59 research outputs found
SynthĂšse diastĂ©rĂ©osĂ©lective et Ă©nantiosĂ©lective de dĂ©rivĂ©s cyclopropaniques 1,2,3-substituĂ©s Ă lâaide de carbĂ©noĂŻdes gem-dizinciques
Les dĂ©rivĂ©s cyclopropaniques 1,2,3-substitutĂ©s sont des composĂ©s intĂ©ressants dans de nombreux domaines de la chimie. Au cours de cet ouvrage, nous nous sommes intĂ©ressĂ©s Ă la synthĂšse, tout dâabord diastĂ©rĂ©osĂ©lective puis Ă©nantiosĂ©lective de ces composĂ©s. Nous nous sommes en particulier intĂ©ressĂ©s Ă lâutilisation de la zinciocyclopropanation pour lâobtention de ces dĂ©rivĂ©s cyclopropaniques 1,2,3-substitutĂ©s. Cette mĂ©thode consiste en lâutilisation dâun carbĂ©noĂŻde gem-dizincique pour effectuer une rĂ©action de type Simmons-Smith. Cette stratĂ©gie a lâavantage dâĂȘtre diastĂ©rĂ©osĂ©lective favorisant la formation du zinciocyclopropane dont lâatome de zinc est dans une configuration cis avec le groupement directeur quâest lâoxygĂšne allylique basique.
Lors de cette rĂ©action, lâexistence dâune rĂ©action compĂ©titive avec un rĂ©actif monozincique diminuait lâutilitĂ© de la zinciocyclopropanation. Lâissue de la rĂ©action sâest avĂ©rĂ©e dĂ©pendre fortement de la nature du carbĂ©noĂŻde utilisĂ©, de la tempĂ©rature rĂ©actionnelle et de la prĂ©sence de ZnI2 dans le milieu. LâĂ©tude par GCMS de nombreuses conditions pour la formation des diffĂ©rents carbĂ©noĂŻdes a permis dâidentifier les paramĂštres clĂ©s conduisant Ă la zinciocyclopropanation.
Ces dĂ©couvertes ont notamment permis dâĂ©tendre la rĂ©action de zinciocyclopropanation aux alcools allyliques portant un seul groupement directeur (ie. non dĂ©rivĂ© du 1,4-butĂ©nediol). Dans ces conditions, la rĂ©action sâest avĂ©rĂ©e extrĂȘmement diastĂ©rĂ©osĂ©lective favorisant la formation du zinciocyclopropane dont lâatome de zinc est dans une configuration cis avec le groupement directeur. Afin de fonctionnaliser les zinciocyclopropanes ainsi obtenus, plusieurs rĂ©actions de fonctionnalisation in situ ont Ă©tĂ© dĂ©veloppĂ©es. Chacune de ces mĂ©thodes a montrĂ© une conservation totale de la diastĂ©rĂ©osĂ©lectivitĂ© obtenue lors de la rĂ©action de zinciocyclopropanation. La versatilitĂ© de la zinciocyclopropanation a donc Ă©tĂ© dĂ©montrĂ©e.
Avec une mĂ©thode diastĂ©rĂ©osĂ©lective efficace pour la formation de zinciocyclopropanes Ă partir dâalcools allyliques ne portant quâun seul groupement directeur, il est devenu possible dâenvisager le dĂ©veloppement Ă©nantiosĂ©lectif de la rĂ©action. Lâutilisation dâun dioxaborolane Ă©nantiopur a permis la zinciocyclopropanation avec de trĂšs bons excĂšs Ă©nantiomĂšres de divers alcools allyliques chiraux. La prĂ©sence sur la mĂȘme molĂ©cule dâun lien CâZn nuclĂ©ophile est dâun atome de bore Ă©lectrophile a conduit Ă un Ă©change bore-zinc in situ, formant un cyclopropylborinate Ă©nantioenrichi. La formation de ce composĂ© bicyclique a permis dâobtenir une diastĂ©rĂ©osĂ©lectivitĂ© parfaite. De nombreux alcools allyliques ont pu ainsi ĂȘtre convertis en cyclopropylborinates. Une rĂ©action de Suzuki subsĂ©quente a permis la formation de dĂ©rivĂ©s cyclopropaniques 1,2,3-trisubstituĂ©s avec de trĂšs bons excĂšs Ă©nantiomĂšres et une excellente diastĂ©rĂ©osĂ©lectivitĂ©.
Les cyclopropylborinates obtenus Ă lâissue de la zinciocyclopropanation Ă©nantiosĂ©lective se sont avĂ©rĂ©s ĂȘtre des unitĂ©s trĂšs versatiles puisque de nombreuses mĂ©thodes ont pu ĂȘtre dĂ©veloppĂ©s pour leur fonctionnalisation.1,2,3-Substituted cyclopropanes are useful compounds present in several chemical domains. This thesis considers both the diastereo- and enantioselective synthesis of these compounds, particularly focusing on zincocyclopropanation methodologies. This method relies on a gem-diorganozinc carbenoid undergoing a Simmons-Smith type cyclopropanation. This method is advantageous due to its diastereoselectivity, forming the cyclopropylzinc adduct, where the zinc atom is cis relative to the directing group involved in the cyclopropanation.
