Concurrent Pathway Research Articles

Fundamental mechanistic insights into the catalytic reactions of Li─S redox by Co single-atom electrocatalysts via operando methods.

Lithium-sulfur batteries represent an attractive option for energy storage applications. A deeper understanding of the multistep lithium-sulfur reactions and the electrocatalytic mechanisms are required to develop advanced, high-performance batteries. We have systematically investigated the lithium-sulfur redox processes catalyzed by a cobalt single-atom electrocatalyst (Co-SAs/NC) via operando confocal Raman microscopy and x-ray absorption spectroscopy (XAS). The real-time observations, based on potentiostatic measurements, indicate that Co-SAs/NC efficiently accelerates the lithium-sulfur reduction/oxidation reactions, which display zero-order kinetics. Under galvanostatic discharge conditions, the typical stepwise mechanism of long-chain and intermediate-chain polysulfides is transformed to a concurrent pathway under electrocatalysis. In addition, operando cobalt K-edge XAS studies elucidate the potential-dependent evolution of cobalt's oxidation state and the formation of cobalt-sulfur bonds. Our work provides fundamental insights into the mechanisms of catalyzed lithium-sulfur reactions via operando methods, enabling a deeper understanding of electrocatalysis and interfacial dynamics in electrical energy storage systems.

Concurrent pathway and unexpected products in the CuAAC reaction of ethyl prop-2-ynyl methylphosphonate with aromatic azides

The CuI-mediated click reaction of aromatic azides, containing the carboxyl moiety in the ortho position to the azido group, with ethylprop-2-ynyl methylphosphonate proceeded via a concurrent pathway whereby the formation of acrylamides predominated over "classical" cycloaddition products 1,2,3-triazoles. The reaction appears to be specific toward the ortho-carboxyl-substituted aromatic azides, while aryl azides with other substituents do not give the "reduction" products, but form the expected click products: (1-aryl-1 H -1,2,3-triazol-4-yl)methyl ethyl methylphosphonates. The reaction mechanism is discussed.

Electrosynthesis of Cobalt Telluride Thin Films by Voltammetry Combined with Electrochemical Quartz Crystal Microgravimetry

Cobalt telluride (CoTe) thin films were electrodeposited for the first time using alkaline solutions containing nitrilotriacetic acid (NTA), CoCl2, and K2TeO3. NTA was employed in order to shift the reduction potential of cobalt in the negative direction and to stabilize Co2+ ions in alkaline electrolytes via the formation of Co-NTA complexes. The electrodeposition mechanism was investigated by linear sweep voltammetry (LSV) combined with electrochemical quartz crystal microgravimetry (EQCM). The formation of CoTe is proposed to occur through the reaction of Co2+ with HTe−, which is generated by the reduction of TeO32− via a 6-electron reduction pathway. A concurrent pathway consists of the stepwise reduction of TeO32− to Te by a 4-electron process, followed by the 2-electron process reduction of Te to HTe−. The electrodeposited CoTe films were characterized by a variety of physical methods including scanning electron microscopy, energy dispersive X-ray, X-ray diffraction, and X-ray photoelectron spectroscopy. An optical energy bandgap of ∼1.86 eV was obtained by diffuse reflectance spectroscopy.

SIRT1 and Estrogen Signaling Cooperation for Breast Cancer Onset and Progression.

Breast cancer remains a significant female mortality cause. It constitutes a multifactorial disease for which research on environmental factors offers little help in predicting onset or progression. The pursuit for its foundations by analyzing hormonal changes as a motive for disease development, indicates that increased exposure to estrogens associates with increased risk. A prevalent number of breast cancer cases show dependence on the increased activity of the classic nuclear estrogen receptor (ER) for cell proliferation and survival. SIRT1 is a Type III histone deacetylase which is receiving increasing attention due to its ability to perform activities over relevant non-histone proteins and transcription factors. Interestingly, concomitant SIRT1 overexpression is commonly found in ER-positive breast cancer cases. Both proteins had been shown to directly interact, in a process related to altered intracellular signaling and aberrant transcription, then promoting tumor progression. Moreover, SIRT1 activities had been also linked to estrogenic effects through interaction with the G-protein coupled membrane bound estrogen receptor (GPER). This work aims to summarize present knowledge on the interplay between SIRT1 and ER/GPER for breast cancer onset and progression. Lastly, evidences on the ability of SIRT1 to interact with TGFß signaling, a concurrent pathway significantly involved in breast cancer progression, are reported. The potential of this research field for the development of innovative strategies in the assessment of orphan breast cancer subtypes, such as triple negative breast cancer (TNBC), is discussed.

