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Long-term exposure to gold nanoparticles accelerates larval metamorphosis without affecting mass in wood frogs (Lithobates sylvaticus) at environmentally relevant concentrations. - Environmental toxicology and chemistry / SETAC
Nanoparticles are environmental contaminants of emerging concern. Exposure to engineered nanoparticles has been shown to have detrimental effects on aquatic organisms. We synthesized gold nanoparticles (18.1â€‰Â±â€‰3.5â€‰nm) and tested their effects on time to and weight at metamorphosis in wood frog (Lithobates sylvaticus) tadpoles, a species known to be sensitive to environmental stressors. Continuous exposure to all concentrations of gold nanoparticles (0.05, 0.5, and 5 pM in particles) for up to 55 days significantly reduced time to metamorphosis by as much as an average of three days (pâ€‰<â€‰0.05). However, exposure to gold nanoparticles had no effect on tadpole mass at metamorphosis. The âˆ¼18â€‰nm gold nanoparticles used in this study were metastable in dechlorinated tap water resulting in a change in surface charge and aggregation over time leading to negatively charged aggregates that are on the order of 60-110â€‰nm. Nanoparticle aggregation could exacerbate the effect on time to metamorphosis. To our knowledge, this is the first report on the effect of engineered nanoparticles of any kind on life history variables in an amphibian, a taxonomic group that has been declining globally for at least 25 years. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
Gabapentin Effects on PKC-ERK1/2 Signaling in the Spinal Cord of Rats with Formalin-Induced Visceral Inflammatory Pain. - PloS one
Currently, the clinical management of visceral pain remains unsatisfactory for many patients suffering from this disease. While preliminary animal studies have suggested the effectiveness of gabapentin in successfully treating visceral pain, the mechanism underlying its analgesic effect remains unclear. Evidence from other studies has demonstrated the involvement of protein kinase C (PKC) and extracellular signal-regulated kinase1/2 (ERK1/2) in the pathogenesis of visceral inflammatory pain. In this study, we tested the hypothesis that gabapentin produces analgesia for visceral inflammatory pain through its inhibitory effect on the PKC-ERK1/2 signaling pathway. Intracolonic injections of formalin were performed in rats to produce colitis pain. Our results showed that visceral pain behaviors in these rats decreased after intraperitoneal injection of gabapentin. These behaviors were also reduced by intrathecal injections of the PKC inhibitor, H-7, and the ERK1/2 inhibitor, PD98059. Neuronal firing of wide dynamic range neurons in L6-S1 of the rat spinal cord dorsal horn were significantly increased after intracolonic injection of formalin. This increased firing rate was inhibited by intraperitoneal injection of gabapentin and both the individual and combined intrathecal application of H-7 and PD98059. Western blot analysis also revealed that PKC membrane translocation and ERK1/2 phosphorylation increased significantly following formalin injection, confirming the recruitment of PKC and ERK1/2 during visceral inflammatory pain. These effects were also significantly reduced by intraperitoneal injection of gabapentin. Therefore, we concluded that the analgesic effect of gabapentin on visceral inflammatory pain is mediated through suppression of PKC and ERK1/2 signaling pathways. Furthermore, we found that the PKC inhibitor, H-7, significantly diminished ERK1/2 phosphorylation levels, implicating the involvement of PKC and ERK1/2 in the same signaling pathway. Thus, our results suggest a novel mechanism of gabapentin-mediated analgesia for visceral inflammatory pain through a PKC-ERK1/2 signaling pathway that may be a future therapeutic target for the treatment of visceral inflammatory pain.
