Progress of Imaging Histology in the Diagnosis and TNM Staging of Gastric Cancer

Gastric cancer is one of the most common malignant tumours with complex dynamic heterogeneity and aggressiveness, and the information that can be evaluated by traditional imaging is limited and subjective. With the development of machine learning, radiomics can combine medical imaging with genomics and proteomics to discover latent information, a feature that makes it a beneficial aid to assist physicians in clinical decision making and is used in all areas of gastric cancer diagnosis and treatment. In this paper, we describe the workflow of radiomics and the research progress in gastric cancer diagnosis.

Ammonia promotes the proliferation of bone marrow-derived mesenchymal stem cells by regulating the Akt/mTOR/S6k pathway

Ammonia plays an important role in cellular metabolism.However,ammonia is considered a toxic product.In bone marrow-derived mesenchymal stem cells,multipotent stem cells with high expression of glutamine synthetase(GS)in bone marrow,ammonia and glutamate can be converted to glutamine via glutamine synthetase activity to support the proliferation of MSCs.As a major nutritional amino acid for biosynthesis,glutamine can activate the Akt/mTOR/S6k pathway to stimulate cell proliferation.The activation of mTOR can promote cell entry into S phase,thereby enhancing DNA synthesis and cell proliferation.Our studies demonstrated that mesenchymal stem cells can convert the toxic waste product ammonia into nutritional glutamine via GS activity.Then,the Akt/mTOR/S6k pathway is activated to promote bone marrow-derived mesenchymal stem cell proliferation.These results suggest a new therapeutic strategy and potential target for the treatment of diseases involving hyperammonemia.

Low levels of neutralizing antibodies against XBB Omicron subvariants after BA.5 infection

The COVID-19 response strategies in Chinese mainland were recently adjusted due to the reduced pathogenicity and enhanced infectivity of Omicron subvariants.In Chengdu,China,an infection wave was predominantly induced by the BA.5 subvariant.It is crucial to determine whether the hybrid anti-SARS-CoV-2 immunity following BA.5 infection.

Tripterin liposome relieves severe acute respiratory syndrome as a potent COVID-19 treatment

For coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),15–30%of patients are likely to develop COVID-19-related acute respiratory distress syndrome(ARDS).There are still few effective and well-understood therapies available.Novel variants and short-lasting immunity are posing challenges to vaccine efficacy,so finding antiviral and antiinflammatory treatments remains crucial.Here,tripterin(TP),a traditional Chinese medicine,was encapsulated into liposome(TP lipo)to investigate its antiviral and antiinflammatory effects in severe COVID-19.By using two severe COVID-19 models in human ACE2-transgenic(hACE2)mice,an analysis of TP lipo’s effects on pulmonary immune responses was conducted.Pulmonary pathological alterations and viral burden were reduced by TP lipo treatment.TP lipo inhibits SARS-CoV-2 replication and hyperinflammation in infected cells and mice,two crucial events in severe COVID-19 pathophysiology,it is a promising drug candidate to treat SARS-CoV-2-induced ARDS.

Incorporation of a Toll-like receptor 2/6 agonist potentiates mRNA vaccines against cancer and infectious diseases

mRNA vaccines have emerged rapidly in recent years as a prophylactic and therapeutic agent against various diseases including cancer and infectious diseases.Improvements of mRNA vaccines have been underway,among which boosting of efficacy is of great importance.Pam2Cys,a simple synthetic metabolizable lipoamino acid that signals through Toll-like receptor(TLR)2/6 pathway,eliciting both humoral and cellular adaptive immune responses,is an interesting candidate adjuvant.To investigate the enhancement of the efficacies of mRNA vaccines by Pam2Cys,the adjuvant was incorporated into mRNA-lipid nanoparticles(LNPs)to achieve co-delivery with mRNA.Immunization with the resulting mRNA-LNPs(Pam2Cys)shaped up the immune milieu in the draining lymph nodes(dLNs)through the induction of IL-12 and IL-17,among other cytokines.Antigen presentation was carried out mainly by migratory and dLNresident conventional type 2 DCs(cDC2s)and significantly more potent antitumor responses were triggered in both prophylactic and therapeutic tumor models in a CD4^(+) and CD8^(+) T cell-dependent fashion.Accompanying memory antitumor immunity was also established.Moreover,the vaccine also stimulated much more robust humoral and cellular immunity in a surrogate COVID-19 prophylactic model.Last but not the least,the new vaccines exhibited good preliminary safety profiles in murine models.These facts warrant future development of Pam2Cys-incorporated mRNA vaccines or relevant mRNA therapeutics for clinical application.

