The tumor microenvironment_ a pitch for multiple players

REVIEW ARTICLE

published:17April2013

doi:10.3389/fonc.2013.00090 The tumor microenvironment:a pitch for multiple players

Giovanna Schiavoni,Lucia Gabriele and Fabrizio Mattei*

Department of Hematology,Oncology and Molecular Medicine,Istituto Superiore di Sanità,Rome,Italy

Edited by:

Catherine Sautes-Fridman,UMRS 872,France

Reviewed by:

Muller Fabbri,Keck School of Medicine University of Southern California,USA

Julian Pardo,Fundación Agencia Aragonesa para la Investigación y el Desarrollo,Spain

*Correspondence:

Fabrizio Mattei,Department of Hematology,Oncology and Molecular Medicine,Istituto Superiore di Sanità, Viale Regina Elena299,00161Rome, Italy.

e-mail:fabrizio.mattei@iss.it The cancer microenvironment may be conceptually regarded as a pitch where the main players are resident and non-resident cellular components,each covering a de?ned role and interconnected by a complex network of soluble mediators.The crosstalk between these cells and the tumor cells within this environment crucially determines the fate of tumor progression.Immune cells that in?ltrate the tumor bed are transported there by blood circulation and exert a variety of effects,either counteracting or favoring tumor out-growth.Here,we review and discuss the multiple populations composing the tumor bed, with special focus on immune cells subsets that positively or negatively dictate neoplas-tic progression.In this scenario,the contribution of cancer stem cells within the tumor microenvironment will also be discussed.Finally,we illustrate recent advances on new integrated approaches to investigate the tumor microenvironment in vitro.

Keywords:tumor microenvironment,dendritic cells,macrophages,myeloid-derived suppressor cells,NK cells, T lymphocytes,cancer stem cells,solid tumors

THE TUMOR MICROENVIRONMENT:RESIDENT AND

NON-RESIDENT POPULATIONS

Similarly to the majority of normal tissues,solid tumors are com-posed by two distinct compartments,the parenchyma and the stroma.The parenchyma is representative of cancer cells them-selves,whereas all non-malignant cells and the other connective tissue elements belong to the stromal compartment(Dvorak et al., 2011).The stroma is a very heterogeneous milieu including var-ious cell types and adhesion molecules,both contributing to the functional activity and structural support of the tumor microen-vironment itself.Thus,the stromal and parenchymal regions may often be undistinguishable.For this reason,we can conveniently subdivide the cancer microenvironment into non-resident and resident components(Table1).

Through this de?nition the resident component comprises cell populations and structural factors stably resident within the milieu of the stroma.In particular,endothelial cells and pericytes are res-ident cellular components surrounding and composing the blood vessels.Pericytes are structural cell components of blood vessels whose importance has been recently de?ned relatively to the can-cer environment.Pericytes are commonly present in several organs and multicomponent cell structures(Fernandez-Klett et al.,2012; Iwasaki et al.,2012;Hellerbrand,2013;Ren et al.,2013).Of interest, a functional role for these structures has been recently reported in the activation of innate immunity(Stark et al.,2013).In addition, pericytes can also display a functional property in cancer progres-sion.This was shown in a study employing a transgenic mouse model expressing the viral thymidine kinase(tk)under control of the NG2promoter(NG2-tk mice)and transplanted with4T1 breast cancer cells.In this work,Cooke et al.(2012)reported that treatment with Ganciclovir induced depletion of pericytic struc-tures in tumors from NG2-tk mice but not in those from control mice,that was associated with markedly increased breast can-cer progression and metastatic potential in mutant animals.The mesenchyma is another macrostructure belonging to the resident components,and is composed by several cellular types constantly present in this environment,such as?broblasts,mesenchymal cells,and cancer stem cells(CSC).Other structural components such as adhesion molecules,cytokines,chemokines,and other bio-logical compounds of functional relevance are all essential and confer to mesenchyma a time-and space-dependent functional role for the expansion of the tumor mass.

Belonging to the non-resident constituent are different immune cell populations with the ability to in?ltrate the cancer microenvironment by extravasation or through the help of blood vessels.In this scenario,resident and non-resident elements of the tumor microenvironment constantly interact and together repre-sent a new forming,independent organ within the body(Table1) (Dvorak et al.,2011).Hence,resident cancer cells produce selected chemokines that will set the composition of the in?ltrating,non-resident fraction through the recruitment of leukocytes expressing speci?c chemokine receptors(reviewed in Toh et al.,2012;Viola et al.,2012).An example of cancer microenvironment compo-sition is depicted in Figure1(Mattei et al.,2012),illustrating a section of a B16.F10melanoma tumor grown in C57/Bl6syn-geneic mice.Hematoxylin/Eosin staining evidences the presence of in?ltrating leukocytes surrounding the tumor mass(Figure1A) as well as blood vessels and other structural components inside the tumor milieu(Figure1B).

Recent studies indicate a role for microRNAs(miRs), pleiotropic regulators of gene expression,as critical components of the tumor microenvironment.Deregulation of miR expression at the tumor site has been reported to affect tumor progression and metastasis(Li et al.,2013).It has been evidenced that can-cer cells are endowed with the ability to produce some classes of miRs,such as miR21and miR29a(Fabbri,2012;Fabbri et al., 2012).When produced by cancer cells,these little,non-coding, sequences of RNA were internalized by exosomes and secreted

T able1|Main structural and cellular components of the tumor

microenvironment.

Macrostructure Subcomponents

RESIDENT

Blood vessels Endothelial cells

Pericytes

Mesenchyma Mesenchymal stem cells

Mesenchymal cancer cells

Fibroblasts

Cancer-associated?broblasts

Cancer stem cells

Structural components Adhesion molecules

Cytokines

Chemokines

NON-RESIDENT

In?ltrating leukocytes T lymphocytes

B lymphocytes

Monocytes

Dendritic cells

Macrophages

Myeloid suppressor cells

Natural killer cells

Circulating stem cells

Tumor-derived cells Metastatic cancer cells

Cancer stem cells

outside the cell,diffusing in the tumor milieu.By exploiting their expression of TLRs,such as TLR-7(in mice)and TLR-8 (in humans),neighboring immune cells promptly captured these RNA sequences and internalized them via the exosomes.At this point,miR21and miR29a exert their action by altering the tran-scriptional machinery of the cells(Fabbri,2012;Fabbri et al., 2012).Of note,all immune cells expressing TLRs,such as DCs,are potentially exposed to this scenario.Therefore,miRs can be seen as integrated components of the tumor bed,acting as paracrine biological factors that contribute to the crosstalk between cancer and immune cells,together with the cytokine network generated therein,and orchestrating the fate of cancer progression. IMMUNE CELLS INFILTRATING THE TUMOR MICROENVIRONMENT:ROLE IN CANCER PROGRESSION Immune cell in?ltration within a solid tumor is a naturally occur-ring event,when cells belonging to immune system enter within the tumor microenvironment by means of tumor-forming blood vessels and/or extravasation.This event can sometimes lead to blocking of cancer progression and thus limit or even prevent the generation of metastasis(Vesely et al.,2011).In general,this occurs when tumor progression is at early stages as a result of host immunosurveillance.At this point,if the organism is able to generate a prompt tumor-speci?c immune response,cancer pro-gression is contrasted by immune forces and sometimes inhibited. In many cases,unfortunately,the host is unable to generate an effector immune response toward the tumor,due to the ability of the tumor to activate immunosuppressive mechanisms

that

FIGURE1|Composition of the tumor microenvironment from a

mouse melanoma tumor.C57BL/6mice were injected subcutaneously

with0.75×106B16.F10melanoma cells.After14days tumors were

excised and sections stained with the Hematoxylin/Eosin method.(A)40×Magni?cation.Blood vessel with red blood cells(red circular cells)is shown.(B)Detail of the blood vessel depicted in(A)with the indication of the various functional structures linking blood vessel and tumor milieu.

Y ellow arrows,tumor-in?ltrating leukocytes;red arrows,red blood cells;

black arrows,melanoma cells.

circumvent or dampen immunity forces,thus leading to tumor escape from host immunosurveillance.In this scenario,the bal-ance of immune populations endowed with effector vs.suppressive activities at the tumor site,is a critical parameter predicting cancer progression.

MACROPHAGES

Macrophages represent a signi?cant portion of the tumor mass, and they certainly operate as fundamental actors in various types of solid cancers(Hao et al.,2012).These cells are gen-erated from blood monocytes,which differentiate into two dis-tinct macrophage types,schematically identi?ed as M1(or clas-sically activated)and M2(or alternatively activated)(Hao et al., 2012).In presence of LPS/IFN-γ,monocytes differentiate in the

M1-polarized macrophages,characterized by the production of high levels of IL-1,IL-10,IL-23,TNF-alpha as well as CXCL10. Instead,M2-polarized cells are generated when monocytes dif-ferentiate in presence of IL-4,IL-10,and IL-13(Martinez et al., 2009;Pollard,2009).M1-and M2-polarized macrophages are endowed with opposite functional roles in terms of tumor suppres-sion and immune stimulation.Indeed,whereas M1cells,by virtue of their ability to elicit Mydd88/TLR pathways,enhance immune responses and restrain tumor progression,M2macrophages switch-off the immune system and promote tumor development (Solinas et al.,2009).Moreover,human renal cell carcinoma has been reported to be frequently in?ltrated with M2tumor-associated macrophages(TAMs)promoting cancer progression. These TAMs produce high levels of IL-10and CCL2,and display an elevated expression of15-lipoxygenase-2(15-LOX2)enzyme. Together,these factors allow in?ltrating TAMs to promote in?am-mation,immunosuppression,and malignant progression of renal cancer carcinoma(Daurkin et al.,2011;Eruslanov et al.,2011). Furthermore,melanoma-in?ltrating macrophages produce sig-ni?cant amount of adrenomedullin,which acts in an autocrine manner to promote their polarization toward the M2phenotype. The generation of M2macrophages enforce malignant progression and suppresses Cytotoxic T lymphocytes(CTL)activity as well as angiogenesis(Chen et al.,2011).Likewise,M2macrophages were shown to play a crucial role in colon cancer progression.In a mouse model of colorectal cancer,TAMs were shown to play an indi-rect role by eliciting the recruitment of CCR6+T REG lymphocytes inside the tumor mass,which then promote neoplastic progres-sion by stimulating the secretion of CCL20(Liu et al.,2011).In addition to sustaining tumor progression,M2macrophages also promote angiogenesis.In this regard,mature F4/80+CD68+alter-natively activated M2macrophages were shown to be endowed with a strong CTL-suppressive activity in a murine BW-Sp3T cell lymphoma model(Van Ginderachter et al.,2006;Chen et al., 2011).

