Cancer Metastasis & Angiogenesis

Cyclooxygenase‐2 (COX‐2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo‐ and radiotherapy. COX‐2 is released by cancer‐associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX‐2 induces cancer stem cell (CSC)‐like activity, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells. COX‐2 mediated hypoxia within the TME along with its positive interactions with YAP1 and antiapoptotic mediators are all in favor of cancer cell resistance to chemotherapeutic drugs. COX‐2 exerts most of the functions through its metabolite prostaglandin E2. In some and limited situations, COX‐2 may act as an antitumor enzyme. Multiple signals are contributed to the functions of COX‐2 on cancer cells or its regulation. Members of mitogen‐activated protein kinase...

of the chapter In this chapter, we, first give an overview about cancer mechanism. We detail, the importance of histopathology grading by Pathologists and its implication in patient prognosis and therapies. We focus on both breast cancer and colorectal cancer based on the alarming statistics reported recently by WHO. Finally, we emphasis the role of blood vessel as a major component of the tumour micro-environment matrix and its interaction with other tumour micro-environment components.

PET (Positron Emission Tomography) allows imaging of the in vivo distribution of biochemical compounds labeled with a radioactive tracer, mainly 18F-FDG (2-deoxy-2-[18F] fluoro-D-glucose). 18F only allows a relatively poor spatial resolution (2-3 mm) which does not allow imaging of small tumors or specific small size tissues, e.g. vasculature. Unfortunately, angiogenesis is a key process in various physiologic and pathologic processes and is, for instance, involved in modern anticancer approaches. Thus ability to visualize angiogenesis could allow early diagnosis and help to monitor the response of cancer to specific chemotherapies. Therefore, indirect analytical techniques are required to assess the localization of fluorinated compounds at a micrometric scale. Multimodality imaging approaches could provide accurate information on the metabolic activity of the target tissue. In this article, PIGE method (Particle Induced Gamma-ray Emission) was used to determine fluorinated tracers by the nuclear reaction of 19F(p,p′γ)19F in tissues. The feasibility of this approach was assessed on polyfluorinated model glucose compounds and novel peptide-based tracer designed for angiogenesis imaging. Our results describe the first mapping of the biodistribution of fluorinated compounds in both vascularized normal tissue and tumor tissue.

In this paper, the presented correlations in scientific literature for friction factor of turbulent flow in the base fluid and nanofluid has been analyzed statistically. In order to perform the statistical analysis and select the best probability distribution function for the friction factor, from 48 probability distribution functions and 3 statistic of Kolmogorov-Smirnov, Anderson-Darling and chi squared has been used. The results show that, based on all three statistics, the probability distribution function of the friction factor in the base fluid and nanofluid is the Johnson SB probability distribution function. Furthermore, it was observed that the probability distribution function of the friction factor of the base fluid and nanofluid is wider than the normal distribution function. On the other side, the probability distribution function of Johnson SB has a right skewness.

The health of an individual is determined by the interaction of genetic and individual factors with wider social and environmental elements. Public health approaches to improving the health of disadvantaged populations will be most effective if they optimise influences at each of these levels, particularly in the early part of the life course. In order to better ascertain the relative contribution of these multi-level determinants there is a need for robust studies, longitudinal and prospective in nature, that examine individual, familial, social and environmental exposures. This paper describes the study background and methods, as it has been implemented in an Australian birth cohort study, Environments for Healthy Living (EFHL): The Griffith Study of Population Health. EFHL is a prospective, multilevel, multi-year longitudinal birth cohort study, designed to collect information from before birth through to adulthood across a spectrum of eco-epidemiological factors, including genetic material from cord-blood samples at birth, individual and familial factors, to spatial data on the living environment. EFHL commenced the pilot phase of recruitment in 2006 and open recruitment in 2007, with a target sample size of 4000 mother/infant dyads. Detailed Trial Registration Number: ACTRN12610000931077.

