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NO also is co linked to VEGF which in turn increases the antiapoptotic gene bcl-2

The other important influence of NO is in its inhibition of the proapoptoic caspases cascade. This in turn protects the cells from intracellular preprogrammed death.

nitric oxide in immune suppression in relation to oxygen radicals is its inhibitory effect on the binding of leukocytes (PMN) at the endothelial surface

Inhibition of inducible Nitric Oxide Synthase (iNOS)

NO from the tumor cells actually suppresses the iNOS, and in addition it reduces oxygen radicals to stop the formation of peroxynitrite in these cells. But NO is not the only inhibitor of iNOS in cancer.

Spermine and spermidine, from the rate limiting enzyme for DNA synthases, ODC, also inhibit iNOS

tolerance in the immune system that decreases the immune response to antigens on the tumors

Freund’s adjuvant

increase in kinases in these cells which phosphorylate serine, and tyrosine

responsible for activation of many growth factors and enzymes

phosphorylated amino acids suppress iNOS activity

Hexokinase II

Prostaglandin E2, released from tumor cells is also an inhibitor of iNOS, as well as suppressing the immune system

Th-1 subset of T-cells. These cells are responsible for anti-viral and anti-cancer activities, via their cytokine production including Interleukin-2, (IL-2), and Interleukin-12 which stimulates T-killer cell replication and further activation and release of tumor fighting cytokines.

Th-2 subset of lymphocytes, on the other hand are activated in allergies and parasitic infections to release Interleukin-4 and Interleukin-10

These have respectively inhibitory effects on iNOS and lymphocyte Th-1 activation

Mast cells contain histamine which when released increases the T suppressor cells, to lower the immune system and also acts directly on many tumor Histamine receptors to stimulate tumor growth

Tumor cells release IL-10, and this is thought to be one of the important areas of Th-1 suppression in cancer patients

IL-10 is also increased in cancer causing viral diseases such as HIV, HBV, HCV, and EBV

IL-10 is also a central regulator of cyclooxygenase-2 expression and prostaglandin production in tumor cells stimulating their angiogenesis and NO production

nitric oxide in tumor cells even prevents the activation of caspases responsible for apoptosis

early stages of carcinogenesis, which we call tumor promotion, one needs a strong immune system, and fewer oxygen radicals to prevent mutations but still enough to destroy the tumor cells should they develop

later stages of cancer development, the oxygen radicals are decreased around the tumors and in the tumor cells themselves, and the entire cancer fighting Th-1 cell replication and movement are suppressed. The results are a decrease in direct toxicity and apoptosis, which is prevented by NO, a suppression of the macrophage and leukocyte toxicity and finally, a suppression of the T-cell induced tumor toxicity

cGMP is increased by NO

NO in cancer is its ability to increase platelet-tumor cell aggregates, which enhances metastases

the greater the malignancies and the greater the metastatic potential of these tumors

The greater the NO production in many types of tumors,

gynecological

elevated lactic acid which neutralizes the toxicity and activity of Lymphocyte immune response and mobility

The lactic acid is also feeding fungi around tumors and that leads to elevated histamine which increases T-suppressor cells.  Histamine alone stimulates many tumor cells.

T-regulatory cells (formerly,T suppressor cells) down regulate the activity of Natural killer cells

last but not least, the Lactic acid from tumor cells and acidic diets shifts the lymphocyte activity to reduce its efficacy against cancer cells and pathogens in addition to altering the bacteria of the intestinal tract.

intestinal tract bacteria in cancer cells release sterols that suppress the immune system and down regulate anticancer activity from lymphocytes.

In addition to the lactic acid, adenosine is also released from tumors. Through IL-10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state

Adenosine up regulates the PD1 receptor in T-1 Lymphocytes and inhibits their activity

Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells

Adenosine appears to up-regulate the PD1 receptor in T-1 Lymphocytes and inhibits the immune system further

Mast cells with their release of histamine lower the immune system and also stimulate tumor growth and activate the metalloproteinases involved in angiogenesis and metastases

COX 2 inhibitors or all trans-retinoic acid

Cimetidine, an antihistamine has been actually shown to increase in apoptosis in MDSC via a separate mechanism than the antihistamine effect

interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis

In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha)

these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target

the percentage of macrophages in a given adipose tissue depot is positively correlated with adiposity and adipocyte size

Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes

Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NFκB activation by reducing IKK activity [38]

adipose tissue macrophages are responsible for nearly all adipose tissue Tnf expression and a significant portion of Nos2 and Il6 expression

One theory holds that the expansion of adipose tissue leads to adipocyte hypertrophy and hyperplasia and that large adipocytes outstrip the local oxygen supply leading to cell autonomous hypoxia with activation of cellular stress pathways

The use of the anti-inflammatory compounds, salicylate and its derivative aspirin, for treating symptoms of T2DM dates back over 100 years

elevated levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin resistant states

overnutrition and obesity are often accompanied by elevations in tissue and circulating FFA concentrations, and saturated FFAs can directly activate pro-inflammatory responses

Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity

In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter

macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the “classically activated” pro-inflammatory macrophage, to the M2 state or the “alternatively activated” non-inflammatory cell

saturated fatty acids are the most potent inducers of this inflammatory response

Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes iNOS (reviewed in [33]

Adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid (FFA) efflux out of adipocytes.

In the liver, insulin inhibits the expression of key gluconeogenic enzymes and, therefore, insulin resistance in liver leads to elevated hepatic glucose production

elevated JNK activity in liver, adipose tissue and skeletal muscle of obese insulin resistant mice, and knockout of Jnk1 (Jnk1−/−) leads to amelioration of insulin resistance in high fat diet

Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance

C-reactive protein (CRP)

these studies highlight the possibility that increased iNOS activity plays a direct role in the pathogenesis of insulin resistance

the important role of Ikkb in the development of obesity and inflammation-induced insulin resistance.

It is probable that local concentrations of inflammatory mediators, such as FFAs, Tnf or other cytokines/adipokines contribute to this polarity switch

Tnf and other cytokines/chemokines are symptomatic of inflammation, and while they propagate and/or maintain the inflammatory state, they are not the initial cause(s) of inflammation

Tlr4, in particular, is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria

Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system.

Tlr4 stimulation results in the activation of both Ikkb/NFκB and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1, etc. (reviewed in [57

it is clear that E2 can stimulate antibody production by B cells, probably by inhibiting T cell suppression of B cells

In cycling women, the largest quantities of Ig were detected before ovulation

In contrast, E2 at high concentrations leads to a suppression of B-lymphocyte lineage precursors

E2 at periovulatory to pregnancy serum levels is able to stimulate antibody secretion under healthy conditions but also in autoimmune diseases, whereas similar serum levels of E2 lead to a suppression of bone marrow B cell lineage precursors

In chronic inflammatory disorders, where B cells play a decisive role, E2 would promote the disease when autoaggressive B cells are already present, whereas chronically elevated E2 would inhibit initiation of an autoimmune disease when no such B cells are available. This might be a good reason why particularly B cell-dependent diseases such as SLE, mixed connective tissue disease (Sharp syndrome), IgA nephropathy, dermatitis herpetiformis, gluten sensitive enteropathy, myasthenia gravis, and thyroiditis appear in women in the reproductive years, predominantly, in the third or fourth decades of life

Th17 cells are thought to be the main responsible cells for chronic inflammatory tissue destruction in autoimmune diseases

IFN-γ, IL-12, and TNF were allocated to Th1 reactions

IL-4, IL-5, and IL-10 to Th2 responses

antiinflammatory T regulatory cells producing TGF-β and proinflammatory T helper type 17 cells (Th17) producing IL-17

no direct effects of estrogens on Th17 cells or IL-17 secretion have been described until now.

So-called Th17 cells producing IL-17 are the main T cells responsible for chronic inflammation.

Because IFN-γ has been allocated a Th17-inhibiting role (Fig. 1⇑), its increase by E2 at pregnancy doses and the E2-mediated inhibition of TNF must be viewed as a favorable effect in chronic inflammation

in humans and mice, E2 at periovulatory to pregnancy levels stimulates IL-4, IL-10, and IFN-γ but inhibits TNF from CD4+ T cells

In humans and mice, E3 and E2, respectively, at pregnancy levels inhibit T cell-dependent delayed type hypersensitivity

increased IL-4, IL-10, and IFN-γ in the presence of low TNF support an antiaggressive immune response

secretion of IL-1β is increased at periovulatory/proestrus to early pregnancy levels, whereas IL-1 secretion is inhibited at high pregnancy levels

The dichotomous effect of E2 on IL-1β and TNF at high and low concentrations is most probably due to inhibition of NF-κB at high concentrations

experiments with mouse and rat macroglial and microglial cells demonstrate that E2 at proestrus to pregnancy levels exerts neuroprotective effects by increasing TGF-β and by inhibiting iNOS and NO release, and reducing expression of proinflammatory cytokines and prostaglandin E2 production.

