Synthesis, characterization, and evaluation of Cd[L-proline] 2 , a novel histone deacetylase inhibitor that induces epigenetic modification of histone deacetylase isoforms in A549 cells

Summary

Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression through their effects on the compact chromatin structure. In clinical studies, several classes of histone deacetylase inhibitors (HDACi) have demonstrated potent anticancer activities with metal complexes. Hence, we synthesized cadmium–proline complexes using both the D- and L-isomers of proline and evaluated their biological activities by observing the efficiency of their inhibition of HDAC activity, ability to reduce the expression of HDAC isoforms in A549 cells and effect on apoptosis. The synthesized compounds were characterized by UV, IR, NMR spectroscopy and elemental analysis. In-vitro cell toxicity was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and the 50% inhibitory concentration (IC₅₀; 2 μM) was obtained at 12 h. The morphological study at nuclear levels was performed by acridine orange/ethidium bromide (AO/EB) and Hoechst staining, and the results showed an association with cell cycle arrest at the G2/M phase. Both cadmium–proline complexes intensely inhibited HDAC activity at 2 μM concentration. Interestingly, Cd[L-proline]₂ was found to be a potent inhibitor for all HDAC isoforms, whereas Cd[D-proline]₂ inhibited only HDAC1 and 2. HDACi are novel chemotherapeutic drugs that induce hyperacetylation of histones H3 and H4, counteracting the aberrant repression of genes, such as insulin-like growth factor-binding protein 3 (IGFBP-3), p53, and p21. ERK/MAPK signaling pathway resulted in the downregulation of the expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), contributing to the inhibition of metastasis in A549 cells. Apoptosis induction was accompanied by the activation of death receptors and their ligands which recruit initiator caspase 8, decrease in mitochondrial membrane potential (ΔΨm), as well as increased Bax/Bcl₂ ratio, followed by activation of caspases 9 and 3. Our finding suggests that Cd[L-proline]₂ complex accelerates epigenetic rearrangement by HDAC inhibition, which may be the key mechanism for its anticancer activity.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2fah7As
via IFTTT

FDA Announces Plan to Lower Nicotine in Cigarettes to Non-Addictive Levels

The FDA has announced a new comprehensive plan for tobacco and nicotine regulation designed to serve as a road map to better protect American children and reduce tobacco-related disease and death. (Source: CancerNetwork)

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2hpOyQ3
via IFTTT

Erratum to: Prenatal nicotine exposure induces HPA axis-hypersensitivity in offspring rats via the intrauterine programming of up-regulation of hippocampal GAD67

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u1ZcOW
via IFTTT

Cisplatin Increases Sensitivity to FGFR Inhibition in Patient-Derived Xenograft Models of Lung Squamous Cell Carcinoma

Lung squamous cell carcinoma (SqCC) is a molecularly complex and genomically unstable disease. No targeted therapy is currently approved for lung SqCC, although potential oncogenic drivers of SqCC have been identified, including amplification of the fibroblast growth factor receptor 1 (FGFR1). Reports from a recently completed clinical trial indicate low response rates in patients treated with FGFR tyrosine kinase inhibitors, suggesting inadequacy of FGFR1 amplification as a biomarker of response, or the need for combination treatment. We aimed to develop accurate models of lung SqCC and determine improved targeted therapies for these tumors. We show that detection of FGFR1 mRNA by RNA in situ hybridization is a better predictor of response to FGFR inhibition than FGFR1 gene amplification using clinically relevant patient-derived xenograft (PDX) models of lung SqCC. FGFR1-overexpressing tumors were observed in all histologic subtypes of non–small cell lung cancers (NSCLC) as assessed on a tissue microarray, indicating a broader range of tumors that may respond to FGFR inhibitors. In FGFR1-overexpressing PDX tumors, we observed increased differentiation and reduced proliferation following FGFR inhibition. Combination therapy with cisplatin was able to increase tumor cell death, and dramatically prolonged animal survival compared to single-agent treatment. Our data suggest that FGFR tyrosine kinase inhibitors can benefit NSCLC patients with FGFR1-overexpressing tumors and provides a rationale for clinical trials combining cisplatin with FGFR inhibitors. Mol Cancer Ther; 16(8); 1610–22. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vrusKM
via IFTTT

U1 Adaptors Suppress the KRAS-MYC Oncogenic Axis in Human Pancreatic Cancer Xenografts

Targeting KRAS and MYC has been a tremendous challenge in cancer drug development. Genetic studies in mouse models have validated the efficacy of silencing expression of both KRAS and MYC in mutant KRAS-driven tumors. We investigated the therapeutic potential of a new oligonucleotide-mediated gene silencing technology (U1 Adaptor) targeting KRAS and MYC in pancreatic cancer. Nanoparticles in complex with anti-KRAS U1 Adaptors (U1-KRAS) showed remarkable inhibition of KRAS in different human pancreatic cancer cell lines in vitro and in vivo. As a nanoparticle-free approach is far easier to develop into a drug, we refined the formulation of U1 Adaptors by conjugating them to tumor-targeting peptides (iRGD and cRGD). Peptides coupled to fluorescently tagged U1 Adaptors showed selective tumor localization in vivo. Efficacy experiments in pancreatic cancer xenograft models showed highly potent (>90%) antitumor activity of both iRGD and (cRGD)₂-KRAS Adaptors. U1 Adaptors targeting MYC inhibited pancreatic cancer cell proliferation caused by apoptosis in vitro (40%–70%) and tumor regressions in vivo. Comparison of iRGD-conjugated U1 KRAS and U1 MYC Adaptors in vivo revealed a significantly greater degree of cleaved caspase-3 staining and decreased Ki67 staining as compared with controls. There was no significant difference in efficacy between the U1 KRAS and U1 MYC Adaptor groups. Our results validate the value in targeting both KRAS and MYC in pancreatic cancer therapeutics and provide evidence that the U1 Adaptor technology can be successfully translated using a nanoparticle-free delivery system to target two undruggable genes in cancer. Mol Cancer Ther; 16(8); 1445–55. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u2qHYL
via IFTTT

Inhibition of Heparanase in Pediatric Brain Tumor Cells Attenuates their Proliferation, Invasive Capacity, and In Vivo Tumor Growth

Curative therapy for medulloblastoma and other pediatric embryonal brain tumors has improved, but the outcome still remains poor and current treatment causes long-term complications. Malignant brain tumors infiltrate the healthy brain tissue and, thus despite resection, cells that have already migrated cause rapid tumor regrowth. Heparan sulfate proteoglycans (HSPG), major components of the extracellular matrix (ECM), modulate the activities of a variety of proteins. The major enzyme that degrades HS, heparanase (HPSE), is an important regulator of the ECM. Here, we report that the levels of HPSE in pediatric brain tumors are higher than in healthy brain tissue and that treatment of pediatric brain tumor cells with HPSE stimulated their growth. In addition, the latent, 65 kDa form of HPSE (that requires intracellular enzymatic processing for activation) enhanced cell viability and rapidly activated the ERK and AKT signaling pathways, before enzymatically active HPSE was detected. The HPSE inhibitor PG545 efficiently killed pediatric brain tumor cells, but not normal human astrocytes, and this compound also reduced tumor cell invasion in vitro and potently reduced the size of flank tumors in vivo. Our findings indicate that HPSE in malignant brain tumors affects both the tumor cells themselves and their ECM. In conclusion, HPSE plays a substantial role in childhood brain tumors, by contributing to tumor aggressiveness and thereby represents a potential therapeutic target. Mol Cancer Ther; 16(8); 1705–16. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vrfUei
via IFTTT

Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas

High-grade gliomas, such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG), are characterized by an aggressive phenotype with nearly universal local disease progression despite multimodal treatment, which typically includes chemotherapy, radiotherapy, and possibly surgery. Radiosensitizers that have improved the effects of radiotherapy for extracranial tumors have been ineffective for the treatment of GBM and DIPG, in part due to poor blood–brain barrier penetration and rapid intracranial clearance of small molecules. Here, we demonstrate that nanoparticles can provide sustained drug release and minimal toxicity. When administered locally, these nanoparticles conferred radiosensitization in vitro and improved survival in rats with intracranial gliomas when delivered concurrently with a 5-day course of fractionated radiotherapy. Compared with previous work using locally delivered radiosensitizers and cranial radiation, our approach, based on the rational selection of agents and a clinically relevant radiation dosing schedule, produces the strongest synergistic effects between chemo- and radiotherapy approaches to the treatment of high-grade gliomas. Mol Cancer Ther; 16(8); 1456–69. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u2qoNr
via IFTTT

Reactivation of the p90RSK-CDC25C Pathway Leads to Bypass of the Ganetespib-Induced G2-M Arrest and Mediates Acquired Resistance to Ganetespib in KRAS-Mutant NSCLC

A subset of non–small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations, including the most frequently observed driver mutant KRAS, which is associated with a poor prognosis. As direct RAS targeting in the clinic has been unsuccessful to date, use of Hsp90 inhibitors appeared to be a promising therapy for KRAS-mutant NSCLC; however, limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib, and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit. Here, we investigated the mechanism(s) of resistance to ganetespib and explored why the combination with docetaxel failed in the clinic. We have not only identified a critical role for the bypass of the G₂–M cell-cycle checkpoint as a mechanism of ganetespib resistance (GR) but have also found that GR leads to cross-resistance to docetaxel. Reactivation of p90RSK and its downstream target, CDC25C, was critical for GR and mediated the bypass of a G₂–M arrest. Overexpression of either p90RSK or CDC25C lead to bypass of G₂–M arrest and induced ganetespib resistance in vitro and in vivo. Moreover, resistance was dependent on p90RSK/CDC25C signaling, as synthetic lethality to ERK1/2, p90RSK, or CDC25C inhibitors was observed. Importantly, the combination of ganetespib and p90RSK or CDC25C inhibitors was highly efficacious in parental cells. These studies provide a way forward for Hsp90 inhibitors through the development of novel rationally designed Hsp90 inhibitor combinations that may prevent or overcome resistance to Hsp90i. Mol Cancer Ther; 16(8); 1658–68. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vrIsnK
via IFTTT

Tumor-targeted Nanoparticle Delivery of HuR siRNA Inhibits Lung Tumor Growth In Vitro and In Vivo By Disrupting the Oncogenic Activity of the RNA-binding Protein HuR

