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REVIEW ARTICLE
Year : 2017  |  Volume : 6  |  Issue : 2  |  Page : 73-81

Synergetic immunotherapies and current molecular targets in oral cancer treatment


1 Department of Oral Pathology and Microbiology, Vishnu Dental College, Vishnupur, Andhra Pradesh, India
2 Department of Oral Pathology, SJM Dental College, Chitradurga, Karnataka, India

Date of Web Publication13-Jun-2017

Correspondence Address:
N Pallavi
Department of Oral Pathology and Microbiology, Vishnu Dental College, Vishnupur, Bhimavaram - 534 202, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JDRNTRUHS.JDRNTRUHS_6_17

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  Abstract 


The development of cancer therapies depends on identifying exploitable differences between the host immune response and the tumorigenicity. These include anatomic, metabolic, cell cycle kinetics, and presumed antigenic differences between the normal tissue and tumor cells. Immunotherapy also called biologic therapy is a treatment that uses body's own immune system to fight against cancer. Cells such as dendritic cells (DCs), natural killer cells, effector T-cells, and molecules such as complement can be used in various treatment modalities which are segregated as “active” and “passive” based on their ability to engage the host immune system. Further both active and passive immunotherapies can be subdivided into specific and nonspecific approaches. Thus, it is essential to understand the therapeutic approaches and the vaccines made based on the role played by these cells and molecules to circumvent the barriers of tumor microenvironment for an antitumor response. Hence, through this article efforts were made to comprehensively explain the concepts of cancer vaccines and immunotherapies in the treatment of oral cancer.

Keywords: Adoptive cell therapy, cancer vaccine, complements, dendritic cells, immunotherapy, natural killer cells, oral cancer, tumor-targeted monoclonal antibodies, tumor microenvironment


How to cite this article:
Nalabolu GK, Pallavi N, Hiremath SS, Birajdar SS. Synergetic immunotherapies and current molecular targets in oral cancer treatment. J NTR Univ Health Sci 2017;6:73-81

How to cite this URL:
Nalabolu GK, Pallavi N, Hiremath SS, Birajdar SS. Synergetic immunotherapies and current molecular targets in oral cancer treatment. J NTR Univ Health Sci [serial online] 2017 [cited 2017 Sep 26];6:73-81. Available from: http://www.jdrntruhs.org/text.asp?2017/6/2/73/208011




  Introduction Top


Tumors are immunogenic,[1] i.e., they can evoke an immune response through the antigens expressed over the cancer cells which are recognized by the immune system.[1] Immune system consists of cells, tissues, and molecules which also form components of tumor microenvironment. These components of immune system are considered as important aspects in cancer biology.[2] Immune-mediated cells such as dendritic cells (DCs), NK (natural killer) cells, effector T-cells, and complement molecules drives antitumor immune responses whereas tumor cells induce immunosuppressive tumor microenvironment. The immune cells balance the immunosuppressive subpopulation such as myeloid derived suppressor cells and T-regulatory cells (which suppress the function of other T-cells and limit the immune responses) maintaining an equilibrium, resulting in termination of tumor progression. Loss of equilibrium favors upregulation of immunosuppressive sub-population which is in favor of tumor microenvironment to bring about tumor growth.[3],[4] This reflects that the immune system and the developing tumors are intertwined.[3],[4] Thus tumor microenvironment is a platform for Tumor initiation and progression as well as for therapeutic responses.

Understanding the complexity of immunomodulation by tumor is important in developing various treatment strategies to intervene therapeutically at critical points to promote antitumor immune responses. Such interventions broadly fall under the entity “immunotherapy”. Immunotherapies can be classified into two broad categories: active (attempts to induce host immune responsiveness towards the tumor) and passive (are immunologically active reagents directly transferred to host to mediate antitumor response) [Table 1].[4],[5]
Table 1: List of anticancer immunotherapies

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Tumor-targeting monoclonal antibodies (mAbs) and adoptively transferred T-cells are passive forms of immunotherapy conversely anticancer vaccines and checkpoint inhibitors act as active forms of immunotherapy. As in all such classifications, these distinctions were poorly elucidated.[4] For example, mAbs usually passive may induce a host specific antitumor response indirectly performing active therapeutics.