The effects of antidepressants appear to be rapid and at environmentally relevant concentrations. - Environmental toxicology and chemistry / SETAC
The effects of antidepressants on wildlife are currently raising some concern because of an increased number of publications indicating biological effects at environmentally relevant concentrations (<100â€‰ng/L). These results have been met with some scepticism because of the higher concentrations required to detect effects in some species and the perceived slowness to therapeutic effects recorded in humans and other vertebrates. Because their mode of action is thought to be by modulation of the neurotransmitters serotonin, dopamine, and norepinephrine, aquatic invertebrates that possess transporters and receptors sensitive to activation by these pharmaceuticals are potentially affected by them. The authors highlight studies on the effects of antidepressants, particularly on crustacean and molluskan groups, showing that they are susceptible to a wide variety of neuroendocrine disruptions at environmentally relevant concentrations. Interestingly, some effects observed in these species can be observed within minutes to hours of exposure. For example, exposure of amphipod crustaceans to several selective serotonin reuptake inhibitors can invoke changes in swimming behavior within hours. In mollusks, exposure to selective serotonin reuptake inhibitors can induce spawning in male and female mussels and foot detachment in snails within minutes of exposure. In the light of new studies indicating effects on the human brain from selective serotonin reuptake inhibitors using magnetic resonance imaging scans, the authors discuss possible reasons for the discrepancy in former results in relation to the read-across hypothesis, variation in biomarkers used, modes of uptake, phylogenetic distance, and the affinity to different targets and differential sensitivity to receptors. Environ Toxicol Chem 2016;35:794-798. Â© 2015 SETAC.Â© 2015 SETAC.
Stage I granulosa cell tumours: A management conundrum? Results of long-term follow up. - Gynecologic oncology
Optimal management of women with early stage granulosa cell tumours (GCT) presents a management conundrum - they have excellent prognosis but a third will relapse. Advances uncovering the molecular characteristics of GCT have not been matched by improvements in our understanding and treatment.Stage I GCT patients referred to Auckland City Hospital (1955-2012) and Princess Margaret Cancer Centre (1992-2012) were identified. Baseline characteristics, histopathology and outcomes were recorded retrospectively.One hundred and sixty stage I GCT patients were identified with a median age of 49 years. Median follow-up was 7.0 years (range 0.1-44.2 years). Fifty-one patients (32%) relapsed with a median time to relapse (TTR) of 12.0 years (1.3-17.7 years) - 20 initial relapses occurred 10 years post-diagnosis. Higher relapse rates (43% vs. 24% p=0.02) and shorter TTR (10.2 vs. 16.2 years p=0.007) were seen with stage Ic versus stage Ia disease. Cyst rupture was associated with increased relapse (p=0.03). Surgery was the main therapeutic modality at relapse. Eighty six percent of patients received non-surgical management at least once post-relapse. Clinical benefit rate was 43% with chemotherapy, 61% with hormonal therapy and 86% with radiation. Five- and 10-year overall survival (OS) were 98.5 and 91.6%, respectively. Median OS was similar in patients with (24.3 years) and without relapse (22.3 years).Surgery remains fundamental at diagnosis and relapse. Caution should be exercised in recommending adjuvant chemotherapy at initial diagnosis given median OS was greater than 20 years even with relapse. Hormonal therapy at relapse appears encouraging but needs further assessment. Novel treatment strategies need exploration with international collaboration essential for this.Copyright Â© 2015 Elsevier Inc. All rights reserved.