Selective downregulation of the human antigen R (HuR) protein by siRNA may provide a powerful approach for treating lung cancer. To this end, we investigated the efficacy of transferrin receptor-targeted liposomal nanoparticle-based HuR siRNA (HuR-TfNP) therapy and compared with control siRNA (C)-TfNP therapy both, in vitro and in vivo using lung cancer models. In vitro studies showed HuR-TfNP, but not C-TfNP, efficiently downregulated HuR and HuR-regulated proteins in A549, and HCC827 lung cancer cells, resulting in reduced cell viability, inhibition of cell migration and invasion, and induction of G₁ cell-cycle arrest culminating in apoptosis. However, HuR-TfNP activity in normal MRC-9 lung fibroblasts was negligible. In vivo biodistribution study demonstrated that fluorescently labeled HuR-siRNA or ICG dye–loaded TfNP localized in tumor tissues. Efficacy studies showed intratumoral or intravenous administration of HuR-TfNP significantly inhibited A549 (>55% inhibition) and HCC827 (>45% inhibition) subcutaneous tumor growth compared with C-TfNP. Furthermore, HuR-TfNP treatment reduced HuR, Ki67, and CD31 expression and increased caspase-9 and PARP cleavage and TUNEL-positive staining indicative of apoptotic cell death in tumor tissues compared with C-TfNP treatment. The antitumor activity of HuR-TfNP was also observed in an A549-luc lung metastatic model, as significantly fewer tumor nodules (9.5 ± 3.1; P < 0.001; 88% inhibition) were observed in HuR-TfNP–treated group compared with the C-TfNP–treated group (77.7 ± 20.1). Significant reduction in HuR, Ki67, and CD31 expression was also observed in the tumor tissues of HuR-TfNP-treatment compared with C-TfNP treatment. Our findings highlight HuR-TfNP as a promising nanotherapeutic system for lung cancer treatment. Mol Cancer Ther; 16(8); 1470–86. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u1XAER
via IFTTT

Risk of Pneumonitis Associated with Programmed Cell Death 1 Inhibitors in Cancer Patients: A Meta-analysis

Pneumonitis, a rare but potentially life-threatening adverse event in cancer patients receiving programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors, has been reported in case reports, clinical trials, and retrospective studies. We performed a systematic review and meta-analysis to calculate the RR of pneumonitis associated with the use of PD-1/L1 inhibitors in randomized clinical trials (RCT). We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant RCTs comparing PD-1/L1 inhibitors to control with available data on pneumonitis. The pooled incidence, RR, and 95% confidence intervals (CI) were calculated using fixed effects or random effects model according to the heterogeneity of included trials. Twelve RCTs were eligible for the meta-analysis, yielding a total of 5,775 patients included in trials evaluating a PD-1 inhibitor; no eligible trials evaluated a PD-L1 inhibitor. The pooled incidence of all-grade pneumonitis for patients treated with PD-1 inhibitors was 3.2% (95% CI, 2.3–4.5), and that of high-grade pneumonitis was 1.1% (95% CI, 0.7–1.7). The RR of all-grade and high-grade pneumonitis was 4.36 (95% CI, 2.58–7.38) and 2.86 (95% CI, 1.30–6.31), respectively. In a sensitivity analysis, PD-1 inhibitors were also associated with significantly increased risk of pneumonitis per person-month (for all grade, RR = 3.37; 95% CI, 1.97–5.76; for high grade, RR = 2.25; 95% CI, 1.03–4.94). PD-1 inhibitors were associated with a significant increase of all-grade and high-grade pneumonitis both per treatment episode and per person-month. Mol Cancer Ther; 16(8); 1588–95. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vrf15v
via IFTTT

Photodynamic Therapy Using Photosensitizer-Encapsulated Polymeric Nanoparticle to Overcome ATP-Binding Cassette Transporter Subfamily G2 Function in Pancreatic Cancer

Chlorin-based photosensitizers are commonly used in photodynamic therapy (PDT). These drugs are effluxed by cell membrane transporters, such as the ATP-binding cassette subfamily G member 2 (ABCG2). PDT efficacy is limited in tumor cells expressing high levels of these proteins. Pancreatic cancer cell lines AsPC-1 and MIA PaCa-2, which have high and low ABCG2 expression, respectively, were used, and ABCG2-overexpressing MIA PaCa-2 cells were generated. We compared PDT efficacy between chlorin e6 (Ce6) and cationic photosensitizer–encapsulated polymeric nanoparticle (PS-pNP), which is comprised with Ce6, polyethylene glycol, and polyethylenimine. The intracellular concentration of Ce6 was significantly higher in MIA PaCa-2 cells than in AsPC-1 or ABCG2-overexpressing MIA PaCa-2 cells. PS-pNP increased intracellular levels of the photosensitizer in all cell lines. The cell viability experiments indicated increased Ce6 resistance in ABCG2-overexpressing cells. In contrast, PS-pNP produced similar levels of cytotoxicity in each of the cancer cell lines tested. Singlet oxygen production was higher in cells treated with PS-pNP than in those treated with Ce6. Furthermore, in heterotopic and orthotopic AsPC-1 xenograft mouse models, PDT using PS-pNP significantly reduced tumor volume in comparison with that of Ce6 treatment. PS-pNP could increase intracellular Ce6 concentration, which was related with reduced ABCG2-mediated efflux of Ce6, thereby enhancing the effects of PDT in pancreatic cancer cells. Mol Cancer Ther; 16(8); 1487–96. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u2jvMi
via IFTTT

Sensitization of EGFR Wild-Type Non-Small Cell Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitor Erlotinib

The benefit of EGFR–TKI in non–small cell lung cancer has been demonstrated in mutant EGFR tumors as first-line treatment but the benefit in wild-type EGFR tumors is marginal as well as restricted to maintenance therapy in pretreated patients. This work aimed at questioning the effects of cisplatin initial treatment on the EGFR pathway in non–small cell lung cancer and the functional consequences in vitro and in in vivo animal models of patient-derived xenografts (PDX). We establish here that cisplatin pretreatment specifically sensitizes wild-type EGFR-expressing cells to erlotinib, contrary to what happens in mutant EGFR cells and with a blocking EGFR antibody, both in vitro and in vivo. The sensitization entails the activation of the kinase Src upstream of EGFR, thereafter transactivating EGFR through a ligand-independent activation. We propose a combination of markers that enable to discriminate between the tumors sensitized to erlotinib or not in PDX models, which should be worth testing in patients. These markers might be useful for the selection of patients who would benefit from erlotinib as a maintenance therapy. Mol Cancer Ther; 16(8); 1634–44. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vrrupA
via IFTTT

The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells

Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34⁺ AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34⁺ stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses. Mol Cancer Ther; 16(8); 1497–510. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u2auCP
via IFTTT

Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here, we report that two novel nonsteroidal and highly selective GR modulators (SGRM), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect androgen receptor (AR) signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR–expressing, but not in low GR–expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo. Together, these data suggest that GR-selective nonsteroidal SGRMs potently inhibit GR activity and prostate cancer growth despite AR pathway inhibition, demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC. Mol Cancer Ther; 16(8); 1680–92. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vriktg
via IFTTT

Vulnerability of Small-Cell Lung Cancer to Apoptosis Induced by the Combination of BET Bromodomain Proteins and BCL2 Inhibitors

Ten percent to 15% of all lung cancers are small-cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extraterminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis, such as MYC, CCND2, and BCL2L1. Here, we demonstrate that approximately 50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075. The majority of these SCLC cell lines underwent apoptosis in response to ABBV-075 treatment via induction of caspase-3/7 activity. ABBV-075 enhanced the expression of proapoptotic protein BIM and downregulated antiapoptotic proteins BCL2 and BCLxl to a lesser extent. Furthermore, BET inhibition increased BCL2–BIM complex, thus priming the cells for apoptosis. Indeed, strong synergy was observed both in vitro and in vivo when cotreating the cells with BET inhibitor and the BH3-mimetic, BCL2 inhibitor venetoclax (ABT-199). ABBV-075 interaction with venetoclax positively correlated with BCL2 expression. Taken together, our studies provide a rationale for treating SCLC with BET and BCL2 inhibitors in tumors with high BCL2 protein expression. Mol Cancer Ther; 16(8); 1511–20. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u2qWmq
via IFTTT

Highlights of This Issue

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vrj9SV
via IFTTT

Niclosamide and Bicalutamide Combination Treatment Overcomes Enzalutamide- and Bicalutamide-Resistant Prostate Cancer

Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants play a role in bicalutamide resistance, we developed bicalutamide-resistant LNCaP cells (LNCaP-BicR) and found that these resistant cells express significantly increased levels of AR variants, particularly AR-V7, both at the mRNA and protein levels. Exogenous expression of AR-V7 in bicalutamide-sensitive LNCaP cells confers resistance to bicalutamide treatment. Knockdown of AR-V7 in bicalutamide- and enzalutamide-resistant CWR22Rv1, enzalutamide-resistant C4-2B (C4-2B MDVR), and LNCaP-BicR cells reversed bicalutamide resistance. Niclosamide, a potent inhibitor of AR variants, significantly enhanced bicalutamide treatment. Niclosamide and bicalutamide combination treatment not only suppressed AR and AR variants expression and inhibited their recruitment to the PSA promoter, but also significantly induced apoptosis in bicalutamide- and enzalutamide-resistant CWR22Rv1 and C4-2B MDVR cells. In addition, combination of niclosamide with bicalutamide inhibited the growth of enzalutamide-resistant tumors. In summary, our results demonstrate that AR variants, particularly AR-V7, drive bicalutamide resistance and that targeting AR-V7 with niclosamide can resensitize bicalutamide-resistant cells to bicalutamide treatment. Furthermore, combination of niclosamide with bicalutamide inhibits enzalutamide resistant tumor growth, suggesting that the combination of niclosamide and bicalutamide could be a potential cost-effective strategy to treat advanced prostate cancer in patients, including those who fail to respond to enzalutamide therapy. Mol Cancer Ther; 16(8); 1521–30. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u2mYKQ
via IFTTT

Identification of the Serine Biosynthesis Pathway as a Critical Component of BRAF Inhibitor Resistance of Melanoma, Pancreatic, and Non-Small Cell Lung Cancer Cells