Search for the accurate treatment of oral cancer has added several layers of complexity into the scientific literature. Hence to understand the anticancer treatment modalities, it requires a comprehension of molecular basis of immunity. Present review summarize the recent advances of immunologic approaches for cancer treatment covering both active and passive modes of therapies as mentioned in [Table 1].

Tumor-targeting monoclonal antibodies in Immunotherapy

The antigens on the cancer cells are over expressed, mutated or selectively expressed when compared to the normal cells.[1] These antigens should be identified so that they are suitable for antibody based therapeutics. Also these should be accessible, abundant, and their expression should be homogenous, consistent, and exclusive to tumor cells. Antibodies identifying these antigens on cancer cells can be made in the lab and used in cancer therapeutics. Such antibodies are termed as mAbs. mAbs act by targeting the: (1) Receptors present on the malignant cells which consequently alters the signaling process [Figure 1] and [Figure 2]; (2) Trophic signals produced by the malignant cells or stromal cells by binding to the signals or neutralizing them [Figure 3]; (3) Selective recognition of tumor-associated antigens (TAA) expressed on the malignant cells; which is the common target for mAb [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8].[6],[7],[8],[9]
Figure 1: Direct killing of tumor cells through activating their lethal receptors by mAb; TRAIL-R: Tumor necrosis factor (TNF) related apoptosis inducing ligand receptor

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Figure 2: Receptor antagonism by mAb resulting in loss of dimerization and disruption for signal cascade leading to reduced proliferation of tumor cells and induction of apoptosis

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Figure 3: Enzymes required for initiation of signaling in the tumor cells are neutralized by the mAb which prevents tumor cell apoptosis leading to their survival. The image also depicts tumor associated antigen and drug conjugated antibody complex for the delivery of drug either into the cytoplasm or nucleus of tumor cell causing their death

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Figure 4: Fc dependent phagocytosis – tumor cells opsonized with mAb are recognized by the Fc receptors on macrophages stimulating lysosomal degradation of tumor cells

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Figure 5: Complement pathway – Tumor cells opsonized with mAb are identified by complement molecules which lead to formation of membrane attack complex thereby tumor cell death

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Figure 6: Antibody dependent cellular cytotoxicity is mediated through the mAb that are recognized by Fc receptors on natural killer (NK) cells. NK cell releases granzyme and perforin which causes apoptosis of tumor cells

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Figure 7: Chimeric T-cells kills the tumor cells and secretes T-cell effector cytokines to promote endogenous antitumor immune response

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Figure 8: Tumor cells coated with mAb mediate cross presentation of tumor derived antigen or peptide to CD8 T-cells along with CD4 T-cells resulting in T-cell activation and tumor cell death. Antibodies targeting negative regulatory receptors like cytotoxic T lymphocyte associated antigen 4 (CTLA 4) also enhances T-cell activation and thus tumor cell death

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The tumor targeting mAb can function in five functionally distinct forms. (1) Naked mAb that inhibits the signaling pathway of neoplastic cells [Figure 2]; e.g., cetuximab (2) Naked mAb that activates lethal receptors on neoplastic cells [Figure 1]; e.g., tigatuzumab (3) TAA specific mAb coupled to toxins or radionucleotides commonly known as immune conjugates [Figure 3]; e.g., gemtuzumab, ozogamicin (4) Naked TAA specific mAb that opsonize neoplastic cells and promotes; antibody-dependent cell-mediated cytotoxicity (ADCC) [Figure 4], complement-mediated cytotoxicity (CDC) [Figure 5], antibody-dependent cellular phagocytosis (ADCP)[Figure 6]; e.g., rituximab (5) A chimeric protein with two single-chain variable fragments from mAb with one for TAA and other for T-cell surface antigen that is called as “biphasic T-cell engagers” [Figure 7]; e.g., blinatumomab [Table 2].[6],[7],[8],[9]
Table 2: Various mechanisms of tumour cell killing

