Comparison of phase III trials testing weekly paclitaxel in the adjuvant setting. All values given as weekly vs. q3w.
\r\n\tUnstoppable progress in the technologies of synthesis of diamond, graphene, and its compounds with stable parameters will provide materials for the industry of devices for integrated, radio, Opto- and quantum electronics and photonics.
\r\n\tIn most electronic and optical properties, diamond and graphene are superior to traditional and perspective semiconductors. It is safe to say that silicon and gallium arsenide are materials for electronics and optoelectronics of the past, gallium nitride and silicon carbide are high-tech today, and diamond and graphene are the future of electronics and photonics.
Over a quarter of a million women are diagnosed with epithelial ovarian cancer (EOC1) each year and it is responsible for around 140,000 deaths worldwide. There is no effective screening program so the majority present with advanced disease. Despite improved surgical technique most patients are never cured. Novel systemic treatments are needed both to prolong overall survival
Despite the emergence of alternate antineoplastic strategies, chemotherapy remains the backbone of EOC treatment. Although EOC is chemosensitive, with most patients responding initially, the majority will eventually relapse and subsequent responses are poorer. Efforts are being made to try and enhance the efficacy of ‘traditional’ cytotoxic chemotherapy. These include manipulation of dosing schedules, efforts to understand resistance and discovery of novel agents. These strategies are discussed in this subsection.
\nDose densification refers to the administration of an agent more frequently than in the ‘standard’ regimen. It can imply dose intensification (i.e. increasing the net mg/m2/week) but some authors use it to describe splitting the standard scheduled dose into weekly fragments while maintaining the same (rather than increased) dose intensity [1].
\nThe rationale for dose-dense treatment stems from the Norton-Simon hypothesis (Figure 1).
\nThe Norton-Simon hypothesis assumes a Gompertzian model of tumour growth (left). This was combined with their observation that after treatment, smaller tumours regress faster than larger ones. Crucial to their mathematical model is the fact that ‘log-kill’ is not constant for a given dose of therapy but instead depends on tumour size, being greater for smaller tumours. Their model predicts that a dose-dense approach is more likely to eradicate a tumour [
The rationale for dose densification extends beyond the Norton-Simon hypothesis. Firstly, the pharmacokinetics of a dose-dense approach may reduce toxicity. For example, paclitaxel-induced myelosuppression is dependent on the time during which the plasma level exceeds 50 nM [3]. This is considerably shorter for 80 mg/m2 weekly compared to 240 mg/m2 q3w [4]. Secondly, weekly paclitaxel may confer an additional anti-angiogenic effect compared to q3w scheduling [5].
\nWeekly paclitaxel was initially studied in the recurrent setting. Notably in one trial patients resistant to the q3w regimen achieved an objective response rate (ORR) of 25% with the weekly regimen possibly due to the additional anti-angiogenic effect of this schedule [6].
\nWeekly paclitaxel has also been studied in the adjuvant setting (Table 1).
\nStudy | \nEligibility | \nTreatment | \nEfficacy (months) | \nSafety (grade ≥ 3, P < 0.001) | \n
---|---|---|---|---|
JGOG 3016 [10] | \nStage II-IV | \nCarbo q3w + either taxol q3w | \nPFS 28.2 vs. 17.5 OS 100.5 vs. 62.2 | \nAnaemia 69% vs. 44% Discontinuation due to tox. 60% vs. 43% | \n
GOG 0262 [11] | \nIncompletely resected III or IV | \nAs above + uncontrolled bevacizumab2 | \nPFS 14.7 vs. 14.0 (not significant) | \nAnaemia 36% vs. 16% Neutropenia 72% vs. 83% | \n
MITO-7 [12] | \nStage IC-IV | \nCarobplatin/paclitaxel either q3w | \nPFS 18.3 vs. 17.3 (not significant) | \nNeutropenia 42% vs. 50% Thrombocytopenia 1% vs. 7% | \n
Comparison of phase III trials testing weekly paclitaxel in the adjuvant setting. All values given as weekly vs. q3w.
1Carboplatin AUC 6, paclitaxel 180 mg/m2 (q3w) or 80 mg/m2 (weekly).
2Carboplatin AUC 6, paclitaxel 175 mg/m2 (q3w) or 80 mg/m2 (weekly). 84% of patients received bevacizumab.
3Carboplatin AUC 6, 175 mg/m2 (q3w) or carboplatin AUC 2, paclitaxel 60 mg/m2 (weekly).
In JGOG 3016 patients derived both PFS and OS benefit from the dose-dense approach, whereas in GOG 0262, there was no PFS difference in the intention to treat (ITT) population [7−9]. The two trials, however, had key differences. Patients in GOG 0262 were allowed bevacizumab (BEV) in an uncontrolled fashion. Since weekly paclitaxel has an anti-angiogenic effect, this may have been negated by the addition of BEV in 85% of the trial population. Consistent with this, in those who didn’t receive BEV, weekly paclitaxel improved PFS (14.2 vs. 10.3 months). Pharmacogenomic differences in the two trial populations may also have been important. There are consequently unanswered questions about dose-dense chemotherapy which may be answered by two phase III trials yet to report. In the 3-arm ICON 8 trial (NCT01654146), q3w carboplatin/paclitaxel is compared to 2 dose-dense regimens without BEV. In ICON 8B (NCT01654146), bevacizumab use is allowed but is controlled and pre-specified.
\nEOC is initially chemosensitive so efforts to understand resistance could improve outcomes. Acquired resistance is secondary to diverse mechanisms which includes alterations to DNA repair and/or response to DNA damage. Mk-1775 is an anti-Wee1 tyrosine kinase inhibitor (TKI) that may sensitize cells to chemotherapy by abrogating the G2 checkpoint (crucial in P53 deficient cells) causing premature entry into mitosis [10]. It has shown promising results in several phase II trials [11]. In a different approach, the 2-arm PiSARRO trial (NCT02098343) involves the addition of APR-246 (capable of restoring mutant P53 to wild-type confirmation) to platinum-based therapy with the aim of restoring the apoptotic-response to chemotherapy-induced DNA damage. There are many other pre-clinical and early clinical efforts aiming to reverse chemoresistance including efforts to target primary resistance by targeting cancer stem cells and epithelial to mesenchymal transition [12].
\nLurbinectedin is a recently discovered marine-derived antineoplastic agent that has a multimodal mechanism of action similar to trabectedin. It showed promising results in a phase II trial in platinum-resistant EOC and is being investigated in a phase III trial against either PLD or topotecan [13]. It has also shown
Key mediators of physiological angiogenesis include products of the vascular endothelial growth factor (VEGF) gene family including VEGF-A (often abbreviated to VEGF), VEGF-B, C and D and placental growth factor. The receptor family includes VEGFR-1, 2 and 3. Different combinations of ligand-receptor interaction result in diverse outcomes such as promotion of survival, proliferation of endothelium, increased permeability and lymphangiogenesis. The binding of VEGF-A to VEGFR-2 is most important in endothelial proliferation and the regulation of permeability [15].
\nIn physiology VEGF is important for the cyclical angiogenesis that takes place in the female reproductive tract [16]. Many tumour cell lines overexpress VEGF and in one series over 97% of human ovarian lines had overexpression [17]. Clinically, expression levels have been found to be an independent prognostic factor in several studies [18] and have also been found to correlate with peritoneal dissemination and ascites formation [19].
\nGiven the role of VEGF in physiology as well as pre-clinical and observational data supporting a role for VEGF in cancer, several VEGF-directed therapies exist.
\nBevacizumab (BEV) is a humanized monoclonal antibody able to bind all VEGF-A isoforms [20]. It is the most extensively studied of the antiangiogenic agents in EOC. Two phase III studies (GOG-218 and ICON7) tested adjuvant BEV. In GOG-218 [21] patients received 6 cycles of carboplatin/paclitaxel q3w and either 1) placebo (cycles 2–22), 2) BEV induction (cycles 2–6) then placebo maintenance (7–22) or 3) BEV induction (cycles 2–6) then maintenance (7–22). BEV was given at 15 mg/kg. The median PFS was 14.1 months in the BEV throughout arm compared to 11.2 months in the induction-only arm and 10.3 months for the control. Overall survival was not significantly different. 22.9% developed grade ≥ 2 hypertension in the BEV throughout arm vs. 7.2% in the control arm. In ICON7 [22], high-risk patients were given carboplatin/paclitaxel q3w with either placebo or bevacizumab (7.5 mg/kg) for cycles 2–18. Median PFS was 19.0 months in the BEV arm vs. 17.3 months (HR 0.81, p < 0.01). Among patients with incompletely resected IIIC or IV disease the median PFS was 15.9 vs. 10.5 months in the control arm. Bleeding (39 vs. 11%), hypertension (18 vs. 2%), thromboembolism (7 vs. 3%) and GI perforations (10 vs. 3 patients) were higher with BEV. Mean global QoL score was higher, at 54 weeks, in the control arm (76.1 vs. 69.7 points - EORTC questionnaire) [23]. Recent exploratory analysis of a ‘high-risk’ subgroup revealed significantly increased OS (restricted means) in the BEV group of 39.3 vs. 34.5 months [24].
