Review of 10 years of research on breast cancer patients:Focus on indoleamine 2,3-dioxygenase

Therapeutic manipulation of the immune system in cancer has been an extensive area of research in the field of oncoimmunology.Immunosuppression regulates antitumour immune responses.An immunosuppressive enzyme,indoleamine 2,3-dioxygenase(IDO)mediates tumour immune escape in various malignancies including breast cancer.IDO upregulation in breast cancer cells may lead to the recruitment of regulatory T(T-regs)cells into the tumour microenvironment,thus inhibiting local immune responses and promoting metastasis.Immunosuppression induced by myeloid derived suppressor cells activated in an IDOdependent manner may enhance the possibility of immune evasion in breast cancer.IDO overexpression has independent prognostic significance in a subtype of breast cancer of emerging interest,basal-like breast carcinoma.IDO inhibitors as adjuvant therapeutic agents may have clinical implications in breast cancer.This review proposes future prospects of IDO not only as a therapeutic target but also as a valuable prognostic marker for breast cancer.

以高水平科技创新赋能标准化工作高质量发展

The Ministry of Science and Technology(MOST)has carried out a series of work in the areas such as strengthening the building of technological supporting system for technical standards,deploying the development of standards on new technologies and products,and pushing forward the internationalization of standards,so as to actively drive the integrative development of standardization and technological innovation,and promote the high-quality standardization development with technological innovation.

p38 mitogen-activated protein kinase regulates type-Ⅰ vs type-Ⅱ phenotyping of human vascular endothelial cells

AIM: To identify kinases involved in phenotype regulation of vascular endothelial cells(VECs): Proproliferative G-protein signaling 5(RGS5)^(high)(typeⅠ) vs anti-proliferative RGS5^(low)(typeⅡ) VECs.METHODS: Proteomic kinase assays were performed to identify the crucial kinase involved in the phenotype regulation of human VECs using typeⅠ VECs, which promotes the proliferation of human vascular smooth muscle cells(VSMCs), and typeⅡ VECs, which suppress the proliferation of human VSMCs. The assays were performed using multiple pairs of typeⅠ and typeⅡ VECs to obtain the least number of candidates. The involvement of the candidate kinases was verified by evaluating the effects of their specific inhibitors on the phenotype regulation of human VECs as well as the expression levels of regulator of RGS5, which is the causative gene for the "typeⅡ to typeⅠ" phenotype conversion of human VECs. RESULTS: p38α mitogen-activated protein kinase(p38α MAPK) was the only kinase that showed distinctive activities between typeⅠ and typeⅡ VECs: p38α MAPK activities were low and high in type-Ⅰand typeⅡ VECs, respectively. We found that an enforced expression of RGS5 indeed lowered p38α MAPK activitiesin typeⅡ VECs. Furthermore, treatments with a p38α MAPK inhibitor nullified the anti-proliferative potential in typeⅡ VECs. Interestingly, MAPK inhibitor treatments enhanced the induction of RGS5 gene. Thus, there is a vicious cycle between "RGS5 induction" and "p38α MAPK inhibition", which can explain the unidirectional process in the stress-induced "typeⅡ to typeⅠ" conversions of human VECs. To understand the upstream signaling of RGS5, which is known as an inhibitory molecule against the G protein-coupled receptor(GPCR)-mediated signaling, we examined the effects of RGS5 overexpression on the signaling events from sphingosine-1-phosphate(S1P) to N-cadherin, because S1 P receptors belong to the GPCR family gene and N-cadherin, one of their downstream effectors, is reportedly involved in the regulation of VEC-VSMC interactions. We found that RGS5 specifically bound with S1P1. Moreover, N-cadherin localization at intercellular junctions in typeⅡ VECs was abolished by "RGS5 overexpression" and "p38α MAPK inhibition".CONCLUSION: p38α MAPK plays crucial roles in "type-Ⅰ vs type-Ⅱ" phenotype regulations of human VECs at the downstream of RGS5.

