Background:
In multiple sclerosis, development of screening tools for remyelination-promoting molecules is timely.
Objective:
A Xenopus transgenic line allowing conditional ablation of myelinating ...oligodendrocytes has been adapted for in vivo screening of remyelination-favoring molecules.
Methods:
In this transgenic, the green fluorescent protein reporter is fused to E. coli nitroreductase and expressed specifically in myelinating oligodendrocytes. Nitroreductase converts the innocuous pro-drug metronidazole to a cytotoxin. Spontaneous remyelination occurs after metronidazole-induced demyelinating responses. As tadpoles are transparent, these events can be monitored in vivo and quantified. At the end of metronidazole-induced demyelination, tadpoles were screened in water containing the compounds tested. After 72 h, remyelination was assayed by counting numbers of oligodendrocytes per optic nerve.
Results:
Among a battery of molecules tested, siponimod, a dual agonist of sphingosine-1-phosphate receptor 1 and 5, was among the most efficient favoring remyelination. Crispr/cas9 gene editing showed that the promyelinating effect of siponimod involves the sphingosine-1-phosphate receptor 5.
Conclusion:
This Xenopus transgenic line constitutes a simple in vivo screening platform for myelin repair therapeutics. We validated several known promyelinating compounds and demonstrated that the strong remyelinating efficacy of siponimod implicates the sphingosine-1-phosphate receptor 5.
The test methods that currently exist for the identification of thyroid hormone system-disrupting chemicals are woefully inadequate. There are currently no internationally validated in vitro assays, ...and test methods that can capture the consequences of diminished or enhanced thyroid hormone action on the developing brain are missing entirely. These gaps put the public at risk and risk assessors in a difficult position. Decisions about the status of chemicals as thyroid hormone system disruptors currently are based on inadequate toxicity data. The ATHENA project (Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies) has been conceived to address these gaps. The project will develop new test methods for the disruption of thyroid hormone transport across biological barriers such as the blood-brain and blood-placenta barriers. It will also devise methods for the disruption of the downstream effects on the brain. ATHENA will deliver a testing strategy based on those elements of the thyroid hormone system that, when disrupted, could have the greatest impact on diminished or enhanced thyroid hormone action and therefore should be targeted through effective testing. To further enhance the impact of the ATHENA test method developments, the project will develop concepts for better international collaboration and development in the area of thyroid hormone system disruptor identification and regulation.
Intramedullary metastasis (IMM) is a rare disease with poor prognosis. The incidence of IMMs has increased, which has been linked to improved systemic treatment in many cancers. Surgery and/or ...radiotherapy are the most commonly used treatments; only small-sample retrospective studies and case reports on stereotactic body radiotherapy (SBRT) have reported acceptable results in terms of local control and clinical improvement, with no reported toxicity. Thus, we performed this monocentric retrospective study on five cases treated with SBRT for IMMs, which we supplemented with a systematic review of the literature.
We included all patients treated for IMM with SBRT. The target tumor volume, progression-free survival, prescription patterns in SBRT, survival without neurological deficit, neurological functional improvement after treatment, and overall survival were determined.
Five patients treated with a median dose of 30 Gy in a median number of fractions of 5 (prescribed at a median isodose of 86%) included. The median follow-up duration was 23 months. Two patients showed clinical improvement. Three patients remained stable. Radiologically, 25% of patients had complete response and 50% had stable disease. No significant treatment-related toxicity was observed.
SBRT appears to be a safe, effective, and rapid treatment option for palliative patients.
Biomass‐derived 5‐hydroxymethyl furfural (5‐HMF) is a promising starting substrate for producing two high value‐added products 2,5‐diformylfuran (DFF) and 2,5‐furandicarboxylic acid (FDCA). DFF, ...which is produced by selectively oxidizing the hydroxymethyl group of 5‐HMF to an aldehyde group, has many applications in pharmaceuticals, macrocyclic ligands and fluorescent materials. Oxidizing both aldehyde and hydroxymethyl groups of 5‐HMF leads to FDCA, which is an important monomer in the production of a bioplastic polyethylene furanoate polymer. Electrochemical conversion of 5‐HMF is a potential route for sustainable chemical production of DFF and FDCA. In fact, using 2,2,6,6‐tetramethyl‐ piperidine‐1‐oxyl (TEMPO) as a redox mediator leads to a highly efficient and selective electro‐oxidation of 5‐HMF into FDCA in a basic buffer solution. In this report, the direct and TEMPO‐mediated electro‐oxidation of 5‐HMF was investigated in various organic and hydro‐organic media at room temperature. Direct electro‐oxidation leads to a low selective conversion of 5‐HMF to DFF (10 % of yield) and the formation of unwanted products such as formic acid and protoanemonin (90 % and 37 % of yield respectively) in acetonitrile. Electrocatalytic 5‐HMF conversion in the presence of TEMPO as a redox mediator achieved a near‐quantitative yield of DFF in acetonitrile and γ‐valerolactone. Importantly, we demonstrate the role of water in the conversion of aldehydes to carboxylic acids.