Metastatic melanoma cells commonly acquire resistance to BRAF V600E inhibitors (BRAFi). In this study, we identified serine biosynthesis as a critical mechanism of resistance. Proteomic assays revealed differential protein expression of serine biosynthetic enzymes PHGDH, PSPH, and PSAT1 following vemurafenib (BRAFi) treatment in sensitive versus acquired resistant melanoma cells. Ablation of PHGDH via siRNA sensitized acquired resistant cells to vemurafenib. Inhibiting the folate cycle, directly downstream of serine synthesis, with methotrexate also displayed similar sensitization. Using the DNA-damaging drug gemcitabine, we show that gemcitabine pretreatment sensitized resistant melanoma cells to BRAFis vemurafenib and dabrafenib. We extended our findings to BRAF WT tumor cell lines that are intrinsically resistant to vemurafenib and dabrafenib. Pretreatment of pancreatic cancer and non–small cell lung cancer cell lines with sublethal doses of 50 and 5 nmol/L of gemcitabine, respectively, enhanced killing by both vemurafenib and dabrafenib. The novel aspects of this study are the direct identification of serine biosynthesis as a critical mechanism of BRAF V600E inhibitor resistance and the first successful example of using gemcitabine + BRAFis in combination to kill previously drug-resistant cancer cells, creating the translational potential of pretreatment with gemcitabine prior to BRAFi treatment of tumor cells to reverse resistance within the mutational profile and the WT. Mol Cancer Ther; 16(8); 1596–609. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vrslXd
via IFTTT

Resistance to RET-Inhibition in RET-Rearranged NSCLC Is Mediated By Reactivation of RAS/MAPK Signaling

Oncogenic rearrangements in RET are present in 1%–2% of lung adenocarcinoma patients. Ponatinib is a multi-kinase inhibitor with low-nanomolar potency against the RET kinase domain. Here, we demonstrate that ponatinib exhibits potent antiproliferative activity in RET fusion–positive LC-2/ad lung adenocarcinoma cells and inhibits phosphorylation of the RET fusion protein and signaling through ERK1/2 and AKT. Using distinct dose escalation strategies, two ponatinib-resistant LC-2/ad cell lines, PR1 and PR2, were derived. PR1 and PR2 cell lines retained expression, but not phosphorylation of the RET fusion and lacked evidence of a resistance mutation in the RET kinase domain. Both resistant lines retained activation of the MAPK pathway. Next-generation RNA sequencing revealed an oncogenic NRAS p.Q61K mutation in the PR1 cell. PR1 cell proliferation was preferentially sensitive to siRNA knockdown of NRAS compared with knockdown of RET, more sensitive to MEK inhibition than the parental line, and NRAS dependence was maintained in the absence of chronic RET inhibition. Expression of NRAS p.Q61K in RET fusion expressing TPC1 cells conferred resistance to ponatinib. PR2 cells exhibited increased expression of EGFR and AXL. EGFR inhibition decreased cell proliferation and phosphorylation of ERK1/2 and AKT in PR2 cells, but not LC-2/ad cells. Although AXL inhibition enhanced PR2 sensitivity to afatinib, it was unable to decrease cell proliferation by itself. Thus, EGFR and AXL cooperatively rescued signaling from RET inhibition in the PR2 cells. Collectively, these findings demonstrate that resistance to ponatinib in RET-rearranged lung adenocarcinoma is mediated by bypass signaling mechanisms that result in restored RAS/MAPK activation. Mol Cancer Ther; 16(8); 1623–33. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vrs0E5
via IFTTT

Colony-Stimulating Factor 1 Receptor Blockade Inhibits Tumor Growth by Altering the Polarization of Tumor-Associated Macrophages in Hepatocellular Carcinoma

Colony-stimulating factor-1 (CSF-1) and its receptor, CSF-1R, regulate the differentiation and function of macrophages and play an important role in macrophage infiltration in the context of hepatocellular carcinoma. The therapeutic effects of CSF-1R blockade in hepatocellular carcinoma remain unclear. In this study, we found that CSF-1R blockade by PLX3397, a competitive inhibitor with high specificity for CSF-1R tyrosine kinase, significantly delayed tumor growth in mouse models. PLX3397 inhibited the proliferation of macrophages in vitro, but intratumoral macrophage infiltration was not decreased by PLX3397 in vivo. Gene expression profiling of tumor-associated macrophages (TAM) showed that TAMs from the PLX3397-treated tumors were polarized toward an M1-like phenotype compared with those from vehicle-treated tumors. In addition, PLX3397 treatment increased CD8⁺ T-cell infiltration, whereas CD4⁺ T-cell infiltration was decreased. Further study revealed that tumor cell–derived CSF-2 protected TAMs from being depleted by PLX3397. In conclusion, CSF-1R blockade delayed tumor growth by shifting the polarization rather than the depletion of TAMs. CSF-1R blockade warrants further investigation in the treatment of hepatocellular carcinoma. Mol Cancer Ther; 16(8); 1544–54. ©2017 AACR.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u2dRK7
via IFTTT

Augmented reflective learning and knowledge retention perceived among students in classrooms involving virtual laboratories

Abstract

Learning theories converge on the principles of reflective learning processes and perceive them as fundamental to effective learning. Traditional laboratory education in science and engineering often happens in highly resource-constrained environments that compromise some of the learning objectives. This paper focuses on characterizing three learning attributes associated with reflective learning i.e. metacognition (M), analogical reasoning (A) and transfer of knowledge (T) and assessed college laboratory education blended with ICT-enabled virtual laboratories. Key contributions of this study include: 1) Development of assessment of MAT attributes using a combination of multiple choice questions, True/False statements and descriptive questions 2) assessment of conceptual learning occurring in the laboratory environment and of learning attributes using Virtual Laboratories (VLs) in classroom education. Feedback data indicated using virtual laboratories in classrooms for training students before using physical laboratories demonstrated a significant improvement (>100% change) in learning in comparison to physical laboratories without VLs. We also show using VLs as pre-lab or post-lab exercise augmented reflective learning and information retention among 145 students in this blended learning case study, compared to an independent control group of 45 students who had no virtual laboratory training.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vvm91s
via IFTTT

Editorial Board

Publication date: September 2017
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 213





from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2uYtchJ
via IFTTT

OBC

Publication date: September 2017
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 213





from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2w8xP7v
via IFTTT

Regulator of G protein signaling 14 (RGS14) is expressed pre- and postsynaptically in neurons of hippocampus, basal ganglia, and amygdala of monkey and human brain

Abstract

Regulator of G protein signaling 14 (RGS14) is a multifunctional signaling protein primarily expressed in mouse pyramidal neurons of hippocampal area CA2 where it regulates synaptic plasticity important for learning and memory. However, very little is known about RGS14 protein expression in the primate brain. Here, we validate the specificity of a new polyclonal RGS14 antibody that recognizes not only full-length RGS14 protein in primate, but also lower molecular weight forms of RGS14 protein matching previously predicted human splice variants. These putative RGS14 variants along with full-length RGS14 are expressed in the primate striatum. By contrast, only full-length RGS14 is expressed in hippocampus, and shorter variants are completely absent in rodent brain. We report that RGS14 protein immunoreactivity is found both pre- and postsynaptically in multiple neuron populations throughout hippocampal area CA1 and CA2, caudate nucleus, putamen, globus pallidus, substantia nigra, and amygdala in adult rhesus monkeys. A similar cellular expression pattern of RGS14 in the monkey striatum and hippocampus was further confirmed in humans. Our electron microscopy data show for the first time that RGS14 immunostaining localizes within nuclei of striatal neurons in monkeys. Taken together, these findings suggest new pre- and postsynaptic regulatory functions of RGS14 and RGS14 variants, specific to the primate brain, and provide evidence for unconventional roles of RGS14 in the nuclei of striatal neurons potentially important for human neurophysiology and disease.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u69vFK
via IFTTT

Genetically improved BarraCUDA

BarraCUDA is an open source C program which uses the BWA algorithm in parallel with nVidia CUDA to align short next generation DNA sequences against a reference genome. Recently its source code was optimised u...

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2umaGMw
via IFTTT

Cancers, Vol. 9, Pages 100: Crosstalk between microRNA and DNA Methylation Offers Potential Biomarkers and Targeted Therapies in ALK-Positive Lymphomas

Cancers, Vol. 9, Pages 100: Crosstalk between microRNA and DNA Methylation Offers Potential Biomarkers and Targeted Therapies in ALK-Positive Lymphomas

Cancers doi: 10.3390/cancers9080100

Authors: Coralie Hoareau-Aveilla Fabienne Meggetto

The discovery of microRNA (miRNA) has provided new and powerful tools for studying the mechanism, diagnosis and treatment of human cancers. The down-regulation of tumor suppressive miRNA by hypermethylation of CpG island (CpG is shorthand for 5′-C-phosphate-G-3′, that is, cytosine and guanine separated by only one phosphate) is emerging as a common hallmark of cancer and appears to be involved in drug resistance. This review discusses the role of miRNA and DNA methylation in drug resistance mechanisms and highlights their potential as anti-cancer therapies in Anaplastic Lymphoma Kinase (ALK)-positive lymphomas. These are a sub-type of non-Hodgkin's lymphomas that predominantly affect children and young adults and are characterized by the expression of the nucleophosmin (NPM)/ALK chimeric oncoprotein. Dysregulation of miRNA expression and regulation has been shown to affect several signaling pathways in ALK carcinogenesis and control tumor growth, both in cell lines and mouse models. These data suggest that the modulation of DNA methylation and/or the expression of these miRNA could serve as new biomarkers and have potential therapeutic applications for ALK-positive malignancies.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2ulPYwc
via IFTTT

Dr. Mark Hyman: Are You Still Consuming Dairy? - EcoWatch

EcoWatch

Dr. Mark Hyman: Are You Still Consuming Dairy? EcoWatch Dairy consumption can lead to increased cancer risk, increased fracture risk, constipation, irritable bowel, bloating, gas, diarrhea, allergies, eczema and acne. None of that sounds good to me! One dairy product that many people can tolerate is ghee ...

