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We tested five chemically and metabolically stable prostaglandin (PG) receptor agonists in a mouse model of dexamethasone-induced ocular hypertension (OHT). Whilst all compounds significantly (p < 0.05, ANOVA) lowered intraocular pressure (IOP) after twice-daily bilateral topical ocular dosing (5 µg/dose) over three weeks, the time course and magnitude of the responses varied. The onset of action of NS-304 (IP-PG receptor agonist) and rivenprost (EP4-PG receptor agonist) was slower than that of misoprostol (mixed EP2/EP3/EP4-PG receptor agonist), PF-04217329 (EP2-PG receptor agonist), and butaprost (EP2-PG receptor agonist). The rank order of IOP-lowering efficacies aligned with the onset of actions of these compounds. Peak IOP reductions relative to vehicle controls were as follows: misoprostol (74.52%) = PF-04217329 (74.32%) > butaprost (65.2%) > rivenprost (58.4%) > NS-304 (55.3%). A literature survey indicated that few previously evaluated compounds (e.g., latanoprost, timolol, pilocarpine, brimonidine, dorzolamide, cromakalim analog (CKLP1), losartan, tissue plasminogen activator, trans-resveratrol, sodium 4-phenyl acetic acid, etc.) in various animal models of steroid-induced OHT were able to match the effectiveness of misoprostol, PF-04217329 or butaprost. Since a common feature of the latter compounds is their relatively high affinity and potency at the EP2-PG receptor sub-type, which activates the production of intracellular cAMP in target cells, our studies suggest that drugs selective for the EP2-PG receptor may be suited to treat corticosteroid-induced OHT.

The extraction of butter from cocoa seeds involves various processing steps that weaken the lipid-storing cell walls of cocoa cotyledons. Roasting is particularly critical, making cocoa nibs porous and brittle. In this study, the degree of disruption of the microstructure of cocoa nibs, and the quality and aroma profile of cocoa butter, were evaluated using two roasting techniques, forced convective oven, and fluidized bed. Fluidized bed roasting, recognized for its energy efficiency and low-carbon footprint, was 12 times faster than oven roasting. This technique allowed a rapid release of steam when parenchyma cell walls were still in a glassy state, while oven roasting caused gradual physical modification allowing the cell wall to become more elastic. Consequently, small pores expanded and coalesced to produce larger pores. X-ray tomographic analysis showed a total porosity in unroasted cocoa nibs of 8.5 ± 2.0% (vol/vol), which was doubled upon oven roasting and triplicated upon fluidized bed roasting. The higher porosity in fluidized-bed-roasted nibs was reflected in the lowest densities and highest cocoa butter yield. Cocoa butter obtained from fluidized-bed roasted cocoa showed a higher presence of pyrazines and 3-methylbutanal, and a lower concentration of hydroperoxides, thus enhancing the chocolate flavor and quality. In this paper, we proved that the pore structure of cocoa nibs is a key quality descriptor of roasting processing, and we concluded by quality considerations that fluidized bed roasting technique should be preferred for cocoa nibs roasting over conventional roasting.

[ES] La presente tesis doctoral aborda el desarrollo de nuevos procesos catalíticos centrados en la valorización del glicerol, subproducto principal en la síntesis de biodiesel. El objetivo principal del trabajo consiste en utilizarlo como fuente de carbono para la producción de heterociclos nitrogenados de interés industrial, en concreto, para la producción de 2-metilpiperazina y 2-metilpirazina. Debido a la baja reactividad del glicerol y las drásticas condiciones de reacción que serían necesarias para llevar a cabo las transformaciones a estos heterociclos, se ha planteado como paso previo el estudio de la optimización y el entendimiento del proceso de deshidratación selectiva de glicerol a hidroxiacetona (o acetol). A través de la obtención de este compuesto intermedio, se han podido desarrollar procesos de producción de los heterociclos nitrogenados eficientes y selectivos, en condiciones de reacción moderadas. A este respecto, los precursores de hidrotalcitas del tipo Cu-Mg-Al dan lugar a una familia de materiales basados en óxidos mixtos Cu-Mg-Al capaces de llevar a cabo la deshidratación selectiva de glicerol a acetol en continuo con rendimientos del ¿40%. Además, estos catalizadores son estables durante más de 8 horas, mostrando también excelente capacidad de regeneración y reusabilidad. Del mismo modo, la combinación de centros ácido-base y redox exhibida por estos materiales ha permitido, a través de la combinación de estudios catalíticos y de caracterización, avanzar en el estado del arte en lo que respecta a la comprensión de esta reacción de deshidratación catalítica de glicerol. De esta forma, se ha podido comprobar el papel fundamental de las especies de Cu y, en concreto de las especies Cu(I) presentes en los catalizadores, en la generación de gliceraldehido como intermedio clave para la producción de acetol. Del mismo modo, los centros ácidos del catalizador facilitan la primera adsorción del glicerol, acelerando así la reacción. No obstante, la ne, [CA] La present tesi doctoral aborda el desenvolupament de nous processos catalítics centrats en la valorització del glicerol, subproducte principal en la síntesi de biodièsel, utilitzant-lo com a font de carboni per a la producció d'heterocicles nitrogenats d'interès industrial. En concret, per a la producció de 2-metilpiperazina i 2-metilpirazina. A causa de la baixa reactivitat del glicerol i les dràstiques condicions de reacció que serien necessàries per a dur a terme les transformacions a aquests heterocicles, s'ha plantejat com a pas previ un estudi detallat escometent l'optimització i l'enteniment del procés de deshidratació selectiva de glicerol a hidroxiacetona (o acetol). A través de l'obtenció d'aquest compost intermedi, s'han desenvolupat processos de producció dels heterocicles nitrogenats eficients i selectius, en condicions de reacció moderades. Referent a això, els precursors hidrotalcítics Cu-Mg-Al donen com a resultat una família de materials basats en òxids mixtos Cu-Mg-Al capaços de dur a terme la deshidratació selectiva de glicerol a acetol en continu amb rendiments del 40%. Així mateix, aquests catalitzadors són estables durant més de 8 hores, mostrant a més una excel·lent regenerabilitat i reusabilitat. De la mateixa manera, la combinació de centres àcid-base i redox exhibida per aquests materials ha permès, a través de la combinació d'estudis catalítics i de caracterització, avançar significativament en l'estat de l'art pel que fa a la comprensió d'aquesta reacció catalítica. D'aquesta manera, s'ha pogut comprovar el paper fonamental del Cu i, en concret del Cu(I), en la generació de gliceraldehid com a intermedi de reacció clau. Per altra banda, els centres àcids del catalitzador faciliten la primera adsorció del reactiu, accelerant així la reacció. No obstant això, la necessitat d'aconseguir productivitats de acetol més elevades per a assegurar l'èxit de l'estratègia global va motivar l'ús, en aquest procés de deshidratació selectiva de gli, [EN] This doctoral thesis addresses the development of new catalytic processes centered on glycerol valorization, which is the main by-product of biodiesel synthesis. In this sense, the main aim focused on using it as a carbon source to generate nitrogen heterocycles of industrial interest, specifically, to produce 2-methylpiperazine and 2-methylpyrazine. Due to the low reactivity of glycerol and the severe reaction conditions necessary to carry out the transformations towards these N-heterocycles, previous detailed research to optimize and understand the selective dehydration process of glycerol to hydroxyacetone (or acetol) was undertaken. Through obtaining this intermediate compound, it has been possible to develop efficient and selective nitrogen heterocycles production processes, under moderate reaction conditions. In this regard, Cu-Mg-Al hydrotalcite precursors give rise to a family of materials based on Cu-Mg-Al mixed oxides capable of carrying out the selective dehydration of glycerol to acetol continuously with yields of 40%. In addition, these catalysts are stable for more than 8 hours under operational conditions, showing excellent regeneration capacity and reusability. In the same way, through the combination of catalytic and characterization studies, the interesting mix of acid-base and redox centers exhibited by these materials has allowed for advancing significantly in the state of the art regarding understanding this glycerol catalytic dehydration reaction. Hence, it has been possible to verify the fundamental role of Cu species and, specifically, Cu(I) species present in the catalysts, in the generation of glyceraldehyde as a critical reaction intermediate for acetol production. Similarly, the acid centers of the catalyst facilitate the first adsorption of glycerol, thus accelerating the reaction. However, the need to achieve higher acetol productivities from glycerol to stand a chance to succeed in the overall strategy motivated the development an