Second-line dovitinib (TKI258) in patients with FGFR2-mutated or FGFR2-non-mutated advanced or metastatic endometrial cancer: a non-randomised, open-label, two-group, two-stage, phase 2 study. - The Lancet. Oncology
Activating FGFR2 mutations are found in 10-16% of primary endometrial cancers and provide an opportunity for targeted therapy. We assessed the safety and activity of dovitinib, a potent tyrosine-kinase inhibitor of fibroblast growth factor receptors, VEGF receptors, PDGFR-Î², and c-KIT, as second-line therapy both in patients with FGFR2-mutated (FGFR2(mut)) endometrial cancer and in those with FGFR2-non-mutated (FGFR2(non-mut)) endometrial cancer.In this phase 2, non-randomised, two-group, two-stage study, we enrolled adult women who had progressive disease after first-line chemotherapy for advanced or metastatic endometrial cancer from 46 clinical sites in seven countries. We grouped women according to FGFR2 mutation status and gave all women dovitinib (500 mg per day, orally, on a 5-days-on and 2-days-off schedule) until disease progression, unacceptable toxicity, death, or study discontinuation for any other reason. The primary endpoint was proportion of patients in each group who were progression-free at 18 weeks. For each group, the second stage of the trial (enrolment of 20 additional patients) could proceed if at least eight of the first 20 treated patients were progression free at 18 weeks. Activity was assessed in all enrolled patients and safety was assessed in all patients who received at least one dose of dovitinib. The completed study is registered with ClinicalTrials.gov, number NCT01379534.Of 248 patients with FGFR2 prescreening results, 27 (11%) had FGFR2(mut) endometrial cancer. Between Feb 17, 2012, and Dec 13, 2013, we enrolled 22 patients in the FGFR2(mut) group and 31 patients in the FGFR2(non-mut) group. Seven (31Â·8%, 95% CI 13Â·9-54Â·9) patients in the FGFR2(mut) group and nine (29Â·0%, 14Â·2-48Â·0) in the FGFR2(non-mut) group were progression-free at 18 weeks. On the basis of predefined criteria, neither group continued to stage two: seven (35%) of the first 20 patients in the FGFR2(mut) group were progression free at 18 weeks, as were five (25%) of the first 20 in the FGFR2(mut) population. Rates of treatment-emergent adverse events were similar between groups and events were most frequently gastrointestinal. Overall, the most common grade 3 or 4 adverse events suspected to be related to the study drug were hypertension (nine patients; 17%) and diarrhoea (five; 9%). The most frequently reported serious adverse events suspected to be related to study drug were pulmonary embolism (four patients; 8%), vomiting (four; 8%), dehydration (three; 6%), and diarrhoea (three; 6%). Only one death was deemed to be treatment-related: one patient in the FGFR2(non-mut) group died from cardiac arrest with contributing reason of pulmonary embolism (grade 4, suspected to be study drug related) 4 days previously.Second-line dovitinib in FGFR2(mut) and FGFR2(non-mut) advanced or metastatic endometrial cancer had single-agent activity, although it did not reach the prespecified study criteria. Observed treatment effects seemed independent of FGFR2 mutation status. These data should be considered exploratory and additional studies are needed.Novartis Pharmaceuticals.Copyright Â© 2015 Elsevier Ltd. All rights reserved.
Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. - The Lancet. Oncology
Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer.In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244.From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8Â·4 months (IQR 3Â·7-16Â·6). Median radiographic progression-free survival was 13Â·8 months (95% CI 13Â·1-14Â·9) with orteronel plus prednisone and 8Â·7 months (8Â·3-10Â·9) with placebo plus prednisone (hazard ratio [HR] 0Â·71, 95% CI 0Â·63-0Â·80; p<0Â·0001). After a median follow-up of 20Â·7 months (IQR 14Â·2-25Â·4), median overall survival was 31Â·4 months (95% CI 28Â·6-not estimable) with orteronel plus prednisone and 29Â·5 months (27Â·0-not estimable) with placebo plus prednisone (HR 0Â·92, 95% CI 0Â·79-1Â·08; p=0Â·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone.In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer.Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.Copyright Â© 2015 Elsevier Ltd. All rights reserved.
Clinical experience with sunitinib dose escalation in metastatic renal cell carcinoma. - Asia-Pacific journal of clinical oncology
The oral multi-targeted tyrosine kinase inhibitor sunitinib malate is a standard first-line therapy in clear-cell metastatic renal cell carcinoma (mRCC). Sunitinib is usually administered daily for 4 weeks, followed by 2 weeks without treatment. Some patients experience worsening of disease symptoms during the treatment break. We report three cases of mRCC in whom continuous daily dosing and dose escalation were evaluated. In two cases, sunitinib was well tolerated at doses of 75â€‰mg continuously and in all cases escalation of dose enabled regain of disease control. This suggests that continuous higher daily dosing of sunitinib is feasible and may provide additional clinical benefit for selected patients who experience minimal toxicity on the standard schedule.Â© 2015 Wiley Publishing Asia Pty Ltd.