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2hpRxID
via IFTTT

See One, Do One, Teach One: No More

Anatomic dissection prior to examining and treating a living person dates back to Alexandria, Greece in the third century bc.1 For Otolaryngologist-Head and Neck Surgeons, anatomic dissections, the original "simulators," have served to prepare them for open approaches to the face, head, and neck, for temporal bone surgery, and for paranasal sinus procedures. But, as with diagnostic and surgical methods and tools, simulation tools and techniques have evolved, most rapidly over the past several years.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2hpweXr
via IFTTT

Simulation in Otolaryngology

At present, simulation is widely accepted as a means of providing surgical education outside of the clinical environment. Recent advances in simulation technology and medical education reform coupled with political and societal demands have provided the impetus toward the exponential growth of this field. Research in this area supports the use of simulation to train and assess individuals in both psychomotor and team-based skills. Further benefits include translation of these improved skills to patient care practices with better patient outcomes and reduced health care costs.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2f9Nz66
via IFTTT

See One, Do One, Teach One: No More

Anatomic dissection prior to examining and treating a living person dates back to Alexandria, Greece in the third century bc.1 For Otolaryngologist-Head and Neck Surgeons, anatomic dissections, the original "simulators," have served to prepare them for open approaches to the face, head, and neck, for temporal bone surgery, and for paranasal sinus procedures. But, as with diagnostic and surgical methods and tools, simulation tools and techniques have evolved, most rapidly over the past several years.

from ! ORL Sfakianakis via paythelady.61 on Inoreader http://ift.tt/2hpweXr
via IFTTT

Simulation in Otolaryngology

At present, simulation is widely accepted as a means of providing surgical education outside of the clinical environment. Recent advances in simulation technology and medical education reform coupled with political and societal demands have provided the impetus toward the exponential growth of this field. Research in this area supports the use of simulation to train and assess individuals in both psychomotor and team-based skills. Further benefits include translation of these improved skills to patient care practices with better patient outcomes and reduced health care costs.

from ! ORL Sfakianakis via paythelady.61 on Inoreader http://ift.tt/2f9Nz66
via IFTTT

Factors Affecting the Acceptance of Telehealth Services by Heart Failure Patients: An Integrative Review

Telemedicine and e-Health , Vol. 0, No. 0.


from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2f9mEHo
via IFTTT

Wheat productivity responses in the rice-based system under different no-till techniques and nitrogen sources

Abstract

No-till wheat is gaining popularity in rice-based cropping system as it provides a better chance for timely planting of wheat, management of crop residues, as well as environmental and soil sustainability. However, fertilizer application in no-tillage requires careful attention in order to optimize efficiency of fertilizer use by crops. The present study was conducted to develop the most favorable and economical no-till technique along with best blend of nitrogen for successful wheat production in residue-based cropping system. The experiment was composed of five no-till techniques viz., (1) even spreading of loose rice residue and wheat sowing with turbo seeder, (2) even spreading of loose rice residue and wheat sowing with happy seeder, (3) even spreading of loose rice residue and wheat sowing with zone disc tiller, (4) wheat sowing with conventional zero tillage drill after manual removal of rice residues, and (5) wheat sowing with conventional zero tillage drill after burning of rice residues. There were five blends of nitrogen (N) including (1) 100% N from urea, (2) 75% N from urea and 25% N from ammonium sulfate (AS), (3) 50% N from urea and 50% N from AS, (4) 25% N from urea and 75% N from AS, and (5) 100% N from AS. Different no-till techniques and N treatments significantly affected the stand establishment and yield-related traits of wheat during both growing seasons. Soil physical condition was improved by turbo seeder treatment, while it remained poor in residue burned field sown by conventional zero tillage drill. The results over the years revealed that turbo-seeded wheat with N fertilization in the form of 50% urea + 50% AS performed better in terms of productive tillers, grain yield and benefit cost ratio than other no-till techniques along different blends of nitrogen during both years of study. In crux, wheat sowing by turbo seeder along N fertilization in the form of 50% urea + 50% AS treatment is a viable and economical option to increase the wheat production in rice-based production system.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u6nBa7
via IFTTT

TCRαβ+ and CD19+ cell depleted Haploidentical and Mismatched Hematopoietic Stem Cell Transplantation in Primary Immune Deficiency

CD3+TCRαβ+ and CD19+ cell depleted haploidentical or mMUD HSCT has reproducible outcomes in children with a range of PIDs resulting in good immune reconstitution. Viral infections before or after HSCT are major contributors to mortality and morbidity.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vraLCX
via IFTTT

A synergistic role of IRP1 and FBXL5 in coordinating iron metabolism during cell proliferation [Metabolism]

Iron regulatory protein 1 (IRP1) belongs to a family of RNA binding proteins that modulate metazoan iron metabolism. Multiple mechanisms are employed to control the action of IRP1 in dictating changes in the uptake and metabolic fate of iron. Inactivation of IRP1 RNA binding by iron primarily involves insertion of a [4Fe-4S] cluster by the cytosolic iron sulfur cluster assembly (CIA) system converting it into cytosolic aconitase (c-acon) but can also involve iron-mediated degradation of IRP1 by the E3 ligase FBXL5 that also targets IRP2. How CIA and FBXL5 collaborate to maintain cellular iron homeostasis through IRP1 and other pathways is poorly understood. Since impaired Fe-S cluster biogenesis associates with human disease we determined the importance of FBXL5 for regulating IRP1 when CIA is impaired. Suppression of FBXL5 expression coupled with induction of an IRP1 mutant (IRP13C>3S) that cannot insert the Fe-S cluster, or along with knockdown of the CIA factors NUBP2 or FAM96A, reduced cell viability. Iron supplementation reversed this growth defect and was associated with FBXL5- dependent polyubiquitination of IRP1. Phosphorylation of IRP1 at S138 increased when CIA was inhibited and was required for iron rescue. Impaired CIA activity, as noted by reduced c-acon activity, was associated with enhanced FBXL5 expression and a concomitant reduction in IRP1 and IRP2 protein level and RNA binding activity. Conversely, expression of either IRP induced FBXL5 protein level demonstrating a negative feedback loop limiting excessive accumulation of IRE RNA binding activity which when disrupted reduces cell growth. We conclude that a regulatory circuit involving FBXL5 and CIA acts through both IRP to control iron metabolism and promote optimal cell growth.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2w8dbEd
via IFTTT

Crystal structures of TdsC, a dibenzothiophene monooxygenase from the thermophile Paenibacillus sp. A11-2, reveal potential for expanding its substrate selectivity [Enzymology]

Sulfur compounds in fossil fuels are a major source of environmental pollution, and microbial desulfurization has emerged as a promising technology for removing sulfur under mild conditions. The enzyme TdsC from the thermophile Paenibacillus sp. A11-2 is a two-component Flavin-dependent monooxygenase that catalyzes the oxygenation of dibenzothiophene (DBT) to its sulfoxide (DBTO) and sulfone (DBTO2) during microbial desulfurization. The crystal structures of the apo and flavin mononucleotide (FMN)-bound forms of DszC, an ortholog of TdsC, were previously determined, although the structure of the ternary substrate-FMN-enzyme complex remained unknown. Herein, we report the crystal structures of the DBT-FMN-TdsC and DBTO-FMN-TdsC complexes. These ternary structures revealed many hydrophobic and hydrogen-bonding interactions with the substrate, and the position of the substrate could reasonably explain the two-step oxygenation of DBT by TdsC. We also determined the crystal structure of the indole-bound enzyme because TdsC, but not DszC, can also oxidize indole, and observed that indole binding did not induce global conformational changes in TdsC with or without bound FMN. We also found that the two loop regions close to the FMN-binding site are disordered in apo-TdsC and become structured upon FMN binding. Alanine substitutions of Tyr93 and His388, which are located close to the substrate and FMN bound to TdsC, significantly decreased benzothiophene oxygenation activity, suggesting their involvement in supplying protons to the active site. Interestingly, these substitutions increased DBT oxygenation activity by TdsC, indicating that expanding the substrate-binding site can increase the oxygenation activity of TdsC on larger sulfur-containing substrates, a property that should prove useful for future microbial desulfurization applications.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2hprTn5
via IFTTT

Activation of mas-related G-protein coupled receptors by the house dust mite cysteine protease Der p1 provides a new mechanism linking allergy and inflammation [Signal Transduction]

Cysteine and serine proteases function via protease-activated (PARs) and mas-related G-protein coupled receptors (Mrgprs) to contribute to allergy and inflammation. Der p1 is a cysteine protease and major allergen from the house dust mite and is associated with allergic rhinitis and allergic asthma. Der p1 activates PAR2 and induces the release of the pro-inflammatory cytokine IL-6 from cells. However, the possibility that Der p1 acts on Mrgprs has not been considered. We report here that ratiometric calcium imaging reveals that Der p1 activates the human receptor MRGPRX1 and the mouse homolog MrgprC11, implicated previously in itch. Der p1 cleavage of N-terminal receptor peptides followed by site-directed mutagenesis of the cleavage sites links receptor activation to specific amino acid residues. Der p1 also induced the release of IL-6 from heterologous cells expressing MRGPRX1. In summary, activation of Mrgprs by the allergen Der p1 may contribute to inflammation.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2f9IhYl
via IFTTT

Leucine-rich repeat-containing G protein coupled receptor 4 (Lgr4) is necessary for prostate cancer metastasis via epithelial-mesenchymal transition [Signal Transduction]

Prostate cancer is a highly penetrant disease among men in industrialized societies, yet the factors regulating the transition from indolent to aggressive and metastatic cancer remain poorly understood. We found that men with prostate cancers expressing high levels of the G protein-coupled receptor LGR4 had a significantly shorter recurrence-free survival compared to patients with cancers having low LGR4 expression. LGR4 expression was elevated in human prostate cancer cell lines with metastatic potential. We therefore generated a novel transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model to investigate the role of Lgr4 in prostate cancer development and metastasis in vivo. TRAMP Lgr4-/- mice exhibited an initial delay in prostate intraepithelial neoplasia (PIN) formation, but the frequency of tumor formation was equivalent between TRAMP and TRAMP Lgr4-/- mice by 12 weeks. The loss of Lgr4 significantly improved TRAMP mouse survival and dramatically reduced the occurrence of lung metastases. LGR4 knockdown impaired the migration, invasion and colony formation of DU145 cells and reversed epithelial-mesenchymal transition (EMT) as demonstrated by upregulation of E-cadherin and decreased expression of the EMT transcription factors ZEB, Twist, and Snail. Overexpression of LGR4 in LNCaP cells had the opposite effects. Orthotopic injection of DU145 cells stably expressing shRNA targeting LGR4 resulted in decreased xenograft tumor size, reduced tumor EMT marker expression, and impaired metastasis, in accord with our findings in TRAMP Lgr4-/- mice. In conclusion, we propose that Lgr4 is a key protein necessary for prostate cancer EMT and metastasis.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2hpO5O7
via IFTTT