[ES] La presente tesis doctoral aborda el desarrollo de nuevos procesos catalíticos centrados en la valorización del glicerol, subproducto principal en la síntesis de biodiesel. El objetivo principal del trabajo consiste en utilizarlo como fuente de carbono para la producción de heterociclos nitrogenados de interés industrial, en concreto, para la producción de 2-metilpiperazina y 2-metilpirazina. Debido a la baja reactividad del glicerol y las drásticas condiciones de reacción que serían necesarias para llevar a cabo las transformaciones a estos heterociclos, se ha planteado como paso previo el estudio de la optimización y el entendimiento del proceso de deshidratación selectiva de glicerol a hidroxiacetona (o acetol). A través de la obtención de este compuesto intermedio, se han podido desarrollar procesos de producción de los heterociclos nitrogenados eficientes y selectivos, en condiciones de reacción moderadas. A este respecto, los precursores de hidrotalcitas del tipo Cu-Mg-Al dan lugar a una familia de materiales basados en óxidos mixtos Cu-Mg-Al capaces de llevar a cabo la deshidratación selectiva de glicerol a acetol en continuo con rendimientos del ¿40%. Además, estos catalizadores son estables durante más de 8 horas, mostrando también excelente capacidad de regeneración y reusabilidad. Del mismo modo, la combinación de centros ácido-base y redox exhibida por estos materiales ha permitido, a través de la combinación de estudios catalíticos y de caracterización, avanzar en el estado del arte en lo que respecta a la comprensión de esta reacción de deshidratación catalítica de glicerol. De esta forma, se ha podido comprobar el papel fundamental de las especies de Cu y, en concreto de las especies Cu(I) presentes en los catalizadores, en la generación de gliceraldehido como intermedio clave para la producción de acetol. Del mismo modo, los centros ácidos del catalizador facilitan la primera adsorción del glicerol, acelerando así la reacción. No obstante, la ne, [CA] La present tesi doctoral aborda el desenvolupament de nous processos catalítics centrats en la valorització del glicerol, subproducte principal en la síntesi de biodièsel, utilitzant-lo com a font de carboni per a la producció d'heterocicles nitrogenats d'interès industrial. En concret, per a la producció de 2-metilpiperazina i 2-metilpirazina. A causa de la baixa reactivitat del glicerol i les dràstiques condicions de reacció que serien necessàries per a dur a terme les transformacions a aquests heterocicles, s'ha plantejat com a pas previ un estudi detallat escometent l'optimització i l'enteniment del procés de deshidratació selectiva de glicerol a hidroxiacetona (o acetol). A través de l'obtenció d'aquest compost intermedi, s'han desenvolupat processos de producció dels heterocicles nitrogenats eficients i selectius, en condicions de reacció moderades. Referent a això, els precursors hidrotalcítics Cu-Mg-Al donen com a resultat una família de materials basats en òxids mixtos Cu-Mg-Al capaços de dur a terme la deshidratació selectiva de glicerol a acetol en continu amb rendiments del 40%. Així mateix, aquests catalitzadors són estables durant més de 8 hores, mostrant a més una excel·lent regenerabilitat i reusabilitat. De la mateixa manera, la combinació de centres àcid-base i redox exhibida per aquests materials ha permès, a través de la combinació d'estudis catalítics i de caracterització, avançar significativament en l'estat de l'art pel que fa a la comprensió d'aquesta reacció catalítica. D'aquesta manera, s'ha pogut comprovar el paper fonamental del Cu i, en concret del Cu(I), en la generació de gliceraldehid com a intermedi de reacció clau. Per altra banda, els centres àcids del catalitzador faciliten la primera adsorció del reactiu, accelerant així la reacció. No obstant això, la necessitat d'aconseguir productivitats de acetol més elevades per a assegurar l'èxit de l'estratègia global va motivar l'ús, en aquest procés de deshidratació selectiva de gli, [EN] This doctoral thesis addresses the development of new catalytic processes centered on glycerol valorization, which is the main by-product of biodiesel synthesis. In this sense, the main aim focused on using it as a carbon source to generate nitrogen heterocycles of industrial interest, specifically, to produce 2-methylpiperazine and 2-methylpyrazine. Due to the low reactivity of glycerol and the severe reaction conditions necessary to carry out the transformations towards these N-heterocycles, previous detailed research to optimize and understand the selective dehydration process of glycerol to hydroxyacetone (or acetol) was undertaken. Through obtaining this intermediate compound, it has been possible to develop efficient and selective nitrogen heterocycles production processes, under moderate reaction conditions. In this regard, Cu-Mg-Al hydrotalcite precursors give rise to a family of materials based on Cu-Mg-Al mixed oxides capable of carrying out the selective dehydration of glycerol to acetol continuously with yields of 40%. In addition, these catalysts are stable for more than 8 hours under operational conditions, showing excellent regeneration capacity and reusability. In the same way, through the combination of catalytic and characterization studies, the interesting mix of acid-base and redox centers exhibited by these materials has allowed for advancing significantly in the state of the art regarding understanding this glycerol catalytic dehydration reaction. Hence, it has been possible to verify the fundamental role of Cu species and, specifically, Cu(I) species present in the catalysts, in the generation of glyceraldehyde as a critical reaction intermediate for acetol production. Similarly, the acid centers of the catalyst facilitate the first adsorption of glycerol, thus accelerating the reaction. However, the need to achieve higher acetol productivities from glycerol to stand a chance to succeed in the overall strategy motivated the development an

Sickle cell disease (SCD) is characterized by the production of sickle hemoglobin (HbS), which when deoxygenated, polymerizes leading to red blood cell damage and hemolytic anemia, a defining feature of SCD. Voxelotor (Oxbryta) is a small molecule inhibitor of HbS polymerization that disrupts the polymerization mechanism by binding HbS to increase HbS oxygen affinity. Voxelotor is approved in the United States for the treatment of SCD in patients greater than or equal to 12 years of age at a 1500 mg once-daily (q.d.) dose. These exposure-response analyses aimed to evaluate the relationships between voxelotor whole blood concentration and change from baseline (CFB) in clinical measures of anemia and hemolysis and between voxelotor whole blood and plasma concentrations and the incidence of selected safety end points to confirm the voxelotor mechanism of action and to support the clinical dose recommendation. In patients treated with voxelotor up to 72 weeks, CFB hemoglobin (Hb) increased linearly (p < 0.001) with increasing voxelotor concentration and percent Hb occupancy and increases in CFB Hb corresponded to improvements in measures of hemolysis. The target 1 g/dl increase in CFB Hb was achieved with 1500 mg voxelotor q.d. Significant relationships were observed between voxelotor exposures and grade greater than or equal to 1 increased alanine aminotransferase and decreased white blood cell count; however, most events were grade 1. No clinically important covariate effects on voxelotor efficacy or safety were observed. Overall, these analyses support 1500 mg q.d. as the therapeutic dose for voxelotor in adults and adolescents.