The antidepressants venlafaxine ("Effexor") and fluoxetine ("Prozac") produce different effects on locomotion in two species of marine snail, the oyster drill (Urosalpinx cinerea) and the starsnail (Lithopoma americanum). - Marine environmental research
Human antidepressants have been previously shown to induce foot detachment from the substrate in aquatic snails. Prior to foot detachment, antidepressants also affect snail crawling speed. We tested two commonly prescribed antidepressants, venlafaxine ("Effexor") and fluoxetine ("Prozac") on crawling speed and time to reach the air-water interface in two species of marine snail, the oyster drill Urosalpinx cinerea and the American starsnail Lithopoma americanum. Exposure to venlafaxine increased crawling speed in both species, while fluoxetine slowed them down. Our lowest LOEC (lowest observed effect concentration) was 31.3Â Î¼g/L venlafaxine in Urosalpinx. Similarly, snails (L.Â americanum) exposed to venlafaxine tended to move faster and more often to the air-water interface, but exposure to fluoxetine slowed them down. Our lowest LOEC was 345Â Î¼g/L fluoxetine in Lithopoma. These results indicate that venlafaxine boosts locomotion, while fluoxetine reduces it, and both behaviors are preludes to foot detachment. The different effects of these two antidepressants on snail locomotion suggest differing physiological mechanisms of action in marine snails as well as possible ecological consequences.Copyright Â© 2014 Elsevier Ltd. All rights reserved.
Management and characteristics of patients with metastatic prostate cancer in a cohort of New Zealand men. - Oncology
This study aims to (1) characterise men diagnosed with metastatic prostate cancer, (2) describe their management and (3) look at their survival.We identified patients registered with prostate cancer in the New Zealand Cancer Registry in the Midland Cancer Network region in 2009-2012 and examined these patients' clinical records to identify the metastatic cases. We investigated the patients' characteristics and the treatment pattern. All-cause survival was estimated by the Cox proportional hazards model.Of the 2,127 men diagnosed with prostate cancer, 234 (26 Maori/Pacific and 208 non-Maori/non-Pacific) were diagnosed with metastatic prostate cancer. After the diagnosis, 194 (82.9%) patients received androgen deprivation therapy (ADT), 5 had chemotherapy and 104 (44.4%) had radiotherapy. Of the patients treated with ADT, 46 (23.7%) had no monitoring prostate-specific antigen tests. Fifty-nine percent of the patients were alive after 12 months and 35% after 24 months. The hazard ratio for the Maori/Pacific men was 1.49.Overall, the survival of patients with metastatic prostate cancer was poor. There seems to be a strong case for the development of New Zealand guidelines on the management of metastatic disease including the use of first-line treatments, the ongoing monitoring for the development of castration-resistant prostate cancer (CRPC) and the treatment of CRPC.Â© 2014 S. Karger AG, Basel.
Gynecologic Cancer InterGroup (GCIG) consensus review for ovarian sex cord stromal tumors. - International journal of gynecological cancer : official journal of the International Gynecological Cancer Society
Sex cord stromal tumors (SCST) are rare cancers of the ovarian area in adults. They constitute a heterogeneous group of tumors that develop from the sex cords and the ovarian stroma. These tumors are detected typically at an early stage, and they may recur as late as 30 years after the initial treatment. Because 70% of the patients present with stage I tumors, surgery represents the most important therapeutic arm. There are no data to support any kind of postoperative adjuvant treatment for patients with stage IA or IB SCSTs, given the indolent nature of these neoplasms and the overall good prognosis. The long natural history of the disease may lead to repeated surgical procedure should a relapse occurs. Platinum-based chemotherapy is currently used for patients with advanced stage SCSTs or recurrent disease, with an overall response rate of 63% to 80%. The indolent nature of SCSTs with the tendency for late recurrence requires long-term follow-up.
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