Background and Aim
By using an in vivo phenotypic screening assay in zebrafish, we identified Convolamine, a tropane alkaloid from Convulvus plauricalis, as a positive modulator of the sigma‐1 ...receptor (S1R). The wfs1abKO zebrafish larva, a model of Wolfram syndrome, exhibits an increased visual‐motor response due to a mutation in Wolframin, a protein involved in endoplasmic reticulum‐mitochondria communication. We previously reported that ligand activating S1R, restored the cellular and behavioral deficits in patient fibroblasts and zebrafish and mouse models.
Experimental Procedures
We screened a library of 108 repurposing and natural compounds on zebrafish motor response.
Key Results
One hit, the tropane alkaloid Convolamine, restored normal mobility in wfs1abKO larvae without affecting wfs1abWT controls. They did not bind to the S1R agonist/antagonist binding site nor dissociated S1R from BiP, an S1R activity assay in vitro, but behaved as a positive modulator by shifting the IC50 value of the reference agonist PRE‐084 to lower values. Convolamine restored learning in Wfs1∆Exon8, Dizocilpine‐treated, and Aβ25‐35‐treated mice. These effects were observed at low ~1 mg/kg doses, not shared by Convolvine, the desmethyl metabolite, and blocked by an S1R antagonist.
Conclusion and Implications
Convolamine therefore acts as an S1R positive modulator and this pharmacological action is relevant to the traditional use of Shankhpushpi in memory and cognitive protection.
An in vivo phenotypic screening in a zebrafish model of Wolfram syndrome identified Convolamine out of a 108 repurposing and natural compounds library. The alkaloid behaves as a sigma‐1 receptor positive modulator, with anti‐amnesic and neuroprotective properties.
Palynological long sequences offer a unique possibility to study the effect of pronounced climate change on vegetation dynamics over several glacial-interglacial cycles. Such long sequences are rare, ...especially outside of the Mediterranean realm. Additionally, they often lack robust chronologies, which are a precondition for comparisons across records and proxies. In this study we present a refined chronology of the Velay pollen sequence (0–423 ka) from south-central France by tuning it to the recently published Lake Ohrid pollen sequence from the southern Balkans, which itself has a vegetation-independent, numerical chronology. Furthermore, we use ordination techniques in combination with independent palaeo-temperature proxies and seasonality as explanatory variables for both sites. This allows us to infer climatic responses of interglacial vegetation over a broad ecological gradient, i.e., from a cool-temperate to a submediterranean site. Our analysis shows that temperature is a significant determinant for interglacial vegetation composition at both sites but explains slightly more variance at cool-temperate Velay compared to submediterranean Lake Ohrid, where precessional-driven moisture availability might have had a greater influence. Temperate oceanic taxa such as Abies and Taxus were most affected by comparably cool or warm interglacials at Velay, whereas at Lake Ohrid, the same accounts for Mediterranean taxa such as Quercus ilex, Q. cerris, or Ostrya/Carpinus orientalis. Responses of single taxa and vegetation groups to seasonality changes over the last five interglacials suggest that species-specific niche preferences have remained stable since 423 ka. Additionally, we suggest that unless a future climate exceeds the MIS 5e anomaly of c. +1.3 °C (if compared to the Holocene), evergreen Mediterranean taxa such as Quercus ilex will not expand into temperate biomes north of the Alps. However, even temperature rises below +1.3 °C will cause a restructuring of the current vegetation in both areas.
•We present a novel age-depth model for the palynological long sequence of Velay, Massif Central, France.•We use climate proxy data to quantify the impact of temperature on interglacial vegetation across two biomes.•Temperate oceanic vegetation was most affected interglacial intensity in the Massif Central.•Our results suggest that species-specific responses to seasonality have remained constant since 423 ka.
Oral β-alanine (βA) doses larger than 800 mg commonly result in unpleasant sensory symptoms (paresthesia). However, the association of form (pure vs. slow-release) with side-effects has not been ...fully described. The aim of this single-blinded, randomized three-arm clinical trial was to compare plasma kinetics and symptoms following βA bolus administration in solution or in slow-release tablet form. Eleven healthy adults ingested 1.6 g of a pure βA reference solution (REF), 1.6 g in slow-release βA tablets (TAB) or a placebo (PLA) after an overnight fast. During the next 6 h, urinary and plasma βA concentrations were measured and questionnaires about intensity, nature (pins and needles, itching, flushing, irritation, numbness, soreness), and spatial distribution of unusual sensations were filled in. TAB resulted in a smaller peak plasma concentration than REF (82 vs. 248 μmol L
−1
,
p
< 0.001), delayed time to peak (1.0 vs. 0.5 h,
p
< 0.01) no difference in area under the curve, reduced loss in urine (202 vs. 663 μmol,
p
< 0.0001), and improved retention (98.9 vs. 96.3%,
p
< 0.001). Symptoms described as “pins and needles” were perceived rapidly on the skin of the arms and trunk after REF (
T
max
= 15 min) and their time course nearly mimicked plasma concentrations. Maximum intensity scores were weaker with TAB (“very low”) than with REF (“low”,
p
< 0.001), while TAB and PLA did not differ with respect to side-effects. In summary, ingesting 1.6 g βA in slow-release tablets rather than pure in solution results in slower absorption kinetics, improved whole body retention and sensory side-effects that cannot be differentiated from PLA.
Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB–C or stage IV melanoma, showed significant improvements in recurrence-free ...survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results.
This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB–C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30, 2020. This study is registered with ClinicalTrials.gov, NCT02388906.
Between March 30 and Nov 30, 2015, 906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months (IQR 41·6–52·7) with nivolumab and 50·9 months (36·2–52·3) with ipilimumab; 4-year recurrence-free survival was 51·7% (95% CI 46·8–56·3) in the nivolumab group and 41·2% (36·4–45·9) in the ipilimumab group (hazard ratio HR 0·71 95% CI 0·60–0·86; p=0·0003). With 211 (100 22% of 453 patients in the nivolumab group and 111 25% of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77·9% (95% CI 73·7–81·5) with nivolumab and 76·6% (72·2–80·3) with ipilimumab (HR 0·87 95% CI 0·66–1·14; p=0·31). Late-emergent grade 3–4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneumonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported.
At a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB–C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab.
Bristol Myers Squibb and Ono Pharmaceutical.
Mutations in the cardiac desmosomal protein desmoglein-2 (DSG2) are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). We studied the explanted heart of a proband carrying the ...DSG2-N266S mutation as well as transgenic mice (Tg-NS) with cardiac overexpression of the mouse equivalent of this mutation, N271S-dsg2, with the aim of investigating the pathophysiological mechanisms involved. Transgenic mice recapitulated the clinical features of ARVC, including sudden death at young age, spontaneous ventricular arrhythmias, cardiac dysfunction, and biventricular dilatation and aneurysms. Investigation of transgenic lines with different levels of transgene expression attested to a dose-dependent dominant-negative effect of the mutation. We demonstrate for the first time that myocyte necrosis is the key initiator of myocardial injury, triggering progressive myocardial damage, including an inflammatory response and massive calcification within the myocardium, followed by injury repair with fibrous tissue replacement, and myocardial atrophy. These observations were supported by findings in the explanted heart from the patient. Insight into mechanisms initiating myocardial damage in ARVC is a prerequisite to the future development of new therapies aimed at delaying onset or progression of the disease.
In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage ...IIIB-C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings.
Patients with resected stage IIIB-C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS.
At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60-0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value.
Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome. See related commentary by Augustin and Luke, p. 3253.
Immunotherapy is becoming a standard of care for many cancers. Immune-checkpoint inhibitors (ICI) can generate immune-related adverse events. Interstitial lung disease (ILD) has been identified as a ...rare but potentially severe event.Between December 2015 and April 2016, we conducted a retrospective study in centres experienced in ICI use. We report the main features of ICI–ILD with a focus on clinical presentation, radiological patterns and therapeutic strategies.We identified 64 (3.5%) out of 1826 cancer patients with ICI–ILD. Patients mainly received programmed cell death-1 inhibitors. ILD usually occurred in males, and former or current smokers, with a median age of 59 years. We observed 65.6% grade 2/3 severity, 9.4% grade 4 severity and 9.4% fatal ILD. The median (range) time from initiation of immunotherapy to ILD was 2.3 (0.2−27.4) months. Onset tended to occur earlier in lung cancer versus melanoma: median 2.1 and 5.2 months, respectively (p=0.02). Ground-glass opacities (81.3%) were the predominant lesions, followed by consolidations (53.1%). Organising pneumonia (23.4%) and hypersensitivity pneumonitis (15.6%) were the most common patterns. Overall survival at 6 months was 58.1% (95% CI 37.7–73.8%).ICI–ILD often occurs early and displays suggestive radiological features. As there is no clearly identified risk factor, oncologists need to diagnose and adequately treat this adverse event.
Abstract Objective Despite convincing evidence regarding the risk of highway accidents due to sleepiness at the wheel, highway drivers still drive while sleepy. Sleep disorders can affect driving ...skills, but the relative impact of sleep complaints among a large population of highway drivers is still unknown. Methods Out of 37,648 questionnaires completed by frequent highway users (registered in an electronic payment system), we ran our analyses on 35,004 drivers who responded to all items. The questionnaire previously used in a telephone survey included socio-demographics, driving and sleep disorders items (Basic Nordic Sleep Questionnaire) and the Epworth Sleepiness Scale. Results Of all drivers, 16.9% complained of at least one sleep disorder, 5.2% reported obstructive sleep apnea syndrome, 9.3% insomnia, and 0.1% narcolepsy and hypersomnia; 8.9% of drivers reported experiencing at least once each month an episode of sleepiness at the wheel so severe they had to stop driving. One-third of the drivers (31.1%) reported near-miss accidents (50% being sleep-related), 2520 drivers (7.2%) reported a driving accident in the past year, and 146 (5.8%) of these driving accidents were sleep-related. The highest risk of accidents concerned patients suffering from narcolepsy and hypersomnia (odds ratio 3.16, p < .01) or multiple sleep disorders (odds ratio 1.46, p < .001). Other major risk factors were age 18–30 years (OR 1.42, p < .001) and being unmarried (OR 1.21-fold, p < .01). Conclusions In regular highway drivers, sleepiness at the wheel or sleep disorders such as hypersomnia and narcolepsy are responsible for traffic accidents independent of age, sex, marital status or socio-professional categories.
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