Thrombospondin-1 (TSP1), a multifunctional extracellular matrix glycoprotein, has been shown to suppress the angiogenic response in vivo and in vitro. We hypothesized that TSP1 might play a role in the inhibition of capillary morphogenesis during the endometrial cycle and examined its expression in 46 human endometrial specimens. Our results show that the expression of TSP1 in the endometrium is (a) cycle-dependent, (b) associated with periods of low capillary growth, and (c) regulated by progesterone. TSP1 protein was identified in the basement membrane of capillaries of the functional endometrium during the secretory phase. Abundant expression of TSP1 mRNA in the secretory phase was also detected by in situ hybridization, in contrast to the low levels seen in the proliferative phase. These findings were confirmed by Northern analysis of proliferative and secretory endometrium. Transcripts for TSP1 were observed predominantly in stromal cells, but signal was also detected in some endothelial and smooth muscle cells. Since the proliferation of endometrial tissue is regulated by steroid hormones, we tested the effects of estrogen and progesterone on TSP1 expression by stromal cells isolated from human endometrium. We found that levels of TSP1 mRNA and protein were increased after incubation with progesterone. Maximal stimulation of mRNA was observed after 8 h of treatment with 10-50 M progesterone, and the effect was suppressed by the progesterone antagonist RU-486. Induction by progesterone was cell-specific and equivalent to the stimulation mediated by PDGF. Finally, the levels of TSP1 present in progesterone-stimulated cultures were sufficient to inhibit the migration of endothelial cells in vitro; this effect was nullified by anti-TSP antibodies. We therefore propose that the production of TSP1 at later stages of the endometrial cycle is linked to the inhibition of vessel formation and that TSP1 expression is progesterone-dependent in this tissue.

Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1β as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/β, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic e...

We have previously shown that a loss of stromal Cav-1 is a biomarker of poor prognosis in breast cancers. Mechanistically, a loss of Cav-1 induces the metabolic reprogramming of stromal cells, with increased autophagy/mitophagy, mitochondrial dysfunction and aerobic glycolysis. As a consequence, Cav-1-low CAFs generate nutrients (such as L-lactate) and chemical building blocks that fuel mitochondrial metabolism and the anabolic growth of adjacent breast cancer cells. It is also known that a loss of Cav-1 is associated with hyperactive tGF-β signaling. However, it remains unknown whether hyperactivation of the tGF-β signaling pathway contributes to the metabolic reprogramming of Cav-1-low CAFs. to address these issues, we overexpressed tGF-β ligands and the tGF-β receptor I (tGF-β-RI) in stromal fibroblasts and breast cancer cells. Here, we show that the role of tGF-β in tumorigenesis is compartment-specific, and that tGF-β promotes tumorigenesis by shifting cancer-associated fibroblasts toward catabolic metabolism. Importantly, the tumorpromoting effects of tGF-β are independent of the cell type generating tGF-β. thus, stromal-derived tGF-β activates signaling in stromal cells in an autocrine fashion, leading to fibroblast activation, as judged by increased expression of myofibroblast markers, and metabolic reprogramming, with a shift toward catabolic metabolism and oxidative stress. We also show that tGF-β-activated fibroblasts promote the mitochondrial activity of adjacent cancer cells, and in a xenograft model, enhancing the growth of breast cancer cells, independently of angiogenesis. Conversely, activation of the tGF-β pathway in cancer cells does not influence tumor growth, but cancer cell-derived-tGF-β ligands affect stromal cells in a paracrine fashion, leading to fibroblast activation and enhanced tumor growth. In conclusion, ligand-dependent or cellautonomous activation of the tGF-β pathway in stromal cells induces their metabolic reprogramming, with increased oxidative stress, autophagy/mitophagy and glycolysis, and downregulation of Cav-1. these metabolic alterations can spread among neighboring fibroblasts and greatly sustain the growth of breast cancer cells. our data provide novel insights into the role of the tGF-β pathway in breast tumorigenesis, and establish a clear causative link between the tumor-promoting effects of tGF-β signaling and the metabolic reprogramming of the tumor microenvironment.

Three complexes of an ONS donor ligand of the Schiff base [C 21 H 19 NO 2 S] (HL), [Cu(C 21 H 18 NO 2 S) 2 ] (1) [Co (C 21 H 18 NO 2 S) 2 ] (2) and [Pd(C 21 H 18 NO 2 SCl)] (3), were synthesized and characterized by elemental analysis, FT-IR, 1 H NMR, UV-Visible spectroscopy and single-crystal X-ray diffraction analysis. Single crystal X-ray diffraction analysis reveals that the copper complex acquires a distorted pyramidal structure and the palladium complex acquires a square planar structure. All the compounds are stable at room temperature and they show very good antibacterial activities against gram-positive and gram-negative bacteria. DNA binding activities of the ligand and its Cu(II), Pd(II) and Co(II) complexes with CT-DNA were carried out in DMF and tris-buffer (5 mM, pH 7.3) solution; all the three complexes along with the ligand show a very good intercalative mode of DNA interaction with K b values of 1.56(±0.03) Â 10 5 for 1 and 1.02 (±0.09) Â 10 5 for 3. The DNA binding activity has also been confirmed by a hydrodynamic study (viscosity). The order of DNA binding activity is 1 > 3 > 2.

