-dependent manner, and can effectively redirect and activate CD8+ and CD4+ cells. ImmTAC shows multifunctional reaction by secreting various cytokines, such as TNF-α, IFN-γ, IL-6, MIP1α-β and IFN-γ inducible protein 10.

In addition, selecting the appropriate target antigen is the key to ImmTACs, and mass spectrometry and MHC polymer technology are helpful to identify the appropriate antigen. It is worth noting that TCR engineered T cells also show unexpected targeted toxicity. Generally speaking, ImmTACs has been proved to enhance the anti-tumor response of TCR-T cells, but its safety needs further study.

T cell receptor fusion structure

T cell receptor fusion structure (TRuCs), an antibody binding domain fused with T cell receptor subunits, is designed to effectively recognize tumor surface antigens. TRuCs is composed of specific antibodies targeting tumor-associated antigens fused to the extracellular N- terminal of five TCR subunits (TCRα, TCRβ, CD3, CD3γ and CD3δ), which provides new targeting specificity and HLA-independent target cell clearance for engineered T cells and can be activated by corresponding target cells.

Compared with the second generation of CAR-T cells, this method shows better anti-tumor effect. In addition, TRuCs dominates all the signal mechanisms of TCR complex, while CARs only uses the limited signal of the isolated intracellular segment of CD3ζ.

T cell antigen coupling agent (TAC)

T cell antigen coupling agent is another engineered TCR cell, which can induce more effective anti-tumor response and reduce toxicity in an MHC-independent way. TAC chimeric protein can form TCR/CD3 complex and get more T cell responses by binding to CD3 domain.

The activity of TAC receptor is closely related to the selection of CD3 binding domain. For example, a single chain antibody from OKT3(muromonab-CD3) has lower cytokine production and cytotoxicity compared with UCHT1, which may lead to substantially different functional results. Compared with the second generation of CARs, T cells engineered with TAC gene are not only beneficial to the greater infiltration in solid tumors after adoption, but also reduce the expansion and extratumoral toxicity of T cells in healthy tissues expressing antigens.

Workflow of TCR-T cell therapy 　

In order to isolate therapeutic TCR, antigen-specific T cells must be isolated from the blood of patients or healthy blood donors and amplified in vitro with specific peptide antigens and cytokines (such as IL-2 and IL-15). This process needs to determine the specific tumor-related peptide targets that can be safely targeted to patients in advance. After selecting the target antigen, different methods can be used to screen TCR with the required high affinity and tumor specificity. Pre-clinical safety testing is also necessary to ensure the minimum off-target effect and cross-reactivity of isolated high affinity TCR. Viral vectors are usually used to genetically modify autologous patient T cells to express the proven therapeutic TCR, and then transfuse it back into patients.

Determine the target antigen

Melanoma antigen 1(MART-1) recognized by T cells is the first tumor-related antigen targeted in TCR-T clinical trials. After this breakthrough, TCR-T therapies for various tumor antigens have been developed, including TCR-T therapies for MAGE-A3, MAGE-A4, GD2, mesothelin, gp100, MART1, AFP, CEA, NY-ESO-1 and viral peptides derived from HPV and EBV. Among them, NY-ESO-1 has been proved to be one of the most promising targets of TCR-T cells, and it has achieved success in the treatment of synovial sarcoma, with an objective effective rate of 67%.

The ideal TCR-T target antigen shows the following characteristics: (1) the ability to induce immune response; (2) It is related to driving tumor phenotype (such as oncogene) to reduce the risk of antigen loss and tumor immune escape; And (3) expression on tumor stem cells to promote permanent tumor eradication.

Identification method of tumor-associated antigen

High-resolution mass spectrometry (MS) has been proved to be the most powerful Qualcomm method to promote the direct identification of HLA-I binding peptides from tumor cells. In this method, HLA-I/ peptide complexes are separated from tumor tissues or cell lines by immunoprecipitation (IP), and then the binding peptide antigens are separated from HLA-I molecules and antibodies for IP by fully washing and applying acidic elution buffer. This strategy allows each tumor sample to identify thousands of validated peptide targets, and has been used to identify HLA-I ligands of glioblastoma (GB), melanoma, renal cell carcinoma (RCC) and colorectal cancer (CRC).

Identification method of new tumor antigen

Although MS-based technology can be used to identify new antigens, it is more difficult to identify them, especially for tumor samples with limited size, because of their relatively low abundance and limited sensitivity of MS. However, the development of new generation sequencing technology is helpful to identify and locate such tumor targets. All-exon DNA sequencing, combined with computational prediction algorithm, allows to identify specific genetic changes in cancer cells, which can produce mutant peptides and present them on tumor HLA-I molecules.

All somatic mutant genes can be analyzed by computer to predict the potential high affinity epitopes that may bind to HLA-I molecules of patients, so as to be recognized by T cells. With the use of large MS elution peptide database, HLA-I peptide binding prediction algorithm is constantly updated and improved, and other prediction algorithms try to consider biological variables related to the complexity of intracellular processes.

Another commonly used method is tumor RNA sequencing, which allows the selection of new antigens with the highest transcriptional expression. It is worth noting that although these prediction methods usually show very good accuracy in identifying presented and highly immunogenic new antigens, the number of new antigen targets they usually predict is 1 to 2 orders of magnitude higher than the actual number of real targets.

Discovering new antigens by trogocytosis is a new method in recent years. Trogocytosis is a biological phenomenon in the process of cell combination, in which cells share and transfer membrane and membrane-related proteins. Li et al. found that T cell membrane proteins were specifically transferred to tumor target cells, which presented homologous HLA-I/ peptide complexes. Using these T cell-target cell interactions, they created a new antigen discovery system by incubating T cells expressing orphan TCR with homologous target cells. By transferring fluorescent markers from T cells to target cells, this method can isolate these target cells and sequence homologous TCR ligands, thus establishing a new antigen library.