T LYMPHOCYTES

Both preclinical and clinical studies suggest a strict correlation between the presence of tumor-in?ltrating lymphocytes(TILs) with a favorable prognosis in a wide number of solid tumors (Galon et al.,2006;Fridman et al.,2012;Senovilla et al.,2012), although not all lymphocyte types are endowed with anti-tumor activity(Vesely et al.,2011).CTL play a relevant role in the process of tumor rejection.They are de?ned as CD8+T cells produc-ing massive amounts of IFN-γand compounds necessary for their cytotoxic activity,such as granzyme B and perforin.The key role of CTL both in immunosurveillance against rising malignancies and in contrasting the metastatic expansion has been demonstrated in mouse models exploiting UV-induced skin cancers(Ward et al., 1990),chemically induced papilloma(Yusuf et al.,2008),and in the ret oncogene transgenic model of spontaneous melanoma(Eyles et al.,2010).High frequencies of circulating CD8+T lympho-cytes were detected in patients with metastatic melanoma,speci?c for Melan-A/MART-1,MAGE-10,and Ny-Eso-1,and CTL have also been found in?ltrating melanoma metastases(Clark et al., 1989;Clemente et al.,1996;van Houdt et al.,2008;Fuertes et al., 2011).On this basis,adoptive transfer of CTL is therapeutically effective for mouse tumor models,although to a minor extent for cancer patients(Mempel and Bauer,2009).These T cells, attracted by chemotactic stimuli secreted by the tumor mass, acquire the ability to migrate toward it.CTL do not require integrin to interact with neoplastic cells and are endowed with the ability to shift between components of tumor mass by means of ame-boid locomotion(Weigelin et al.,2011).Time-lapse microscopy in a mouse melanoma model illustrated that melanoma-speci?c CTL effectively traf?c to the melanoma site,where they engage contact with the B16.F10cells via TCR/MHC-peptide interac-tions(Weigelin et al.,2011).Subsequently,tumor cells undergo apoptotic cell death induced by cytotoxic activity of CTL.These forming apoptotic bodies are made available for tumor-in?ltrating dendritic cells(DC)that are thus allowed to sustain the sys-temic tumor-speci?c immunosurveillance by migrating to tumor-draining lymph nodes and other distant lymphoid organs,such as spleen,in order to present the processed peptides to na?ve T cells.Moreover,it is also widely documented that the presence of TILs,including CTLs,is correlated with a favorable prognosis for several types of cancers,such as colon,breast,lung,ovar-ian,and esophagus cancer,just to cite a few(Naito et al.,1998; Schumacher et al.,2001;Zhang et al.,2003;Sato et al.,2005; Alexe et al.,2007;Al-Shibli et al.,2008;Fridman et al.,2012). The killing ef?ciency of target tumor cells by CTL is dependent on several factors,such as the cytokine/chemokine patterns pro-duced by the tumor microenvironment,the molecular plasticity of tumor cells to evade CTL-induced killing and the strength of TCR/MHC-peptide interactions.In this regard,melanoma cells have been shown to down-regulate the MHC-I surface expression, thus bypassing the interaction with CTL via TCR(Mempel and Bauer,2009).Of note,some reports demonstrated that induction of co-stimulatory molecule expression in human melanoma cell surface led to stimulation of CTL activity by Natural killer(NK) cells(Tarazona et al.,2004).

A signi?cant fraction of TILs is composed by the regulatory T (T REG)cells,endowed with potent suppressive activity that coun-teract anti-tumor effector responses and favor tumor escape and progression.T REG cells were reported to in?ltrate a wide range of mouse and human tumors,such as melanoma,lung adenocarci-noma,breast cancer,and gastrointestinal tumors(Quezada et al., 2011;Wang et al.,2012b).Elevated frequencies of T REG cells in peripheral blood and at the tumor site of cancer patients correlate with poor prognosis and reduced survival.However the mecha-nisms driving T REG cell expansion,accumulation,and migration to the tumor site are currently unknown.It is likely,that factors relevant within the tumor microenvironment,such as the pres-ence of TGF-βand low antigen stimulation,may play a role in the induction of T REG cells in vivo(Quezada et al.,2011).Through the secretion of inhibitory cytokines and the expression of sur-face markers,T REG cells inhibit the effector function of most immune cells,including T and

B cells,DC,macrophages,and NK cells(Wang et al.,2012b).FoxP3+T REG cells within tumor burden express elevated levels of multiple suppressive receptors such as PD-1,CTLA-4,TIM-3,LAG-3,and GITR(Sakuishi et al., 2010;Park et al.,2012b).The identi?cation of these receptors has gained interest for the development of targeted anti-tumor strategies aimed at selectively depleting T REG cells at the tumor

site(Menetrier-Caux et al.,2012a,b;Wang et al.,2012b).For example,simultaneous blockade of CTLA-4and PD-1was shown to reduce the frequencies of T REG cells and to increase the numbers of effector TILs in mice bearing established B16.F10melanoma, improving the ef?cacy of tumor vaccines(Curran et al.,2010). Similar encouraging results have been obtained with melanoma patients,suggesting that approaches aimed at combining T REG cell depletion-based immunotherapy with current tumor treat-ment protocols may be promising strategies in clinical oncology (Hodi et al.,2010).However,since PD-1and CTLA-4are not uniquely expressed by T REG cells,these results may be attributable to the blockade or re-activation of other T cell subsets(Badoual et al.,2013).In some cases T REG cells may also contrast tumor pro-gression.Indeed,T REG lymphocyte in?ltration has been associated with favorable prognosis in several types of solid cancers,such as ovarian,bladder,head/neck,and colorectal tumors(Badoual et al., 2009;Fridman et al.,2012).The mechanisms by which T REG cells exert opposite function,depending on the tumor type,are still under investigation,although it is plausible to hypothesize that the phenotypical uniqueness of each cancer microenvironment may elicit the recruitment of different T REG cell subsets(Fridman et al.,2012).

DENDRITIC CELLS

The involvement of DC in neoplastic progression became increas-ingly evident in the past10years,and has been shown by different research groups(Preynat-Seauve et al.,2006;Shurin et al.,2006; Fuertes et al.,2011;Galluzzi et al.,2012).Indeed,DC have been shown to in?ltrate different types of primary solid tumors.The crucial role of these cells in the process of cancer progression is dictated by their unique property of potent antigen present-ing cells(APC)capable to prime na?ve T lymphocytes.Several investigations indicate that DC can be endowed with capability to yield an active tumor-speci?c immune response that ultimately re?ects in tumor rejection(Preynat-Seauve et al.,2006).It has been demonstrated that DC present tumor-speci?c peptides to activated T lymphocytes during melanoma progression in tumor-draining lymph nodes(Fuertes et al.,2011;Gerlini et al.,2012a,b). On the other hand,the cancer immunosuppressive environment may cause DC to develop functional impairments resulting in fail-ure to activate T cells.(Chaux et al.,1997a,b;Vicari et al.,2002). In this respect,DC may be viewed as a double-edged sword at the tumor site affecting either positively or negatively the anti-tumor response,depending on the composition of the tumor microenvironment.

Tumor-in?ltrating DC(TIDC)are present in different types of solid cancers,including colon lesions and epitheliomas (Michielsen et al.,2011,2012),but the largest number of TIDC has been found in melanoma(Furumoto et al.,2004).These TIDC are composed by myeloid and to a lesser extent plasma-cytoid DC(Mattei et al.,2012).The latter display an immature phenotype in situ,but retain the ability to mature into fully compe-tent APC following dissociation from the tumor bulk,without the need of cytokine or bacterial product exposure(Preynat-Seauve et al.,2006).In this regard,dying tumor cells are thought to pro-vide maturation signals.Therefore,DC spontaneously in?ltrate melanoma and other types of solid cancers,and are potentially endowed with the capability to process a soluble tumor-associated antigen(Preynat-Seauve et al.,2006).These TIDC then migrate toward draining lymph nodes in order to activate both na?ve CD4+and CD8+T lymphocytes(Fuertes et al.,2011;Gerlini et al., 2012a,b).Therefore,newly generated cytotoxic CD8+T cells may further contribute to tumor rejection by migrating toward the tumor site.The extent of tumor in?ltration by mature DC has been often correlated with favorable prognosis in a wide array of clinical cancers(Cox et al.,2005;Ladanyi et al.,2007;Park et al., 2012c).In a mouse model of melanoma,it was recently shown that host immunode?ciency results in poor tumor in?ltration by effec-tor immune cells,such as T cells and DC,and closely associates with melanoma progression(Mattei et al.,2012).In this model, melanoma phenotype was shown to be shaped directly by cells of the immune system through release of soluble factors within the tumor microenvironment(Businaro et al.,2013).

Recent work demonstrated the crucial role of CD8α+DC in the natural mechanisms of cancer immunosurveillance through response to endogenous type I IFN and induction of CTL-mediated tumor rejection(Diamond et al.,2011;Fuertes et al., 2011).The importance of CD8α+DCs in anticancer response stems in their unique ability to process and present cellular anti-gens,in a process known as cross-presentation(den Haan et al., 2000;Joffre et al.,2012).Cross-presentation is the ability of APC to process exogenous antigens and present the derived peptides to the MHC-I molecules,rather than conveying them to the classi-cal MHC-II pathway.Cross-presentation allows APCs to present those antigens that are not expressed by the APC itself and is crucial for the generation of CTLs against intracellular pathogens or tumors of non-hematopoietic origin.This occurs through a process named cross-priming and requires optimal stimulation of the cross-presenting DC(referred to as DC licensing)by means of“danger signals,”such as those emitted from damaged cells,or by in?ammation(Kurts et al.,2010).In fact,in the absence of an activation stimulus that“licenses”DC,antigen cross-presentation does not result in cross-priming,but rather in cross-tolerance. Of note,type I IFN have been shown to provide strong signal for CD8α+DCs promoting CD8+T cell cross-priming in vivo against antigens derived from dying tumor cells(Lorenzi et al., 2011).However,the extent of a tumor-speci?c immune response in cancer patients is a rare event.It has been hypothesized that the reasons why a patient fails rather than succeed to give an effective immune response toward the tumor are essentially three, all strictly related to the composition of the cancer microenvi-ronment:(i)immunosuppressive cytokines such as IL-10,TGF-β, VEGF,or PGE2,interfering with the generation of immunity(Par-doll,2003),(ii)tumor-secreted chemokines that sequester antigen-loaded DC,thus impeding them to migrate toward lymph nodes (Hirao et al.,2000),(iii)inadequate ability of TIDC to capture tumor antigen,due to poor apoptosis within cancer microenvi-ronment(den Haan et al.,2000).A recent research of Chiba and co-workers evidenced that the transmembrane protein TIM-3can act as a molecular switch by which TIDC regulate innate immune responses against tumors.Indeed,several tumorigenic and angio-genic factors,such as VEGF and IL-10,released by the tumor in situ induce TIM-3expression on TIDC surface,resulting in the sup-pression of innate immune responses to nucleic acids by binding

to the damage-associated molecular pattern molecule,HMGB1 (Chiba et al.,2012;Mattei and Schiavoni,2013).These?ndings have revealed a novel strategy of tumor escape from host innate responses to nucleic acids involving TIDC and provided important insights for therapy design involving TIM-3targeting.

Some interesting?ndings suggest that tumor-speci?c immune responses can also occur in certain structures distinct from sec-ondary lymphoid organs,the so called Tertiary Lymphoid Struc-tures.Originally discovered for their importance in autoimmunity diseases(Takemura et al.,2001),these singular structures have sub-sequently been identi?ed in human lung cancers(Dieu-Nosjean et al.,2008)and more recently in melanoma metastases(Cipponi et al.,2012).Tertiary Lymphoid Structures exhibit a well de?ned organization,with mature DC and T cells adjacent to B cell fol-licles,thus suggesting that these structures may be a site where tumor-speci?c T cell activation occurs(Fridman et al.,2012). NATURAL KILLER CELLS

Natural killer cells are large granular lymphocytes acting by their cytotoxic capacity and massive cytokine production.NK cells share with macrophages the surface expression of CD16(FcyRIII),but are diversi?ed from them by expression of CD7,CD56,and CD57 (Milush et al.,2009;Yasuda et al.,2011;Senovilla et al.,2012)and by mechanisms of pathogen killing.Indeed,whereas macrophages kill target cells by phagocytosis,NK cells mediate target cell lysis by secretion of perforin-and granzyme B-containing granules(Pardo et al.,2009;Afonina et al.,2010).A recent report demonstrated that NK cells are endowed with a potent ability to secrete cal-cium ions,and that this function allow these cells to increase their killing ability(Schwarz et al.,2012).For their killing activity,NK cells cover an important role in immune responses against tumors. Another interesting function of NK cells is the so called“DC edit-ing.”This term speci?es the ability of activated NK cells to interact with autologous DC and kill those cells that are not fully mature. Through this process,NK cells contribute to maintain the reser-voir of immunogenic DC by killing potentially tolerogenic DC thus optimizing effector anti-tumor responses(Moretta,2002;Moretta et al.,2006;Morandi et al.,2012).

