Investigation of Water Impacts on Surface Properties and Performance of Air-Electrode in Reversible Protonic Ceramic Cells.

Water, being abundant and readily accessible, gains widespread usage as proton source in many catalysis and energy conversion technologies, including applications like reversible protonic ceramic cells (R-PCCs). Revealing the influence of water on the electrode surface and reaction kinetics is critical for further improving their electrochemical performance. Herein, a hydrophilic air-electrode PrBa0.875Cs0.125Co2O5+δ is developed for R-PCC, which demonstrates a remarkable peak power density of 1058 mW cm-2 in fuel cell mode and a current density of 1354 mA cm-2 under 1.3 V in electrolyzing steam at 650 °C. For the first time on R-PCC, surface protons' behavior in response to external voltages is captured using in situ FTIR characterizations. Further, it is shown that contrary to the bulk proton uptake process that is thought to follow hydrogenation reactions and lead to cation reductions. The air-electrode presents enriched surface protons occurring through oxidizing surface cations, as confirmed by depth-profiling XPS results. H/D isotope exchange experiments and subsequent electrochemical characterization analyses reveal that the presence of protons enhances surface reactions. This study fills the knowledge gap between water-containing atmospheres and electrochemical performance by providing insights into the surface properties of the material. These new findings provide guidance for future electrode design and optimization.

Fe-Doped Ceria-Based Ceramic Cathode for High-Efficiency CO2 Electrolysis in Solid Oxide Electrolysis Cell.

In the quest for sustainable energy solutions, solid oxide electrolysis cell (SOEC) emerges as a key technology for converting CO2 into fuels and valuable chemicals. This work focuses on pure ceramic Fex Sm0.2 Ce0.8 O2- δ (xFe-SDC) as the fuel electrodes, and Sr-free ceria-based ceramic electrodes can be successfully constructed for x ≤ 0.05. The incorporation of Fe into the ceria lattice increases the oxygen vacancy concentration and promotes the formation of catalytic sites crucial for the CO2 reduction reaction (CO2 RR). Density functional theory calculations indicate that Fe enhances electrochemical performance by decreasing the CO2 RR energy barrier and facilitating oxygen ion diffusion. At 800 °C and 1.5 V, single cells with 0.05Fe-SDC cathodes manifest attractive performance, attaining current densities of -1.98 and -2.26 A cm-2 under 50% CO2 /CO and pure CO2 atmospheres, respectively. These results suggest the great potential of xFe-SDC electrodes as promising avenues for high-performance fuel electrodes in SOEC.

Fe-Doped SDC Solid Solution as an Electrolyte for Low-to-Intermediate-Temperature Solid Oxide Fuel Cells.

Ceria-based oxides, such as samaria-doped ceria (SDC), are potential electrolytes for low-to-intermediate-temperature solid oxide fuel cells (SOFCs). The sinterability of these materials can be improved by adding iron as the sintering aid. This work reveals that Fe is soluble in SDC, forming an Fe-doped SDC solid solution. It is found that the solubility is affected by the sintering temperature. Fe doping has obvious effects on electrolyte properties, including sintering characteristics, thermal expansion behaviors, and electrical conductivities in both air and hydrogen atmospheres. The conductivity obviously increases while the activation energy decreases by doping Fe. Compared with that of the bare SDC electrolyte, the performance of the single cell with the Fe-doped SDC is enhanced; for example, the peak power density is increased by 52.8% to 0.726 W cm-2 at 600 °C when humidified hydrogen is used as the fuel and ambient air is used as the oxidant. The single cell showed stable operation at 600 °C under a constant current density of 0.3 A cm-2 for 150 h. Therefore, the Fe-doped SDC solid solution shows promise as a potential electrolyte for low-to-intermediate-temperature SOFCs.

A Superior Catalytic Air Electrode with Temperature-Induced Exsolution toward Protonic Ceramic Cells.