This study will compare the incidence of major adverse cardiovascular events (MACEs) with androgen deprivation therapy (ADT) among men with advanced prostate cancer who are being treated with a gonadotropinreleasing hormone (GnRH) antagonist versus a GnRH agonist. BACKGROUND Treatment of advanced prostate cancer with ADT might increase the risk of subsequent cardiovascular events among men with known atherosclerotic cardiovascular disease (ASCVD), but a recent meta-analysis suggested that this risk might be lower with ADT using a GnRH antagonist versus a GnRH agonist. METHODS PRONOUNCE is a multicenter, prospective, randomized, open, blinded endpoint trial that will enroll approximately 900 patients with advanced prostate cancer and pre-existing ASCVD who will be treated with ADT. Participants will be randomized to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide as ADT for 12 months. The primary endpoint is time from randomization to first confirmed, adjudicated occurrence of a MACE, which is defined as a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke through 12 months of ADT treatment. Baseline cardiovascular biomarkers (high-sensitivity C-reactive protein, high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide), as well as serial inflammatory and immune biomarkers, will be evaluated in exploratory analyses. RESULTS As of October 1, 2019, a total of 364 patients have been enrolled. The mean age is 74 years, 90% are white, 80% have hypertension or dyslipidemia, 30% diabetes mellitus, 40% have had a previous myocardial infarction, and 65% have had previous revascularization. Regarding prostate cancer features at randomization, 48% of the patients had localized disease, 23% had locally advanced disease, and 18% had metastatic disease. CONCLUSIONS PRONOUNCE is the first prospective cardiovascular outcomes trial in advanced prostate cancer that will delineate whether the risk of subsequent cardiovascular events associated with ADT is lower with a GnRH antagonist versus a GnRH agonist for men with pre-existing ASCVD. (A Trial Comparing Cardiovascular Safety of

Renal Cell Carcinoma (RCC) is the most common type of cancer in the kidney and is mostly asymptomatic. Previous studies have supported the important role of sex hormones in RCC pathophysiology and that targeted hormone receptor therapy, such as estrogen receptor targeting, is a promising treatment strategy. However, to the best of our knowledge, it remains unknown whether hormonal therapy, such as controlled ovarian stimulation for in vitro fertilization, serves a role in the development and progression of RCC. The present report describes a case of RCC developed after a fertility stimulation therapy and provides a summary of the known literature on the role of hormone receptors in the development and progression of RCC. A 35-year-old woman received fertility stimulation treatment with follitropin alfa 900 units, human chorionic gonadotropic hormone 5,000 units, injectable leuprolide 1 mg/0.2 ml and cetrotide 0.25 mg. The patient presented to the hospital with shortness of breath and weight loss. The patient had no known genetic predisposition or family history of malignancies and no exposure to chemicals. The patient never used tobacco, alcohol or recreational drugs. Imaging revealed a 17x19 mm, heterogeneously enhancing, and partially exophytic mass in the right kidney. After partial nephrectomy, the pathological evaluation confirmed the diagnosis of clear cell RCC. To the best of our knowledge, this was the first time that a case of ovarian stimulation therapy was associated with the development of RCC. This case raises concerns about the potential oncogenic effect of controlled ovarian stimulation therapy in RCC promotion, suggesting a need for systematic research to clarify the clinical significance of existing pre-clinical data.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Two Pore Channels (TPCs) are an emerging family of intracellular channels, expressed on acidic compartments, which mediate calcium signaling evoked by NAADP. In particular, we demonstrated that TPC2 isoform has a main role in angiogenesis (Favia et al. PNAS 2014 Nov 4;111(44):E4706-15). TPC2 inhibition is emerging as a key therapeutic step in a range of important pathological conditions including the progression and metastatic potential of cancer, Parkinson’s disease, and Ebola virus infection. We introduce naringenin, a natural flavonoid, as a novel TPC2 inhibitor as shown by electrophysiological evidence in a heterologous system, i.e. Arabidopsis vacuoles lacking endogenous TPCs. In view of the control exerted by TPC2 on intracellular calcium signaling and angiogenesis, we demonstrate that naringenin dampens intracellular calcium responses of human endothelial cells stimulated with VEGF, histamine or NAADP-AM, but not with ATP or Angiopoietin-1. The ability of naringenin to impair...