The functionality of NK cells is fundamental for contrasting the growth and metastatic process of several types of cancers.For example,several reports have elucidated the role of NK cells in killing cancer cells in murine models of melanoma,colon cancer, lung cancer,and breast cancer(Azogui et al.,1991;Pham-Nguyen et al.,1999;Velthuis et al.,2003;Carrega et al.,2009;Frings et al., 2011;Kim et al.,2011;Takeda et al.,2011;Vesely et al.,2011; Roberti et al.,2012a;Srivastava et al.,2012).There are several NK receptors,such as DNAM-1,CD155,CD16,CD69,NKp30,and NKp46,whose surface expression is fundamental for maintaining cancer immunosurveillance(Clausen et al.,2003;Garcia-Iglesias et al.,2009;Lakshmikanth et al.,2009;Chan et al.,2010;Levy et al., 2011;Pfeiffer et al.,2011;Gleason et al.,2012;Park et al.,2012a). In this regard,some research groups investigated the intratumoral phenotypic pro?le and functions of NK cells in primary human tumors of non-small cell lung carcinoma(NSCLC)by using the NK cell marker NKp46.The data showed that intratumoral NK cells from these patients display a deeply altered phenotype that strongly contributed to the NSCLC progression in these patients (Platonova et al.,2011).These results strengthen the key role of the cancer microenvironment and its composition,and identify NK cells as important predictive biomarkers of neoplastic disease pro-gression.A recent study utilizing mouse tumor models elucidated the importance of NK cells in a vaccination strategy against lung cancer.A survivin-based vaccination,coupled to the use of novel form of the4-1BBL co-stimulatory molecule as an adjuvant has been effective in completely suppressing3LL lung carcinoma pro-gression.The vaccine ef?cacy was correlated with potent killing responses of NK cells(Srivastava et al.,2012).Another report highlighted the role of NK cells resident in lung tissue during the generation of lung metastases.These?ndings have elucidated that IFN-γproduction by these lung-resident NK cells markedly repressed the formation of metastases in an experimental mouse melanoma model(Takeda et al.,2011).

Defects in NK cell number or phenotype are events that dic-tate the fate of neoplastic diseases other than lung carcinoma. Several investigations de?ned the key role of NK cell receptors in melanoma.This is the case of DNAM-1that interacts with the CD155NK-speci?c receptor and promote the killing of melanoma metastasis and the generation of a“cytokine storm”that con-tributes to the killing activity(Chan et al.,2010).Many studies reported possible mechanisms by which melanoma cells escape killing activity of NK cells(Balsamo et al.,2012;Pietra et al.,2012; Wang et al.,2012a).Nevertheless,strategies aimed at promoting and sustain the melanoma-speci?c killing activity of NK cells are only at early stages or poorly effective.A recent report showed an active role of the chemotherapeutic drug dacarbazine,largely used for this type of neoplastic disease,in activating the expression of NK1G receptor on NK cell surface,thus restoring the killing activity of NK cells toward melanoma cells(Hervieu et al.,2012). Similar encouraging approaches have been recently started for breast cancer by using the chemotherapeutic agent Cetuximab. This drug was shown to be effective in promoting NK cell killing activity in high relapse rate,triple negative breast cancer patients. Indeed,Cetuximab restored IL-2/IL-15-mediated NK cell killing activity,thus markedly improving the outcome of these patients (Roberti et al.,2012b).Taken together,these data strongly sup-port a key role of NK cells in tumor progression.Indeed,when activated,NK cells?ght malignant cells inside the microenviron-ment by direct killing as well as by contrasting the generation of metastatic foci.

MYELOID-DERIVED SUPPRESSOR CELLS

Cancer patients and tumor-bearing experimental mice undergo dramatic changes in their hematopoietic progeny.These modi?-cations are mainly due to accumulation of myeloid cells,including myeloid-derived suppressor cells(MDSC)(Sera?ni et al.,2004). These cells represent a heterogeneous population,either of mono-cytic or granulocytic origin,generated by and released from the bone marrow in response to a wide array of stimuli(Solito et al., 2011).MDSC are characterized by the surface expression of CD11b and Gr-1markers,and their common functional feature is the repression of the effector functions of T lymphocytes and NK cells(Sera?ni et al.,2004;Gabrilovich and Nagaraj,2009).For their potential to compromise both innate and adaptive immunity, tumor-in?ltrating MDSC critically control cancer progression.

By using STAT6?/?mice models transplanted with4T1cancer cells,Sinha et al.(2005)showed that MDSC render4T1mam-mary tumors poorly immunogenic by suppressing the activation of CD4+and CD8+T cells.The involvement of STAT signal-ing in the immunosuppressive activity of MDSC in cancer has been further evidenced in studies on human head and neck squa-mous cell carcinoma and breast cancer,suggesting a pivotal role of STAT3and STAT1pathways,respectively,for MDSC suppres-sive activity within cancer microenvironment(Hix et al.,2013; Vasquez-Dunddel et al.,2013).Other independent investigations demonstrated that mice injected with4T1cells and subsequently treated with cyclophosphamide displayed tumor progression and metastatic spread despite drug treatment.Strikingly,the microen-vironment of these tumor-bearing mice displayed a very high number of in?ltrating MDSC,and this explained the unwanted inef?cacy of chemotherapeutic cure.In addition,CD4+and CD8+ T in?ltrating cells have been shown to promote and sustain this effect by releasing IFN-γ(Guo et al.,2012b).Because the main property of MDSC is to contrast the immunosurveillance mech-anisms of CD8+and CD4+T lymphocytes,the balance between T cells and MDSC within the cancer microenvironment may be a crucial cornerstone in dictating the fate of the neoplastic dis-ease.Another recent report employing transgenic mouse models evidences that NK cells can potentially render T cells resistant to the suppressor activity of MDSC,and this markedly con-tribute to the generation of an effective adoptive transfer therapy with HER-2/neu tumor-reactive T cells and activated non-T cells, including NK cells(Kmieciak et al.,2011).In the mouse model of 4T1metastatic breast carcinoma,accumulation of CD11b+Gr-1+MDSCs within the tumor tissue has been associated with tumor progression and bone metastasis(Bunt et al.,2007;Danilin et al.,2012)and a recent report showed that MDSC recruit-ment is triggered by Macrophage Migration Inhibitory Factor,an in?ammatory cytokine expressed by the tumor(Simpson et al., 2012).Likewise,marked tumor in?ltration and systemic expan-sion of CD11b+Gr-1+MDSC was found to be associated with enhanced tumor growth and malignant phenotype in an immuno-compromised IRF-8?/?mouse model transplanted with B16.F10 melanoma(Mattei et al.,2012).Together,these data strongly sug-gest a close correlation between intratumoral MDSC expansion with tumor progression and metastatic process.

The immunosuppressive functions of MDSC have been stud-ied in several models of neoplastic diseases.It appears that MDSC may mediate T cell suppression through cell–cell con-tact or,alternatively,through release of soluble mediators,such as nitric oxide,arginase-1,reactive oxygen species or suppres-sive cytokines(e.g.,IL-10)(Gabrilovich et al.,2012;Kerkar and Restifo,2012).Studies on B16.F10tumor-bearing mice have demonstrated that CCL5,a chemokine largely produced by MDSC (Zhang et al.,2012),is required for intratumoral recruitment of T REG cells and melanoma expansion(Schlecker et al.,2012). Moreover,MDSCs have been shown to skew the differentiation of CD4+T cells into T REG(Huang et al.,2006),to induce an M2phenotype in macrophages and to impair DC function,sug-gesting the existence of multiple overlapping regulatory mech-anisms that dampen anti-tumor effector responses(Gabrilovich et al.,2012).Finally,MDSC facilitate tumor growth by producing pro-angiogenic factors,such as VEGF-A(Finke et al.,2011).Over-all,MDSC exert pro-tumorigenic activity both through direct mechanisms and by employing a myriad of immunosuppres-sive mechanisms at the tumor site that blunt effector T cell responses.

OTHER TUMOR-INFILTRATING IMMUNE CELL SUBSETS:γδT AND NKT CELLS

Besides the traditional players of anti-tumor immunity,emerg-ing evidences suggest that other subsets of immune cells in?ltrate solid tumors and may also contribute in cancer growth control. Among these,γδT cells represent a small part of the lymphocyte population that share,with all T cells,the surface expression of TCR.UnlikeαβT cells,γδT lymphocytes express a TCR com-plex where CD3is associated to aγandδchains(Wu et al., 1988).These lymphocytes were originally characterized as strong cytotoxic and IFN-γ-producing cells,thus making them pro-totypic anti-tumor mediators.Indeed,γδT lymphocytes have been linked to cancer progression since the early1990s,when an encouraging study demonstrated their in?ltration in human skin tumors,even though no clear indications about their function was given(Miescher et al.,1990).About a decade later,by employ-ing mice lackingγδT cells,Girardi et al.(2001,2003)observed that these mice were highly exposed to carcinogen-induced cuta-neous tumors,thus directly demonstrating the protective role of these cells in skin tumors.In the murine B16melanoma model,γδT cells were shown to in?ltrate tumor lesions soon after trans-plantation and to provide an early source of IFN-γ(Gao et al., 2003).Other recent examples demonstrating a protective role of γδT cells have been provided by two signi?cant reports suggest-ing the presence ofγδT lymphocytes as a favorable prognostic factor for human breast cancer and melanoma(Kabelitz et al., 2007;Cordova et al.,2012;Ma et al.,2012).On the other hand, studies in mouse tumor models have demonstrated thatγδT cells within the tumor microenvironment exert an inhibitory action on CTL and NK cytolytic activity through production of IL-10 and TGF-β,resulting in the induction of tumor-speci?c immune tolerance(Seo et al.,1999;Ke et al.,2003).Recently,by employ-ing IL-17?/?mice two independent groups reported a subset of IL-17-producingγδT cells in?ltrating murine tumors,although opposite results were obtained regarding the anti-tumor activity of these cells.Wakita et al.(2010)showed that IL-17produced by tumor-in?ltratingγδT cells promotes tumor progression by inducing angiogenesis in mouse models of methylcholanthrene-induced transplantable?brosarcoma,skin,and colon carcinoma. In contrast,Zitvogel’s group showed in several subcutaneous tumor lines that early cancer in?ltration by IL-17-producingγδT cells is required for optimal tumor colonization of IFN-γ-producing CD8+T cells and therapeutic ef?cacy of anticancer chemotherapy,in a mechanism requiring IL-1R1and IL-1β,thus implying a bene?cial role of IL-17-producingγδT cells in anti-tumor defense(Ma et al.,2011;Mattarollo et al.,2011).Thus, the role of tumor-in?ltratingγδT cells in cancer immunosurveil-lance is still controversial and a more detailed characterization of γδT cells is necessary in a wider set of preclinical tumor mod-els that takes into account the phenotype of functionalγδT cell subsets.