\nThere were similarities and differences between these trials. Both suggested greater benefit in a subpopulation with higher stage and suboptimal debulking. They also agreed that QoL was not improved with BEV. Conversely, different doses and durations of treatment were used and overall survival data also differed, perhaps confounded by the 40% crossover in GOG 218. BEV received regulatory approval from the EMA using 15 mg/kg [25] although ESMO guidelines supported the 7.5 mg/kg dose used in ICON7, which is also prescribed in the UK currently [26]. Analysis of both trials showed greatest separation of the PFS curves at the end of BEV treatment (12 or 15 months), raising questions about extending maintenance duration. This is being investigated in the phase III BOOST study (NCT01462890).
\nBev has also been studied for recurrence. In AURELIA [27], patients with platinum-resistant disease and ≤2 prior lines of chemotherapy were given single agent investigator-choice chemotherapy either alone or with BEV continued until progression/toxicity. Median PFS was higher in the BEV arm, 6.7 vs. 3.4 months with an ORR of 27.3 vs. 11.1%. Of the 113 patients with baseline ascites 17% required paracentesis in the control arm vs. 2% in the BEV arm and PROMs for GI symptoms were better with BEV [28]. OS was not significantly different in the context of 40% crossover but a recent exploratory analysis suggestive a survival advantage in those who received BEV during or after the study [29]. Adverse events were consistent with previous studies. BEV has been granted FDA and EMA approval for this indication.
\nIn the OCEANS study [30], the addition of BEV to carboplatin/gemcitabine in patients with platinum-sensitive disease resulted in a median PFS of 12.4 months vs. 8.4 months. OS was not significantly (38% crossover). Hypertension, proteinuria and non-CNS bleeding were significantly more common in the BEV arm. BEV was also tested in the platinum-sensitive setting with carboplatin/paclitaxel, in the factorial GOG-213 trial [31]. Median OS with BEV was 42.2 months compared to 37.3 months without (p = 0.056). BEV has EMA regulatory approval in this setting.
\nWhereas BEV binds directly to VEGF, VEGFR TKIs affect signalling via competitive inhibition of the intracellular kinase domain. They have the advantage of being orally bioavailable and multitargeted. Conversely, plasma concentration is unpredictable and off-target effects narrow the therapeutic window.
\nCediranib inhibits VEGR-1,2 and 3 and c-Kit. ICON 6 [32] randomised patients with recurrent platinum-sensitive disease to chemotherapy plus: placebo concurrently + maintenance (Arm A), cediranib concurrently + placebo maintenance (Arm B) or cediranib concurrently + maintenance (Arm C). Median PFS was 11 months in Arm C vs. 8.7 months in Arm A (p < 0.0001). Recent OS data [33] by restricted means showed 34.2 months vs. 29.4 months in Arms C and A respectively (95% CI for the difference: −0.1-9.8). During chemotherapy grade ≥ 3 fatigue (16 vs. 8%), diarrhoea (10 vs. 2%), hypertension (12 vs. 3%), febrile neutropenia (7 vs. 3%) and thrombosis (3 vs. 1%) were higher with cediranib. 48% discontinued treatment due to toxic effects in Arm C compared to 17% in Arm A and 37% in B. Although recent analysis showed no detriment in QOL at 1 year [34], filing for regulatory approval for cediranib had been previously withdrawn. Nonetheless cediranib maintenance is undergoing investigation in ICON9 (see below).
\nPazopanib inhibits VEGR1,2 and 3, c-Kit and PDGFR. The AGO-OVAR 16 study [35] evaluated first-line maintenance pazopanib. PFS was 17.9 months for pazopanib compared to 12.3 months for control. Grade 3/4 adverse events were significantly higher for pazopanib including hypertension (30.8%), neutropenia (9.9%) and diarrhoea (8.2%). Discontinuation due to AEs occurred in 33% in the pazopanib arm compared to 5.6% in the placebo arm. Regulatory approval filing was withdrawn due to perceived imbalance in benefit–risk ratio.
\nOther VEGFR TKIs have been studied in ovarian cancer [35]. Nintedanib was given in the first-line setting with chemotherapy and then maintenance. Again, a PFS benefit was seen but no significant OS advantage [36]. Other multitargeted VEGFR TKIs such as sunitinib and sorafenib have also been studied with similar outcomes. As a class the TKIs appear to have some effect however their multi-targeted nature and unpredictable bioavailability means that their perceived risk:benefit ratio has not led to any regulatory approvals as yet.
\nThe Ang-Tie pathway is distinct from the VEGF axis, involved in vascular remodelling. Trebananib is peptide-Fc fusion protein that binds Angiopoietin 1 and 2 and prevents interaction with Tie on endothelium. Although promising results were seen in phase II [37], a phase III trial (TRINOVA-2) [38] failed to meet its PFS endpoint and a third terminated early for futility (NCT01493505).
\nVascular disrupting agents (VDAs), in contrast to inhibiting formation of new vessels, target existing tumour vasculature. The VDA’s combretastatin and fosbretabulin disrupt the endothelial cytoskeleton (by binding tubulin) aiming to cause endothelial detachment and eventual vessel obstruction. Tumour vasculature lacks pericytes and smooth muscle making them selectively susceptible. Fosbretabulin is being examined for synergy with bevacizumab and chemotherapy in platinum-resistant disease in a phase II/III trial (NCT02641639).
\nThere is pre-clinical rationale for the combination of VEGF-targeted therapy with poly (ADP-ribose) polymerase inhibitors (PARPi); anti-VEGF induced hypoxia can impair DNA repair and sensitize otherwise insensitive cells to PARPi. In a phase II trial of olaparib and cediranib [39] PFS with the combination was prolonged (17.7 vs. 9.0 months) and, consistent with pre-clinical rationale, the difference was most marked in BRCA wild-type patients. Grade 3/4 toxicity however was 70% with the combination vs. 7% for olaparib monotherapy. The combination is currently undergoing phase III testing (ICON 9). The combination of bevacizumab and olaparib in first-line maintenance is also being studied (NCT02477644).
\nCombining VEGF blockade and immunotherapy also has pre-clinical rationale (see below). Combinations of anti-angiogenesis and chemotherapy have been discussed in the paragraphs above. Of note, an early phase trial of pazopanib with carboplatin/paclitaxel was terminated early because of toxicity (GI perforations and myelotoxicity).
\nGiven the relatively modest median PFS benefits and lack of OS benefit in some trials combined with toxicity and economic considerations, biomarkers for patient selection are needed. None have yet been validated for routine use although many have been suggested. Studies have been retrospective and focussed on different markers including gene-expression signatures, serum and tissue proteomic biomarkers. There have been some intriguing results including a 63-gene signature that identifies an immune subgroup that may be harmed by bevacizumab treatment [40]. Prospective validation is needed for this and other candidate markers.
\nDNA constantly undergoes single and double-strand breaks (SSBs/DSBs). SSBs are repaired predominantly by base excision repair (BER). PARPs are nuclear proteins with diverse functions including in BER and chromatin remodelling. PARP-1 is the most abundant member which upon binding to SSBs activates its ADP-ribosyltransferase catalytic domain allowing PARylation and recruitment of DNA repair effectors [41]. DSBs are mostly repaired by homologous recombination (HR) or non-homologous end joining (NHEJ), the latter being error-prone [42]. HR involves a number of key proteins including BRCA1, BRCA2, RAD51 and PALB2. A detailed discussion is beyond the scope of this chapter but the process of HR is reviewed here [43]
\nThe Australian Ovarian Cancer Study Group screened 1001 patients with stage I-IV ovarian cancer for point mutations or large deletions in BRCA genes. 14.4% of patients overall had a germline mutation (including 17.1% with serous histology) [44]. A similar frequency was found in The Cancer Genome Atlas (TCGA) [45] although globally the prevalence varies between ethnic groups. In addition to germline mutations, BRCA genes can be somatically mutated, epigenetically silenced or the protein inactivated through post-translational mechanisms, e.g. EMSY amplification [46]. Various series have found somatic mutations of BRCA in 3–6% of EOC [47]. In contrast to somatic mutations, epigenetic silencing by promoter methylation is a dynamic process and may be harder to quantify. Studies report prevalence in the region of 5–30% of ovarian cancers.
