The NADPH oxidase (NOX) family of enzymes produces ROS as their sole function and is becoming recognized as key modulators of signal transduction pathways with a physiological role under acute stress ...and a pathological role after excessive activation under chronic stress. The seven isoforms differ in their regulation, tissue and subcellular localization and ROS products. The most studied are NOX1, 2 and 4. Genetic deletion of NOX1 and 4, in contrast to NOX2, has revealed no significant spontaneous pathologies and a pathogenic relevance of both NOX1 and 4 across multiple organs in a wide range of diseases and in particular inflammatory and fibrotic diseases. This has stimulated interest in NOX inhibitors for therapeutic application. GKT136901 and GKT137831 are two structurally related compounds demonstrating a preferential inhibition of NOX1 and 4 that have suitable properties for in vivo studies and have consequently been evaluated across a range of disease models and compared with gene deletion. In contrast to gene deletion, these inhibitors do not completely suppress ROS production, maintaining some basal level of ROS. Despite this and consistent with most gene deletion studies, these inhibitors are well tolerated and slow or prevent disease progression in a range of models of chronic inflammatory and fibrotic diseases by modulating common signal transduction pathways. Clinical trials in patients with GKT137831 have demonstrated excellent tolerability and reduction of various markers of chronic inflammation. NOX1/4 inhibition may provide a safe and effective therapeutic strategy for a range of inflammatory and fibrotic diseases.
Linked Articles
This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc
Treatment of recurrent ovarian cancer Pignata, S; C Cecere, S; Du Bois, A ...
Annals of oncology,
2017-Nov-01, 2017-11-00, 20171101, Letnik:
28, Številka:
suppl_8
Journal Article
Recenzirano
Odprti dostop
Despite optimal surgery and appropriate first-line chemotherapy, ∼70%-80% of patients with epithelial ovarian cancer will develop disease relapse. The same modalities as used primarily are available ...for treatment of recurrent ovarian cancer (ROC). The rationale for repetitive surgery in ROC was based on a stable body of retrospective data; however, prospective data were missing. Now, preliminary data from the prospective AGO-DESKTOP III give evidence that surgery for ROC seems to be of benefit for selected patients with platinum-sensitive relapse undergoing complete resection. With respect to systemic therapy, tumor histology, BRCA status, the platinum-free interval (PFI) and previous treatment with bevacizumab (anti-VEGF monoclonal antibody) are considered the most important features that influence treatment choice in ROC. In patients with resistant or refractory relapse (PFI < 6 months), monotherapy with a non-platinum drug or participation in clinical trials is indicated. The association of non-platinum monotherapy with bevacizumab, followed by maintenance has been approved in this setting in some European countries due to PFS benefit. In patients with partially sensitive relapse (PFI between 6 and 12 months), two options are available: platinum doublets or non-platinum therapy (single agent or combination). The pegylated liposomal doxorubicin/trabectedin combination represents a viable alternative in patients that cannot receive platinum. In platinum-sensitive patients, treatment with platinum-based combinations is associated with PFS advantage compared with single agents or non-platinum combinations. The presence of germline or somatic BRCA mutations allows platinum-responsive patients to optimize chemotherapy efficacy and prolonging PFS by the use of olaparib (PARP inhibitor) given as maintenance therapy until progression. In patients not pretreated with bevacizumab in first line, the carboplatin/gemcitabine/bevacizumab combination, followed by maintenance is a viable alternative in platinum-sensitive patients (PFI> 6 months). The integration of surgery, with a 'personalized' approach by the use of antiangiogenic agent and of PARP inhibitors is affecting survival of patients with recurrent disease and will help epithelial ovarian cancer to become a chronic disease.
Management of borderline ovarian tumors du Bois, A; Trillsch, F; Mahner, S ...
Annals of oncology,
04/2016, Letnik:
27 Suppl 1, Številka:
suppl_1
Journal Article
Recenzirano
Odprti dostop
Borderline ovarian tumors (BOT) are epithelial tumors of the ovaries with both malignant and non-malignant aspects. On the one hand, they are characterized by cellular proliferation and nuclear ...atypia but, on the other hand, they usually do not show infiltrative growth pattern. Balancing radicality between oncologic safety and treatment burden has already led to remarkable changes in the management pattern over the last decades and is still a challenging task.
This review is based on both a systematic review published by the authors and added with evidence gained from actually published literature.
As they frequently affect younger patients, the clinical management of BOT is complicated by aspects as preserving fertility and reducing postoperative morbidity. Over the past decades, the surgical therapy shifted from a radical approach to more conservative treatment. Today, fertility-sparing surgery is first-choice treatment in younger patients. In addition, minimal-invasive surgery has become the preferred surgical approach in these patients. Even recurrences are curable in most patients because only a minority of relapses transform to invasive cancer.