Evolution and clinical impact of genomic alterations detectable in circulating tumor DNA of 1150 advanced EGFR-mutant (mt) lung cancer patients.

9009 Background: Advanced EGFR-mt lung adenocarcinomas (LUAD) frequently harbor additional genetic alterations. The clinical significance of these concurrent alterations and how they evolve with treatment are unclear. Methods: We performed next-generation sequencing (NGS) of ~70 cancer related genes from the circulating tumor DNA (ctDNA) of 1150 consecutive advanced LUAD patients (pts) with detectable EGFR mts. The analysis included 113 samples from 81 pts for whom clinical outcome data were known. Clinical response to EGFR TKI treatment was correlated to mutational status in 12 cancer-related pathways. Results: EGFR-mt cases contained an average of 3.6 genetic alterations (range 1-18). There was enrichment for co-alterations in TP53, CDK6, CTNNB1 and SMAD4 in EGFR-mt cases compared to a control cohort of 1008 EGFR WT cases. Enrichment for the EGFR T790M mutation was found upon progression to first-line EGFR TKI treatment, as expected. Analysis of 450 T790M-mt cases showed enrichment for co-alterations in genes controlling the cell cycle (28% vs. 21%, p = 0.01), DNA repair (12% vs. 8%, p = 0.03), and WNT (16% vs. 11%, p = 0.03) signaling. The number of genetic alterations increased during progression on each line of therapy in a manner unlinked to age, gender, or tobacco exposure (mean 3.2 pre-TKI vs. 6.4 after 2nd line, p = 0.001). Upon progression to second-line treatment, analysis revealed further selection for co-alterations in TP53, CCNE1, MYC and PIK3CA and the associated pathway-level classifications. We found an increased frequency of co-alteration in cell cycle genes in EGFR TKI non-responders versus responders (33% vs. 0%, p = 0.0005). Conclusions: Within the landscape of advanced EGFR-mt LUAD, we uncover features of evolutionary selection for multiple concurrent oncogenic pathway alterations including TP53, WNT, PI3K, MYC, and cell cycle genes. This large clinical and genetic dataset prompts a re-evaluation of the prevailing paradigm of monogenic-based molecular stratification to monotherapy, and highlights an alternative model of genetic collectives as a previously underappreciated determinant of lung cancer progression and therapy resistance.

Abstract CT303: A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors

Abstract Background: Preclinical work showed improved anticancer efficacy with the combination of an mTOR and a PI3K inhibitor over either agent alone. We conducted a phase I study to determine the recommended phase II dose (RP2D) of the combination of everolimus (E), an mTOR inhibitor and buparlisib or BKM120 (B), a pan-PI3K inhibitor. Methods: Patients with advanced solid malignancies who have exhausted standard treatment options were enrolled. Main eligibility criteria include ECOG performance status 0-2, adequate end organ function and absence of glucose intolerance, uncontrolled hepatitis, anxiety or depression. Dose escalation was performed using a Bayesian Escalation with Overdose Control (EWOC) design to evaluate different doses of E (5mg or 10mg) and B (20, 40, 60 and 80 mg,) once daily continuously. Eligible patients were enrolled in cohorts of 3 patients. Pharmacokinetic (PK) assessment was conducted in cycle 1 on day 8 using peripheral blood samples collected at time 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours and prior to dosing on cycle 1 D day 15. Pharmacodynamic (PD) impact on mTOR/PI3K pathway modulation was evaluated in skin punch biopsies collected at baseline and at end of cycle 1. Results: We enrolled 35 patients: Median age 63yrs (range:40-79), 21 females (58%); 2 Latinos (6%), 7 Blacks (20%) and 26 Caucasians (74%); with cancers of the lung (8), colorectal (7), sarcomas (3), salivary gland (3), breast (3), thyroid (3), thymic (2), bladder (2), ovarian (2), head and neck (1) and PNET (1). The safety of 6 different dose combinations of E and B (5/20; 10/20; 5/40; 5/60; 10/60; 5/80) was assessed. The most frequent toxicities were: hyperglycemia, diarrhea, nausea, fatigue and AST elevation. The dose limiting toxicities observed in 6 patients were: fatigue (3), hyperglycemia (1), mucositis (1), acute renal failure (1) and urinary tract infection (1). The 5/60 combination was defined as the RP2D. The median number of cycles completed was 2 (range: 0-20). Of the 25 patients evaluable for efficacy, 8 (32%) had disease progression while 17 (68%) achieved stable disease (SD). Median duration of SD was 18 weeks (range: 2-83) and 7 patients had SD lasting ≥6 months. Steady-state PK data for both agents in 24 evaluable patients showed no evidence of drug-drug interaction, with dose-normalized maximum concentrations (Cmax) and area-under-the-curve (AUC0-∞) values for E and B in combination being comparable to single agent data. Preliminary signal of efficacy for the combination was observed in patients with thymic, breast and lung cancer. PD analysis is ongoing and will be presented at the meeting. Conclusion: The safety profile of the combination of everolimus plus buparlisib is well tolerated and the RP2D is 5mg/day and 60mg/day respectively on a continuous daily schedule. The efficacy data are encouraging and warrant further evaluation in phase II studies. Citation Format: Taofeek Kunle Owonikoko, R.Donald Harvey, Colleen Lewis, Zhengjia Chen, John S. Kauh, Meredith Renfroe, Rijalda Deovic, Gabriel L. Sica, Bradley C. Carthon, Wayne Bernard Harris, Bassel F. El-Rayes, Suresh S. Ramalingam, Fadlo R. Khuri. A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT303. doi:10.1158/1538-7445.AM2015-CT303