Isolation of tumor-specific T cells and TCR

Using HLA-I polymer, single cell TCR sequencing or antigen-negative humanized mice, tumor-reactive T cells and TCR can be identified from autologous, allogeneic or xenogeneic cell banks.

Using HLA-I multimer method, antigen-specific CD8+T cells can be directly separated by multimer staining and flow cytometry. Before isolating the paired full-length TCR sequences, these polyclonal T cells were tested for homologous peptide recognition and anti-tumor function. TCR with high affinity and specificity can be obtained by using a highly sensitive PCR-based single cell TCR analysis method (TCR-SCAN).

Another method uses humanized mouse TCR gene bank, which will not cause T cell clone deletion or tolerance in humans. Therefore, Li et al. used the whole human TCRα/β gene locus and chimeric HLA-A2 transgene to construct transgenic mice to isolate human TCR against human TAA.

Single cell sequencing method represents a more promising method to isolate tumor-specific TCR coding genes by Qualcomm method. Using RNA bait libraries targeting each individual V and J element in TCRα and TCRβ loci, TCR coding genomic elements can be selectively isolated from excised genomic DNA(gDNA) fragments for subsequent paired terminal deep sequencing. This makes it possible to identify antigen-specific TCR from human materials or oligoclonal T cell populations of TCR humanized mice.

Infantile T cells can also be used as TCR sources for TCR-T therapy. TAA and new antigen-specific T cells can be derived and amplified from low-frequency precursors in peripheral blood of cancer patients, and can be reinfused or used as the source of antigen-specific TCR. Because cancer patients usually show immunosuppression or dominant T cell tolerance, the original sequence of HLA-I matched healthy donors also represents a reliable source, because it has a huge diversity of TCR sequences, and theoretically T cells have any antigen specificity, including new tumor antigens. A Qualcomm-quantity technology platform has been developed to find the original sequence, so as to quickly and effectively identify the rare but valuable TCR for personalized adoptive T cell therapy.

Cloning of TCR

Most TCR-based gene therapy methods rely on in vitro transduction of T cells with viral vectors, and adenovirus is the earliest vector used for gene therapy. However, due to their inability to integrate transgenes into the host genome, TCR expression will be lost during T cell proliferation. In addition, the immune genetic characteristics of adenovirus also limit its application as a gene therapy vector. In contrast, retroviruses show greater prospects as gene transfer vectors, because they can infect a variety of cells and have the ability to insert transgenes into the host genome, thus making the ectopic TCRα/β chain stably expressed.

Retroviral vectors derived from γ -retroviruses such as mouse leukemia virus (MLV) have been widely used for gene transfer into human T cells. This method has been used to transfer various genes, including suicide gene, TCR and CARs. The main disadvantage is that they cannot transduce non-proliferative target cells, which excludes the application of resting T cells in TCR-T therapy. In addition, retrovirus insertion mutation may cause potential side effects.

Recently, lentiviral vectors (LV) have attracted more attention as gene transfer vectors, because they can transfer genes into mitotic and non-splinter cell. Various techniques, such as Golden Gate cloning and LR cloning, are usually used to construct a vector for inserting TCRα/β gene.

Adeno-associated virus (AAV) is another widely used virus vector. Compared with adenovirus vector, AAV has lower immunogenicity and wider cell tropism, so it has been widely used in tumor gene therapy. In order to promote the integration of transgenes, people have developed self-complementary AAV vector (scAAV) to make AAV independent of the complementary strand synthesis of host cells. scAAV is more effective than traditional AAV in preclinical model.

At the same time, some non-viral gene editing methods have also been developed. MRNA electroporation has been proved to achieve transient expression of TCR and CAR, thus minimizing the risk of persistent virus components. Clinical data show that both TCR-T and CAR T cells modified by mRNA are feasible and safe, and there is no obvious evidence that they have non-targeted toxicity to normal tissues. However, the lack of continuous TCR expression may limit the curative effect and require repeated infusion. In addition, the non-viral sleeping beauty retrotransposon system is also used for the transduction of TCR and CARs.

Gene editing can insert large gene fragments into target cells specifically and efficiently through homologous directional repair (HDR). TCR-T cells developed by CRISPR/CAS9 have been proved to specifically recognize tumor antigens in vitro and induce a productive anti-tumor response in vivo.

Verification method of TCR

After TCR cloning, extensive preclinical verification is needed to prove the specificity and safety of engineered TCR-T cells. Verification includes evaluating the affinity of TCR by titration of homologous peptide antigens and measuring the killing effect of a group of HLA-I matched tumor cell lines. If there is no such tumor cell line, the target cells can transductively express related antigens and related HLA-I molecules. The new antigen can also be expressed in autologous antigen presenting cells to evaluate the antigen reactivity of TCR.

The safety test includes testing the ability of candidate TCR-T to identify HLA-I matching primary tissues, so as to ensure that there is no normal tissue as the target, which may lead to non-targeted toxicity. In at least two clinical trials of TCR-T cell therapy, there was a cross reaction between normal brain cells and heart cells, which led to the death of patients. These test results emphasize the importance of extensive safety tests before TCR enters clinical trials.

Safety of TCR-T 　

The ACT of TCR-T cells showed high tumor killing, but some serious adverse events also appeared in some clinical studies. It is very important to optimize TCR affinity in engineered T cells, and receptor affinity can determine the safety and effectiveness of T cell therapy. In terms of curative effect, affinity TCR interaction is enough to activate T cells, but strong affinity is needed to maintain the expansion of T cells.

In phase I/II ACT clinical trials, engineered T cells with low affinity show safer characteristics, but their anti-tumor response is weak. By identifying the TCR-pMHC interaction of T cells, engineered T cells can be divided into high affinity type and low affinity type. In addition, some technologies have been developed to improve the safety of TCR-T.

The safety switch mechanism based on engineered T cells is an attractive strategy. Thymidine kinase gene from herpes simplex virus type I (HSV-TK) is one of the most common suicide genes.