NMDA receptors mediate leptin signaling and regulate potassium channel trafficking in pancreatic {beta}-cells [Membrane Biology]

NMDA receptors (NMDARs) are Ca2+-permeant, ligand-gated ion channels activated by the excitatory neurotransmitter glutamate and have well-characterized roles in the nervous system. The expression and function of NMDARs in pancreatic β cells, by contrast, are poorly understood. Here, we report a novel function of NMDARs in β-cells. Using a combination of biochemistry, electrophysiology, and imaging techniques we now show that NMDARs have a key role in mediating the effect of leptin to modulate β-cell electrical activity by promoting AMP-activated protein kinase (AMPK)-dependent trafficking of KATP and Kv2.1 channels to the plasma membrane. Blocking NMDAR activity inhibited the ability of leptin to activate AMPK, induce KATP and Kv2.1 channel trafficking, and promote membrane hyperpolarization. Conversely, activation of NMDARs mimicked the effect of leptin, causing Ca2+ influx, AMPK activation, increased trafficking of KATP and Kv2.1 channels to the plasma membrane, and triggered membrane hyperpolarization. Moreover, leptin potentiated NMDAR currents and triggered NMDAR-dependent Ca2+ influx. Importantly, NMDAR-mediated signaling was observed in rat insulinoma 832/13 cells and in human β-cells indicating that this pathway is conserved across species. The ability of NMDARs to regulate potassium channel surface expression and thus, β-cell excitability provides mechanistic insight into the recently reported insulinotropic effects of NMDAR antagonists, and therefore highlights the therapeutic potential of these drugs in managing type 2 diabetes.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2faypxc
via IFTTT

A computational-combinatorial approach identifies a protein inhibitor of superoxide dismutase 1 misfolding, aggregation, and cytotoxicity [Molecular Bases of Disease]

Molecular agents that specifically bind and neutralize misfolded and toxic superoxide dismutase 1 (SOD1) mutant proteins may find application in attenuating the disease progression of familial amyotrophic lateral sclerosis (fALS). However, high structural similarities between the wild-type and mutant SOD1 proteins limit the utility of this approach. Here, we addressed this challenge by converting a promiscuous natural human IgG binding domain, the hyperthermophilic variant of protein G (HTB1), into a highly specific aggregation inhibitor (designated HTB1M) of two fALS-linked SOD1 mutants, SOD1G93A and SOD1G85R. We utilized a computational algorithm for mapping protein surfaces predisposed to HTB1 intermolecular interactions to construct a focused HTB1 library, complemented with an experimental platform based on yeast surface display for affinity and specificity screening. HTB1M displayed high binding specificity toward SOD1 mutants, inhibited their amyloid aggregation in vitro, prevented the accumulation of misfolded proteins in living cells, and reduced the cytotoxicity of SOD1G93A expressed in motor neuron like cells. Competition assays and molecular docking simulations suggested that HTB1M binds to SOD1 via both its alpha helical and beta sheet domains at the native dimer interface that becomes exposed upon mutated SOD1 misfolding and monomerization. Our results demonstrate the utility of computational mapping of the protein protein interaction potential for designing focused protein libraries to be used in directed evolution. They also provide new insight into the mechanism of the conversion of broad-spectrum immunoglobulin binding proteins, such as HTB1, into target-specific proteins, thereby paving the way for the development of new selective drugs targeting the amyloidogenic proteins implicated in a variety of human diseases.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2hpZsW8
via IFTTT

Regulation of the Epithelial Na+ Channel by Paraoxonase-2 [Cell Biology]

Paraoxonase-2 (PON-2) is a membrane-bound lactonase with unique anti-oxidative and anti-atherosclerotic properties. PON-2 shares key structural elements with MEC-6, an endoplasmic reticulum resident molecular chaperone in Caenorhabditis elegans. MEC-6 modulates the expression of a mechano-transductive ion channel comprised of MEC-4 and MEC-10 in touch receptor neurons. Because pon-2 mRNA resides in multiple rat nephron segments, including aldosterone-sensitive distal nephron where the epithelial Na+ channel (ENaC) is expressed, we hypothesized that PON-2 would similarly regulate ENaC expression. We observed PON-2 expression in aquaporin 2 positive principal cells of the distal nephron of adult human kidney. PON-2 also co-immunoprecipitated with ENaC when co-expressed in HEK293 cells. When PON-2 was co-expressed with ENaC in Xenopus oocytes, ENaC activity was reduced, reflecting a reduction in ENaC surface expression. MEC-6 also reduced ENaC activity when co-expressed in Xenopus oocytes. The PON-2 inhibitory effect was ENaC-specific, as PON-2 had no effect on functional expression of the renal outer medullary potassium channel. PON-2 did not alter the response of ENaC to extracellular Na+, mechanical shear stress, or α-chymotrypsin-mediated proteolysis, suggesting that PON-2 did not alter the regulation of ENaC by these factors. Together, our data suggest that PON-2 regulates ENaC activity by modulating its intracellular trafficking and surface expression.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2f9SxzK
via IFTTT

Lazarus syndrome with crizotinib in a non-small-cell lung cancer patient with ROS1 rearrangement and disseminated intravascular coagulation

Lung cancer is the solid-tumor cancer most frequently diagnosed among patients admitted to the intensive care unit (ICU) with acute respiratory distress syndrome (ARDS) possibly due to its high prevalence (1–3). Despite recent improvement in management of patients presenting with advanced-stage lung cancer in ICUs, short-term survival of such patients proves to be poor, especially for those requiring mechanical ventilation.(1,2,4) That said, intensive care should not be considered futile in these patients, as their outcome may in fact be better than previously reported (5).

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vuQL37
via IFTTT

A customised digitally engineered solution for fixed dental rehabilitation in severe bone deficiency: A new innovative line extension in implant dentistry

In the 1940s, Dahl first introduced and described subperiosteal implants that were placed onto the alveolar ridge without rigid fixation (Dahl, 1943), but due to high complication rates, including implant loss, exposure, and flap dehiscence, subperiosteal implants have not been recommended for decades. However, the principle of subperiosteal implant placement onto the alveolar ridge rather than drilling implants into the bone might prove to be both simple and innovative, and could be a potential strategy for avoiding soft tissue complications leading to peri-implantitis, and bone and implant loss in complex cases (Lin et al., 2013).

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vrnzJm
via IFTTT

Aesthetic facial perception and need for intervention in laterognathism in women of different ethnicities

This study compared the perception of facial pleasantness and the need for intervention, as assessed by orthodontists, oral and maxillofacial (OMF) surgeons, and laypersons, in people of different ethnicities showing varying degrees of simulated laterognathism. Facial photographs were modified to simulate deviations in the lower face of women of African, Asian and Caucasian descent, ascending in two-degree steps from zero to eight degrees of deviation. Three groups of 20 individuals each (OMF surgeons, orthodontists, and laypersons) assessed the images and rated facial pleasantness on a numerical scale ranging from 0 to 10.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2hpGRtq
via IFTTT

Canalicular adenoma: a systematic review

Canalicular adenoma (CA) is an uncommon but unique benign tumor of salivary gland origin. It is the third most common benign tumor of minor salivary glands, representing less than 1% of all salivary neoplasms. A systematic review is presented of reported cases of CA, to determine trends in presentation, diagnostic features, treatment, and patient outcome.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vv7cwm
via IFTTT

Relationship Between Spiritual Well-Being and Hope in Patients with Cardiovascular Disease

Abstract

Spirituality and hope have been identified as important constructs in health research, since both are thought to enhance a person's ability to cope with the consequences of serious illness. The aim of this study was to examine the relationship between spiritual well-being and hope in patients with cardiovascular disease. Using descriptive, correlational methodology, the investigator gathered data on a convenience sample of 500 patients with cardiovascular disease who were hospitalized in a medical institution in Iran. The study was conducted over a four-month period. Participants completed a demographic questionnaire, the Spiritual Well-Being Scale (SWBS) and the Herth Hope Index (HHI). The mean score on the SWBS and HHI was 86.21 (SD 12.46) and 34.80 (SD 5.05), respectively. Multivariate predictors for spiritual well-being were female gender (p = 0.047), religiosity (p = 0.018), and hope (p < 0.001). Significant predictors of hope were marital status (p < 0.001), educational status (p < 0.001), economic status (p < 0.001), and spiritual well-being (p < 0.001). Findings suggest that multiple factors may impact spiritual well-being and hope. Therefore, this study has implications for those providing care to patients with cardiovascular disease.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2w8rbxR
via IFTTT

Global Head and Neck Cancer Partnering 2010 to 2017 - PR Newswire (press release)

Global Head and Neck Cancer Partnering 2010 to 2017 PR Newswire (press release) Description The Global Head and Neck Cancer Partnering Terms and Agreements since 2010 report provides understanding and access to partnering deals and agreements entered into by the world's leading healthcare companies. Read the full report: ...