NKT cells have also been reported to in?ltrate solid tumors. Initially identi?ed in1981by Minato et al.(1981)as a population expressing both a TCR and NK cell markers,NKT lymphocytes are currently known as a subset of innate-like T cell that recognizes Ag presented by CD1d(Kawano et al.,1997;Godfrey et al.,2004; Van Kaer,2007).The best known subset of CD1d-restricted NKT cells,referred to as type I or invariant NKT(iNKT)cells,is charac-terized by surface expression of de?ned variants ofαandβchain of the TCR,such as those encoded by vα24,vα14,vβ11,and Jα281 gene segments(Cui et al.,1997;Kawano et al.,1997;Kronenberg, 2005).These cells are conserved between humans and mice and are implicated in many immunological processes,such as production of massive amounts of several cytokines,both pro-in?ammatory (i.e.,IL-2,IL-17,IFN-γ,and TNF-α)and regulatory(i.e.,IL-4, IL-10,and IL-13),which re?ect their capacity to differently regu-late anti-tumor responses(Swann et al.,2004;Bendelac et al.,2007; Exley et al.,2011).Pioneering work by Cui et al.(1997)showed that mice de?cient for vα14+iNKT cells were unable to mediate IL-12-induced rejection of tumors and that lack of in?ltration of vα14 iNKT cell in melanoma tissue resulted in cancer progression and metastatic expansion.Subsequently,it was shown that the defec-tive tumor immunity observed in Jα18-/-mice,selectively de?cient for iNKT cells,against methylcholanthrene-induced sarcomas and melanoma lung metastasis could be restored by adoptive trans-fer of IFN-γ-producing iNKT cells from WT donor mice(Crowe et al.,2005).iNKT cells can be recruited to the tumor by inducing local expression of chemokines,such as CCL21or CXCL16(Turn-quist et al.,2007;Kee et al.,2013)and be functionally activated by the alpha-galactosylceramide producing bene?cial effects in a variety of solid tumors(Nakagawa et al.,2000;Osada et al.,2004; Nagato et al.,2012).iNKT cell in?ltration in primary tumors has been correlated with a favorable outcome in patients with colorec-tal carcinoma(Tachibana et al.,2005),neuroblastoma(Metelitsa et al.,2004),and hepatocellular carcinoma(Guo et al.,2012a). On the other hand,iNKT cells have also been described to sup-press tumor immunosurveillance based on their production of Th2cytokines(Terabe et al.,2000;Exley et al.,2011).It has been proposed that the instauration of a protective or suppressive anti-tumoral activity of iNKT cells may depend on the cytokine pattern of the cancer microenvironment and on the action of suppres-sive populations,such as MDSC and TAMs(Smyth and Godfrey, 2000;Terabe et al.,2003;Liu et al.,2012).Other,less characterized, CD1d-reactive NKT cells that have non-V24(V14)invariant or variable TCR(type II NKT)as well as some non-CD1d-reactive NKT cell subsets that share with the NK cells the surface expres-sion of a number of NK-associated receptors,such as CD161 (NK1.1),CD16,and CD56,have been described(Godfrey et al., 2004;Bendelac et al.,2007;Metelitsa,2011).Several reports have demonstrated that type II NKT cells can mediate suppression of tumor immunosurveillance in multiple mouse tumor models by counteracting iNKT cell activities(Terabe et al.,2005;Berzofsky and Terabe,2008;Izhak et al.,2013).However,these type II NKT cells have not been characterized in tumor in?ltrates yet,indi-cating the need of further exploration for possible relevance of these cells in the local control of tumor growth and metastatic process.CANCER STEM CELLS IN THE TUMOR MICROENVIRONMENT: RESIDENT OR NON-RESIDENT?

In the recent years,many reports proposed the de?nition of a new hierarchical model of cell organization,based on the discovery of a CSC.In this new model these tissue-speci?c,resident CSC acquire and retain the features of self-renewal,multilineage,dif-ferentiation,and tumor initiation both in vitro and in vivo(Boral and Nie,2012).Importantly,CSC is the unique cell type of the tumor microenvironment able to initiate and maintain the for-mation of the environment itself and allow cancer progression. On the other hand,CSC are also equipped with the capability to colonize distant sites(Sengupta and Cancelas,2010).Thus,in the context of solid tumors,CSC belong to both resident and non-resident compartments(Table1).Nevertheless,despite a constantly increasing number of reports seem to stress a crucial role for CSC in carcinogenesis,there is so far no direct evidence that CSC are phenotypically tumorigenic cells signi?cantly differ-ent from non-tumorigenic ones.All these reports postulate the Cancer Resident Cell(CRC)assumption on the simple obser-vation that carcinogenesis is the result of cumulative mutations that develop during cancer progression.Genetic and epigenetic forces seem to work as main actors in this scenario.Hence,each mutated cell generates an independent,self-renewing clone of CRC,that will take part to the tumor mass contributing to its development(Gupta et al.,2009).As a consequence,it appears that the tumor microenvironment may theoretically be composed of an epigenetically heterogeneous population of CSC,representing self-renewing“stem clones”by which each tumor cell originates (Figure2).CSC were?rst discovered in hematologic malignancies as the Acute Myeloid Leukemia tumor initiating cell,a primitive CD34+hematopoietic cell susceptible to leukemic transforma-tion(Bonnet and Dick,1997),and successively identi?ed in solid tumors,such as melanoma(Visvader and Lindeman,2008;Shack-leton and Quintana,2010).The presence of melanoma CSC was discovered by using the immunocompromised mice NOD/SCID xenotransplanted with single human melanoma cell obtained from cancer biopsies(Quintana et al.,2008).Although the results demonstrated,for the?rst time in solid tumors,the existence of a single cell potentially endowed with the ability to generate a true tumor mass,no information was given about surface markers distinguishing the CSC phenotype(Quintana et al.,2008).

It has been recently elucidated that CSC can directly or indi-rectly interact with several immune cell populations,both in vitro and within the tumor microenvironment.These interactions are thought to in?uence the outcome of cancer progression.An inter-esting example comes from T REG cells,endowed with the ability to produce and release TGF-βin the cancer microenvironment. TGF-βsignaling and TGF-β-induced Endothelial-Mesenchymal Transition(EMT)are viewed as key orchestrators in the reg-ulation of CSCs and T REG participate in this process through producing TGF-β(Yu et al.,2012).Strikingly,a relevant research demonstrates that TGF-βand leukemia inhibitory factor(LIF) are responsible for the formation of neurospheres and the self-renewal ability of glioma-initiating cell(GICs)and that the effect of TGF-βis dependent on induction of LIF and JAK-STAT path-way(Penuelas et al.,2009).Moreover,T REG cells,in concert with

FIGURE2|Role of the cancer stem cells in the development of the tumor microenvironment.Cancer progression is generated and sustained by several factors,such as epigenetic forces,somatic mutations,and EMT.On the other hand,these events lead to the generation of distinct cancer stem cell clones inside the cancer moiety,and enrich the cancer stem cell niche.During the late stages of tumor progression these stem cell clones sustain the cancer expansion with their self-renewal ability.Thus,the cancer stem cell niche can also be regarded as a reservoir of self-sustaining cells for the tumor microenvironment.

CSC,could affect the angiogenesis and VEGF-A level at the tumor site,especially when its microenvironment is hypoxic.This elic-its vascularization extent and thus facilitates angiogenesis itself, which in turn allow CSC proliferation and maintenance inside the cancer microenvironment(Facciabene et al.,2011;Yu et al.,2012).

Effector T lymphocytes exert opposite effects to those observed with T REG cells by induction of CTL capable to repress the expan-sion of CSC in ovarian cancer.This effect has been exploited to direct CTL to effectively killing ovarian CSC(OCSC)in a chemotherapeutic context.In this report,cell chimeras generated by fusion of DC and OCSC to speci?cally target the OCSC subpop-ulations were shown to activate T cells to express elevated levels of IFN-γwith potent killing activity of CD44+OVCA cells(Weng et al.,2011).The NK have also been reported to affect CSC activi-ties.It has been demonstrated that NK cells are endowed with the ability to kill human melanoma stem cells with high levels of the CD133marker(Pietra et al.,2009).In this study,the authors were able to show that CD133-positive melanoma CSC,isolated from a FO-1melanoma cell line by cell enrichment,were effectively killed by activated NK cells.Moreover,myeloid-derived cells such as DC may be effective in targeting Glioma stem cells(GSC),leading to the complete eradication of this malignant primary brain tumor(Ji et al.,2013).Here,the authors prepared a tumor vaccine by loading DC with U251human GSC lysates and showed that these antigen-loaded DC are endowed with the ability to induce tumor-speci?c CTLs that killed glioma cells in vitro.TAM have also been shown to modulate the tumorigenic and angiogenic potential of CSC within tumor transplanted mouse model(Jinushi et al.,2011).A recent study reported that inhibition of TAM by targeting either the myeloid cell receptors CSF1R or CCR2decreases the num-ber of tumor initiating cells in pancreatic tumors(Mitchem et al., 2012).Thus,inhibiting macrophages function can lead to cancer eradication via diminishing the presence of CSC inside the tumor microenvironment.Finally,little is known about the interactions between MDSC and CSC.However,since MDSC are pivotal for the generation and maintenance of an aggressive cancer microen-vironment,it has been recently hypothesized that these cells may also act as a distinct tumor niche whose main function is the main-tenance of self-renewal ability of the niche itself,thus functionally resembling to CSC(Ye et al.,2010).

Overall,CSC are an important and integrated component of the cancer microenvironment.Through their self-renewal abil-ity,CSC also function by tightly interacting with the other resi-dent and non-resident component of the environment,thus cru-cially controlling cancer progression and maintaining the tumor mass.

T able 2|Immune cells in?ltrating the tumor microenvironment and their role in tumor progression.Cell type

Representative in?ltrating population

Outcome

Main features of in?ltrating cells inside the tumor microenvironment

Macrophages

M1TR Activation of immune responses by MyDD88/TLR pathways M2

TP Promotion of angiogenesis;suppression of CTL function;recruitment of CCR6+T REG ;positive modulation of the tumorigenic and angiogenic potential of CSC

T lymphocytes

CTL TR Speci?c tumor cell killing activity

T REG

TP/TR

TP:functional suppression of CTL,DC,NK cells,and macrophages.

TR:correlation with good prognosis in some solid tumors,hypothetically due to lacking of suppressor activity and other unidenti?ed activities

γδT cells

TP/TR

TP:inhibition of CTL and NK cell activity;promotion of angiogenesis

TR:cytotoxic activity,IFN-γproduction

Dendritic cells

CD8α+DC

TR

Processing and presentation of soluble tumor-associated antigens;Type I IFN-dependent CD8+T cell cross-priming against antigens released from dying tumor cells

Plasmacytoid DC TR Processing and presentation of soluble tumor associated antigens

TIM-3+DC

TP

Suppression of HMGB1-dependent innate immune responses

NK cells

NKp46+TR Speci?c tumor cell killing activity by secretion of perforin and granzyme B-containing granules as well as release of calcium ions;DC editing;killing activity against CSC

NKp30+DNAM-1+CD69+CD155+

NKT cells

NK receptors TP/TR TP:CD1d-restricted cytotoxic activity;IFN-γproduction;APC stimulation

TCR-αchain variants CD1d-restricted TR:Th2cytokine production

CD57+

Myeloid-derived suppressor cells

CD11b +Gr-1+

TP

Repression of the effector function of T lymphocytes and NK cells;highly present in late stages of tumor progression;promotion of T REG functions;promotion and sustainment of angiogenesis;present in elevated number in highly aggressive microenvironments

Cancer stem cells

CD34+CD133+

TP

Self-renewal function;tumor initiating activity;promotion and sustainment of angiogenesis;tumor resistance;sustainment of the tumor mass

TP ,tumor progression;TR,tumor regression.

NEW APPROACHES TO STUDY THE CANCER MICROENVIRONMENT

Exploiting complex experimental systems such as confocal microscopy,electron microscopy or two photon microscopy allow oncoimmunologists to “capture”suggestive images ?nely repre-senting the cell–cell interactions occurring in biological systems.However,the existent traditional experimental protocols do not allow monitoring and visualizing in real time the interactions between immune and tumor cells occurring inside the cancer microenvironment.Over the past decade,innovative approaches devoted to the reproduction of biological systems at the microscale,such as micro?uidic platforms,have gained interest for the study of one or multiple biological systems.The ?rst pioneering studies on biosen-sors performed in 1990s to investigate on the kinetics between the antigen-antibody interactions gave a decisive boost on this research area (Karlsson et al.,1991).This subsequently led to the engineering of micro?uidic systems to investigate on biological ?uids (Wilding et al.,1994)and,subsequently,on cell systems (Li and Harrison,1997).Since 2004micro?uidic approaches have

been employed to investigate on cells belonging to immune sys-tem to investigate migratory and morphological parameters in response to external stimuli(Lin et al.,2004;Wong et al.,2008;But-ler et al.,2010;Li et al.,2011).In addition,a magnetic micro?uidic chip has been developed to isolate circulating human colon cancer cells(Choi et al.,2010;Xia et al.,2011)or to study chemoattrac-tant properties of tumor cells(Goerge et al.,2007).Other studies have exploited cell-on-chip based platforms to investigate the sus-ceptibility of tumor cells to chemotherapeutic drugs(Liu et al., 2007;Siyan et al.,2009;Kim et al.,2012).Thus,the extreme versa-tility and the high customization potential of micro?uidic-based technologies have open promising perspectives on the use of these approaches for cancer biology studies(Wlodkowic and Cooper, 2010;Wlodkowic and Darzynkiewicz,2010).