The functional significance of the chemokine receptor CCR5 in human breast cancer epithelial cells is poorly understood. Here, we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5 þ breast cancer epithelial cells formed mammospheres and initiated tumors with >60fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative breast cancer cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents. Single-cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and cell survival signaling. As CCR5 augments DNA repair and is reexpressed selectively on cancerous, but not normal breast epithelial cells, CCR5 inhibitors may enhance the tumor-specific activities of DNA damage response-based treatments, allowing a dose reduction of standard chemotherapy and radiation. Significance: This study offers a preclinical rationale to reposition CCR5 inhibitors to improve the treatment of breast cancer, based on their ability to enhance the tumor-specific activities of DNA-damaging chemotherapies administered in that disease.

Brain metastases from prostate cancer are rare and occur at a late stage in the natural history of the disease. Men usually present with neurological manifestations. We present a 66-year-old asymptomatic man who had incidental brain metastases detected on 68 Ga-PSMA PET/CT, which was later confirmed on biopsy to be prostate adenocarcinoma. With newer androgen deprivation agents and improved imaging capabilities increasing the mean survival and thus the incidence of brain metastases from prostate cancer, it is important to consider this important differential not only in men who display neurological symptoms but also in men who are asymptomatic.

Prirojene nepravilnosti sečil vključujejo širok spekter malformacij, ki so posledica neustreznega embrionalnega razvoja sečil in se pogosto se pojavljajo v sklopu sindromov. Čeprav je etiologija prirojenih napak sečil v večini primerov verjetno multifaktorska, je v redkih primerih razvoj nepra vilnosti sečil povezan z monogenskimi ali kromosomski mi vzroki, in sicer s patogenimi različicami v posameznem genu ali kromosomu. Verjetnost genetske etiologije je več ja pri kompleksnih kliničnih slikah, kot je obojestranska parenhimska prizadetost ledvic, in ob pozitivni družinski anamnezi prirojenih nepravilnosti sečil in/ali sindromskega stanja. Pri diagnosticiranju prirojenih nepravilnosti sečil vse pogosteje uporabljamo genetske preiskave, ki temeljijo na metodi sekvenciranja naslednje generacije, pri pridruženih razvojnih nepravilnostih več organskih sistemov ter razvoj nem zaostanku in/ali dizmorfnih znakih pa tudi molekularno kariotipizacijo.

Prirojene nepravilnosti sečil vključujejo širok spekter malformacij, ki so posledica neustreznega embrionalnega razvoja sečil in se pogosto se pojavljajo v sklopu sindromov. Čeprav je etiologija prirojenih napak sečil v večini primerov verjetno multifaktorska, je v redkih primerih razvoj nepra vilnosti sečil povezan z monogenskimi ali kromosomski mi vzroki, in sicer s patogenimi različicami v posameznem genu ali kromosomu. Verjetnost genetske etiologije je več ja pri kompleksnih kliničnih slikah, kot je obojestranska parenhimska prizadetost ledvic, in ob pozitivni družinski anamnezi prirojenih nepravilnosti sečil in/ali sindromskega stanja. Pri diagnosticiranju prirojenih nepravilnosti sečil vse pogosteje uporabljamo genetske preiskave, ki temeljijo na metodi sekvenciranja naslednje generacije, pri pridruženih razvojnih nepravilnostih več organskih sistemov ter razvoj nem zaostanku in/ali dizmorfnih znakih pa tudi molekularno kariotipizacijo.

Objective: The study aimed to investigate the anticancer effect of E-prostanoid receptor 1 (EP1) antagonist, SC19220, alone or in combination with the COX-2 inhibitor Celecoxob(CXB) ® in mice bearing solid Ehrlich carcinoma (SEC). Methods: The tumors were induced in 40 female mice, which were divided randomly into four equal groups (n= 10 in each group): Tumor control, CXB, EP1 antagonist, and co-treatment. CXB (10mg/kg) and EP1 antagonist (2mg/kg) were given intraperitoneally every three days, six times in total, then tissue was extracted and prepared for histopathology and measurement of weight, PGE2, and gene expression of EP1 and β 1 integrin. Results: Both inhibitors, alone or in combination, showed a significant (p<0.001) antitumorigenic effect by decreasing, significantly (p<0.001), each of the tumor weights, tumor volumes, PGE2 levels, EP1 and β1-integrin gene expression along with increasing, significantly (p<0.001), the P53 tumor suppressor protein. The survival rate was improved from 80% in the control group to reach 100% in the treated groups. The co-treatment by CXB and EP1 antagonist showed a marked decrease in tumor weights and volumes as compared with the single treatment. In parallel, the histopathological findings showed enhanced apoptosis and diminished necrosis in the co-treated group. Conclusion: EP1 antagonist proved an antitumorigenic effect alone or combined with CXB and could play a new therapeutic strategy against breast cancer.