Although HSV-TK shows safety in cell-based immunotherapy, it is necessary to introduce phosphorylated nucleoside analogues. Another safer induced T cell safety switch is called inducible caspase-9(iC9). IC9 is a modified human FK binding protein, which can be activated by a small molecule compound AP1903, and this process depends on the mitochondrial apoptosis pathway.

The immunogenicity of iC9 suicide gene is low, and the immune response to transgenic cells is reduced. IC9-based safety switch has been proved to be more potential for cell therapy than previous suicide genes.

Clinical status of TCR-T cell therapy 　

As of August 9, 2021, there are 175 studies using TCR-T therapy in ClinicalTrials, 71 of which are specific TCR for specific TAA or new antigen, and 32 studies have been completed. NY-ESO-1 is the most common targeted antigen, which is expressed in many cancers, including myeloma and melanoma. Other tumor testis-associated antigens, such as PRAME and MAGE proteins, melanoma differentiation antigens MART-1 and gp100, and recent cancer drivers, such as WT1, KRAS and TP53, are also popular TCR-T targets.　 　 　 　 　 　 　 　 　 　 　

　　　　

A total of 83 sponsors/collaborators initiated or participated in the research of TCR-T cell therapy, including the National Institutes of Health (NIH), government organizations, industries and universities/academic institutions. At present, the National Cancer Institute (NCI) has supported 53 TCR-T projects, accounting for 20% of all ongoing projects.

Among the 29 pharmaceutical companies developing TCR-T therapy, GlaxoSmithKline and Adaptimunime initiated the most clinical trials, with 11 and 7 respectively. Recently, a phase 1 clinical trial (NCT02858310) of TCR-T cells targeting human papillomavirus (HPV)-16 E7 protein in the treatment of metastatic human papillomavirus-related epithelial cancer was reported. In this study, 6 of the 12 patients who received treatment showed objective clinical response and observed steady tumor regression. This is a landmark clinical trial of TCR-T cell therapy, which proves that targeted virus antigen has good clinical effect on patients with virus-related cancer. Other viral antigens explored as TCR targets include HPV-E6 protein, antigens from Epstein-Barr virus (EBV) and human endogenous retrovirus (HERV) targets, such as Herv-E.

MART-1 and NY-ESO-1 TCR-T therapy targeting TAAs also showed clinical efficacy in advanced melanoma, myeloma and non-small cell lung cancer. The total effective rate (ORR) of TCR-T clinical trial is between 0 and 60%. It is worth noting that most of these TCR-T clinical trials only enrolled a small number of patients (2 to 25), so ORR may not be statistically accurate. Therefore, larger-scale phase II and III clinical trials are needed to confirm the actual clinical efficacy of these TCR-T therapies.

Challenges and potential solutions of TCR-T cell therapy 　

Although immunotherapy based on TCR-T cells has shown certain clinical efficacy in most patients receiving treatment, it still faces many challenges in many fields. These challenges include: (1) Immunotoxicity caused by targeting normal tissues; (2) The expression of TCR in engineered T cells is insufficient or transient; (3)T cell exhaustion and dysfunction; (4) tumor immune escape, and (5) most cancer patients lack effective tumor-specific antigens as targets. Overcoming these challenges will be the key to greater clinical success in the future.　 　 　 　 　 　　

　 　 　 　 　 　

Discovery of new targets

At present, the target of peptide antigen for effective and safe immunotherapy of TCR-T is very limited. At present, most of the targets used are TAA. Although it is up-regulated in tumor tissues, it still maintains a low level of expression in normal tissues, which may lead to autoimmune toxicity. Therefore, the new antigen seems to be the safest target for TCR-T cancer treatment. However, the main challenges of developing new antigens in TCR-T clinic include: (1) the mutation of new antigens is individualized to a great extent, and there are differences among cancer patients, so it is difficult to develop widely used immunotherapy products; (2) The expression of new antigens in tumor tissues is often heterogeneous.

Nevertheless, recent reports have highlighted the emergence of new immunogenic antigens widely shared by tumor cells, including mutated KRAS and TP53. Many other studies have also demonstrated the immunogenicity of shared new antigens that can be used to generate potential therapeutic tumor-specific TCR. With the development of next generation sequencing technology, especially single cell DNA sequencing, transcriptome sequencing and mature in vitro verification methods, TCR-T immunotherapy targeting personalized new antigens may become a popular cancer treatment method in the next few years. In addition, the emerging TAA class, such as carcinoembryonic antigen, may also constitute a feasible target for the future development of TCR-T.

Maximize therapeutic TCR expression

The correct pairing of transgenic α and β chains is one of the main challenges that hinder the development of TCR-T cells. Since each transduced T cell includes two endogenous TCR chains and two transformed TCR chains, heterodimers with unknown specificity can lead to potential autoimmune consequences. Another related problem is that improper α/β chain TCR pairing will compete for CD3 complex, thus reducing the surface expression and signal transduction of therapeutic TCR.

There are several methods to properly pair the transduced TCR chains, including: (1) the constant region of partially murine TCR; (2) adding cysteine residues to promote the introduction of disulfide bonds in TCR chains; (3) changing the secondary structure of the constant region of endogenous TCR; (4) adding a signal domain to the intracellular part transduced with TCR; (5) Introducing TCR-α/β chain into substitute effector cells or constructing single-stranded TCR.

Methods to enhance the expression of therapeutic TCR include: (1) codon optimization of TCR-α and TCR-β chain transgene, and (2) changing the configuration of TCR-α/TCR-β vector to optimize expression.

Reduce adverse events

Usually, targeting non-tumor toxicity is the main key obstacle of TAA, and this risk urges researchers to study common new antigens more carefully. At present, several oncogene hot spot mutations are being studied as potential TCR targets, such as phosphoinositide -3- kinase (PI3K), KRAS and TP53. In addition, genetically engineered TCR-T cells with suicide genes are an important safety measure. Obviously, it is very important to develop reliable, identifiable, personalized, highly specific and immunogenic tumor antigen targets to reduce adverse events related to TCR-T cell therapy.