In this reaction, the existence of a competitive pathway involving a monoorganozinc reagent dramatically decreased the efficiency of the zincocyclopropanation. Reactivity studies, and screening of numerous conditions for the formation of the carbenoids highlighted the crucial parameters favouring the zincocyclopropanation reaction. This work demonstrated that the outcome of the reaction strongly depends on the nature of the carbenoid used, the temperature, and the presence of ZnI2 in the reaction mixture.
Due to these findings, zincocyclopropanation was extended to allylic alcohols bearing one directing group only (i.e. not derived from 1,4-butenediol). As predicted, under these optimized conditions the zincocyclopropanation was highly cis-diastereoselective. To functionalize these cyclopropylzinc reagents many in situ functionalization reactions were developed. All these methods demonstrated total retention of the diastereoselectivity, and as such, the versatility of zincocyclopropanation for the synthesis of 1,2,3-susbtituted cyclopropanes is demonstrated.
With a diastereoselective method in hand for the synthesis of 1,2,3-substituted cyclopropanes, we explored the development of an enantioselective version for this reaction. The use of a dioxaborolane-based ligand allowed the zincocyclopropanation of various allylic alcohols with high enantioselectivity. The presence of a nucleophilic C-Zn bond and an electrophilic boron center within the same molecule led to an in situ zinc-boron exchange and the formation of a cyclopropylborinate. This intramolecular zinc to boron exchange is responsible of the perfect diastereoselectivity of the reaction. These cyclopropylborinates were submitted to a Suzuki cross-coupling reaction leading to various 1,2,3-substituted cyclopropane with high enantioselectivities and excellent diastereoselectivities. These cyclopropylborinates are versatile intermediates as other functionalization reactions have been developed for these compounds
Early Exanthema Upon Vemurafenib Plus Cobimetinib Is Associated With a Favorable Treatment Outcome in Metastatic Melanoma: A Retrospective Multicenter DeCOG Study
Background: The combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome.
Methods: This multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS).
Results: A total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema.
Conclusions: The development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment
Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors
Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs.
Methods: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs.
Findings: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-Îł (IFN-Îł) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs.
Conclusions: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs.
Funding: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen
Impact of radiotherapy and sequencing of systemic therapy on survival outcomes in melanoma patients with previously untreated brain metastasis: a multicenter DeCOG study on 450 patients from the prospective skin cancer registry ADOREG
BACKGROUND: Despite of various therapeutic strategies, treatment of patients with melanoma brain metastasis (MBM) still is a major challenge. This study aimed at investigating the impact of type and sequence of immune checkpoint blockade (ICB) and targeted therapy (TT), radiotherapy, and surgery on the survival outcome of patients with MBM. METHOD: We assessed data of 450 patients collected within the prospective multicenter real-world skin cancer registry ADOREG who were diagnosed with MBM before start of the first non-adjuvant systemic therapy. Study endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Of 450 MBM patients, 175 (38.9%) received CTLA-4+PD-1 ICB, 161 (35.8%) PD-1 ICB, and 114 (25.3%) BRAF+MEKâTT as first-line treatment. Additional to systemic therapy, 67.3% of the patients received radiotherapy (stereotactic radiosurgery (SRS); conventional radiotherapy (CRT)) and 24.4% had surgery of MBM. 199 patients (42.2%) received a second-line systemic therapy. Multivariate Cox regression analysis revealed the application of radiotherapy (HR for SRS: 0.213, 95%âCI 0.094 to 0.485, p1 cm: 1.977, 95%âCI 1.117 to 3.500, p=0.019), age (HR for age >65 years: 1.802, 95%âCI 1.016 to 3.197, p=0.044), and ECOG performance status (HR for ECOG â„2: HR: 2.615, 95%âCI 1.024 to 6.676, p=0.044) as independent prognostic factors of OS on first-line therapy. The type of first-line therapy (ICB vs TT) was not independently prognostic. As second-line therapy BRAF+MEK showed the best survival outcome compared with ICB and other therapies (HR for CTLA-4+PD-1 compared with BRAF+MEK: 13.964, 95%âCI 3.6 to 54.4, p<0.001; for PD-1 vs BRAF+MEK: 4.587 95%âCI 1.3 to 16.8, p=0.022 for OS). Regarding therapy sequencing, patients treated with ICB as first-line therapy and BRAF+MEK as second-line therapy showed an improved OS (HR for CTLA-4+PD-1 followed by BRAF+MEK: 0.370, 95%âCI 0.157 to 0.934, p=0.035; HR for PD-1 followed by BRAF+MEK: 0.290, 95%âCI 0.092 to 0.918, p=0.035) compared with patients starting with BRAF+MEK in first-line therapy. There was no significant survival difference when comparing first-line therapy with CTLA-4+PD-1 ICB with PD-1 ICB. CONCLUSIONS: In patients with MBM, the addition of radiotherapy resulted in a favorable OS on systemic therapy. In BRAF-mutated MBM patients, ICB as first-line therapy and BRAF+MEK as second-line therapy were associated with a significantly prolonged OS
