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In this study, we found that curcumin down-regulated DNMT1 expression in AML cells. This occurred, at least in part, through down-modulation of two positive regulators of DNMT1: Sp1 and the NF-κB component, p65. We also found that curcumin-mediated down-regulation of DNMT1 was associated with reactivation of TSGs and tumor suppression, both in vivo and in vitro.

curcumin may selectively downregulate DNMT1 expression in tumor cells, but not in normal cells

DNMT1 expression is positively regulated by Sp1 and the NF-κB signaling component

indicating that curcumin may have significant anti-tumor activity in AML

We found that, compared to the vehicle control, curcumin treatment reduced tumor weight by 70%

Surprisingly, although curcumin significantly inhibited tumor growth in these mice, we were unable to find any obvious toxicity associated with curcumin treatment

Consistent with our observations regarding curcumin’s ability to inhibit tumor growth in vivo (Figure 4) and down-regulate DNMT1 expression in vitro and ex vivo (Figure 1), we found that decreased levels of DNMT1 protein and mRNA were expressed by tumor cells isolated from curcumin-treated mice

we identified curcumin as a substance which acts as an inhibitor of DNA methyltransferase enzymatic activity and induces significant global DNA hypomethylation in AML cells

In this study, we first demonstrated that curcumin decreases DNMT1 mRNA and protein expression levels, most likely through inhibiting expression of positive regulators of DNMT1, such as Sp1 and the p65 component of NF-κB component, and/or altering their ability to bind to the promoter region of DNMT1

it does appear to inhibit rejoining of RT-induced DNA breaks more than is commonly observed after RT alone

HT damages cells and enhances RT and CT sensitivity as a function of both temperature and duration of treatment

as temperature or duration increase, the rate of cell killing also increases

At temperatures above 42 °C, tumor vasculature is damaged, resulting in decreased blood flow

Cancer cells are particularly vulnerable to heating; in vivo studies have shown that temperatures in the range of 40–44 °C cause more selective damage to tumor cells

cancerous blood vessels are chaotic, leaky, and inefficient

selective cytotoxic effect on tumor cells include inhibition of key cancer cell-signaling pathways such as AKT, inducing apoptosis, suppression of cancer stem cell proliferation, and others

increase in immunological attacks against tumors after HT, which were believed to be achieved through activation of HSPs and subsequent modulation of the innate and adaptive immune responses against tumor cells

HT does lead to activation of the immune system and HSP-induced cell death through modification of the tumor cell surface

These HSPs and tumor antigens are taken up by dendritic cells and macrophages and go on to induce specific anti-tumor immunity

In vivo studies demonstrate HT-enhancement of NK cell activity, and HT has been shown to increase neutrophilic granulocytes with anti-tumor activity

it has become increasingly clear that HT results in immune stimulation, through both direct heat-mediated cell killing as well as innate and adaptive immune system modulation

The term hyperthermia is used in this review to refer to heating within the clinically accepted range of 40–45 °C

temperatures above 42.5–43 °C the exposure time can be halved with each 1 °C increase while maintaining equivalent cell killing

gradual heating at 43 °C for 1 h worked through an apoptotic pathway

A more recent finding by the same group shows that a plant miRNA from honeysuckle is able to inhibit Influenza A replication22, indicating that plant miRNAs may be useful for treating human diseases.

We found that plant miR159 could be detected in human sera and its levels were inversely correlated with BC incidence and progression.

We further identified TCF7 as a mammalian target for miR159 and showed the anti-proliferative function of miR159 in BC cells using in vitro and in vivo models, demonstrating for the first time that a plant miRNA is able to influence BC cell growth.

certain dietary miRNAs from plants and other species may serve as highly affordable and powerful means of treatment with minimal inconvenience to patients.

miR159 which (using a synthetic mimic) targets TCF7 to inhibit the proliferation of cells whose growth is dependent on TCF7 such as the BC cells MDA-MB-231

our study using a BC model clearly indicates the anti-tumor effect of orally administered synthetic miR159 in its naturally existing form with the plant-specific 2'-O-methylation, suggesting the feasibility of using synthetic forms of plant miRNAs as dietary supplements in the treatment of human cancers, including those outside of the GI track

Far more important than the SUVmax is the pattern rather than intensity of metabolic abnormality and the correlative CT findings

Descriptively, we define SUV < 5 as “low intensity”, 5–10 as “moderate”, 10–15 as “intense” and >15 as “very intense”

Evolving literature suggests that intensity of uptake is an independent prognostic factor and in some tumour subtypes superior to histopathologic characterisation.

aerobic glycolysis

Our practice of thresholding the grey and colour scale to liver as detailed above results in similar image intensity to a fixed upper SUV threshold of 8 to 10

