The introduction of immune-checkpoint blockade in the cancer therapy led to a paradigm change of the management of late stage cancers. There are already multiple FDA approved checkpoint inhibitors and many other agent...The introduction of immune-checkpoint blockade in the cancer therapy led to a paradigm change of the management of late stage cancers. There are already multiple FDA approved checkpoint inhibitors and many other agents are undergoing phase 2 and early phase 3 clinical trials. The therapeutic indication of immune checkpoint inhibitors expanded in the last years, but still remains unclear who can benefit. Micro RNAs are small RNAs with no coding potential. By complementary pairing to the 3' untranslated region of messenger RNA, microRNAs exert posttranscriptional control of protein expression. A network of microRNAs directly and indirectly controls the expression of checkpoint receptors and several microRNAs can target multiple checkpoint molecules,mimicking the therapeutic effect of a combined immune checkpoint blockade. In this review, we will describe the microRNAs that control the expression of immune checkpoints and we will present four specific issues of the immune checkpoint therapy in cancer:(1) imprecise therapeutic indication,(2) difficult response evaluation,(3) numerous immunologic adverse-events, and(4)the absence of response to immune therapy. Finally, we propose microRNAs as possible solutions for these pitfalls. We consider that in the near future microRNAs could become important therapeutic partners of the immune checkpoint therapy.展开更多
Ten eleven translocation(TET)enzymes are composed of three representatives:TET1/2/3 which are involved in the hydroxymethylation of methylated cytosines.Because of the wide array of processes that are governed by thes...Ten eleven translocation(TET)enzymes are composed of three representatives:TET1/2/3 which are involved in the hydroxymethylation of methylated cytosines.Because of the wide array of processes that are governed by these epigenetic marks,there have been a wide range of clinical effects associated with TET alterations.Even though many research groups have focused on analyzing the effect of TET alterations within certain cells,few have taken into consideration the effect of TET in the context of intercellular communication.One important entity through which intercellular communication occurs is represented by exosomes.Thus,in the current viewpoint we discussed the direct transfer of TET by exosomes,its alterations in the cell targeted by exosomes and the effect of TET alterations on exosome secretion.展开更多
On December 7,2022,China adjusted public health control measures,there have been widespread of SARS-CoV-2 infections in Chinese mainland.As the number of infected people increased,the mutation probability of SARS-CoV-...On December 7,2022,China adjusted public health control measures,there have been widespread of SARS-CoV-2 infections in Chinese mainland.As the number of infected people increased,the mutation probability of SARS-CoV-2 is also raised.Therefore,it is of great importance to monitor SARS-CoV-2 variants and its mutations in China.In this current study,665 SARS-CoV-2 genomes from China deposited in the public database were used to analyze the proportion of different variants;to determine the composition of variants in China across different provinces;and analyze specific mutation frequency,focusing on 12 immune escape residues.The results showed that no new mutations were generated on the 12 immune escape residues.The evolutionary analysis of the BF.7 variant circulating in China showed that there is an independent evolutionary branch with unique mutation sites,officially named BF.7.14 by PANGO.This variant may have been imported from Russia to Inner Mongolia at the end of September 2022 and continued its spread in China.The evolutionary analysis of BA.5.2 variant shows that the variant is composed of two sub-variants,named BA.5.2.48 and BA.5.2.49 by PANGO,respectively.This variant may have been imported from abroad to Beijing at the beginning of September 2022 and formed two sub-variants after domestic transmission.Finally,this study showed that current epidemic variants in China were already circulating in other countries,and there were no additional mutations on immune escape residues that could pose a threat to other countries.展开更多
