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Alzheimer’s disease (AD) is a crippling condition that affects millions of elderly adults each year, yet there remains a serious need for improved methods of diagnosis. Metabolomic analysis has been proposed as a potential methodology to better investigate and understand the progression of this disease; however, studies of human brain tissue metabolomics are challenging, due to sample limitations and ethical considerations. Comprehensive comparisons of imaging measurements in animal models to identify similarities and differences between aging- and AD-associated metabolic changes should thus be tested and validated for future human non-invasive studies. In this paper, we present the results of our highresolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) studies of AD and wild-type (WT) mouse models, based on animal age, brain regions, including cortex vs. hippocampus, and disease status. Our findings suggest the ability of HRMAS NMR to differentiate between AD and WT mice using brain metabolomics, which potentially can be implemented in in vivo evaluations.

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Toll-like receptors (TLR) are key players of the innate and adaptive immune response in vertebrates. The original protein Toll in Drosophila melanogaster regulates both host defense and morphogenesis during development. Making use of real-time PCR, in situ hybridization, and immunohistochemistry we systematically examined the expression of TLR1-9 and the intracellular adaptor molecules MyD88 and TRIF during development of the mouse brain. Expression of TLR7 and TLR9 in the brain was strongly regulated during different embryonic, postnatal, and adult stages. In contrast, expression of TLR1-6, TLR8, MyD88, and TRIF mRNA displayed no significant changes in the different phases of brain development. Neurons of various brain regions including the neocortex and the hippocampus were identified as the main cell type expressing both TLR7 and TLR9 in the developing brain. Taken together, our data reveal specific expression patterns of distinct TLRs in the developing mouse brain and lay the foundation for further investigation of the pathophysiological significance of these receptors for developmental processes in the central nervous system of vertebrates.

Alzheimer's disease (AD) is a crippling condition that affects millions of elderly adults each year, yet there remains a serious need for improved methods of diagnosis. Metabolomic analysis has been proposed as a potential methodology to better investigate and understand the progression of this disease; however, studies of human brain tissue metabolomics are challenging, due to sample limitations and ethical considerations. Comprehensive comparisons of imaging measurements in animal models to identify similarities and differences between aging- and AD-associated metabolic changes should thus be tested and validated for future human non-invasive studies. In this paper, we present the results of our highresolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) studies of AD and wild-type (WT) mouse models, based on animal age, brain regions, including cortex vs. hippocampus, and disease status. Our findings suggest the ability of HRMAS NMR to differentiate between AD and WT mice using brain metabolomics, which potentially can be implemented in in vivo evaluations.

The current high mortality of human lung cancer stems largely from the lack of feasible, early disease detection tools. An effective test with serum metabolomics predictive models able to suggest patients harboring disease could expedite triage patient to specialized imaging assessment. Here, using a training-validation-testing-cohort design, we establish our high-resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS)-based metabolomics predictive models to indicate lung cancer presence and patient survival using serum samples collected prior to their disease diagnoses. Studied serum samples were collected from 79 patients before (within 5.0 y) and at lung cancer diagnosis. Disease predictive models were established by comparing serum metabolomic patterns between our training cohorts: patients with lung cancer at time of diagnosis, and matched healthy controls. These predictive models were then applied to evaluate serum samples of our validation and testing cohorts, all collected from patients before their lung cancer diagnosis. Our study found that the predictive model yielded values for prior-to-detection serum samples to be intermediate between values for patients at time of diagnosis and for healthy controls; these intermediate values significantly differed from both groups, with an F1 score = 0.628 for cancer prediction. Furthermore, values from metabolomics predictive model measured from prior-to-diagnosis sera could significantly predict 5-y survival for patients with localized disease., Competing Interests: The authors declare no competing interest.

