[Expert Comments]

　　 Intangible heritage is an important part of excellent traditional culture. Protecting and inheriting intangible cultural heritage plays an important role in forging a solid sense of the Chinese nation’s community and enhancing cultural self-confidence. In December 2022, General Secretary of the Supreme Leader made important instructions on the protection of intangible cultural heritage, emphasizing the need to do a solid job in the systematic protection of intangible cultural heritage, better meet the people’s growing spiritual and cultural needs, and promote cultural self-confidence.

　　 According to the data of the Ministry of Culture and Tourism, up to now, there are 1,557 national intangible heritage projects and 3,062 national intangible heritage inheritors in China. There are 43 projects in China listed in the UNESCO Intangible Cultural Heritage List, ranking first in the world. China’s overall protection of intangible heritage has achieved fruitful results.

　　 Intangible heritage protection is not easy. Because intangible cultural heritage itself has no physical form, and it has to rely on live transmission, it has become very fragile in the rapid changes of society. It is often futile to protect intangible cultural heritage projects and inheritors. In this context, the concept of "cultural and ecological protection zone" came into being. The Measures for the Administration of National Cultural and Ecological Protection Zones, which was implemented in 2019, pointed out that national cultural and ecological protection zones refer to specific areas with the protection of intangible cultural heritage as the core and the overall protection of cultural forms with rich historical and cultural accumulation, good survival status, important values and distinctive characteristics, and approved by the Ministry of Culture and Tourism.

　　 Up to now, there are 16 national cultural and ecological protection zones in China. Cultural and ecological reserves bear the internal motivation and suitable environment for the formation and development of intangible cultural heritage. Building cultural and ecological reserves is an important practice to implement the systematic protection of intangible cultural heritage.

　　 The main protection contents of the cultural ecological protection zone are: first, to protect the intangible cultural heritage projects and representative inheritors; second, to protect the natural environment and human environment related to intangible cultural heritage; third, to protect and repair the cultural ecological system, and to maintain the balance of the cultural ecological system, so as to coordinate it with the regional natural ecological protection and economic and social development. To this end, we must adhere to the "two combinations" and build a cultural ecological protection zone that conforms to China’s national conditions, completely covers material and cultural heritage such as cultural relics protection units and historical and cultural cities, towns and villages, and takes intangible cultural heritage protection as the core. At the same time, it will link up national cultural parks and major national cultural engineering construction projects, activate the use of cultural heritage, and let intangible cultural heritage "see people, see things and see life".

　　 (Author: Zhou Jianming, a professor-level senior urban planner of China Urban Planning and Design Institute)

　　In view of the pronunciation of the place name Lu ‘an, Anhui Province, which caused controversy recently, the Division of Geographical Names of the Ministry of Civil Affairs gave an authoritative statement.

　　On May 15th, a netizen left a message on the portal of the Ministry of Civil Affairs asking about the pronunciation of the word "six" in Lu ‘an City, Anhui Province: "According to the phonetic notation of Lu ‘an City in the Administrative Division of the People’s Republic of China 2015, ‘ Luan Shi’ According to the latest edition of the administrative divisions of the People’s Republic of China, Lu ‘an City, Anhui Province ‘ Six ’ Has there been any change in the speech? Are you still studying for six (Lu) Ann? "

　　In this regard, on May 19, the Division of Geographical Names of the Ministry of Civil Affairs replied that in the "Administrative Division of the People’s Republic of China 2020", the pinyin of Lu’ an was "Lu’ an Shi”。

　　Located in the west of Anhui Province, Lu ‘an, commonly known as "West Anhui", is a regional central city in Dabie Mountain, a sub-central city in Hefei Economic Circle, a connecting city in Wanjiang City, an industrial transfer and radiation city in Yangtze River Delta, and a national land transportation hub city.

　　Recently, Lu ‘an City has attracted social attention due to the local COVID-19 epidemic, while its pronunciation has also caused controversy. In recent news programs broadcast by CCTV News Channel, many anchors read Lu ‘an as "Li Φ ā n", while in news programs of anhui tv and Lu ‘an Radio and Television Station, anchors still read Lu ‘an as "Li Φ ā n".

　　　　Citroen, an old French automobile manufacturer, mentions its proud C4. Some people will remember the chariot of Loeb, the champion driver of WRC Citroen team, and others will think of Sega, the main model of China C4 Dongfeng Citroen. Among C4 families with global sales of over one million, there is a C4 Coupe with low appearance rate in China. What is its strength? Yes, I didn’t know until the mule or horse "walked".

　　　　Citroen C4 Coupe’s three-door, five-seat hatchback design directly conveys the designer’s ideas to the world. It is full of personality but not publicity. In addition, its appearance frequency is not high, which makes it have a high turn-back rate, which makes many people look askance.

　　　　Compared with Sega, C4 Coupe’s family features show that they are of the same ancestry and have a "blood relationship" without looking at the second eye, but even the mistresses are not the same, not to mention that these two are only close relatives, and the difference is revealed in the "eyes". The size of C4 Coupe’s headlights and fog lights is delicate and smart, just as it is not only those with big eyes who are beautiful. The lines of the whole car are smooth, unlike most sports cars with sharp lines or rising waistlines, which is precisely the unobtrusive part of their personality.

　　　　The three-door hatchback is designed to show its sporty temperament. The VTS logo "Hot S" at the place where the cars are placed directly tells the theme, and the roof starts to slowly fall from the B-pillar and goes to the rear in one go. The sports tail at the tail is one of the highlights, and the 17-inch Ribalta aluminum wheel, as the second highlight, has a strong texture. These two details have made great contributions to highlighting its sports characteristics.

　　　　The size of the rear windshield and the rear body is just right, which not only takes into account a certain rear view, but also does not lose beauty. There is a saying that the taillights are arranged because of the limited space at the tail. From this point of view, the current taillight design is really a blessing in disguise, with a unique shape on the shoulders, which plays a good role in embellishing the overall beauty of the tail.

　

　　Since the beginning of this year, innovative pharmaceutical companies have gone out to sea again. Pharmaceutical companies such as Yaoming Bio, Maiwei Bio and Anrui Bio have announced that they have reached overseas authorized transactions. The insiders believe that intensive overseas authorized transactions fully prove that the R&D strength of innovative pharmaceutical enterprises in China has been recognized by international pharmaceutical companies. The ecological pattern of domestic biomedical industry is being reshaped, and the mode of cooperation with foreign pharmaceutical companies will be more diversified in the future. With the adjustment of industry structure, it is expected that 2024 will be a year in which transactions and mergers and acquisitions among pharmaceutical enterprises will become more frequent.

　　R&D strength continues to increase.

　　With the rapid development of the industry, the research and development strength of biomedical enterprises in China has been continuously enhanced. According to incomplete statistics, there were at least 120 overseas authorized transactions of innovative drugs in China from 2021 to 2023, with a total transaction amount of nearly $85 billion. In 2024, innovative drugs went out to sea to speed up. As of January 14th, domestic enterprises have completed more than 10 foreign authorization transactions, including many transactions exceeding 1 billion US dollars.

　　Genxi Bio has announced that AstraZeneca has completed the acquisition of the company. After the merger, Genxi Bio became a wholly-owned subsidiary of AstraZeneca. AstraZeneca previously said that the acquisition of Genxi Bio will further consolidate AstraZeneca’s strength in the field of cell therapy.

　　Since the beginning of this year, several products of Anrui Bio have obtained overseas authorization, including an exclusive option and a global license agreement with AstraZeneca, and the development and commercialization of a new allosteric inhibitor targeting the mutation of epidermal growth factor receptor (EGFR)L858R as a potential new treatment for advanced EGFR mutation non-small cell lung cancer (NSCLC). With the transfer agreement with Avenzo Therapeutics,Inc.(Avenzo) of the United States, Avenzo will gain the global (except Greater China) development and commercialization rights of a cyclin-dependent kinase 2(CDK2) selective inhibitor ARTS-021 independently developed by Anrui Bio, and another pre-clinical project will be submitted to IND (new drug clinical trial) in early 2025.

　　Ding Qiang, co-founder and CEO of Anrui Bio, said that through cooperation, the company can obtain significant economic benefits and accelerate the development and listing of innovative drugs.

　　Chen Kan, a partner of Qiming Venture Capital, said that the cooperation between Anrui Bio and foreign pharmaceutical companies all involved small-molecule drugs, which on the one hand proved Anrui Bio’s research and development strength, and on the other hand reflected that small-molecule drugs could also be "put out to sea".

　　In addition to well-known biotech listed companies, there have been an increase in overseas authorized transactions of small biotech companies such as Yilian Bio, Anrui Bio and Bowang Pharmaceutical, as well as traditional pharmaceutical companies such as Hengrui Pharma and Haosen Pharmaceutical.

　　In Chen Kan’s view, China pharmaceutical companies and overseas pharmaceutical companies have reached a heavy cooperation, reflecting the recognition of domestic new drugs by international pharmaceutical companies. At the same time, domestic pharmaceutical companies can get cash support. In the process of cooperation with large international pharmaceutical companies, including joint promotion of clinical trials, China Biotechnology Company can also learn a lot of experience.

　　Share risks and obtain resources.

　　Ding Qiang said that cooperation with overseas pharmaceutical companies should be based on comprehensive consideration of the company’s strategic objectives, research and development capabilities and market demand. The cooperation between the company’s two pipelines and AstraZeneca and Avenzo Therapeutics is based on comprehensive considerations. Drug R&D costs a lot and risks are high. Cooperation with large pharmaceutical companies can share risks to a certain extent, especially in clinical trials and marketing stages. In addition, cooperation with overseas pharmaceutical companies can obtain many resources, including funds and market channels, which is very important for accelerating product development and commercialization. Of course, cooperation needs to consider whether the goals of both parties are the same, whether they can support their long-term development strategy, and how to protect their intellectual property rights and avoid the loss of core technologies.

　　Sinopharm plays an important role in two overseas authorized projects reached by Anrui Bio. It is reported that Sinopharm is an innovative company focusing on helping domestic biomedical enterprises to authorize projects overseas. Ding Qiang introduced that Sinopharm provided the whole process service for the company, from the preparation and modification of materials, strategic analysis and optimization, to assisting Anrui to connect and communicate with potential partners, and to negotiate and negotiate relevant terms, which greatly helped the company to reach overseas authorization.