Purpose Bone metastasis is observed in up to 70% of breast cancer patients. The currently available treatment options are palliative in nature. Chemokine receptor 5 (CCR5) has gained attention as therapeutic target in various malignancies. Here, we investigated the effects of targeting CCR5 by its antagonist maraviroc in metastatic breast cancer cells. Methods In response to maraviroc exposure, cytotoxicity was assessed using an MTT proliferation assay, whereas the effects on colony formation and migration were assessed using colony formation, transwell chamber migration and scratch wound healing assays, respectively. Apoptosis-related activities were investigated using nuclear staining, annexin-V FITC staining and Western blotting. Cell cycle changes were analysed using flow cytometry and qRT-PCR for cell cycle relevant genes. A nude rat model for breast cancer bone metastasis was used to evaluate the in vivo efficacy of CCR5 targeting by maraviroc. Circulatory levels of the three cognate ligands for CCR5 (CCL3, CCL4, CCL5) were analysed in sera of breast cancer patients using ELISA. Results We found that blockade of CCR5 attenuated the proliferation, colony formation and migration of metastatic breast cancer cells, and induced apoptosis and arrest in the G1 phase of the cell cycle. Expression profiling highlighted the involvement of cell cycle related signalling cascades. We also found that treatment with maraviroc significantly inhibited bone metastasis in nude rats implanted with MDA-MB-231 breast cancer cells. Finally, we found that the circulatory levels of three cognate ligands for the CCR5 receptor varied between breast cancer patients and healthy controls. Conclusion Our findings indicate that targeting CCR5 may be an effective strategy to combat breast cancer bone metastasis.

Clinically, superficial tumors (stages Ta, Tis, and T1) account for 75% to 85% of bladder neoplasms, while the remaining 15% to 25% are invasive (T2, T3, T4) or metastatic lesions at the time of initial presentation. More than 70% of patients with superficial tumors will have one or more recurrences after initial treatment, and about one third of those patients will progress and eventually die of the disease. New methods are needed to identify and monitor patients presenting with "high-risk" superficial tumors likely to develop into invasive carcinoma. Once invasive into muscle, the natural history is quite variable but highly lethal. Despite aggressive surgical resection, radiotherapy, and/or chemotherapy, the overall cure rate remains in the range of 20% to 50%. New biological determinants are needed both for proper selection of therapy and monitoring. In this review, we describe and update molecular alterations reportedly associated with bladder tumorigenesis and cancer progression. We also review novel genes and "signaling networks" identified by the use of high-throughput technologies. The concept of alterations affecting "genetic pathways" is becoming more than just a molecular biology exercise. The challenge is to evaluate such targets for therapeutic development, as well as to translate progression and outcome biomarkers into improved clinical management. Integration of data generated from in-depth clinical evaluation, histologic tumor characteristics, and validated biomarkers could provide highly accurate, predictive tools for management of the bladder cancer patient.

A novel transduction pathway for the powerful angiogenic factor VEGF has been recently shown in endothelial cells to operate through NAADP-controlled intracellular release of Ca(2+). In the present report the possible involvement of NAADP-controlled Ca(2+) signaling in tumor vascularization, growth and metastatic dissemination was investigated in a murine model of VEGF-secreting melanoma. Mice implanted with B16 melanoma cells were treated with NAADP inhibitor Ned-19 every second day for 4 weeks and tumor growth, vascularization and metastatization were evaluated. Control specimens developed well vascularized tumors and lung metastases, whereas in Ned-19-treated mice tumor growth and vascularization as well as lung metastases were strongly inhibited. In vitro experiments showed that Ned-19 treatment controls the growth of B16 cells in vitro, their migratory ability, adhesive properties and VEGFR2 expression, indicating NAADP involvement in intercellular autocrine signaling. To this ...