E2 at periovulatory to pregnancy levels inhibits NF-κB activation, which must be viewed as an antiinflammatory signal

It was shown that E2 concentrations equal to or above 10−10 m are necessary to inhibit NF-κB activation

important proinflammatory cytokines are typically inhibited at periovulatory (proestrus) to pregnancy levels of E2, which is evident for IL-6, IL-8, and TNF

low E2 concentrations were demonstrated to have no or even stimulatory effects

This renders a woman in the postmenopausal phase to a more proinflammatory situation

most in vitro studies demonstrated a stimulatory effect of E2 on secretion of IL-4, IL-10, and TGF-β typically at periovulatory to pregnancy levels

E2 at periovulatory to pregnancy levels has an ameliorating effect on chronic inflammatory diseases as long as B cell-dependent immunity or an overshooting fibrotic tissue repair process do not play a crucial pathogenic role. However, when the B cell plays an important role, E2 might even stimulate the disease process as substantiated by flare-ups in SLE during pregnancy

Short-term administration of E2 at pregnancy levels was shown to induce an inflammatory response specific to the lateral prostate of the castrated male rat

single agent mitoxantrone or vinorelbine were recommended as reasonable choices

ACC is subdivided into 3 histological groups based on solid components of the tumor including cribriform, tubular, and solid

Cribriform and tubular ACCs usually exhibit a more indolent course, whereas the solid subtype is associated with worse prognosis

ACC consists of two different cell types: inner luminal epithelial cells and outer myoepithelial cells

epithelial cells express c-kit, cox-2 and Bcl-2

myoepithelial cells express EGFR and MYB

a balanced translocation of the v-myb avian myeloblastosis viral oncogene homolog-nuclear factor I/B (MYB-NFIB) is considered to be a signature molecular event of ACC oncogenesis

As a transcription factor, MYB is known to modulate multiple genetic downstream targets involved in oncogenesis, such as cox-2, c-kit, Bcl-2 and BclX

Various signaling cascades are essential for cancer cells to survive and grow. The PI3K/Akt/mTOR pathway is one of them

This pathway regulates cell survival and growth and is upregulated in many cancers

Mutations in genes associated with DNA repair are frequently found in familial cancer syndromes, such as hereditary breast-ovarian cancer syndrome (HBOC), hereditary non-polyposis colorectal cancer (HNPCC, also called Lynch syndrome) and Li-Fraumeni syndrome [30, 31]. These mutations were also reported in non-hereditary cancers

70% of ACC samples (58 of 84) were found to have genetic alterations in the MYB/MYC pathway, indicating that changes in this pathway are crucial in ACC pathogenesis

The second most frequently mutated pathway was involved in chromatin remodeling (epigenetic modification), a pathway that includes multiple histone related proteins, and was altered in 44% of samples

C-kit

VEGF, iNOS and NF-κB were noted to be highly expressed in ACC cells as compared to normal salivary gland cells

members of the SOX family, such as SOX 4 and SOX10, are overexpressed in ACC

FABP7 (Fatty acid binding protein 7) and AQP1 (Aquaporin 1) tend to be overexpressed in ACC cell lines

considerable variability in HER2 overexpression ranging from 0–58% in patients with ACC

the study with cetuximab and concurrent chemoradiation or chemotherapy showed the highest ORR (total 43%, 9.5% CR and 33% PR), but this regimen was only given to the EGFR positive patients

Cancer immunotherapy can be classified into 3 major groups. Active immunization using anti-tumor vaccines to induce and recruit T cells, passive immunization based on monoclonal antibodies, and adoptive cell transfer to expand tumor-reactive autologous T cells ex vivo and then reintroduce these cells into the same individual

LAK cells showed cytotoxicity against ACC cells

cytokine-induced cell apoptosis and the cytotoxic effect of the LAK cells contributed to tumor regression

molecular finding of the MYB-NFIB fusion gene has the greatest potential to target what appears to be a fundamental event in disease pathogenesis