Electrooxidation of biomass‐derived 5‐Hydroxymethyl furfural (5‐HMF) to produce 2,5‐diformylfuran (DFF), either direct and 2,2,6,6‐tetramethyl‐ piperidine‐1‐oxyl (TEMPO)‐mediated, is investigated in various organic and hydro‐organic media at room temperature. The direct electrooxidation mainly yields unwanted products such as formic acid and protoanemonin, near‐quantitative yields of DFF are obtained in acetonitrile and γ‐valerolactone.
To retrospectively analyze and assess the outcomes and prognostic factors in a large number of patients with atypical and malignant meningiomas.
Ten academic medical centers participating in this ...Rare Cancer Network contributed 119 cases of patients with atypical or malignant meningiomas treated with external beam radiotherapy (EBRT) after surgery or for recurrence. Eligibility criteria were histologically proven atypical or anaplastic (malignant) meningioma (World Health Organization Grade 2 and 3) treated with fractionated EBRT after initial resection or for recurrence, and age >18 years. Sex ratio (male/female) was 1.3, and mean (+/-SD) age was 57.6 +/- 12 years. Surgery was macroscopically complete (Simpson Grades 1-3) in 71% of patients; histology was atypical and malignant in 69% and 31%, respectively. Mean dose of EBRT was 54.6 +/- 5.1 Gy (range, 40-66 Gy). Median follow-up was 4.1 years.
The 5- and 10-year actuarial overall survival rates were 65% and 51%, respectively, and were significantly influenced by age >60 years (p = 0.005), Karnofsky performance status (KPS) (p = 0.01), and high mitotic rate (p = 0.047) on univariate analysis. On multivariate analysis age >60 years (p = 0.001) and high mitotic rate (p = 0.02) remained significant adverse prognostic factors. The 5- and 10-year disease-free survival rates were 58% and 48%, respectively, and were significantly influenced by KPS (p = 0.04) and high mitotic rate (p = 0.003) on univariate analysis. On multivariate analysis only high mitotic rate (p = 0.003) remained a significant prognostic factor.
In this multicenter retrospective study, age, KPS, and mitotic rate influenced outcome. Multicenter prospective studies are necessary to clarify the management and prognostic factors of such a rare disease.
Initial staging and assessment of treatment activity in metastatic prostate cancer (PCa) patients is controversial. Indications for the various available imaging modalities are not well-established ...due to rapid advancements in imaging and treatment.
We conducted a critical literature review of the main imaging abnormalities that suggest a diagnosis of metastasis in localized and locally advanced PCa or in cases of biological relapse. We also assessed the role of the various imaging modalities available in routine clinical practice for the detection of metastases and response to treatment in metastatic PCa patients.
In published clinical trials, the most commonly used imaging modalities for the detection and evaluation of therapeutic response are bone scan, abdominopelvic computed tomography (CT), and pelvic and bone magnetic resonance imaging (MRI). For the detection and follow-up of metastases during treatment, modern imaging techniques i.e., choline-positron emission tomography (PET), fluciclovine-PET, or Prostate-specific membrane antigen (PSMA)-PET provide better sensitivity and specificity. This is particularly the case of fluciclovine-PET and PSMA-PET in cases of biochemical recurrence with low values of prostate specific antigen.
In routine clinical practice, conventional imaging still have a role, and communication between imagers and clinicians should be encouraged. Present and future clinical trials should use modern imaging methods to clarify their usage.
Given that postprostatectomy recurrence of prostate cancer occurs in 10-40% of patients, the best use of immediate postoperative radiotherapy (RT) in high-risk patients and salvage RT for biochemical ...recurrence remains a topic of debate. We assessed the levels of evidence (in terms of efficacy, prognostic factors, and toxicity) for the following treatment strategies: immediate postoperative RT alone, salvage RT alone, and the addition of androgen deprivation therapy to the two RT strategies.
A systematic literature search for controlled randomized trials, noncontrolled trials, and retrospective studies between 1990 and 2008 was performed on PubMed, CancerLit, and MEDLINE. Only relevant articles that had appeared in peer-reviewed journals were selected. We report on the levels of evidence (according to the National Cancer Institute guidelines) supporting the various treatment strategies.