\nHowever, BRCA1 and 2 are just two of many proteins involved in HR. TCGA undertook exomic analysis of 316 ovarian cancers as well as studies of promoter methylation, RNA expression and copy number changes [45]. Pathway analysis demonstrated that 51% of tumours had either mutations or silencing of components in the HR pathways. (Figure 2).
\nDistribution of HR gene mutations in EOC. Adapted from Ref. [
HR deficiency (HRD) in EOC provides a target that can be exploited therapeutically. It was noted that cells with non-functioning PARP develop increased nuclear foci of Rad51 implying an increased burden of lesions being repaired by HR in these cells [48]. Farmer et al. [49] tested the hypothesis that BRCA 1/2 dysfunction would hypersensitize cells to PARP inhibition and were able to demonstrate this in BRCA deficient cell lines. This example of ‘synthetic lethality’ whereby either defect alone is tolerable but the combination is fatal has been exploited in the generation of a family of drugs, the PARP inhibitors. (Figure 3).
\nSchematic of synthetic lethality of PARP inhibition in HR deficient cells.
Following this, further work began on designing a PARP inhibitor (PARPi) suitable for clinical use. Early agents mimicked the substrate-enzyme interaction between NAD+ and the catalytic domain of PARP1/2 and further optimization led to the design of Compound 47, that would be developed as Olaparib [50]. Since Olaparib, several agents have been developed (discussed later) designed to inhibit PARP 1/2 catalytic activity.
\nIn addition to catalytic inhibition, a distinct antitumour mechanism of PARPi, ‘PARP-trapping’ has been described. Trapped PARP-DNA complexes were more cytotoxic than unrepaired SSBs in PARP deficient cells and different PARP inhibitors had different PARP-trapping potency which was not correlated with their catalytic inhibitory properties [51].
\nOlaparib is an orally bioavailable small molecule with a nicotinamide moiety that competes with NAD+ for binding to PARP. The MTD for olaparib was established from early phase trials at 400 mg BD. Objective responses were seen mainly in patients with germline BRCA mutations (gBRCAm) [52] Further support for the efficacy of olaparib in in the gBRCAm population came from a proof-of-concept phase II where the ORR in the 400 mg BD cohort was 33% including some complete responses (CRs) [53]. Of note, one heavily pre-treated patient developed acute myeloid leukaemia (AML) 9 months after cessation.
\nA further phase II study gave 193 heavily pre-treated EOC platinum-resistant/unsuitable patients with gBRCA mutations olaparib at a dose of 400 mg BD [54]. The ORR was 31%. AEs were similar to those seen in earlier trials with a grade 3/4 rate of 54% including anaemia (17%) and fatigue (6%). Two patients developed leukaemia and one myelodysplastic syndrome, all were heavily pre-treated (25, 26 and 34 cycles each). These results (along with other applicant-submitted data) earnt olaparib FDA approval as monotherapy for patients with gBRCA mutations after three prior lines. The recent phase III SOLO3 study randomised patients with gBRCA mutations who have received at least 2 prior lines of platinum-based therapy and who are deemed at least partially platinum-sensitive to either Olaparib 300 mg BD or single agent chemotherapy of investigators choice [55]. Results are awaited. While the previous formulation of Olaparib required 16 capsules a day, the current tablet formulation requires only four raising hopes that some of the gastrointestinal toxicity will be mitigated.
\nIn the aforementioned studies olaparib was given as monotherapy for treatment of ‘active’ disease. In contrast, Study 19 randomised patients with recurrent platinum-sensitive cancer with at least 2 prior lines to
The phase III SOLO1 has completed accrual and randomised patients with BRCAm following first-line platinum-based chemotherapy to either Olaparib 300 mg BD or placebo.
\nNiraparib is a potent PARP1 and PARP2 inhibitor whose pharmacokinetics allows once daily dosing. A phase I dose escalation trial established the MTD as 300 mg/day. Dose-limiting toxicities included fatigue, reversible pneumonitis (in the context of recent chest wall irradiation) and reversible grade 4 thrombocytopenia. Of the 20 patients with gBRCA mutations and evaluable tumours the ORR (at doses between 80 and 400 mg) was 40% [58].
\nThe pivotal phase III NOVA trial enrolled patients with platinum-sensitive disease who had received at least two prior lines of chemotherapy and who had measurable disease of <2 cm post-treatment [59]. Patients were randomised to niraparib 300 mg or placebo as maintenance till PD or unacceptable toxicity. Patients were stratified into gBRCA mutations vs. those without. Those without gBRCA mutations were further stratified into those with or without a positive HRD score (see below) and a predefined cut-off. PFS in the gBRCA mutated group was 21 vs. 5.5 months in the niraparib and control arms respectively (HR 0.30) and 12.9 vs. 3.8 months (HR 0.45) in the HRD positive cohort.
\nQUADRA is an ongoing single-arm phase II trial in patients pre-treated with 3–4 lines of chemotherapy and who were platinum sensitive at first recurrence regardless of BRCA mutation status. Patients who entered the trial underwent testing for homologous recombination deficiency (HRD) using a validated commercial assay. This assesses tumour samples for three SNP array-based ‘signatures’ of genomic instability (loss of heterozygosity, telomeric allelic imbalance and large scale transition) to derive an overall ‘HRD score’ that should predict sensitivity to PARP inhibition [NCT02354586].
\nPRIMA is an ongoing phase III of niraparib maintenance after 1st line chemotherapy. Unlike SOLO1, patients are enrolled on the basis of HRD score rather than gBRCA mutation status.
\nRucaparib is another orally bioavailable PARPi with both catalytic inhibitory and PARP-trapping activity, the potency of the latter being equivalent to olaparib [60].
\nRucaparib was granted accelerated FDA approval largely based on composite data from 2 phase II studies. 106 patients with gBRCA mutations who had received at least 2 prior lines of chemotherapy received continuous rucaparib at 600 mg BD [61]. The confirmed ORR by RECIST was 54%. Toxicity at ≥ grade 3 included anaemia (27%), fatigue (15%), transient AST/ALT elevation (13%), vomiting (6%) and nausea (4%).
\nPart 1 of the ARIEL2 trial (from which the gBRCA mutation data was pooled in the above analysis) enrolled 206 patients who had been received at least 1 prior platinum containing chemotherapy regimen and who had progressed after at least 6 months after their most recent course [62]. Patients were prospectively divided into three subgroups based on their HRD status: 1) germline or somatic BRCA mutations 2) BRCA wild-type and LOH-high 3) BRCA wild-type and LOH-low. LOH was assessed using a next generation sequencing assay and a cut-off of 14% was assigned using microarray and survival data from TCGA. Based on this pre-specified score, PFS was 12.8 months, 5.7 months and 5.2 months in the BRCA mutated, BRCA wild-type/LOH-high and BRCA wild-type/LOH-low subgroups. Although median PFS was similar in the latter groups, the HR for PFS was significantly in favour of the LOH-high subgroup (0.62 95% CI 0.42–0.90), and ORR by RECIST (29% vs. 10%) and 1 year survival (28% vs. 10%) were also better for the LOH-high subgroup. Of note, LOH exists on a continuum and exploratory post-hoc analysis revealed that a cut-off of 16% provided better discrimination between the two subgroups [63]. Also importantly, there were patients in the LOH-negative group with very good partial and even complete responses (by ca125). In this single arm phase II study, it is not possible to exclude the possibility that LOH-high tumours simply have a better prognosis and that LOH is a prognostic rather than predictive marker. In order to address this question (in a maintenance setting at least) the NGS assay is being prospectively applied in the phase III Ariel 3 study which is investigating maintenance rucaparib in platinum-sensitive ovarian cancer. The phase III Ariel 4 study is will compare rucaparib as an active treatment vs. standard of care chemotherapy in platinum-sensitive disease after at least 2 prior lines.