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2ulEr01
via IFTTT

Faith Lewis benefit dinner Aug. 5 at MC First Baptist - Buffalo Reflex (subscription)

Faith Lewis benefit dinner Aug. 5 at MC First Baptist Buffalo Reflex (subscription) A benefit spaghetti dinner is planned for Faith Bartron Lewis at 6 p.m. Saturday, Aug. 5, at Macks Creek First Baptist Church to help offset some of her medical expenses. She is battling salivary gland cancer.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u67NUU
via IFTTT

Periodic characterization of alkyl-naphthalenes in stack gas and ambient air around a medical waste incinerator

Abstract

Due to the subtle occurrence of environmental polycyclic aromatic hydrocarbon (PAHs) pollution from incinerators, it is seldom considered a significant source of PAH pollution. However, considering the recent build-up of toxics in urban air, this may be a serious concern around the incinerator vicinity due to the potential consequences of PAHs on human health. Hence, this study determined 11 alkyl-naphthalene contributions from a hospital waste incinerator (HWI_0) into ambient air receptor points (HWI_1 to HWI_5) for a 1-year period: June 2014–May 2015. The HWI_0 and ambient gases were sampled using filter-sorbent sampling system and polyurethane foam (PUF) passive samplers, respectively, and all alkyl-naphthalenes were determined using GC-MS. Results showed that the source concentrations were in the range of 0–14.0 ng/m³ and generally higher than the receptor points. The receptor point concentration trends were mainly HWI_1 > HWI_2 ≥ HWI_3 ≥ HWI_5 ≥ HWI_4. Multivariate receptor model analysis suggested high correlations between source and the receptor points though there might be some significant contributions from other emission sources. The average monthly concentrations (∑alkyl-naphthalene) at HWI_0 and the receptors HWI_1, HWI_2, HWI_3, HWI_4 and HWI_5 were 67.4 ± 24.3, 57.9 ± 20.1, 42.8 ± 16.9, 39.7 ± 12.2, 36.5 ± 22.2 and 37.8 ± 15.4 ng/m³, respectively. Though these concentrations were lower than the estimated minimal risk level (MRL) for chronic inhalation exposure to naphthalene and its derivatives 0.003 mg/m³, continuous exposure to these pollutants might result in chronic effects. Finally, this study may be used to evaluate the environmental contribution of alkyl-naphthalenes from typical medical waste incinerator in Nigeria.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2wnlkEe
via IFTTT

Mushrooms: from nutrition to mycoremediation

Abstract

Mushrooms are well known as important food items. The uses of mushrooms in the cuisine are manifolds and are being utilized for thousands of years in both Oriental and Occidental cultures. Medicinal properties of mushrooms show an immense potential as drugs for the treatment of various diseases as they are rich in a great variety of phytochemicals. In this review, we attempted to encompass the recent knowledge and scientific advancement about mushrooms and their utilization as food or curative properties, along with their natural ability to accumulate (heavy) metals/radionuclides, which leads to an important aspect of bioremediation. However, accumulation of heavy metals and radionuclides from natural or anthropogenic sources also involves potential nutritional hazards upon consumption. These hazards have been pointed out in this review incorporating a selection of the most recently published literature.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vv1rin
via IFTTT

Adsorption mechanism of chromium(III) using biosorbents of Jatropha curcas L.

Abstract

The removal of Cr³⁺ from water solutions by biosorbents from the rind, endosperm, and endosperm + episperm of the Jatropha curcas was evaluated. Adsorption tests were performed in batch systems for evaluating the influence of the solution's pH, adsorbent mass, contact time, initial Cr³⁺ concentrations, and solution temperature during the adsorption process. Kinetic, adsorption isotherm, and thermodynamic studies were performed to investigate the mechanisms that control adsorption. Ideal conditions for the adsorption process included pH of the solution of 5.5 and 8 g L⁻¹ adsorbent mass, within 60 min time contact between adsorbent and adsorbate. Maximum adsorption capacities by Langmuir model for rind, endosperm, and endosperm + episperm of the J. curcas were, respectively, 22.11, 18.20, and 22.88 mg g⁻¹, with the occurrence of chemosorption in mono and multilayers. Results show that the biosorbents obtained from J. curcas have a high potential to recuperate Cr³⁺ from contaminated water sources.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2wnyUY9
via IFTTT

Use of cone beam computed tomography to assess significant imaging findings related to mandibular third molar impaction

Publication date: Available online 2 August 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): LH Matzen, L Schropp, R Spin-Neto, A Wenzel
ObjectiveTo identify risk factors for pathosis related to mandibular third molars observed in CBCT.Study designCBCT-volumes of 410 mandibular third molars were assessed by three observers according to angulation and position of the third molar in relation to the second molar. Moreover, pathosis (marginal bone loss, resorption of the second molar, increased follicular and lingual bone perforation) were assessed. Logistic regression analyses tested if angulation and position of the third molar were risk factors for pathosis.ResultsOn average 41% of second molars had resorption; mesio-angulated (OR 11-107, P<.001) and horizontally positioned (OR 13-120, P<.001) third molars located cervically at the second molar (OR 2-3, P<.027) highly increased the risk. On average 49% of second molars had marginal bone loss; mesio-angulated (OR 16-85, P<.001) and horizontally positioned (OR 61-573, P<.001) third molars increased the risk. For the third molar, an increased follicular space was seen in 25% of cases, distal (OR 5-9, P<.001) and vertical positions (OR 5, P<.002) increased the risk. Lingual bone perforation was not related to a specific angulation.ConclusionSpecific angulations of the mandibular third molar are risk factors for marginal bone loss and resorption of the second molar.



from ! ORL Sfakianakis via paythelady.61 on Inoreader http://ift.tt/2ulA8BQ
via IFTTT

Quantitative assessment of mandibular canal compression assessed by cone beam ct

Publication date: Available online 2 August 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Fatima M. Jadu, Daniah Alhazmi, Fatma F. Badr, Ahmed M. Jan
ObjectiveTo objectively quantify the topographic relation of the mandibular canals, impacted third molars, and cortical plates using cone beam CT (CBCT).Study designA retrospective chart review was conducted using the database of a university-based imaging service. Two calibrated reviewers examined the CBCT images of 100 cases scheduled for mandibular third molar removal. They characterized the position and condition of the mandibular canal and measured its dimensions at three different points relative to the third molars.ResultsThe mandibular canal is more often located buccal to the third molars but is more likely to be compressed when in a lingual position. The vertical dimensions (cephalocaudal) of the mandibular canal change significantly as the canal progresses towards the ramus. The horizontal dimensions (buccolingual) of the mandibular canal fluctuate very little but significantly narrow in proximity to the third molars. Thinning of the lingual cortical plate is common, whereas grooving of molar roots is uncommon.ConclusionsMinor variations in the horizontal dimensions of the mandibular canal close to the third molars signify an effect on the canal. This effect may indicate an increased risk of neurovascular injury. The mandibular canal can have a direct or indirect effect on the cortical plates.



from ! ORL Sfakianakis via paythelady.61 on Inoreader http://ift.tt/2u5RvLG
via IFTTT

Macrophage migration inhibitory factor enhances Pseudomonas aeruginosa biofilm formation potentially contributing to cystic fibrosis pathogenesis [Research]

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator that we have previously shown to be associated with an aggressive clinical phenotype in cystic fibrosis. It possesses unique tautomerase enzymatic activity. However, to date, no human-derived substrate has been identified that has the capacity to interact with this cytokine's unique tautomerase activity. This led us to hypothesize that MIF may have the capacity to interact with external substrates. We describe for the first time how Pseudomonas aeruginosa can utilize human recombinant MIF (rMIF) to significantly (P < 0.01) enhance its endogenous biofilm formation. Our in vivo studies demonstrate that utilizing a small-molecular-weight inhibitor targeting MIF's tautomerase activity (SCD-19) significantly reduces the inflammatory response in a murine pulmonary chronic P. aeruginosa model. In addition, we show that in in vitro experiments, pretreatment of P. aeruginosa with rMIF is associated with reduced bacterial killing by tobramycin. Our novel findings support the concept of an anti-MIF strategy that targets this enzymatic activity as a potential future antibacterial therapeutic approach.—Tynan, A., Mawhinney, L., Armstrong, M. E., O'Reilly, C., Kennedy, S., Caraher, E., Jülicher, K., O'Dwyer, D., Maher, L., Schaffer, K., Fabre, A., McKone, E. F., Leng, L., Bucala, R., Bernhagen, J., Cooke, G., Donnelly, S. C. Macrophage migration inhibitory factor enhances Pseudomonas aeruginosa biofilm formation potentially contributing to cystic fibrosis pathogenesis.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vv8Gqe
via IFTTT

The glucocorticoid receptor in monocyte-derived macrophages is critical for cardiac infarct repair and remodeling [Research]

Cell- and tissue-specific actions of glucocorticoids are mediated by the glucocorticoid receptor. Here, we demonstrate that the glucocorticoid receptor (GR) in macrophages is essential for cardiac healing after myocardial infarction. Compared with GR^flox (wild-type controls), GR^LysMCre mice that lacked GR in myeloid cells showed increased acute mortality as a result of cardiac rupture. Seven days after left coronary artery ligation, GR^LysMCre mice exhibited worse cardiac function and adverse remodeling associated with impaired scar formation and angiogenic response to ischemic injury. Inactivation of GR altered the functional differentiation/maturation of monocyte-derived macrophages in the infarcted myocardium. Mechanistically, CD45⁺/CD11b⁺/Ly6G^–/F4/80⁺ macrophages isolated from GR^LysMCre infarcts showed deregulation of factors that control inflammation, neovascularization, collagen degradation, and scar tissue formation. Moreover, we demonstrate that cardiac fibroblasts sorted from the ischemic myocardium of GR^LysMCre mice compared with cells isolated from injured GR^flox hearts displayed higher matrix metalloproteinase 2 expression, and we provide evidence that the macrophage GR regulates myofibroblast differentiation in the infarct microenvironment during the early phase of wound healing. In summary, GR signaling in macrophages, playing a crucial role in tissue-repairing mechanisms, could be a potential therapeutic target during wound healing after ischemic myocardial injury.—Galuppo, P., Vettorazzi, S., Hövelmann, J., Scholz, C.-J., Tuckermann, J. P., Bauersachs, J., Fraccarollo, D. The glucocorticoid receptor in monocyte-derived macrophages is critical for cardiac infarct repair and remodeling.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2wny6CB
via IFTTT

Angiotensin II regulates phosphorylation of actin-associated proteins in human podocytes [Research]

Within the kidney, angiotensin II (AngII) targets different cell types in the vasculature, tubuli, and glomeruli. An important part of the renal filtration barrier is composed of podocytes with their actin-rich foot processes. In this study, we used stable isotope labeling with amino acids in cell culture coupled to mass spectrometry to characterize relative changes in the phosphoproteome of human podocytes in response to short-term treatment with AngII. In 4 replicates, we identified a total of 17,956 peptides that were traceable to 2081 distinct proteins. Bioinformatic analyses revealed that among the increasingly phosphorylated peptides are predominantly peptides that are related to actin filaments, cytoskeleton, lamellipodia, mammalian target of rapamycin, and MAPK signaling. Among others, this screening approach highlighted the increased phosphorylation of actin-bundling protein, l-plastin (LCP1). AngII-dependent phosphorylation of LCP1 in cultured podocytes was mediated by the kinases ERK, p90 ribosomal S6 kinase, PKA, or PKC. LCP1 phosphorylation increased filopodia formation. In addition, treatment with AngII led to LCP1 redistribution to the cell margins, membrane ruffling, and formation of lamellipodia. Our data highlight the importance of AngII-triggered actin cytoskeleton-associated signal transduction in podocytes.—Schenk, L. K., Möller-Kerutt, A., Klosowski, R., Wolters, D., Schaffner-Reckinger, E., Weide, T., Pavenstädt, H., Vollenbröker, B. Angiotensin II regulates phosphorylation of actin-associated proteins in human podocytes.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vuB24d
via IFTTT