Abstract B120: Preclinical assessment of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC.

Abstract Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond well to first generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, attributable in 60% of cases to a secondary mutation of EGFR at T790M. In addition, patients also experience skin and GI toxicity due to wild type (WT) EGFR inhibition. CO-1686 is a novel, irreversible and orally delivered kinase inhibitor that specifically targets the most frequently observed front-line and acquired resistance mutant forms of EGFR, while exhibiting minimal activity towards WT EGFR. Selectivity of CO-1686 was demonstrated using two separate biochemical assays in which CO-1686 was at least 10-fold more selective for mutant EGFR as compared to the WT receptor. In human cancer cell lines, CO-1686 potently inhibited in vitro proliferation of cells expressing mutant EGFR, while minimally affecting proliferation of WT EGFR-dependent cells. To confirm this selectivity in vivo, CO-1686 was evaluated in WT (A431), front line (HCC827, transgenic), and second line (NCI-H1975, LUM1868, transgenic) xenograft models. CO-1686 dosed at 50 mg/kg BID exhibited a minimal reduction in tumor growth in the A431 xenograft model with no significant alterations in body weight and EGFR WT pathway signaling. Comparatively, both erlotinib (75 mg/kg QD) and afatinib (20 mg/kg QD) administration resulted in profound tumor regression, but with concurrent body weight loss and EGFR WT pathway inhibition. CO-1686, when dosed as a single agent at 50 mg/kg BID and/or 100 mg/kg QD, caused tumor regressions in the HCC827 (del19), NCI-H1975 (L858R/T790M), and patient-derived lung tumor xenograft model LUM1868 (L858R/T790M). The efficacy of CO-1686 was also examined in EGFR-L858R and EGFR-L858R-T790M genetically engineered mouse (GEM) models that develop lung adenocarcinoma upon human mutant EGFR transgene induction in the lung epithelium. In both models, CO-1686 administration (50 mg/kg BID) resulted in potent anti-tumor activity as measured by MRI and histological assessment. Following a 3-week dosing period, animals treated with CO-1686 demonstrated a complete regression of established lesions. Comparatively, in the EGFR-L858R-T790M GEM model, afatinib dosed at the maximum tolerated dose (20 mg/kg QD) resulted in limited efficacy. In summary, CO-1686 exhibits potent and significant anti-tumor activity as a single agent in xenograft models driven by the most frequently observed front-line and acquired resistance mutant forms of EGFR, while exhibiting minimal activity towards WT EGFR. These data suggest that CO-1686 may have utility in both front-line and acquired resistance EGFR-mutated NSCLC, and CO-1686 is currently being evaluated in a phase I/II clinical trial in previously treated mutant EGFR NSCLC patients (ClinicalTrials.gov identifier: NCT01526928). Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B120. Citation Format: Andrew D. Simmons, Henry J. Haringsma, Annette O. Walter, Robert Tjin Tham Sjin, Zoe Weaver, Andrew Allen, Thomas C. Harding. Preclinical assessment of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B120.