Graft-versus-host disease of allogeneic T cells

Using allogeneic T cells is a very promising scheme, which can overcome manufacturing problems, patient-related immune cell defects and treatment delays. In order to use allogeneic T cells, it is necessary to control graft-versus-host disease caused by transduced allogeneic reactive lymphocytes and rejection of engineered lymphocytes by host immune system.

The deletion of endogenous TCR gene, HLA-I locus or CD52 molecule is one of the strategies to avoid the failure of TCR-T transplantation, which can be achieved by many methods, such as gene editing or using siRNA. In addition, pluripotent stem cell technology is also considered as a potential solution.

　 summarize

In recent years, engineered T cells have shown excellent curative effect in the treatment of hematological tumors. TCR regulation is very important for T cell reactivation, immune response and its clinical effect on foreign antigens. TCR-T cells have incomparable advantages over CAR-T cells, and show great potential in preclinical and clinical research.

However, there are still several key challenges to improve the anti-tumor efficacy of TCR-T immunotherapy, including how to safely increase the affinity of therapeutic TCR, how to identify the common tumor-specific antigen and TCR in the patient population, and how to regulate the expression of TCR and achieve the best function. The solution of these problems will help to give full play to the potential of TCR-T cell therapy and bring hope to cancer patients to relieve their pain.

References:

1.Engineered TCR-T CellI mmunotherapy in Anticancer Precision Medicine: Pros and Cons. Front Immunol.　2021; 12: 658753.

2. Evolution of CD8+　T Cell Receptor(TCR) Engineered Therapies for the Treatment of Cancer. Cells.　2021 Sep; 10(9): 2379.

　　synopsis

　　Socialist core values are the concentrated expression of contemporary China spirit, which embodies the common value pursuit of all China people and is a powerful force to unite people’s hearts and gather people’s strength. In the new era, the construction of socialist core values has been further promoted and achieved remarkable results. We should adhere to the guidance of Socialism with Chinese characteristics Thought of the Supreme Leader in the New Era, thoroughly study and implement the cultural thought of the Supreme Leader, focus on cultivating and practicing socialist core values, and better inspire China’s strength with the spirit of China.

　　Core values are an important stabilizer of a country. Whether we can build core values with strong appeal is related to social harmony and stability and the long-term stability of the country. General Secretary of the Supreme Leader made important instructions on propaganda and ideological and cultural work, emphasizing "focusing on cultivating and practicing socialist core values". Cultivating and practicing the socialist core values is the basic project to gather the spirit and strengthen the foundation. Since the 18th National Congress of the Communist Party of China, the CPC Central Committee with the Supreme Leader as the core has attached great importance to ideological work and incorporated upholding the socialist core value system into the basic strategy of upholding and developing Socialism with Chinese characteristics in the new era. In the new era and new journey, propaganda and ideological and cultural work is facing new situations and new tasks. We should adhere to the guidance of the Supreme Leader’s Socialism with Chinese characteristics Thought in the new era, thoroughly study and implement the cultural thought of the Supreme Leader, focus on cultivating and practicing socialist core values, further promote the construction of socialist spiritual civilization, and gather the majestic strength of unity and struggle for the great rejuvenation of the Chinese nation.

　　Cultivating and practicing the socialist core values is the basic project to gather the spirit and strengthen the foundation.

　　The socialist core values are the concentrated expression of contemporary China spirit, which embodies the common value pursuit of all China people. Cultivating and practicing the socialist core values is an important task to uphold and develop Socialism with Chinese characteristics in the new era, and it is also an inevitable requirement to unite social consensus and enhance people’s spiritual strength. It is necessary to cultivate and practice the socialist core values, so that all the people can closely unite in ideals, beliefs, values and moral concepts, and constantly consolidate and develop the common ideological foundation for the United struggle of all the people.

　　An important way to unite social consensus. General Secretary of the Supreme Leader pointed out: "There are various values and orientations in any society. To unite the will and strength of the whole society, we must have a set of core values that are compatible with the economic foundation and political system and can form a broad social consensus." People’s heart is the biggest politics, and consensus is the driving force for forging ahead. Human society is in a period of great development, great change and great adjustment. All kinds of ideas and cultures around the world are stirring with each other, and our social ideas and concepts have undergone profound changes. Cultivating and practicing socialist core values and adhering to the guidance of socialist core values are conducive to correctly handling the relationship between main melody melody and diversity, consistency and diversity, effectively integrating social consciousness, striving for the greatest common denominator, drawing the greatest concentric circle, mobilizing all positive factors to the maximum extent, uniting all those who can unite, and maximizing the consensus and joint efforts of the whole society.

　　The inherent requirement of strengthening people’s spiritual strength. General Secretary of the Supreme Leader pointed out: "Socialist core values and Chinese excellent traditional culture are powerful forces to unite people’s hearts and gather people’s strength." To realize the great rejuvenation of the Chinese nation requires not only strong material strength, but also strong spiritual strength. Socialist core values are formed in the great practice of leading hundreds of millions of people to struggle for a long time. They have profound historical background and solid realistic foundation, profound nationality, distinctive times, inherent advancement and extensive inclusiveness. Cultivating and practicing the socialist core values will help us hold high the banner of ideals and beliefs, carry forward the national spirit and the spirit of the times, improve the ideological realm of the people, enrich the spiritual world of the people, unite the national will with common ideals and beliefs, and inspire China’s strength with the spirit of China.