More studies on BOT are needed and longer follow-up and better characterization of high-risk subtypes are crucial to better understand long-term risk of BOT and avoid the rare but the fatal outcome in those few patients being undertreated by the current management strategies.
Molecular mechanisms underlying renal complications of diabetes remain unclear. We tested whether renal NADPH oxidase (Nox) 4 contributes to increased reactive oxygen species (ROS) generation and ...hyperactivation of redox-sensitive signaling pathways in diabetic nephropathy. Diabetic mice (db/db) (20 wk) and cultured mouse proximal tubule (MPT) cells exposed to high glucose (25 mmol/l, D-glucose) were studied. Expression (gene and protein) of Nox4, p22(phox), and p47(phox), but not Nox1 or Nox2, was increased in kidney cortex, but not medulla, from db/db vs. control mice (db/m) (P < 0.05). ROS generation, p38 mitogen-activated protein (MAP) kinase phosphorylation, and content of fibronectin and transforming growth factor (TGF)-β1/2 were increased in db/db vs. db/m (P < 0.01). High glucose increased expression of Nox4, but not other Noxes vs. normal glucose (P < 0.05). This was associated with increased NADPH oxidase activation and enhanced ROS production. Nox4 downregulation by small-interfering RNA and inhibition of Nox4 activity by GK-136901 (Nox1/4 inhibitor) attenuated d-glucose-induced NADPH oxidase-derived ROS generation. High d-glucose, but not l-glucose, stimulated phosphorylation of p38MAP kinase and increased expression of TGF-β1/2 and fibronectin, effects that were inhibited by SB-203580 (p38MAP kinase inhibitor). GK-136901 inhibited d-glucose-induced actions. Our data indicate that, in diabetic conditions: 1) renal Nox4 is upregulated in a cortex-specific manner, 2) MPT cells possess functionally active Nox4-based NADPH, 3) Nox4 is a major source of renal ROS, and 4) activation of profibrotic processes is mediated via Nox4-sensitive, p38MAP kinase-dependent pathways. These findings implicate Nox4-based NADPH oxidase in molecular mechanisms underlying fibrosis in type 2 diabetic nephropathy.
Objective: To systematically review the evidence of effectiveness of surgical vs. non‐surgical therapy for the treatment of chronic periodontal disease.
Methods: A search was conducted for ...randomized controlled trials of at least 12 months duration comparing surgical with non‐surgical treatment of chronic periodontal disease. Data sources included the National Library of Medicine computerised bibliographic database MEDLINE, and the Cochrane Oral Health Group (COHG) Specialist Trials Register. Screening, data ion and quality assessment were conducted independently by multiple reviewers (L.H., F.H., L.T.). The primary outcome measures evaluated were gain in clinical attachment level (CAL) and reduction in probing pocket depth (PPD).
Results: The search provided 589 s of which six randomized controlled trials were included. Meta‐analysis evaluation of these studies indicated that 12 months following treatment, surgical therapy resulted in 0.6 mm more PPD reduction (WMD 0.58 mm; 95% CI 0.38, 0.79) and 0.2 mm more CAL gain (WMD 0.19 mm; 95% CI 0.04, 0.35) than non‐surgical therapy in deep pockets (>6 mm). In 4–6 mm pockets scaling and root planing resulted in 0.4 mm more attachment gain (WMD −0.37 mm; 95% CI −0.49, −0.26) and 0.4 mm less probing depth reduction (WMD 0.35 mm; 95% CI 0.23, 0.47) than surgical therapy. In shallow pockets (1–3 mm) non‐surgical therapy resulted in 0.5 mm less attachment loss (WMD −0.51 mm; 95% CI −0.74, −0.29) than surgical therapy.
Conclusions: Both scaling and root planing alone and scaling and root planing combined with flap procedure are effective methods for the treatment of chronic periodontitis in terms of attachment level gain and reduction in gingival inflammation. In the treatment of deep pockets open flap debridement results in greater PPD reduction and clinical attachment gain.
We study ultrafast magnetization quenching of ferromagnetic iron following excitation by an optical versus a terahertz pump pulse. While the optical pump (photon energy of 3.1 eV) induces a strongly ...nonthermal electron distribution, terahertz excitation (4.1 meV) results in a quasithermal perturbation of the electron population. The pump-induced spin and electron dynamics are interrogated by the magneto-optic Kerr effect (MOKE). A deconvolution procedure allows us to push the time resolution down to 130 fs, even though the driving terahertz pulse is about 500 fs long. Remarkably, the MOKE signals exhibit an almost identical time evolution for both optical and terahertz pump pulses, despite the 3 orders of magnitude different number of excited electrons. We are able to quantitatively explain our results using a nonthermal model based on quasielastic spin-flip scattering. It shows that, in the small-perturbation limit, the rate of demagnetization of a metallic ferromagnet is proportional to the excess energy of the electrons, independent of the precise shape of their distribution. Our results reveal that, for simple metallic ferromagnets, the dynamics of ultrafast demagnetization and of the closely related terahertz spin transport do not depend on the pump photon energy.