Atrioventricular nodal reentry tachycardia (AVNRT) is the most common regular supraventricular tachycardia (SVT). Slow pathway modification (SPM) is the accepted first line treatment with reported success rates around 95%. Information regarding possible predictors of AVNRT recurrence is scarce.Out of 4170 consecutive patients with SPM in our department from 1993-2018, we identified 78 patients (1.9%) receiving > 1 SPM (69% female, median age 50 years) with a recurrence of AVNRT after a successful SPM. We matched these patients for age, gender and number of radiofrequency applications during first SPM with 78 patients who received one successful SPM in our center without AVNRT recurrence. Both groups were analyzed for possible predictors of a recurrence of AVNRT during long-term follow-up. The recurrence group contained a significantly lower proportion of patients with an occurrence of junctional beats during SPM (69% versus 89%, P = 0.006). Moreover, significantly more cases of previously diagnosed atrial fibrillation/tachycardia (AF/AT; 21% versus 5%, P = 0.007) and inducible AF/AT during electrophysiology study (23% versus 6%, P = 0.006) were present in the recurrence group. While more than half of patients had a recurrence within the first year, in 20% symptoms reappeared ≥ 4 years after ablation.In a small percentage of patients, AVNRT recurs after an initially successful ablation. Interestingly, these patients had significantly fewer junctional beats during ablation and a higher rate of other (inducible) arrhythmias. AVNRT recurrence spanned a considerable timeframe and should remain a differential diagnosis, even years after ablation.

Venous thromboembolism event (VTE) is a common and morbid complication in cancer patients. Patients with gastrointestinal cancers often suffer from symptomatic or incidental splanchnic vein thrombosis, impaired liver function and/or thrombocytopenia. These characteristics require a thorough risk/benefit evaluation for individual patients. Considering the risk factors for the development of VTE and bleeding events in addition to recent study results may be helpful for correct initiation of primary pharmacological prevention and treatment of cancer-associated thrombosis (CAT), preferably with low molecular weight heparins (LMWH). Whereas thromboprophylaxis is most often recommended in hospitalized surgical and non-surgical patients with malignancy, there is less agreement as to its duration. With regard to ambulatory cancer patients, the lack of robust data results in low grade recommendations against routine use of anticoagulant drugs. Anticoagulation with LMWH for the first months is the evidence-based treatment for acute CAT, but duration of secondary prevention and the drug of choice are unclear. Based on published guidelines and literature, this review will focus on prevention and treatment strategies of VTE in patients with gastrointestinal cancers.

Background: The efficacy of platinum- and ifosfamide-based chemotherapy regimens as salvage treatment in metastatic breast cancer (MBC) has not yet been sufficiently evaluated., Patients and Methods: Patients with MBC treated with cisplatin plus ifosfamide with (PEI) and without (PI) etoposide in our clinic between 04/2005 and 04/2014 were retrospectively analyzed., Results: A total of 20 patients (median four prior chemotherapies) treated with PEI/PI were identified, out of whom 18 were evaluable for objective response. Treatment with PEI/PI resulted in one complete remission, nine partial remissions and two cases of stable disease. The median (range) progression-free survival was 4 (0-18) months and median overall survival from therapy initiation was 8.5 (0-50) months. PEI/PI therapy caused grade 3/4 toxicities (mainly hematological) in 80% of patients., Conclusion: PEI/PI is an adequate salvage treatment for patients with MBC but cannot be generally recommended due to toxicity. However, comparison with platinum monotherapy trials suggests that PEI/PI might be a more effective treatment for patients with triple-negative breast cancer., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: BCR-ABL-positive (BCR-ABL(+)) leukemia is very difficult to treat although much improvement has been achieved due to the clinical application of imatinib and the second-generation tyrosine kinase inhibitors (TKIs). This study aimed to evaluate for the first time the treatment value of the multiple tyrosine kinase inhibitor TKI258 in BCR-ABL(+) leukemia., Materials and Methods: Proliferation of different BCR-ABL(+) leukemic cells was measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; cell apoptosis with Annexin V/propidium iodide (PI) and flow cytometry. Gene expression at the protein level was determined by western blotting., Results: This drug showed treatment efficacy in naïve and imatinib-resistant BCR-ABL(+) leukemia cells, particularly in cells harboring T315I-mutated BCR-ABL, for which no effective inhibitor is available to date. By combination with the mTOR inhibitor RAD001, a synergistic effect on cell proliferation was observed in these cell lines., Conclusion: TKI258 may become a potent therapeutic agent, either alone or in combination with RAD001, for treatment of BCR-ABL(+) leukemia., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: The goal of the present study was to evaluate if the multiple tyrosine kinase inhibitor (TKI) TKI258 has any treatment value for infant/childhood acute lymphoblatic leukemia (ALL), especially those ALLs bearing the mixed lineage leukemia (MLL) genes., Materials and Methods: Cell proliferation was measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; cell apoptosis and cell-cycle distribution with flow cytometry. Gene expression at the protein level was determined by western blotting., Results: These ALL cells were extremely sensitive to TKI258 treatment with a concentration for 50% inhibition of cell proliferation (IC50) values in the nanomolar range in vitro. By combination with mTOR inhibitor RAD001, a synergistic effect on cell death and cell proliferation was observed in these cells., Conclusion: TKI258 may become a potent therapeutic agent, either alone or in combination with RAD001, for treatment of ALL, especially the entity with MLL genes., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: It was our purpose to analyze long-term clinical outcome and to identify prognostic factors after Linac-based fractionated stereotactic radiotherapy (Linac-based FSRT) and stereotactic radiosurgery (SRS) in patients with intracranial meningiomas., Materials and Methods: Between 10/1995 and 03/2009, 297 patients with a median age of 59 years were treated with FSRT for intracranial meningioma. 50 patients had a Grade I meningioma, 20 patients had a Grade II meningioma, 12 patients suffered from a Grade III tumor, and in 215 cases no histology was obtained (Grade 0). Of the 297 patients, 144 underwent FSRT as their primary treatment and 158 underwent postoperative FSRT. 179 patients received normofractionated radiotherapy (nFSRT), 92 patients received hypofractionated FSRT (hFSRT) and 26 patients underwent SRS. Patients with nFSRT received a mean total dose of 57.31 ± 5.82 Gy, patients with hFSRT received a mean total dose of 37.6 ± 4.4 Gy and patients who underwent SRS received a mean total dose of 17.31 ± 2.58 Gy., Results: Median follow-up was 35 months. Overall progression free survival (PFS) was 92.3% at 3 years, 87% at 5 years and 84.1% at 10 years. Patients with adjuvant radiotherapy showed significantly better PFS-rates than patients who had been treated with primary radiotherapy. There was no significant difference between PFS-rates of nFSRT, hFSRT and SRS patients. PFS-rates were independent of tumor size. Patients who had received nFSRT showed less acute toxicity than those who had received hFSRT. In the Grade 0/I group the rate of radiologic focal reactions was significantly lower than in the atypical/malignant histology group., Conclusion: This large study showed that FSRT is an effective and safe treatment modality with high PFS-rates for intracranial meningioma. We identified "pathological grading" and and "prior surgery" as significant prognostic factors.