　　An important support for maintaining the independence of national spirit. General Secretary of the Supreme Leader pointed out: "Cultivating and carrying forward the socialist core values and enhancing Socialism with Chinese characteristics’s road confidence, theoretical confidence, institutional confidence and cultural confidence are important supports for maintaining the independence of the national spirit." Core values are the spiritual ties that a nation depends on and carry the spiritual pursuit of a country and a nation. Only by standing up and standing firmly in spirit can a nation stand firm in the tide of history. In today’s world, exchanges and exchanges between different civilizations are more frequent. We must speed up the construction of a value system that fully reflects China’s characteristics, national characteristics and characteristics of the times, and strive to seize the commanding heights of the value system. Cultivating and practicing the socialist core values is conducive to strengthening our faith and confidence in our own value pursuit, consolidating cultural subjectivity, constantly strengthening the "four self-confidences" and standing among the nations of the world with a high degree of national pride and self-confidence.

　　Significant achievements have been made in cultivating and practicing socialist core values in the new era.

　　Thought is the forerunner of action, and theory is the guide of practice. General Secretary of the Supreme Leader pointed out: "It is necessary to strengthen the construction of the socialist core value system, actively cultivate and practice the socialist core values, comprehensively improve the moral quality of citizens, and cultivate a good fashion of knowing honor and disgrace, stressing righteousness, making contributions and promoting harmony." A series of important expositions by the Supreme Leader General Secretary provide a scientific action guide for cultivating and practicing socialist core values. Under the scientific guidance of the Supreme Leader’s Socialism with Chinese characteristics Thought in the new era, the construction of China’s socialist core values has been further promoted and achieved remarkable results.

　　The CPC Central Committee with the Supreme Leader as the core has taken a series of major measures to cultivate and practice the socialist core values. Give full play to the policy-oriented role, and successively formulate and issue a series of guiding policy documents such as Opinions on Cultivating and Practicing Socialist Core Values and Guiding Opinions on Further Integrating Socialist Core Values into the Construction of the Rule of Law. The socialist core values run through the daily situation propaganda, achievement propaganda, theme propaganda, typical propaganda, hot spot guidance and public opinion supervision, and run through the cultural activities and literary works that the people love, and actively promote the online promotion of socialist core values. Insist on cultivating people with socialist core values, promote socialist core values into textbooks, classrooms and minds, and strive to cultivate new people of the times who are responsible for national rejuvenation. Promote the integration of socialist core values into various spiritual civilization creation activities, and strive to draw rich nutrition from Chinese excellent traditional culture, so as to better cultivate the spiritual world of contemporary Chinese. Closely link the promotion of socialist core values with people’s daily lives, make efforts to implement them in detail, and strive to transform socialist core values into people’s emotional identity and behavior habits. We will continue to strengthen institutional guarantees, improve the codes of conduct such as citizens’ conventions, village rules and regulations, and student codes, integrate socialist core values into the rule of law, and promote the normalization and long-term promotion of cultivating and practicing socialist core values.

　　From advocacy to practice, from concept to action, the core values of socialism have been widely promoted, and the people’s ideological consciousness, moral standards and civilized accomplishment have been significantly improved. In the process of cultivating and practicing socialist core values, the exemplary role of advanced models has been fully exerted, the activities of mass spiritual civilization have been deepened, the construction of social morality, professional ethics, family virtues and personal morality has achieved fruitful results, the soft power of national culture and the influence of Chinese culture have been significantly improved, and the socialist core values have been internalized, externalized and educated to the public, giving full play to the important role of rallying social consensus and enhancing people’s spiritual strength. By cultivating and practicing the socialist core values, and constantly strengthening the spiritual calcium of the Chinese nation and the soul of rejuvenating the country in contemporary China, the "four self-confidences" of the whole party and people of all ethnic groups have been significantly enhanced and their mental outlook has become more energetic.

　　Give further play to the leading role of socialist core values

　　In the new era and new journey, there must be new weather and new actions. To build a socialist modern country in an all-round way and promote the great rejuvenation of the Chinese nation in an all-round way, we need to further play the leading role of socialist core values and let the people of all ethnic groups in the country think in one place and work hard in one place. We should adhere to the guidance of Socialism with Chinese characteristics Thought of the Supreme Leader in the new era, thoroughly study and implement the cultural thought of the Supreme Leader, focus on cultivating and practicing socialist core values, and gather stronger spiritual strength for the great rejuvenation of the Chinese nation.

　　Promote the normalization and institutionalization of ideal and belief education and build a common ideological foundation for the United struggle of people of all ethnic groups throughout the country. Vigorously carry forward the spiritual pedigree of the Communist Party of China (CPC) people with the great spirit of party building as the source, carry out publicity and education on the history of the Party, the history of New China, the history of reform and opening up, the history of socialist development and the history of the development of the Chinese nation, deepen the education of patriotism, collectivism and socialism, guide people to strengthen the "four self-confidences", and enhance their confidence and determination to stick to their common ideals and realize their common dreams. Strengthen the protection and utilization of red sites, revolutionary cultural relics and memorial facilities, make good use of communist party Historical Exhibition Hall and patriotism education base, and play the role of red tourism education. Make good use of the "fresh values" of advanced models, persistently publicize the revolutionary heroes, the model of the times, the moral model, the most beautiful figures, etc., and publicize the typical figures from all walks of life who study hard and dedicate themselves, and carry forward the power of example.

　　Grasp the key groups of young people and cultivate new people of the times who can shoulder the heavy responsibility of national rejuvenation. Guided by socialist core values, we should cultivate talents who can shoulder the heavy responsibility of the times, run socialist core values through basic education, higher education, vocational education and continuing education, innovate working methods, promote the integration of ideological and political education in universities, primary and secondary schools, and guide young people to buckle their first buttons and take the first step in life. Adhere to moral education and moral education as the first priority, cultivate innovative consciousness, encourage young people to be brave in hardships and dangers, unite and struggle, shoulder the heavy responsibility of the times to realize the great rejuvenation of the Chinese nation, and ensure that the party’s cause and the construction of a socialist modernization power will be followed by others.

