Theranostics Nuclear Medicine in Prostate Cancer.

Theranostic Nuclear Medicine is based on the idea of combining the same molecule (or drug) with different radioisotopes for both diagnosis and treatment, a concept that emerged in the early 1940s with the use of radioactive iodine for thyroid diseases. Theranostic Nuclear Medicine has since expanded to diseases of higher incidence, such as prostate cancer, with several imaging methods used to assess the extent of the disease and the corresponding radiopharmaceuticals used for treatment. For example, by detecting osteoblastic metastases by bone scintigraphy, corresponding radiopharmaceuticals with therapeutic properties can be administered to eliminate or reduce pain associated with metastases and/or determine overall survival gain.

Association of Inherited Copy Number Variation in and Pseudogenes with Oropharynx Cancer Risk and Outcome.

Inherited copy number variations (CNVs) can provide valuable information for cancer susceptibility and prognosis. However, their association with oropharynx squamous cell carcinoma (OPSCC) is still poorly studied. Using microarrays analysis, we identified three inherited CNVs associated with OPSCC risk, of which one was validated in 152 OPSCC patients and 155 controls and related to pseudogene-microRNA-mRNA interaction.

Association of JAK/STAT genetic variants with cutaneous melanoma.

Background: The Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway regulates cutaneous melanoma (CM) development and progression. The JAK1, JAK2, and STAT3 proteins are encoded by polymorphic genes. This study aimed to verify whether single-nucleotide variants (SNVs) in (c.

Intronic variants of MITF (rs7623610) and CREB1 (rs10932201) genes may enhance splicing efficiency in human melanoma cell line.

We previously reported that intronic single nucleotide variations (SNVs) in MITF (c.938-325G>A, rs7623610) and CREB1 (c.303+373G>A, rs10932201) genes were associated with risk, aggressiveness, and prognosis of cutaneous melanoma (CM).

microRNAs deregulation in head and neck squamous cell carcinoma.

Head and neck (HN) squamous cell carcinoma (SCC) is the eighth most common human cancer worldwide. Besides tobacco and alcohol consumption, genetic and epigenetic alterations play an important role in HNSCC occurrence and progression. microRNAs (miRNAs) are small noncoding RNAs that regulate cell cycle, proliferation, development, differentiation, and apoptosis by interfering in gene expression.

Inherited variations in human pigmentation-related genes modulate cutaneous melanoma risk and clinicopathological features in Brazilian population.

Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The study was conducted in two stages.

CASP8 (rs3834129) and CASP3 (rs4647601) polymorphisms in oropharynx cancer risk, tumor cell differentiation, and prognosis in a cohort of the Brazilian population.

The objective of this research was to assess the association of genetic polymorphisms related to intrinsic apoptosis pathway CASP8 rs3834129 and CASP3 rs4647601 with the risk, clinical and pathological aspects, and survival of oropharynx squamous cell carcinoma (OPSCC) patients that received cisplatin and radiotherapy. The genotypes were identified in 198 patients with OPSCC and 200 controls using polymerase chain reaction methods. Chi square or Fisher's exact test and logistic regression were applied for the detection of differences between groups.

Influence of functional variants Asp312Asn and Lys751Gln of Xeroderma Pigmentosum Group D (XPD) and Glutathione S-transferase Mu 1 (GSTM1) and Theta 1 (GSTT1) genes on cutaneous melanoma susceptibility and prognosis.

We aimed to evaluate whether variants in repair (XPD Asp312Asn, XPD Lys751Gln) and detoxification (GSTM1, GSTT1) genes alter risk, clinicopathological aspects and survival of cutaneous melanoma (CM). Genotyping was performed in 229 CM patients and 258 controls. Individuals with XPD 312Asp/Asn or Asn/Asn plus GSTT1 null genotype were under 2.

Gene expression of thyroid-specific transcription factors may help diagnose thyroid lesions but are not determinants of tumor progression.

Purpose: The role of thyroid-specific transcription factors in thyroid malignancy is still poorly understood, so we investigate thyroid-specific transcription factors gene expression both in benign and in malignant thyroid nodules, aiming to study a possible clinical utility of these molecules.

Methods: We quantified TTF-1, FOXE1 and PAX8 mRNA levels, relating their expression to diagnostic and prognostic features of thyroid tumors. RNA was extracted from 4 normal thyroid tissues, 101 malignant [99 papillary thyroid carcinomas (PTC) and 2 anaplastic thyroid carcinomas] and 99 benign thyroid lesion tissues [49 goiter and 50 follicular adenomas (FA)].