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Airflow within the airways is determined directly by the lumenal area of that airway. In this paper, we consider several factors which can reduce airway lumenal area, including thickening and/or active constriction of the airway smooth muscle (ASM). The latter cell type can also contribute in part to inflammation, another feature of asthma, through its ability to take on a synthetic/secretory phenotype. The ASM therefore becomes a strategically important target in the treatment of asthma, given these key contributions to the pathophysiology of that disease. Pharmacological approaches have been developed to elicit relaxation of the ASM, but these are not always effective in all patients, nor do they address the long-term structural changes which impinge on the airway lumen. The recent discovery that thermal energy can be used to ablate smooth muscle has led to the development of a novel physical intervention—bronchial thermoplasty—in the treatment of asthma. Here, we review the evolu...

ABSTRACT. A novel distorted square-planar palladium(II) complex of the type [Pd(Hdz)(PPh3)Cl], where (Hdz = dithizone mono deprotonate and PPh3 = triphenylphosphine), was synthesized in dichloromethane reactions between PdCl2 and a mixture of Hdz and PPh3. The new Pd(II) complex has been identified by FT-IR, electronic spectra, DFT calculations, molar conductivity, and single-crystal X-ray diffraction. An X-ray diffraction study revealed the structure of this complex, indicating distorted square planar coordination geometry around the Pd(II) ion by N, S, P, and Cl donor atoms. XRD analysis has also shown that the Pd(II) complex contains one five-membered ring formed by the coordination of the Hdz ligand through the nitrogen and sulfur atoms to the palladium metal center. To comprehend the strength of nucleophilic and electrophilic attack between the ligands and metal ions, the natural bond orbital (NBO) was used. Finally, density functional theory (DFT) was used to show the molecula...

Eucaryotic chromosome endings (telomeres) replication problem was solved in the 1980’s by discovery of the telomerase enzyme. The Nobel Prize in Physiology or Medicine was awarded in 2009 for the discovery of telomerase. Altered telomerase expression in cancer, and human dream of eternal youth have accelerated the development of pharmacological telomerase inhibitors and activators. However, after 15 years of development they are still not available on the market. In the present article we reviewed pharmacological agents that target telomerase activity, which have entered clinical trials. Current drugs in development are mostly not intended to be used alone, as telomerase inhibitors under clinical trials are used in combination with the existing chemotherapeutics and anti-telomerase vaccines in combination with immuno-stimulants. Apart from cancer and aging, there are other diseases linked to deregulated activity of telomerase/telomeres and we also discuss technical and legal problem...

Cytokines have been introduced as critical inducers in the development of Th subpopulations.Cytokines like IL-10 are involved in inducing regulatory T cells such as Type 1 regulatory T (Tr1) cells cells. IL-22 is a member of IL-10 family of cytokines, and IL-28A is a member of IFN-γ family. In this study, cord blood mononuclear cells (CBMC) from normal healthy individuals were isolated by Ficoll and then naïve T cells were purified by CD4+CD25+ Regulatory T cell Isolation kit. The effect of these two cytokines on production of IL-5, TGF-β, IL-10, IL-4 and IFN-γ cytokines from cord blood T cells was investigated to identify Tr1 cells as well as Th1 and Th2 polarization. Flow cytometric analysis showed that IL-28A and IL-22 were not effective in expression of IL-5 and TGF-β either alone or in synergy, but in view of IL-10, IL-4 and IFN-γ, the results showed that IL-22 increased IL-10 and IL-4 but had a decreasing effect on IFN-γ. The results showed that IL-28A was not effective in inc...

Basal cell carcinoma (BCC) is the most commonly diagnosed cancer in humans, usually affecting elderly Caucasian men and skin regions mostly exposed to the sun, that rarely metastasizes. We report an unusual and aggressive case of multiple, non-syndromic metastatic BCC with an uncommon primary site in the chest and pulmonary metastases, treated successfully with surgery and vismodegib. A 51-year-old woman presented with a large pigmentary lesion of the chest, close to the sternum. She had the lesion for &gt; 25 years and lately noticed multiple facial lesions. The diagnosis of multiple BCC was suspected and a punch biopsy of the primary lesion was performed. Diagnosis was confirmed by immunohistochemistry (BerEp4+, EMA− phenotype). After excision, staging with a thorax computed tomography scan revealed metastatic micro-nodules in the left lung, confirmed histologically after video-assisted thoracic surgical biopsy. Adjuvant chemotherapy with vismodegib was proposed and administered. ...

