| 1. |
- Menden, MP, et al.
(author)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Journal article (peer-reviewed)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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| 2. |
- Hu, Wenjun, et al.
(author)
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Heterogeneous nuclear ribonucleoprotein L facilitates recruitment of 53BP1 and BRCA1 at the DNA break sites induced by oxaliplatin in colorectal cancer
- 2019
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In: Cell Death and Disease. - : NATURE PUBLISHING GROUP. - 2041-4889. ; 10
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Journal article (peer-reviewed)abstract
- Although oxaliplatin is an effective chemotherapeutic drug for treatment of colorectal cancer (CRC), tumor cells can develop mechanisms to evade oxaliplatin-induced cell death and show high tolerance and acquired resistance to this drug. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) has been proved to play a critical role in DNA repair during IgH class switch recombination (CSR) in B lymphocytes, while, its role in CRC and chemotherapeutic resistance remain unknown. Our study aims to uncover an unidentified mechanism of regulating DNA double-strand breaks (DSBs) by hnRNP L in CRC cells treated by oxaliplatin. In present study, we observed that knockdown of hnRNP L enhanced the level of DNA breakage and sensitivity of CRC cells to oxaliplatin. The expression of key DNA repair factors (BRCA1, 53BP1, and ATM) was unaffected by hnRNP L knockdown, thereby excluding the likelihood of hnRNP L mediation via mRNA regulation. Moreover, we observed that phosphorylation level of ATM changed oppositely to 53BP1 and BRCA1 in the CRC cells (SW620 and HCT116) which exhibit synergistic effect by oxaliplatin plus hnRNP L impairment. And similar phenomenon was observed in the foci formation of these critical repair factors. We also found that hnRNP L binds directly with these DNA repair factors through its RNA-recognition motifs (RRMs). Analysis of cell death indicated that the RRMs of hnRNP L are required for cell survival under incubation with oxaliplatin. In conclusion, hnRNP L is critical for the recruitment of the DNA repair factors in oxaliplatin-induced DSBs. Targeting hnRNP L is a promising new clinical approach that could enhance the effectiveness of current chemotherapeutic treatment in patients with resistance to oxaliplatin.
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| 3. |
- Ma, Zaifei, et al.
(author)
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A Facile Method to Enhance Photovoltaic Performance of Benzodithiophene-Isoindigo Polymers by Inserting Bithiophene Spacer
- 2014
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In: Advanced Energy Materials. - : Wiley. - 1614-6840 .- 1614-6832. ; 4:6, s. Art. no. 1301455-
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Journal article (peer-reviewed)abstract
- This study describes the synthesis and characterization of four polymers based on benzo[1,2-b:4,5-b']dithiophene (BDT) and isoindigo with zero, one, two, and three thiophene spacer groups. Results have demonstrated that the use of bithiophene as a spacer unit improves the geometry of the polymer chain, making it planar, and hence, potentially enhanced π- π stacking occurs. Due to favorable interaction of the polymer chains, enhanced absorption coefficient, and optimal morphology, PBDT-BTI, which possesses bithiophene as a spacer, revealed high current and fill factor leading to a power conversion efficiency of 7.3% in devices, making this polymer the best performing isoindigo-based material in polymer solar cells (PSCs). Also, PBDT-BTI could still maintain efficiency of over 6% with the active layer thickness of 270 nm, making it a potential candidate for a material in printed PSCs. These results demonstrate that the use of thiophene spacers in D-A polymers could be an important design strategy to produce high-performance PSCs.
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| 4. |
- Ruilope, LM, et al.
(author)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Journal article (peer-reviewed)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 5. |
- Shin, Su Ryon, et al.
(author)
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Cell-laden Microengineered and Mechanically Tunable Hybrid Hydrogels of Gelatin and Graphene Oxide
- 2013
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In: Advanced Materials. - : Wiley. - 0935-9648 .- 1521-4095. ; 25:44, s. 6385-6391
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Journal article (peer-reviewed)abstract
- Incorporating graphene oxide inside GelMA hydrogels enhances their mechanical properties and reduces UV-induced cell damage while preserving their favorable characteristics for 3D cell encapsulation. NIH-3T3 fibroblasts encapsulated in GO-GelMA microgels demonstrate excellent cellular viability, proliferation, spreading, and alignment. GO reinforcement combined with a multi-stacking approach offers a facile engineering strategy for the construction of complex artificial tissues.