　　For pharmaceutical companies planning to "go out to sea", Jung Lee, senior vice president of business development of Sinogold Pharmaceuticals, suggested that China Biotechnology Company must ensure that the product lines are differentiated and meet the unfinished medical needs. In addition, setting up branches overseas can better understand the current biotechnology trends and cutting-edge scientific progress.

　　Ding Qiang said that enterprises planning to go to sea need to have the world’s leading scientific research strength and unique product innovation. At the same time, it is necessary to deeply understand the situation of potential partners, especially the pipeline layout and the overall strategy of the enterprise. Multinational pharmaceutical companies have their own strategic direction and different layouts in different fields of disease treatment. A deep understanding of the business scope, market strategy and corporate culture of their partners can help the two sides establish closer and more efficient cooperative relations. In the cooperation agreement, many terms and details need special attention, including key factors such as intellectual property ownership, economic sharing, milestone payment, etc. It is necessary to make legal risk assessment and compliance preparation in advance to ensure that the cooperation activities meet the requirements of local laws and regulations.

　　Watch the three subdivided tracks

　　Looking forward to 2024, Chen Kan judged that the number of pharmaceutical companies "going out to sea" in China will remain high. From the past transactions, the clinical data of pharmaceutical companies in China have gained more and more global recognition. Overall, we are optimistic about the three sub-segments of tumor, metabolism and autoimmune.

　　Chen Kan believes that it is necessary for most new drug R&D companies to "go out to sea", especially to develop some small varieties of new drugs that are less suitable for people. Drug pricing in overseas markets is relatively high, and pharmaceutical companies "going out to sea" can expand the market and improve the input-output ratio. The domestic pharmaceutical industry will improve in 2024.

　　From the perspective of cooperation modes, Chen Kan said that there are more and more cooperation modes for domestic and foreign pharmaceutical companies, including obtaining down payment through overseas authorization, acquisition and joint development. Jung Lee believes that more and more innovative drugs from China will go global, and there will be more transactions between China biotechnology companies and multinational pharmaceutical companies than before.

　　Great Wall Securities believes that the "going out to sea" mode of Chinese pharmaceutical enterprises is mainly based on overseas authorization. From January 1 to February 4, 2024, the amount of overseas authorized transactions in China reached 9.146 billion US dollars. In 2024, China’s pharmaceutical "going out to sea" is expected to explode.

State and municipal people’s governments, provincial committees, offices, departments and bureaus:

　　In order to thoroughly implement the spirit of "Several Opinions of the State Council on Promoting Foreign Trade to Stabilize and Improve" (Guo Fa [2016] No.27), actively respond to the complicated and severe situation facing foreign trade, reverse the continuous downward trend of foreign trade, and promote the stabilization and improvement of foreign trade in the province, combined with the actual situation in our province, we hereby put forward the following opinions:

　　First, make every effort to promote foreign trade to stabilize and improve.

　　(1) Intensify market development. Continue to consolidate traditional markets such as ASEAN, South Asia, the European Union and North America, vigorously explore emerging markets such as Oceania, Africa and South America, accelerate the expansion of national and regional markets along the Belt and Road, and gradually diversify the foreign trade market. Support all kinds of business associations and intermediaries to organize enterprises to participate in well-known exhibitions at home and abroad, and help enterprises meet customers, seize orders and open up markets. Give support to enterprises participating in large-scale exhibitions at home and abroad.(The Provincial Department of Commerce, the Department of Finance, and the Yunnan International Expo Bureau are respectively responsible for their duties.)

　　(2) Strengthening the role of an open economic development platform. Give full play to the policies and supporting advantages of export-oriented parks such as national economic and technological development zones, high-tech industrial development zones, comprehensive bonded zones, border economic cooperation zones, cross-border economic cooperation zones, and key development and opening-up pilot zones, promote the formation of a number of foreign trade transformation and upgrading bases with strong driving effects, obvious industrial advantages, distinctive features and perfect public service system, accelerate the transformation of foreign trade development mode, and improve the quality and level of foreign trade development. We will promote the construction of demonstration zones for the quality and safety of agricultural products exported at the county level, improve the quality and safety level of agricultural products, enhance international competitiveness, and promote the steady growth of agricultural products exports. Support the identified provincial-level foreign trade transformation and upgrading bases and county-level export agricultural products quality and safety demonstration zones. Promote the continuous operation of China-Europe trains, encourage enterprises to export products to Europe through China-Europe trains, reduce the comprehensive cost of enterprises, enhance the international competitiveness of our products exported to Europe, and expand the scale of exports to Europe. Give support to transport enterprises through China-Europe trains.(Provincial Department of Commerce, Development and Reform Commission, Agriculture Department, Finance Department, Industry and Information Technology Commission, kunming railway administration, Kunming Customs and Yunnan Entry-Exit Inspection and Quarantine Bureau are respectively responsible according to their duties)

　　(3) Promoting the coordinated development of foreign investment and foreign trade. Taking various development zones, industrial clusters, characteristic parks and special customs supervision zones as carriers, we will increase the investment attraction of large export-oriented projects, promote the undertaking of cluster and industrial chain projects, and improve the quality of foreign investment introduction. Actively guide foreign investment in biomedicine, advanced equipment manufacturing, new materials, modern logistics, food and consumer goods manufacturing, plateau-featured agricultural products, information, tourism culture and other fields, attract regional headquarters of multinational corporations and functional institutions such as marketing centers, procurement centers and logistics centers to settle in our province, and accelerate the cultivation of new foreign trade growth points.(The Provincial Department of Commerce and the China Merchants Cooperation Bureau are responsible for their respective duties)

　　(D) Play the role of "going out" to promote trade. Encourage our province’s advantageous enterprises and industries with surplus production capacity to invest in South Asia, Southeast Asia and countries and regions along the Belt and Road, integrate into the global supply chain by means of new establishment, mergers and acquisitions, and establish an international marketing network, export product service system and cross-border electronic commerce overseas warehouse. Support key enterprises to establish production bases and industrial parks overseas, strengthen international capacity cooperation, and promote the export of relevant equipment and products. Accelerate the infrastructure construction of interconnection with neighboring countries, support enterprises in our province to carry out international cooperation and project contracting for major projects, and drive the export of equipment, materials, products, technologies, standards and services in our province. Support the export of materials under overseas investment cooperation.(The Provincial Department of Commerce and the Development and Reform Commission are respectively responsible for their duties)

　　(5) Further expand imports. Implement the national import discount policy and further improve the import encouragement policy of our province. Expand the import of advanced technology, key equipment and spare parts, and scarce resource products in our province to promote industrial upgrading in our province. Stabilize the import of resource products, seize the opportunity of low import prices of bulk commodities, and steadily expand the import of resource products. Reasonably increase the import of consumer goods, expand the import of consumer goods such as fruits, grain and meat, and support the construction of designated ports for inspection and quarantine in places where conditions permit; Support the establishment of duty-free shops at ports to guide the return of consumption abroad. Accelerate the promotion of Yunnan PetroChina International Enterprise Company to obtain crude oil import qualification, crude oil sales and operation qualification and refined oil wholesale sales qualification, and carry out crude oil import business as soon as possible.(The Provincial Department of Commerce, the Development and Reform Commission, the Commission of Industry and Information Technology, the Department of Finance, Kunming Customs and Yunnan Entry-Exit Inspection and Quarantine Bureau are respectively responsible for their duties)

　　Second, consolidate the traditional competitive advantage of foreign trade

　　(6) Expand border trade. Study and formulate policies and measures to promote the development of border trade in our province, increase the transfer payment to border areas, ensure the implementation of policies to grassroots first-line areas and support the development of border trade. Focus on the export of key commodities such as mechanical and electrical products, electronic products, textiles and clothing, as well as the import of fruits, seafood, natural gas, crude oil, ore and other commodities and raw materials. Accelerate the introduction of measures for the management of border trade in our province, improve the construction of infrastructure such as supervision places, standardize the management of border trade, promote transformation and upgrading, and expand the scale of border trade.(The Provincial Department of Finance, the Department of Commerce, Kunming Customs and Yunnan Entry-Exit Inspection and Quarantine Bureau are respectively responsible for their duties)

　　(seven) to expand the scale of processing trade. Increase investment attraction, comprehensively apply fiscal, land and financial policies, and actively undertake industrial transfer. Taking advantage of the convenience of various open parks and the preferential policies and measures of the state to support the transfer of processing trade to the central and western regions, we will hold a promotion meeting on Yunnan’s processing trade investment environment in coastal areas such as the Pearl River Delta and the Yangtze River Delta, focusing on key areas such as mechanical and electrical products, non-ferrous metals, electronic products, textiles and clothing, toys and bags, biomedicine, etc., and "one-on-one" tracking and docking key enterprises and projects, and relying on the advantages of various places to implement accurate investment promotion. To study and formulate the implementation opinions on promoting the development of processing trade in our province, and give support to large-scale projects that have strong import and export driving ability and can promote the quality and efficiency of processing trade in our province in terms of land supply, factory rent, logistics and financing guarantee. Strive to create a national demonstration zone for gradient transfer of processing trade, and strive to increase the proportion of import and export of processing trade.