Oxbryta (voxelotor) is a small-molecule inhibitor of sickle hemoglobin (Hb) polymerization approved for patients with sickle cell disease (SCD) aged greater than or equal to 12 years at a dose of 1500 mg once daily (q.d.). Voxelotor binds preferentially to Hb, and voxelotor partitioning into red blood cells is an effective predictor of Hb occupancy. The objectives of these analyses were to develop a population pharmacokinetic (PopPK) model for voxelotor in both plasma and whole blood in adults and adolescents to support the dose selection for optimal target engagement and to identify covariates that have a significant effect on voxelotor pharmacokinetics (PK) in plasma and whole blood. An integrated plasma and whole blood PopPK model with two compartments, first-order absorption and elimination, and a site-of-action effect compartment adequately described the concentration-time profiles of voxelotor in plasma and whole blood in patients treated up to 72 weeks. Covariates with significant effects on voxelotor PK included baseline blood volume on apparent volume of the central compartment and time-varying hematocrit and dose on whole blood partitioning, indicating that clinical markers of voxelotor effect can, in turn, influence its PK. Furthermore, the model confirmed that voxelotor PK in plasma and whole blood is linear with dose and time and comparable for adults and adolescents. No clinically important covariate effects on voxelotor PK that warranted dose adjustment were identified in this analysis. Overall, the PopPK analyses contributed significantly to the voxelotor label and support 1500 mg q.d. as the therapeutic dose in adults and adolescents with SCD.

The phase 3 Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (ADMIRAL) trial demonstrated the superiority of the FLT3 inhibitor, gilteritinib, to salvage chemotherapy (SC) in patients with FLT3-mutated relapsed or refractory (R/R) AML. Baseline comutations, FLT3-internal tandem duplication (ITD) allelic ratio and length, and treatment-emergent mutations were analyzed in patients in the ADMIRAL trial. Baseline comutations were grouped according to gene subgroups (DNA methylation/hydroxymethylation, transcription, chromatin-spliceosome, receptor tyrosine kinase-Ras signaling, TP53-aneuploidy, NPM1, DNMT3A, DNMT3A/NPM1, WT-1, and IDH1/IDH2). Across all but 1 gene subgroup (TP53-aneuploidy), higher pretransplant response rates and a trend toward longer overall survival were observed with gilteritinib vs SC. Patients with DNMT3A/NPM1 comutations who received gilteritinib had the most favorable outcomes of any molecular subgroup analyzed. Survival outcomes with gilteritinib were not adversely affected by FLT3-ITD allelic ratio, FLT3-ITD length, or multiple FLT3-ITD mutations. Among patients who relapsed on gilteritinib, Ras/mitogen-activated protein kinase (MAPK) pathway and FLT3 F691L gene mutations were the most common mutational events associated with treatment resistance. However, the occurrence of Ras/MAPK pathway gene mutations at baseline did not preclude a clinical benefit from gilteritinib. Acquisition of multiple Ras/MAPK pathway gene mutations at relapse suggests a high level of pathway reactivation is needed to overcome the gilteritinib treatment effect. These findings provide insight into the R/R AML molecular profile and the impact of FLT3 inhibitors on mutational evolution associated with treatment resistance and benefit of gilteritinib across a wide spectrum of molecular and genetic subgroups in FLT3-mutated R/R AML. This trial was registered at w

PurposeProgrammed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton's tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti-PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC.Patients and methodsPatients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival.ResultsSeventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3-4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4-6.8] months in the combination arm and 1.7 (95% CI, 1.4-4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size.ConclusionsDespite lack of clinical efficacy, immune subset analyse

The phase 3 Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (ADMIRAL) trial demonstrated the superiority of the FLT3 inhibitor, gilteritinib, to salvage chemotherapy (SC) in patients with FLT3-mutated relapsed or refractory (R/R) AML. Baseline comutations, FLT3-internal tandem duplication (ITD) allelic ratio and length, and treatment-emergent mutations were analyzed in patients in the ADMIRAL trial. Baseline comutations were grouped according to gene subgroups (DNA methylation/hydroxymethylation, transcription, chromatin-spliceosome, receptor tyrosine kinase-Ras signaling, TP53-aneuploidy, NPM1, DNMT3A, DNMT3A/NPM1, WT-1, and IDH1/IDH2). Across all but 1 gene subgroup (TP53-aneuploidy), higher pretransplant response rates and a trend toward longer overall survival were observed with gilteritinib vs SC. Patients with DNMT3A/NPM1 comutations who received gilteritinib had the most favorable outcomes of any molecular subgroup analyzed. Survival outcomes with gilteritinib were not adversely affected by FLT3-ITD allelic ratio, FLT3-ITD length, or multiple FLT3-ITD mutations. Among patients who relapsed on gilteritinib, Ras/mitogen-activated protein kinase (MAPK) pathway and FLT3 F691L gene mutations were the most common mutational events associated with treatment resistance. However, the occurrence of Ras/MAPK pathway gene mutations at baseline did not preclude a clinical benefit from gilteritinib. Acquisition of multiple Ras/MAPK pathway gene mutations at relapse suggests a high level of pathway reactivation is needed to overcome the gilteritinib treatment effect. These findings provide insight into the R/R AML molecular profile and the impact of FLT3 inhibitors on mutational evolution associated with treatment resistance and benefit of gilteritinib across a wide spectrum of molecular and genetic subgroups in FLT3-mutated R/R AML. This trial was registered at w

PurposeProgrammed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton's tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti-PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC.Patients and methodsPatients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival.ResultsSeventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3-4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4-6.8] months in the combination arm and 1.7 (95% CI, 1.4-4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size.ConclusionsDespite lack of clinical efficacy, immune subset analyse

Sickle cell disease (SCD) is characterized by the production of sickle hemoglobin (HbS), which when deoxygenated, polymerizes leading to red blood cell damage and hemolytic anemia, a defining feature of SCD. Voxelotor (Oxbryta) is a small molecule inhibitor of HbS polymerization that disrupts the polymerization mechanism by binding HbS to increase HbS oxygen affinity. Voxelotor is approved in the United States for the treatment of SCD in patients greater than or equal to 12 years of age at a 1500 mg once-daily (q.d.) dose. These exposure-response analyses aimed to evaluate the relationships between voxelotor whole blood concentration and change from baseline (CFB) in clinical measures of anemia and hemolysis and between voxelotor whole blood and plasma concentrations and the incidence of selected safety end points to confirm the voxelotor mechanism of action and to support the clinical dose recommendation. In patients treated with voxelotor up to 72 weeks, CFB hemoglobin (Hb) increased linearly (p < 0.001) with increasing voxelotor concentration and percent Hb occupancy and increases in CFB Hb corresponded to improvements in measures of hemolysis. The target 1 g/dl increase in CFB Hb was achieved with 1500 mg voxelotor q.d. Significant relationships were observed between voxelotor exposures and grade greater than or equal to 1 increased alanine aminotransferase and decreased white blood cell count; however, most events were grade 1. No clinically important covariate effects on voxelotor efficacy or safety were observed. Overall, these analyses support 1500 mg q.d. as the therapeutic dose for voxelotor in adults and adolescents.