Spontaneous apoptosis of cells in therapeutic stem cell preparation exert immunomodulatory effects through release of phosphatidylserine

Mesenchymal stem cell(MSC)-mediated immunomodulation has been harnessed for the treatment of human diseases,but its underlying mechanism has not been fully understood.Dead cells,including apoptotic cells have immunomodulatory properties.It has been repeatedly reported that the proportion of nonviable MSCs in a MSC therapeutic preparation varied from 5-50%in the ongoing clinical trials.It is conceivable that the nonviable cells in a MSC therapeutic preparation may play a role in the therapeutic effects of MSCs.We found that the MSC therapeutic preparation in the present study had about 5%dead MSCs(DMSCs),characterized by apoptotic cells.Namely,1×10^(6) MSCs in the preparation contained about 5×10^(4) DMSCs.We found that the treatment with even 5×10^(4) DMSCs alone had the equal therapeutic effects as with 1×10^(6) MSCs.This protective effect of the dead MSCs alone was confirmed in four mouse models,including concanavalin A(ConA)-and carbon tetrachloride(CCI4)-induced acute liver injury,LPS-induced lung injury and spinal cord injury.We also found that the infused MSCs died by apoptosis in vivo.Furthermore,the therapeutic effect was attributed to the elevated level of phosphatidylserine(PS)upon the injection of MSCs or DMSCs.The direct administration of PS liposomes(PSLs)mimic apoptotic cell fragments also exerted the protective effects as MSCs and DMSCs.The Mer tyrosine kinase(MerTK)deficiency or the knockout of chemokine receptor C-C motif chemokine receptor 2(CCR2)reversed these protective effects of MSCs or DMSCs.These results revealed that DMSCs alone in the therapeutic stem cell preparation or the apoptotic cells induced in vivo may exert the same immunomodulatory property as the'living MSCs preparation"through releasing PS,which was further recognized by MerTK and participated in modulating immune cells.

Targeting folate receptorβpositive tumor-associated macrophages in lung cancer with a folate-modified liposomal complex

Tumor-associated macrophages(TAMs)facilitate cancer progression by promoting tumor invasion,angiogenesis,metastasis,inflammatory responses,and immunosuppression.Folate receptorβ(FRβ)is overexpressed in TAMs.However,the clinical significance of FRβ-positive macrophages in lung cancer remains poorly understood.In this study,we verified that FRβoverexpression in lung cancer TAMs was associated with poor prognosis.We utilized a folate-modified lipoplex comprising a folatemodified liposome(F-PLP)delivering a BIM-S plasmid to target both lung cancer cells and FRβ-positive macrophages in the tumor microenvironment.Transfection of LL/2 cells and MH-S cells with F-PLP/pBIM induced cell apoptosis.Injection of F-PLP/pBIM into LL/2 and A549 lung cancer models significantly depleted FRβ-positive macrophages and reduced tumor growth.Treatment of tumor-bearing mice with F-PLP/pBIM significantly inhibited tumor growth in vivo by inducing tumor cell and macrophage apoptosis,reducing tumor proliferation,and inhibiting tumor angiogenesis.In addition,a preliminary safety evaluation demonstrated a good safety profile of F-PLP/pBIM as a gene therapy administered intravenously.This work describes a novel application of lipoplexes in lung cancer targeted therapy that influences the tumor microenvironment by targeting TAMs.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells

Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

Intranasal administration of a recombinant RBD vaccine induces long-term immunity against Omicron-included SARS-CoV-2 variants

The outbreak of coronavirus disease 2019(COVID-19)has posed great threats to global health and economy.Several effective vaccines are available now,but additional booster immunization is required to retain or increase the immune responses owing to waning immunity and the emergency of new variant strains.The deficiency of intramuscularly delivered vaccines to induce mucosal immunity urged the development of mucosal vaccines.Here,we developed an adjuvanted intranasal RBD vaccine and monitored its long-term immunogenicity against both wild-type and mutant strains of severe acute respiratory syndrome coronavirus-2(SARSCoV-2),including Omicron variants,in mice.Three-dose intranasal immunization with this vaccine induced and maintained high levels of neutralizing IgG antibodies in the sera for at least 1 year.Strong mucosal immunity was also provoked,including mucosal secretory IgA and lung-resident memory T cells(TRM).We also demonstrated that the long-term persistence of lung TRM cells is a consequence of local T-cell proliferation,rather than T-cell migration from lymph nodes.Our data suggested that the adjuvanted intranasal RBD vaccine is a promising vaccine candidate to establish robust,long-lasting,and broad protective immunity against SARS-CoV-2 both systemically and locally.

Correction: Spontaneous apoptosis of cells in therapeutic stemcell preparation exert immunomodulatory effects throughrelease of phosphatidylserine

After online publication of the article1,the authors noticed one inadvertent mistake in Fig.5a that needs to be corrected.In detail,the pathological picture of PBS group in Fig.5a is inadvertently duplicated as the image of PBS group in Fig.7b in the main text.This duplication is a result of errors in figure assembly,and the correct Fig.5 is provided as follows.The key findings of the article are not affected by these corrections.

Spike protein of SARS‐CoV‐2 Omicron(B.1.1.529)variant has a reduced ability to induce the immune response

Dear Editor,The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant Omicron(B.1.1.529)has attracted great concerns since its identification in South Africa.Omicron is the fifth variant of concern(VOC)after Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1)and Delta(B.1.617.2),and set a record with the shortest duration from variants of interest(VOI)to VOC so far.Within 2 months after its first report,over 80%of global sequenced samples are verified as Omicron according to GISAID(https://cov-spectrum.org/explore/World/AllSamples/from=2021-12-15&to=2022-01-15/variants?pangoLineage=B.1.1.529*).

Inactivated SARS-CoV-2 induces acute respiratory distress syndrome in human A CE2-transgenic mice

The development of animal models for COVID-19 is essential for basic research and drug/vaccine screening.Previously reported COVID-19 animal models need to be established under a high biosafety level condition for the utilization of live SARS-CoV-2,which greatly limits its application in routine research.Here,we gen erate a mouse model of COVID-19 un der a gen eral laboratory condition that captures multiple characteristics of SARS-CoV-2-induced acute respiratory distress syndrome(ARDS)observed in huma ns.Briefly,human ACE2-tra nsge nic(MCE2)mice were in tratracheally in stilled with the formaldehyde-inactivated SARS-CoV-2,resulting in a rapid weight loss and detrimental changes in lung structure and function.The pulmonary pathologic changes were characterized by diffuse alveolar damage with pulmonary consolidation,hemorrhage,necrotic debris,and hyaline membrane formation.The production of fatal cytokines(IL-β,TNF-α,and IL-6)and the infiltration of activated neutrophils,inflammatory monocyte-macrophages,and T cells in the lung were also determined,suggesting the activation of an adaptive immune response.Therapeutic strategies,such as dexamethasone or passive antibody therapy,could effectively ameliorate the disease progression in this model.Therefore,the established mouse model for SARS-CoV-2-induced ARDS in the current study may provide a robust tool for researchers in the standard open laboratory to investigate the pathological mechanisms or develop new therapeutic strategies for COVID-19 and ARDS.