The advantage of using the liver as a reference tissue is also aided by this organ having rather low variability in metabolic activity

When the liver is abnormal and cannot be used as a reference organ, we use the default SUV setting of an upper SUV threshold of 8

One of the most challenging aspects of oncologic FDG PET/CT review, however, is to recognise all the patterns of metabolic activity that are not malignant and which consequently confound interpretation

Many benign and inflammatory processes are also associated with high glycolytic activity

Future articles in the “How I Read” series will address the specific details of reading PET/CT in various cancers

The intensity of uptake in metastases usually parallels that in the primary site of disease

For example, discordant low-grade activity in an enlarged lymph node in the setting of intense uptake in the primary tumour suggests it is unlikely malignant and more likely inflammatory or reactive

By CT criteria the enlarged node is ‘pathologic’ but the discordantly low metabolic signature further characterises this is as non-malignant since such a node is not subject to partial volume effects and therefore the intensity of uptake should be similar to the primary site

The exception is when the lymph node is centrally necrotic as a small rim of viable tumour is subject to partial volume effects with expectant lower intensity of uptake; integrating the CT morphology is therefore critical to reaching an accurate interpretation

Small nodes that are visualised on PET are conversely much more likely to be metastatic as such nodes are subject to partial volume effects.

The exception to this rule is tumours with a propensity for tumour heterogeneity at different sites

The combination of FDG and a more specific tracer, which visualises the well-differentiated disease can be very useful to characterise this phenomenon

“metabolic signature”

For the majority of malignant processes, the intensity of metabolic abnormality correlates with degree of aggressiveness or proliferative rate.

a negative PET/CT study in a patient with biopsy proven malignancy would be considered false-negative

Warburg effect

There, however, are a significant minority of tumours that utilise substrates other glucose such as glutamine or fatty acids as a source of the carbon atoms required for growth and proliferation

This includes a subset of diffuse gastric adenocarcinomas, signet cell colonic adenocarcinomas and some sarcomas, particularly liposarcoma

There may be a role for other radiotracers such as fluorothymidine (FLT) or amino acid substrates in this setting.

Some tumours harbour mutations that result in defective aerobic mitochondrial energy metabolism, effectively simulating the Warburg effect

patients with hereditary paraganglioma and pheochromocytoma highlight this phenomenon

These have intense uptake on FDG PET/CT despite often having low proliferative rate.

Uterine fibroids, hepatic adenomas, fibroadenomas of the breast and desmoid tumours are benign or relatively benign lesions that can have quite high FDG-avidity.

Metabolic activity switches off rapidly following initiation of therapy

Common examples where patients have commenced active therapy but the referrer is requesting “staging” includes hormonal therapy (eg. tamoxifen) in breast cancer, oral capecitabine in colorectal cancer or high dose steroids in Hodgkin’s lymphoma

It is therefore critical to perform PET staging before commencement of anti-tumour therapy

The potential advantage of routine diagnostic CT is improved anatomic localisation and definition

Without intravenous contrast, additional identification of typical oncologic complications such as pulmonary embolism or venous thrombosis cannot be identified

If the study is performed as an “interim” restaging study after commencement of therapy but before completion, in order to reach a valid or clinically useful conclusion findings must be interpreted in the context of known changes that occur at a specific timing and type of therapy

The most well studied use of interim PET is in Hodgkin’s lymphoma where repeat PET after two cycles of ABVD-chemotherapy provides powerful prognostic information and may improve outcomes by enabling early change of management

Eighty-five percent of lung cancers are non-small-cell lung cancer (NSCLC)

Studies have shown that the production of nagalase has a mutual relationship with Gc-MAF level and immunosuppression

It has been demonstrated that serum levels of nagalase are good prognosticators of some types of cancer

The nagalase level in serum correlates with tumor burden and it has been shown that Gc-MAF therapy progresses, nagalase activity decreases

It has been shown that Gc-MAF can inhibit the angiogenesis induced by pro-inflammatory prostaglandin E1

The effect of Gc-MAF on chemotaxis or activation of tumoricidal macrophages is likely the main mechanism against angiogenesis.

Administration of Gc-MAF stimulates immune-cell progenitors for extensive mitogenesis, activates macrophages and produces antibodies. “This indicates that Gc-MAF is a powerful adjuvant for immunization.”

Cancer cell lines do not develop into tumor genes in mouse models after Gc-MAF-primed immunization (29-31) and the effect of Gc-MAF has been approved for macrophage stimulation for angiogenesis, proliferation, migration and metastatic inhibition on tumors induced by MCF-7 human breast cancer cell line

The protocol included: "a high dose of second-generation Gc-MAF (0.5 ml) administered twice a week intramuscularly for a total of 21 injections.”