In this context,the reconstitution on-chip of the cancer microenvironment may allow to elucidate the?ne mechanisms that mechanically regulate the interactions of tumor cells with other resident and non-resident components,such as the immune cells,as well as the mechanisms driving the differentiation and metastatic mobilization.Recently,a simple cell-on-chip approach has been developed to investigate the crosstalk between two com-plex biological systems,such as immune system and cancer(Busi-naro et al.,2013).By using a micro?uidic platform consisting of three wide,parallel chambers interconnected via an array of short and narrow capillary migration channels,Businaro and Col-leagues were able to visualize and follow,“under the microscope,”the interactions between the immune and cancer cells.The goal of the study was to investigate the role of IRF-8immune de?-ciency on immune response to melanoma.Thus,splenic immune cells from IRF-8?/?mice or WT controls were allowed to interact with B16.F10melanoma cells into the micro?uidic structure.The results evidenced a marked inability of IRF-8?/?immune cells to migrate toward and interact with melanoma cells with respect to WT cells.In turn,melanoma cells acquired a more invasive behav-ior in the presence of immunode?cient cells,indicating a crosstalk between cancer and immune cells shaping the phenotype of tumor cells.Notably,these results are fully compatible with the?ndings reported in vivo by the same group,suggesting the reliability of the system(Mattei et al.,2012).The observations reported in this study are dif?cult to obtain with the standard well plate culture experiments,but are easily available with the use of a micro?u-idic platform.Thus,customized micro?uidic platform may be potentially helpful to study,follow,and mimic the plethora of events occurring inside the cancer microenvironment.In addition they can also be utilized as helpful tools in preclinical and clinical investigations.

CONCLUDING REMARKS

Immune cell in?ltration within the tumor microenvironment is a crucial requisite for a successful and prompt eradication of the primary tumor itself.Each cell type herein supports the main-tenance of the microenvironment itself both functionally and biochemically,by orchestrating cell–cell interactions and secret-ing a plethora of chemokines and cytokines.This leads to a?ne tuning of the timing and modality of immune response,as well as to an appropriate modulation and maintenance of angiogenic processes.The?nal effect of such a strictly related phenomena may either be the generation of a tumor-speci?c immune response or tumor escape(Table2).

Thus,a better knowledge of the crosstalk between cancer cells and immune system cells occurring inside the tumor bed is of interest for further improving cancer therapies.In this respect, great bene?t for anticancer research and clinical practice may arise from exploiting new versatile biotechnologies,such as micro?uidic cell-on-chip platforms.

ACKNOWLEDGMENTS

We thank Dr.Paola Sestili for the helpful technical assistance in preparation of histochemistry sections from tumor-bearing mice. This work was supported by the Italian Association for Research against Cancer(AIRC)project no.11610to Lucia Gabriele and project no.10720to Filippo Belardelli.

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Con?ict of Interest Statement:The

authors declare that the research was

conducted in the absence of any com-

mercial or?nancial relationships that

could be construed as a potential con-

?ict of interest.

Received:31January2013;accepted:03

April2013;published online:17April

2013.

Citation:Schiavoni G,Gabriele L

and Mattei F(2013)The tumor

microenvironment:a pitch for multi-

ple players.Front.Oncol.3:90.doi:

10.3389/fonc.2013.00090

This article was submitted to Frontiers in

Tumor Immunity,a specialty of Frontiers

in Oncology.

Copyright?2013Schiavoni,Gabriele

and Mattei.This is an open-access arti-

cle distributed under the terms of the

Creative Commons Attribution License,

which permits use,distribution and

reproduction in other forums,provided

the original authors and source are cred-

ited and subject to any copyright notices

concerning any third-party graphics etc.

LCD拼接屏建设方案详细

LCD液晶拼接显示墙系统 技术文件

中达电通股份有限公司二〇一九年十二月

目录 第1章方案概述 (4) 1.1 系统设计原则 (4) 1.1.1 系统的先进性 (4) 1.1.2 系统的可靠性 (4) 1.1.3 系统的扩展性 (5) 1.1.4 系统的集成性 (5) 1.2 中达LCD液晶拼接显示墙技术优势 (5) 1.2.1 最新三星DID液晶面板 (6) 1.2.2 超薄窄边箱体单元设计 (6) 1.2.3 最新第二代单元箱体设计 (7) 1.2.4 精致美观的铝合金型材支架 (7) 1.2.5 先进的内置图像信号处理技术 (8) 1.2.6 工作状态LED指示屏 (8) 1.2.7 独特的延时开机功能 (9) 1.2.8 领先的外置拼接控制器系统 (9) 1.2.9 任意的拼接形式 (9) 1.2.10 个性化的系统方案 (10) 第2章系统设计方案 (11) 2.1 系统组成 (11) 2.2 显示墙安装尺寸 (12) 2.1 显示墙安装效果 (12) 2.2 系统结构示意图 (13) 2.3 系统显示功能 (13) 2.3.1 视频信号显示 (13) 2.3.2 计算机和工作站RGB信号显示 (14) 2.3.3 多种信号混合显示 (15) 2.3.4 全屏显示 (15) 2.4 系统软硬件设备特点及技术规格 (15) 2.4.1 LW-5580显示单元 (15) 2.4.2 VisionCON图像拼接控制器 (19) 2.4.3 VisionDWCS大屏幕管理软件 (25) 第3章工程施工管理 (41) 3.1 工程项目管理 (41) 3.2 工程实施管理 (42) 3.2.1 工程进度计划 (42) 3.2.2 设计联络计划 (42) 3.2.3 包装/发货计划 (43) 3.2.4 工程验收计划 (43) 第4章工程环境要求 (44) 4.1 对供电系统的要求 (44) 4.2 对接地系统的要求 (44) 4.3 对装修的要求 (44) 4.4 对消防系统的要求 (45) 4.5 对照明系统的要求 (45) 第5章售后服务及培训 (46)

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建筑名词解释,(虽然都学过,但是实际用的时候都忘了,留着以后用的着) 1、什么是相对标高？答：地面到假定水准面的铅垂距离. 什么是绝对标高? 答:地面点到大地水准面的铅垂距离. 2、什么是定位轴线？答：定位轴线是用来确定建筑物主要结构或构件的位 置及其标志尺寸的线。 3、什么是横向、纵向？什么是横向轴线、纵向轴线？答：（1）、横向， 指建筑物的宽度方向。（2）、纵向，指建筑物的长度方向。 4、什么是框架结构？答：框架结构指由柱子、纵向梁、横向梁、楼板等构 成的骨架作为承重结构，墙体是围护结构。 5、什么是建筑密度？答：建筑密度是项目总占地基地面积与总用地面积的 比值。一般用百分数表示。 6、什么是过梁？其作用是什么？答：过梁是门窗洞口上方的横梁，其作用 是承受门窗洞口上部的荷载，并把它传到门窗两侧的墙上，以免门窗框被压坏或变形。过梁的长度一般为门窗洞口的跨度加500mm。 7、什么是绿地率（绿化率）？答：绿地率是项目绿地总面积与总用地面积 的比值。一般用百分数表示。 8、什么是日照间距？答：日照间距，就是前后两栋建筑之间，根据日照 时间要求所确定的距离。日照间距的计算，一般以冬至这一天正午正南方向房屋底层窗台以上墙面，能被太阳照到的高度为依据。 9、建筑物与构筑物有何区别？答：凡供人们在其中生产、生活或其他活动 的房屋或场所都叫做建筑物，如公寓、厂房、学校等；而人们不在其中生产或生活的建筑，则叫做构筑物，如烟囱、水塔、桥梁等。 10、什么是建筑“三大材”？答：建筑“三大材”指的是钢材、水泥、木材。 11、建筑安装工程费由哪三部分组成？答：建筑安装工程费由人工费、材 料费、机械费三部分组成。 12、什么是标志尺寸、构造尺寸、实际尺寸？答：（1）、标志尺寸是用 以标注建筑物定位轴线之间（开间、进深）的距离大小，以及建筑制品、建筑构配件、有关设备位置的界限之间的尺寸。标志尺寸应符合模数制的规定。（2）、构造尺寸是建筑制品、建筑构配件的设计尺寸。构造尺寸小于或大于标志尺寸。一般情况下，构造尺寸加上预留的缝隙尺寸或减去必要的

液晶显示器背光灯管更换与维修..