Protonic ceramic cells merit extensive exploration, attributed to their innate capabilities for potent and environmentally benign energy conversion. In this work, a temperature-induced exsolution methodology to synthesize SrCo0.5Nb0.5O3-δ (SCN) nanoparticles (NPs) with notably elevated activity on the surface of PrSrCo1.8Nb0.2O6-δ (PSCN) is proposed, directly addressing the extant challenge of restrained catalytic activity prevalent in air electrode materials. In situ assessments reveal that SCN NPs commence exsolution from the matrix at temperatures surpassing 900 °C during straightforward calcination processes and maintain stability throughout annealing. Notably, the resultant SCN-PSCN interface facilitates vapor adsorption and protonation processes, which are poised to enhance surface reaction kinetics pertaining to the proton-involved oxygen reduction and evolution reaction (P-ORR and P-OER). A fuel-electrode-supported protonic ceramic cell leveraging SCN-PSCN as the air electrode manifests compelling performance, attaining a peak power density of 1.30 W·cm-2 in the fuel cell modality and a current density of 1.91 A·cm-2 at 1.3 V in the electrolysis mode, recorded at 650 °C. Furthermore, density functional theory calculations validate that the introduction of SCN NPs onto the PSCN surface conspicuously accelerates electrode reaction rates correlated with P-ORR and P-OER, by significantly mitigating energy barriers associated with surface oxygen and vapor dissociation.

Phase 1 trial of ADI-PEG 20 and liposomal doxorubicin in patients with metastatic solid tumors.

BACKGROUND: Arginine depletion interferes with pyrimidine metabolism and DNA damage repair pathways. Preclinical data demonstrated that depletion of arginine by PEGylated arginine deiminase (ADI-PEG 20) enhanced liposomal doxorubicin (PLD) cytotoxicity in cancer cells with argininosuccinate synthase 1 (ASS1) deficiency. The objective of this study was to assess safety and tolerability of ADI-PEG 20 and PLD in patients with metastatic solid tumors. METHODS: Patients with advanced ASS1-deficient solid tumors were enrolled in this phase 1 trial of ADI-PEG 20 and PLD following a 3 + 3 design. Eligible patients were given intravenous PLD biweekly and intramuscular (IM) ADI-PEG 20 weekly. Toxicity and efficacy were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0) and Response Evaluation Criteria in Solid Tumors (version 1.1), respectively. RESULTS: Of 15 enrolled patients, 9 had metastatic HER2-negative breast carcinoma. We observed no dose-limiting toxicities or treatment-related deaths. One patient safely received 880 mg/m2 PLD in this study and 240 mg/m2 doxorubicin previously. Treatment led to stable disease in 9 patients and was associated with a median progression-free survival time of 3.95 months in 15 patients. Throughout the duration of treatment, decreased arginine and increased citrulline levels in peripheral blood remained significant in a majority of patients. We detected no induction of anti-ADI-PEG 20 antibodies by week 8 in one third of patients. CONCLUSION: Concurrent IM injection of ADI-PEG 20 at 36 mg/m2 weekly and intravenous infusion of PLD at 20 mg/m2 biweekly had an acceptable safety profile in patients with advanced ASS1-deficient solid tumors. Further evaluation of this combination is under discussion.

Theoretical and Experimental Investigations on K-doped SrCo0.9 Nb0.1 O3-δ as a Promising Cathode for Proton-Conducting Solid Oxide Fuel Cells.

Improving proton conduction in cathodes is regarded as one of the most effective methods to accelerate the sluggish proton-involved oxygen reduction reaction (P-ORR) for proton-conducting solid oxide fuel cells (P-SOFCs). In this work, K+ dopant was used to improve the proton uptake and migration ability of SrCo0.9 Nb0.1 O3-δ (SCN). K+ -doped SCN (KSCN) demonstrated great potential to be a promising cathode for P-SOFCs. Density functional theory calculations suggested that doping with K+ led to more oxygen vacancies and more negative values of hydration enthalpy, which was helpful for the improvement of proton concentration. Importantly, the proton migration barriers could be depressed, benefiting proton conduction. Electrochemical investigations signified that the cell using KSCN cathode had a peak power density of 967 mW cm-2 at 700 °C, about 54.1 % higher than that using a SCN cathode. This research highlights the K+ -doping strategy to improve electrochemical performance of cathodes for P-SOFCs.