　　Cancel the examination and approval of processing trade business in the whole province, establish and improve the supervision system after the event, speed up the establishment of pilot supervision of goods in Honghe and Kunming comprehensive bonded zones, and give qualified enterprises the qualification of general VAT taxpayer on the premise of "fair tax burden and controllable risks". Processing trade enterprises can pay the land transfer price by stages in accordance with the contract, and the land for industrial projects with priority development and intensive land use determined by our province can be determined according to 70% of the corresponding standards of the land. Support processing trade enterprises in our province to participate in direct electricity trading. Do a solid job in the implementation of the relevant policies to reduce the social insurance premium rate in stages.(Provincial Department of Commerce, China Merchants Cooperation Bureau, Department of Finance, Department of Human Resources and Social Security, Department of Land and Resources, Kunming Customs, Provincial State Taxation Bureau, and the people’s governments of the states, cities, counties and districts shall be responsible respectively according to their duties)

　　Third, accelerate the cultivation of new advantages in foreign trade competition

　　(eight) to cultivate and introduce foreign trade comprehensive service enterprises. Accelerate the cultivation and introduction of a number of key foreign trade comprehensive service enterprises to provide comprehensive foreign trade services such as customs clearance, logistics, warehousing and financing for small and medium-sized micro-foreign trade enterprises. We will provide more convenient measures and services in customs clearance, inspection and quarantine, settlement and sale of foreign exchange, export tax rebate, export credit insurance and other links for the recognized provincial-level foreign trade comprehensive service enterprises, and reward those foreign trade comprehensive service enterprises that have made remarkable achievements in promoting the export growth of small and medium-sized enterprises. Further implement the classified management measures for tax refund (exemption) of foreign trade comprehensive service enterprises, and accelerate the establishment of a management model suitable for the development of foreign trade comprehensive service enterprises.(The Provincial Department of Commerce, the Department of Finance and the Financial Office, Kunming Customs, Yunnan Entry-Exit Inspection and Quarantine Bureau, the Provincial State Taxation Bureau and the Yunnan Branch of the Foreign Exchange Bureau are respectively responsible for their duties)

　　(9) Accelerate the development of cross-border electronic commerce. Earnestly learn from the experience of China (Hangzhou) cross-border electronic commerce Comprehensive Experimental Zone, accelerate the construction of cross-border e-commerce comprehensive service platform, cultivate key e-commerce enterprises, and support the construction of cross-border e-commerce innovation, design and research, platform construction, marketing and promotion, e-commerce incubation for small and medium-sized enterprises, warehousing and logistics, publicity and training and other comprehensive service systems. Support cross-border e-commerce platforms and enterprises that promote the substantial growth of foreign trade import and export. Strengthen communication and coordination, and strive for national approval of Kunming as the National cross-border electronic commerce Comprehensive Experimental Zone.(Provincial Department of Commerce, Industry and Information Technology Commission, Kunming Customs, Yunnan Entry-Exit Inspection and Quarantine Bureau, Provincial State Taxation Bureau, Kunming Central Sub-branch of the People’s Bank of China, and Kunming Municipal People’s Government are respectively responsible according to their duties)

　　(ten) actively strive for market procurement trade pilot. Strive for national approval of Kunming Luosiwan International Trade City to carry out market procurement trade pilot. By optimizing supervision and innovating foreign trade management and service system, we can effectively reduce business operating costs, improve foreign trade efficiency, further improve the development level of commodity markets, and promote the coordinated development of domestic and foreign trade. Encourage qualified States and cities to carry out market procurement trade pilot projects, provide convenience for merchants in South Asia and Southeast Asia, and expand product exports.(Provincial Department of Commerce, Kunming Customs, Yunnan Entry-Exit Inspection and Quarantine Bureau, Provincial State Taxation Bureau, Kunming Central Sub-branch of the People’s Bank of China, and the state and municipal people’s governments are responsible respectively according to their duties)

　　(eleven) vigorously cultivate independent brands of foreign trade. Establish export brand support and statistical system in our province, guide enterprises to strengthen brand building and improve export quality. Vigorously support enterprises in our province to explore the international market, and increase the brand cultivation and promotion in our province through high-level visits, product promotion activities, and participation in large-scale international exhibitions. Actively encourage foreign trade enterprises in our province to establish their own brands, encourage powerful enterprises to acquire foreign brands, vigorously support the brand promotion of export products in our province, and focus on cultivating regional and industrial brands in South Asia and Southeast Asian countries. Support enterprises to carry out foreign registration protection of trademarks and patents, deal with intellectual property disputes, adopt international product certification and other ways, and increase the promotion of Yunnan brands overseas. Support the cultivation and promotion of Yunnan export brands.(The Provincial Department of Commerce, the Department of Finance, and the Yunnan Entry-Exit Inspection and Quarantine Bureau are respectively responsible for their duties)

　　(12) Vigorously develop trade in services. Fully implement the opinions on promoting the development of service trade and accelerate the construction of service trade policy system. As soon as possible, the management measures for the identification of service outsourcing demonstration cities, demonstration parks and demonstration bases will be introduced, and the policy environment for service trade in our province will be continuously improved. Expand the opening of service trade in border areas and encourage foreign investors to invest in tourism, logistics and retail industries. Identify a number of provincial service outsourcing demonstration cities, demonstration parks, demonstration enterprises and key cultivation enterprises. Support the development of a number of leading enterprises in service trade, and focus on cultivating a number of potential service outsourcing cultural trade enterprises and key projects, enterprises and institutions in traditional Chinese medicine service trade.(The Provincial Department of Commerce, the Cultural Products Office, the Commission of Industry and Information Technology, the Health and Family Planning Commission and the Food and Drug Administration are respectively responsible for their duties)

　　Fourth, strengthen fiscal, taxation, finance and credit insurance support

　　(thirteen) increase financial support. Expand the scale of provincial foreign trade development funds and increase the support of financial transfer payments for foreign trade development. Focus on supporting the export of agricultural products, mechanical and electrical products, non-ferrous metals, phosphorus chemicals and other superior products and the import of advanced technologies, key equipment parts and products with scarce resources, encourage the construction of open economic development platforms such as foreign trade transformation and upgrading bases, export agricultural products safety demonstration zones and foreign trade comprehensive service platforms, vigorously develop new foreign trade formats such as market procurement trade and cross-border electronic commerce, and cultivate and promote Yunnan export brands. Governments at all levels should arrange certain funds to support the development of foreign trade in light of the actual situation. (The Provincial Department of Finance and the Department of Commerce, and the people’s governments at the state and municipal levels are respectively responsible for their duties)

　　(fourteen) to speed up the progress of export tax rebate. Strengthen the analysis, prediction, scheduling, implementation and assessment of the export tax rebate plan, and actively strive for the export tax rebate plan. Standardize the management of export goods correspondence, improve the pertinence of sending letters, and check and confirm the reply in time. Fully implement the classified management of export tax rebate, standardize the export tax rebate process, and improve the efficiency of export tax rebate. Under the premise of sufficient tax refund plan, the export enterprises shall declare the tax refund (exemption) that meets the requirements, complete the examination and approval within the prescribed time limit and complete the relevant tax refund (exemption) procedures to ensure timely and full tax refund.(Responsible by the Provincial State Taxation Bureau)

　　(15) Strengthen financial support. Increase financing support for enterprises with orders and benefits. Guide commercial banks to carry out bank-enterprise docking with key foreign trade enterprises, tailor international settlement and trade financing solutions according to the needs of enterprises, and help enterprises effectively control exchange rate risks. Improve the facilitation level of RMB settlement in cross-border trade, guide and encourage commercial banks to increase the innovation of business products, continuously introduce cross-border RMB settlement and trade financing products that meet the needs of the market, and guide enterprises to expand the settlement scale. Increase support for small and medium-sized enterprises through policies such as refinancing and rediscounting. Encourage commercial banks to carry out export tax rebate account custody loans, export credit insurance policy financing, foreign trade order financing and other businesses. Support the bank loans and guarantee fees used by foreign trade enterprises to carry out foreign trade.(The Provincial Finance Office, the Department of Finance and the Department of Commerce, and the Kunming Central Sub-branch of the People’s Bank of China are respectively responsible for their duties)

　　(sixteen) increase credit insurance support. Further expand the scale of short-term export credit insurance, and increase support for electromechanical and high-tech products, agricultural products, small and medium-sized enterprises and emerging markets. Support various insurance institutions to carry out export credit insurance business, and further reduce the rate of short-term export credit insurance. Expand the coverage of credit insurance, and realize the full coverage of export financing of large-scale complete sets of equipment.(Yunnan Insurance Regulatory Bureau, Provincial Finance Office and Department of Commerce are respectively responsible for their duties)

　　V. Optimizing the environment for foreign trade development

　　(seventeen) to further standardize the import and export fees. We will fully implement the list system of import and export link fees, and reserve the administrative fees related to import and export links and the operating and service fees set or guided by the government, and clarify the charging items, charging standards and management authority. Accelerate the market-oriented reform of import and export services, resolutely ban "red-top intermediaries" that rely on administrative organs and administrative power to provide compulsory services, break monopoly and form a fully competitive service market. Severely crack down on illegal charging behaviors such as compulsory service and charging only without service, increase the investigation and punishment of e-government platform charges, and conduct a comprehensive inspection of e-government platforms of customs, entry-exit inspection and quarantine, taxation, commerce and other departments. Actively promote the province’s comprehensive pilot project on exempting foreign trade enterprises from inspection without problems from lifting and shifting storage costs, and effectively reduce the burden on foreign trade enterprises.(The Provincial Development and Reform Commission, the Department of Finance, the Department of Commerce, the Commission of Industry and Information Technology, the Department of Transportation, Kunming Customs and Yunnan Entry-Exit Inspection and Quarantine Bureau are respectively responsible for their duties)

　　(eighteen) to improve the level of trade facilitation. Accelerate the construction of "three mutual" customs clearance at Yunnan port, improve the cooperation mechanism between customs and inspection, optimize the work of "one declaration, one inspection and one release", fully implement the "double random" reform, and gradually increase the proportion of non-invasive inspection and machine inspection. Accelerate the construction of port informatization, give full play to the function of Yunnan electronic port platform, and promote the construction of "single window" of international trade. Deepen the paperless reform of customs clearance operations, and realize paperless customs clearance throughout the customs area during the year. Further expand the pilot scope of direct release of export commodities, export customs clearance forms and paperless inspection and quarantine. Further optimize and adjust the inspection rate of import and export goods, and implement a low proportion of random inspection of import and export goods of customs credit system certification enterprises.(The Provincial Department of Commerce, the Department of Finance, the Department of Transportation, Kunming Customs, Yunnan Entry-Exit Inspection and Quarantine Bureau, and Yunnan Branch of the Foreign Exchange Bureau are respectively responsible for their duties.)

　　Sixth, strengthen organizational leadership

　　(nineteen) to strengthen the main responsibility. The people’s governments of all prefectures and cities should earnestly strengthen their leadership over foreign trade, attach great importance to the steady growth of foreign trade, conscientiously study and formulate supporting measures and methods to promote the steady growth of foreign trade in light of local conditions, strive to achieve a stable and positive foreign trade in our province, and ensure the completion of the foreign trade import and export objectives and tasks issued by the provincial people’s government.(Provincial Department of Commerce, state and municipal people’s governments shall be responsible for their respective duties)

　　(20) Strengthen supervision and inspection. Relevant departments at the provincial level shall, according to their respective functions and responsibilities, strengthen cooperation and coordinate to solve the difficulties and problems in the development of foreign trade in our province. The provincial government supervision room should strengthen supervision and inspection, and departments and regions that fail to implement foreign trade policies and work measures should intensify supervision and implement serious accountability to ensure that all policies and measures are implemented and achieved practical results.(Provincial departments, the provincial government supervision room in accordance with the responsibilities are responsible for)

　

Yunnan Provincial People’s Government

July 20, 2016

(This piece is publicly released)

　　Cctv news(Reporter Wei Junhao) As the first dictionary in China, how many words are included in Shuo Wen Jie Zi? How to build a bridge between ancient characters and later generations?