The specialized pro-resolving lipid mediator maresin 1 protects hepatocytes from lipotoxic and hypoxia-induced endoplasmic reticulum stress [Research]

Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are hallmarks of nonalcoholic fatty liver disease (NAFLD), which is the hepatic manifestation of the metabolic syndrome associated with obesity. The specialized pro-resolving lipid mediator maresin 1 (MaR1) preserves tissue homeostasis by exerting cytoprotective actions, dampening inflammation, and expediting its timely resolution. Here, we explored whether MaR1 protects liver cells from lipotoxic and hypoxia-induced ER stress. Mice were rendered obese by high-fat diet feeding, and experiments were performed in primary hepatocytes, Kupffer cells, and precision-cut liver slices (PCLSs). Palmitate-induced lipotoxicity increased ER stress and altered autophagy in hepatocytes, effects that were prevented by MaR1. MaR1 protected hepatocytes against lipotoxicity-induced apoptosis by activating the UPR prosurvival mechanisms and preventing the excessive up-regulation of proapoptotic pathways. Protective MaR1 effects were also seen in hepatocytes challenged with hypoxia and TNF-α–induced cell death. High-throughput microRNA (miRNA) sequencing revealed that MaR1 actions were associated with specific miRNA signatures targeting both protein folding and apoptosis. MaR1 also prevented lipotoxic-triggered ER stress and hypoxia-induced inflammation in PCLSs and enhanced Kupffer cell phagocytic capacity. Together, these findings describe the ability of MaR1 to oppose ER stress in liver cells under conditions frequently encountered in NAFLD.—Rius, B., Duran-Güell, M., Flores-Costa, R., López-Vicario, C., Lopategi, A., Alcaraz-Quiles, J., Casulleras, M., Lozano, J. J., Titos, E., Clària, J. The specialized pro-resolving lipid mediator maresin 1 protects hepatocytes from lipotoxic and hypoxia-induced endoplasmic reticulum stress.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2wn1Wau
via IFTTT

Feasibility and safety of virtual-reality-based early neurocognitive stimulation in critically ill patients

Growing evidence suggests that critical illness often results in significant long-term neurocognitive impairments in one-third of survivors. Although these neurocognitive impairments are long-lasting and devas...

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2v13veA
via IFTTT

Assessment of sepsis-induced immunosuppression at ICU discharge and 6 months after ICU discharge

Increase in mortality and in recurrent infections in the year following ICU discharge continues in survivors of septic shock, even after total clinical recovery from the initial septic event and its complicati...

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vjuapS
via IFTTT

CYP106A2 – a versatile biocatalyst with high potential for biotechnological production of selectively hydroxylated steroid and terpenoid compounds

Publication date: Available online 2 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Daniela Schmitz, Simon Janocha, Flora Marta Kiss, Rita Bernhardt
CYP106A2 from Bacillus megaterium ATCC13368, was identified in the 1970s as one of the first bacterial steroid hydroxylases responsible for the conversion of progesterone to 15β-hydroxyprogesterone. Later on it has been proven to be a potent hydroxylase of numerous 3-oxo-Δ⁴ as well as 3-hydroxy-Δ⁵-steroids and has recently also been characterized as a regioselective allylic bacterial diterpene hydroxylase. The main hydroxylation position of CYP106A2 is thought to be influenced by the functional groups at C3 position in the steroid core leading to a favored 15β-hydroxylation of 3-oxo-Δ⁴-steroids and 7β-hydroxylation of 3-hydroxy-Δ⁵-steroids. However, in some cases the hydroxylation is not strictly selective, resulting in the formation of undesired side-products. To overcome the unspecific hydroxylations or, on the contrary, to gain more of these products in case they are of industrial interest, rational protein design and directed evolution have been successfully performed to shift the stereoselectivity of hydroxylation by CYP106A2. The subsequently obtained hydroxylated steroid and terpene derivatives are especially useful as drug metabolites and drug precursors for the pharmaceutical industry, due to their diverse biological properties and hardship of their chemical synthesis. As a soluble prokaryotic P450 with broad substrate spectrum and hydroxylating capacity, CYP106A2 is an outstanding candidate to establish bioconversion processes. It has been expressed with respectable yields in Escherichia coli and Bacillus megaterium and was applied for the preparative hydroxylation of several steroids and terpenes. Recently, the application of the enzyme was assessed under process conditions as well, depicting a successfully optimized process development and getting us closer to industrial scale process requirements and a future large scale application. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.



from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2hpAlmf
via IFTTT

Seasonal variations of natural radionuclides, minor and trace elements in lake sediments and water in a lignite mining area of North-Western Greece

Abstract

The radiological and chemical pollution of a cluster of four lakes in a lignite mining area of North-Western Greece was investigated using a variety of analytical techniques. Alpha spectrometry was applied to measure the activity concentrations of the uranium radioisotopes (U-234, U-235, and U-238) in waters. The mass activities of U-238, Th-232, and K-40 in sediments were measured by high-resolution gamma spectrometry. Furthermore, the determination of the minor and trace elements was carried out by instrumental neutron activation analysis (INAA) in both water and sediments samples, respectively. Pollution levels were also evaluated by calculating enrichment factors (EFs), contamination factors (CFs) and pollution load index (PLI). The data were discussed taking into account several parameters such as the distance from the pollution source, temperature, and location and showed that the environmental impact in this region could not be considered as negligible. The deviation of the isotopic ratio of U-234/U-238 from the equilibrium value indicated waters with intensive dissolution of uranium. The activity values in both waters and sediments found to be low in cool periods and increased in warm periods. Moreover, the concentrations of the elements U, Zn, and Fe were raised in water samples indicating possible pollution as well as the CFs and PLI denoted accumulation in the sediments and moderate to severe contamination for Zn and Cr in some cases.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2ulkZk1
via IFTTT

Canada online pharmacy - Amoxicillin contraceptive pill does affect pill - Hayati Magazine (blog)

Hayati Magazine (blog)

Canada online pharmacy - Amoxicillin contraceptive pill does affect pill Hayati Magazine (blog) Does amoxicillin help swollen tonsils a New an in that some from or the Between side for other price almost can the blues 60 where erectile change informed man the Best some by to herbs goals. ... AM at You up Edex on occurred multilingual person ... and more »

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vqQFbQ
via IFTTT

NOX4 drugs deliver knock-out blow to multiple cancers

Targeting healthy cells that have been hijacked by cancer cells could help treat many different types of the disease, according to research funded by Cancer Research UK and published in the Journal of the National Cancer Institute. Scientists found that...

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vuUxcy
via IFTTT

Current and Promising Pharmacotherapies for Substance Use Disorders among Justice-Involved Populations

Abstract

Growing recognition of the biological underpinnings of substance use disorders (SUDs) has led to increased acceptance of pharmacotherapy-based treatments for general populations and, more recently, for individuals under criminal justice supervision, including those in correctional settings. This paper focuses on pharmacotherapies that have been approved by the United States Food and Drug Administration (FDA) for treatment of alcohol use disorder and opioid use disorder. For alcohol use disorder, these medications are disulfiram, naltrexone, and acamprosate; for opioid use disorder, these are methadone, buprenorphine, and naltrexone. Promising pharmacotherapies for stimulant use disorder are also briefly summarized. The paper concludes with three "lessons learned," specifically: (1) treatment and policy should reflect the fact that substance misuse and addiction is a medical disorder, (2) interventions for SUDs should be integrated into primary care, and (3) reductions in substance use among pharmacotherapy-treated patients do not necessarily lead to concomitant reductions in crime (nor should this be the primary rationale for providing such treatment).

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2hpK3VG
via IFTTT

In Vitro Antibacterial and Antibiofilm Activity of Lippia alba Essential Oil, Citral, and Carvone against Staphylococcus aureus

In vitro antimicrobial and antibiofilm activities of the Lippia alba essential oil and its major components (citral and carvone) against Staphylococcus aureus were investigated. Essential oils (LA1EO, LA2EO, and LA3EO) were extracted from the aerial parts of three L. alba specimens by hydrodistillation and analyzed by gas chromatography coupled to a mass spectrometer. Minimum Inhibitory Concentrations (MIC) and Minimum Bacterial Concentration (MBC) were determined by the microdilution method. For the antibiofilm assays, the biomass formation in the biofilm was evaluated by the microtiter-plate technique with the crystal violet (CV) assay and the viability of the bacterial cells was analyzed. All oils and their major components presented antibacterial activity, and the lowest MIC and MBC values were 0.5 mg mL−1 when LA1EO and citral were used. Potential inhibition (100%) of S. aureus biofilm formation at the concentration of 0.5 mg mL−1 of all EOs was observed. However, the elimination of biofilm cells was confirmed at concentrations of 1 mg mL−1, 2 mg mL−1, 2 mg mL−1, and 0.5 mg mL−1 for LA1EO, LA2EO, LA3EO, and citral, respectively. The results obtained in the present research point to the promising antibacterial and antibiofilm potential of L. alba EOs against S. aureus, a species of recognized clinical interest.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vqoTMI
via IFTTT

Calcium Phosphate Product Is Associated with Subclinical Carotid Atherosclerosis in Type 2 Diabetes

Aims. To assess whether circulating 25-hydroxyvitamin D3 (25OHD) and mineral metabolism-related factors (serum phosphate, calcium, and parathormone) are associated with subclinical carotid atherosclerosis (SCA), defined as the presence of carotid atherosclerotic plaques (main study outcome), in patients with type 2 diabetes mellitus (T2DM) without kidney disease or previous cardiovascular disease. Methods. We undertook a post hoc analysis of a cross-sectional study in adults with T2DM in whom we evaluated SCA. A total of 303 subjects with T2DM were included. Clinical variables and carotid ultrasound imaging were obtained. Results. We found no association of 25OHD with the presence of SCA. However, calcium phosphate (CaP; mg2/dL2) product was positively associated with the presence of carotid plaques (ORadj = 1.078; 95% CI: 1.017–1.142). An inverse association was observed between higher levels of 25OHD (≥30 ng/mL versus