Phase 1 trial of ADI-PEG20 plus cisplatin in patients with pretreated metastatic melanoma or other advanced solid malignancies.

BACKGROUND: Arginine depletion interferes with pyrimidine metabolism and DNA damage-repair pathways, and pairing arginine deiminase pegylated with 20,000-molecular-weight polyethylene glycol (ADI-PEG20) with platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs. METHODS: This single-centre, Phase 1 trial was conducted using a 3 + 3 dose escalation designed to assess safety, tolerability and determine the recommended Phase 2 dose (RP2D) of ADI-PEG20. RESULTS: We enrolled 99 patients with metastatic argininosuccinate synthetase 1 (ASS1) deficient malignancies. We observed no dose-limiting toxic effects or treatment-related mortality. Three percent of patients discontinued treatment because of toxicity. After treatment, 5% (5/99) of patients had partial responses, and 41% had stable disease. The median progression-free and overall survival durations were 3.62 and 8.06 months, respectively. Substantial arginine depletion and citrulline escalation persisted in most patients through weeks 24 and 8, respectively. Tumour responses were associated with anti-ADI-PEG20 antibody levels at weeks 8 and 16 (p = 0.031 and p = 0.0357, respectively). CONCLUSION: Concurrently administered ADI-PEG20 and cisplatin had an acceptable safety profile and had shown antitumour activity against metastatic ASS1-deficient solid tumours. Further evaluation of this treatment combination is warranted.

Infiltrated Ni0.08Co0.02CeO2-x@Ni0.8Co0.2 Catalysts for a Finger-Like Anode in Direct Methane-Fueled Solid Oxide Fuel Cells.

Direct utilization of methane in solid oxide fuel cells (SOFCs) is greatly impeded by the grievous carbon deposition and the much depressed catalytic activity. In this work, a promising anode, taking finger-like porous YSZ as the anode substrate and impregnated Ni0.08Co0.02Ce0.9O2-δ@Ni0.8Co0.2O as the novel catalyst, is fabricated via the phase conversion-combined tape-casting technique. This anode shows commendable mechanical strength and excellent catalytic activity and stability toward the methane conversion reactions, which is attributed to the exsolved alloy nanoparticles and the active oxygen species on the reduced Ni0.08Co0.02Ce0.9O2-δ catalyst as well as the facilitated methane transport rooting in the special open-pore microstructure of the anode substrate. Strikingly, this button cell delivers an excellent peak power density of 730 mW cm-2 at 800 °C in 97% CH4/3% H2O fuel, only 9% lower than that in 97% H2/3% H2O. Our work shed new light on the SOFC anode developments.

Associated Effects and Efficiency Evaluation between Wastewater Pollution and Water Disease Based on the Dynamic Two-Stage DEA Model.

The lack of basic water supply and treatment facilities during China's urbanization and industrialization process has resulted in a large amount of wastewater pollution, with the most serious water diseases being water-borne endemic fluorosis and arsenic poisoning, which have affected more than 20 million people. This research therefore uses the improved modified undesirable dynamic network model to analyze data of 31 provincial administrative regions to focus on the associated effects and efficiency evaluation between wastewater pollution and water disease in China. The results show that the efficiency of water pollution disease in all four regions of the country and the total efficiency in the east, west, and central regions all show a decreasing trend, while the efficiency scores and rankings of all provinces and cities within the region fluctuate greatly. The eastern region with the most developed economy has the best overall performance, with higher efficiency in water consumption and water disease control. However, the efficiency of wastewater treatment in northeast China is stable and better. Given the high level of the nation's economic development and the results of efficiency in water pollution and water diseases, improving the efficiency and quality of wastewater treatment in China is regarded as an important factor for achieving the strategic goal of green growth.

A Durable Ruddlesden-Popper Cathode for Protonic Ceramic Fuel Cells.