Pro-vs anti-stenotic capacities of type-Ⅰ vs type-Ⅱ human induced pluripotent-derived endothelial cells

AIM:To verify in vivo relevance of the categorization of human vascular endothelial cells(VECs)into type-I(proproliferative)and type-II(anti-proliferative).METHODS:Endothelial layers of murine femoral arteries were removed by wire injury(WI)operation,a common technique to induce arteriostenosis.Type-I and type-II VECs produced from human induced pluripotent stem cells(iPSCs),whose characters were previously determined by their effects on the proliferation of vascular smooth muscle cells in in vitro co-culture experiments,were mixed with Matrigel?Matrix.The mixtures were injected into subcutaneous spaces around WI-operated femoral arteries for the transplanted human iPSC-derived VECs(iPSdECs)to take a route to the luminal surface via vasa vasorum,a nutrient microvessel for larger arteries.Histologies of the femoral arteries were examined over time.The presence of human iPSdECs was checked by immunostaining studies using an antibody that specifically recognizes human VECs.Degrees of stenosis of the femoral arteries were calculated after three weeks.To determine the optimal experimental condition,xenotransplantation experiments were performed under various conditions using immunocompromised mice as well as immunocompetent mice with or without administration of immunosuppressants.RESULTS:Because immunocompromised mice showed unexpected resistance to WI-induced arteriostenosis,we performed xenotransplantation experiments using immunocompetent mice along with immunosuppressant administrations.After one week,luminal surfaces of the WI-operated arteries were completely covered by human iPSdECs,showing the efficacy of our novel transplantation technique.After three weeks,type-IiPSdECs-transplanted arteries underwent total stenosis,while type-II-iPSdECs-transplanted arteries remained intact.However,untransplanted arteries of immunosuppressant-treated mice also remained intact by unknown reasons.We found that transplanted human VECs had already been replaced by murine endothelial cells by this time,indicating that a transient existence of human type-II-iPSdECs on arterial luminal surfaces can sufficiently prevent the development of stenosis.Thus,we re-performed xenotransplantation experiments using immunocompetent mice without administrating immunosuppressants and found that arteriostenosis was accelerated or prevented by transplantation of type-I or type-II iPSdECs,respectively.Similar results were obtained from the experiments using human embryonic stem cell-derived VECs at early passages(i.e.,type-II)and late passages(i.e.,type-I).CONCLUSION:Pro-and anti-stenosis capacities of type-I and type-II human iPSdECs were verified,respectively,promising a therapeutic application of allogenic iPSdECs.

New categorization of human vascular endothelial cells by pro-vs anti-proliferative phenotypes

AIM: To integrally understand the effects of human vascular endothelial cells(VECs) on the proliferation of vascular smooth muscle cells(VSMCs).METHODS: Various kinds of human VECs of different origins were co-cultured with human aortic smooth muscle cells, a representative of human VSMCs. To exclude the irrelevant effects due to growth competition between VECs and VSMCs, the proliferation of VECs had previously been arrested via a low-dose gamma rayirradiation. To discriminately analyze the proliferation of VSMCs from that of VECs, the former cells were labeled with red fluorescent dye while the latter cells were labeled with green fluorescent dye before performing coculture experiments. After 4 d, total cells were harvested and subjected to flow cytometric analyses. Decrements in red fluorescence intensities due to proliferationmediated dilutions were measured and mathematically processed using a specific software to quantitatively evaluate the proliferation of VSMCs. The findings obtained from the flow cytometry-based analyses were further validated by microscopic observations. RESULTS: Commercially available primary cultured human VECs exclusively promoted VSMC proliferation regardless of their tissue origins and we termed these pro-proliferative VECs as "typeⅠ". By contrast, VECs freshly generated from human bone marrow-derived endothelial progenitors cells or human pluripotent stem cells including embryonic stem cells and induced pluripotent stem cells suppressed VSMC proliferation and we termed these anti-proliferative VECs as "typeⅡ". Repetitive subcultures as well as oxidative stress induced "type Ⅱ VECs to typeⅠ" conversion along with an induction of Regulator of G-protein signaling 5(RGS5)Compatibly, anti-oxidant treatments suppressed both the subculture-dependent "typeⅡ to typeⅠ" conversion and an induction of RGS5 gene. Immunostaining studies of clinical specimens indicated that RGS5 protein expressions in endothelial layers were low in norma arteries but they were up-regulated in pathologica arteries including hypertension, atherosclerosis and autoimmune vasculitis in a dose-dependent manner Overexpression and knockdown of RGS5 caused that"typeⅡ to typeⅠ" and "typeⅠ to type Ⅱ" phenotype conversions of VECs, respectively. CONCLUSION: Human VECs are categorized into two types: pro-proliferative RGS5^(high) VECs(typeⅠ) and antiproliferative RGS5 ^(low) VECs(typeⅡ).