　　On February 20th, "Freehand brushwork in China — — Exploring the Origin of Chinese Characters ",the online theme propaganda interview group entered the Xu Shen Cultural Park in Luohe City, Henan Province, to see how Xu Shen, the sage of Chinese characters, explained Chinese characters and opened the door to Chinese characters.

　　In September 121 AD, Xu Chong, the son of Xu Shen, a famous Confucian scholar and philologist in the Eastern Han Dynasty, presented Shuo Wen Jie Zi to Emperor Han An. China’s first dictionary came out.

　　This book, which took Xu Shen’s life’s efforts, has 15 volumes, including 9353 words, 1163 "tautology" (i.e. variant characters), and 133441 words for explanation and explanation. Zhang Han, deputy director of Xu Shen Cultural Research and Protection Center, said that Xu Shen put the original scattered Chinese characters into 540 radicals by analyzing the font structure, and created a dictionary compilation method with radicals as the command, which made the shape, sound and meaning of Chinese characters tend to be standardized and unified.

　　Since then, there has been a unified standard and norm for Chinese character writing, both official and folk, which has been followed by future generations and has been used to this day.

　　According to reports, the earliest writing system in China, represented by Oracle Bone Inscriptions, has undergone profound changes for thousands of years and has written a profound history of Chinese civilization, among which Shuo Wen Jie Zi played an important role.

　　Shuo Wen Jie Zi has also become the first most authoritative Chinese dictionary in China. It is highly praised by emperors and literati in previous dynasties for its ladder and bridge to study pre-Qin characters. After reading this book, Zeng Guofan in Qing Dynasty spoke highly of it: "Xu Shu has only 200 words, and the ancient mirror has swept away the dust for thousands of years. Seal script has become popular, and the explanation is especially refreshing. The old Confucianism in Ganjia is elegant and elegant, and the strict section in the southeast is unparalleled. " After reading this set of Shuowen Jiezi, you will be familiar with the history of languages for thousands of years.

　　Xu Shen was also honored as "the sage of Chinese characters" and "the master of Chinese characters" by later generations. Today, more than 1000 years later, in order to carry forward Xu Shen culture and inherit Chinese character civilization, Luohe, the hometown of Zisheng, has built Xu Shen Cultural Park, a national 4A-level cultural tourist attraction, held many international seminars on Xu Shen culture, organized and carried out projects such as Xu Shen culture entering the campus, family and community all the year round, started the construction of a famous Chinese character cultural city, and promoted Chinese characters and Xu Shen spirit with the help of the whole city.

　　The market is concerned about the recovery of offline retail.

　　The long-lost () recently attracted great attention from the market because of a cooperation news.

　　On May 8, Yonghui Supermarket’s share price went up by a daily limit, closing at 2.62 yuan that day, with a total market value of 23.7 billion. However, one day later, at the close of May 9, its share price fell back to 2.55 yuan/share, down 2.67%.

　　In the news, on May 7th, Yu Donglai, the chairman of Fat Donglai, appeared in Yonghui Supermarket in Zhengzhou, Henan Province. At the closed meeting after this visit, Yu Donglai made a decision and started to help and reform Yonghui Supermarket.

　　In this regard, the relevant person of Yonghui Supermarket told 21st century business herald that "we are learning from Fat East now, and the company will put performance first, so it is not convenient to disclose the progress of assistance".

　　As two major supermarket brands born out of low-tier cities, Yonghui and Pangdonglai have similar growth genes. However, when Yonghui made great strides in the first-tier market in the past two decades, Pangdonglai chose to deepen the Henan market and became popular on social networks with high cost performance and "meticulous service" last year. This cooperation between the two has once again strengthened the market’s expectation for the recovery of offline retail.

　　Zhu Danpeng, a senior researcher at China Food Industry Research Institute, said in an interview with 21st century business herald that the offline retail consumer market in China has entered a diversified and multi-level node, and the market must use multiple formats to meet and match the core needs and demands of consumers. "Some people talk about cost performance, some talk about quality and price ratio, some talk about brand tonality, some talk about differentiation, and some talk about high quality." Zhu Danpeng said that the advantage of Fat East is actually an extension of the "five-plus strategy" of multi-brand, multi-category, multi-scene, multi-channel and multi-consumer groups, which can better meet the diverse needs of Chinese people. Help Yonghui Supermarket and BBK

　　21st century business herald reporter learned that the two start-up stores of Fat Donglai are Yonghui Supermarket Hanhai Beijindian Store and Xinxiang Baolong Plaza Store, and the renovation work is expected to start at the beginning of June and the end of June respectively. In the process of helping the reform, the team from Fat Donglai will be responsible for leading the management work, and Yonghui Supermarket will also set up a special "Yonghui Supermarket Reform Team" to cooperate with and support the smooth progress of the whole reform work.

　　In terms of specific transformation measures, referring to the previous adjustment and reform of BBK by Fat Donglai, it mainly involves three aspects: adjusting the layout of stores to provide more convenient and smoother shopping routes; Adjust commodities to provide first-line brand commodities with better quality and more reasonable price; Improve the treatment of employees and stimulate their heartfelt sense of service.

　　According to relevant media reports, for the adjustment and reform of Yonghui, first, in terms of merchandise in the store, we will comprehensively refer to the commodity structure of Pangdonglai, focusing on Yonghui’s existing supply chain system, with Pangdonglai as a structural supplement to greatly improve the quality of goods. Second, it will improve the salary of Yonghui-related store employees and shorten working hours.

　　The adjustment and reform will focus on the team management of Pangdonglai, with Guan Na, the general manager of Pangdonglai Supermarket, and Wang Ming, the general manager of Pangdonglai Xinxiang as the two places. Zhang Xuansong, the chairman of Yonghui Supermarket, is located in Zhengzhou, and transferred the national elite to form the "Yonghui Supermarket Adjustment and Reform Team" to cooperate with the on-site adjustment and reform.

　　However, it is worth noting that it seems more realistic to interpret the cooperation between the two companies as "mutual benefit" than the outside world’s belief that Fat Donglai unilaterally "helped" Yonghui Supermarket. As Yonghui Supermarket, which is known for its advantages in supply chain, it is natural to make up for its own shortcomings in store design and operators while its business situation is improving.

　　According to the report of Yonghui Supermarket in the first quarter of 2024, in the first quarter of 2024, Yonghui achieved an operating income of 21.665 billion yuan, an increase of 30.87% from the fourth quarter of 2023; The net profit of returning to the mother reached 736 million yuan, a year-on-year increase of 4.57%; The net profit of returning to the mother after deduction was 599 million yuan; The weighted average return on equity reached 11.68%, an increase of 2.58 percentage points. In 2023, Yonghui achieved a revenue of 78.642 billion yuan last year, a year-on-year decrease in net profit attributable to its mother of 1.434 billion yuan, and a cash flow from operating activities of 4.569 billion yuan.

　　In fact, this is not the first time that Fat Donglai has replicated and promoted his own business model.

　　From March 31st to April 2nd this year, at the invitation of Wang Tian, the founder of BBK, Yu Donglai led a senior management team to Hunan to start the adjustment and rectification of BBK. As the first modified store, BBK Meixihu Store has made a comprehensive adjustment from the aspects of store layout, product structure, quality and price, environment and personnel service.

　　According to public information, before the reform, the store had an average daily sales of about 150,000 yuan and an average daily passenger flow of 2,000 people. On the first day of the reform, the sales reached 210,000 yuan and the passenger flow reached 4,200. On April 20th and 21st, the store’s sales exceeded 1.42 million yuan for two consecutive days. On the first day of the May Day holiday, the store sales reached 2.4 million yuan, and the sales passenger flow reached 17,700.

　　In addition to BBK after the "explosive reform", there are all kinds of self-owned brand products from Fat East to attract consumers to the store. According to Cailian News Agency, on April 11th, online celebrity’s "Big Moon Cake" was sold out soon after the sale. On April 12th, Fat Donglai’s own brand products, such as DL brewed wheat beer, DL fruit juice and DL free-love liquor, were put on the shelves one after another, and were also quickly snapped up. "Fat East" mode

　　Pang Donglai was once called "the existence of China retail industry" by Lei Jun.

　　According to public information, Pangdonglai Trading Group Co., Ltd. was established in 1997, and has never carried out large-scale chain expansion. Due to years of deep cultivation of services and products, and not excessive pursuit of scale exaggeration, Pangdonglai has become a representative of the supermarket industry. At present, its stores are only opened in Xinxiang and Xuchang.

　　However, at the moment when physical retail is facing difficulties, Fat Donglai is living very well. According to Yu Donglai’s introduction, Fat Donglai’s revenue in 2023 is estimated to exceed 10 billion, with a tax revenue of 300 million to 400 million and a profit of 300 million to 400 million.

　　Previously, when asked why he didn’t open a shop in Zhengzhou, Yu Donglai explained that compared with Xuchang, Zhengzhou’s store cost and employee benefits were much higher, so it was not suitable for copying.

　　Regarding the question of "can’t leave Henan", he also responded in an interview: "Fat Donglai wants to be an example and let more people learn, not how many companies he wants to be, and he has not left the concept of Henan."

　　In fact, the "password" of Fat Donglai, which lasted for many years and became popular on the Internet in the near future, is also hidden in the refined service and warm corporate culture.

　　Previously, because of service problems, the management staff of Fat Donglai were all demoted for three months, and they came to apologize for customers with gifts and 500 yuan Service Complaint Award.

　　But at the same time, Fat Donglai is also very protective of employees. It stipulates that customers’ rights and interests can be fed back through complaint channels, but they can’t yell at employees at the scene. This is a serious act that hurts personality and dignity. Where is the offline retail going?

　　In fact, in the eyes of the industry, the capital market’s violent reaction to Fat Donglai’s help to Yonghui Supermarket, in addition to individual stock factors, implies more expectations for the supermarket format to get out of the current predicament.