Protonic ceramic fuel cells (PCFCs) have been proved as an efficient energy converter at intermediate temperatures. To accelerate the kinetics of the proton-involved oxygen reduction reaction (p-ORR), developing efficient and durable cathodes is of great importance for improving PCFCs. In this work, a new triple-layered Ruddlesden-Popper (R-P) structure oxide, Sr3 EuFe2.5 Co0.5 O10-δ (3-SEFC0.5 ), was developed as a potential single-phase cathode for PCFCs, showing high oxygen non-stoichiometry and desirable structural thermal stability. By employing this highly active and stable single-phase cathode, the PCFC demonstrated unprecedented low polarization resistances and exceptionally great peak power densities, which were approximately 0.030â€…Ω cm2 and 900 mW cm-2 measured at 700 °C, respectively. These findings not only manifest the effectiveness of optimal doping in improving the structural stability and electrocatalytic activity in the multi-layered perovskite family, but also highlight the great potential of using multi-layered R-P series oxides as highly active and durable catalysts for PCFCs.

Vanadium-Doped Strontium Molybdate with Exsolved Ni Nanoparticles as Anode Material for Solid Oxide Fuel Cells.

Vanadium-doped strontium molybdate (SVM) has been investigated as a potential anode material for solid oxide fuel cells due to its high electronic conductivity of about 1000 S cm-1 at 800 °C in reducing atmospheres. In this work, NiO is introduced to SVM with the B-site excess design to induce in situ growth of Ni nanoparticles in the anodic operational conditions. The Ni particles are exsolved from the parent oxide phase as clearly demonstrated with various techniques including X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, and transmission electron microscopy. The exsolved Ni nanoparticles significantly boost the electrocatalytic activity toward fuel oxidation reaction, improving the peak power density by 160% from 0.21 to 0.56 W cm-2 at 800 °C when using H2 as the fuel, meanwhile reducing the total interfacial polarization resistance by 56% from 0.81 to 0.36 Ω cm2. The Ni-exsolved SVM anode also shows excellent catalytic activity toward H2S-containing and hydrocarbon fuels, providing peak power densities of 0.43, 0.36, and 0.22 W cm-2 at 800 °C for H2-50 ppm H2S, syngas, and ethanol, respectively. In addition, the cell with the Ni-exsolved SVM anode presents a stable power output, indicating that the Ni-SVM is a potential SOFC anode electrocatalyst for various fuels.

A Stable and Efficient Cathode for Fluorine-Containing Proton-Conducting Solid Oxide Fuel Cells.

Substitution of anions such as F- and Cl- can effectively improve the stability of proton-conducting electrolytes at no expense to proton conduction. However, during operation, F- and Cl- in electrolytes can transfer to the cathodes, which reduces the stability of the electrolytes. In this work, F- -doped Ba0.5 Sr0.5 Co0.8 Fe0.2 O3-δ [Ba0.5 Sr0.5 Co0.8 Fe0.2 O2.9-δ F0.1 (F-BSCF)] was prepared as a potential cathode for proton-conducting solid oxide fuel cells with BaCe0.8 Sm0.2 F0.1 O2.85 electrolyte. The incorporation of F- in the cathode depressed F- diffusion from the electrolyte and improved the stability of button cells. Temperature-changing X-ray photoelectron spectroscopy and electronic conductivity relaxation results demonstrated that the incorporation of F- enhanced the oxygen incorporation kinetics at intermediate temperatures and improved the cathode catalytic performance. Moreover, a button cell prepared with this novel cathode was stable for 270 h at a current density of 300 mA cm-2 and 700 °C, which was much superior than those containing a BSCF cathode.

Well-Coupled Nanohybrids Obtained by Component-Controlled Synthesis and in Situ Integration of Mn xPd y Nanocrystals on Vulcan Carbon for Electrocatalytic Oxygen Reduction.

