Combined Treatment of MCF-7 Cells with AICAR and Methotrexate, Arrests Cell Cycle and Reverses Warburg Metabolism through AMP-Activated Protein Kinase (AMPK) and FOXO1.

Cancer cells are characterized by metabolic alterations, namely, depressed mitochondrial oxidation, enhanced glycolysis and pentose phosphate shunt flux to support rapid cell growth, which is called the Warburg effect. In our study we assessed the metabolic consequences of a joint treatment of MCF-7 breast cancer cells with AICAR, an inducer of AMP-activated kinase (AMPK) jointly with methotrexate (MTX), a folate-analog antimetabolite that blunts de novo nucleotide synthesis. MCF7 cells, a model of breast cancer cells, were resistant to the individual application of AICAR or MTX, however combined treatment of AICAR and MTX reduced cell proliferation.

Individual and combined in vitro (anti)androgenic effects of certain food additives and cosmetic preservatives.

The individual and combined (binary mixtures) (anti)androgenic effect of butylparaben (BuPB), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate (PG) was evaluated using the MDA-kb2 cell line. Exposing these cells to AR agonists results in the expression of the reporter gene (encoding for luciferase) and luminescence can be measured in order to monitor the activity of the reporter protein. In case of the evaluation of the anti-androgenic effect, the individual test compounds or binary mixtures were tested in the presence of a fixed concentration of a strong AR agonist (1000 pM 5-alpha-dihydrotestosterone; DHT).

The influence of 5-HT(2A) activity on a 5-HT(2C) specific in vivo assay used for early identification of multiple acting SERT and 5-HT(2C) receptor ligands.

As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1-phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2-aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated.

Transmembrane TNF-α Reverse Signaling Inhibits Lipopolysaccharide-Induced Proinflammatory Cytokine Formation in Macrophages by Inducing TGF-β: Therapeutic Implications.

TNF-α, a potent proinflammatory cytokine, is generated in a precursor form called transmembrane (m)TNF-α that is expressed as a type II polypeptide on the surface of certain cells. mTNF-α was shown to act both as a ligand by binding to TNF-α receptors, as well as a receptor that transmits outside-to-inside (reverse) signals back into the mTNF-α-bearing cells. In this study, we show that nonactivated macrophages express basal levels of mTNF-α and respond to anti-TNF-α Abs by triggering the MAPK kinase 4 signaling pathway.

The dopamine D₃-preferring D₂/D₃ dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia.

Current antipsychotic medication is largely ineffective against the negative and cognitive symptoms of schizophrenia. One promising therapeutic development is to design new molecules that balance actions on dopamine D2 and D3 receptors to maximise benefits and limit adverse effects. This study used two rodent paradigms to investigate the action of the dopamine D3-preferring D3/D2 receptor partial agonist cariprazine.

Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology.

Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia.

The Role of β-Carboline Alkaloids in the Pathogenesis of Essential Tremor.

Essential tremor (ET) is one of the most prevalent neurological disorders in the world. Environmental factors have been implicated in the pathogenesis of ET. In particular, epidemiological studies have suggested that neurotoxic agents, especially β-carboline alkaloids (βCAs), might be generated through Maillard-type reaction.

Five new rotundabaloghiid mites (Acari: Uropodina) from South-East Asia.

Five new species of the family Rotundabaloghiidae are described from Indonesia and Malaysia. Angulobaloghia pedunculata sp. nov.

In vitro modulation of estrogen receptor activity by norfluoxetine.

Background And Aims: Selective serotonin reuptake inhibitors (SSRIs) are antidepressants increasingly prescribed for pregnancy and postpartum depression. However, these compounds can cross the placenta and also pass into breast milk, thus reaching the fetus and infant during critical developmental stages, potentially causing adverse effects. Fluoxetine, a widely used SSRI, has been shown to affect (neuro)endocrine signaling in various organisms, including humans.

Estrogenic/antiestrogenic activity of selected selective serotonin reuptake inhibitors.