The main problem of therapeutic efficiency lies in the crossing of cellular membranes. Therefore, significant effort is being made to develop agents which can cross these barriers and deliver ...therapeutic agents into cellular compartments. In recent years, a large amount of data on the use of peptides as delivery agents has accumulated. Several groups have published the first positive results using peptides for the delivery of therapeutic agents in relevant animal models. These peptides, called cell-penetrating peptides (CPPs), are short peptides (fewer than 30 residues) with a net positive charge and acting in a receptor- and energy-independent manner. Here, we give an extensive review of peptide-mediated delivery systems and discuss their applications, with particular focus on the mechanisms leading to cellular internalization.
When should Surgery be used for Recurrent Ovarian Carcinoma? Bommert, M.; Harter, P.; Heitz, F. ...
Clinical oncology (Royal College of Radiologists (Great Britain)),
August 2018, 2018-08-00, 20180801, Letnik:
30, Številka:
8
Journal Article
Recenzirano
Cytoreductive surgery is an important column in the treatment of primary ovarian cancer. Surgical outcome is one of the most important prognostic factors and one of the few prognostic variables that ...can be influenced by therapists. Retrospective studies suggested that only complete cytoreduction was associated with a benefit. Therefore, definition of predictors of complete resection is of the utmost importance to avoid surgical burden in patients with both limited benefit of the procedure and limited overall life expectancy. Two prospective multicentre randomised surgical trials in platinum-sensitive recurrent ovarian cancer (DESKTOP III NCT #01166737 and GOG 213 NSC #704865) comparing secondary cytoreductive surgery followed by platinum-based chemotherapy versus chemotherapy alone have been conducted. The results of the DESKTOP III were recently presented at the American Society of Clinical Oncology meeting in Chicago. It showed a benefit of secondary cytoreductive surgery exclusively in patients with complete resection with a progression-free survival of 5.6 months (P < 0.001). This overview aims to support this task and concentrates on the currently available data regarding surgery in recurrent ovarian cancer.
Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor ...rechallenge.
This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint.
Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022; 1-year PFS rates were 19% versus 0% (Kaplan–Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan–Meier estimates). No new safety signals were identified with olaparib rechallenge.
In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.
•OReO is the first study to show that maintenance olaparib rechallenge provides a PFS benefit in relapsed ovarian cancer.•Statistically significant PFS benefit is seen with olaparib rechallenge over placebo independent of BRCA mutation status.•A proportion of the OReO population was still progression free at 1 year.•No new safety signals were observed with maintenance olaparib rechallenge.•Further investigation may reveal identifiable characteristics of those patients deriving the most clinical benefit.
Objectives
To compare crestal bone modeling at three bone level design implants; Astra Tech Osseospeed™ Implant (AOI), Straumann® Bone Level Implant (SBLI) and NobelReplace™ Tapered Groovy Implant ...(NBTI).
Materials and methods
In 12 minipigs one implant of each design was placed on each side of the mandible with submerged healing. The implant platform was placed at the level of the crest (Group 0), and 1 mm above the crest (Group + 1 mm). In addition, one Straumann® Tissue Level Implant STLI was placed as a control on each side of the mandible. At 4 weeks, six animals were sacrificed. In the remaining six animals healing abutments were connected until 12 weeks. Clinical, radiographic, and histologic analyses were made. ANOVA and Mann–Whitney U‐tests were used to evaluate differences in bone levels between implant designs.
Results
At 4 weeks there was no statistically significant difference in bone changes between implant designs. At 12 weeks implants in Group + 1 mm had minimal bone changes with no differences between implant designs. In Group 0, the AOI and SBLI preserved more crestal bone than NBTI (P < 0.01). Mean distance from the implant platform to the buccal bone was −0.1 ± 0.2 mm for AOI, −0.3 ± 0.3 mm for SBLI, and −1.0 ± 0.3 mm for NBTI. Mean radiographic bone levels from the implant platform were −0.1 ± 0.4 mm for AOI, 0.0 ± 0.3 mm for SBLI and −0.9 ± 0.8 mm for NBTI.
Conclusion
Greater bone preservation was observed for the AOI and SBLI compared with the NBTI.
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