HYDROXYACETONITRILE (HOCH2CN) FORMATION IN ASTROPHYSICAL CONDITIONS. COMPETITION WITH THE AMINOMETHANOL, A GLYCINE PRECURSOR

This contribution is focused on the concurrent pathway to the Strecker synthesis of amino acids in an astrophysical-like environment. We indeed use experimental and modeling simulations to investigate the possibility to form the aminomethanol (HOCH2NH2) in concurrence with the hydroxyacetonitrile (HOCH2CN) from ices containing at 40 K formaldehyde (CH2O), ammonia (NH3), and cyanide ion (CN−). We demonstrate using infrared spectroscopy and mass spectrometry that the formation of the aminomethanol (Ea = 4.5 kJ mol−1) is competing with the hydroxyacetonitrile formation (Ea = 3.9 kJ mol−1). The ratio between aminomethanol and hydroxyacetonitrile depends on the initial ratio in the ice between ammonia and cyanide. An increase of cyanide ion provides a decrease in aminomethanol formation. Since the aminomethanol is the first step through the formation of glycine in astrophysical environments, these data are important for understanding the possibility of forming glycine in such environments. Furthermore, using a reduced kinetic model, we evaluate the astrophysical environments in which the aminomethanol and hydroxyacetonitrile can be formed and evolved without degradation. The results suggest that these two molecules could be formed in molecular clouds or protostellar disks, and subsequently incorporated inside comets or asteroids. Therefore, hydroxyacetonitrile and aminomethanol could be formed before the formation of the solar system, which suggests that hydroxyacids and amino acids, such as those detected inside meteorites, have been formed in various astrophysical environments.

Proliferation pathway aberration frequencies in BRCA1- and BRCA2-mutated ovarian cancers.

5074 Background: Large-scale genomic analyses of high-grade, advanced-stage serous ovarian cancers by The Cancer Genome Atlas (TCGA) project revealed aberrations in genes comprising key proliferation and survival pathways (RB-E2F, RAS, PI3K) in the majority of tumors. Patients with germline BRCA1/2-mutations have more favorable prognoses than non-BRCA carriers, and recent work suggests that BRCA2 carriers do better than BRCA1. We hypothesized that concurrent proliferation pathway aberrations and BRCA1/2 mutations in tumors might play a role in patient outcome. Methods: Mutation, copy number, and clinical data for 309 TCGA-profiled serous ovarian tumors were downloaded from the MSKCC cBIO web portal. Each tumor was scored as aberrant for a pathway if any gene (RB: RB1, CDKN2A, CCND1, CCND2, E2F3, CCNE1; PI3K: PIK3CA, PTEN, AKT1, AKT2; RAS: KRAS, BRAF, NF1) in that pathway was mutated, amplified, or deleted. Results: 205 of 309 tumors had an aberration in at least one of these pathways. The frequency of pathway alteration differed significantly in BRCA1 (82%, 28/34), BRCA2 (52%, 17/33) and BRCA1/2 WT (66%, 160/242) tumors (BRCA1 vs. BRCA2: Fisher’s p= 0.0096). BRCA1 tumors more frequently contained alterations in multiple pathways than BRCA2 or WT tumors (41% vs. 24% or 25%, respectively). RB-E2F pathway alteration frequency was significantly different (BRCA1: 56%, BRCA2: 18%, WT: 43%, p=0.0043), but no significant differences in PI3K and RAS pathway aberration frequencies (BRCA1%: 41, 38; BRCA2%: 36, 27; WT% 28, 27), respectively, were observed. In agreement with the previous report, BRCA2 patients had significantly better overall survival (OS) than either BRCA1 or WT patients (median OS months for BRCA1: 35.9, BRCA2 45.4, BRCA1/2 WT 27.8; p=0.001). Presence of pathway alterations was not significantly associated with OS in BRCA1, BRCA2, or WT patients in this cohort. Conclusions: These results show a negative association between BRCA2 mutations and aberrations in key proliferation and survival pathways. Beyond BRCA1 and BRCA2 genetic mutations, the elevated frequency of pathway alteration in BRCA1 vs. BRCA2 tumors highlights differences that may be important for patient prognosis as well as therapy responses.

SULT1A1 Arg213His polymorphism and susceptibility of environment-related cancers: a meta analysis of 5,915 cases and 7,900 controls

The common genetic polymorphism for SULT1A1 is Arg213His polymorphism, which may affect the sulfation process of various environmental carcinogens and thus is suggested to be related to susceptibility of several cancers. However, studies on the association between SULT1A1 Arg213His polymorphism and cancer susceptibility are inconsistent. To assess the relationship between Arg213His polymorphism and environmental-related cancers systematically, we performed a meta analysis from 20 case-control studies including 5,915 cases and 7,900 controls. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of risk, we found a significant association between SULT1A1 Arg213His polymorphism and environment-related cancers (for dominant model: OR 1.22, 95% CI 1.07-1.39, P = 0.003). When stratified by ethnicity, a significant risk was observed in Asian cases, compared with controls (for dominant model: OR 1.69, 95% CI 1.17-2.43, P = 0.005). When we chose only smokers in our analysis, we also found a significantly increased risk between Arg213His polymorphism and susceptibility of environment-related cancers for participants exposed to a smoking environment. In conclusion, SULT1A1 Arg213His polymorphism, ethnicity, smoking may modulate environment-related cancer risk. Studies on gene-gene interactions in the sequential or concurrent metabolic pathway and gene-environment interactions need to be further conducted to explore the susceptibility of cancer occurrence.