Dynamic Analysis of Nanosized Arbitrary Shape Inclusion under SH Waves

The scattering of shear waves (SH waves) by nano-scale arbitrary shape inclusion in infinite plane is studied by complex variable function theory. Firstly, the governing equation and the relationships between stress and displacement are given by classical elastic theory. Secondly, the arbitrary shape inclusion in the two-dimensional plane is transformed into a unit circle domain by conformal mapping, the incident wave field and the scattered wave field are presented. Next, the stress and displacement boundary conditions are established by considering surface elasticity theory, The infinite algebraic equations for solving the unknown coefficients of the scattered and standing waves are obtained. Finally, the influence of surface effect, non-dimensional wave number, Shear modulus and hole curvature on the dynamic stress concentration factor are analyzed by some examples, the numerical results show that the surface effect weakens the dynamic stress concentration. With the increase of wave number, the dynamic stress concentration factor (DSCF) decreases. Shear modulus and hole curvature have significant effects on DSCF.

Meta-Analysis of the Association of HLA-DRB1 with Anti-Citrullinated Protein Antibody-Positive and Anti-Citrullinated Protein Antibody-Negative Rheumatoid Arthritis

Because of genetic complex and variations of auto antibodies of rheumatoid arthritis (RA) in different populations, the data on the association of HLA-DRB1 alleles in anti-citrullinated protein antibody of (ACPA) RA were inconsistent. The purpose of the study is to systematically summarize results of published data through performing a meta-analysis using data in which HLA-DRB1 alleles are associated with ACPApositive RA and ACPA-negative RA. In this study, we collected data from 12 studies with 13,861 cases and 12,896 controls. Information in these studies included HLADRB1 typing and ACPA status from different countries. Odds ratios (ORs) and corresponding 95% confidence intervals (CI) were used to analyze the association of different HLA-DRB1 alleles with ACPA-positive RA or ACPA-negative RA. To correct skewing data, the analysis of ACPA-status was stratified by patient distribution. Our analyses indicate that in ACPA-positive RA, all patients with RA had significantly higher frequencies of HLA-DRB1*01, *04, *0401, *0405, *07, *11, *13 and *14 than controls. One of the HLA-DRB1*07, *11, *13 and *14 showed protective association with RA. In addition, HLA-DRB1*03, *10 and *12 had more influence than control to RA in European populations;the HLA-DRB1*03 and *12 alleles were associated with the protection. In ACPA-negative RA, only DRB1*07 was associated with the protection (OR 0.53 [95% CI 0.36 - 0.76]) among all HLA-DRB1 alleles in European populations. In ACPA-positive RA, currently available results indicate that *01, *04, *0401 and *0405 are susceptible, while HLA-DRB1*07, *11, *13 and *14 are protective in all populations. While the HLA-DRB1*10 is susceptible, HLA-DRB1*03 and *12 show protective association with RA in European populations. Additionally, regardless of the positive or negative ACPA, the DRB1*07 is always associated with protection in European populations.

The Scattering of SH Wave in a Nano Hole Embedded the Infinite Inhomogeneous Medium

Scattering of the shear waves by a nano-sized cylindrical hole embedded the inhomogeneous is investigated in this study. The Helmholtz equation with a variable coefficient is transformed the standard Helmholtz equation by the complex function method and the conformal mapping method. By wave function expanding method, the analytical expressions of the displacement field and stress field in the inhomogeneous medium are obtained. Considering the surface effect and using the generalized Young-Laplace equation, we obtain the boundary conditions at nano arbitrary-shaped hole, then the field equations satisfying boundary conditions are attributed to solving a set of infinite algebraic equations. Numerical results show that when the radius of the cylindrical cavity shrinks to nanometers, surface energy becomes a dominant factor that affects the dynamic stress concentration factor (DSCF) around the cylindrical cavity. The influence the density variation of the inhomogeneity on the DSCF is discussed at the same time.