Reaction of ligand, L-Ch 2 Ph with Na 2 PdCl 4 in acetonitrile yielded palladium(II) complex, [Pd(L)Cl] via CeS bond cleavage. It is characterized by several spectroscopic techniques and the structure is confirmed by single crystal X-ray study. The complex exhibits quasi-reversible oxidation couple at 0.86 V corresponds to ligand based thiophenolato to thiyl radical oxidation. Electronic structure, solution spectrum and redox properties are interpreted by DFT and TDDFT calculations.

The effects of the nonsteroidal antiandrogen bicalutamide (Casodex TM) and the luteinizing hormone releasing hormone agonist leuprolide depot (Procren Depot TM , Lupron Depot TM) on serum prostate-specific antigen (PSA), acid phosphatase (ACP), and prostatic acid phosphatase (PAP) in patients with benign prostatic hyperplasia (BPH) were determined. Thirty patients with BPH were randomised to receive bicalutamide 50 mg orally once daily or a placebo for 24 weeks, followed by 24 weeks of follow-up (bicalutamide study). In another study 55 men were randomised between 3.75 mg leuprolide depot intramuscularly at every 28 days for 24 weeks or placebo injections (leuprolide study). In both studies blood sampling was performed at baseline, at week 12 at week 24 and 24 weeks after the end of therapy. Androgen suppression with bicalutamide 50 mg daily for 24 weeks resulted in a median of 56% reduction of PSA (P < 0.001 when compared to placebo). Acid phosphatase and PAP did not change. Leuprolide resulted in a median of 87% reduction of serum PSA (P < 0.001) and a 39% reduction of PAP (P ¼ 0.023), whereas ACP was unchanged. Both bicalutamide and leuprolide induced a pronounced decline in serum PSA in BPH patients. The studies suggest a stronger androgen suppressive effect of leuprolide than of bicalutamide, but this difference might largely be due to too low a dosage of bicalutamide. ACP and PAP were relatively insensitive to androgen suppression. Our study suggests a different degree of androgen suppression on PSA originating from benign tissue versus cancer tissue, and that the direction of this discrepancy might be different for various androgen suppressive regimens.

The role of tumor-associated macrophages (TAMs) in the development of colon carcinoma is still controversial. Therefore, the present study aimed to investigate the TAM-driven processes that may affect colon cancer cell proliferation. To achieve this purpose, murine macrophages were co-cultured with C26 murine colon carcinoma cells at a cell density ratio that approximates physiological conditions for colon carcinoma development in vivo. In this respect, the effects of TAM-mediated angiogenesis, inflammation and oxidative stress on the proliferative capacity of C26 murine colon carcinoma cells were studied. To gain insight into the TAM-driven oxidative stress, NADPH oxidase, the main pro-oxidant enzyme in macrophages, was inhibited. Our data revealed that the stimulatory effects of TAMs on C26 cell proliferation may be related mainly to their pro-oxidant actions exerted by NADPH oxidase activity, which maintains the redox status and the angiogenic capacity of the tumor microenvironment. Additionally, the anti-inflammatory and pro-angiogenic effects of TAMs on tumor cells were found to create a favorable microenvironment for C26 colon carcinoma development and progression. In conclusion, our data confirmed the protumor role of TAMs in the development of colon carcinoma in an oxidative stress-dependent manner that potentiates the angiogenic capacity of the tumor microenvironment. These data may offer valuable information for future tumor-targeted therapies based on TAM 're-education' strategies.

Recently, angiogenesis and pulmonary vascular remodeling in COPD has been investigated. It has been hypothesized that endothelial dysfunction might be an initiating event that promotes vessel remodeling in COPD. Inflammatory tissue--a pivotal pathological feature of COPD--often hypoxic, can induce angiogenesis through upregulation of factors such as VEGF or FGF and regulators of angiogenesis such as chemokines (CXC family), acting either as angiogenic or angiostatic. Angiopoietins are distinct molecules that act in association with VEGF at different stages of angiogenic process. The regulation of angiogenesis is determined by a dual, yet opposing balance of angiogenic and angiostatic factors that promote or inhibit neovascularization, respectively, not yet elucidated in detail in COPD. Recent studies suggested an increased expression of VEGF in pulmonary muscular arteries of patients with moderate COPD and also in smokers with normal lung function. This was also associated with enla...