　　Adhere to the rule of virtue and law, and integrate socialist core values into the whole process of rule of law construction and social governance. Constantly improve the legal and policy system to carry forward the socialist core values, improve the people’s awareness of the rule of law and moral consciousness, integrate the mandatory provisions of laws and regulations with the internal spirit of the socialist core values, and cultivate people’s legal beliefs and concepts of the rule of law. Strengthen the supporting role of morality in the rule of law, implement the civic morality construction project, lead the construction of social morality, professional ethics, family virtues and personal morality with socialist core values, improve the long-term mechanism of honesty construction, and create a social trend of advocating morality and doing good.

　　Promote the construction of socialist spiritual civilization and make socialist core values become people’s emotional identity and behavior habits. Insist on breaking and breaking at the same time, be guided by trees and establish rules, and resolutely resist, confuse and clarify the words and deeds of advocating money worship, hedonism and extreme individualism, and the phenomena of breaking through the bottom line of value, subverting moral cognition and violating public order and good customs. Adhere to the people as the center, optimize the selection and commendation activities of civilized cities, civilized villages and towns, civilized units, civilized families and civilized campuses, and improve the effectiveness of work. Innovate ways and means of spiritual civilization construction, enrich people’s spiritual and cultural life, and constantly satisfy people’s yearning for a better life. Integrating the socialist core values into all aspects of social development and social life has become people’s emotional identity and behavior habits. Let the socialist core values be as ubiquitous and ubiquitous as the air, become the common value pursuit of all the people, and become the code of conduct that the people use every day without knowing it.

　　(Written by: Xu Zhong Wang Qingjie)

[Original of Truck House] Because pulling agricultural and sideline products can enjoy high-speed and free policy treatment, many card friends are also more willing to pull green links, but we should keep our eyes open about pulling green links.

Since it is a "green channel", there must be many restrictions. It is impossible for all agricultural products to take the green channel. Recently, card friends in Shaanxi have suffered in this respect.

Recently, when a netizen dragged Apple through Shaanxi Ankang Expressway toll station, the toll collector said that the card friend’s vehicle could not enjoy the green channel treatment. Although the load of the vehicle met the requirements of Lutong, the toll must be paid in full.

Here, many card friends are puzzled. Ran He is listed in the catalogue of fresh agricultural products. Why does Ankang toll collector decide that the car apple does not belong to Lutong? Is this apple kicked out of the catalogue of agricultural products by Ankang?

The toll collector said that it is true that apples are green products, but the apples on the car have rotted in a large area and do not meet the definition of "fresh".freshIs the first condition to take the green link.Since you don’t meet the requirements, why can you enjoy green treatment?

The staff of Shaanxi Traffic and Transportation Service Hotline responded to the incident, saying that there is no dispute that apples belong to Lutong products. According to the on-site toll collector’s inspection, the apples loaded on the vehicle are all rotten apples, commonly known as "falling fruit". Therefore, even if the load of the whole vehicle is within the standard range, the cargo occupies more than 80% of the car volume, but because the fruits on the vehicle are rotting in a large area and are very stale, it is compliant not to let Lutong go.

The staff of Shaanxi Expressway Baihe Management Office introduced that enjoying the green channel policy refers to fresh vegetables and fruits, and the staff checked the vehicles, and the loaded goods (apples) had obvious rot.It does not meet the requirements of "liveliness" stipulated in the document, so it is feasible not to give green channel treatment.

According to the spirit of the document "Notice on Further Optimizing the Green Passage Policy of Fresh Agricultural Products Transportation" issued by the three ministries and commissions, fresh agricultural products enjoying the "green passage" policy refer to fresh vegetables, fruits, fresh aquatic products, live livestock and poultry, fresh meat, eggs and milk. If it is found that it is mixed or counterfeit and does not meet the policy requirements, it needs to be handled according to the regulations.

That is to say, the toll collectors have the right to inspect the vehicles carrying Lutong. As long as the loaded goods do not meet the requirements and specifications in the Catalogue of Fresh Agricultural Products, or the bearing quality does not meet the minimum load requirements of the documents, they are not allowed to take the green channel and must pay the toll.

● 　Postscript

Not all green products are green links. There used to be pineapple, pineapple and cherry cherries, but now there are fresh and rotten ones. I wonder what card friends think about the fact that rotten fruits are not green links. You can make your voice heard in the comments section. (Text/Wei Qingbo Source/Shaanxi Expressway Baihe Management Office)

---

---

1111 Super Shopping Carnival Feast, reduced by 100 at 599, sent to Kajia jackets at 1800, and found more good goods at Kajia Mall: https://j.youzan.com/k9OEp8.

CCTV News:Yesterday (October 4th), the reporter learned from China Railway Kunming Bureau Group Co., Ltd. that China-Laos Railway has sent 7.39 million passengers and transported 8.51 million tons of goods, including 1.54 million tons of cross-border goods. In September, 1.25 million tons of goods were transported, breaking the monthly record, and the number of goods increased from more than 100 in the early days to more than 1,200.

On October 3rd, China-Laos Railway "Lanmei Express" international freight train broke through 200 trains. The "Lan-Mei Express Line" has been favored by many cross-border enterprises since it was launched. It has expanded from an initial on-demand operation to a fixed operation at least three times a week, and the cargo transportation has covered Laos, Thailand, Myanmar, Malaysia, Cambodia and Singapore.

　　Cctv newsOn the evening of 25th local time, a snowstorm started from southern Wyoming and headed for central Colorado. At present, the snowfall has exceeded 30cm, and the gust speed has reached 72km/h.. Up to now, this winter storm has caused hundreds of flights to be cancelled at Denver International Airport in Colorado, and more than 1,000 passengers stayed overnight at the airport. Another interstate highway was closed due to snowstorm.