Phosphorylation-independent mTORC1 inhibition by the autophagy inducer Rottlerin.

We recently found that Rottlerin not only inhibits proliferation but also causes Bcl-2- and Beclin 1-independent autophagic death in apoptosis-resistant breast adenocarcinoma MCF-7 cells. Having excluded a role for canonical signaling pathways, the current study was aimed to investigate the contribution of the AMPK/mTOR axis in autophagy induction and to search for the upstream signaling molecules potentially targeted by Rottlerin. Using several enzyme inhibitors, Western blotting analysis, mTOR siRNA and pull down assay, we demonstrate that the Rottlerin-triggered autophagy is mediated by inhibition of mTORC1 activity through a novel AMPK and mTORC1 phosphorylation-independent mechanism, likely mediated by the direct interaction between Rottlerin and mTOR.

Comparative effects between electronic and cigarette smoke in human keratinocytes and epithelial lung cells.

Information about the harmful effects of vaping is sparse and inconsistent, therefore, since the use of electronic cigarettes (e-CIGs) has become increasingly popular as a tool to limit tobacco smoking, it is urgent to establish the toxicity of the commercial e-CIGs. Skin (HaCaT) and lung (A549) cells, the main targets of cigarette smoke (CS), were exposed to e-CIG vapor and CS using an in vitro system. The cytotoxic effect of the exposure was analyzed in both cell types by ultrastructural morphology, Trypan Blue exclusion test and LDH assay.

Alternative Pathways of Cancer Cell Death by Rottlerin: Apoptosis versus Autophagy.

Since the ability of cancer cells to evade apoptosis often limits the efficacy of radiotherapy and chemotherapy, autophagy is emerging as an alternative target to promote cell death. Therefore, we wondered whether Rottlerin, a natural polyphenolic compound with antiproliferative effects in several cell types, can induce cell death in MCF-7 breast cancer cells. The MCF-7 cell line is a good model of chemo/radio resistance, being both apoptosis and autophagy resistant, due to deletion of caspase 3 gene, high expression of the antiapoptotic protein Bcl-2, and low expression of the autophagic Beclin-1 protein.

Rottlerin and curcumin: a comparative analysis.

Rottlerin and curcumin are natural plant polyphenols with a long tradition in folk medicine. Over the past two decades, curcumin has been extensively investigated, while rottlerin has received much less attention, in part, as a consequence of its reputation as a selective PKCδ inhibitor. A comparative analysis of genomic, proteomic, and cell signaling studies revealed that rottlerin and curcumin share a number of targets and have overlapping effects on many biological processes.

Brain imaging findings in symptomatic patients after allogeneic haematopoietic stem cell transplantation: correlation with clinical outcome.

Objective: To investigate the risk factors for, and the incidence of, structural abnormalities on brain imaging in allogeneic haematopoietic stem cell transplant (HSCT) patients, and correlate these findings with survival.

Methods: We retrospectively reviewed all brain computed tomography (CT) and/or magnetic resonance imaging (MRI) studies obtained during the first post-HSCT year from 2004 thru 2007 in allogeneic HSCT recipients.

Results: A total of 128 patients had brain imaging in the first post-HSCT year.

Rottlerin and cancer: novel evidence and mechanisms.

Because cancers are caused by deregulation of hundreds of genes, an ideal anticancer agent should target multiple gene products or signaling pathways simultaneously. Recently, extensive research has addressed the chemotherapeutic potential of plant-derived compounds. Among the ever-increasing list of naturally occurring anticancer agents, Rottlerin appears to have great potentiality for being used in chemotherapy because it affects several cell machineries involved in survival, apoptosis, autophagy, and invasion.

Rottlerin exhibits antiangiogenic effects in vitro.

Rottlerin, a natural product purified from Mallotus philippinensis, has a number of target molecules and biological effects. We recently found that Rottlerin caused growth arrest in MCF-7 breast cancer cells and human immortalized keratinocytes, through inhibition of NFκB and downregulation of cyclin D-1. To evaluate whether this effect could be generalized to primary cells, human microvascular endothelial cells were treated with Rottlerin.

Novel PKCs activate ERK through PKD1 in MCF-7 cells.