Over the past two years,scientists throughout the world have completed more than 6 million SARS-CoV-2 genome sequences.Today,the number of SARS-CoV-2 genomes exceeds the total number of all other viral genomes.These g...Over the past two years,scientists throughout the world have completed more than 6 million SARS-CoV-2 genome sequences.Today,the number of SARS-CoV-2 genomes exceeds the total number of all other viral genomes.These genomes are a record of the evolution of SARS-CoV-2 in the human host,and provide information on the emergence of mutations.In this study,analysis of these sequenced genomes identified 296,728 de novo mutations(DNMs),and found that six types of base substitutions reached saturation in the sequenced genome population.Based on this analysis,a“mutation blacklist”of SARS-CoV-2 was compiled.The loci on the“mutation blacklist”are highly conserved,and these mutations likely have detrimental effects on virus survival,replication,and transmission.This information is valuable for SARS-CoV-2 research on gene function,vaccine design,and drug development.Through association analysis of DNMs and viral transmission rates,we identified 185 DNMs that positively correlated with the SARS-CoV-2 transmission rate,and these DNMs where classified as the“mutation whitelist”of SARS-CoV-2.The mutations on the“mutation whitelist”are beneficial for SARS-CoV-2 transmission and could therefore be used to evaluate the transmissibility of new variants.The occurrence of mutations and the evolution of viruses are dynamic processes.To more effectively monitor the mutations and variants of SARS-CoV-2,we built a SARS-CoV-2 mutation and variant monitoring and pre-warning system(MVMPS),which can monitor the occurrence and development of mutations and variants of SARSCoV-2,as well as provide pre-warning for the prevention and control of SARS-CoV-2(https://www.omicx.cn/).Additionally,this system could be used in real-time to update the“mutation whitelist”and“mutation blacklist”of SARS-CoV-2.展开更多
The United Nations Secretary-General Mechanism(UNSGM)for investigation of the alleged use of chemical and biological weapons is the only established international mechanism of this type under the UN.The UNGSM may laun...The United Nations Secretary-General Mechanism(UNSGM)for investigation of the alleged use of chemical and biological weapons is the only established international mechanism of this type under the UN.The UNGSM may launch an international investigation,relying on a roster of expert consultants,qualified experts,and analytical laboratories nominated by the member states.Under the framework of the UNSGM,we organized an external quality assurance exercise for nominated laboratories,named the Disease X Test,to improve the ability to discover and identify new pathogens that may cause possible epidemics and to determine their animal origin.The“what-if”scenario was to identify the etiological agent responsible for an outbreak that has tested negative for many known pathogens,including viruses and bacteria.Three microbes were added to the samples,Dabie bandavirus,Mammarenavirus,and Gemella spp.,of which the last two have not been taxonomically named or published.The animal samples were from Rattus norvegicus,Marmota himalayana,New Zealand white rabbit,and the tick Haemaphysalis longicornis.Of the 11 international laboratories that participated in this activity,six accurately identified pathogen X as a new Mammarenavirus,and five correctly identified the animal origin as R.norvegicus.These results showed that many laboratories under the UNSGM have the capacity and ability to identify a new virus during a possible international investigation of a suspected biological event.The technical details are discussed in this report.展开更多
One of the major challenges in oncology is drug resistance,which triggers relapse and shortens patients’survival.In order to promote drug desensitization,cancer cells require the establishment of an ideal tumor micro...One of the major challenges in oncology is drug resistance,which triggers relapse and shortens patients’survival.In order to promote drug desensitization,cancer cells require the establishment of an ideal tumor microenvironment that accomplishes specific conditions.To achieve this objective,cellular communication is a key factor.Classically,cells were believed to restrictively communicate by ligand-receptor binding,physical cell-to-cell interactions and synapses.Nevertheless,the crosstalk between tumor cells and stroma cells has also been recently reported to be mediated through exosomes,the smallest extracellular vesicles,which transport a plethora of functionally active molecules,such as:proteins,lipids,messenger RNA,DNA,microRNA or long non-coding RNA(lncRNAs).LncRNAs are RNA molecules greater than 200 base pairs that are deregulated in cancer and other diseases.Exosomal lncRNAs are highly stable and can be found in several body fluids,being considered potential biomarkers for tumor liquid biopsy.Exosomal lncRNAs promote angiogenesis,cell proliferation and drug resistance.The role of exosomal lncRNAs in drug resistance affects the main treatment strategies in oncology:chemotherapy,targeted therapy,hormone therapy and immunotherapy.Overall,knowing the molecular mechanisms by which exosomal lncRNA induce pharmacologic resistance could improve further drug development and identify drug resistance biomarkers.展开更多