Oxbryta (voxelotor) is a small-molecule inhibitor of sickle hemoglobin (Hb) polymerization approved for patients with sickle cell disease (SCD) aged greater than or equal to 12 years at a dose of 1500 mg once daily (q.d.). Voxelotor binds preferentially to Hb, and voxelotor partitioning into red blood cells is an effective predictor of Hb occupancy. The objectives of these analyses were to develop a population pharmacokinetic (PopPK) model for voxelotor in both plasma and whole blood in adults and adolescents to support the dose selection for optimal target engagement and to identify covariates that have a significant effect on voxelotor pharmacokinetics (PK) in plasma and whole blood. An integrated plasma and whole blood PopPK model with two compartments, first-order absorption and elimination, and a site-of-action effect compartment adequately described the concentration-time profiles of voxelotor in plasma and whole blood in patients treated up to 72 weeks. Covariates with significant effects on voxelotor PK included baseline blood volume on apparent volume of the central compartment and time-varying hematocrit and dose on whole blood partitioning, indicating that clinical markers of voxelotor effect can, in turn, influence its PK. Furthermore, the model confirmed that voxelotor PK in plasma and whole blood is linear with dose and time and comparable for adults and adolescents. No clinically important covariate effects on voxelotor PK that warranted dose adjustment were identified in this analysis. Overall, the PopPK analyses contributed significantly to the voxelotor label and support 1500 mg q.d. as the therapeutic dose in adults and adolescents with SCD.

Heterocyclic ring compounds are not only ubiquitous in prime diversity of vital natural products and synthetic pharmaceuticals and thus highly important in organic synthesis. They have an extensive range of applications.  They are mainly used as veterinary products and as agrochemicals. They are also utilized as corrosion inhibitors, sanitizers, antioxidants, dye stuff and as copolymers. They are accustomed as an important source in the synthesis of bioactive organic compounds. Some natural products like antibiotics such as tetracyclines, cephalosporin, penicillin, aminoglycosides, alkaloids such as morphine, vinblastine, atropine, reserpine, tryptamine, reserpine etc. have heterocyclic constituent. Hence, synthesis of heterocyclic compounds from new procedures have been always demanding. Due to wide range of applications of heterocyclic compounds, this study is a survey of literature of last one decade, describing the methods for the heterocyclic ring formation from the oxime ether.

Patient-derived organoids (PDOs) recapitulate tumor architecture, contain cancer stem cells and have predictive value supporting personalized medicine. Here we describe a large-scale functional screen of dual-targeting bispecific antibodies (bAbs) on a heterogeneous colorectal cancer PDO biobank and paired healthy colonic mucosa samples. More than 500 therapeutic bAbs generated against Wingless-related integration site (WNT) and receptor tyrosine kinase (RTK) targets were functionally evaluated by high-content imaging to capture the complexity of PDO responses. Our drug discovery strategy resulted in the generation of MCLA-158, a bAb that specifically triggers epidermal growth factor receptor degradation in leucine-rich repeat-containing G-protein-coupled receptor 5-positive (LGR5+) cancer stem cells but shows minimal toxicity toward healthy LGR5+ colon stem cells. MCLA-158 exhibits therapeutic properties such as growth inhibition of KRAS-mutant colorectal cancers, blockade of metastasis initiation and suppression of tumor outgrowth in preclinical models for several epithelial cancer types.

The linear and nonlinear optical (NLO) properties of a series of A-shaped derivatives containing a 4,5-dicyanopyrazine acceptor unit, N,N-dimethylamino donor groups and systematically enlarged pi-conjugated linkers are investigated by means of UV/Visible and Hyper-Rayleigh scattering spectroscopies. Density functional theory calculations are also carried out to rationalize the magnitude and symmetry of the NLO responses. The results demonstrate that these compounds possess two low-lying excited electronic states close to each other in energy, which are accessible through one-photon optical transitions respectively polarized perpendicular and parallel to the two-fold molecular axis. These two states contribute additively to the first hyperpolarizability, which exhibits a dominant dipolar character. We also show that the NLO responses significantly deviate from Kleinman's index permutation symmetry., Nelineární optické vlastnosti (NLO) série derivátů 4,5-dikyanpyrazinu tvaru L nesoucích N,N-dimethylamino donorní skupinu a systematicky se prodlužující pi-konjugovaný linker byly studovány prostřednictvím UV/vis a Hyper-Rayleigh spektroskopie. Rovněž byly provedeny DFT kalkulace.

SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.

SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.

PurposeAmong Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL).MethodsPatients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed noninferiority of progression-free survival (PFS).ResultsOverall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients.ConclusionIn this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.

Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3 internal tandem duplication and D835/I836 tyrosine kinase domain (TKD) mutations. Sequencing studies in patients have uncovered less common, noncanonical (NC) mutations in FLT3 and have implicated secondary TKD mutations in FLT3 TKI resistance. We report that gilteritinib is active against FLT3 NC and TKI resistance-causing mutations in vitro. A mutagenesis screen identified FLT3 F691L, Y693C/N, and G697S as mutations that confer moderate resistance to gilteritinib in vitro. Analysis of patients treated with gilteritinib revealed that 2/9 patients with preexisting NC FLT3 mutations responded and that secondary TKD mutations are acquired in a minority (5/31) of patients treated with gilteritinib. Four of 5 patients developed F691L mutations (all treated at <200 mg). These studies suggest that gilteritinib has broad activity against FLT3 mutations and limited vulnerability to resistance-causing FLT3 TKD mutations, particularly when used at higher doses.

Background and purposeTetramethylpyrazine (TMP) was originally isolated from the traditional Chinese herb ligusticum and the fermented Japanese food natto and has since been synthesized. TMP has a long history of beneficial effects in the treatment of many cardiovascular diseases. Here we have evaluated the therapeutic effects of TMP on pulmonary hypertension (PH) in animal models and in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH).Experimental approachThree well-defined models of PH -chronic hypoxia (10% O2 )-induced PH (HPH), monocrotaline-induced PH (MCT-PH) and Sugen 5416/hypoxia-induced PH (SuHx-PH) - were used in Sprague-Dawley rats, and assessed by echocardiography, along with haemodynamic and histological techniques. Primary cultures of rat distal pulmonary arterial smooth muscle cells (PASMCs) were used to study intracellular calcium levels. Western blots and RT-qPCR assays were also used. In the clinical cohort, patients with PAH or CTEPH were recruited. The effects of TMP were evaluated in all systems.Key resultsTMP (100 mg·kg-1 ·day-1 ) prevented rats from developing experimental PH and ameliorated three models of established PH: HPH, MCT-PH and SuHx-PH. The therapeutic effects of TMP were accompanied by inhibition of intracellular calcium homeostasis in PASMCs. In a small cohort of patients with PAH or CTEPH, oral administration of TMP (100 mg, t.i.d. for 16 weeks) increased the 6-min walk distance and improved the 1-min heart rate recovery.Conclusion and implicationsOur results suggest that TMP is a novel and inexpensive medication for treatment of PH. Clinical trial is registered with www.chictr.org.cn (ChiCTR-IPR-14005379).