Indoleamine 2,3-dioxygenase: As a potential prognostic marker and immunotherapeutic target for hepatocellular carcinoma

Tumor cells induce an immunosuppressive microen-vironment which leads towards tumor immune escape. Understanding the intricacy of immunomodulation by tumor cells is essential for immunotherapy. Indoleamine 2,3-dioxygenase(IDO) is an immunosuppressive enzyme which mediates tumor immune escape in various cancers including hepatocellular carcinoma(HCC). IDO up-regulation in HCC may lead to recruitment of regulatory T-cells into tumor microenvironment and therefore inhibit local immune responses and promote metastasis. HCC associated fibroblasts stimulate natural killer cells dysfunction through prostaglandin E2 and subsequently IDO promotes favorable condition for tumor metastasis. IDO up-regulation induces immuno-suppression and may enhance the risk of hepatitis C virus and hepatitis B virus induced HCC. Therefore, IDO inhibitors as adjuvant therapeutic agents may have clinical implications in HCC. This review proposes future prospects of IDO not only as a therapeutic target but also as a prognostic marker for HCC.

Forkhead box P3 and indoleamine 2,3-dioxygenase co-expression in Pakistani triple negative breast cancer patients

BACKGROUND Forkhead box P3(FOXP3)is a specific marker for immunosuppressive regulatory T(T-reg)cells.T-regs and an immunosuppressive enzyme,indoleamine 2,3-dioxygenase(IDO),are associated with advanced disease in cancer.AIM To evaluate the co-expression of FOXP3 and IDO in triple negative breast cancer(TNBC)with respect to hormone-positive breast cancer patients from Pakistan.METHODS Immunohistochemistry was performed to analyze the expression of FOXP3,IDO,estrogen receptor,progesterone receptor,and human epidermal growth factor receptor on tissues of breast cancer patients(n=100):Hormone-positive breast cancer(n=51)and TNBC(n=49).A total of 100 patients were characterized as FOXP3 negative vs positive and further categorized based on low,medium,and high IDO expression score.Univariate and multivariate logistic regression models were used.RESULTS Out of 100 breast tumors,25%expressed FOXP3 positive T-regs.A significant coexpression of FOXP3 and IDO was observed among patients with TNBC(P=0.01)compared to those with hormone-positive breast cancer.Two variables were identified as significant independent risk factors for FOXP3 positive:IDO expression high(adjusted odds ratio(AOR)5.90;95%confidence interval(CI):1.22-28.64;P=0.03)and TNBC(AOR 2.80;95%CI:0.96-7.95;P=0.05).CONCLUSION Our data showed that FOXP3 positive cells might be associated with high expression of IDO in TNBC patients.FOXP3 and IDO co-expression may also suggest its involvement in disease,and evaluation of FOXP3 and IDO expression in TNBC patients may offer a new therapeutic option.

Architecture of severe fever with thrombocytopenia syndromevirus

Dear Editor,Severe fever with thrombocytopenia syndrome(SFTS)is an acute infectious disease caused by severe fever with thrombocytopenia syndrome virus(SFTSV)and is characterized by rapid onset,high mortality and widespread distribution.The fatality rate can be as high as 10%-30%,which is significantly higher than that of the hemorrhagic fever caused by Hantavirus in the same area(Song et al.,2018).However,no effective treatments or vaccines are available yet,and the underlying pathogenic mechanisms of the virus are poorly understood.

Transplantation of autologous adipose-derived stem cells ameliorates cardiac function in rabbits with myocardial infarction