Yamamoto et al. showed that the administration of Gc-MAF to 16 patients with prostate cancer led to improvements in all patients without recurrence

Inui et al. reported that a 74-year-old man diagnosed with prostate cancer with multiple bone metastases was in complete remission nine months after initiation of GcMAF therapy simultaneously with hyper T/NK cell, high-dose vitamin C and alpha lipoic acid therapy

It has also been approved for non-neoplastic diseases such as autism (41), multiple sclerosis (42, 43), chronic fatigue syndrome (CFS) (40), juvenile osteoporosis (44) and systemic lupus erythematous (45).

Gc-MAF has been verified for use in colon, thyroid (38), lung (39), liver, thymus (36), pancreatic (40), bladder and ovarian cancer and tongue squamous carcinoma

Prostate, breast, colon, liver, stomach, lung (including mesothelioma), kidney, bladder, uterus, ovarian, head/neck and brain cancers, fibrosarcomas and melanomas are the types of cancer tested thus far

weekly administration of 100 ng Gc-MAF to cancer at different stages and types showed curative effects at different follow-up times

this treatment has been suggested for non-anemic patients

Studies have shown that weekly administration of 100 ng Gc-MAF to cancer patients had curative effects on a variety of cancers

Because the half-life of the activated macrophages is approximately one week, it must be administered weekly

In vivo weekly intramuscular administration of Gc-MAF (100 ng) for 16-22 weeks was used to treat patients with breast cancer

individuals harboring different VDR genotypes had different responses to Gc-MAF and that some genotypes were more responsive than others

Administration of Gc-MAF for cancer patients exclusively activates macrophages as an important cell in adaptive immunity

Gc-MAF supports humoral immunity by producing, developing and releasing large quantities of antibodies against cancer. Clinical evidence from a human model of breast cancer patients supports this hypothesis

There is also evidence that confirms the tumoricidal role of Gc-MAF via Fc-receptor mediation

It is likely that the best therapeutic responses will be observed when the nutritional and inflammatory aspects are taken together with stimulation of the immune system

it should be noted that no harmful side effects of Gc-MAF treatment have been reported, even when it was successfully administered to autistic children

The natural activation mechanism of macrophages by Gc-MAF is so natural and it should not have any side effects on humans or animal models even in cell culture

Besides the Gc-MAF efficacy on macrophage activity, it can be a potential anti-angiogenic agent (28) and an inhibitor of the migration of cancerous cells in the absence of macrophages (47).

Activating or modifying natural killer cells, dendritic cells, DC, CTL, INF and IL-2 have all been recommended for cancer immunotherapy

It has been reported that nagalase cannot deglycosylate Gc-MAF as it has specificity for Gc globulin alone

inflammation-derived macrophage activation with the participation of B and T lymphocytes is the main mechanism

macrophages highly-activated by the addition of Gc-MAF can show tumoricidal activity

Previous clinical investigations have confirmed the efficacy of Gc-MAF. In addition to activating existing macrophages, Gc-MAF is a potent mitogenic factor that can stimulate the myeloid progenitor cells to increase systemic macrophage cell counts by 40-fold in four days

High density level of PGR in the TE was an independent prognostic factor for CF.

Our large-sized study demonstrates a wide distribution of PGR in stromal and epithelial cells of both benign and malignant prostate tissue

there seems to be a general agreement of PGR presence in the stromal cells of PCa

In line with our findings, several have also reported a high PGR expression in TE of PCa [9,10,23,25]. In contrast, others have demonstrated a total lack of PGR expression in TE

the actions of progesterone are tissue specific

In our work univariate analysis demonstrated a high PGR expression in TS to be associated with clinical failure in PCa patients. So far we have not yet demonstrated the mechanism underlying this association

Several non-genomic proliferative actions of progesterone have been proposed in tumor cells of other organs, including breast [35–37], astrocytoma [38] and osteosarcoma [39] cell lines. However, such results are contradicted by suggestions of anti-proliferative actions of progesterone in endometrial cancer

Yu et al. found PGR to be negatively regulating stromal cell proliferation in vitro

high PGR density level in TE was associated with CF in patients with Gleason score ≥ 7

Bonkhoff et al. have suggested progressive emergence of PGR during PCa progression and metastasis

Latil and co-workers found a decreased PGR expression in clinically localized tumors and increased PGR expression in hormone-refractory tumors, when compared with normal prostate tissue

Our findings provide further support to these findings, indicating that PGR plays a role in the pathogenesis of PCa

Ki67 and PGR in TE were correlated with CF (S3 Text), indicating an association between PGR and proliferative activity