The lymphatic vasculature provides a major route for tumor metastasis and inhibiting neolymphangiogenesis induced by tumors can reduce metastasis in animal models. Developmental biology studies have identified the transcription factor SOX18 as a critical switch for lymphangiogenesis in the mouse embryo. Here, we show that SOX18 is also critical for tumor-induced lymphangiogenesis, and we show that suppressing SOX18 function is sufficient to impede tumor metastasis. Immunofluorescence analysis of murine tumor xenografts showed that SOX18 is reexpressed during tumor-induced neolymphangiogenesis. Tumors generated by implantation of firefly luciferase-expressing B16-F10 melanoma cells exhibited a reduced rate of metastasis to the regional draining lymph node in Sox18-deficient mice, as assessed by live bioluminescence imaging. Lower metastatic rates correlated with reduced tumoral lymphatic vessel density and diameter and with impaired drainage of peritumoral injected liposomes specific...

To analyze genetic alterations of p53 gene in Slovenian gastric cancer patients and to compare these alterations with clinicopathological parameters in order to assess the value of p53 as a prognostic factor. We analyzed the samples from 230 Slovenian patients with gastric cancer, collected between 1983 and 2001. p53 expression was evaluated immunohistochemically with DO-7 monoclonal antibody. In addition, loss of heterozigosity (LOH) and microsatellite instability (MSI) of p53 gene were evaluated, as well as its mutational status in the selected population of patients. p53 expression was associated with poorer survival and it was an independent predictor in multivariate analysis, along with TNM (T--size of tumor, N--nodal involvement, M--distant metastasis) stage status. Loss of heterozigosity and microsatellite instability status did not influence survival, however we found association of loss of heterozigosity with Lauren&#39;s (Mantel-Haenszel test, P=0.004) and Ming&#39;s (Mant...

Although most prostate cancer (PCa) patients nowadays are diagnosed at an early stage of disease, unfortunately still a significant number of patients will develop advanced PCa or will be diagnosed at an advanced (or metastatic) stage of disease. The group of patients showing the highest increase in incidence are those with rising prostate specific antigen (PSA) after radical therapy. In the last quarter of 2004, a Medline search has been performed targeting publications on patients diagnosed with advanced PCa, as well as with PSA relapse after previous radical therapy. This review aims at providing guidance to optimise hormone therapy in those selected groups of patients by addressing three pivotal questions; (i) who should receive hormonal treatment, (ii) what type of hormonal therapy should the patient be offered and (iii) what is the best timing of starting hormonal treatment. In patients relapsing after radical therapy, the PSA doubling time (PSA DT) has become a critical instrument to distinguish patients to have innocuous PSA evolution from patients at high risk for disease progression. A PSA DT of 3 months seems to be the cutoff point for identifying patients at risk. Therefore patients with a PSA DT of less than 3 months should be advised to initiate hormonal therapy. Antiandrogen monotherapy may be considered in this setting as it has been shown to delay progression; however, significant survival data are not yet available. Whether luteinising hormone releasing hormone (LHRH) agonists should be given continuously or intermittently (IHT) remains subject of debate. Surgical castration has been the standard of care in patients diagnosed with advanced PCa. Currently, LHRH agonists have become the preferred way of suppressing testosterone. Combination of an antiandrogen and a LHRH agonist (CAB) shows a modest benefit over LHRH agonist monotherapy. As CAB leads to increased side effects and costs, LHRH agonist monotherapy is preferred in the majority of patients. Conflicting data have been published concerning the optimal timing of LHRH agonist therapy. So it is not clear whether LHRH agonist therapy should be started immediately or deferred until appearance of symptoms. When initiating continuous hormone therapy, patients should be carefully monitored for the risk of long term androgen deprivation (anaemia, osteopenia and osteoporosis).

Basal cell carcinoma (BCC) is the most commonly diagnosed cancer in humans, usually affecting elderly Caucasian men and skin regions mostly exposed to the sun, that rarely metastasizes. We report an unusual and aggressive case of multiple, non-syndromic metastatic BCC with an uncommon primary site in the chest and pulmonary metastases, treated successfully with surgery and vismodegib. A 51-year-old woman presented with a large pigmentary lesion of the chest, close to the sternum. She had the lesion for &gt; 25 years and lately noticed multiple facial lesions. The diagnosis of multiple BCC was suspected and a punch biopsy of the primary lesion was performed. Diagnosis was confirmed by immunohistochemistry (BerEp4+, EMA− phenotype). After excision, staging with a thorax computed tomography scan revealed metastatic micro-nodules in the left lung, confirmed histologically after video-assisted thoracic surgical biopsy. Adjuvant chemotherapy with vismodegib was proposed and administered. ...