Hépatite C, Interféron α et dépression : principales hypothèses physiopathologiques

Hépatite C, Interféron α et dépression : principales hypothèses physiopathologiques

Nucleophilic coupling of alkali 2-naphthoxides with 1-bromo-2 naphthols. Ion-pairing and halogen dance in the formation of 1,1′-binaphthalene-2,2′-diols

A very pronounced effect of solvent and cation has been found in the investigated reaction, indicating that ion-pairing is indispensable in the title product formation. A simple rationale has been provided assuming self assembly of the complementary reactants driven by hydrogen bonding and ion-pairing interactions. Concomitantly, halogen exchange between the reaction partners has been demonstrated to be a concurrent pathway, resulting from the nucleophilic 2-naphthoxide attack at the bromine terminus of the Cα–Br bond in the participating 1-bromo-2-naphthol.

Role of intermolecular reactions in thermolysis of aromatic nitro compounds in supercritical aromatic solvents

Several nitroarenes were decomposed isothermally in dilute supercritical solution in benzene or toluene and in the vapor phase in the temperature range of 290-380°C in sealed glass tubes with pressures up to 100 MPa. The mechanisms of thermolysis are inferred from kinetic studies and product analysis. The intial rate-controlling step for nitrobenzene and p-nitrotoluene decompsition is probably intermolecular hydrogen abstraction to form an ArNO 2 H radical intermediate. The nature of the transition state is deduced from the activation volume (ΔV*), H/D kinetic-isotope effect, and a linear free-energy relationship between the ionization potential of the hydrogen donor and the logarithm of the decomposition rate. A concurrent pathway for o-nitrotoluene is an intramolecular reaction in which anthranil is an intermediate. Activation parameters are given and detailed mechanisms proposed

Retrosynthesis vs ketene loss in electron-ionization-induced decompositions of 1,5-benzodiocapine, 1,5-benzodiazepine, 1,5-benzodithiepine, 1,5-benzoxazepine and 1,5-benzoxathiepine

The 70 eV electron ionization mass spectrometry of the title compounds has shown the presence of two concurrent primary decomposition pathway, corresponding to the retrosynthetic process and to CH2CO loss. The yields of the two pathways can be related tothe XCO bond strengths: as the XCO bond becomes weaker, [MCH2CO]+˙ ion formation is favoured.

Nucleophilic displacement reactions at carbon, phosphorus and sulphur centres: reaction of aryl methanesulphonates with ethoxide; change in mechanism with change in leaving group

The reactions of ethoxide ion with aryl methanesulphonate esters (1a–c) in anhydrous ethanol at 25 °C have been investigated in order to determine the effect of leaving group nucleofugality on the balance between substitution and elimination pathways. The reactions of p-nitrophenyl-(1a), m-nitrophenyl-(1b) and p-trifluoromethylphenyl-(1c) methanesulphonates have been examined by means of kinetic studies, sulphene trapping experiments, and deuterium exchange experiments. It is concluded that the para-nitre-substituted ester reacts predominantly by an Elcb-type elimination mechanism via a sulphene intermediate, with nucleophilic substitution as a minor concurrent pathway. Conversely, the meta-nitro-substituted ester reacts predominantly by substitution, with elimination as a minor concurrent pathway. The evidence available indicates that the para-trifluoromethyl-substituted ester reacts solely by substitution. Thus, the mechanism of reaction changes from nucleophilic substitution to elimination–addition as leaving group nucleofugality increases.

Facile Photorearrangement of Some Crowded Azoxyarenes via Two Concurrent Pathways

Abstract Naphthalene-1-ONN-azoxybenzenes and some unsymmetrically ortho-substituted ONN- and NNO-azoxybenzenes were prepared, and their photochemical behavior in ethanol was compared. The crowded azoxyarenes tend to undergo a facile Wallach rearrangement via the known azoxy-ortho oxygen mirgation and a concurrent pathway involving ONN–NNO isomerization. The relative contribution of the two pathways was affected by substituents.