PKCs can have opposite effects on ERK phosphorylation. Novel (n)PKCs can inhibit ERK by phosphorylation of Raf-1, classical and atypical PKCs can activate ERK by removing an inhibitory protein from Raf-1. The aim of this work was to clarify how PMA-activated PKCs lead to ERK activation in MCF-7 cells expressing mainly nPKCs.

Critical appraisal of the MTT assay in the presence of rottlerin and uncouplers.

Rottlerin is a natural product isolated from Mallotus philippinensis. This polyphenolic compound, originally described as a selective inhibitor of PKCδ, can inhibit many other PKC-unrelated kinases and has a number of biological actions, including mitochondrial uncoupling effects. We recently found that Rottlerin inhibits the transcription factor nuclear factor κB in different cell types, causing downregulation of cyclin D1 and growth arrest.

Rottlerin inhibits the nuclear factor kappaB/cyclin-D1 cascade in MCF-7 breast cancer cells.

In the course of a project aimed to clarify the molecular mechanisms by which phorbol 12-myristate 13-acetate (PMA)-activated forms of protein kinase C (PKC) promote growth arrest in an MCF-7 cell line, we found that the PKCdelta inhibitor Rottlerin was able by itself to block cell proliferation. In the current study, we investigated further the antiproliferative response to Rottlerin. Western blotting analysis of cytoplasmic/nuclear extracts showed that the drug did not prevent either extracellular signal-regulated kinase (ERK) activation by PMA or Akt phosphorylation, but did interfere with the NFkappaB activation process (both basal and PMA-stimulated), by lowering the levels of phospho-IkappaBalpha and preventing p65 nuclear migration.

Antiproliferative and survival properties of PMA in MCF-7 breast cancer cell.

Although PKCs are assumed to be the main targets of phorbol esters (PMA), additional PMA effectors, such as chimaerins (a family of RacGTPase activating proteins) and RasGRP (exchange factor for Ras/Rap1), can counteract or strengthen the PKC pathways. In this study, we evaluated the proliferative behavior of PMA-treated MCF-7 breast cancer cell and found that: PMA induced growth arrest and inhibited cell death; PMA activated ERKs, which, in turn, induced p21; and inhibitors of ERK (PD98059) and PKC (GF109203X) prevented p21 induction and abolished the PMA survival effect. We conclude that PMA inhibits MCF-7 cell growth and simultaneously stimulates cell survival; both responses are linked to ERK-dependent and p53-independent p21 induction.

Cutaneous MMPs are differently modulated by environmental stressors in old and young mice.

Skin is frequently exposed to pro-oxidative insults such as UV light, ozone (O(3)) and cigarette smoke (CS), which are able to deplete antioxidants and induce oxidation products affecting skin pathophysiology. Skin turnover and regeneration are largely dependent on extracellular matrix metabolism, which is under the control of matrix metalloproteinases, MMPs. The present study evaluated cutaneous MMPs activity upon environmental pollutants exposure and analyzed the response of old and young animals.

Functional interactions of protein kinase A and C in signalling networks: a recapitulation.

On the basis of evidence collected from the literature, we propose a general model by which protein kinase (PK) A and the different PKC isoforms can inversely affect cell growth. Molecular switches, which are able to direct the signal towards antiproliferative or mitogenic pathways, are the different isoforms of Raf and PKC. Conflicting data are also reported and discussed in an attempt to reconcile them.

Role of PTHrp and PTHrp-engaged pathways in MCF-7 cells migration/invasion.

In this paper the effect of N-terminal parathyroid hormone-related protein (PTHrp) and PTHrp-engaged pathways on MCF-7 breast cancer cell migration/invasivity and matrix metalloproteinases (MMPs) production were investigated. We found that: a) migration is not affected by PTHrp and Forskolin (FK)-activated PKA, while Phorbol Myristate Acetate (PMA)-activated PKC strongly stimulates MCF-7 cells motility. b) MMPs production was unaffected by PTHrp, but FK reduced membrane-type (MT)-1 MMP expression.

Multiple plasma proteins control atrial natriuretic peptide (ANP) aggregation.

We have recently demonstrated that human alpha-atrial natriuretic peptide (alpha-hANP), an amyloidogenic peptide responsible for isolated atrial amyloidosis, binds to a dimeric form of apo A-I belonging to small high-density lipoproteins (HDL). This binding phenomenon is considered a protective mechanism since it inhibits or strongly reduces the ANP aggregation process. The observation that plasma exhibits at least four times greater amyloid inhibitory activity than HDL prompted us to determine whether small HDL are the only ANP plasma-binding factors.