Bioluminescence has long been used to image biological processes in vivo. This technology features luciferase enzymes and luciferin small molecules that produce visible light. Bioluminescent photons can be detected in tissues and live organisms, enabling sensitive and noninvasive readouts on physiological function. Traditional applications have focused on tracking cells and gene expression patterns, but new probes are pushing the frontiers of what can be visualized. The past few years have also seen the merger of bioluminescence with optogenetic platforms. Luciferase-luciferin reactions can drive light-activatable proteins, ultimately triggering signal transduction and other downstream events. This review highlights these and other recent advances in bioluminescence technology, with an emphasis on tool development. We showcase how new luciferins and engineered luciferases are expanding the scope of optical imaging. We also highlight how bioluminescent systems are being leveraged not just for sensing-but also controlling-biological processes.

Tubers are important crops as well as staple foods in human nutrition. Among tubers, the potato in particular has been investigated for its health effects. However, except for its contribution to energy and effects related to resistant starch, the role of potatoes and other tubers in human health is still debated. In order to establish firm evidence for the health effects of dietary tubers and processed tuber products, it is essential to assess total intake accurately. The dietary assessment in most studies relies mainly on self-reporting and may give imprecise quantitative information on dietary intakes. Biomarkers of food intake (BFIs) are useful objective means to assess intake of specific foods or may be used as an additional measure to calibrate the measurement error in dietary reports. Here, intake biomarkers for common tubers, including potatoes and heated potato products, sweet potato, cassava, yam, and Jerusalem artichoke, are reviewed according to the biomarker of food intake reviews (BFIRev) standardized protocols for review and validation. Candidate BFIs for heated potato product include α-chaconine, α-solanine, and solanidine; less evidence is available to indicate peonidin 3-caffeoylsophoroside-5-glucoside and cyanidin 3-caffeoylsophoroside-5-glucoside as putative biomarkers having high potential specificity for purple sweet potato intake; linamarin may in addition be considered as a putative BFI for cassava. Other tubers also contain toxic glycosides or common contaminants as characteristic components but their putative use as intake biomarkers is not well documented. Alkyl pyrazines, acrylamide, and acrolein are formed during cooking of heated potato products while these have not yet been investigated for other tubers; these markers may not be specific only to heated potato but measurements of these compounds in blood or urine may be combined with more specific markers of the heated products, e.g., with glycoalkaloids to assess heated potato products

Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9-97.3%). Duration of PR was 125-401 days; median SD duration was 297 days (min-max, 50-1519 days). Median progression-free survival was 19.5 months (95% CI 10.4-28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.

[ES] Los recursos fósiles se han empleado durante años para producir energía y productos químicos. Sin embargo, las múltiples desventajas de estos recursos no-renovables han llevado a investigar fuentes alternativas para la producción sostenible de energía y compuestos químicos. En este sentido, la biomasa destaca como la única fuente renovable de carbono orgánico para producir energía, combustibles (o biocombustibles) y productos químicos. En relación al biodiesel, uno de estos biocombustibles, el coste económico de su producción a partir de biomasa es relativamente elevado, debido principalmente a la generación de subproductos durante el proceso, siendo el glicerol el subproducto más abundante. Éste último puede emplearse para la síntesis de productos químicos de mayor valor añadido, como pirazinas. Las pirazinas y alquilpirazinas son compuestos ampliamente utilizados en la síntesis de fragancias y agroquímicos, y como moléculas de partida para la producción de medicamentos. En los últimos años, la síntesis de pirazinas a partir de glicerol ha ganado mayor interés, convirtiéndose en una forma rentable de valorar este subproducto y disminuir el costo general de la producción de biodiesel. En este proyecto, se desarrolló un material catalítico para realizar la síntesis de 2-metilpirazina a partir de glicerol (o de sus derivados) en un reactor de lecho fijo y flujo continuo. El catalizador está basado en CuO soportado sobre óxidos metálicos, diferenciándose de los catalizadores basados en cromita comúnmente empleados, evitando así la toxicidad inherente a estos materiales. Las propiedades fisicoquímicas y texturales de los catalizadores fueron caracterizadas mediante distintas técnicas (i.e. XRD, ICP, TPR y adsorción de N2). Los experimentos catalíticos realizados en este trabajo resultaron en la obtención de 2-metilpirazina a partir de acetol (derivado del glicerol) y etilendiamina utilizando los catalizadores 10%CuO/Al2O3 y 10%CuO/ZrO2. El proceso alcanzó elevadas, [EN] Fossil resources have been used for years to produce energy and chemicals. Nevertheless, the multiple disadvantages of these non-renewable sources have led to investigate alternative resources for energy and chemicals production. Namely resources that are renewable and green. In this sense, biomass outstands as the only renewable source of organic carbon to produce energy, fuels (so-called bio-fuels) and chemicals. Regarding the biodiesel, one of these bio-fuels, the economic cost of its production starting from biomass is relatively high, mainly due to the by-products generation during the process, glycerol being the most abundant by-product. The latter can be used for the synthesis of more valuable chemicals, such as pyrazines. Pyrazines and alkyl-pyrazines are widely used in fragrances and agrochemicals synthesis, and as building blocks to produce drugs. Over the last years the synthesis of pyrazines out of glycerol has gained more and more interest, becoming a profitable way to valorise the glycerol obtained as a by-product in biodiesel production and to decrease the overall cost of the process. In this project, a catalytic material was developed to carry out the synthesis of 2-methylpyrazine from glycerol (or its derivatives) in a fixed bed continuous flow reactor. The catalyst is based on CuO supported onto simple metallic oxides and different from the commonly used Cr2O3-based material, this allowing avoiding toxicity issues. Physico-chemical and textural properties of the catalysts were deeply characterized by using different techniques (i.e. XRD, ICP, TPR and N2 adsorption). The catalytic experiments performed in this work resulted in the attainment of 2-methylpyrazine from acetol (a glycerol derivative) and ethylendiamine by using both 10wt%CuO/Al2O3 and 10wt%CuO/ZrO2 catalysts. The process resulted in a high diamine and acetol conversion (>90%) with an alkyl-pyrazine selectivity close to 60%.