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u1HgUv
via IFTTT

A New Nonlinear Chaotic Complex Model and Its Complex Antilag Synchronization

Another chaotic nonlinear Lü model with complex factors is covered here. We can build this riotous complex system when we add a complex nonlinear term to the third condition of the complex Lü system and think of it as if every one of the factors is mind boggling or complex. This system in real adaptation is a 6-dimensional continuous autonomous chaotic system. Different types of chaotic complex Lü system are developed. Also, another sort of synchronization is presented by us which is simple for anybody to ponder for the chaotic complex nonlinear system. This sort might be called a complex antilag synchronization (CALS). There are irregular properties for CALS and they do not exist in the literature; for example, (i) the CALS contains or fused two sorts of synchronizations (antilag synchronization ALS and lag synchronization LS); (ii) in CALS the attractors of the main and slave systems are moving opposite or similar to each other with time lag; (iii) the state variable of the main system synchronizes with a different state variable of the slave system. A scheme is intended to accomplish CALS of chaotic complex systems in light of Lyapunov function. The acquired outcomes and effectiveness can be represented by a simulation case for our new model.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vqHTul
via IFTTT

Socioeconomic Drivers of Environmental Pollution in China: A Spatial Econometric Analysis

This paper studies the environmental pollution and its impacts in China using prefecture-level cities and municipalities data. Moran's I, the widely used spatial autocorrelation index, provides a fairly strong pattern of spatial clustering of environmental pollution and suggests a fairly high stability of the positive spatial correlation. To investigate the driving forces of environmental pollution and explore the relationship between fiscal decentralization, economic growth, and environmental pollution, spatial Durbin model is used for this analysis. The result shows that fiscal decentralization of local unit plays a significant role in promoting the environmental pollution and the feedback effect of fiscal decentralization on environmental pollution is also positive, though it is not significant. The relationship of GDP per capita and environmental pollution shows inverted U-shaped curve. Due to the scale effect of secondary industry, the higher the level of secondary industry development in a unit is, the easier it is to attract the secondary industry in adjacent units, which mitigates the environmental pollution in adjacent units. Densely populated areas tend to deteriorate local environment, but environmental regulation in densely populated areas is often tighter than other areas, which reduces environmental pollution to a certain extent.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u1FVgs
via IFTTT

Influence of Friction Stir Welding on Mechanical Properties of Butt Joints of AZ61 Magnesium Alloy

In this study, the effect of heat input on the mechanical properties and fracture behaviors of AZ61 magnesium alloy joints has been studied. Magnesium alloy AZ61 plates with thickness of 5 mm were welded at different ratios of tool rotational speed to welding speed (). The average ultimate tensile strength of all weld conditions satisfying a ratio of 3 reached 100% of the strength of the base material. Fractures occurred at the interface between the thermomechanical affected zone at advancing side and the stir zone in all welded specimens. From the scanning electron microscope and electron backscatter diffraction analysis, it was determined that the interface between the thermomechanical affected zone and the stir zone, which is the region where the grain orientation changes, was the weakest part; the advancing side region was relatively weaker than the retreating side region because the grain orientation change occurred more dramatically in the advancing side region.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u1zUR9
via IFTTT

Optimal Trajectory Determination and Mission Design for Asteroid/Deep-Space Exploration via Multibody Gravity Assist Maneuvers

This paper discusses the creation of a genetic algorithm to locate and optimize interplanetary trajectories using gravity assist maneuvers to improve fuel efficiency of the mission. The algorithm is implemented on two cases: (i) a Centaur-class target close to the ecliptic plane and (ii) a Centaur-class target with a high inclination to the ecliptic plane. Cases for multiple numbers of flybys (up to three) are discussed and compared. It is shown that, for the targets considered here, a single flyby of Jupiter is the most efficient trajectory to either target with the conditions and limitations discussed in this paper. In this paper, we also iterate on possible reasons for certain results seen in the analysis and show how these previously observed behaviors could be present in any trajectory found. The parameters and methods used in the algorithm are explained and justified over multiple real-life interplanetary missions to provide deeper insights into the development choices.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u1HdrN
via IFTTT

Split-Hand Malformation in a 4-Year-Old Child

Split-hand deformity is one of the milder manifestations of a congenital disorder called split-hand/split-foot malformation. We present a case of a 4-year-old child with split-hand malformation in his left hand since birth. A median cleft was present in the affected hand with absence of the 3rd and 4th digits, giving rise to a characteristic lobster-claw appearance. Functionality of the affected hand was modestly impaired. As none of the close family members of the patient had similar limb malformations, the deformity was postulated to arise most likely from a de novo mutation. The patient was discharged after the parents were provided with genetic counseling.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vr25wp
via IFTTT

Cosmetic Remodeling of the Smile: Combining Composite Resin and Ceramics over Teeth and Implants

The aim of this paper is to describe a restorative approach to the cosmetic remodeling of the teeth of a young adult patient with right maxillary lateral hypodontia and left lateral microdontia. A conservative restorative management was proposed to improve smile esthetics by combining direct composite resins and ceramics. Initially, periodontal therapy and dental bleaching were performed. Subsequently, direct composite resins were applied to the central incisors and canines to reestablish the sizes and shapes of these teeth. Finally, ceramics were placed on the implant and the microdontia to unite with the new alignment and color of the anterior teeth. Thus, conservative remodeling to improve the harmony of the smile was provided.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u1FSkM
via IFTTT

Enhanced Expression of IL-18 and IL-18BP in Plasma of Patients with Eczema: Altered Expression of IL-18BP and IL-18 Receptor on Mast Cells

IL-18 has been found to be associated with eczema. However, little is known of the role of IL-18 binding protein (BP) and IL-18 receptor (R) in eczema. We therefore investigated the expression of IL-18, IL-18BP, and IL-18R on mast cells by using flow cytometry analysis and mouse eczema model. The results showed that plasma free IL-18 and free IL-18BP levels in eczema patients were higher than those in healthy controls. IL-18 provoked up to 3.1-fold increase in skin mast cells. IL-18 induced also an increase in IL-18BP+ mast cells, but a reduction of IL-18R+ mast cells in mouse eczema skin. It was found that house dust mite allergen Der p1 and egg allergen OVA induced upregulation of the expression of IL-18, IL-18BP, and IL-18R mRNAs in HMC-1 cells following 2 and 16 h incubation. In conclusion, correlation of IL-18 and IL-18BP in eczema plasma suggests an important balance between IL-18 and IL-18BP in eczema. The decrease in molar concentration ratio of plasma IL-18BP/IL-18 and allergen-induced upregulated expression of IL-18 and IL-18R in skin mast cells of the patients with eczema suggests that anti-IL-18 including IL-18BP therapy may be useful for the treatment of eczema.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vqIVGO
via IFTTT

An Acquisition Algorithm with NCCFR for BOC Modulated Signals

With the development of satellite navigation technology, BOC (Binary Offset Carrier) signals are proposed and applied in navigation system. However, in the advantages of enhancing the utilized rating of the band resource, some new problems are also emerging in the acquisition processing. On the basis of analyzing the limitations of the existing methods in suppressing side peaks, a NCCFR (New Cross-Correlation Function Reconstruction) algorithm is proposed, in which different modulation coefficients are used to construct correlation function with a shifter phase. The simulation results show that the new algorithm can suppress first side peaks and restrain other side peaks.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2u1mO6o
via IFTTT

A Pilot Genome-Wide Association Study in Postmenopausal Mexican-Mestizo Women Implicates the RMND1/CCDC170 Locus Is Associated with Bone Mineral Density

To identify genetic variants influencing bone mineral density (BMD) in the Mexican-Mestizo population, we performed a GWAS for femoral neck (FN) and lumbar spine (LS) in Mexican-Mestizo postmenopausal women. In the discovery sample, 300,000 SNPs were genotyped in a cohort of 411 postmenopausal women and seven SNPs were analyzed in the replication cohort (). The combined results of a meta-analysis from the discovery and replication samples identified two loci, RMND1 (rs6904364, ) and CCDC170 (rs17081341, ), associated with FN BMD. We also compared our results with those of the Genetic Factors for Osteoporosis (GEFOS) Consortium meta-analysis. The comparison revealed two loci previously reported in the GEFOS meta-analysis: SOX6 (rs7128738) and PKDCC (rs11887431) associated with FN and LS BMD, respectively, in our study population. Interestingly, rs17081341 rare in Caucasians (minor allele frequency 

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vqqUZ8
via IFTTT

Extracts of Terminalia sericea Enhance Cell Migratory Activity of Endothelial Hybrid and Fibroblast Cells In Vitro

Planta Med
DOI: 10.1055/s-0043-113324

Terminalia sericea is a plant that has been used amongst others medicinally to treat wounds. The aim of this study was to assess the in vitro wound healing ability of T. sericea. Hot water, methanol, ethyl acetate, and hexane extracts were prepared. Thin layer chromatography (TLC) and ultra-performance liquid chromatography time of flight mass spectrometry (UPLC-TOF-MS) were used to determine the phytochemical classes and genus specific compounds present in the plant. Cytotoxicity was assessed in the SC-1 fibroblast and EA.hy926 endothelial hybrid cell lines using the sulforhodamine B assay. The effect of the extracts on cellular migration in both cell lines was assessed using the scratch assay. The major phytochemical classes detected in the extracts using TLC were alkaloids, coumarins, flavonoids, glycosides, phenolics, saponins, sterols, and terpenoids. The genus-specific compounds punicalagin, sericoside, anolignan B, and arjunic acid were identified in the extracts by means of UPLC-QTOF-MS. Cytotoxicity was not observed after 24 h of exposure and a generally low cytotoxic trend was noted after 72 h. A significant (p < 0.05) enhancement of cell migration in both cell lines was noted in the scratch assay. The wound healing ability of T. sericea is mainly attributed to the migratory and proliferative activity of the extracts responsible for the acceleration of wound closure. Isolation and individualized testing of the active compounds is warranted.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2f9TQyL
via IFTTT