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The first two forms have intrinsic antineoplastic activity and also mediate immunostimulatory effects such as execution of antiangiogenesis, boosting B and T-cell tumor infiltration while inhibiting regulatory T-cells.[6] There can also be lack of tumor response to antibody therapy because of antigen or receptor heterogenecity, mutation, low antibody-to-receptor concentration, receptor saturation, ineffective blockade of receptor dimerization, and signaling.[7]

Adoptive cellular therapy

“Adoptive cell transfer”/“Adoptive cellular therapy” (ACT) involves selection and collection of circulating lymphocytes. The collected T-cells include tumor infiltrating lymphocytes (TILs), T-cells engineered to express a cancer-specific T-cell receptor (TCR) and an chimeric antigen receptor (CAR).[10],[11],[12],[13]

CARs are hybrid receptors on T-cells constituting an ectodomain, transmembrane domain, and endodomain. Ectodomain comprises of the single chain variable fragments (scFv) from both heavy and light chains of mAb which usually form the antigen binding site. Ectodomain recognizes the TAA present on the tumor cells. Transmembrane domain is the structural link between ectodomain and endodomain. Endodomain is an intracellular signaling domain that transmits signals to the T-cell molecule.[14],[15],[16] CAR-T-cells recognize TAA and exert cytotoxic effect in an major histocompatibility complex independent mode (MHC-independent mode).[17],[18] Those collected T-cells are then expanded, activated ex vivo and (re-) administrated into patients. These infused T-cells are enriched with potentially tumor-reactive immune response [Figure 9].[12],[13],[17],[18] Several cytokines are required for expansion, activation, and migration of transferred T-cells. Few cytokines are delivered by the host and few are introduced exogenously. The exogenous cytokines like IL-2(interleukin-2), IL-15 and IL-21 stimulate the host cytokine cascade which endows survival and activation of adopted T-cell.[6]
Figure 9: Step-wise illustration of adoptive cellular therapy

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The genetically engineered T-cells have the benefit of unique antigen specificity, an increased proliferative potential, an improved secretory profile, an elevated tumor infiltrating capacity, and superior cytotoxicity.[6],[19],[20]

There are also certain disadvantages in genetic engineered T-cells, i.e., unexpected toxicities. Toxicity can arise when an unintended structure is recognized by the T-cells owing to antigenic mimicry or cross-reactivity. In due course these toxicities can result in tissue destruction and can cause cytokine storm.[21] To prevent the adverse toxicity new technologies are introduced for obliteration of T-cells that are made to express inducible form of caspase-9 which upon activation by a biocompatible drug causes T-cell death.[20]

Dendritic cells

DCs are produced in bone marrow, they have two life stages; mature and immature. These DCs link the innate and the adaptive immune response. The mature cells continuously monitor the tumor microenvironment, capture the tumor antigen, and transport them to local lymph nodes. In lymph nodes, they present peptide epitope to specific T lymphocytes through MHC molecule and a costimulatory molecule such as B7 whereas the immature DCs can also internalize antigens through Fc receptor-mediated endocytosis.[22],[23] Toll-like receptors (TLRs) aid in activating DCs to prime T-cells which leads to T-cell clone expansion and differentiation into effector cells to promote immune response respectively [24] [Illustration:1] and [Illustration:2].



DCs biology can be used to develop immunotherapy for patients; there are two general approaches to achieve this end: ex vivo and in vivo activation. These immunotherapies targets by introducing tumor specific effector T-cells which can thereby eliminate the tumor mass and induce immunological memory to control tumor revert. Ex vivo strategies include generation of DCs from circulating monocytes via subsequent culture and from circulating hematopoietic stem cells (HSCs). US Food and Drug Administration (FDA) has approved ex vivo activated DCs, Sipuleucel T (trade name) which is generated by incubating a patient's monocytes with a fusion protein that associates the target antigen to cytokine granulocyte-monocyte colony-stimulating factor (GM-CSF). GM-CSF serves to mature the monocytes toward DCs, and assists in internalization of the antigen. After ex vivo incubation, the cellular product along with maturing DCs is re-infused into patients.[10],[25]