基金supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination(OSC)the NIH/NCI grant 1 R01 CA182905-01+6 种基金a U54 grant-UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Projecta Team DOD (Grant No.CA160445P1) granta Ladies Leukemia League granta CLL Moonshot Flagship projecta SINF 2017 grantthe Estate of C.G.Johnson,Jr.supported by a POC grant, entitled "Clinical and economical impact of personalized targeted anti-microRNA therapies in reconverting lung cancer chemoresistance"-CANTEMIR, Competitively Operational Program, 2014-2020, Grant No.35/01.09.2016,My SMIS 103375
文摘The introduction of immune-checkpoint blockade in the cancer therapy led to a paradigm change of the management of late stage cancers. There are already multiple FDA approved checkpoint inhibitors and many other agents are undergoing phase 2 and early phase 3 clinical trials. The therapeutic indication of immune checkpoint inhibitors expanded in the last years, but still remains unclear who can benefit. Micro RNAs are small RNAs with no coding potential. By complementary pairing to the 3' untranslated region of messenger RNA, microRNAs exert posttranscriptional control of protein expression. A network of microRNAs directly and indirectly controls the expression of checkpoint receptors and several microRNAs can target multiple checkpoint molecules,mimicking the therapeutic effect of a combined immune checkpoint blockade. In this review, we will describe the microRNAs that control the expression of immune checkpoints and we will present four specific issues of the immune checkpoint therapy in cancer:(1) imprecise therapeutic indication,(2) difficult response evaluation,(3) numerous immunologic adverse-events, and(4)the absence of response to immune therapy. Finally, we propose microRNAs as possible solutions for these pitfalls. We consider that in the near future microRNAs could become important therapeutic partners of the immune checkpoint therapy.
文摘Ten eleven translocation(TET)enzymes are composed of three representatives:TET1/2/3 which are involved in the hydroxymethylation of methylated cytosines.Because of the wide array of processes that are governed by these epigenetic marks,there have been a wide range of clinical effects associated with TET alterations.Even though many research groups have focused on analyzing the effect of TET alterations within certain cells,few have taken into consideration the effect of TET in the context of intercellular communication.One important entity through which intercellular communication occurs is represented by exosomes.Thus,in the current viewpoint we discussed the direct transfer of TET by exosomes,its alterations in the cell targeted by exosomes and the effect of TET alterations on exosome secretion.
基金This work was supported by grants from consultancy project(2022-JB-06)by the Chinese Academy of Engineering(CAE).
文摘On December 7,2022,China adjusted public health control measures,there have been widespread of SARS-CoV-2 infections in Chinese mainland.As the number of infected people increased,the mutation probability of SARS-CoV-2 is also raised.Therefore,it is of great importance to monitor SARS-CoV-2 variants and its mutations in China.In this current study,665 SARS-CoV-2 genomes from China deposited in the public database were used to analyze the proportion of different variants;to determine the composition of variants in China across different provinces;and analyze specific mutation frequency,focusing on 12 immune escape residues.The results showed that no new mutations were generated on the 12 immune escape residues.The evolutionary analysis of the BF.7 variant circulating in China showed that there is an independent evolutionary branch with unique mutation sites,officially named BF.7.14 by PANGO.This variant may have been imported from Russia to Inner Mongolia at the end of September 2022 and continued its spread in China.The evolutionary analysis of BA.5.2 variant shows that the variant is composed of two sub-variants,named BA.5.2.48 and BA.5.2.49 by PANGO,respectively.This variant may have been imported from abroad to Beijing at the beginning of September 2022 and formed two sub-variants after domestic transmission.Finally,this study showed that current epidemic variants in China were already circulating in other countries,and there were no additional mutations on immune escape residues that could pose a threat to other countries.
基金This study was supported by funding from the Foundation of the Committee on Science and Technology of Tianjin(19YFZCSN00080)the State Key Research and Development Plan(2019YFC1605004)the National Key Programs for Infectious Diseases of China(2017ZX10303405-001).