Background Adipose-derived stem cells （ADSCs） are capable of differentiating into cardiomyogenic and endothelial cells in vitro. We tested the hypothesis that transplantation of ADSCs into myocardial scar may regenerate infracted myocardium and restore cardiac function. Methods ADSCs were isolated from the fatty tissue of New Zealand white rabbits and cultured in Iscove＇s modified dulbecco＇s medium. Three weeks after ligation of left anterior descending coronary artery of rabbits, either a graft of untreated ADSCs （UASCs, n=14）, 5-azacytidine-pretreated ADSCs （AASCs, n=13）, or phosphate buffer saline （n=13） were injected into the infarct region. Transmural scar size, cardiac function, and immunohistochemistry were performed 5 weeks after cell transplantation. Results ADSCs in culture demonstrated a fibroblast-like appearance and expressed CD29, CD44 and CD105. Five weeks after cell transplantation, transmural scar size in AASC-implanted hearts was smaller than that of the other hearts. Many ADSCs were differentiated into cardiomyocytes. The AASCs in the prescar appeared more myotube-like. AASCs in the middle of the scar and UASCs, in contrast, were poorly differentiated. Some ADSCs were differentiated into endothelial cells and participate in vessel-like structures formation. All the ADSC-implanted hearts had a greater capillary density in the infarct region than did the control hearts. Statistical analyses revealed significant improvement in left ventricular ejection fraction, myocardial performance index, end-diastolic pressure, and peak ＋dP/dt, in two groups of ADSC-implanted hearts relative to the control hearts. AASC-implanted hearts had higher peak -dP/dt values than did control, higher ejection fraction and peak ＋dP/dt values than did UASC-implanted hearts. Conclusions ADSCs transplanted into the myocardial scar tissue formed cardiac islands and vessel-like structures, induced angiogenesis and improved cardiac function. 5-Azacytidine pretreatment before implantation is desirable for augmenting myogenesis. Transplantation of 5-azacytidine-treated ADSCs into the myocardial scar was more efficient than that of untreated ADSCs in preservation of cardiac function.

A bibliometric analysis of publications on precision poverty alleviation in China

[Background]Since China’s President Xi Jinping proposed the strategy of"precise poverty alleviation(PPA)",it has received increasing attention of many scholars.A bibliometric analysis of publications on PPA may provide a direction of hot topics and future research trends.[Methods]All the papers on PPA published between 2014 and 2018 were scanned in the Chinese Social Sciences Citation Index(CSSCI)database."Precision Poverty Alleviation(精准扶贫)"was used as the keywords to get the relevant publications.VOSviewer was applied to perform the bibliometric analysis of these articles.[Results]The publications on PPA have been growing rapidly.There are relatively few high-productivity authors,so more in-depth study is needed.Journal publishing PPA papers are mainly distributed in the field of humanities and social sciences.From the results of clustering analysis,it can be seen that the research field focuses on the four aspects of PPA:connotation and definition,operation mechanism,realization path and performance evaluation.Therefore,precise identification of the poor population,effective implementation of assistance measures,and clear procedures and criteria for poverty quitting are crucial to the completion of the task of poverty eradication.

cFLIPS regulates alternative NLRP3 inflammasome activation in human monocytes

The innate immune responses,including inflammasome activation,are paramount for host defense against pathogen infection.In contrast to canonical and noncanonical inflammasome activation,in this study,heat-killed gram-negative bacteria(HK bacteria)were identified as single-step stimulators of the NLRP3 inflammasome in human monocytes,and they caused a moderate amount of IL-1βto be released from cells.Time course experiments showed that this alternative inflammasome response was finished within a few hours.Further analysis showed that the intrinsically limited NLRP3 inflammasome activation response was due to the negative regulation of caspase-8 by the short isoform of cFLIP(cFLIPs),which was activated by NF-κB.In contrast,overexpressed cFLIPS,but not overexpressed cFLIPL,inhibited the activation of caspase-8 and the release of IL-1βin response to HK bacteria infection in human monocytes.Furthermore,we demonstrated that TAK1 activity mediated the expression of cFLIPs and was upstream and essential for the caspase-8 cleavage induced by HK bacteria in human monocytes.The functional specificity of cFLIPs and TAK1 revealed unique responses of human monocytes to a noninvasive pathogen,providing novel insights into an alternative regulatory pathway of NLRP3 inflammasome activation.

Variant PRC1 subunit RYBP/YAF2 forms condensate with RING1B and promotes H2AK119ub deposition

Dear Editor,Polycomb group(Pc G)proteins represent important roles in repressing gene expression throughout development.The Polycomb repressive complexes(PRCs)have been subdivided into two central protein complexes,PRC1 and PRC2.PRC1 catalyzes H2AK119ub and PRC2catalyzes H3K27me1/2/3(Fursova et al.,2019).PRC1 is further categorized as CBX-containing canonical PRC1(c PRC1)and RYBP/YAF2-containing variant PRC1(v PRC1)(Blackledge and Klose,2021).