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2近侧发展律（瘦的精细动作，近-远，粗-细，简单-复杂）3向心律（童年期和青春期，下肢先于上肢，四肢早于躯干）。（3）Scammon生长模式：1一般型：肌肉、骨骼脏器等，两次突增；2神经系统型：发育最早，一次突增，先快后稳；3淋巴系统型：发育最旺盛，一次突增，有升有降；4生殖系统型：发育开始最晚，一次突增，先慢后快。5.子宫型：子宫，肾上腺发育在出生时较大，其后迅速变小，青春期开始前才恢复到出生时的大小；其后迅速增大。（4）生长轨迹现象和生长关键期：1生长轨迹现象：在外环境五特殊变化的条件下，个体儿童的发育过程比较稳定，呈现一种轨迹现象，其中遗传基因起关键作用；2赶上生长：因某种因素生长发育受阻的儿童，在阻碍生长的因素被克服后表现出的加速生长，并恢复到正常轨迹的现象；3生长关键期：生长关键期是器官和组织的快速生长期，此时受到干扰，常导致永久性的缺陷和功能性障碍。 体能：是指人体具备的能胜任日常工作和学习而不感到疲劳，同时有余力能充分享受休闲娱乐生活，又可应付突发紧急状况的能力。（体能发育过程的不均衡性、阶段性、不平衡性和性别特征） 体成分（身体成分）：指人体总重量中不同身体成分的构成比例，属化学生长的范畴。（体成分的两成分模型由体脂重和去脂体重） 青春期（adolescence）：是个体从童年向成年的逐渐过渡的时期，是生长发育过程中的一个极其重要的阶段。青春期的年龄区间为10~20岁，WHO把青春期定义为这样一个时期：1.是个体从出现第二性征到性成熟的生理发展过程；2.是个体从儿童认知方式发展到成人认知方式的心理过程；3.是个体从社会经济的依赖性到相对独立状态的过渡。女性青春期的时间跨度一般为10~18岁，男孩为12~20岁。 青春期的发育特点：1.体格生长加速，以身高为代表的形态指标出现第二次生长突增；2.各内脏器官体积增大、重量增加，功能日趋成熟；3.内分泌功能活跃，与生长发育有关的激素分泌明显增加；4.生殖系统功能发育骤然加快，迅速成熟，到青春晚期已具有繁殖后代的能力；5.男女外生殖器和第二性征迅速发育，使两性的外部形态特征差异更明显；6.青春期心理发展骤然加快，产生相应的心理-行为变化，可能出现一些青春期特有的心理-行为问题。 青春期发育类型：早熟型（盆宽窄肩的矮胖体型，突增维持1年左右）、晚熟型（瘦高，维持2年以上）、一般型（介于二者之间，维持两年左右） 矮身材：身高低于其性别--年龄组正常值的第三百分位P3。垂体性侏儒症、甲状腺功能低下症、遗传代谢性疾病、生长迟缓、家族性矮身材、体质性生长迟缓。高身材指个体的身高高于其性别年龄相应标准的第97百分位数以上。按原因分：家族性高身材、体质性生长发育加速、巨人症。 性早熟（sexual preiocity）：是一种以性成熟提前为特征的性发育异常，一般指男9岁以前出现睾丸增大，女8岁前出现乳房增大活10岁前出现月经初潮。一般分真性性早熟，由下丘脑-垂体-性腺轴过早启动引起；假性性早熟，多因性腺或肾上腺皮质肿瘤等导致性激素分泌过多，环境污染物种的激素成分，外源性性激素药物，含性激素制剂的不当应用也可引起；部分性早熟，患儿仅有某一方面的单独提前发育现象、不伴随其他异常表现；体质性性早熟，女孩8~8.5岁前出现第二特征指标一项以上发育或10岁前来初潮男孩9~9.5岁前出现睾丸增大或阴毛生长，本质上属健康人群。 青春期性发育障碍(delay puberty)：一般指男童14岁未出现睾丸增大，女童13岁未出现乳房发育为判断标准。 影响生长发育的因素有：遗传和环境因素，其中前者决定了生长发育的可能性，即决定了生长发育的潜力。后者决定了生长发育的现实性。即在不同程度上影响该潜力的正常发挥，决定发育的速度以及最终可达到的程度。①遗传因素：遗传的家族.种族影响：如家族聚集性和种族差异，是遗传影响的具体表现，身高、 性成熟早晚、生长突增模式、月经初潮年龄，都与家 庭遗传有关，种族影响对个体的体型、躯干、和四肢 的长度的比例等作用很大；双生子研究。②环境因素： 1）营养2）体育锻炼3）疾病4）生活作息制度5） 气候和季节6）环境污染7）社会家庭因素。 双生子研究：MZ同卵，DZ异卵 遗传度：是衡量遗传、环境因素各自对表型性状总变 异相对作用大小。越接近1，遗传作用越大。 生长发育调查方法含义以及特点：1）横断面调查； 在某一较短时间和一定地区范围内，选择有代表性的 对象对某几种指标的一次性大标本调查。特点：通过 其，可在短期内获得大量的资料。在一个较大地区范 围内通过调查得出某项指标的正常值，建立该地区儿 童少年生长发育的标准；也可将本地区本人群的调查 结果与其他地区人群结果作比较，以了解本地区儿童 少年的生长发育水平，并作为评价本地区儿童少年保 健工作效果依据；对同地区同人群的连续多次调查， 可比较不同时期的动态变化，分析生长长期趋势。调 查规模达时间短，需较多测试人员，调查前应该有详 细的计划严格的人员分工和测试程序，调查项目不宜 过多，根据调查目的确定调查对象具有代表性，对所 处的内外环境属性有明确规定2）追踪性调查；是一 种动态观察，通过选择一定数量的对象，在较长一段 时间内进行的定期，连续多次的调查，观察儿童少年 的生长发育动态。制定生长速度正常值，揭示生长发 育规律性，系统深入的观察分析某些内外因素对生长 发育的长期影响。调查对象自始至终是同一组人群， 故反应的生长发育规律较横断面调查更加准确，更能 确切的反映人群或个体的生长速度。费时长，调查中 人员和对象都容易流失，从调查开始即应采取措施保 证其稳定性，最大限度减少样本流失。尽量使用同一 型号的测试器材，技术标准保持一致，使前后结果有 可比性。3）半纵向调查；将横断面和追踪调查两种 方法混合，克服追踪调查所需年限太长，研究样本易 流失的缺点。节约时间和工作量。只具有部分的追踪 性质，获得生长发育速度是近似的，将会出现两组不 同对象的重叠，产生差异，需利用适当的统计方法修 匀。 生长发育的评价的实际意义：1.了解个体、群体的生 长发育现状，处于什么等级、发展趋势如何；2.为评 价遗传--环境影响因素，考察学校卫生工作实效、开 展保健干预提供依据；3.筛查、诊断生长发育障碍。 生长发育评价既针对个体也针对群体，由生长发育水 平、生长速度、发育匀称度（指标间相互关系）和体 质综合评价报告等四类内容组成。 生长发育评价方法：一：等级评价法和离差曲线图法 （正态分布的计量资料）；二：指数法：利用数学公 式，根据身体各部分比例关系，将两项或多项指标相 连，转化成指数进行评价。身高坐高指数：根据人体 躯干与下肢的比例关系，从纵截面角度反映体型，分 为长躯型、中躯型、短躯型（坐高cm/身高cm*100%）； 反映生理功能指数：身高肺活量指数和体重肺活量指 数=肺活量/身高或体重；BMI营养状况指数。三：Z 分法：Z标准差法，是一种特殊类型离差法。它不以 均数加减标准差表示，而是以中位数为中心，将资料 从偏态分布大体转换为正态分布，再取＋－1Z、＋－ 2Z、＋－3Z为界值点，建立正常值。通过正态转换过 程，实测值即被转换成Z分，由此确定发育等级。四， LMS法：三大优势：1.对百分位数法、Z分法既沿袭 又修正。2.只要使用的样本量达到要求，所制成的正 常值或标准课精确到个位。3.各相邻百分位数值间不 会出现交叉、颠倒或重叠，从而使所定正常值或标准 的精确性显著提高。五：发育年龄评价法：是指用某 些身体形态、生理功能指标和第二性征的发育水平及 其正常变异，制成标准年龄，评价个体发育状况。（四 种：形态年龄，第二性征年龄，齿龄，骨龄） 心理卫生（精神卫生）：是研究如何维护和促进人类 心理健康的科学。包括一切旨在改善心理健康的措施， 使人能按自己的身心潜能进行活动。（对儿童来说， 就是促进心理健康发展、培养健全性格、提高儿童对 环境的适应能力、预防精神方面的各种问题） 儿童少年心理健康的标准：心1.智力发展2.情绪反应 适度 3.心理行为特点与年龄相符。4.行为协调，反 应能力适度5。人际关系的心理适应。6，个性的稳 定和健全 心理障碍:儿童在心理健康方面存在的偏倚称心理卫 生问题，若其严重程度、持续时间超过相应年龄的允 许范围，称心理障碍。（20%） 儿童期心理行为问题的表现主要有： 1、学业相关问题学习困难、注意力障碍、自控力 差等，多发生在小学阶段，特别是初入学儿童。注意 有些属于学龄前期向学龄期过渡时出现的暂时性适 应不良。 （ADHD注意缺陷多动障碍：俗称儿童多动症，是以 注意力不集中、情绪冲动、过度活动、学习困难为特 征的综合征。通常起病于7岁之前， LD学习障碍：是指学龄儿童在阅读、书写、拼写、表 达、推理、计算能力等学习过程中存在一种或一种以 上的特殊性障碍，包括阅读障碍、数学障碍、书写障 碍、非特定性学习障碍等。） 2、情绪问题紧张焦虑、孤僻、强迫行为、恐怖。（焦 虑指突如其来出现的、无明显躯体原因的恐惧感，若 经常反复出现，已形成儿童焦虑障碍，是儿童期最常 见的情绪障碍之一。强迫行为：指儿童以强迫观念和 强迫动作为主，伴焦虑情绪和适应困难的一类症候群。 恐惧：当参与某项活动或面临某种情景式产生过分强 烈、持续的紧张、恐惧和回避情绪。心境障碍：又称 情感性障碍，是一组以显著而持久的心经高涨或低落 为主要症状的精神障碍，伴有相应的思维和行为改 变。） 3、品行问题如偷窃、经常撒谎、攻击性行为。 4、 不良习惯如习惯性抽动、吮指、咬指甲、口吃、遗 尿。5、广泛性发育障碍：孤独症谱系障碍ASD：也 称自闭症，是由脑发育不良引起的，以社会功能、语 言沟通缺陷为主，伴异常狭窄的兴趣和行为特征的儿 童期发育行为障碍。表现：交流障碍、言语发育障碍、 行为刻板重复、智力落后、感觉异常。 青春期心理咨询：专指处于青春发育阶段的少年（尤 其是那些存在心理问题者），运用心理商谈的技术、 程序和方法，帮助其对自己与环境形成正确的认识， 矫正其心理上的不平衡，以改变其态度与行为，并对 社会生活产生良好的适应。原则：保密、限时、自愿、 情感自限、延期决定、伦理规范。 生长发育指标：发育水平、营养状况、智力。 生命指标：婴儿死亡率：IMR是指在所给定的年份内 每1000名活产儿在0~1岁期间的死亡人数，反映活 产儿一年内的死亡概率。它是国际公认的衡量一个国 家/地区社会经济文化、居民健康状况、卫生保健事业 发展的重要标志。 疾病指标：因病缺课率：以月为单位计算因病缺课的 人时数或人日数占授课总时数的比例。反映学生健康 状况的重要指标。 生命质量指标：包括日常功能指标、心理社会功能评 定、专门性生活质量评定量表、综合性生活质量评定 量表。 六、视力不良：视力低下，是在采用远视力表站在5m 远处检查时，裸眼视力低于 5.0 。（近视不能仅凭上 述检查而必须通过眼科的散瞳验光才能确诊）。 近视：是指眼睛辨认远方（5米以上）目标的视力低 于正常，但视近正常，它是由于屈光不正所致。严 格定义是在不使用调节功能状态下，远处来的平行光 在视网膜感光层前方聚焦。 预防近视的措施：1.限制近距离用眼时间：预防近视 眼的基本措施是限制过多的长时间近距离视近活动， 每日可3~4次向5m以外的远处眺望，远望时宜选择 固定目标，每次5~10分钟，避免刺眼的强光刺激； 2.重视读写卫生：阅读、书写时坐姿要端正，眼书距 离保持在30~35cm左右，避免在光线过强或过弱的地 方读写；3.开展体育锻炼，增加室外活动，认真做好 眼保健操：活动有助使眼压下降；4.合理饮食，注意 营养：合理营养是预防近视眼的综合措施之一；5.改 善学习环境6.定期检查视力：学校应每年两次进行视 力检查；7.健康教育：开展用眼卫生的健康宣教。8. 加强围生期保健，减少早产儿。低体重儿的发生。 七、龋齿：龋齿是牙齿在身体内外因素作用下，硬组 织脱矿，有机质溶解，牙组织进行性破坏，导致牙齿 缺损的儿童少年常见病。患牙不能自愈。患龋后不仅 引起疼痛，而且影响食欲、咀嚼和消化功能，对生长 发育造成不利影响。 流行病学特点：1.龋患率：幼儿园儿童高于小学生， 小学生高于中学生；城市高于农村，大城市高于中小 城市。2.龋均（总龋牙数/受检总人数）和患者龋均（总 龋数/患龋总人数）都是反映龋齿患病程度的重要指标， 防龋工作重点在幼儿园儿童和小学生人群上。3.5岁 乳牙无龋率，12岁恒压龋均。4.好发牙和好发部位： 乳龋的好发牙是第1、2乳磨牙（第4、5乳牙），尤 其第2乳磨牙；恒龋的好发牙是第1、2恒磨牙（第6、 7恒牙）尤其第1恒磨牙（俗称“六龄齿”）；恒龋的 好发部位相同都以咬合面为主。 四联致病因素论：1、细菌和菌斑，是根本原因。主 要的致龋菌是变形链球菌，可合成葡糖基转移酶，使 蔗糖转化为高分子细胞外多糖，使牙齿内的酸度增加， 有利于菌斑的形成。2、食物因素，是物质基础，碳 水化合物（尤其蔗糖）是致龋的主要食物，不仅可以 酵解产酸，降低菌斑的PH值，而且参与菌斑形成和 作用，流行病学调查显示，蔗糖消耗量和龋齿发病率 间存在高度正相关。3、宿主，是重要条件。指牙齿 对龋病的抵抗力或敏感性。。4、时间因素是发生过程。 儿童系统防龋法：1.定期检查、早期诊断。2.控制牙 菌斑。3.讲究饮食卫生，增强宿主抗龋力。4.健全学 校口腔疾病防治网。 八、缺铁性贫血：是由不同程度缺铁引起的以小细胞、 血红蛋白低下为特征一类贫血总述。防治要点：一般 治疗（饮食），病因治疗，铁剂治疗，针对性防治综 合措施，预防铁中毒。 九、肥胖：肥胖是在遗传、环境的交互作用下，因能 量摄入超过能量消耗，导致体内脂肪积聚过多，从而 危害健康的一类慢性代谢性疾病。 肥胖的两种类型：一种是单纯性肥胖，主要因摄食量 过多、“以静代动”的生活方式、缺乏运动等原因引 起；另一种是继发性肥胖，因神经-内分泌功能失调或 代谢性疾病引起。 男女18岁时都分别取BMI值24和28为超重和肥胖 界指点。体脂率男超过20%，女14岁以下超过25% 或14岁以上超过30%为肥胖。肥胖的防治：养成良 好的饮食习惯，纠正偏爱高糖、高脂、高热量饮食的 不良习惯。限制过量进食，对体重定期检测，加强体 育锻炼与户外活动。 体育锻炼的卫生要求？1适合年龄、性别和健康情况 2培养体育锻炼的兴趣和习惯3体育教学必须遵循的 基本原则：①循序渐进②全面锻炼③准备和整理运动 ④运动与休息交替 体育课的结构：开始部分2-3min，准备部分6-12min， 基本部分25-30min，结束部分3-5min 体育课的运动负荷决定于课程强度，密度，时间三大 因素 靶心率：达到最大运动强度60%—70%的心率，是判 断体育课运动负荷的常用指标，是运动时需要达到的 目标心率，是判断有氧运动的主要指标。健康人 130-180。=安静心率+（最大心率-安静心率）×60% 评价体育课的运动负荷指标还有脉搏（心率）曲线图、 平均脉搏、脉搏指数（=平均脉搏/安静脉搏）（中学生 1.6~1.8） 学生一天应有至少1小时的体育锻炼时间。注意饭前 饭后一个小时不宜剧烈运动。运动时大量排汗，必须 少量多次饮水，适量补充水分和盐分。在补充水分和 电解质的同时，还应注意适当补充钙等无机盐。 预防运动性创伤方案？1安全防范法2保护帮助法3 量力适应法4准备活动法 体育锻炼的自我监督：1主观感觉，包括运动时的排 汗量，运动后的心情，睡眠食欲等方面的自我感觉， 其他身体疲劳感觉、睡眠、食欲、运动情绪等2客观 评价：内容包括测试脉搏，监测体重，分析运动成绩 的变化、进行体能和其他形态、功能的测量等。 健康监测体系（三部分）：健康体检、检测结果报告、 建立健康档案。 健康教育基本内容：健康行为与生活方式，疾病预防， 心理健康，生长发育青春期保健，安全应急与避险。 大脑皮层功能活动特性及卫生意义：1始动调节：大 脑皮层的工作能力在刚开始时，因脑细胞和其他相关 器官、系统的功能尚处于较低水平，需要一定的起动 时间。伴随工作时的能量消耗，工作能力将逐渐提高， 该现象称~。据此，在学日、学周、学期开始时规定 的学习难度、学习强度都不宜太大，应逐渐增强。2 优势法则：各种脑、体力活动内容，在大脑皮质上各 有其代表区域。皮质能从机体受到的大量刺激中，选 择最符合自身目的和兴趣的一些刺激，在脑皮质引起 强烈的兴奋区域，即优势兴奋性。其兴奋性高于其他 区域，而且能将皮质其他部位的兴奋性吸引过来，加 强自身的兴奋性，又使那些部位处于抑制状态。因此， 优势兴奋性的形成可明显提高学习效率。所以，组织 教学内容时，一定要注意该内容的持续时间应适应受 教育者的年龄特点。3动力定型：如果儿童体内外的 条件刺激按一定顺序多次重复后，在大脑上的兴奋、 抑制过程及与此相关的神经环路将相对固定下来，形 成动力定型。因此，有规律的生活作息、良好的学习 态度、健康的行为方式应从小培养。4镶嵌式活动： 伴随学习性质的变化，脑皮层的功能在定位上（兴奋 区与抑制区，工作区与休息区）相互轮换，称为~。 因此，教学安排中应注意课程性质的轮换，脑力与体 力活动交替，以确保脑皮层在较长时间内保持旺盛的 工作能力。5保护性抑制：一旦大脑皮层的活动超过 其功能限度，皮层反馈性的进入抑制状态，称为保护 性抑制。~是一种生理状态，也是早期疲劳的表现， 对保护脑皮层免受功能衰竭发挥重要作用。因此，教 育过程中如果能注意到学生的早期疲劳表现，适当组 织休息或安排其他活动，脑皮层功能活性将很快恢复； 如果任其发展，不采取劳逸结合措施，学生的疲劳状 态就会持续下去并逐步加重，甚至发展成病理性的 “过劳”状态。 影响脑力工作能力的因素？年龄；性别；健康状况； 遗传；学习动机和兴趣；学习生活条件；养育和生活 方式。 疲劳：在过强、过猛的刺激或刺激强度虽不大但持续 长时间的作用下，使大脑皮层细胞的功能消耗超过限 度，所产生的保护性抑制。是一种生理现象，出现早 期疲劳是学习生理负荷达到临界限度的指标。 试述学生学习疲劳的表现和评价学习疲劳的意义。第 一阶段又称早期疲劳。机制是优势兴奋性降低，不能 实行对周围区域的抑制（内抑制障碍）。表现为上课 时坐立不安，小动作多；注意力转移。条件反射实验 出现错误反应增加。有些人的早期疲劳内抑制表现不 明显，主要反应是兴奋过程出现障碍。早期疲劳的重 要特点是：兴奋过程或内抑制过程中的一个方面有障 碍性表现。第二阶段又称显著疲劳。机制是大脑皮层 的保护性抑制加深、扩散，特点是兴奋过程和内抑制 都减弱或发生障碍。具体表现：上课打呵欠和瞌睡； 对条件刺激的错误反应增多，反应量减少，反应时延 长，有时甚至出现后抑制现象。 学校的作息制度符合哪些原则？1、符合皮层的功能 的特点和脑力工作能力的变化规律，使学习活动与休 息的交替安排合理化2、对不同年龄阶段，不同健康 水平的儿童少年应区别对待，分别制度3、既能满足 学习任务，又要保证学生德智体美全面发展4、学校 与家庭作息制度相互协调统一5、制度一经确定，不 要轻易改变 一日生活制度：1课业学习：小学1、2年级不超过 4h，3、4年级5h，5、6年级6h，初中7h，高中8h； 2、每节课持续时间:小学40分钟；中学45分钟；大 学50分钟3、课外活动：小学生不少于3-3.5h，中学 生2-2.5h，其中至少有1h体育锻炼时间。中学生每周 参加课外体育活动不宜少于3次，每次45min。4、睡 眠：小学生10h，中学生9h，大学生8h。5、休息： 每节课休息10min，第2、3节课间休息20min。炎热 夏季保证短时间午睡。6、自由活动：每天看电视或 课余上网时间不宜超过1h。7、进餐 青少年健康危险行为：凡是给青少年健康、完好状态 乃至成年期健康和生活质量造成直接或间接损害的 行为。特征：1.明显偏离个人、家庭、学校乃至社会 的期望。2.对健康的危害程度各异。3.有个体聚集性 和群体聚集性。4.有鲜明的后天习得性。5.青少年行 为有良好的可塑性。导致的危害：危及健康和生命， 产生潜在危险，引发性传播疾病。分类：易导致非故 意伤害的行为、致故意伤害行为、物质滥用行为、精 神成瘾行为、危险性行为、不良饮食和体重控制行为、 缺乏体力活动行为。 伤害：是由各种物理性、化学性、生物性事件和心理 行为因素等导致个体发生暂时性或永久性损伤、残疾 或死亡的一类疾病的总称。分为非故意伤害和故意伤 害。 儿童青少年意外伤害的危险因素有：宿主因素（年龄 性别种族心理行为特征生理缺陷与特征），家庭因素， 社会因素，物理因素（地区因素），其中伤害事故出 现的两个高峰在婴儿期和青春期 儿童青少年意外伤害的预防控制干预包括教育干预， 技术干预，工程干预，经济干预，称为“四E策略”。 暴力是指蓄意滥用权力或躯体力量，对自身、他人、 群体或社会进行威胁或伤害，导致身心损伤、死亡、 发育障碍或权利剥夺的一类行为 校园暴力：发生在校园内、上下学途中、其他与学校 活动相关的所有暴力行为。分为躯体暴力、言语/情感 暴力、性暴力三种形式。 教学楼的卫生原则：1.保证教学顺利进行。2.光线好、 通风好。3.方便师生课间休息和户外活动。4.保证师 生安全。 教室内部设计的卫生要求？1 足够的室内面积 2 良 好的采光照明和室内微小气候 3防止噪音干扰 4 便 于学生就座和通行，便于清扫和养成良好的卫生习惯。 采光系数：或称自然照度系数，为综合评价教室的采 光状况，指室内某一工作面的天然光照度与同时室外 开阔天空散射光的水平照度的比。一般最低采光系数 不低于2.0% 教室课桌面的平均照度不应低于300lx，黑板面平均 垂直照度不应低于500lx，照度均匀度不低于0.7 教室人工照明的卫生要求：保证课桌面和黑板面上有 足够照度，照度充分均匀；不产生或少产生阴影，没 有或者尽量减少眩光作用；不因人工照明导致室内温 度过高而影响空气的质量和安全性。 桌椅高差：为桌近缘高与椅高之差。1/3坐高+1~2cm 课桌椅尺寸有11个型号，不同身高不同型号，桌椅 配套，同号搭配。 教室自然采光的卫生要求：满足采光标准，课桌面和 黑板上有足够光照；照度分布均匀；单侧采光的光线 应自学生作为左侧射入，双侧采光也应将主要采光窗 设在左侧；避免产生较强的眩光作用，创造愉快、舒 适的学习环境。 玻地面积比不低于1：5 黑板反射系数<20% 投射角不小于20~22°，最小开角不小于5°。 室深系数不小于1:2。 采光方向：南北向双侧，左侧 学校卫生监督：是指卫生行政部门依据国家相关法律、 政策和学校卫生标准，对学校建筑设备、学校生活环 境、学生用品、学校卫生服务工作等进行监督检查的 系列性执法活动。