\nAnother orally bioavailable PARP inhibitor, veliparib is far less potent at PARP-trapping than the previously mentioned agents although it is a more potent catalytic inhibitor than niraparib and has been shown to cross the blood–brain barrier [51]. In a phase I trial 40% of the 28 BRCAm positive evaluable patients had an ORR at the MTD (400 mg BD). Commonest toxicities were nausea, vomiting and lymphopenia and 2 patients had grade 2 seizures [NCT01472783].
\nIn a phase II trial in patients with gBRCAm who had been treated with 3 or fewer prior regimens (median 2) and of whom 60% were platinum resistant, the ORR was 26% (35% in the platinum-sensitive cohort). Grade 3 fatigue, nausea and neutropenia occurred in 6%, 4% and 2% respectively with no other grade 3 toxicities. Veliparib is currently being explored in phase III trial concurrently with carboplatin/paclitaxel and then continued as maintenance (NCT02470585, see below).
\nTalazoparib is a novel PARPi that traps PARP approximately 100-fold more efficiently than olaparib and rucaparib and exhibits cytotoxicity at nanomolar (compared to micromolar) concentrations) [60]. At an MTD of 1 mg/kg, 5/12 patients with BRCAm ovarian cancer achieved an ORR with a 24% and 18% rate of G3 anaemia and thrombocytopenia respectively [64]. Given its unique potency for trapping, there is hope that it may have efficacy as a second line agent for patients who have progressed on a previous PARPi [65].
\nPARPi were originally developed as potential chemo/radiosensitizers. There is obvious rationale in combining PARPi with other agents, especially in tumours that are HR proficient. When combining PARPi with chemotherapy, rational combination necessitates consideration of the mechanism of action of the chemotherapy plus the relative catalytic inhibitory/trapping properties of the PARPi. For example, PARPi combination with topo-1 inhibitors is synergistic primarily because of catalytic PARP inhibition whereas synergy with alkylating agents relies on trapping too [66]. Several PARPi/chemotherapy combinations are in trials, reviewed here [67]. Synergistic toxicity (e.g. myelotoxicity) will have to be borne in mind. PARPi/VEGFR targeting combinations have previously been discussed. Other targeted combinations include PI3K/MTOR pathway inhibitors, HSP90 and CHK1/2 inhibitors [67]. Finally, talazoparib had immunomodulatory effects in a pre-clinical mouse model; studies looking at immunotherapy with PARPi are underway (NCT0257172).
\nSeveral putative mechanisms of resistance have been described. These include a secondary mutation in BRCA which either restores the correct open reading frame (i.e. where the original mutation caused a frameshift) or which fully reverts the original mutation to wild-type. This also causes platinum resistance and in one study of platinum resistance in BRCAm patients, 46% had acquired a secondary BRCA mutation [68]. Other mechanisms include upregulation of P-glycoprotein and loss of 53BP1 (which usually promotes NHEJ and prevents HR). Knowledge of the specific resistance mechanism may have clinical relevance as some (e.g. secondary mutations) cause platinum resistance too whereas others do not. Also, 53BP1 loss causes resistance in BRCA1 but not BRAC2 deficient tumours.
\nIn 2003 Zhang and colleagues showed that the presence or absence of tumour-infiltrating lymphocytes (TILs) in EOC is an independent prognostic factor (in multivariate analysis) for PFS and OS. Of 174 patients, those with TILs had a median overall survival of 50.3 months compared to 18.0 months in the 72 patients without [69]. Tumour-associated antigens discovered in EOC include mesothelin, Her2, NY-ESO and ca125 amongst others [70].
\nAround 50% of EOC has genomic/epigenetic changes in genes implicated in HRD [45]. Therefore there is a subset of EOC with a higher mutational burden possibly more likely to benefit from immunotherapy. Analysis of TCGA data showed a significantly higher predicted neoantigen load in HRD vs. HR proficient tumours [71]. In addition, BRCA1/2 status and neoantigen load were independent predictors of OS in multivariate analysis and BRCA mutated tumours had an increased TIL burden and PD-L1 expression. Lastly, tumour burden/volume is an important factor in predicting the response to immunotherapy [72]. Ovarian cancer is unusual as patients presenting
Co-inhibitory checkpoints usually act to minimize collateral tissue damage during immune-activation. Upregulation of these checkpoints can subvert anti-tumour immunity. The binding of CTLA-4 to B7.1/B7.2 is one such inhibitory interaction that can be prevented by the anti CTLA-4 monoclonal antibody ipilimumab.
\nIn a phase I study including 2 patients with ovarian cancer, one patient had a 43% reduction in ca125 levels while the other developed a plateau in ca125 levels despite rapidly rising levels before treatment [73]. In a follow-up study of 9 patients one developed a radiologic PR with complete resolution of mesenteric lymphadenopathy. Three others achieved radiographic and ca125-defined stable disease of 2, 4 and >6 months duration. In a phase II study of 40 patients with recurrent platinum-sensitive EOC (NCT01611558), 50% developed at least G3 toxicity and the ORR was 10.9% by RECIST. A phase II trial testing a combination of nivolumab and ipilimumab for recurrent ovarian cancer is currently underway (NCT02498600).
\nA trial using another CTLA4 antagonist, tremelimumab, is currently enrolling patients for phase I trials in combination with olaparib (NCT02571725, NCT02485990).
\nAnother inhibitory checkpoint interaction is between PD-1 (on T-cells) and PD-L1 (that may be upregulated on tumour cells and their microenvironment). Avelumab, a fully humanised IgG1 anti-PD-L1 antibody, was tested in a phase Ib trial in 124 patients with platinum resistant/refractory disease after a median of 4 lines of therapy [73, 74]. The drug was well tolerated with a grade 3/4 adverse event rate of 6.4%. ORR in this heavily pre-treated population was 9.7% and the relationship between germline BRCA status and probability of response is being investigated. Avelumab is currently being tested in two randomised phase III trials. The three-arm JAVELIN Ovarian 200 study (NCT02580058)I is recruiting patients with their first platinum resistant/refractory relapse and randomising to either Avelumab or PLD alone or in combination. In JAVELIN Ovarian 100 (NCT02718417) patients with previously untreated III/IV ovarian cancer are randomised to carboplatin and paclitaxel followed by placebo or avelumab maintenance or carboplatin and paclitaxel with concurrent
Atezolizumab is also a fully humanized IgG1 anti-PD-L1 antibody. In the phase III ATALANTE trial (NCT02891824) patients with platinum-sensitive relapse are being randomised to platinum-based chemotherapy with concurrent and maintenance bevacizumab + placebo (control arm) or bevacizumab + avelumab (experimental arm). The combination of bevacizumab and avelumab is a rational one based on evidence that endogenous VEGF signalling has a variety of immunomodulatory effects. VEGF-A has been postulated to suppress dendritic cell maturation, increase the presence of immunosuppressive CD34+ haematopoetic progenitor cells in the tumour microenvironment and inhibit T-cell maturation [75]. Another trial combining atezolizumab with bevacizumab (NCT02839707) in a phase II/III setting is randomising platinum resistant patients between 3 arms each containing PLD with either bevacizumab alone (control), atezolizumab alone or bevacizumab and atezolizumab.
\nInstead of targeting PD-L1, pembrolizumab is a humanized anti PD-1 antibody. Keynote-028 included 26 EOC patients. 1 patient had a CR and 2 had PR by RECIST. The median duration of response was not reached (range 24.9+ to 26.5+) [76]. There are currently several ongoing phase I/II trials with pembrolizumab both as monotherapy and in combination with chemotherapy, niraparib and various small molecule inhibitors in the frontline and recurrent settings (NCT02865811, NCT02520154, NCT02440425, NCT02674061).
\nNivolumab, a PD-1 blocking antibody, was given to 20 patients with platinum resistant EOC. 40% of patients developed G3/4 toxicity (lymphopenia, anaemia, hypoalbuminaemia, maculopapular rash, fever, ALT increase). Three patients (15%) had an OR including 2 CRs. One of these was in a patient with clear cell carcinoma (often chemoresistant) and this response was ongoing at the time of study reporting [77]. As with the pembrolizumab data, although the ORR was modest, there was evidence of durable responses in both studies. Nivolumab is being studied in several ongoing trials including in combination with ipilimumab for (NCT02498600), in combination with bevacizumab (NCT02873962) and with a vaccine against the tumour-associated antigen WT1 (NCT02737787).