Aim: Despite advances in the the first- and second-line treatment of metastatic breast cancer, there remains a large unmet need for additional treatment options. As preclinical studies have suggested that combining everolimus with carboplatin may produce higher activity than each drug by itself, we initiated a phase I study of this combination., Patients and Methods: Patients with pre-treated metastatic breast cancer received weekly carboplatin at AUC2 and daily oral everolimus at different dose-levels (level I: 2.5 mg; II: 5 mg; III: 7.5 mg; IV: 10 mg). Three patients were assigned to dose-levels I to III, and six to dose-level IV. The primary end-point was to determine the maximum tolerated dose (MTD)., Results: Fifteen patients were recruited to the study. The median number of previous chemotherapies was four (range: 1-11). No dose-limiting toxicity occurred at levels I-III during the first cycle. Based on the pre-determined definition, the maximum planned dose-level IV was selected as the MTD. Patients received a median of four cycles of treatment (range 1-13). Most frequent grade 3 and 4 toxicities included leukopenia, thrombocytopenia and infection. Response rates were as follows: 21% partial response, 43% stable disease, and 36% progressive disease., Conclusion: Carboplatin and everolimus is a well-tolerated combination for heavily pre-treated metastatic breast cancer. Everolimus (10 mg/d) and carboplatin (AUC2 weekly) were defined as the MTD. This dose is currently being employed in an ongoing phase II trial.