Other common approach of DC-based immunotherapy includes maturation of immature monocytes into DCs, which is brought about by culturing them for several days in GM-CSF with IL-4. The DCs will be loaded with tumor-specific peptides or with whole protein antigens. The selection of tumor antigens or peptides loaded in DCs is important. The DC will process the peptides or whole protein loaded within them and presents them to T-cells. Ex vivo stimulation of DCs often results in quantifiable immune and clinical responses with no dose limiting toxicities. However, this DCs based therapy had overall low clinical response rates.[10],[25] We hypothesize that this could be due to constant mutations occurring in tumor cells leading to variability in peptide structures and inability to recognize those peptides by T-cells.

The in-vivo approach of DCs based therapy includes: (1) Use of an adjuvant, (2) Signaling antibodies in tumor-specific antigen and (3) Injection of irradiated—cytokine-secreting whole tumor cells. After which DCs phagocytize the tumor cells and present tumor antigens to T-cells.[26] These therapy targets antigens precisely towards DCs that elicits CD4 and CD8 T-cell mediated immune response.[25] Other approaches that promote in vivo DCs priming of tumor-specific T-cells involve tumor cells loaded DCs which are matured ex-vivo and re-infused into patients thereby leading to their activation. DCs can also be activated by exposure of tumor cells which are killed by chemotherapy or targeted therapy.[26]

Peptide and DNA-based cancer vaccines

Therapeutic cancer vaccines should have ability to kill tumor cells with specificity and impart enduring immune response. Cancer vaccine should select an antigen (which should be homogenously expressed on tumor cells, but not on normal cells) involved in pathogenesis of cancer. Also, the antigen must be presented to the immune system in an effective vaccine platform that can drive cellular responses specifically targeting the antigen.[27],[28]

Malignant cells express antigens or polypeptides that are invariably different from normal cells. These antigens or peptides can be harnessed to elicit specific immune responses. This can be achieved by administrating purified or recombinant TAAs or peptides in the presence of immunostimulatory agents, i.e., adjuvants [29] such as TLRs, alum, liposomes, and emulsions.[30] One such approach is peptide based cancer vaccines which are prepared from single epitopes, (the minimal immunogenic region of an antigen).[31] Short and long peptides can be used. The therapeutic activity of synthetic long peptides is superior comparatively, when they include epitopes recognized by both cytotoxic and helper T-cells or when conjugated to efficient adjuvants; e.g., vitespen.[6] Peptide vaccines are simple, safe, stable, and economical, as well as easy to produce and store. They have poor results that are probably due to immunosuppressive tumor microenvironment that evades natural and therapeutic endowed immune surveillance leading towards tumor progression.[31]

DNA-based vaccines either become a source of TAA or transform antigen presenting cells (APCs) to elicit immune response. The vaccine in the presence of adjuvants stimulates DCs or APCs to prime immune responses targeting TAAs, thereby promoting host immune system to mediate antineoplastic activity.[6]

Immune check point blockades

T-cell activation, a relatively complex process plays an essential role in adaptive antitumor immune response. It is influenced by several cytokines which modulate the function of signal transducers and activator of transcription (STAT) proteins especially STAT 4 necessary for T-cell mediated antitumor immune response. STAT 4 is activated by IL-12, bringing about skewing of T-cells towards T-helper Th phenotype and interferon-γ (IFN-γ) production. IFN-γ are usually produced by NK cells, NKT cells, CD4 and CD8 cells. These cells activate macrophages and MHC molecules resulting in antigen recognition and T-cell activation.[10]