Background And Aims: Selective serotonin reuptake inhibitors (SSRIs) are one of the most prescribed classes of psychotropics. Even though the SSRI class consists of 6 molecules (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline), only fluoxetine was intensively studied for endocrine disruptive effects, while the other SSRIs received less attention. This study was designed to evaluate the estrogenic/antiestrogenic effect of fluoxetine, sertraline and paroxetine.

Open radical cystectomy: still the gold standard for muscle invasive bladder cancer.

Introduction: Muscle invasive bladder cancer is an unforgiving disease, and if untreated, it leads to death within 2 years of the diagnosis in >85 % of the patients. Long-term oncologic efficacy remains the ultimate standard that all procedures have to be measured by. In the past decades, open radical cystectomy (RC), extended pelvic lymph node dissection (PLND), and urinary diversion have been established as the gold standard.

Structural Basis of Ribosomal S6 Kinase 1 (RSK1) Inhibition by S100B Protein: MODULATION OF THE EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) SIGNALING CASCADE IN A CALCIUM-DEPENDENT WAY.

Mitogen-activated protein kinases (MAPK) promote MAPK-activated protein kinase activation. In the MAPK pathway responsible for cell growth, ERK2 initiates the first phosphorylation event on RSK1, which is inhibited by Ca(2+)-binding S100 proteins in malignant melanomas. Here, we present a detailed in vitro biochemical and structural characterization of the S100B-RSK1 interaction.

Metastasis-associated S100A4 is a specific amine donor and an activity-independent binding partner of transglutaminase-2.

Transglutaminase-2 (TG2) is best known as a Ca(2+)-dependent cross-linking enzyme; however, some of its extracellular matrix-related functions are independent of its catalytic activity and include matrix remodelling, adhesion and migration. S100A4 belongs to the Ca(2+)-binding EF-hand S100 protein family and acts both intra- and extra-cellularly through binding to various partners. It regulates cell migration and its overexpression is strongly associated with metastasis and poor survival in various cancers.

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Due to the climate change zoonoses, dirofilariasis in particular is spreading. Hence, it is likely that we will encounter with this problem more frequently in the future Our intention with this case presentation is to draw attention to the increasing number of nematodes that cause differential diagnostic problems. The patient underwent surgery with suspicion of pulmonary malignancy suggested by a peripheral rounded opacity in imaging, but histological examination revealed dirofilariasis.

Influence of disc-fovea angle and retinal blood vessels on interindividual variability of circumpapillary retinal nerve fibre layer.

Background: To assess whether intersubject variability of circumpapillary retinal nerve fibre layer (RNFL) thickness in healthy subjects acquired with spectral domain optical coherence tomography (SD-OCT) can be reduced by considering the disc-fovea angle (DFA), either alone or together with a compensation based on retinal blood vessel distribution (RVD).

Methods: 106 healthy volunteers underwent SD-OCT examination centred on the optic disc (OD) and on the macula. OD contours and foveal positions were automatically calculated.

Multivariate Model of the Intersubject Variability of the Retinal Nerve Fiber Layer Thickness in Healthy Subjects.

Purpose: We present and validate a multivariate model that partially compensates for retinal nerve fiber layer (RNFL) intersubject variability.

Methods: A total of 202 healthy volunteers randomly attributed to a training (TS) and a validation (VS) sample underwent complete ophthalmic examination, including Fourier-domain optical coherence tomography (FD-OCT). We acquired FD-OCT data centered at the optic disc (OD) and the macula.

Cariprazine delays ouabain-evoked epileptiform spikes and loss of activity in rat hippocampal slices.

In the only bipolar cycling in vitro model, rat hippocampal slices are treated with the sodium pump inhibitor ouabain, which induces epileptiform activity, followed by refractory activity loss that recovers and cycles back to epileptiform activity. Thus, clinical cycling seen in patients with bipolar disorder is modeled on a cellular level as alternating hyperactivity and hypoactivity interspersed with normal activity. In this study, we tested the ability of cariprazine a new antipsychotic candidate to block ouabain-induced changes in rat hippocampal slices.

Does Stepwise Voltage Ramping Protect the Kidney from Injury During Extracorporeal Shockwave Lithotripsy? Results of a Prospective Randomized Trial.