　　According to the National Weather Service, the storm will then cross Nebraska and Kansas eastward, bringing 15.2~30.5 cm of snowfall to the areas along the way. At the same time, the National Weather Service also said that another snowstorm, which started on the night of 26th local time, is expected to bring heavy snow to parts of the northwest Pacific coast and reach the snowstorm level in Oregon and northern California. As two snowstorms occurred during Thanksgiving, it is expected to disrupt the plans of tens of millions of Americans to travel during the Thanksgiving holiday. (CCTV reporter Xu Wei)

　　The benchmark interest rate for provident fund loans is 3.25%, which is a better choice.

　　The mortgage interest rate is lowered, and the cost of buying a house is reduced.

　　On May 20th, the central bank lowered the quoted market interest rate (LPR) of loans over five years by 15 basis points to 4.45%, which is the largest adjustment of LPR over five years since the establishment of the LPR mechanism in 2019. The data shows that, as far as the current mainland interest rate level is concerned, it is currently at a relatively low historical level. The adjustment of mortgage interest rate means that the monthly supply amount is reduced and the cost of buying a house is reduced. According to industry insiders, there are many things to pay attention to in the downward stage of interest rates, whether to buy a home or not, and how to apply for a more favorable mortgage interest rate.

　　Text/Figure Guangzhou Daily All-Media Reporter Liu Liqin

　　Pay attention to the agreed time line for handling loans when waiting for preferential interest rates.

　　Recently, with the downward adjustment of mortgage interest rate, the market is also undergoing subtle changes.

　　Miss Zhao recently bought a house to improve her residence. After paying the down payment, she negotiated with the sales department to apply for a mortgage. She found that there were many banks on site to provide consultation. One bank said that she could apply for a mortgage interest rate of 5.0%, while the other bank said that according to her stable work and strong income and repayment ability, she and her husband were confirmed as high-quality customers of the bank and could apply for a loan of 4.8%, that is, LPR plus 20 basis points.

　　Miss Zhao immediately decided to choose a bank offering a more favorable interest rate to handle the mortgage loan, but in the process of handling it, the LPR for more than five years was lowered to 4.45%, so the mortgage interest rate of Miss Zhao was finally set at 4.65%.

　　In fact, since the mortgage was loosened in November 2021, in the past six months, the national mortgage interest rate has dropped by more than 50 basis points, and some cities have dropped by 100 basis points.

　　The mortgage interest rate changed quite rapidly in May. As of May 28th, the average interest rate of the first home loan and the second home loan in 32 key first-and second-tier cities monitored by Kerui was 4.5% and 5.2%, respectively.

　　[suggestion]

　　Faced with the downward trend of mortgage interest rate, industry insiders said that buyers often communicate with several banks to choose banks that offer more favorable interest rates according to their own work income and repayment ability.

　　It should be noted that there is a certain time lag between the mortgage interest rate policy and the bank’s implementation, which also has an impact on some ongoing transactions. Recently, some property buyers have chosen to suspend the loan approval process and re-apply for more favorable interest rates in the face of lowered interest rates. Need to be reminded that buyers need to pay attention to the mortgage processing time agreed in the purchase contract. If the application time is too long to obtain interest rate concessions, there may be a breach of contract and losses. Therefore, it is best to confirm the approval time with the bank.

　　How many times can the couple borrow the provident fund?

　　Compared with commercial loans, the benchmark interest rate of provident fund loans is 3.25%, which is naturally a better choice. It is the third time for Mr. Li’s family to buy a house. Both of the two properties purchased in the early years used provident fund loans, one of which has been sold and the remaining one has been settled. Hearing that the provident fund can be used twice, Mr. Li was very surprised. Using the provident fund loan to buy a house again can save a lot of interest.

　　According to "Guangzhou Provident Fund Personal Housing Loan Measures", each paid employee can use provident fund loans twice, and the number of family housing units is "recognized" and "recognized", and differentiated down payment and interest rate policies are implemented. Then both husband and wife have paid the provident fund, how many times can they borrow it?

　　Mr. Li told reporters that they only knew through inquiry that one of the two previously purchased suites used his wife’s name to apply for provident fund loans, and the other was jointly applied by the two. After paying off the loan, Mr. Li still has a place to use the provident fund loan. This time, Mr. Li applied for a provident fund loan of 600,000 yuan.

　　The reporter consulted the Guangzhou Housing Provident Fund Management Center and learned that the husband and wife can theoretically borrow up to four times, but from the specific situation, some families do not need to borrow many times. Mainly depends on the family’s real estate and loan situation at the time of application.

　　If the husband has bought two suites, but he and his wife have never used the provident fund, he can still apply for provident fund loans twice as long as he sells both suites and has no real estate in the family name. If the loans of the two suites are paid off and sold, he can borrow again in the name of his wife.

　　The single-person provident fund loan amount is 600,000 yuan, and the double-person loan amount is 1 million yuan. In actual application, many people apply together in the name of husband and wife, so they can’t have four chances.

　　[suggestion]

　　Property buyers who have used provident fund loans can check the quota of provident fund loans through banks or provident fund management centers when applying for loans. If there are still quotas, they can use them as much as possible.

　　Whether it is cost-effective to repay the mortgage in advance needs comprehensive consideration.

　　Due to the downward trend of mortgage interest rate, the mortgage interest rate approved by some property buyers has been high. Even if the LPR is lowered, the plus point is unchanged. How to deal with it? Some people will choose to repay the loan in advance.

　　According to the social financing data released by the People’s Bank of China in February and April, the newly-increased medium-and long-term loans of residents are negative, which shows that some people are actively choosing to reduce their liabilities. At the same time, at the end of April, many banks lowered their deposit interest rates. Taking the four major state-owned banks as examples, they lowered the interest rate of three-year fixed deposits from 3.25% to 3.15%, and the interest rate of three-year certificates of deposit from 3.25% to 3.15%. Savings have increased, while the rate of return on low-risk assets has gradually declined, which has increased residents’ willingness to repay their mortgages in advance.

　　In the case that the approved mortgage interest rate is higher than the current mainstream interest rate, can I choose to repay the loan in advance?