\nAdoptive T-cell therapy (ATT) involves the direct administration of various types of anti-tumour T-cells to the patient. Given the prognostic value of TILs (see above), TIL-based ATT seems logical. In one study, 13 patients who had no residual disease after surgery and adjuvant therapy were treated with TIL infusion. A matched control group was followed up concurrently [78]. In this small study 3 year OS was 100% in the TIL group vs. 67.5% in the control group. TIL-based trials are ongoing (NCT02482090, NCT01883297). Another ATT approach involves using chimeric antigen receptor (CAR) T-cells that have been engineered to express a CAR with an extracellular single chain variable fragment incorporating immunoglobulin heavy and light chains capable of targeting any extracellular target (not just those complexed with MHC). There are currently over 20 trials registered on ClinicaTrials.gov testing CAR-T-cell-based therapy in ovarian cancer against targets including Her2, mesothelin, folate receptor-α (FRα) and NY-ESO-1.
\nThe field of immunotherapy is advancing rapidly and various other approaches are in early phase trials. Vaccine based therapy has yielded objective responses demonstrating proof-of-concept, for example using a dendritic cell whole-tumour based approach [79]. Although clinical trials for vaccines have been disappointing, various techniques for optimisation are leading to renewed enthusiasm [80]. Another approach used a tri-functional antibody, catumaxomab, which binds to epithelial cell adhesion molecule (EpCAM), CD3 (found on T-cells) and has an Fc portion that is recognised by various cells including macrophages. This allows immune cells to colocalize with tumour and cause cytotoxicity. EpCAM positive cells are found in 70–100% of malignant effusions and in a phase II study intraperitoneal (IP) administration of catumaxomab significantly improved the puncture free interval in heavily pre-treated patients [81]. It was given EMA approval for IP administration but the manufacturer withdrew this for commercial reasons in July 2017. One of the problems of ‘targeted’ immune therapy such as this is toxicity with systemic administration. Consequently, IP administration may be the only viable route with some therapies.
\nCombination immune therapy PARP inhibitors, VEGF therapy and chemotherapy have already been mentioned. In addition, checkpoint inhibition has recently been combined with epacadostat, an inhibitor of 2,3-dioxygenase (IDO). IDO activation in tumours is associated with immune escape via T-cell dysfunction. Combining epacadostat and pembrolizumab has shown efficacy in patients with EOC although randomised trials are needed to ascertain the effect of epacadostat over and above pembolizumab monotherapy [82].
\nThe aforementioned systemic strategies are of most relevance because they are either already in (or close to) the clinic. There are however various other strategies being explored, some of which have already been trialled in clinical studies. One approach involves targeting folate receptor and, specifically, the α isoform (FRα). This receptor is absent from normal ovarian epithelium but expressed on the majority of EOC [83]. The receptor has been targeted by various classes of therapy including folate-drug conjugates, small molecule FRα inhibitors, monoclonal antibodies, vaccines and oncolytic viruses. The phase III trial of vintafolide (folate conjugated with a derivative of vinblastine) in combination with PLD (NCT01170650) was discontinued for futility. Further trials of folate-drug conjugates are ongoing [84]. Farletuzumab, a monoclonal antibody that causes antibody and complement- dependant cellular cytotoxicity is being investigated in combination with platinum-based chemotherapy in patients with relapsed EOC and low ca125 following promising sub-group analysis from a previous phase III trial (NCT02289950). Phase I results for ONX-0801, a FRα-targeted thymidylate synthase inhibitor that accumulates in EOC cells generated a PR in 5/11 patients at the MTD with 4/4 FRα expressing tumours showing response [85].
\nAside from FRα targeting therapy, there are multiple other targeted strategies in EOC in pre-clinical and early clinical phases. Cell cycle targeting with WEE-1 inhibition has been discussed but other strategies including CHK1/2 inhibition with prexasertib (which yielded a PR in 5/13 patients in cohort 1 of a recent phase II trial [86]) are being explored. PI3k/AKT/mTOR, Her2 and molecules in the apoptotic machinery are amongst a plethora of other avenues being explored. As our understanding of the molecular basis of EOC progresses, future therapies are likely to employ biomarker or other selection criteria within trial protocols. For example, clear cell ovarian carcinoma is known to harbour mutations in the PI3K/AKT/mTOR pathway and the GOG-0268 trial of temsirolimus in addition to carboplatin/paclitaxel as first-line therapy was restricted to the clear cell population for this reason. Beyond the ‘traditional’ histological subtyping of EOC, analysis of TCGA data and recent advances in bioinformatics as led different groups to propose various molecular classifications of high grade serous EOC. Once such classification proposes four subtypes; mesenchymal, immunoreactive, differentiated and proliferative. Prospectively defined subgroup analysis of future trials using such novel molecular classifications may allow us to tailor therapy to maximise efficacy.
\nSeveral distinct strategies have been discussed. PARP inhibition have probably had the biggest clinical impact however mature OS data is awaited from many trials and further work is required to understand resistance and the potential role of combination therapy and sequencing of PARPi. Anti-angiogenic strategies have had a modest impact overall but research into patient selection may identify a subset who have more marked benefit. Similarly, with immunotherapy, the majority of patients do not show objective response but a subset has durable benefit. It seems, therefore that future success will depend on improved patient selection for trials, possibly through continued progress in understanding the molecular landscape of EOC. While progress has been made, there is a long way to go and the next few years should see continued incremental benefit in this difficult to treat disease.
\nNeuroinflammation has been identified in epilepsy-related tissue from both experimental and clinical evidence and is suspected to participate in the formation of neuronal cell death, reactive gliosis, and neuroplastic changes in the hippocampus, which may contribute to epileptogenesis [1, 2, 3, 4]. The role of active microglia in neuroinflammation is tightly regulated under neurodegenerative processes. Therefore, the microglial regulation of neuroinflammation may provide a therapeutic target for the treatment of severe or chronic neuroinflammation (Figure 1).
The relationship of neuroinflammation and epileptogenesis. Pilocarpine induces epilepsy. AUDA suppress epilepsy. Microglia plays an important role between epilepsy and neuroinflammation.
During neuroinflammation, the pro-inflammatory-related cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), are produced by active microglia or astrocytes and next provoked pathological signaling cascades through phospholipase C and phospholipase A2 activations [5, 6]. Finally, the oxidized enzymes released the non-esterified arachidonic acid (AA) from cellular phospholipids and the formation of lysophospholipids and bioactive eicosanoids (Figure 2).
The mechanism of pilocarpine (pilo) and sEH in the activation and inflammation in microglia. Muscarinic acetylcholine receptor (M3), PLC (phospholipase C), PLA2 (phospholipases A2), PKC (protein kinase C), DAG (diacylglycerol), COX (cyclooxygenase), LOX (lipoxygenase), sEH (soluble epoxide hydrolase), sEHI (soluble epoxide hydrolase inhibitors), AA (arachidonic acid), EETs (epoxyeicosatrienoic acids), DHET (dihydroxyeicosatrienoic acids), and NF-
In total, 1–3% of people in the world approximately suffer from epilepsy. Pharmacotherapy is the main treatment for most epileptic patients [7, 8, 9, 10]. Moreover, the surgery is another option for epileptic patients according to the clinical doctors’ diagnosis by referring to brain imaging and seizure mapping techniques. When epileptic patients cannot control seizures, by treatment with antiepileptic drugs (AEDs) or are not viable for surgery, vagal nerve stimulation will be a third possible option [11, 12, 13, 14, 15, 16]. Unfortunately, a number of epileptic patients cannot control seizures. Herein, it is needed to research and develop more efficacious therapies for these epileptic patients with uncontrolled seizures [17, 18, 19, 20].
The cyclooxygenases, lipoxygenases, and cytochrome P450 (CYP) epoxygenases participated in metabolizing released AA to lipid metabolites as leukotrienes, epoxyeicosatrienoic acids (EETs), and prostaglandins (Figure 2). Brain parenchymal tissue metabolizes AA to EETs via the CYP epoxygenase, which regulates cerebral blood flow (CBF) and against neuroinflammation and apoptosis. Recently, hypoxia and ischemic preconditioning experiments have shown that the increased expression of CYP epoxygenase and EETs in the brain may confer protection from an ischemic stroke induced by middle cerebral artery occlusion (MCAO) in the animal model. It also suggests that EETs signaling may suppress the ischemia-evoked inflammatory cytokine response in the brain, supporting an anti-neuroinflammatory role for EETs in the brain circulation [21, 22, 23, 24, 25, 26, 27, 28].