For antitumor immune response the T-cells should recognize the cognate antigen with appropriate costimulatory molecules expressed over them, i.e., CD28 on T-cells and B7 on APCs. CD28 functions by increasing the T-cell expression of antiapoptotic proteins (Bcl-xL) and autocrine growth factors such as IL-2. Disruption of this interaction by cytotoxic T lymphocyte antigen-4(CTLA4) on T-cells with B7 is referred to as coinhibition. In addition to CTLA-4, TILs may express the negative regulatory receptors such as programmed cell death protein 1 (PD1), lymphocyte activation gene 3 protein (LAG3), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3). Blockade of CTLA-4, negative regulatory receptors could mitigate inhibition of antitumor immune responses and improved antitumor immunity respectively. These can be used as biomarker for checkpoint blockade therapy. The ultimate result is that the tumor vaccine produced should activate APCs to express appropriate costimulatory molecules to promote antitumor immune response mediated through intracellular signaling pathways [Illustration:3].[10],[32],[33]



Followed by activation of T-cells, a sub-population becomes memory cells with comparatively enhanced functional responses on re-encounter of antigen. These cells have potential to decrease the metastatic spread and prevent regrowth of tumor after the first incidence. The other function of memory cells is to limit the de-novo stimulation of secondary malignancies. Thus aids in antitumor immune response.[10],[33]

Natural killer (NK) cell-mediated immunotherapy

Surgery, chemo, and radiotherapies have played key roles in treatment of cancer but in many cases they do not represent a cure because the host immune system does not work efficiently. There is every need to improve the host immune system against cancer which is brought about by NK cells [Illustration:4]. Cancer cells also develop mechanism to escape NK cells or induce defective NK cells.[34]



NK cells get activated through administration of cytokines (IL-2, IL-12, IL-15, IL-18, IL-21, and type I IFNs) which later differentiate into lymphokine-activated killer (LAK) cells. These cells endow cytotoxic effects on the malignant cells through upregulation of effector molecules such as perforin, granzymes, FasLigand (FasL), tumor necrosis factor related apoptosis-inducing ligand (TRAIL). LAK cells also enhance cytokine production which mediates cytotoxic tumor cell death and production of antitumor antibodies. NK cell tumor interaction can be boosted up by certain genetic modifications inorder to express cytokine transgene, to overexpress activating receptors, silencing inhibitory receptors, and retargeting NK cells by using chimeric receptor. These modifications are beneficial for increased proliferative rate, survival ability, and in vivo antitumor activity.[34],[35],[36]

Another approach known as NK cell-based autologous immune enhancement therapy (AIET) is one such treatment method in which some NK cells are taken from peripheral blood of a patient and cultured In such a way thatl they are resistant to cancer. Later they are readministered into patient for expansion of NK cells. into patient. These cells attach to the membrane of the Cancer cells and inject toxic granules (ADCC). This causes quick dissolution of target cell; it is said that it takes less than 5 min for such dissolution. NK cell during its life time (7–10 days) can kill 27 cancer cells.[34],[37]

Cytokines in immunotherapy

Cytokines are molecular messengers that communicate with the immune effector cells and stromal cells at the tumor site and enhances cytotoxic T-cells. They are administered systemically for the treatment of various human tumors. The largest clinical experience is with IL-2 administered in high doses alone or in conjunction with LAK cells. By administration of IL-2, there is increase in numbers of T lymphocytes, B lymphocytes and NK cells resulting in increased serum tumor necrosis factor (TNF), IL-1, and IFN-γ concentrations.[3]

Administration of type I IFNs (α and β) induces MHC I display by the tumor cells and mediate maturation of DCs. They also activate cytotoxic T-cells, NK cells and macrophages by exerting apoptotic and antiangiogenic effect. The severe toxicities associated with high doses of IL-2, IL-2+LAK cells and type I IFNs include fever, pulmonary edema, and capillary leak syndrome.[38],[39]