S19W,T27W,and N33OY mutations in ACE2 enhance SARS-CoV-2 S-RBD binding toward both wild-type and antibody-resistant viruses and its molecular basis

SARS-CoV-2 recognizes,via its spike receptor-binding domain(S-RBD),human angiotensin-converting enzyme 2(ACE2)to initiate infection.Ecto-domain protein of ACE2 can therefore function as a decoy.Here we show that mutations of S19W,T27W,and N330Y in ACE2 could individually enhance SARS-CoV-2 S-RBD binding.Y330 could be synergistically combined with either W19 or W27,whereas W19 and W27 are mutually unbeneficial.The structures of SARS-CoV-2S-RBD bound to the ACE2 mutants reveal that the enhan ced binding is mainly con tributed by the van der Waals interactio ns mediated by the aromatic side-chai ns from W19,W27,and Y330.While Y330 and W19/W27 are distantly located and devoid of any steric interference,W19 and W27 are shown to orient their side-chains toward each other and to cause steric conflicts,explai ning their in compatibility.Finally,using pseudotyped SARS-CoV-2 viruses,we dem on strate that these residue substitutions are associated with dramatically improved entry-inhibition efficacy toward both wild-type and antibody-resistant viruses.Taken together,our biochemical and structural data have delineated the basis for the elevated S-RBD binding associated with S19W,T27W,and N330Y mutations in ACE2,paving the way for potential application of these mutants in dinical treatment of COVID-19.

A mouse model for SARS-CoV-2-induced acute respiratory distress syndrome

Dear Editor,The COVID-19 pandemic has covered more than 200 countries and regions around the world since its outbreak in January 2020.To date,the SARS-CoV-2 virus has caused>1.2 million deaths.The mortality rate of COVID-19 is closely concerned with the clinical symptoms of the patients from mild-to-severe disease.Notably,in its most severe form,COVID-19 leads to life-threatening pneumonia and acute respiratory distress syndrome(ARDS),which is mostly accom-panied by a hyperactive immune response called"cytokine storm"and has high death rates from 40 to 50%.

Cationic nanocarriers as potent adjuvants for recombinant S-RBD vaccine of SARS-CoV-2

Dear Editor,The worldwide outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has urged the investigation of preventive vaccines.Recently,our team has developed a recombinant protein vaccine,targeting receptor binding domain(RBD)of the spike protein(S-RBD)of SARS-CoV-2,which could induce a potent antibody response and protect non-human primates from SARS-CoV-2 challenge.1 The recombinant RBD protein is proved as a potent antigen and a novel adjuvant is in demand for the effective stimulation of adaptive immunity.

Cationic nanocarriers as potent adjuvants for recombinant S-RBD vaccine of SARS-CoV-2

Dear Editor,The worldwide outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has urged the investigation of preventive vaccines.Recently,our team has developed a recombinant protein vaccine,targeting receptor binding domain(RBD)of the spike protein(S-RBD)of SARS-CoV-2,which could induce a potent antibody response and protect non-human primates from SARS-CoV-2 challenge.1 The recombinant RBD protein is proved as a potent antigen and a novel adjuvant is in demand for the effective stimulation of adaptive immunity.Therefore,to improve the efficacy of the vaccine and seek a novel adjuvant that can stimulate both humoral and cellular immunity,we investigated the potential of series of cationic nanocarriers as adjuvants of the recombinant S-RBD vaccine for SARS-CoV-2.As the surface charge of a nanocarrier might dramatically affect the immunogenicity of a vaccine and enhance and/or shape antigen-specific immune responses,we also used anionic nanocarriers and neutral nanocarriers as controls(Supplementary Table S1).S-RBD vaccines with adjuvant candidates were administered intranasally or intramuscularly in the present study.