[ES] Los recursos fósiles se han empleado durante años para producir energía y productos químicos. Sin embargo, las múltiples desventajas de estos recursos no-renovables han llevado a investigar fuentes alternativas para la producción sostenible de energía y compuestos químicos. En este sentido, la biomasa destaca como la única fuente renovable de carbono orgánico para producir energía, combustibles (o biocombustibles) y productos químicos. En relación al biodiesel, uno de estos biocombustibles, el coste económico de su producción a partir de biomasa es relativamente elevado, debido principalmente a la generación de subproductos durante el proceso, siendo el glicerol el subproducto más abundante. Éste último puede emplearse para la síntesis de productos químicos de mayor valor añadido, como pirazinas. Las pirazinas y alquilpirazinas son compuestos ampliamente utilizados en la síntesis de fragancias y agroquímicos, y como moléculas de partida para la producción de medicamentos. En los últimos años, la síntesis de pirazinas a partir de glicerol ha ganado mayor interés, convirtiéndose en una forma rentable de valorar este subproducto y disminuir el costo general de la producción de biodiesel. En este proyecto, se desarrolló un material catalítico para realizar la síntesis de 2-metilpirazina a partir de glicerol (o de sus derivados) en un reactor de lecho fijo y flujo continuo. El catalizador está basado en CuO soportado sobre óxidos metálicos, diferenciándose de los catalizadores basados en cromita comúnmente empleados, evitando así la toxicidad inherente a estos materiales. Las propiedades fisicoquímicas y texturales de los catalizadores fueron caracterizadas mediante distintas técnicas (i.e. XRD, ICP, TPR y adsorción de N2). Los experimentos catalíticos realizados en este trabajo resultaron en la obtención de 2-metilpirazina a partir de acetol (derivado del glicerol) y etilendiamina utilizando los catalizadores 10%CuO/Al2O3 y 10%CuO/ZrO2. El proceso alcanzó elevadas, [EN] Fossil resources have been used for years to produce energy and chemicals. Nevertheless, the multiple disadvantages of these non-renewable sources have led to investigate alternative resources for energy and chemicals production. Namely resources that are renewable and green. In this sense, biomass outstands as the only renewable source of organic carbon to produce energy, fuels (so-called bio-fuels) and chemicals. Regarding the biodiesel, one of these bio-fuels, the economic cost of its production starting from biomass is relatively high, mainly due to the by-products generation during the process, glycerol being the most abundant by-product. The latter can be used for the synthesis of more valuable chemicals, such as pyrazines. Pyrazines and alkyl-pyrazines are widely used in fragrances and agrochemicals synthesis, and as building blocks to produce drugs. Over the last years the synthesis of pyrazines out of glycerol has gained more and more interest, becoming a profitable way to valorise the glycerol obtained as a by-product in biodiesel production and to decrease the overall cost of the process. In this project, a catalytic material was developed to carry out the synthesis of 2-methylpyrazine from glycerol (or its derivatives) in a fixed bed continuous flow reactor. The catalyst is based on CuO supported onto simple metallic oxides and different from the commonly used Cr2O3-based material, this allowing avoiding toxicity issues. Physico-chemical and textural properties of the catalysts were deeply characterized by using different techniques (i.e. XRD, ICP, TPR and N2 adsorption). The catalytic experiments performed in this work resulted in the attainment of 2-methylpyrazine from acetol (a glycerol derivative) and ethylendiamine by using both 10wt%CuO/Al2O3 and 10wt%CuO/ZrO2 catalysts. The process resulted in a high diamine and acetol conversion (>90%) with an alkyl-pyrazine selectivity close to 60%.

[ES] Los recursos fósiles se han empleado durante años para producir energía y productos químicos. Sin embargo, las múltiples desventajas de estos recursos no-renovables han llevado a investigar fuentes alternativas para la producción sostenible de energía y compuestos químicos. En este sentido, la biomasa destaca como la única fuente renovable de carbono orgánico para producir energía, combustibles (o biocombustibles) y productos químicos. En relación al biodiesel, uno de estos biocombustibles, el coste económico de su producción a partir de biomasa es relativamente elevado, debido principalmente a la generación de subproductos durante el proceso, siendo el glicerol el subproducto más abundante. Éste último puede emplearse para la síntesis de productos químicos de mayor valor añadido, como pirazinas. Las pirazinas y alquilpirazinas son compuestos ampliamente utilizados en la síntesis de fragancias y agroquímicos, y como moléculas de partida para la producción de medicamentos. En los últimos años, la síntesis de pirazinas a partir de glicerol ha ganado mayor interés, convirtiéndose en una forma rentable de valorar este subproducto y disminuir el costo general de la producción de biodiesel. En este proyecto, se desarrolló un material catalítico para realizar la síntesis de 2-metilpirazina a partir de glicerol (o de sus derivados) en un reactor de lecho fijo y flujo continuo. El catalizador está basado en CuO soportado sobre óxidos metálicos, diferenciándose de los catalizadores basados en cromita comúnmente empleados, evitando así la toxicidad inherente a estos materiales. Las propiedades fisicoquímicas y texturales de los catalizadores fueron caracterizadas mediante distintas técnicas (i.e. XRD, ICP, TPR y adsorción de N2). Los experimentos catalíticos realizados en este trabajo resultaron en la obtención de 2-metilpirazina a partir de acetol (derivado del glicerol) y etilendiamina utilizando los catalizadores 10%CuO/Al2O3 y 10%CuO/ZrO2. El proceso alcanzó elevadas, [EN] Fossil resources have been used for years to produce energy and chemicals. Nevertheless, the multiple disadvantages of these non-renewable sources have led to investigate alternative resources for energy and chemicals production. Namely resources that are renewable and green. In this sense, biomass outstands as the only renewable source of organic carbon to produce energy, fuels (so-called bio-fuels) and chemicals. Regarding the biodiesel, one of these bio-fuels, the economic cost of its production starting from biomass is relatively high, mainly due to the by-products generation during the process, glycerol being the most abundant by-product. The latter can be used for the synthesis of more valuable chemicals, such as pyrazines. Pyrazines and alkyl-pyrazines are widely used in fragrances and agrochemicals synthesis, and as building blocks to produce drugs. Over the last years the synthesis of pyrazines out of glycerol has gained more and more interest, becoming a profitable way to valorise the glycerol obtained as a by-product in biodiesel production and to decrease the overall cost of the process. In this project, a catalytic material was developed to carry out the synthesis of 2-methylpyrazine from glycerol (or its derivatives) in a fixed bed continuous flow reactor. The catalyst is based on CuO supported onto simple metallic oxides and different from the commonly used Cr2O3-based material, this allowing avoiding toxicity issues. Physico-chemical and textural properties of the catalysts were deeply characterized by using different techniques (i.e. XRD, ICP, TPR and N2 adsorption). The catalytic experiments performed in this work resulted in the attainment of 2-methylpyrazine from acetol (a glycerol derivative) and ethylendiamine by using both 10wt%CuO/Al2O3 and 10wt%CuO/ZrO2 catalysts. The process resulted in a high diamine and acetol conversion (>90%) with an alkyl-pyrazine selectivity close to 60%.

Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9-97.3%). Duration of PR was 125-401 days; median SD duration was 297 days (min-max, 50-1519 days). Median progression-free survival was 19.5 months (95% CI 10.4-28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.

In vivo bioluminescence imaging (BLI) has become a standard, non-invasive imaging modality for following gene expression or the fate of proteins and cells in living animals. Currently, bioluminescent reporters used in laboratories are mostly derivatives of two major luciferase families: ATP-dependent insect luciferases and ATP-independent marine luciferases. Inconsistent results of experiments using different bioluminescent reporters, such as Akaluc and Antareas2, have been reported. Herein, we re-examined the inconsistency in several experimental settings and identified the factors, such as ATP dependency, stability in serum, and molecular sizes of luciferases, that contributed to the observed differences. We expect this study will make the research community aware of these factors and facilitate more accurate interpretation of BLI data by considering the nature of each bioluminescent reporter.

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. METHODS: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. RESULTS: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adv

Pyrazine is an attractive molecule that has been incorporated as a bridging ligand between two metal centres. These complexes have been shown to exhibit both magnetic and electrochemical exchange between the metal centres through the pyrazine unit. Addition of functionality onto the 2 and 5 position of pyrazine can reinforce the coordination of 3d octahedral metal ions to the pyrazine ring. The Schiff base condensation of A1 with various primary amine reactants produced three unique ligand systems. The confirmed synthesis of these ligands was verified with a variety of characterisation techniques. A single crystal structure was generated for one ligand system (L3), which revealed both imine – π stacking interactions, as well as alkane hydrogen – pyridine interactions. Several complexations were attempted with the three ligand systems synthesised. Manganese and cobalt complexes were successfully synthesised with L3, the single crystal structures generated showed cyclohelicate triangles, which were unique at the time. The electrochemical analysis of these complexes in MeCN showed similar redox processes as was seen in the electrochemical analysis of L3. Signs of possible metal-metal communication within the cyclohelicate triangles was also noticed, with oxidation (and reduction) processes present. Further analysis is necessary to verify these interpretations, including magnetic analysis. Complexations with identical metal salts and L2 could not be characterised by SCXRD Other techniques such as mass spectrometry and conductivity measurements indicated the likely formation of a polymorphic – potentially cyclohelical structure with this ligand. Complexations with L1 incorporated the inclusion of a larger collection of metal salts. Unfortunately, due to time constraints, only three complexes were suitably characterised. From the various characterisation methods used, it was deduced that all three complexes were likely simple M2L1 systems, where the coordination of the 6