Background: Renal damage is more frequent with new-generation lithotripters. However, animal studies suggest that voltage ramping minimizes the risk of complications following extracorporeal shock wave lithotripsy (SWL). In the clinical setting, the optimal voltage strategy remains unclear.

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Objective: The authors examined pain after thoracotomies in the Department of Thoracic Surgery, University Teaching Hospital Markusovszky and compared two analgetic methods.

Patients And Method: The study was conducted for a period of 10 months, they have processed 268 patients details whose chest were open. The patients were divided in 2 groups: one of them got fentanyl containing plaster which absorbs transdermal as well as intraoperatively applied intercostal bupivacain blockade.

Long-term results of a prospective randomized trial assessing the impact of re-adaptation of the dorsolateral peritoneal layer after extended pelvic lymph node dissection and cystectomy.

Objective: To evaluate the long-term oncological and functional outcomes of re-adaptation of the dorsolateral peritoneal layer after pelvic lymph node dissection (PLND) and cystectomy.

Patients And Methods: A randomized, single-centre, single-blinded, two-arm trial was conducted on 200 consecutive patients who underwent PLND and cystectomy for bladder cancer ( View Article and Find Full Text PDF

Analysis of the effect of locally applied inhomogeneous static magnetic field-exposure on mouse ear edema--a double blind study.

The effect static magnetic field (SMF)-exposure may exert on edema development has been investigated. A 6 h long whole-body (WBSMF) or local (LSMF), continuous, inhomogeneous SMF-exposure was applied on anesthetized mice in an in vivo model of mustard oil (MO)-induced ear edema. LSMF was applied below the treated ear, below the lumbar spine, or below the mandible.

Cariprazine exerts antimanic properties and interferes with dopamine D2 receptor β-arrestin interactions.

Activation of dopamine D2 receptors (D2R) modulates G protein/cAMP-dependent signaling and also engages Akt-GSK-3 signaling through D2R/β-arrestin 2 scaffolding of Akt and PP2A. This G protein-independent pathway may be important in mediating the antimanic effects of mood stabilizers and antipsychotics. The mood stabilizer lithium influences behavior and Akt/GSK-3 signaling in mice and many antipsychotics have been shown to more potently antagonize the activity of the β-arrestin-2 pathway relative to the G protein-dependent pathway.

Optimization of Extracorporeal Shock Wave Lithotripsy Delivery Rates Achieves Excellent Outcomes for Ureteral Stones: Results of a Prospective Randomized Trial.

Purpose: Management of ureteral stones remains controversial. To determine whether optimizing the extracorporeal shock wave lithotripsy delivery rate would improve the treatment of solitary ureteral stones we compared the outcomes of 2 delivery rates in a prospective randomized trial.

Materials And Methods: From July 2010 to October 2012, 254 consecutive patients were randomized to extracorporeal shock wave lithotripsy at a shock wave delivery rate of 60 and 90 pulses per minute in 130 and 124, respectively.

Phosphorylation as conformational switch from the native to amyloid state: Trp-cage as a protein aggregation model.

The 20 residue long Trp-cage miniprotein is an excellent model for both computational and experimental studies of protein folding and stability. Recently, great attention emerged to study disease-related protein misfolding, aggregation, and amyloid formation, with the aim of revealing their structural and thermodynamic background. Trp-cage is sensitive to both environmental and structure-modifying effects.

Bcl-2 predicts response to neoadjuvant chemotherapy and is overexpressed in lymph node metastases of urothelial cancer of the bladder.

Purpose: To assess whether Bcl-2, an inhibitor of the apoptotic cascade, can predict response to neoadjuvant chemotherapy in patients with urothelial cancer of the bladder (UCB).

Methods: Bcl-2 expression was analyzed in 2 different tissue microarrays (TMAs). One TMA was constructed of primary tumors and their corresponding lymph node (LN) metastases from 152 patients with chemotherapy-naive UCB treated by cystectomy and pelvic lymphadenectomy (chemotherapy-naive TMA cohort).