　　According to the test case of Founder Securities Research Institute, in the upward cycle of real estate, if you buy a house in 2018 with a relatively high mortgage interest rate, you apply for a commercial loan of 1 million yuan, the loan period is 30 years, and the mortgage interest rate is 5.7%, and the first repayment is made in October 2018. If you choose to pay it off in one lump sum in October 2022 after four years of repayment, you will finally pay 949,400 yuan in the form of equal principal and interest.

　　If this 949,400 yuan is used for financial management, the annual income can reach 28,500 ~ 38,000 yuan with a yield of 3% ~ 4%. In contrast, the financial return rate is above 3.5%, so it is not cost-effective to repay in advance, and it is even more difficult to ensure that it is cost-effective at other times.

　　[suggestion]

　　According to insiders, due to different interest-bearing methods, it is not possible to simply compare the financial yield with the mortgage interest rate to measure whether it is cost-effective for residents to repay loans in advance, but to analyze specific problems. In addition to the mortgage interest rate and financial yield, it also needs to be evaluated by many factors such as repayment time, repayment method and repayment period.

On December 28th, some bloggers exposed more spy photos of M8, a brand-new model in the world, mainly showing the tail shape of the new car. According to the picture, the tail of the M8 is designed with a penetrating taillight, and the light strip forms a linear effect after lighting. After careful observation, we can find the overall outline of the taillight module, which is similar to the taillight shape of Jiejie M9. It is expected that Jiejie M8 will adopt the same design of Xinghe headlight as M9.

Later this month, the spy photos of the front face of the M8 were also exposed. This model uses a dark red body color scheme, with a rounded front face and split headlights, which continues the family-style design style. Although the pictures of the side and back of the vehicle are not clear, it can be seen that the design of the door handle is relatively flat, and it is expected to adopt a semi-hidden design.

According to previous reports, HarmonyOS Zhixing plans to sell more than 10 models next year, including the M5, M7, M8 and M9. Enjoy the extended range power version of S9, and the models are divided into extended version and travel version; Wisdom S7, r7; Zunjie S800 and the second model of Zunjie. According to the report, as a brand-new model, the Wenjie M8 will be launched in the first half of 2025, and one of its benchmarking roles is the ideal L9.

The exposure of spy photos of the M8 in the world of inquiry not only attracted great attention from the industry and consumers, but also indicated the further expansion of the brand of inquiry in vehicle layout. With the launch of M8, the product line of the brand will be more abundant, providing consumers with more choices. At the same time, the listing of the M8 will also intensify the competition in the medium and large SUV market, especially the competition with the ideal L9 equivalent model.

A few days ago, overseas media once again exposed the latest rendered pictures of a new generation of BMW 3 Series models. The new car is scheduled to debut in 2026 and will be put on sale in 2027. At the same time, a new generation of domestic 3-Series models is expected to be launched one after another in the same year, and the size will be upgraded and optimized, which is more advantageous than the current G chassis series models. The main competitors at the same level include mercedes benz c-Class, Cadillac CT5 and the upcoming A5L models.

According to the introduction of overseas media, BMW’s new generation of 3-series models will adopt many design elements of the current 5-series models, and the head is equipped with a brand-new LED headlight group. The two sides of the car body adopt the same design of 5-series models and provide hidden door handles. The rear part of the car is also equipped with a 5-series LED taillight group, and the hidden exhaust layout is selected below.

In terms of power, BMW’s new generation 3 Series fuel version will continue to be built on the CLAR platform, and 2.0T and 3.0T turbocharged models will be launched simultaneously for consumers to choose, and all of them will be adapted to the 48-volt light mixing system. The original M340i model will also be renamed M350i, the transmission system will be matched with the 8-speed automatic manual transmission, and some models will also be adapted to the four-wheel drive system. The new BMW i3 model will be built based on the new Neue Klasse architecture platform, and the single-motor and dual-motor four-wheel drive models will be launched simultaneously for consumers to choose, and the M3 pure electric model is also expected to be the first to be launched in 2025.

1905 movie network news People are never short of police comrades who "cut the demon and get rid of the demon" all the way like "Monkey King". Song Rukun, the Weifang Public Security Bureau, has been fighting in the front line of criminal investigation to crack down on serious violent crimes since he joined the company in 1997. He has participated in the organization and detection of more than 220 serious criminal cases and arrested more than 2,000 criminal suspects in various criminal cases, playing an indispensable and key role in detecting a series of serious and serious cases such as intentional homicide, kidnapping and robbery.

There is also such a "Sun Dasheng" in a movie to be released on December 21st. In the trailer of the "Demon-slaying and Demonizing" version, Sun Dasheng, a criminal justice policeman played by Wang Qianyuan, took the "the Monkey King" key chain in his hand and comforted the children whose father was bullied by evil forces in the canteen: "Uncle, it’s the police who specialize in catching bad guys." The next part of the trailer shows standing up for justice,

Sun Dasheng, who "killed the demon" all the way: In the old garage, facing the vicious gangsters with sticks, Sun Dasheng responded tactfully, flew over the car to avoid pursuit and fought fiercely with the gangsters; On the rooftop, on the way to hunt down Zhao Tai, a sinister rich second generation played by Bao Beier, he was violently blocked by Zhao Tai’s bodyguards, and Sun Dasheng mercilessly grabbed the gangster’s head and gave him a beating; In the square, Zhao Tai had no way to escape, but still insisted on resisting arrest. Sun Dasheng stepped forward to fight for his life, and he must carry out the "demon-cutting and demon-removing" to the end!

Those powerful "monsters" are not "big shots", but "big shots" should be those police comrades who "cut off demons and get rid of demons" all the way. It is precisely because these people’s policemen like Sun Dasheng fight to the end for justice and evil forces that people can enjoy a peaceful and harmonious life with peace of mind. I also hope that the police uncles can protect themselves and pay tribute to the people’s police in the process of eliminating evils!