文摘Over the past two years,scientists throughout the world have completed more than 6 million SARS-CoV-2 genome sequences.Today,the number of SARS-CoV-2 genomes exceeds the total number of all other viral genomes.These genomes are a record of the evolution of SARS-CoV-2 in the human host,and provide information on the emergence of mutations.In this study,analysis of these sequenced genomes identified 296,728 de novo mutations(DNMs),and found that six types of base substitutions reached saturation in the sequenced genome population.Based on this analysis,a“mutation blacklist”of SARS-CoV-2 was compiled.The loci on the“mutation blacklist”are highly conserved,and these mutations likely have detrimental effects on virus survival,replication,and transmission.This information is valuable for SARS-CoV-2 research on gene function,vaccine design,and drug development.Through association analysis of DNMs and viral transmission rates,we identified 185 DNMs that positively correlated with the SARS-CoV-2 transmission rate,and these DNMs where classified as the“mutation whitelist”of SARS-CoV-2.The mutations on the“mutation whitelist”are beneficial for SARS-CoV-2 transmission and could therefore be used to evaluate the transmissibility of new variants.The occurrence of mutations and the evolution of viruses are dynamic processes.To more effectively monitor the mutations and variants of SARS-CoV-2,we built a SARS-CoV-2 mutation and variant monitoring and pre-warning system(MVMPS),which can monitor the occurrence and development of mutations and variants of SARSCoV-2,as well as provide pre-warning for the prevention and control of SARS-CoV-2(https://www.omicx.cn/).Additionally,this system could be used in real-time to update the“mutation whitelist”and“mutation blacklist”of SARS-CoV-2.
文摘The United Nations Secretary-General Mechanism(UNSGM)for investigation of the alleged use of chemical and biological weapons is the only established international mechanism of this type under the UN.The UNGSM may launch an international investigation,relying on a roster of expert consultants,qualified experts,and analytical laboratories nominated by the member states.Under the framework of the UNSGM,we organized an external quality assurance exercise for nominated laboratories,named the Disease X Test,to improve the ability to discover and identify new pathogens that may cause possible epidemics and to determine their animal origin.The“what-if”scenario was to identify the etiological agent responsible for an outbreak that has tested negative for many known pathogens,including viruses and bacteria.Three microbes were added to the samples,Dabie bandavirus,Mammarenavirus,and Gemella spp.,of which the last two have not been taxonomically named or published.The animal samples were from Rattus norvegicus,Marmota himalayana,New Zealand white rabbit,and the tick Haemaphysalis longicornis.Of the 11 international laboratories that participated in this activity,six accurately identified pathogen X as a new Mammarenavirus,and five correctly identified the animal origin as R.norvegicus.These results showed that many laboratories under the UNSGM have the capacity and ability to identify a new virus during a possible international investigation of a suspected biological event.The technical details are discussed in this report.
基金Dr.Calin is the Felix L.Endowed Professor in Basic Science.Work in Dr.Calin’s laboratory is supported by National Institutes of Health(NIH/NCATS)grant UH3TR00943-01 through the NIH Common Fund,Office of Strategic Coordination(OSC)the NCI grants 1R01 CA182905-01 and 1R01CA222007-01A1,an NIGMS 1R01GM122775-01 grant,a U54 grant#CA096297/CA096300-UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project,a Team DOD(CA160445P1)grant,a Ladies Leukemia League grant,a Chronic Lymphocytic Leukemia Moonshot Flagship project,a Sister Institution Network Fund(SINF)2017 grant,and the Estate of C.G.Johnson Jr.
文摘One of the major challenges in oncology is drug resistance,which triggers relapse and shortens patients’survival.In order to promote drug desensitization,cancer cells require the establishment of an ideal tumor microenvironment that accomplishes specific conditions.To achieve this objective,cellular communication is a key factor.Classically,cells were believed to restrictively communicate by ligand-receptor binding,physical cell-to-cell interactions and synapses.Nevertheless,the crosstalk between tumor cells and stroma cells has also been recently reported to be mediated through exosomes,the smallest extracellular vesicles,which transport a plethora of functionally active molecules,such as:proteins,lipids,messenger RNA,DNA,microRNA or long non-coding RNA(lncRNAs).LncRNAs are RNA molecules greater than 200 base pairs that are deregulated in cancer and other diseases.Exosomal lncRNAs are highly stable and can be found in several body fluids,being considered potential biomarkers for tumor liquid biopsy.Exosomal lncRNAs promote angiogenesis,cell proliferation and drug resistance.The role of exosomal lncRNAs in drug resistance affects the main treatment strategies in oncology:chemotherapy,targeted therapy,hormone therapy and immunotherapy.Overall,knowing the molecular mechanisms by which exosomal lncRNA induce pharmacologic resistance could improve further drug development and identify drug resistance biomarkers.