　　Previously, Shanghai Chengchao’s parent company "Shanghai City Supermarket Co., Ltd.", which had been deeply cultivated in Shanghai for more than 20 years, suddenly announced its closure. According to the "Notice" issued by Shanghai City Supermarket, the operation of Shanghai City Supermarket has been difficult in recent years, and it is still difficult to continue despite various self-help measures. Therefore, it was decided to dissolve and stop the operation of all stores in Shanghai City Supermarket from April 16, 2024.

　　Shanghai City Supermarket, established in 1995, deals in local delicacies all over the world, more than 80% of which are imported goods. It was once one of the largest imported food and daily necessities supermarkets in Shanghai and even the Yangtze River Delta. Due to the focus on high-end imported boutique supermarkets, Shanghai City Supermarket’s stores in Shanghai, such as Shangcheng Store, Jinqiao Store, Lianyang Store and Tianshan Store, are all located in the traditional "high-end residential area".

　　However, in today’s developed e-commerce, the high-input mode of selling imported goods has not helped Shanghai Chengchao to form a differentiated advantage, but has led to unprecedented difficulties in its operation.

　　According to an interview with its founder Cui Yixiong in 2016, Shanghai Chengchao has more than 20,000 products, of which more than 8,000 products are directly purchased from abroad, and its sales account for more than 60% of the total sales. In order to ensure the quality, Shanghai Chengchao has set up direct agricultural bases in Pujiang, Maqiao, Huacao and Huating, Hainan and Yunnan in Shanghai since 1997, and even the employees, feed and seeds used in them are directly controlled by the company. In addition, the company has established direct production bases and logistics.

　　A consumer said that the earliest contact with imported food began in Shanghai city supermarket. Although the price was a bit high, the product quality was not bad. "Later, imported food was available everywhere, so I wouldn’t go to the city supermarket specially."

　　The closure of Shanghai city supermarkets is not a case. According to incomplete statistics, in the first quarter of 2024, at least 31 supermarket brands and more than 140 stores in China closed down, involving well-known brands such as Wal-Mart, RT Mart, Yonghui, Wumei, over the rainbow Supermarket, Boxma Xiansheng and CP Lotus. Among them, there are also some first stores in cities or regions, such as the first store of Wal-Mart in Nanjing, the first store of Yonghui in China, the first store of Fuzhou Pingxi, and the first store of Zhuji in wu mart.

　　Pei Liang, president of China Chain Store & Franchise Association, pointed out to 21st century business herald that the core reason why offline supermarkets in China are in trouble at present is that the production end and brand end of China are too strong, and the client is slightly weak.

　　"China is the largest production base of FMCG in the world, and brands have very rich choices in channels. They can sell their products through e-commerce platforms and other channels. Retailers in Europe and the United States are very strong, occupying a great voice in the channel, so its dominant market position can ensure that it takes the initiative in the development and sales of its own brands, but this is particularly difficult in China. This is determined by the different national conditions and environments of the two places. " Yan Liang said.

Yet we called and urged a thousand times before she started toward us! The second model of Xiaomi Auto, YU7 (pronounced Y-U-7), was officially announced, positioning a pure electric SUV, and it is expected to be officially launched to the market during June and July 2025.

The body size of YU7 is 4999mm long, 1996mm wide and 1600mm high, with a wheelbase of 3000 mm.. The styling design continues the SU7 style, especially the details such as the front contour, headlights and taillights, which are the "family" characteristics of Xiaomi.

According to the application information, YU7 will be adopted. The peak power of the front and rear motors is 220kW and 288kW respectively, and the top speed is as high as 253km/h with Contemporary Amperex Technology Co., Limited.

Tyre size has two options, the basic version is 245/55 R19 and then 245/50 R20, and the front rim is small and then large. Optional upgraded version of the front 245/45 R21 and rear 275/40 R21 specifications, the rim size is the same, but the front is narrow and the rear is wide, which is a typical sports orientation. The brake disc is perforated and ventilated, and the front wheel is equipped with Brembo four-piston calipers.

Combined with the official map and some information previously exposed, we can see the detailed design adjustment and partial configuration of YU7. Comprises a headlight without a lampshade design, and the upper part is changed into a hollow air inlet; Unique black layered wheel arch; Full-coverage front cover and hidden inner button door handle, etc., these details are "heart to heart" with Ferrari.

The black bump on the lower edge of the front windshield may be integrated with a wrap-around HUD. Previously, a test car was photographed with a similar configuration. There is a camera on the B-pillar, which is likely to be a smart driving sensor, or the supporting face will be unlocked.

Lei Jun said that the reason why it will not be listed until the middle of next year is because a lot of road tests are still needed. After the appearance is announced, the body camouflage can be removed, making the test more comprehensive and detailed.

During the first half of next year, it is very likely that Tesla’s new version of Huan will be officially launched, when the two cars will face direct competition. Do you think Xiaomi’s new car sales can surpass Tesla’s? How much will you start pricing this car? Leave your opinion in the comments section.

　　Good morning, listeners! Today is Friday, October 18th, and the 14th day of the ninth lunar month. Beijing is cloudy, 17 degrees to 10 degrees. The following is the executive summary:

　　Top leaders meet with Australian Governor-General Braez;

　　Li Keqiang met with Australian Governor Braez and Tanzanian Prime Minister Pindar respectively;

　　Zhang Gaoli meets Russian guests;

　　The State Council and the Central Military Commission approved the "Measures for the Employment and Resettlement of Military Dependents", and five channels ensured the full employment of military dependents.

　　Beijing passed the Emergency Plan for Heavy Air Pollution, and the Beijing-Tianjin-Hebei Environmental Meteorological Forecasting and Early Warning Center was established in Beijing.

　　Hangzhou takes the people’s livelihood issues that the masses are most concerned about as the first priority, and develops the Party’s mass line education practice activities in depth.

　　The following are the details:

　　Top leaders meet with Australian Governor-General, stressing trust and win-win situation.

　　Beijing, October 18 (Reporter Wen Fei) According to the Voice of China News and Newspaper Summary, the supreme leader of president met with Australian Governor-General Braez in the Great Hall of the People yesterday (17th). The Supreme Leader said that China and Australia are good friends and partners. In recent years, relations between the two countries have developed rapidly and a strategic partnership has been established.

　　As important countries in the Asia-Pacific region, China and Australia have increased common interests and expanded space for cooperation. The two sides should start from a strategic and long-term perspective and jointly create a new situation of friendly cooperation between China and Australia in the spirit of mutual trust and mutual benefit.

　　The supreme leader said that in the next stage, China and Australia should fully tap their potential, create conditions and inject new impetus into China-Australia relations. First, mutual understanding and accommodation, showing flexibility, and promoting an early breakthrough in bilateral free trade agreement negotiations; Second, actively expand cooperation in emerging fields such as energy resources, infrastructure construction, financial services, energy conservation and environmental protection, clean energy, biomedicine, etc., and realize the diversified development of economic and trade cooperation between the two countries; Third, further close exchanges and cooperation in the humanities fields such as education, tourism, science and technology, and youth, so as to enhance mutual understanding and friendship between the two peoples; The fourth is to further strengthen coordination and cooperation within multilateral mechanisms such as the United Nations, the G20 and APEC. The Supreme Leader welcomed Braez to China to attend the 14th China Western International Expo, saying that the development of western China is the new engine of China’s economic growth and will bring broad opportunities to all countries in the world, including Australia. China welcomes more Australian enterprises to invest in western China and achieve common development.

　　Braez expressed his willingness to play complementary advantages with China, expand mutually beneficial cooperation, reach an Australia-China free trade agreement as soon as possible, strengthen cooperation with western China, and strengthen people-to-people exchanges and coordination and cooperation in international and regional affairs.

　　Prior to the meeting, the Supreme Leader held a welcoming ceremony for Braez in the square outside the East Gate of the Great Hall of the People.

　　Li Keqiang met with Australian Governor and Tanzanian Prime Minister respectively.

　　Beijing, October 18 (Reporter Feng Yue) According to the Voice of China News and Newspaper Summary, Li Keqiang, Premier of the State Council of the People’s Republic of China met with Australian Governor Braez and Tanzanian Prime Minister Pindar who came to China to attend the 14th China Western International Expo yesterday (17th).

　　When meeting with Braez, Li Keqiang said that in April this year, China and Australia established a strategic partnership and an annual meeting mechanism between prime ministers, which became a new milestone in bilateral relations. I hope that the two sides will strengthen exchanges and cooperation in the fields of trade and investment, energy resources, education and humanities.

　　Li Keqiang said that Australia is actively upgrading its infrastructure and has conducted a feasibility study on building Australia’s first high-speed rail. China high-speed rail is advanced in technology, safe and reliable, and has cost advantages. I hope the two sides will explore cooperation in this regard. Li Keqiang welcomes more Australian enterprises to actively participate in the development of western China.

　　Braez said that Australia attaches importance to its relations with China and is willing to speed up the negotiation process of the bilateral free trade zone with China and strengthen personnel exchanges, so as to achieve greater development of bilateral relations.

　　When meeting with Pindar, Li Keqiang said that next year will mark the 50th anniversary of the establishment of diplomatic relations between China and Tanzania, and China is willing to implement major project cooperation with Tanzania and continuously promote the comprehensive cooperative partnership between the two countries. China will continue to provide assistance to Tanzania within its capacity, and hopes that Tanzania will provide necessary facilities and support for the development of China enterprises in the region.

　　Pinda said that Tanzania admires China’s great achievements in development and is willing to learn from China’s experience, strengthen cooperation with China within the framework of the Africa-China Cooperation Forum and play a positive role in the development of Africa-China relations.

　　After the meeting, the two prime ministers attended the signing ceremony of a series of cooperation documents on bilateral diplomacy, economy and trade, science and technology, tourism and agriculture.

　　Zhang Gaoli met with Russian oil company President Xie Qin at Diaoyutai State Guesthouse.

　　Beijing, Oct. 18 (Reporter Liu Yulei) According to the Voice of China News and Newspaper Summary, Zhang Gaoli, Vice Premier of the State Council, met with Xie Qin, Secretary General of the Russian President’s Energy Development Strategy and Ecological Security Committee and President of Rosneft, at the Diaoyutai State Guesthouse yesterday.