大屏显示系统技术方案(完整资料).doc

【最新整理，下载后即可编辑】 校园能耗监测平台 拼接屏显示系统方案 2015年4月 一、系统原理说明 大屏幕液晶拼接墙本质就是一台信源可以自由切换、图像可以拼接组合的多功能液晶显示设备；客户视频信号通过矩阵接入液晶拼接单元的视频输入口，通过控制矩阵和大屏拼接软件，就可以实现视频信号的随意拼接显示、或单屏显示或整屏显示。

二、拼接显示系统 1、系统描述 利用液晶拼接控制器（嵌入式硬件拼接系统），在简约灵活的软件操作界面上可以实现大屏开关机，大屏输入信源的切换（有BNC/VGA/DVI/SVideo/YPbPr五种格式信源输入），大屏的随意拼接组合。 2、系统特点 液晶拼接屏建设技术规范 《社会治安动态视频监控系统技术规范》（DB33/T 502—2004） 《视频安防系统技术要求》（GA/T367-2001） 《民用闭路监视电视系统工程技术规范》(GB50198-94) 《信息网络数字视频应用系统规范》（BJ/Z0001-2003） 《信息技术开放系统互连网络层安全协议》（GB/T 17963）《电子计算机机房设计规范》(GB50174-93） 《安全防范工程程序与要求》(GA/T75-94) 《建筑物防雷设计规范》(GB50057-94) 《建筑物电子信息系统防雷技术规范》(GB50343-2004) 《民用建筑电气设计规范》(JGJ/T16-92)