Online analysis of coffee roasting was performed using ion mobility spectrometry–mass spectrometry (IMS-MS) with corona discharge ionization. This is the first time that formation of volatile organic compounds (VOCs) during coffee roasting was monitored not only in positive but also in negative ion mode, and not only with mass spectrometry, but also with ion mobility spectrometry. The temporal evolution of more than 150 VOCs was monitored during the roasting of Brazilian Coffea arabica. Mass-selective ion mobility spectrometry allowed a separation of isobaric and isomeric compounds. In positive ion mode, isomers of alkyl pyrazines were found to exhibit distinct time-intensity profiles during roasting, providing a unique insight into the complex chemistry of this important class of aroma active compounds. Negative ion mode gave access to species poorly detectable by other online methods, such as acids. In this study, the release of fatty acids during coffee roasting was investigated in detail. These increase early on in the roasting process followed by a decrease at the same time as other VOCs start to be formed.

On the basis of a pyrazine core structure, three new adenosine A2B receptor ligands (7a – 7c) were synthesized containing a 2-fluoropyridine moiety suitable for 18F-labeling. Compound 7a was docked into a homology model of the A2B receptor based on X-ray structures of the related A2A receptor, and its interactions with the adenosine binding site were rationalized. Binding affinity data were determined at the four human adenosine receptor subtypes. Despite a rather low selectivity regarding the A1 receptor, 7a was radiolabeled as the most suitable candidate (Ki(A2B) = 4.24 nM) in order to perform in vivo studies with the aim to estimate fundamental pharmacokinetic characteristics of the compound class. Organ distribution studies and a single PET study demonstrated brain uptake of [18F]7a with a standardized uptake value (SUV) of ≈1 at 5 min post injection followed by a fast wash out. Metabolism studies of [18F]7a in mice revealed the formation of a blood-brain barrier penetrable radiometabolite, which could be structurally identified. The results of this study provide an important basis for the design of new derivatives with improved binding properties and metabolic stability in vivo.

On the basis of a pyrazine core structure, three new adenosine A2B receptor ligands (7a – 7c) were synthesized containing a 2-fluoropyridine moiety suitable for 18F-labeling. Compound 7a was docked into a homology model of the A2B receptor based on X-ray structures of the related A2A receptor, and its interactions with the adenosine binding site were rationalized. Binding affinity data were determined at the four human adenosine receptor subtypes. Despite a rather low selectivity regarding the A1 receptor, 7a was radiolabeled as the most suitable candidate (Ki(A2B) = 4.24 nM) in order to perform in vivo studies with the aim to estimate fundamental pharmacokinetic characteristics of the compound class. Organ distribution studies and a single PET study demonstrated brain uptake of [18F]7a with a standardized uptake value (SUV) of ≈1 at 5 min post injection followed by a fast wash out. Metabolism studies of [18F]7a in mice revealed the formation of a blood-brain barrier penetrable radiometabolite, which could be structurally identified. The results of this study provide an important basis for the design of new derivatives with improved binding properties and metabolic stability in vivo.

Online analysis of coffee roasting was performed using ion mobility spectrometry–mass spectrometry (IMS-MS) with corona discharge ionization. This is the first time that formation of volatile organic compounds (VOCs) during coffee roasting was monitored not only in positive but also in negative ion mode, and not only with mass spectrometry, but also with ion mobility spectrometry. The temporal evolution of more than 150 VOCs was monitored during the roasting of Brazilian Coffea arabica. Mass-selective ion mobility spectrometry allowed a separation of isobaric and isomeric compounds. In positive ion mode, isomers of alkyl pyrazines were found to exhibit distinct time-intensity profiles during roasting, providing a unique insight into the complex chemistry of this important class of aroma active compounds. Negative ion mode gave access to species poorly detectable by other online methods, such as acids. In this study, the release of fatty acids during coffee roasting was investigated in detail. These increase early on in the roasting process followed by a decrease at the same time as other VOCs start to be formed.

BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.go

The gut microbiota modulate host biology in numerous ways, but little is known about the molecular mediators of these interactions. Previously, we found a widely distributed family of nonribosomal peptide synthetase gene clusters in gut bacteria. Here, by expressing a subset of these clusters in Escherichia coli or Bacillus subtilis, we show that they encode pyrazinones and dihydropyrazinones. At least one of the 47 clusters is present in 88% of the National Institutes of Health Human Microbiome Project (NIH HMP) stool samples, and they are transcribed under conditions of host colonization. We present evidence that the active form of these molecules is the initially released peptide aldehyde, which bears potent protease inhibitory activity and selectively targets a subset of cathepsins in human cell proteomes. Our findings show that an approach combining bioinformatics, synthetic biology, and heterologous gene cluster expression can rapidly expand our knowledge of the metabolic potential of the microbiota while avoiding the challenges of cultivating fastidious commensals.

This review highlights the recent advances in the field of the synthesis of diazatriphenylenes and their structural analogues, such as phenanthrenes, fused with the thiophene ring, and naphthalenes, condensed with two thiophene rings. Also applications of these compounds are considered. © ARKAT USA, Inc.

BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.go

The gut microbiota modulate host biology in numerous ways, but little is known about the molecular mediators of these interactions. Previously, we found a widely distributed family of nonribosomal peptide synthetase gene clusters in gut bacteria. Here, by expressing a subset of these clusters in Escherichia coli or Bacillus subtilis, we show that they encode pyrazinones and dihydropyrazinones. At least one of the 47 clusters is present in 88% of the National Institutes of Health Human Microbiome Project (NIH HMP) stool samples, and they are transcribed under conditions of host colonization. We present evidence that the active form of these molecules is the initially released peptide aldehyde, which bears potent protease inhibitory activity and selectively targets a subset of cathepsins in human cell proteomes. Our findings show that an approach combining bioinformatics, synthetic biology, and heterologous gene cluster expression can rapidly expand our knowledge of the metabolic potential of the microbiota while avoiding the challenges of cultivating fastidious commensals.

IntroductionFirst-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non-small-cell lung cancer with EGFR-activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes.Patients and methodsWe performed a randomized, double-blind, placebo-controlled phase II study of linsitinib, a dual IGF-1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR-mutation positive, advanced non-small-cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival.ResultsAfter randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression-free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results.ConclusionAdding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer.

Ewing sarcoma (EWS) is an aggressive bone malignancy that mainly affects children and young adults. The mechanisms by which EWS (EWSR1) fusion genes drive the disease are not fully understood. CRM1 (XPO1) traffics proteins from the nucleus, including tumor suppressors and growth factors, and is overexpressed in many cancers. A small-molecule inhibitor of CRM1, KPT-330, has shown therapeutic promise, but has yet to be investigated in the context of EWS. In this study, we demonstrate that CRM1 is also highly expressed in EWS. shRNA-mediated or pharmacologic inhibition of CRM1 in EWS cells dramatically decreased cell growth while inducing apoptosis, cell-cycle arrest, and protein expression alterations to several cancer-related factors. Interestingly, silencing of CRM1 markedly reduced EWS-FLI1 fusion protein expression at the posttranscriptional level and upregulated the expression of the well-established EWS-FLI1 target gene, insulin-like growth factor binding protein 3 (IGFBP3), which inhibits IGF-1. Accordingly, KPT-330 treatment attenuated IGF-1-induced activation of the IGF-1R/AKT pathway. Furthermore, knockdown of IGFBP3 increased cell growth and rescued the inhibitory effects on IGF-1 signaling triggered by CRM1 inhibition. Finally, treatment of EWS cells with a combination of KPT-330 and the IGF-1R inhibitor, linsitinib, synergistically decreased cell proliferation both in vitro and in vivo Taken together, these findings provide a strong rationale for investigating the efficacy of combinatorial inhibition of CRM1 and IGF-1R for the treatment of EWS. Cancer Res; 76(9); 2687-97. ©2016 AACR.

Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer.

Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer.

BackgroundIrreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors.MethodsIn this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion.ResultsThe median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred.ConclusionsIn this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 dele

Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations.

Ewing sarcoma (EWS) is an aggressive bone malignancy that mainly affects children and young adults. The mechanisms by which EWS (EWSR1) fusion genes drive the disease are not fully understood. CRM1 (XPO1) traffics proteins from the nucleus, including tumor suppressors and growth factors, and is overexpressed in many cancers. A small-molecule inhibitor of CRM1, KPT-330, has shown therapeutic promise, but has yet to be investigated in the context of EWS. In this study, we demonstrate that CRM1 is also highly expressed in EWS. shRNA-mediated or pharmacologic inhibition of CRM1 in EWS cells dramatically decreased cell growth while inducing apoptosis, cell-cycle arrest, and protein expression alterations to several cancer-related factors. Interestingly, silencing of CRM1 markedly reduced EWS-FLI1 fusion protein expression at the posttranscriptional level and upregulated the expression of the well-established EWS-FLI1 target gene, insulin-like growth factor binding protein 3 (IGFBP3), which inhibits IGF-1. Accordingly, KPT-330 treatment attenuated IGF-1-induced activation of the IGF-1R/AKT pathway. Furthermore, knockdown of IGFBP3 increased cell growth and rescued the inhibitory effects on IGF-1 signaling triggered by CRM1 inhibition. Finally, treatment of EWS cells with a combination of KPT-330 and the IGF-1R inhibitor, linsitinib, synergistically decreased cell proliferation both in vitro and in vivo Taken together, these findings provide a strong rationale for investigating the efficacy of combinatorial inhibition of CRM1 and IGF-1R for the treatment of EWS. Cancer Res; 76(9); 2687-97. ©2016 AACR.

Condensation of ortho-phenylenediamine derivatives with ortho-quinone moieties at edge planes of graphitic carbon generates graphite-conjugated pyrazines (GCPs) that are active for oxygen reduction electrocatalysis in alkaline aqueous electrolyte. Catalytic rates of oxygen reduction are positively correlated with the electrophilicity of the active site pyrazine unit and can be tuned by over 70-fold by appending electron-withdrawing substituents to the phenylenediamine precursors. Discrete molecular analogs containing pyrazine moieties display no activity above background under identical conditions. This simple bottom up method for constructing molecularly well-defined active sites on ubiquitous graphitic solids enables the rational design of tunable heterogeneous catalysts.

BackgroundExtensive-stage small-cell lung cancer (SCLC) patients who progress after platinum-based chemotherapy are traditionally categorized as platinum sensitive (progression ≥ 90 days from last platinum dose) or refractory (progression < 90 days), a practice arising from seminal observations of worse survival in refractory patients. Subsequent trials accounted for platinum sensitivity, resulting in higher sample sizes and increased resource use.MethodsTo assess whether platinum-sensitivity status remains associated with outcomes, patient-level data from recent Southwest Oncology Group trials in second- and/or third-line extensive-stage SCLC were pooled. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) accounting for platinum sensitivity were calculated using unadjusted and adjusted Cox Proportional Hazard models. Recursive partitioning was performed to define prognostic risk groups.ResultsOf 329 patients, 151 were platinum sensitive and 178 refractory. HRs from unadjusted Cox PFS and OS models for refractory versus sensitive disease were 1.0 (95% confidence interval, 0.81-1.25; p = 0.98) and 1.24 (0.99-1.57; p = 0.06), respectively. Adjusted Cox models showed that only elevated serum lactate dehydrogenase (HR, 2.04; p < 0.001), males (HR, 1.36; p = 0.04), performance status of 1 (HR, 1.25; p = 0.02), and weight loss greater than or equal to 5% (1.53, p = 0.01) were independently associated with OS. Platinum-sensitivity status was not associated with PFS (HR, 1.11; p = 0.49) or OS (HR, 1.25; p = 0.14), except in a model that excluded 36 patients who received more than one prior chemotherapy regimen (HR, 1.34; p = 0.049). Prognostic groups with differential OS outcomes (high, intermediate, and poor risk) were identified.ConclusionsPlatinum-sensitivity status may no longer be strongly associated with PFS or OS in at least one multivariate model. Validation of prognostic risk groups identified here is warranted. These data have

Condensation of ortho-phenylenediamine derivatives with ortho-quinone moieties at edge planes of graphitic carbon generates graphite-conjugated pyrazines (GCPs) that are active for oxygen reduction electrocatalysis in alkaline aqueous electrolyte. Catalytic rates of oxygen reduction are positively correlated with the electrophilicity of the active site pyrazine unit and can be tuned by over 70-fold by appending electron-withdrawing substituents to the phenylenediamine precursors. Discrete molecular analogs containing pyrazine moieties display no activity above background under identical conditions. This simple bottom up method for constructing molecularly well-defined active sites on ubiquitous graphitic solids enables the rational design of tunable heterogeneous catalysts.

BackgroundExtensive-stage small-cell lung cancer (SCLC) patients who progress after platinum-based chemotherapy are traditionally categorized as platinum sensitive (progression ≥ 90 days from last platinum dose) or refractory (progression < 90 days), a practice arising from seminal observations of worse survival in refractory patients. Subsequent trials accounted for platinum sensitivity, resulting in higher sample sizes and increased resource use.MethodsTo assess whether platinum-sensitivity status remains associated with outcomes, patient-level data from recent Southwest Oncology Group trials in second- and/or third-line extensive-stage SCLC were pooled. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) accounting for platinum sensitivity were calculated using unadjusted and adjusted Cox Proportional Hazard models. Recursive partitioning was performed to define prognostic risk groups.ResultsOf 329 patients, 151 were platinum sensitive and 178 refractory. HRs from unadjusted Cox PFS and OS models for refractory versus sensitive disease were 1.0 (95% confidence interval, 0.81-1.25; p = 0.98) and 1.24 (0.99-1.57; p = 0.06), respectively. Adjusted Cox models showed that only elevated serum lactate dehydrogenase (HR, 2.04; p < 0.001), males (HR, 1.36; p = 0.04), performance status of 1 (HR, 1.25; p = 0.02), and weight loss greater than or equal to 5% (1.53, p = 0.01) were independently associated with OS. Platinum-sensitivity status was not associated with PFS (HR, 1.11; p = 0.49) or OS (HR, 1.25; p = 0.14), except in a model that excluded 36 patients who received more than one prior chemotherapy regimen (HR, 1.34; p = 0.049). Prognostic groups with differential OS outcomes (high, intermediate, and poor risk) were identified.ConclusionsPlatinum-sensitivity status may no longer be strongly associated with PFS or OS in at least one multivariate model. Validation of prognostic risk groups identified here is warranted. These data have