　　Zhang Gaoli said that energy cooperation is an important part of China-Russia comprehensive strategic cooperative partnership. In recent years, with the vigorous promotion of the two heads of state and prime ministers, energy cooperation between the two countries has developed rapidly. The meeting is to prepare for the upcoming 18th regular meeting between Chinese and Russian prime ministers. It is hoped that the two sides will make joint efforts to give full play to their complementary advantages in geography, resources, market and technology in accordance with the cooperation consensus reached by the two heads of state, and promote the continuous progress of bilateral cooperation in oil, natural gas, nuclear energy, coal, electric power and new energy, so as to better promote the sustained and healthy development of the two economies. Xie Qin said that China is a reliable strategic energy partner of Russia, and Russia will be firmly committed to expanding and deepening all-round energy cooperation with China.

　　Mongolian Prime Minister Altanhuyag will visit China at the invitation of Li Keqiang.

　　Beijing, October 18 (Reporter Jiao Ying) According to the Voice of China News and Newspaper Summary, at the invitation of Li Keqiang, Premier of the State Council of the People’s Republic of China, Mongolian Prime Minister Norobyn? Altanhuyag will pay an official visit to China from 22nd to 26th.

　　The State Council and the Central Military Commission approved the Measures for Employment and Resettlement of Military Dependents.

　　Beijing, Oct. 18 (Reporter Li Yan, Chen Xin) According to the Voice of China News and Newspaper Summary, the State Council and the Central Military Commission recently approved the Measures for the Employment and Resettlement of Military Dependents by Ministry of Human Resources and Social Security, the General Staff Department of the People’s Liberation Army and the General Political Department, which comprehensively standardized the definition of the scope of military dependents and the principles of resettlement, and set up five channels for the first time to provide classified resettlement for military dependents to ensure full employment.

　　The main contents of the measures include: civil servants who were on-the-job before joining the army should be placed according to the principles of territorial management, professional counterparts and local proximity, and within the scope of the number of posts, according to relevant regulations; Before joining the army, it was the staff of institutions. According to the principle of territorial management, professional counterparts and local proximity, the resident people’s government supervised all institutions to take out some positions in the establishment for targeted recruitment; Survivors of martyrs, survivors of soldiers who died in the line of duty, and dependents of soldiers who won second-class merit awards in wartime need to be placed in employment, and the local people’s government should give priority to placement.

　　The Measures shall come into force on October 8, 2013, and the Armed Police Force shall implement them accordingly. Please pay attention to today’s "News Horizon" program for details.

　　Beijing passed the "Emergency Plan for Heavy Air Pollution". When it is seriously polluted, it will be restricted.

　　Beijing, October 18 (Reporter Randy Du Ximeng) According to the Voice of China News and Newspaper Summary, the Standing Committee of Beijing Municipal Committee recently adopted the Emergency Plan for Heavy Air Pollution in Beijing. When heavy air pollution occurs, Beijing will take emergency measures such as limiting the number of motor vehicles and stopping production of industrial enterprises to slow down the pollution level.

　　As the most powerful emergency plan for heavy air pollution in Beijing so far, the plan divides heavy air pollution into four warning response levels, which are blue, yellow, orange and red in turn from light to heavy.

　　The highest level of "red warning" means that it is predicted that there will be "seriously polluted" weather in Beijing for three days in the future. Serious pollution means that the ambient air quality index AQI reaches more than 300. When a "red warning" is issued, Beijing will impose a single and even number limit on motor vehicles according to the tail number of the license plate. Official vehicles of party and government organs at all levels in Beijing will be stopped by 30% on the basis of single and even numbers. Give play to the exemplary role of official vehicles.

　　Beijing citizens: "To support this policy, the first thing is to support the government and central enterprises to use cars, and their restrictions have been completed. This is correct."

　　It is estimated that the passenger flow of public transport in Beijing will increase by 2 million passengers after the implementation of motor vehicle single and double number restrictions in severely polluted weather. Beijing public transport plans to increase the number of operating trains by more than 20,000, and the night stop time of rail transit will be delayed by half an hour to ensure citizens’ travel. At the same time, Beijing will notify the public in advance through radio, television and other channels 12 hours before the odd and even numbers are restricted, so the public need not be too anxious. Beijing residents expressed their willingness to do their part for Beijing’s environmental protection.

　　Beijing citizen: "I support that I am willing to do my part for Beijing’s environmental protection or smog days."

　　Wang Yuesi, a researcher at the Institute of Atmospheric Research, China Academy of Sciences, said that local motor vehicle pollution accounts for one-third of the total pollution in Beijing, and imported pollution sources account for two-thirds. Although the effect of slowing down pollution by stopping motor vehicles will not be "immediate", it will definitely alleviate it.

　　Wang Yuesi: "The effect of mitigation is definitely there. When all pollutants are formed, foreign pollutants are initiators, and there are a large number of foreign ones, which are strengthened by local motor vehicles."

　　According to Beijing’s emergency plan for heavy air pollution, Beijing has also stopped production of some industrial enterprises, some earthwork and construction sites, stopped setting off fireworks and firecrackers, stopped operating open-air barbecues, and strengthened the "six stops and one rush" measures for roadside cleaning to slow down the degree of heavy pollution.

　　In recent years, with the adjustment and upgrading of the capital’s economic structure and energy structure, the pace of adjusting and clearing polluting enterprises in Beijing has obviously accelerated. This year, Beijing will complete the goal of quitting 200 polluting enterprises, which is the sum of the relocation and adjustment of polluting enterprises in Beijing from 2002 to 2007. From this year to 2016, Beijing will adjust and withdraw from 1200 polluting enterprises. Wang Chunlin, director of pollution prevention department of Beijing Environmental Protection Bureau, said that the proportion of industrial pollution in Beijing’s pollution is getting lower and lower.

　　Wang Chunlin: "Through our preliminary scientific research, industrial pollution accounts for less than 20% of atmospheric pollution, only 15%-16%."

　　At the same time, Beijing has announced the Clean Air Action Plan, which is phased and step by step to ensure the improvement of Beijing’s atmospheric environment. It has become a mandatory requirement that the newly launched industrial projects must implement the reduction of "reducing two and increasing one" in order to pass the EIA. Fang Li, deputy director of the Beijing Municipal Environmental Protection Bureau, said that reducing two and increasing one means how much pollution emissions will be added, so we must first cut its emissions by twice.

　　Fang Li: "In the past, our unit energy consumption was the least in China, and it has been declining. But the total energy consumption is rising. If you subtract two and increase one, you just increase, and I have to find a place to reduce it to ensure that the total pollution is reduced. "

　　Wang Yuesi, a researcher at the Institute of Atmospheric Research, Chinese Academy of Sciences, believes that Beijing needs long-term planning and unremitting efforts to eradicate air pollution. We should also realize that the prevention and control of pollution requires the joint prevention and control of many provinces and cities in the region, so as to get twice the result with half the effort.

　　Wang Yuesi: "Can we make a plan for 10 or 20 years, and reduce it by 3 micrograms every year, and it will be solved in 20 years? It must be realized that pollution comes from regional transportation. If we don’t think of ways from the region, the effect of Beijing’s measures will basically not be very good. "

　　Beijing-Tianjin-Hebei Environmental Meteorological Forecast and Warning Center of China Meteorological Bureau was established in Beijing.

　　Beijing, October 18 (Reporter Guo Miao) According to the Voice of China News and Newspaper Summary, the Beijing-Tianjin-Hebei Environmental Meteorological Forecast and Warning Center of China Meteorological Bureau was established in Beijing a few days ago. This is China’s first regional environmental meteorological center, which will start issuing the warning of Beijing-Tianjin-Hebei polluted weather next month.

　　Qu Xiaobo, deputy director of the Beijing Meteorological Bureau, said: The main function of the Environmental Meteorological Center is to make use of the advantages of the industry to strengthen communication with environmental protection departments and jointly forecast the air pollution and heavy pollution weather in Beijing, Tianjin and Hebei and surrounding areas.

　　Qu Xiaobo: "In the whole system of China Meteorological Bureau, Beijing is a leading unit of the meteorological department in North China. Beijing, Hebei, Tianjin, Inner Mongolia and Shanxi belong to the North China Meteorological Center. This time, China Meteorological Bureau put Shandong into the center to work together to engage in environmental forecasting and early warning in Beijing, Tianjin and Hebei and surrounding areas. We focused on the meteorological conditions of air pollution and a forecast and early warning of fog and haze, mainly in these three aspects. The release forms are through various media: radio stations, TV stations, mobile phone short messages, early warning display screens, Weibo and websites, which are all covered by us. Environmental meteorology is the forecasting task undertaken by our meteorological department. In addition to the weather forecast we usually say, environmental forecasting is also an important branch of our forecast. "

　　Regarding the color problem of the warning level of heavy pollution weather that everyone cares about, Qu Xiaobo said that it needs to be implemented in accordance with the relevant provisions of the Beijing Emergency Plan for Heavy Air Pollution.

　　Qu Xiaobo: "Regarding the color of early warning, the Beijing Municipal Government is organizing relevant departments to formulate standards for early warning in Beijing. We will implement them when the time comes. As far as I know, I am doing it, but I haven’t met you yet. "

　　Qu Xiaobo revealed that the first work focus of the Environmental Meteorological Center has been locked in the prevention and control of air pollution in Beijing, Tianjin and Hebei and surrounding areas during the upcoming winter heating period this year.

　　Qu Xiaobo: "We have agreed with the Municipal Political Commissar to hold the first meeting of this year’s heating period on the 21st. Perhaps with the coming of the heating period, the meteorological conditions of air pollution may not be very good, and the polluted weather will appear in the form of fog and haze. We will monitor it at any time."

　　Hangzhou regards solving the problem of people’s interests as the key to educational practice.

　　Beijing, China, October 18 (Reporter Chen Yuyan, Li Jia) According to the Voice of China News and Newspaper Summary, Hangzhou’s "public comment on the people" campaign, highlighting "face-to-face politics", will solve people’s livelihood issues that people are most concerned about, such as eating, drinking, traveling and social pension, as the key to carrying out the party’s mass line education and practice activities.

　　Representative of the people’s evaluation: "When can all the problems existing in the meat and vegetable traceability device in Hangzhou farmers’ market be repaired completely, when can it be used normally, and when can its function be brought into play?"

　　Zhou Zhiping, deputy director of Hangzhou Trade Bureau: "Our general arrangement is to conduct a comprehensive survey of this problem in combination with the secondary transformation of the farmers’ market."

　　Representative of the people’s evaluation: "How much time do we have to ask?"