Iba1 is specifically expressed in microglia or macrophages and is up-regulated during the activation of these cells following nerve injury, central nervous system ischemia, and several other brain diseases. Additionally, whether soluble epoxide hydrolase (sEH) expression in the microglia should be verified? sEH can perform the metabolic conversion of EETs into their less active form as dihydroxyeicosatrienoic acids. Currently, the inhibition of sEH has been used to increase systemic EETs level and bioactivity. Through applying the pharmacologic inhibitors or genetic deletion, the inhibition of sEH attenuated the cerebral ischemia-induced vascular and neural injury, suggesting sEH might be a novel target for stroke treatment [29, 30, 31, 32, 33, 34, 35, 36, 37].
The reagents were ordered and prepared to perform
Mouse retroviral immortalized microglia BV-2 cells belonging to the C57BL/6 background were grown in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS; Gibco®), 2 mM L-glutamine, 100 U/mL penicillin (Sigma-Aldrich), and 100 μg/mL streptomycin (Sigma-Aldrich) in 5% CO2 atmosphere at 37°C. Cells were treated with 100 μM pilocarpine and/or 100 μM AUDA and cultured for 24 hrs in 10% FBS-DMEM on glass coverslips. Observation of cell morphology with/without treatment was done by light microscope (Olympus CKX41, Olympus Optical Co. Ltd.). Cells were grown to 90% confluency before the experiments.
Measurement of cell viability was measured by MTT assay according to the manufacturer’s instructions. At the experimental points, cell viability was detected by MTT assay. The reduced purple dye intensity of color was estimated by reading at an optical density of 570 nm in a spectrophotometer. Moreover,
A phagocytosis assay was performed in this experiment. BV-2 microglia seeded in six well plates were incubated with 100 μM pilocarpine at 37°C for 30 mins prior to 100 μM AUDA treatment for 24 hrs. After 24 hrs treatment, the phagocytic ability of the microglia was measured by using FITC-labeled dextran (MW 40,000) as a tracer. Briefly, microglia were exposed to 30 μg/mL FITC-labeled dextran for 30 mins. Later, three washing times with cold PBS (pH 7.4) were performed prior to measuring fluorescence at 480 nm excitation and 520 nm emission on a flow cytometer (FACS Calibular, BD Biosciences) or fluorescence microscopy (Olympus BX43, Olympus Optical). As a background, the cultures without FITC-dextran were used. Each culture condition was performed in quadruplicate, and three independent experiments were performed.
Measurement of extracellular nitric oxide production was performed. The nitrite, a stable breakdown product of nitric oxide, was measured with a Griess Reagent System (Promega, Madison, WI). Determination of activated microglial marker and sEH expression by flow cytometric assay was performed. First, BV-2 cells were pretreated with 100 μM pilocarpine for 30 mins then were treated with 100 μM AUDA for 24 hrs in 10% FBS with DMEM. After pilocarpine-AUDA co-treatment, these cells were harvested and fixed in Cytofix/Cytoperm™ (BD Biosciences) at 4°C for 15 mins and washed twice with 1× Perm/Wash™ (BD Biosciences). Fixed cells were stained with various primary antibodies [mouse anti-Iba1 monoclonal antibody (1:100 dilution) (sc-52,328; Santa Cruz Biotechnology) and mouse anti-sEH monoclonal antibody (1:100 dilution) (sc-6260; Santa Cruz Biotechnology)] at 4°C for 30 mins and then washed twice with 1× Perm/Wash™ (BD Biosciences). Secondary antibodies [FITC-labeled goat anti-mouse IgG antibody (1:1000 dilution) (sc-2010; Santa Cruz Biotechnology)] were subsequently stained at 4°C for 30 mins. Finally, cells were stained with 5 μg/mL PI (propidium iodide; BD Biosciences) at room temperature for 5 mins. Cells were analyzed by a flow cytometer (FACSCalibur, BD Biosciences) and WinMDI software (version 2.9). Statistical analysis was performed in this study. The values are reported as mean ± SE. All statistical comparisons were made with two-tailed tests. Statistical evaluation was performed using Student’s
The 100 μM pilocarpine did not affect cell viability and the half-maximal inhibitory concentration (IC50) was 17.5 mM. The 100 μM AUDA did not affect cell viability and the half-maximal inhibitory concentration (IC50) was 0.35 mM. Non-cytotoxic concentration (100 μM) of pilocarpine and AUDA were used in this study (Figure 3A and B). The non-cytotoxic effect was presented after 100 μM pilocarpine combined with 100 μM AUDA treatment (Figure 3C). The mean fluorescence intensity (MFI) of Iba1 expression was significantly increased in the BV-2 microglial cells under direct 100 μM pilocarpine stimulation (Figure 4A). The sEH expression was presented in the BV-2 microglia (Figure 4B). C-terminal inhibitor of she, AUDA (100 μM), significantly decreased Iba1 and sEH expressions in the active BV2 microglia (Figure 4A and B). After microglial activation, cell migration, phagocytosis, and cytotoxicity were enhanced. According to these results, AUDA significantly suppressed cell migration, and phagocytosis (Figure 4C–H). Additionally, alone or combined pilocarpine or AUDA treatment did not affect extracellular nitric oxide production in BV-2 microglia (Figure 4I).
BV-2 microglial cell viability for the pilocarpine and/or AUDA treatment. (A) BV-2 cells treated with the serial two-fold diluted concentration of pilocarpine (0 to 100,000 μM) at 37°C for 24 hrs in 10% serum-DMEM. Cell viability was determined by using MTT assay. The half maximal inhibitory concentration (IC50) of pilocarpine was 17.5 mM. (B) BV-2 cells treated with the serial two-fold diluted concentration of AUDA (0 to 16,000 μM) at 37°C for 24 hrs in 10% serum-DMEM. Cell viability was determined by using MTT assay. 100 μM pilocarpine did not affect cell viability and the half maximal inhibitory concentration (IC50) of AUDA was 0.35 mM. (C) Non-cytotoxic concentration (100 μM) of pilocarpine and AUDA were used in this study. Non-cytotoxic effect was presented after 100 μM pilocarpine combined with 100 μM AUDA treatment at 37°C for 24 hrs in 10% serum-DMEM. Values are reported as mean ±
AUDA significantly inhibited pilocarpine-induce BV-2 microglial activation and cytokine expressions. (A) MFI of Iba1 expression was significantly increased in the BV-2 microglial cells under the direct 100 μM pilocarpine stimulation. AUDA significantly decreased Iba1 expression. (B) sEH expression was presented in the BV-2 microglia. 100 μM AUDA significantly decreased sEH expression in BV-2 microglia. (C, D) AUDA significantly suppressed pilocarpine-active BV-2 cell migration by using wound-healing assay. (E, F) AUDA significantly suppressed pilocarpine-active BV-2 cell migration by using Boyden chamber assay. (G, H) histogram showed 100% phagocytosis in all groups. AUDA significantly suppressed phagocytic abilities of pilocarpine-active BV-2 cells by using flow cytometry. (I) No effects of nitric oxide production were presented in all groups. Values are reported as mean ±
Epilepsy affects approximately 1–3% population of the world, and temporal lobe epilepsy (TLE) is the most common localized epilepsy disorder, accounting for approximately 40% of adults with epilepsy [38]. However, the exact mechanism for the formation of TLE remains unclear. According to the engulfment-promoted cell death theory, nerve cells have special receptors. When nerve cells are injured, activated microglia will recognize this receptor and contact nerve cells, indirectly causing nerve cell death [39]. In addition, some studies have confirmed that microglia can also be directly activated by some activating factors, thereby affecting the function and survival of nerve cells [39]. Previous studies have confirmed that the EETs-sEH pathway is associated with brain inflammation, but whether the EETs-sEH pathway is involved in the formation of TLE remains to be clarified. For these reasons, studying the molecular and cellular mechanisms of the brain’s transition from normal to epilepsy can be used to understand the neurobiological changes in epilepsy formation and provide a new therapeutic strategy. Therefore, this study hopes to find a new treatment by understanding the performance and function of sEH microglia in the resting state and the microglia in the activated state, and using the functional inhibitor of sEH to find out how to regulate the activation of microglia. The method of epilepsy is expected to provide clinicians with a reference for the treatment of epilepsy and the use of AEDs in the future. This study demonstrated that AUDA, an inhibitor of sEH, significantly inhibited sEH expression and pilocarpine-induced microglia activation, including phagocytosis and migration. From these results, pilocarpine can directly activate microglia, and inhibition of the EET-sEH pathway can inhibit activated microglia, including phagocytosis and migration. Based on these research results, it is hoped that in the future, it will be helpful to neuroscience researchers in molecular and cellular research on the pathogenic mechanism of TLE, and provide clinicians with a reference for treating epilepsy and the use of anti-epileptic drugs.