Aim: Metformin appears to interfere directly with cell proliferation and apoptosis in cancer cells in a non-insulin-mediated manner. One of the key mechanisms of metformin's action is the activation of adenosine monophosphate activated protein kinase (AMPK). AMPK is linked with the phosphatidylinositol 3-kinase (PI3K)/ phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) pathway and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) cascades--all known for being frequently dysregulated in breast cancer. Therefore, simultaneously targeting AMPK through metformin and the PI3K/AKT/mTOR pathway by an mTOR inhibitor could become a therapeutic approach. The aim of this study was to evaluate the anticancer effect of metformin alone and in combination with chemotherapeutic drugs and the mTOR inhibitor RAD001., Materials and Methods: The proliferation of breast cancer cells was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; and the cell apoptosis with enzyme-linked immunosorbent assay (ELISA). Gene expression at the protein level was determined by western blot., Results: We tested metformin alone and in combination with RAD001 and/or chemotherapeutic agents (carboplatin, paclitaxel and doxorubicin, respectively) on several human breast cancer cell lines with respect to cell proliferation, apoptosis and autophagy. Metformin alone inhibited cell proliferation and induced apoptosis in different breast cancer cell lines (ERα-positive, HER2-positive, and triple-negative). The cytotoxic effect of metformin was more remarkable in triple-negative breast cancer cell lines than in other cell lines. The cell apoptosis induced by metformin is, at least partly, caspase-dependent and apoptosis inducing factor (AIF)-dependent. Interestingly, we demonstrated that metformin induced cell autophagy. Inhibiting autophagy with chloroquine, enhanced the treatment efficacy of metformin, indicating that autophagy induced by metformin may protect breast cancer cells from apoptosis. We further demonstrated that co-administration of metformin with chemotherapeutic agents and RAD001 intensified the inhibition of cell proliferation. The analysis of cell cycle-regulating proteins cyclin D, cyclin E and p27 by western blot indicated that the synergistic inhibition of G1 phase of the cell cycle by the combination treatment of metformin, chemotherapeutic drugs and/or RAD001 contributed to the synergistic inhibition of cell proliferation., Conclusion: Our investigation provides a rationale for the clinical application of metformin within treatment regimens for breast cancer.

Toll-like receptors (TLR) are key players of the innate and adaptive immune response in vertebrates. The original protein Toll in Drosophila melanogaster regulates both host defense and morphogenesis during development. Making use of real-time PCR, in situ hybridization, and immunohistochemistry we systematically examined the expression of TLR1-9 and the intracellular adaptor molecules MyD88 and TRIF during development of the mouse brain. Expression of TLR7 and TLR9 in the brain was strongly regulated during different embryonic, postnatal, and adult stages. In contrast, expression of TLR1-6, TLR8, MyD88, and TRIF mRNA displayed no significant changes in the different phases of brain development. Neurons of various brain regions including the neocortex and the hippocampus were identified as the main cell type expressing both TLR7 and TLR9 in the developing brain. Taken together, our data reveal specific expression patterns of distinct TLRs in the developing mouse brain and lay the foundation for further investigation of the pathophysiological significance of these receptors for developmental processes in the central nervous system of vertebrates.

Food intake behaviour and energy homeostasis are strongly regulated by a complex system of humoral factors and nerval structures constituting the brain-gut-axis. To date the only known peripherally produced and centrally acting peptide that stimulates food intake is ghrelin, which is mainly synthesized in the stomach. Recent data indicate that the orexigenic effect of ghrelin might be influenced by other gastrointestinal peptides such as cholecystokinin (CCK), bombesin, desacyl ghrelin, peptide YY (PYY), as well as glucagon-like peptide (GLP). Therefore, we will review on the interactions of ghrelin with several gastrointestinal factors known to be involved in appetite regulation in order to elucidate the interdependency of peripheral orexigenic and anorexigenic peptides in the control of appetite.

Aim: To investigate the impact of arachidonic acid (AA) and docosahexaenoic acid (DHA) and their combination on colon cancer cell growth., Methods: The LS-174T colon cancer cell line was used to study the role of the prostaglandin precursor AA and the omega-3 polyunsaturated fatty acid DHA on cell growth. Cell viability was assessed in XTT assays. For analysis of cell cycle and cell death, flow cytometry and DAPI staining were applied. Expression of cyclooxygenase-2 (COX-2), p21 and bcl-2 in cells incubated with AA or DHA was examined by real-time RT-PCR. Prostaglandin E(2) (PGE(2)) generation in the presence of AA and DHA was measured using a PGE(2)-ELISA., Results: AA increased cell growth, whereas DHA reduced viability of LS 174T cells in a time- and dose-dependent manner. Furthermore, DHA down- regulated mRNA of bcl-2 and up-regulated p21. Interestingly, DHA was able to suppress AA-induced cell proliferation and significantly lowered AA-derived PGE(2) formation. DHA also down-regulated COX-2 expression. In addition to the effect on PGE(2) formation, DHA directly reduced PGE(2)-induced cell proliferation in a dose-dependent manner., Conclusion: These results suggest that DHA can inhibit the pro-proliferative effect of abundant AA or PGE(2).