Validation of an open source, remote webâbased eyeâtracking method (WebGazer) for research in early childhood
Measuring eye movements remotely via the participant's webcam promises to be an attractive methodological addition to in-person eye-tracking in the lab. However, there is a lack of systematic research comparing remote web-based eye-tracking with in-lab eye-tracking in young children. We report a multi-lab study that compared these two measures in an anticipatory looking task with toddlers using WebGazer.js and jsPsych. Results of our remotely tested sample of 18-27-month-old toddlers (N = 125) revealed that web-based eye-tracking successfully captured goal-based action predictions, although the proportion of the goal-directed anticipatory looking was lower compared to the in-lab sample (N = 70). As expected, attrition rate was substantially higher in the web-based (42%) than the in-lab sample (10%). Excluding trials based on visual inspection of the match of time-locked gaze coordinates and the participant's webcam video overlayed on the stimuli was an important preprocessing step to reduce noise in the data. We discuss the use of this remote web-based method in comparison with other current methodological innovations. Our study demonstrates that remote web-based eye-tracking can be a useful tool for testing toddlers, facilitating recruitment of larger and more diverse samples; a caveat to consider is the larger drop-out rate
Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.
BACKGROUND
Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs.
METHODS
In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs.
FINDINGS
When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-Îł (IFN-Îł) 1 to 2Â weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory TÂ cells (Tregs) and Ki-67+ CD8+ TÂ cells is also likely to be associated with increased risk of irAEs.
CONCLUSIONS
We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs.
FUNDING
This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen
Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG
Background Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.Methods Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIICâV) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).Results Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.Conclusions In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEKâTT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1
Bedrock geology of DFDP-2B, central Alpine Fault, New Zealand
<p>During the second phase of the Alpine Fault, Deep Fault Drilling Project (DFDP) in the Whataroa River, South Westland, New Zealand, bedrock was encountered in the DFDP-2B borehole from 238.5â893.2â
m Measured Depth (MD). Continuous sampling and meso- to microscale characterisation of whole rock cuttings established that, in sequence, the borehole sampled amphibolite facies, Torlesse Composite Terrane-derived schists, protomylonites and mylonites, terminating 200â400â
m above an Alpine Fault Principal Slip Zone (PSZ) with a maximum dip of 62°. The most diagnostic structural features of increasing PSZ proximity were the occurrence of shear bands and reduction in mean quartz grain sizes. A change in composition to greater mica:quartzâ+âfeldspar, most markedly below c. 700â
m MD, is inferred to result from either heterogeneous sampling or a change in lithology related to alteration. Major oxide variations suggest the fault-proximal Alpine Fault alteration zone, as previously defined in DFDP-1 core, was not sampled.</p
Petrophysical, Geochemical, and Hydrological Evidence for Extensive Fracture-Mediated Fluid and Heat Transport in the Alpine Fault's Hanging-Wall Damage Zone
International audienceFault rock assemblages reflect interaction between deformation, stress, temperature, fluid, and chemical regimes on distinct spatial and temporal scales at various positions in the crust. Here we interpret measurements made in the hangingâwall of the Alpine Fault during the second stage of the Deep Fault Drilling Project (DFDPâ2). We present observational evidence for extensive fracturing and high hangingâwall hydraulic conductivity (âŒ10â9 to 10â7 m/s, corresponding to permeability of âŒ10â16 to 10â14 m2) extending several hundred meters from the fault's principal slip zone. Mud losses, gas chemistry anomalies, and petrophysical data indicate that a subset of fractures intersected by the borehole are capable of transmitting fluid volumes of several cubic meters on time scales of hours. DFDPâ2 observations and other data suggest that this hydrogeologically active portion of the fault zone in the hangingâwall is several kilometers wide in the uppermost crust. This finding is consistent with numerical models of earthquake rupture and offâfault damage. We conclude that the mechanically and hydrogeologically active part of the Alpine Fault is a more dynamic and extensive feature than commonly described in models based on exhumed faults. We propose that the hydrogeologically active damage zone of the Alpine Fault and other large active faults in areas of high topographic relief can be subdivided into an inner zone in which damage is controlled principally by earthquake rupture processes and an outer zone in which damage reflects coseismic shaking, strain accumulation and release on interseismic timescales, and inherited fracturing related to exhumation
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