Type II IFN (IFNγ) activates macrophages and induces expression of MHC I, II, and costimulatory factors by APC. They promote T-helper (Th) 1 differentiation from CD4 effector cells. IL-2 has been effective in activation and expansion of CD4, CD8 and NK cells. It is also effective in inducing measurable tumor regression in patients with advanced melanoma and renal cell carcinoma. Currently, the potential of IL-12 to enhance antitumor effect via T-cells and NK cells has aroused great interest and phase I and II trials are being conducted on patients with advanced cancer. Hematopoietic growth factors, including GM-CSF, G-CSF, and IL-11 are used in cancer treatment protocols to shorten periods of neutropenia and thrombocytopenia after chemotherapy or autologous bone marrow transplantation.[3],[38],[39],[40],[41]

Immunomodulatory mAbs Immunomodulatory mAbs in immunotherapy

In contrast to the tumor targeting mAbs the immunomodulatory mAbs mediate through altering the function of soluble or cellular components of immune system. The alterations are brought about by: (1) Inhibition of immunosuppressive receptors on activated T-cells (CTLA 4 and PD1 – the usual checkpoint blockades) or NK cells (killer cell immunoglobulin-like receptor-KIR), (2) Inhibition of ligands of these immunosuppressive receptors, (3) Activation of costimulatory receptors, (4) Neutralization of immunosuppressive factors such as transforming growth factor (TGF)-β. Immunomodulatory mAbs intervening the checkpoint blockades have shown durable responses; e.g., ipilimumab and nivolumab.[6]

Pattern recognition receptor agonists in Immunotherapy

Exogenous threats and endogenous stress are detected by precise machinery called pattern recognition receptors (PRRs). PRRs are broadly classified based on their location (e.g., plasma membrane, endosomal vesicles, and cytoplasm) and by molecular structural similarities. By structural similarity they include TLRs, nucleotide-oligomerization domain (NOD)-like receptors (NLRs), C-type lectin receptors (CLRs), and the retinoic acid-inducible gene I (-RIG-I)-like receptors (RLRs).[42],[43]

PRRs recognizes pathogens through engaging the pathogen-associated molecular patterns (PAMPs) of all class of microorganisms and danger-associated molecular patterns (DAMPs) that are released by cells during stress, injury, or cell death. PAMPs and DAMPs recognition is followed by initiation of signaling cascade by secretion of proinflammatory cytokines, type I IFN, TNFα, and chemokines. Ultimately this favors the maturation of DCs as well as the activation of macrophages and NK cells to control immune responses. Thus, there is a scope for PRRs to use as adjuvants and as vaccines. The antineoplastic effects of PRR agonists stem from their ability to engage innate and adaptive immune responses, thus ultimately providing interesting prospects in the treatment of cancers; e.g., imiquimod, mifamurtide, and picibanil.[6],[44],[45],[46]

Immunogenic cell death inducers in Immunotherapy

Death of malignant cells by some chemotherapeutics (at regular doses) and radiation therapy stimulates release of DAMPs. Such DAMPs are recognized by PRRs on APCs (such as TLR 4). Subsequently it triggers the maturation of APCs and engulfment of the TAAs and malignant cell debris. Through this process APCs can endow tumor specific immune response and can maintain immunological memory. Such death of malignant cells that had paved a path for the activation of immune system against cancer is called as immunogenic cell death (ICD). Certain stimulus is required for the ICD activation which includes few therapeutic agents and vaccines against cancer; e.g., bleomycin, doxorubicin, mitoxantrone, oxaliplatin.[6],[47],[48],[49]


  Conclusion Top


The immune system is capable of recognizing and rejecting tumors. Both humoral and cell-mediated immune responses are potentially important for tumor immunity. Nevertheless, the fact that some tumors grow progressively despite evidence of immune Recognition. This demonstrates the difficulty of controlling large or metastatic tumors with the immune system. Immunotherapeutic strategies have encountered these obstacles and the on-going research is aimed at better understanding the principles and more effective manipulation of the immune response against oral cancer. These varied efficacious immunotherapies help in better clinical success promoting prolonged patient survival rate, which is absolutely a great success. This great achievement is never far, all but next to our doors in the near future. We conclude that cancer is a disease of host cells so the treatment also should be from the host immune cells.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
 
 
    Tables

  [Table 1], [Table 2]



 

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