Neurological disorders are complicated in the brain and spinal cord and are caused by a loss of neurons and glial cells in these injured areas. Currently, neurological disorders can affect hundreds of millions of people worldwide. More than 50 million people have epilepsy worldwide. The microglia are a key causative factor in the process of neuroinflammation. Commonly, microglia are activated after the brain injury and the activated microglia can induce neurocytotoxic factors. At present, much evidence have demonstrated microglial activation following pilocarpine-induced seizures. Our results suggest a role for sEH in regulating epileptogenesis of BV-2 microglia
The authors thank the Ministry of Science and Technology and the Council of Agriculture, Taiwan for support. The plan number of Council of Agriculture is 111AS-11.3.2-ST-a2.
The authors declare no conflict of interest.
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The presented biological wastewater treatment processes include: (1) bioremediation of wastewater that includes aerobic treatment (oxidation ponds, aeration lagoons, aerobic bioreactors, activated sludge, percolating or trickling filters, biological filters, rotating biological contactors, biological removal of nutrients) and anaerobic treatment (anaerobic bioreactors, anaerobic lagoons); (2) phytoremediation of wastewater that includes constructed wetlands, rhizofiltration, rhizodegradation, phytodegradation, phytoaccumulation, phytotransformation, and hyperaccumulators; and (3) mycoremediation of wastewater. The discussed chemical wastewater treatment processes include chemical precipitation (coagulation, flocculation), ion exchange, neutralization, adsorption, and disinfection (chlorination/dechlorination, ozone, UV light). Additionally, this chapter elucidates and illustrates the wastewater treatment plants in terms of plant sizing, plant layout, plant design, and plant location.",book:{id:"4619",slug:"wastewater-treatment-engineering",title:"Wastewater Treatment Engineering",fullTitle:"Wastewater Treatment Engineering"},signatures:"Mohamed Samer",authors:[{id:"175050",title:"Prof.",name:"Mohamed",middleName:null,surname:"Samer",slug:"mohamed-samer",fullName:"Mohamed Samer"}]},{id:"48803",doi:"10.5772/60770",title:"Bioremediation of Polluted Waters Using Microorganisms",slug:"bioremediation-of-polluted-waters-using-microorganisms",totalDownloads:11381,totalCrossrefCites:36,totalDimensionsCites:79,abstract:"Water pollution is an issue of great concern worldwide, and it can be broadly divided into three main categories, that is, contamination by organic compounds, inorganic compounds (e.g., heavy metals), and microorganisms. In recent years, the number of research studies concerning the use of efficient processes to clean up and minimize the pollution of water bodies has been increasing. In this context, the use of bioremediation processes for the removal of toxic metals from aqueous solutions is gaining considerable attention. Bioremediation can be defined as the ability of certain biomolecules or types of biomass to bind and concentrate selected ions or other molecules present in aqueous solutions. Bioremediation using microorganisms shows great potential for future development due to its environmental compatibility and possible cost-effectiveness. A wide range of microorganisms, including bacteria, fungi, yeasts, and algae, can act as biologically active methylators, which are able to at least modify toxic species. Many microbial detoxification processes involve the efflux or exclusion of metal ions from the cell, which in some cases can result in high local concentrations of metals at the cell surface, where they can react with biogenic ligands and precipitate. Although microorganisms cannot destroy metals, they can alter their chemical properties via a surprising array of mechanisms. The main purpose of this chapter is to provide an update on the recent literature concerning the strategies available for the remediation of metal-contaminated water bodies using microorganisms and to critically discuss their main advantages and weaknesses. The focus is on the heavy metals associated with environmental contamination, for instance, lead (Pb), cadmium (Cd), and chromium (Cr), which are potentially hazardous to ecosystems. The types of microorganisms that are used in bioremediation processes due to their natural capacity to biosorb toxic heavy metal ions are discussed in detail. This chapter summarizes existing knowledge on various aspects of the fundamentals and applications of bioremediation and critically reviews the obstacles to its commercial success and future perspectives.",book:{id:"4602",slug:"advances-in-bioremediation-of-wastewater-and-polluted-soil",title:"Advances in Bioremediation of Wastewater and Polluted Soil",fullTitle:"Advances in Bioremediation of Wastewater and Polluted Soil"},signatures:"Luciene M. Coelho, Helen C. Rezende, Luciana M. Coelho, Priscila\nA.R. de Sousa, Danielle F.O. Melo and Nívia M.M. Coelho",authors:[{id:"163731",title:"Prof.",name:"Nivia",middleName:null,surname:"Coelho",slug:"nivia-coelho",fullName:"Nivia Coelho"},{id:"177651",title:"Dr.",name:"Luciana",middleName:null,surname:"Coelho",slug:"luciana-coelho",fullName:"Luciana Coelho"},{id:"177741",title:"Dr.",name:"Luciene M.",middleName:null,surname:"Coelho",slug:"luciene-m.-coelho",fullName:"Luciene M. Coelho"},{id:"177742",title:"Dr.",name:"Helen C.",middleName:null,surname:"Rezende",slug:"helen-c.-rezende",fullName:"Helen C. Rezende"},{id:"177743",title:"Dr.",name:"Priscila A.R.",middleName:null,surname:"de Sousa",slug:"priscila-a.r.-de-sousa",fullName:"Priscila A.R. de Sousa"},{id:"177744",title:"Dr.",name:"Danielle F.O.",middleName:null,surname:"Melo",slug:"danielle-f.o.-melo",fullName:"Danielle F.O. Melo"}]},{id:"41953",doi:"10.5772/52665",title:"Treatment Technologies for Organic Wastewater",slug:"treatment-technologies-for-organic-wastewater",totalDownloads:10682,totalCrossrefCites:25,totalDimensionsCites:75,abstract:null,book:{id:"2503",slug:"water-treatment",title:"Water Treatment",fullTitle:"Water Treatment"},signatures:"Chunli Zheng, Ling Zhao, Xiaobai Zhou, Zhimin Fu and An Li",authors:[{id:"141286",title:"Dr",name:"An",middleName:null,surname:"Li",slug:"an-li",fullName:"An Li"},{id:"155298",title:"Dr.",name:"Chunli",middleName:null,surname:"Zheng",slug:"chunli-zheng",fullName:"Chunli Zheng"},{id:"155299",title:"Dr.",name:"Ling",middleName:null,surname:"Zhao",slug:"ling-zhao",fullName:"Ling Zhao"},{id:"155300",title:"Dr.",name:"Xiaobai",middleName:null,surname:"Zhou",slug:"xiaobai-zhou",fullName:"Xiaobai Zhou"},{id:"155301",title:"Dr.",name:"Zhimin",middleName:null,surname:"Fu",slug:"zhimin-fu",fullName:"Zhimin Fu"}]},{id:"30860",doi:"10.5772/36310",title:"Use of Agro-Industrial Wastes in Solid-State Fermentation Processes",slug:"use-of-agro-industrial-wastes-in-solid-state-fermentation-processes",totalDownloads:4176,totalCrossrefCites:9,totalDimensionsCites:66,abstract:null,book:{id:"1868",slug:"industrial-waste",title:"Industrial Waste",fullTitle:"Industrial Waste"},signatures:"Solange I. Mussatto, Lina F. Ballesteros, Silvia Martins and José A. Teixeira",authors:[{id:"107810",title:"Dr.",name:"Solange I.",middleName:null,surname:"Mussatto",slug:"solange-i.-mussatto",fullName:"Solange I. Mussatto"},{id:"109520",title:"MSc.",name:"Lina F.",middleName:null,surname:"Ballesteros",slug:"lina-f.