　　This is the scene of the "Public Comment on People" held in Hangzhou this year to ask about food safety issues face to face. Six department-level cadres and 190 people’s evaluation representatives faced the problem directly, and the smell of gunpowder was full. Although this face-to-face way of giving advice is inevitably blushing and sweating, it has revealed the voice of the people, asked questions and achieved positive results.

　　Sun Yuehong, deputy director of Hangzhou Administration for Industry and Commerce, said: "I will take the opinions of the people’s evaluation representatives as the goal of our work, and I will change them as soon as I get back, intensify the rectification and give you a satisfactory answer."

　　In the second half of this year, Hangzhou held four face-to-face political questioning activities with different themes, which set up a platform for finding problems, solving problems and changing work style. In addition, through online interviews, setting up suggestion boxes and online mailboxes, and opening telephone calls for comments, the power of all sectors of society is fully mobilized. According to statistics, the city of Hangzhou has solicited more than 20,000 opinions and suggestions.

　　At the same time, it also fully mobilized the enthusiasm of leading cadres. Hangzhou municipal leading bodies, 106 municipal units, 3,440 party member leading cadres at or above the county level, 3,467 grass-roots party organizations and nearly 60,000 party member participated in the first batch of educational practice activities. Leading cadres in party member put down their ideological burdens, took the lead in finding out the problems, and made every effort to find them accurately and thoroughly.

　　Peng Baohua, deputy director of Hangzhou Urban Management Committee, said: "There is a good atmosphere within the whole urban management system. Everyone is looking for problems, analyzing and rectifying them. Others’ problems are deeply analyzed and accurate, but they have not found them accurately. I will feel embarrassed."

　　By the end of September, all kinds of conference activities in Hangzhou decreased by 35.17%, documents decreased by 17.65%, briefing types decreased by 63.54%, and the "three public" funds decreased by 18%.

　　Traditional villages need to be protected urgently. Moine city development demolishes cultural heritage.

　　Beijing, October 18, 2012 (Reporter Ji Suping) According to the Voice of China News and Newspaper Summary, since April 2012, the Ministry of Housing and Urban-Rural Development and other departments have organized a thorough survey of traditional villages, and found that there are less than 5,000 traditional villages with high protection value in China. Zhao Hui, director of the Rural Construction Department of the Ministry of Housing and Urban-Rural Development, said that traditional villages should not be demolished because of urban development.

　　After investigation, 12,000 traditional villages were reported nationwide. These villages have been formed for a long time, including 80% before the Qing Dynasty and 1/4 before the Yuan Dynasty, including more than 2,000 key cultural relics protection units and more than 3,000 provincial intangible cultural heritage representative projects, covering typical villages of ethnic minorities in China.

　　Zhao Hui said: "There are more than 12,000 traditional villages reported by investigation in China, which only account for 1.9% of administrative villages in our country and 0.5% of natural villages. Among them, there are less than 5,000 villages with high protection value, very few."

　　China will continue its in-depth investigation, improve the list of traditional Chinese villages as soon as possible, and it will take a little more than a year to improve the list and establish archives. It is also necessary to formulate a medium-and long-term outline for the protection and development of traditional villages throughout the country and establish an endangered warning system.

　　Zhao Hui emphasized: "It is better to promote urbanization and new rural construction, and the protection of traditional villages is the first priority. For example, in the expansion and development of some cities, if there are traditional villages, these villages should be protected and avoided, and this piece should not be torn down because the city wants to develop and use it. The construction of new countryside, the construction of new houses, etc. If these needs are met, they must also follow the requirements of protecting traditional villages. Unlike the construction of other villages, new houses cannot be demolished. If they can be repaired, they must be repaired. If they really need to be expanded, they should be guided outside the village. "

　　The largest missile live-fire training of the Navy North Sea Fleet was successfully held.

　　Beijing, China, October 18 (Reporter Sun Jie, Cao Jinping, Wang Qinghou) According to the Voice of China News and Newspaper Summary, yesterday (17th), the North Sea Fleet of the Navy held the largest missile shooting training in history, and there was no plan for the whole process, and the combat effectiveness of the troops was tempered in back-to-back real combat.

　　In a certain sea area of the Yellow Sea, more than 100 surface ships, dozens of fighter planes, as well as shore-guided, shore-based radar and electronic countermeasures forces, were divided into red and blue sides to form a battle. This live-fire training, for the first time, did not preset the "T moment" when the battle started.

　　Ma Kang, director of the North Sea Fleet Training Division: "The T moment in previous years was certain. This year’s T moment was given a time period, which was temporarily determined by the commander at sea and organized according to the real confrontation."

　　For the first time in the training, an air command post was set up, and the early warning aircraft and warning aircraft directly directed and guided the troops to attack the sea. Director Ma Kang said that all the assault targets given by the director department to the red side were also decided on the spot.

　　Ma Kang: "Three fixed targets and four mobile targets. I don’t know who will hit which target when attacking the sea! We will fight whichever you want according to the battle progress, which is also a breakthrough this year! "

　　The blue side’s attack on the red side is also a surprise attack.

　　Ma Kang: "He doesn’t know when I will fight, whether the first target is one or two, which direction to fight, whether it is interference or non-interference. All these need to be handled by the red side."

　　This time, the participating ships include both new guided missile destroyers and the newly-launched Type 056 guided missile frigate, and more than 60 missiles of various types were fired with live ammunition in a high-intensity electromagnetic countermeasure environment. Commander Tanaka of the North Sea Fleet: This training is the largest annual routine training in the history of the North Sea Fleet, with the strongest actual combat antagonism and the largest number of live missiles fired. It is as close to actual combat as possible, and the actual combat scenario is set as much as possible, achieving the goal of improving the winning ability of the troops under the conditions of approximate actual combat.

　　The Fourth Session of a Series of Current Affairs Reports on "Great Powers and Times-China’s Economy in October"

　　Beijing, Oct. 18 (Reporter Tang Ming) According to the News and Newspapers Summary of China Voice, the series of current affairs reports of "Great Country Times-October Talk on China Economy" sponsored by the Voice of the Central People’s Broadcasting Station and Yangguang.com held the fourth report in China Renmin University yesterday (17th), with the theme of "Employment Talk-Where is tomorrow’s work? 》。

　　Student: "I am a graduate student at Renmin University. At that time, when I was taking the postgraduate entrance examination, my family thought it was better to work first. I want to ask experts to help me interpret whether it is better to take the postgraduate entrance examination or work first, and which opportunity cost is high. "

　　This is not only the struggle of many college students, but also a question that several guests need to give an answer. How to solve the Chinese employment dilemma? The three experts expressed their opinions. Cai Fang, director of the Institute of Population and Labor Economics of China Academy of Social Sciences, believes that the employment difficulty of college students in China is only a structural problem now, and college graduates should be given more employment time.

　　Cai Fang: "His job search time may be a little longer than that of ordinary people. It is meaningless to count an employment rate in July, not to mention graduation in June. At the same time, you should also know that even if he is employed, you should not simply look at his starting salary. He may be lower than migrant workers, but you should look at him a few years later because he has higher human capital to constantly adjust and develop himself. "

　　In the eyes of Xiong Bingqi, vice president of the 21st Century Education Research Institute, the problem of college students’ employment difficulty today is a tragedy of the expansion of higher education. Zeng Xiangquan, dean of the School of Labor and Personnel of China Renmin University, believes that to solve the employment problem, on the one hand, we should promote education reform, on the other hand, it is more important to develop the service industry to attract more employment.

　　The series of current affairs reports on "The Great Power Era-China’s Economy in October" will hold the fifth report at the School of Advanced Finance of Shanghai Jiaotong University at 2 pm on the 20th, with the theme of "Currency Talk-What to do with the big country’s money." Speaker: Li Yang, Vice President of China Academy of Social Sciences, Xia Bin, Counselor of the State Council and Dean of National Economic Research Institute of Nankai University.

　　Accompany my father for the last leg of filial piety.

　　Beijing, China, October 18 (Reporter Wei Xue) According to the Voice of China News and Newspaper Summary, my father, who is nearly eighty years old, is suffering from advanced lung cancer, and his greatest wish is to take a plane and visit Beijing once. Hu Xueying, a girl from Hubei, quit her job and took her father to Beijing in a wheelchair to help him fulfill his last wish.

　　I didn’t think of taking him out for a walk, and I did, but because I was too young, I couldn’t, but when I was able, he made me feel very sad at once.

　　Two months ago, the father of Hu Xueying, a girl from Hubei Province, was diagnosed with advanced lung cancer. Hu Xueying, who has been working in his new work unit for a short time, decided to quit his job and take his father to Beijing for a trip.

　　梦想，这是他的梦想，我们完成她的梦想，尽一切最大的努力去完成她的梦想，不能让他带着遗憾走了。

　　胡雪莹说，哪怕是背着，也要完成父亲的心愿。两天的旅途里，胡雪莹推着轮椅上的父亲在天安门广场晒了太阳，看了看故宫。昨天，她又推着父亲去了只在电视里见过的八达岭长城。胡雪莹说自己也是在尽力补偿，而实际上，有些东西一旦错过，怎么弥补都有遗憾。

　　当今这个社会大家都觉得自己的工作都很忙，没有时间陪伴父母，这都是借口，父母除了你给他吃好喝好用好之外，他也需要精神上的赡养和辅助，不要等到最后他有事的时候，你再去做一些事情。

　　央广短评：不管时代如何变迁，孝道始终是中华民族的传统美德。如今，太多人背井离乡，为学业打拼，为事业打拼，空巢老人望眼欲穿。更有甚者，习惯向父母伸手，甘当啃老族。湖北姑娘胡雪莹以她自己的方式行孝敬老，发人深思。100个人也许有100种行孝方式，只要身体力行，让父母开心，就值得尊敬。孝，不仅是私德问题，更是关乎社会发展的公德问题。在老龄化趋势日益凸显的社会，我们更应该倡导孝道。

This issue of the "Precision Frontier" column shared by Zhao Haitao’s research team published inGenome Medicine(IF =11.12) [1], a mutation signature was constructed and verified to predict the prognosis of patients receiving immunotherapy, and the potential immune response of different subtypes was studied by using multidimensional data.