The mechanism behind the PGR up-regulation in PCa has not yet been elucidated

The PGR is, like the glucocorticoid receptor, similar to androgen receptor with 88% sequence homology in the ligand-binding domain

progesterone induced expression of androgen receptor-regulated genes could be a potential mechanism contributing to the development of castrate resistant PCa

A possibility of different roles by the two PGR isoforms in normal prostate tissue and PCa, as is suggested for the estrogen receptors [13], must also be taken into account

Hyperthermia differs fundamentally from fever in that it elevates the core body temperature without changing the physiological set point

hyperthermia is induced by increasing the heat load and/or inactivating heat dissipation

mor cells [2]. Although significant cell killing could be achieved by heating cells or tissues to temperatures > 42°C for 1 or more hours, the application, measurement and consistency of this temperature range within the setting of cancer clinical trials

mild temperature hyperthermia (ie, within the fever-range, 39–41°C)

moderate hyperthermia (41°C)

Hsps are a family of stress-induced proteins

they are key regulators of cellular protein activity, turnover and trafficking

Hsps ensure appropriate post-translational protein folding, and are able to refold denatured proteins, or mark irreversibly damaged proteins for destruction

the ability of fever-range hyperthermia to induce reactive immunity against tumor antigens through DCs and NK-cells is likely mediated by Hsps

thermotolerance

Hsps support the malignant phenotype of cancer cells by not only affecting the cells’ survival, but also participating in angiogenesis, invasion, metastasis and immortalization mechanisms

Hsps released from stressed or dying cells activate dendritic cells (DCs), transforming them into mature APCs

In theory, fever-range hyperthermia may take advantage of tumor cell Hsps by inducing their release from tumor cells and augmenting DC priming against tumor antigens

In several models of hyperthermia, heat-treated tumors exhibited improved DC priming and generation of systemic immunity to tumor cell

hyperthermia alone can enhance antigen display by tumor cells, thus rendering them even more susceptible to programmed immune clearance

Fever-range hyperthermia may also induce Hsps

Hsps may exert an adjuvant effect by bolstering MHC class II and co-stimulatory molecule expression by DCs

thermal ablation of liver tumors in particular has demonstrated an ability to potentiate immune responses [57, 58] and elicit robust T-cell infiltrates at ablation sites

specific Hsp, Hsp70, directly inhibits apoptosis pathways in cancer cells, as demonstrated in human pancreatic, prostate and gastric cancer cells

Cross-priming is the ability of extracellular Hsps complexed to tumor peptides to be internalized and presented in the context of MHC class I molecules on APCs, thus allowing potent priming of CTLs against tumor antigens

It has been reported that Hsps are generated from necrotic tumor cell lysates, but not from tumor cells undergoing apoptosis

tumor cells exposed to hyperthermia in the heat shock range (42°C for 4h) prior to lysing, DC activation and cross-priming were significantly enhanced with the application of heat

Due to the ability of Hsps to activate DCs directly by chaperoning tumor antigens upon their release [28], it is possible that both local and regional immune stimulation can be achieved with hyperthermia.

support the use of hyperthermia as an inducer of Hsps to serve as ‘danger signals’, activating antitumor immune responses

whole-body hyperthermia not only augments immune responses, but also stimulates the migration of skin-derived DCs to draining lymph nodes

suggest a valuable role of hyperthermia in DC cancer vaccine strategies

In mice treated with fever-range whole-body hyperthermia, tumor growth was significantly inhibited and NK-cell infiltration increased

exposure to fever-range hyperthermia resulted in improved endogenous NK-cell cytotoxicity to several cancer types

improved activation and function of DCs and NK cells following hyperthermia

Hyperthermia increases the expression ICAM-1 a key adhesion molecule,

The combined effects of hyperthermia on lymphoid tissue endothelium and lymphocytes can promote immune surveillance and increase the probability of naive lymphocytes leaving the circulation and encountering their cognate antigen displayed by DCs in lymphoid organs.

In independent clinical studies, whole-body hyperthermia resulted in a transient decrease in circulating lymphocytes in patients with advanced cancer [12, 94, 99, 100], a finding which mirrored observations in animal models in which lymphocyte entry into lymph noeds was increased following hyperthermia treatment [93]. Enhanced recruitment of lymphocytes to lymphoid tissues may be exploited in the treatment of malignancies.

The initial tumor antigen presentation and initiation of clonal expansion of CTLs transpires in the lymph nodes and cannot take place outside this specialized compartment

the ability of DCs present in the lymph nodes to stimulate an anti-tumor immune response is critical

hyperthermia has been shown to improve immune surveillance by T-cell

and to increase DC trafficking to lymph nodes