Development of cheap, highly active, and robust bimetallic nanocrystal (NC)-based nanohybrid (NH) electrocatalysts for oxygen reduction reaction (ORR) is helpful for advancing fuel cells or other renewable energy technologies. Here, four kinds of well-coupled Mn xPd y(MnPd3, MnPd-Pd, Mn2Pd3, Mn2Pd3-Mn11Pd21)/C NHs have been synthesized by in situ integration of Mn xPd y NCs with variable component ratios on pretreated Vulcan XC-72 C using the solvothermal method accompanied with annealing under Ar/H2 atmosphere and used as electrocatalysts for ORR. Among them, the MnPd3/C NHs possess the unique "half-embedded and half-encapsulated" interfaces and exhibit the highest catalytic activity, which can compete with some currently reported non-Pt catalysts (e.g., Ag-Co nanoalloys, Pd2NiAg NCs, PdCo/N-doped porous C, G-Cu3Pd nanocomposites, etc.), and close to commercial Pt/C. Electrocatalytic dynamic measurements disclose that their ORR mechanism abides by the direct 4e- pathway. Moreover, their durability and methanol-tolerant capability are much higher than that of Pt/C. As revealed by spectroscopic and electrochemical analyses, the excellent catalytic performance of MnPd3/C NHs results from the proper component ratio of Mn and Pd and the strong interplay of their constituents, which not only facilitate to optimize the d-band center or the electronic structure of Pd but also induce the phase transformation of MnPd3 active components and enhance their conductivity or interfacial electron transfer dynamics. This work demonstrates that MnPd3/C NHs are promising methanol-tolerant cathode electrocatalysts that may be employed in fuel cells or other renewable energy option.

New, Efficient, and Reliable Air Electrode Material for Proton-Conducting Reversible Solid Oxide Cells.

Driven by the demand to minimize fluctuation in common renewable energies, reversible solid oxide cells (RSOCs) have drawn increasing attention for they can operate either as fuel cells to produce electricity or as electrolysis cells to store electricity. Unfortunately, development of proton-conducting RSOCs (P-RSOCs) faces a major challenge of poor reliability because of the high content of steam involved in air electrode reactions, which could seriously decay the lifetime of air electrode materials. In this work, a very stable and efficient air electrode, SrEu2Fe1.8Co0.2O7-δ (SEFC) with layer structure, is designed and deployed in P-RSOCs. X-ray diffraction analysis and High-angle annular dark-filed scanning transmission electron microscopy images of SEFC reveal that Sr atoms occupy the center of perovskite slabs, whereas Eu atoms arrange orderly in the rock-salt layer. Such a special structure of SEFC largely depresses its Lewis basicity and therefore its reactivity with steam. Applying the SEFC air electrode, our button switches smoothly between both fuel cell and electrolysis cell (EC) modes with no obvious degradation over a 135 h long-term test under wet H2 (∼3% H2O) and 10% H2O-air atmospheres. A record of over 230 h is achieved in the long-term stability test in the EC mode, doubling the longest test that had been previously reported. Besides good stability, SEFC demonstrates great catalytic activity toward air electrode reactions when compared with traditional La0.6Sr0.4Co0.2Fe0.8O3-δ air electrodes. This research highlights the potential of stable and efficient P-RSOCs as an important part in a sustainable new energy power system.

SMART Design of a Bulk-Capped Supramolecular Segment for the Assembly into Organic Interdigital Lipid Bilayer-Like (ILB) Nanosheets.

Rational molecular design for the organic nanocrystal morphology still remains a challenge due to the structural diversity and complicated weak intermolecular interactions. In this work, a typical attractor-repulsor molecule N,N-diphenyl-4-(9-phenyl-fluoren-9-yl) phenylamine (TPA-PF) is designed to explore a general assembly strategy for 2D nanocrystals. Via an interdigital lipid bilayer-like (ILB) molecular packing mode, large-sized lamellar 2D nanosheets are obtained with a length:width:thickness ratio as ≈2500:1000:1. The d-spacing of the largest (001) plane is 1.32 nm, which equals to the thickness of a single interdigital stacking layer. The synergetic effect of the attractive supramolecular segment (TPA) and the repulsive bulky group (PF) is supposed to be the critical factor for the ILB packing that leads to the 2D structures. The attractor-repulsor molecule design is expected to be an effective strategy for the growth of 2D nanocrystals based on small organic molecules.