Research background

Immunocheckpoint inhibitors (ICI) have changed the treatment of many cancers. However, the beneficiaries of ICI treatment are limited, so it is necessary to screen and predict biomarkers to classify patients. At present, many biomarkers, such as tumor mutation load (TMB), have been used as indicative biomarkers in clinic. However, some high TMB patients with gene mutation related to immunotherapy resistance are not sensitive to ICI treatment. Therefore, it is necessary to go beyond TMB and identify the specific genetic determinants of ICI treatment response.

research design

The study included genome and clinical data of 12,647 patients. There were 1572 cases in the training set (immunotherapy patients with 9 kinds of cancer) and 932 cases in the verification set (immunotherapy patients with 5 kinds of cancer). The training set was sequenced by MSK-IMPACT panel containing 468 genes.

The authors identified a set of 11 genes based on mutation, which can divide patients into high-risk and low-risk groups. The mutation of these 11 genes is related to the better response to ICI treatment, and this gene set has been proved to be an independent prognostic factor after ICI treatment.

research results

1. Identify mutant gene sets that can predict the outcome of immunotherapy.

Firstly, the survival differences of 468 genes in the training set were compared between wild type and mutant type, and 98 genes related to OS (global survival) were obtained. After that, LASSO COX regression analysis was further screened and 11 important genes were finally obtained. Through COX regression analysis, the risk score of each patient was quantified on the basis of 11 mutant gene sets. In the training concentration, the OS of patients in the high-risk group is shorter than that of patients in the low-risk group (Figure 1B). In order to study whether the gene set is limited to a specific population or suitable for different populations, the subgroup analysis regardless of age, drug use type and cancer species shows that the gene set is significantly related to the OS of patients treated with ICI (Figure 1C-E).

Figure 1. Generation and Verification of Gene Set Based on Mutation

2. Verification of predictable immunotherapy results

In order to further confirm the value of mutation-based gene set in predicting the results of immunotherapy, it was found that the OS of low-risk group was higher than that of high-risk group (Figure 1F). The research results of predicting ICI treatment response in gene set show that the DCB(durable clinical benefit) of ICI treatment in low-risk group is significantly increased compared with that in high-risk group (Figure 1G), and low-risk patients are more likely to respond to ICI treatment (Figure 1H). These results get the same results in the verification set (Figure 1I, J).

3. Gene set is an independent prognostic predictor of immunotherapy.

Next, the author verifies whether the gene set based on mutation is an independent predictor of immunotherapy response. In the training and validation set, univariate COX regression analysis showed that the gene set was related to OS. After adjusting for drug type, tumor type and TMB, multivariate COX regression analysis showed that the gene set was still an independent predictor, which confirmed the stability of its independent prediction of ICI prognosis (Figure 2A, B). In order to determine which factor has the best predictive performance, C-index is used to compare the performance of mutation-based gene sets with TMB and drug types. The results of C-index show that the gene set based on mutation can predict the prognosis more accurately than TMB and drug type in both training set and validation set (Figure 2C, D).

Fig. 2. Relationship between mutation-based gene sets and other characteristics

4. The clinical benefit of ICI treatment can be predicted based on the mutant gene set, disease stage, CTL and 6-IFN-g gene signature.

Considering the stage of disease, CTL and 6-gene IFN-g signature have been proved to be highly predictive of the response to ICI treatment, the authors speculate that they may play a synergistic role in predicting the response to immunotherapy. The author combined the gene set based on mutation with disease stage, CTL and 6-gene IFN-g signature through Nomotograph, and provided a method for clinicians to quantitatively predict the OS of patients treated by ICI. Fig. 2E is the nomogram of Riaz cohort construction, and the calibration curve of fig. 2F shows the consistency of actual and predicted results, indicating that these signature should be integrated into the predicted nomogram of ICI treatment.

5. Potential external immune landscape of high and low risk groups

In order to further explore the relationship between immune system and mutation-based gene set, the authors conducted a multi-group analysis of TCGA cohort, and the risk score divided TCGA cohort into high and low risk groups (Figure 3A). At the genome level, the proportion of white blood cells, lymphocytes and TIL in the low-risk group was significantly higher than that in the high-risk group (Figure 3B-D). The H&E staining results of TIL ratio are consistent with the above results (Figure 3E). In addition, the proportion of immunostimulatory cells (such as CD8 T cells) in the low-risk group is also significantly higher than that in the high-risk group (Figure 3F). The above results were further tested by Danaher et al.’ s immune infiltration score (figure 3G) and immune characteristic score (figure 3H), and it was found that the abundance of immune cells in low-risk group was higher. Then unsupervised clustering was used to cluster the immune characteristic scores of patients in TCGA cohort, and the results were clustered into two immune infiltration modes (Figure 3I), and the high immune infiltration was significantly enriched in the low-risk group (Figure 3J).

Fig. 3. Immune status of high and low risk population in TCGA cohort.

In addition, the immune signature in the low-risk group was significantly higher than that in the adjacent cancer tissue; On the contrary, the immune signature in the high-risk group was significantly lower than that in the adjacent tissues (Figure 4A). The correlation of immune activity in low-risk group was significantly higher than that in high-risk group (Figure 4B, C). GSEA results showed that 13 pathways were significantly enriched in the low-risk group, including 6 immune-related pathways, such as "cytotoxicity mediated by natural killer cells" (Figure 4D). Tumors in the low-risk group are associated with significantly higher CYT scores, and the number of fibroblasts in the high-risk group is now increasing (Figure 4E, F). According to these results, the low-risk group is rich in immune cells, which can respond to ICI treatment, and fibroblasts may help the high-risk group escape. The expression of chemokines in the low-risk group is higher (Figure 4G, H), so the author speculates that the enrichment of chemokines in the low-risk group may trigger an immune response.

Figure 4. Potential external immune landscape of high and low risk groups　

6. Potential inherent immune landscape of high and low risk groups

Some potential factors determining tumor immunogenicity between the two groups were compared. Mutation, new antigen load, TCR and BCR diversity in low-risk group were significantly higher than those in high-risk group, but CNV load and aneuploidy in high-risk group were higher than those in low-risk group (Figure 5A). This result is consistent with previous studies, that is, tumor aneuploidy is related to immunotherapy and decreased immune escape marker response. In addition, the heterogeneity of tumor in high-risk group is higher than that in low-risk group, which further supports the view that tumor will promote the development of heterogeneity in the presence of cytolytic activity and less active infiltration of immune cells. In order to further understand the mutation process of high and low risk groups, the mutation characteristics were described according to somatic mutation data, and four different mutation patterns were determined in TCGA cohort (Figure 5B). The frequency of these four mutation signals in the low-risk group is significantly higher than that in the high-risk group (Figure 5C). In addition, it was also found that immune checkpoint molecules (such as PD-1, PD-L1 and CTLA4) and costimulatory molecules were more highly expressed in the low-risk group (Figure 5E).

Figure 5. Potential innate immune response and escape landscape in high and low risk groups.　

7. Copy number characteristics of high and low risk groups

Significant differences in chromosome variation were detected in high and low risk groups (fig. 6A). Local amplification peaks of immune genes with good characteristics, such as PD-L1 (9p24.1) and PD-L2 (9p24.1), were observed in the low-risk group (fig. 6B, C). GO function annotation of the specifically amplified genes showed that the low-risk group was significantly enriched in two immune-related biological processes, while the high-risk group was significantly enriched in the biological process of "positive regulation of fibroblast proliferation", but not in any immune-related biological processes (Figure 6E). At the level of mRNA expression in TCGA cohort, the expression of PD-L1 and PD-L2 mRNA in low-risk group increased significantly (Figure 6G), which was consistent with CNV data. This finding suggests that CNVs in tumor contributes to the observed difference in immune infiltration.

Figure 6. Variation of copy number in high and low risk groups

discuss

This study is the first time to use an independent cohort to study the comprehensive mutant gene sets of different tumor types. Through PSM algorithm, hierarchical analysis and multivariate COX regression analysis, the application performance of mutation-based gene sets in different types of tumors was tested, and the results showed that mutation-based gene sets were reliable.

This study has the following innovation and practical application value. First, different types of tumors (such as NSCLC (non-small cell lung cancer), melanoma and renal cell carcinoma) are used, which represent the most common types of cancer treated with ICI. Secondly, the application of multiple biomarker prediction model needs to understand the factors that affect the accuracy and precision of Qualcomm analysis in clinical practice. The risk score formula and threshold of mRNA expression calculation are not suitable for verification with other types of data. Therefore, this study developed a gene set based on mutation to predict the clinical efficacy of ICI treatment. The composition of the above mutations is neither affected by tissue types nor adjusted by any other biomarkers. The risk score formula and threshold of gene set based on mutation can be verified by other tumor analysis methods, such as DNA sequencing and single nucleotide polymorphism microarray analysis. Therefore, mutation-based gene sets are not affected by technological changes, even when different platforms are used in different centers. Thirdly, in practice, gene sets based on mutations avoid exposing patients to potential immune-related adverse reactions when they are unlikely to respond, and enable patients to match to potentially more effective treatments more quickly. Fourthly, the prediction performance of gene set based on mutation is compared with other factors that can predict immunotherapy, and it is found that the prediction performance of gene set based on mutation is better than all these factors.

Several limitations of this study. First of all, because some mutations may be enriched in some tumor types, the initial goal of this study is to create a panel instead of identifying a single gene (such as BRAF), because the former can contain more genes to predict the prognosis of different types of tumors. Secondly, although the immune landscape of 11 genes in the gene set based on mutation has been explored, it is still necessary to clarify the molecular mechanism of each gene affecting immunotherapy in vivo and in vitro functional experiments. Thirdly, the enrichment scores of carcinogenic pathways and the expression patterns of immune checkpoints should also be detected by immunohistochemistry.

tag

The mutation-based gene set proposed in this study is the first comprehensive genomic marker systematically identified, which can be used to evaluate the ICI treatment effect of pan-cancer species. This study is also the largest prognostic model discovery project for cancer patients receiving ICI treatment (whether single drug treatment or combined treatment of anti-PD-1 and anti-CTLA-4). Nomoto, which combines mutation-based gene set with TMB and drug types, can help clinicians choose patients who may have a strong response to ICI treatment. In addition, it also reveals the different immune conditions of high and low risk groups, and specific genomic changes may drive the formation of these microenvironments. In a word, this work puts forward a new tumor classification method, which may guide the decision-making of ICI treatment.　END　

References:

[1]　Long, J., Wang, D., Wang, A. et al. A mutation-based gene set predicts survival benefit after immunotherapy across multiple cancers and reveals the immune response landscape. G enome Med 14, 20 (2022). https://doi.org/10.1186/s13073-022-01024-y

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