Immediate postoperative RT improves biochemical and clinical progression-free survival (Level of evidence, 1.ii) but has no significant effect on metastasis-free survival or overall survival. A pathologic review is of particular importance for correctly analyzing the treatment strategies. Low-grade morbidity has been significantly greater in the postoperative groups, but no severe toxicity has been observed. The influence of immediate postoperative RT on postprostatectomy continence appears to be slight; therefore, immediate postoperative RT should be considered in patients with major risk factors for local relapse (Level of evidence, 1.ii). On the basis of extensive retrospective data, salvage RT is effective in biochemical relapse after prostatectomy; some patients with few adverse prognostic factors might also benefit from salvage RT (Level of evidence, 3.ii). The addition of androgen deprivation therapy to immediate postoperative or salvage RT has only been supported by weak, retrospective data (Level of evidence, 3.ii).
Prospective randomized trials are needed to compare immediate postoperative RT with salvage RT and to assess the value of androgen deprivation therapy in this setting.
Currently, there is no standard option for local salvage treatment for local prostate cancer recurrence after radiotherapy. Our objective was to investigate the feasibility and efficiency of Robotic ...Stereotactic Body Radiation Therapy (SBRT) in this clinical setting.
We retrospectively reviewed patients who were treated at our institution with SBRT for local prostate cancer recurrence after External Beam Radiation Therapy (EBRT) or brachytherapy. Multidisciplinary staff approved the treatment, and recurrence was biopsy-proven when feasible. A dose of 36 Gy was prescribed in six fractions. Treatment was delivered every other day.
Between August 2011 and February 2014, 23 patients were treated with SBRT for intra-prostate cancer recurrence with a median follow up of 22 months (6 to 40). Twenty patients had biopsy-proven recurrence. For 19 patients, EBRT was the initial treatment and in four patients, brachytherapy was the initial treatment; the median relapse-time from initial treatment was 65 months (28 to 150). At relapse, 10 patients had an extra-capsular extension. Fourteen patients were treated with androgen deprivation that could be stopped after a median of 1 month after SBRT (range 0-24). A PSA decrease occurred in 82.6% of the patients after SBRT. The 2-year disease-free survival and overall survival rates were 54 and 100%, respectively. Disease progression was observed for nine patients (39.1%) (five local, three metastatic and one nodal progression) after a median of 20 months (7-40 months). The median nadir PSA was 0.35 ng/ml and was achieved after a median of 8 months (1 to 30) after treatment. We observed no grade 4 or 5 toxicity. Two patients presented with grade 3 toxicities (two Cystitis and one neuralgia). Other toxicities included urinary toxicities (five grade 2 and nine grade 1) and rectal toxicities (two grade 2 and two grade 1).
SBRT for local prostate cancer recurrence seems feasible and well tolerated with a short follow up. Prospective evaluation is needed.
Small cell carcinomas of the bladder (SCCB) account for fewer than 1% of all urinary bladder tumors. There is no consensus regarding the optimal treatment for SCCB.
Fifteen academic Rare Cancer ...Network medical centers contributed SCCB cases. The eligibility criteria were as follows: pure or mixed SCC; local, locoregional, and metastatic stages; and age ≥18 years. The overall survival (OS) and disease-free survival (DFS) were calculated from the date of diagnosis according to the Kaplan-Meier method. The log-rank and Wilcoxon tests were used to analyze survival as functions of clinical and therapeutic factors.
The study included 107 patients (mean ±standard deviation, SD age, 69.6 ±10.6 years; mean follow-up time, 4.4 years) with primary bladder SCC, with 66% of these patients having pure SCC. Seventy-two percent and 12% of the patients presented with T2-4N0M0 and T2-4N1-3M0 stages, respectively, and 16% presented with synchronous metastases. The most frequent curative treatments were radical surgery and chemotherapy, sequential chemotherapy and radiation therapy, and radical surgery alone. The median (interquartile range, IQR) OS and DFS times were 12.9 months (IQR, 7-32 months) and 9 months (IQR, 5-23 months), respectively. The metastatic, T2-4N0M0, and T2-4N1-3M0 groups differed significantly (P=.001) in terms of median OS and DFS. In a multivariate analysis, impaired creatinine clearance (OS and DFS), clinical stage (OS and DFS), a Karnofsky performance status <80 (OS), and pure SCC histology (OS) were independent and significant adverse prognostic factors. In the patients with nonmetastatic disease, the type of treatment (ie radical surgery with or without adjuvant chemotherapy vs conservative treatment) did not significantly influence OS or DFS (P=.7).
The prognosis for SCCB remains poor. The finding that radical cystectomy did not influence DFS or OS in the patients with nonmetastatic disease suggests that conservative treatment is appropriate in this situation.
PDF