《建筑钢结构焊接规程》（JGT81-91） 《广东省社会治安视频监控系统数据传输技术规范》《钢筋混凝土施工规范》 47″LCD 单元主要技术指标

拼接墙主要技术指标 LCD屏数量2行×3列(任意行（M）×任意列（N）) 两屏之间间隔 5.5mm（46″） 面板安装方式无键挂入式安装方式 电源输入90～260V AC（50/60HZ） 功率消耗300W×M×N（46″） 工作环境0℃～50℃工作温度10～90%工作湿度 机柜/机架材料全钢/铝合金

建筑名词解释

『台基』建筑名词解释 台基 就是建筑物的底座。四面以砖石砌成，内多填土，地 面铺以砖石。 须弥座xūmízu?原为佛象底座。由印度传入中国後，被用作尊贵建筑的底座。它的组成为圭角、下枋、下枭、束腰、上枭、上枋等。 如故宫三大殿的台基就是简约式的须弥座。 踏跺 tàdu? 就是用来登上台基的阶级。 龙尾道 在坡道较长的情况下，会用平、坡相间形式建造的阶 榜。 慢道较为平缓的阶梯或斜道。 礓碴 jiāngchá是将砖石打侧，以其梭角所砌成的斜道，给人和马车登上台基。形状就像洗衣板。 辇道 niǎndào 有斜度的路，方便马车通行。於唐宋时期，设置於踏跺之间。後来，辇道被加上水、云、龙等雕刻，渐渐演变成今天的「御路」。 陛石bìshí用作铺设御路的石块。 如故宫保和殿北面御路的大石雕。 角石 用于宋式台基的角位，常雕刻有龙、凤、狮子等装饰。 清代台基是不用角石设计。 螭首螭是传说中有角的龙。突出的螭首雕刻设置在台基外

chīshǒu部。除美观外，它用作为排走雨水的出水口。 如天坛祈年殿的龙、凤、云三种形式的螭首。『柱』建筑名词解释 柱zhù就是建筑物的底座。四面以砖石砌成，内多填土，地面则铺以砖石。 柱础是垫著木柱的石墩。 鼓镜是指柱础凸出于地面的部份。 覆盆唐宋时期，常用的鼓镜设计，像倒转的碗。 鼓蹬 因南方天气潮湿，所以柱础都设计成较高身的鼓状石 墩，称之为鼓蹬。 檐柱yánzhù建筑物最外的一列柱子，用来支撑屋檐的重量。通常建筑物有前後两列檐柱。 中柱 位处建筑物中轴线上的柱子，用作支撑屋脊的。但中 柱不包括在山墙之内的柱子。 山柱设在山墙内，顶著屋脊的柱子。 角柱位处山墙两端，建筑物转角的柱子。 金柱除檐柱、中柱、山柱外，其他柱子都称作金柱。 外金柱距离檐柱较近的柱子为外金柱。 里金柱 「里」和「外」是相对的，距离檐柱较远的柱子便称 作里金柱。

儿少卫生学练习题名解+问答

《儿童少年卫生学》预防医学091班 一、名词解释 1、儿童少年卫生学是保护和促进儿童少年身心健康的科学，是预防医学的重要组成部分。 2、生长指细胞繁殖、增大和细胞间质增加，表现为组织、器官、身体各部以至全身的大小、长短和重量的增加以及身体成分的变化，为量的改变。 3、成熟指生长发育基本结束时，形态、功能方面达到成人水平，各器官、系统功能基本完善，骨骼钙化完成，性器官具有繁殖子代的能力。 4、生长轨迹现象人在生长的过程中，一旦因疾病、营养不良、内分泌障碍等因素影响而出现明显的生长发育延迟时，只要及时采取针对性的措施加以校正。就会出现向原有生长曲线靠近的倾向。这种倾向称做生长轨迹现象。 5、头尾发展律指在胎儿期和婴儿期，人体的生长发育首先从头部开始，然后逐渐延伸到尾部（下肢）部。胎儿期和婴儿期生长发育遵循此规律。 6、向心律儿童、青春期的形态发育遵循下肢发育先于上肢，四肢早于躯干，呈现自下而上、自肢体远端向中心躯干发育的规律变化，称为生长发育的向心律。儿童、青春期生长发育遵循此规律。 7、遗传度是指在群体表型特征两变异中，遗传变异所占的比例。遗传度介于1和0之间，越接近于1，提示遗传的作用越大；越接近0，说明环境的作用越大。 8、矮身材指该儿童的身高低于其年龄相应标准的第3百分位数以下。 9、性早熟指男孩在9岁以前出现睾丸增大，女孩在8岁以前出现乳房发育或10岁以前来月经初潮者。 10、注意缺陷多动障碍也称多动症，指由非智力因素引起的、与年龄不相符的注意障碍、冲动、活动过度，并伴有学习困难和社会适应力低下的一组儿童行为异常症候群。 11、青少年健康危险行为 指“凡是给青少年健康、完好状态乃至成年期健康和生活质量造成直接或间接损害的行为”。 12、始动调节大脑皮层的工作能力在工作刚开始时水平较低，经启动过程逐渐提高，这一现象称为始动调节。 13、临界照度室内天然光照度等于标准规定的最低值时的室外照度称为临界照度，也就是需要开启或关闭人工照明时的室外照度极限值。标准规定的的临界照度为5000lx。14、学生健康监测指采用抽样调查方法，对确定的监测学校和目标人群进行生长发育、健康状况等长期的动态观察。 15、玻地面积比采光口有效的采光面积与室内地面积之比。 二、简答题 1、近年来，儿少卫生学的发展特征有哪些？ （1）高度重视主要服务对象；（2）制定工作目标和提出干预措施时，不仅关注生长发育及其影响因素，学生常见病和伤害防治，而且充分考虑其心理—情绪—行为发展特征和实际需求，通过学校健康教育和开展健康促进学校，为儿童少年营造良好的学校环境，满足教育、教学需求，促进良好人际关系的建立；（3）核心任务：针对青春期少年的身心发展过渡性特点和特殊问题，提供良好的教育、保健和医疗服务。 2、请说出儿少卫生学的主要研究内容。 生长发育、疾病防治、心理卫生、教育过程卫生、学校健康教育、学校卫生监督和学校建筑设备卫生。 3、以身高为例阐述青春期生长突增现象。 身高生长突增现象的出现，通常提示了男女儿童进入青春期的开始。突增开始的年龄，女性比男性早2年左右。女孩约在9～11岁开始，男孩约为11～13岁。突增的幅度也不一样。男孩每年可增长7～9cm，最多可达10～12cm，在整个青春期身高平均增加28cm；女孩每年约增长5～7cm，最多可达9～10cm，整个青春期约增长25cm。

大屏多功能系统解决方案

建设单位:XXX控制指挥中心设计编号:KB-20100802-1 设计日期:2010-08-02

前言： 液晶拼接显示屏：DID(Digital Information Display)是目前视频显示行业最流行的一个词汇。他承载着多年来视频领域的一次次变革和发展。从CRT、LED、DLP、LCD、MPDP 再到DID，不仅代表着市场的需要，更代表着人类对高清显示技术的不断追求。 液晶拼接显示屏：凭借着高寿命：60000h，高亮度：1500cd/m2，高对比度：5000： 1、高分辨率：1920×1080、宽视角：178o、高负荷工作：支持365天×24时不间断工作、 高端特殊显示要求。以无环境要求、无须管理要求、无须售后考虑等优点，已屹立于液晶显示系统行业龙头地位。 随着各消费领域对大画面显示要求的不断提高、不断追求,视频显示领域也发生着一次次的变革,从单一的画面显示到多画面显示，再到多块显示屏可任意拼接、任意高清画中画，无一不是挑战人类对无限宽广视角的苛刻追求！ 各领域的显示不同，应用也有所不同。工业电力调度中心、水利调度指挥中心的显示系统；对长时间工作，静态画面的显示提出严格的要求，出色的液晶拼接显示系统解决了其积极严酷的显示难题。 国防指挥中心大屏显示系统、航空航天控制中心拼接显示系统要求在多画面、多功能、高负荷、长时间、高稳定性情况下工作下不能出现任何问题，出色的纯硬件多屏处理器为其解决一切后顾之忧。 公安指挥调度中心、交通运输监管中心、石油勘测、地质资源分析中心、金融贸易、地铁站等大屏幕拼墙显示系统、医疗研究、学术交流中心、电视台演播厅、企业产品展示厅、厂矿、监控中心拼墙显示系统等领域要求多画面独立显示，同时多画面开窗、画面漫游、画面叠加、画面阵列、网络抓图等特殊功能要求，液晶拼接显示系统无不担当着重要任务，液晶多屏拼接处理器出色的完成各项高尖端任务已得到各个显示领域的喝彩！ 液晶显示技术不仅仅在工业领域内工作出色，现在已经延伸到各行各业。丰富多彩的多媒体信息也不得不借助DID LCD的小巧、轻薄、超长时间工作等优点来解决显示问题，在其它各公共场所的发布和显示中无处不见到DID LCD的身影！ 为满足各行各业的现场显示要求，越来越多的显示领域和专业人士均采用新的DID LCD解决方法和工具来解决数据显示和演示分析等问题。中发送的信息我们可以感受到，大画面显示所带来的宽广视野无处不在、无所不能和无限快乐！

建设工程名词解释

建设工程名词解释 饶志辉 1 结构转换层：建筑物某层的上部与下部因平面使用功能不同，该楼层上部与下部采用不同结构类型，并通过该楼层进行结构转换，则该楼层称为结构转换层。 2 冷剂压套筒接头： 3 沥青橡胶应力吸收薄膜： 4 冷桥现象：房屋外墙转角、内外墙交角、楼屋面与外墙搭接角的区域范围，在室内温度高于室外温度时候，产生水雾吸附于墙面的现象称为"冷桥"现象，大多出现在冬季。 5 银粉、金粉：含金属涂料的油漆。 6 （越岭线）垭口：山口。 7 路灯、草坪灯、庭园灯、地灯：路灯：装在道路上照明用的灯。草坪灯：草坪灯的设计主要以外型和柔和的灯光为城市绿地景观增添安全与美丽，并且普遍具有安装方便、装饰性强等特点，可用于公园、花园别墅、广场绿化、等场所的绿化带的装饰性照明。地灯：安装在地面上或接近地面位置上的灯。 8 两带：灞河滨水生活蓝带和浐河城市生态绿带。 9 绿肺：比喻能吸收二氧化碳并释放出氧气的绿地、森林等。 10 电气元器件气候防护：潮湿、盐雾、霉菌以及气压、污染气体对电子设备影响很大，其中潮湿的影响是最主要的。通常采用浸渍、灌封、密封等措施。

11 牛腿、肩梁： 12 声发射定位信号： 13 错层结构：是指在建筑中同层楼板不在同一高度，并且高差大于梁高（或大于500毫米）的结构类型。 14 红外轴温探测系统： 15 虚拟仓库：如果建筑材料市场离得不远的话，可通过信息系统对部分材料建立一个虚拟仓库，从而实现零库存。 16 高压射流技术、真空泵技术、以及射流泵的出现、液压技术的进步、超声波检测技术： 17 WSS无收缩深孔注浆技术： 18 三轴搅拌桩：是长螺旋桩机的一种，同时有三个螺旋钻孔，施工时三条螺旋钻孔同时向下施工，是软基处理的一种有效形式，利用搅拌桩机将水泥喷入土体并充分搅拌，使水泥与土发生一系列物理化学反应，使软土硬结而提高地基强度。 19 工程地质与基坑开挖深度及地连墙墙趾关系图： 20 透水砖：也叫渗水砖、荷兰砖。 21 水幕降尘器：是一种比较传统且常用的降尘方法。 22 水泡泥技术：一种隧道爆破时降低粉尘的技术。水泡泥就是用装水的塑料袋填于炮眼内来代替一部分泡泥，装完药后将其填于炮眼内，尽量不要搞破，然后用黄泥封堵。实践表明，此法降尘效率非常高。 23 单向阀：单向阀是流体只能沿进水口流动，出水口介质却无法回流，俗称单向阀。单向阀又称止回阀或逆止阀。用于液压系统中防止