A first-principles study on divergent reactions of using a Sr3Fe2O7 cathode in both oxygen ion conducting and proton conducting solid oxide fuel cells.

Exploring mechanisms for sluggish cathode reactions is of great importance for solid oxide fuel cells (SOFCs), which will benefit the development of suitable cathode materials and then accelerate cathode reaction rates. Moreover, possible reaction mechanisms for one cathode should be different when operating in oxygen ion conducting SOFCs (O-SOFC) and in proton conducting SOFCs (P-SOFCs), and therefore, they lead to different reaction rates. In this work, a Ruddlesden-Popper (R-P) oxide, Sr3Fe2O7 (SFO), was selected as a promising cathode for both O-SOFCs and P-SOFCs. Using the first-principles approach, a microscopic understanding of the O2 reactions over this cathode surface was investigated operating in both cells. Compared with La0.5Sr0.5Co0.25Fe0.75O3 (LSCF), the low formation energies of oxygen vacancies and low migration energy barriers for oxygen ions in SFO make oxygen conduction more preferable which is essential for cathode reactions in O-SOFCs. Nevertheless, a large energy barrier (2.28 eV) is predicted for oxygen dissociation reaction over the SFO (001) surface, while there is a zero barrier over the LSCF (001) surface. This result clearly indicates that SFO shows a weaker activity toward the oxygen reduction, which may be due to the low surface energies and the specific R-P structure. Interestingly, in P-SOFCs, the presence of protons on the SFO (001) surface can largely depress the energy barriers to around 1.46-1.58 eV. Moreover, surface protons benefit the oxygen adsorption and dissociation over the SFO (001) surface. This result together with the extremely low formation energies and migration energy barriers for protons seem to suggest that SFO could work more effectively in P-SOFCs than in O-SOFCs. It's also suggested that too many protons at the SFO surface will lead to high energy barriers for the water formation process, and thus that over-ranging steam concentrations in the testing atmosphere may have a negative effect on cell performances. Our study firstly and clearly presents the different energy barriers for one cathode performing in both O- and P-SOFCs according to their different working mechanisms. The results will be helpful to find the constraints for using cathodes toward oxygen reduction reactions, and to develop effective oxide cathode materials for SOFCs.

Coralloid Co2P2O7 Nanocrystals Encapsulated by Thin Carbon Shells for Enhanced Electrochemical Water Oxidation.

Core-shell nanohybrids containing cheap inorganic nanocrystals and nanocarbon shells are promising electrocatalysts for water splitting or other renewable energy options. Despite that great progress has been achieved, biomimetic synthesis of metal phosphates@nanocarbon core-shell nanohybrids remains a challenge, and their use for electrocatalytic oxygen evolution reaction (OER) has not been explored. In this paper, novel nanohybrids composed of coralloid Co2P2O7 nanocrystal cores and thin porous nanocarbon shells are synthesized by combination of the structural merits of supramolecular polymer gels and a controllable thermal conversion technique, i.e., temperature programmable annealing of presynthesized supramolecular polymer gels that contain cobalt salt and phytic acid under a proper gas atmosphere. Electrocatalytic tests in alkaline solution show that such nanohybrids exhibit greatly enhanced electrocatalytic OER performance compared with that of Co2P2O7 nanostructure. At a current density of 10 mA cm(-2), their overpotential is 0.397 V, which is much lower than that of Co2P2O7 nanostructures, amorphous Co-Pi nanomaterials, Co(PO3)2 nanosheets, Pt/C, and some reported OER catalysts, and close to that of commercial IrO2. Most importantly, both of their current density at the overpotential over 0.40 V and durability are superior to those of IrO2 catalyst. As revealed by a series of spectroscopic and electrochemical analyses, their enhanced electrocatalytic performance results from the presence of thin porous nanocarbon shells, which not only improve interfacial electron penetration or transfer dynamics but also vary the coordination environment and increase the number of active 5-coordinated Co(2+) sites in Co2P2O7 cores.

GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands.