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| 6. |
- Tang, Shi, et al.
(author)
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Aggregation-Induced Emission by Molecular Design: A Route to High-Performance Light-Emitting Electrochemical Cells
- 2023
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In: Angewandte Chemie - International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 62:23
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Journal article (peer-reviewed)abstract
- The emission efficiency of organic semiconductors (OSCs) often suffers from aggregation caused quenching (ACQ). An elegant solution is aggregation-induced emission (AIE), which constitutes the design of the OSC so that its morphology inhibits quenching π–π interactions and non-radiative motional deactivation. The light-emitting electrochemical cell (LEC) can be sustainably fabricated, but its function depends on motion of bulky ions in proximity of the OSC. It is therefore questionable whether the AIE morphology can be retained during LEC operation. Here, we synthesize two structurally similar OSCs, which are distinguished by that 1 features ACQ while 2 delivers AIE. Interestingly, we find that the AIE-LEC significantly outperforms the ACQ-LEC. We rationalize our finding by showing that the AIE morphology remains intact during LEC operation, and that it can feature appropriately sized free-volume voids for facile ion transport and suppressed non-radiative excitonic deactivation.
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| 7. |
- Tang, Shi, et al.
(author)
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Fluorescent carbon dots from birch leaves for sustainable electroluminescent devices
- 2023
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In: Green Chemistry. - : Royal Society of Chemistry. - 1463-9262 .- 1463-9270. ; 25:23, s. 9884-9895
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Journal article (peer-reviewed)abstract
- The shift from depleting petroleum compounds to regenerating biomass as the raw material for organic semiconductors is a prerequisite if organic electronics is to become truly sustainable. Here, we report on a one-pot solvothermal synthesis of a biomass-based carbon dot (bio-CD) fluorescent semiconductor, using birch leaves as the sole raw material. These bio-CDs are highly soluble in ethanol (45 g L-1), and deliver deep-red and narrowband emission (peak wavelength = 675 nm, full width at half maximum, FWHM = 28 nm) at a high photoluminescence quantum yield of 26% in ethanol solution. Systematic structural characterization shows that molecular pheophytin a is the single fluorophore, and that this fluorophore is localized in the bulk of the bio-CD away from its polar surface. The functionality of the birch-leaf-derived bio-CDs in sustainable organic electronics is demonstrated by its employment as the printable emitter in a light-emitting electrochemical cell, which delivers narrowband deep-red luminance of 110 cd m-2, with a FWHM of 29 nm, at an external quantum efficiency of 0.29%. This study thus reveals a promising avenue for the functional benign synthesis and the practical solution-based implementation of narrowband bio-CDs in sustainable optoelectronic technologies.
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| 8. |
- Wu, Lei, et al.
(author)
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Limited Song Mixing Without Genomic Gene Flow in a Contact Zone Between Two Songbird Species
- 2023
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In: Molecular biology and evolution. - : Oxford University Press. - 0737-4038 .- 1537-1719. ; 40:3
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Journal article (peer-reviewed)abstract
- Song is considered to play an important role in the maintenance of prezygotic reproductive isolation between closely related songbird species. Therefore, song mixing in a contact zone between closely related species is often considered as evidence of hybridization. The Sichuan Leaf Warbler Phylloscopus forresti and the Gansu Leaf Warbler Phylloscopus kansuensis, which diverged 2 million years ago, have formed a contact zone in the south of the Gansu Province of China, where mixed songs have been observed. In this study, we investigated the potential causes and consequences of song mixing by integrating bioacoustic, morphological, mitochondrial, and genomic data with field ecological observations. We found that the two species display no apparent morphological differences, whereas their songs differ dramatically. We demonstrated that ∼11% of the males in the contact zone sang mixed songs. Two males singing mixed song were genotyped, and both were found to be P. kansuensis. Despite the presence of mixed singers, population genomic analyses detected no signs of recent gene flow between the two species, although two possible cases of mitochondrial introgression were identified. We conclude that the rather limited song mixing does not lead to, or result from, hybridization, and hence does not result in the breakdown of reproductive barriers between these cryptic species.
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| 9. |
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