-ballesteros",fullName:"Lina F. Ballesteros"},{id:"109522",title:"MSc.",name:"Silvia",middleName:null,surname:"Martins",slug:"silvia-martins",fullName:"Silvia Martins"},{id:"109523",title:"Prof.",name:"José António",middleName:null,surname:"Teixeira",slug:"jose-antonio-teixeira",fullName:"José António Teixeira"}]}],mostDownloadedChaptersLast30Days:[{id:"49024",title:"Biological and Chemical Wastewater Treatment Processes",slug:"biological-and-chemical-wastewater-treatment-processes",totalDownloads:27708,totalCrossrefCites:55,totalDimensionsCites:103,abstract:"This chapter elucidates the technologies of biological and chemical wastewater treatment processes. The presented biological wastewater treatment processes include: (1) bioremediation of wastewater that includes aerobic treatment (oxidation ponds, aeration lagoons, aerobic bioreactors, activated sludge, percolating or trickling filters, biological filters, rotating biological contactors, biological removal of nutrients) and anaerobic treatment (anaerobic bioreactors, anaerobic lagoons); (2) phytoremediation of wastewater that includes constructed wetlands, rhizofiltration, rhizodegradation, phytodegradation, phytoaccumulation, phytotransformation, and hyperaccumulators; and (3) mycoremediation of wastewater. The discussed chemical wastewater treatment processes include chemical precipitation (coagulation, flocculation), ion exchange, neutralization, adsorption, and disinfection (chlorination/dechlorination, ozone, UV light). Additionally, this chapter elucidates and illustrates the wastewater treatment plants in terms of plant sizing, plant layout, plant design, and plant location.",book:{id:"4619",slug:"wastewater-treatment-engineering",title:"Wastewater Treatment Engineering",fullTitle:"Wastewater Treatment Engineering"},signatures:"Mohamed Samer",authors:[{id:"175050",title:"Prof.",name:"Mohamed",middleName:null,surname:"Samer",slug:"mohamed-samer",fullName:"Mohamed Samer"}]},{id:"52474",title:"Slaughterhouse Wastewater: Treatment, Management and Resource Recovery",slug:"slaughterhouse-wastewater-treatment-management-and-resource-recovery",totalDownloads:6763,totalCrossrefCites:18,totalDimensionsCites:49,abstract:"The meat processing industry is one of the largest consumers of total freshwater used in the agricultural and livestock industry worldwide. Meat processing plants (MPPs) produce large amounts of slaughterhouse wastewater (SWW) because of the slaughtering process and cleaning of facilities. SWWs need significant treatment for a sustainable and safe discharge to the environment due to the high content of organics and nutrients. Therefore, the treatment and final disposal of SWW are a public health necessity. In this chapter, the regulatory frameworks relevant to the SWW management, environmental impacts, health effects, and treatment methods are discussed. Although physical, chemical, and biological treatment can be used for SWW degradation, each treatment process has different advantages and drawbacks depending on the SWW characteristics, best available technology, jurisdictions, and regulations. SWWs are typically assessed using bulk parameters because of the various pollutant loads derived from the type and the number of animals slaughtered that fluctuate amid the meat industry. Thus, an on-site treatment using combined processes would be the best option to treat and disinfect the slaughterhouse effluents to be safely discharged into receiving waters.",book:{id:"6050",slug:"physico-chemical-wastewater-treatment-and-resource-recovery",title:"Physico-Chemical Wastewater Treatment and Resource Recovery",fullTitle:"Physico-Chemical Wastewater Treatment and Resource Recovery"},signatures:"Ciro Bustillo-Lecompte and Mehrab Mehrvar",authors:[{id:"66753",title:"Prof.",name:"Mehrab",middleName:null,surname:"Mehrvar",slug:"mehrab-mehrvar",fullName:"Mehrab Mehrvar"},{id:"189304",title:"Dr.",name:"Ciro",middleName:"Fernando",surname:"Bustillo-Lecompte",slug:"ciro-bustillo-lecompte",fullName:"Ciro Bustillo-Lecompte"}]},{id:"48946",title:"Cogeneration Power-Desalting Plants Using Gas Turbine Combined Cycle",slug:"cogeneration-power-desalting-plants-using-gas-turbine-combined-cycle",totalDownloads:4586,totalCrossrefCites:8,totalDimensionsCites:10,abstract:"The gas-steam turbine combined cycle (GTCC) is the preferred power plant type because of its high efficiency and its use of cheap and clean natural gas as fuel. It is also the preferred type in the Arab Gulf countries where it is used as cogeneration power-desalting plant (CPDP). In this chapter, descriptions and analysis of the GTCC components are presented, namely, the gas turbine cycle (compressor, combustor, gas turbine), heat recovery steam generator, and steam turbine. Combinations of the GTCC with thermally driven desalination units to present CPDP are presented. A parametric study to show the effect of using GTCC on several operating parameters on the CPDP is also presented, as well as cost allocation methods of fuel between the two product utilities (electric power and desalted seawater are also presented).",book:{id:"4613",slug:"desalination-updates",title:"Desalination Updates",fullTitle:"Desalination Updates"},signatures:"M.A. Darwish, H.K. Abdulrahim, A.A. Mabrouk and A.S. Hassan",authors:[{id:"173364",title:"Prof.",name:"Mohamed",middleName:null,surname:"Darwish",slug:"mohamed-darwish",fullName:"Mohamed Darwish"},{id:"173603",title:"Dr.",name:"Hassan",middleName:null,surname:"Abdulrahim",slug:"hassan-abdulrahim",fullName:"Hassan Abdulrahim"},{id:"173774",title:"Dr.",name:"Abdel Nasser",middleName:null,surname:"Mabrouk",slug:"abdel-nasser-mabrouk",fullName:"Abdel Nasser Mabrouk"},{id:"175519",title:"Dr.",name:"Ashraf",middleName:null,surname:"Hassan",slug:"ashraf-hassan",fullName:"Ashraf Hassan"}]},{id:"54201",title:"Pulp Mill Wastewater: Characteristics and Treatment",slug:"pulp-mill-wastewater-characteristics-and-treatment",totalDownloads:4873,totalCrossrefCites:7,totalDimensionsCites:21,abstract:"The production of chemical pulp in recent times is 180 million tons per year; while the production of eucalyptus pulp has increased intensively, especially in the southern hemisphere. The pulp and paper industry has long been considered a large consumer of natural resources (wood and water) and one of the largest sources of pollution to the environment (air, water courses and soil). Important efforts are being made to reduce the pollutant levels and water consumption of the industry. The wastewater composition, and therefore, the efficiency of effluent treatments and characteristics of the discharges to water are strongly dependent on the applied technology and raw materials. Despite a large body of literature on softwood-based wastewater, few studies have examined the characteristics of kraft eucalyptus bleaching effluents and their behaviour in the different biological treatments. The largest secondary treatment systems today use the activated sludge process. Sixty to seventy-five per cent of all the biological effluent treatment plants within the pulp and paper industry use this kind of treatment system. This chapter reviews the current pulping technologies at mills and compares the chemical composition and biological treatment of wastewater between softwood and hardwood bleached pulps.",book:{id:"5417",slug:"biological-wastewater-treatment-and-resource-recovery",title:"Biological Wastewater Treatment and Resource Recovery",fullTitle:"Biological Wastewater Treatment and Resource Recovery"},signatures:"María Noel Cabrera",authors:[{id:"187931",title:"Dr.",name:"María Noel",middleName:null,surname:"Cabrera",slug:"maria-noel-cabrera",fullName:"María Noel Cabrera"}]},{id:"54320",title:"Phosphorus Recovery by Struvite Crystallization from Livestock Wastewater and Reuse as Fertilizer: A Review",slug:"phosphorus-recovery-by-struvite-crystallization-from-livestock-wastewater-and-reuse-as-fertilizer-a-",totalDownloads:2539,totalCrossrefCites:7,totalDimensionsCites:15,abstract:"In China, the intensive livestock farming produces massive livestock wastewater with high concentration of phosphorus. Discharge of these compounds to surface water not only causes water eutrophication but also wastes phosphorus resources for plant growth. Therefore, it’s necessary combining the removal of phosphorus from livestock wastewater with its recovery and reuse as fertilizer. As a valuable slow-release mineral fertilizer, struvite crystallization has become a focus in phosphorus recovery. In this chapter, struvite crystallization mechanism, reaction factors, crystallizers, and the applications of struvite as fertilizer are discussed. Two steps of nucleation and crystal growth for struvite crystallization from generation to growth are introduced. The reaction factors, including molar ratio of magnesium and phosphate, solution pH, coexisting substances, and seeding assist, of struvite crystallization are summarized. Several innovate types of crystallizer, which relate to the shape and size of harvest struvite to realize the phosphorus recycling, are demonstrated. Due to the influence of toxic or harmful impurities in struvite on its reuse as fertilizer, the environmental risk evaluation of struvite application is introduced. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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