The EGFR-targeted monoclonal antibodies are a valid therapeutic strategy for patients with metastatic colorectal cancer (mCRC). However, only a small subset of mCRC patients has therapeutic benefits and there are high demands for EGFR therapeutics with a broader patient pool and more potent efficacy. In this study, we report GC1118 exhibiting a different character in terms of binding epitope, affinity, mode of action, and efficacy from other anti-EGFR antibodies. Structural analysis of the EGFR-GC1118 crystal complex revealed that GC1118 recognizes linear, discrete N-terminal epitopes of domain III of EGFR, critical for EGF binding but not overlapping with those of other EGFR-targeted antibodies. GC1118 exhibited superior inhibitory activity against high-affinity EGFR ligands in terms of EGFR binding, triggering EGFR signaling, and proliferation compared with cetuximab and panitumumab. EGFR signaling driven by low-affinity ligands, on the contrary, was well inhibited by all the antibodies tested. GC1118 demonstrated robust antitumor activity in tumor xenografts with elevated expression of high-affinity ligands in vivo, whereas cetuximab did not. Considering the significant role of high-affinity EGFR ligands in modulating tumor microenvironment and inducing resistance to various cancer therapeutics, our study suggests a potential therapeutic advantage of GC1118 in terms of efficacy and a range of benefited patient pool. Mol Cancer Ther; 15(2); 251-63. ©2015 AACR.

Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies.

PURPOSE: Cancer is a manifestation of aberrant cellular proliferation, and the cell cycle is one of the most successfully drugged targets in oncology. No prior study has been reported that simultaneously targets the 3 principal cell cycle phases populated by proliferating cells--G1, S, and G2/M. METHODS: Temsirolimus (G1 inhibitor), topotecan (S inhibitor), and bortezomib (G2/M inhibitor) were administered in combination to patients with advanced malignancies using a 3+3 dose escalation schedule to assess the safety and establish the maximum tolerated dose (primary endpoints) of this cell cycle targeting approach. An in silico pharmacodynamic model using established effects of each of these agents on the cell cycle was used to validate the regimen and to guide the dosing regimen. RESULTS: Sixty-two subjects were enrolled. The most common adverse events and dose-limiting toxicities were cytopenias, consistent with the cell cycle targeting approach employed. All cytopenias resolved to baseline values upon holding study drug administration. The maximum tolerated dose was temsirolimus 15 mg/kg IV D1, 8, 15; topotecan 2.8 mg/m(2) IV D1, 8; and bortezomib 0.6 mg/m2 IV D1, 4, 8, 11 [DOSAGE ERROR CORRECTED] of a 21-day cycle. In silico modeling suggests the regimen induces cell population shifts from G2/M and S phases to G1 phase and the quiescent G0 phase. Eighteen percent of subjects (11/62) achieved partial response (n = 2, serous ovarian and papillary thyroid) or stable disease for > 6 months (n = 9). CONCLUSION: Combining drugs with inhibitory activity of G1 phase, S phase, and G2/M phase is safe and warrants further evaluation.

Colon cancer-derived oncogenic EGFR G724S mutant identified by whole genome sequence analysis is dependent on asymmetric dimerization and sensitive to cetuximab.

BACKGROUND: Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear. FINDINGS: We describe a case of colorectal adenocarcinoma, which was found to harbor a kinase domain mutation, G724S, in EGFR through whole genome sequencing. We show that G724S mutant EGFR is oncogenic and that it differs from classic lung cancer derived EGFR mutants in that it is cetuximab responsive in vitro, yet relatively insensitive to small molecule kinase inhibitors. Through biochemical and cellular pharmacologic studies, we have determined that cells harboring the colon cancer-derived G719S and G724S mutants are responsive to cetuximab therapy in vitro and found that the requirement for asymmetric dimerization of these mutant EGFR to promote cellular transformation may explain their greater inhibition by cetuximab than small-molecule kinase inhibitors. CONCLUSION: The colon-cancer derived G719S and G724S mutants are oncogenic and sensitive in vitro to cetuximab. These data suggest that patients with these mutations may benefit from the use of anti-EGFR antibodies as part of the first-line therapy.