Despite significant study, the precise mechanisms that dictate the efficiency of organic photovoltaic cells, such as charge separation and recombination, are still debated. Here, we directly observe ...efficient ultrafast free charge generation in the absence of field in annealed poly(3-hexylthiophene):methanofullerene (P3HT:PCBM). However, we find this process is much less efficient in unannealed and amorphous regiorandom blends, explaining the superior short-circuit current and fill-factor of annealed RR-P3HT:PCBM solar cells. We use transient optical spectroscopy in the visible and near-infrared spectral region covering, but not limited to, the previously unobserved and highly relevant time scale spanning 1 to 100 ns, to directly observe both geminate and nongeminate charge recombination. We find that exciton quenching leads directly (time scale less than 100 fs) to two populations: bound charges and free charges. The former do not lead to photocurrent in a photovoltaic cell; they recombine geminately within 2 ns and are a loss channel. However, the latter can be efficiently extracted in photovoltaic cells. Therefore, we find that the probability of ultrafast free charge formation after exciton quenching directly limits solar cell efficiency. This probability is low in disordered P3HT:PCBM blends but approaches unity in annealed blends.
Our aim was to analyze and validate the prognostic impact of the novel International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society ...(ERS) proposal for an architectural classification of invasive pulmonary adenocarcinomas (ADCs) across all tumor stages.
The architectural pattern of a large cohort of 500 patients with resected ADCs (stages I to IV) was retrospectively analyzed in 5% increments and classified according to their predominant architecture (lepidic, acinar, solid, papillary, or micropapillary), as proposed by the IASLC/ATS/ERS. Subsequently, histomorphologic data were correlated with clinical data, adjuvant therapy, and patient outcome.
Overall survival differed significantly between lepidic (78.5 months), acinar (67.3 months), solid (58.1 months), papillary (48.9 months), and micropapillary (44.9 months) predominant ADCs (P = .007). When patterns were lumped into groups, this resulted in even more pronounced differences in survival (pattern group 1, 78.5 months; group 2, 67.3 months; group 3, 57.2 months; P = .001). Comparable differences were observed for overall, disease-specific, and disease-free survival. Pattern and pattern groups were stage- and therapy-independent prognosticators for all three survival parameters. Survival differences according to patterns were influenced by adjuvant chemoradiotherapy; in particular, solid-predominant tumors had an improved prognosis with adjuvant radiotherapy. The predominant pattern was tightly linked to the risk of developing nodal metastases (P < .001).
Besides all recent molecular progress, architectural grading of pulmonary ADCs according to the novel IASLC/ATS/ERS scheme is a rapid, straightforward, and efficient discriminator for patient prognosis and may support patient stratification for adjuvant chemoradiotherapy. It should be part of an integrated clinical, morphologic, and molecular subtyping to further improve ADC treatment.
INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up ...of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days 95% confidence interval (CI), 99-not applicable, compared with 117 days (95% CI, 106-143;
= 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. SIGNIFICANCE: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.
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Smoothed particle hydrodynamics (SPH) is a meshless Lagrangian method that has been successfully applied to computational fluid dynamics (CFD), solid mechanics and many other multi-physics problems. ...Using the method to solve transport phenomena in process engineering requires the simulation of several days to weeks of physical time. Based on the high computational demand of CFD such simulations in 3D need a computation time of years so that a reduction to a 2D domain is inevitable. In this paper gpuSPHASE, a new open-source 2D SPH solver implementation for graphics devices, is developed. It is optimized for simulations that must be executed with thousands of frames per second to be computed in reasonable time. A novel caching algorithm for Compute Unified Device Architecture (CUDA) shared memory is proposed and implemented. The software is validated and the performance is evaluated for the well established dambreak test case.
Program title: gpuSPHASE
Catalogue identifier: AFBO_v1_0
Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AFBO_v1_0.html
Program obtainable from: CPC Program Library, Queen’s University, Belfast, N. Ireland
Licensing provisions: GNU GPLv3
No. of lines in distributed program, including test data, etc.: 128288
No. of bytes in distributed program, including test data, etc.: 1350326
Distribution format: tar.gz
Programming language: C++, CUDA.
Computer: Nvidia CUDA capable devices.
Operating system: Linux, Windows, Mac OS.
Classification: 5, 12.
External routines: Qt5 Core, HDF5, H5Part
Nature of problem:
Free surface fluid dynamics simulations of long running physical phenomena that must be calculated in the order of real-time.
Solution method:
gpuSPHASE is a 2D SPH solver for CUDA capable devices that is optimized for the computation of real-time simulations.
Running time: Depending on the simulated problem the running time varies from seconds to weeks.
DNA methylation is a dynamic and reversible process that governs gene expression during development and disease. Several examples of active DNA demethylation have been documented, involving ...genome-wide and gene-specific DNA demethylation. How demethylating enzymes are targeted to specific genomic loci remains largely unknown. We show that an antisense lncRNA, termed TARID (for TCF21 antisense RNA inducing demethylation), activates TCF21 expression by inducing promoter demethylation. TARID interacts with both the TCF21 promoter and GADD45A (growth arrest and DNA-damage-inducible, alpha), a regulator of DNA demethylation. GADD45A in turn recruits thymine-DNA glycosylase for base excision repair-mediated demethylation involving oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in the TCF21 promoter by ten-eleven translocation methylcytosine dioxygenase proteins. The results reveal a function of lncRNAs, serving as a genomic address label for GADD45A-mediated demethylation of specific target genes.
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•TARID, a TCF21 antisense lncRNA, is downregulated in cancer cells•TARID binds to the TCF21 promoter and mediates transcriptional activation•TARID recruits GADD45A/TDG, thus promoting base excision-mediated demethylation•A lncRNA can serve as an address label for DNA demethylation
The function of most long noncoding RNAs (lncRNAs) is unknown. Arab et al. characterize TARID, a lncRNA that is antisense to the tumor suppressor TCF21, and find that it specifically directs demethylation and activation of TCF21 via GADD45A.
The SARS-CoV-2 pandemic affecting the human respiratory system severely challenges public health and urgently demands for increasing our understanding of COVID-19 pathogenesis, especially host ...factors facilitating virus infection and replication. SARS-CoV-2 was reported to enter cells via binding to ACE2, followed by its priming by TMPRSS2. Here, we investigate ACE2 and TMPRSS2 expression levels and their distribution across cell types in lung tissue (twelve donors, 39,778 cells) and in cells derived from subsegmental bronchial branches (four donors, 17,521 cells) by single nuclei and single cell RNA sequencing, respectively. While TMPRSS2 is strongly expressed in both tissues, in the subsegmental bronchial branches ACE2 is predominantly expressed in a transient secretory cell type. Interestingly, these transiently differentiating cells show an enrichment for pathways related to RHO GTPase function and viral processes suggesting increased vulnerability for SARS-CoV-2 infection. Our data provide a rich resource for future investigations of COVID-19 infection and pathogenesis.
•Co-inhibition of BET proteins and anti-apoptotic BCL-2 proteins induces apoptosis in RMS.•JQ1 and BH3-mimetics synergistically induce cell death in RMS.•Cell death is caspase-dependent and displays ...hallmarks of intrinsic apoptosis.•JQ1/A-1331852-mediated apoptosis is dependent on BIM and NOXA.•JQ1/S638450-mediated apoptosis is dependent on BIM but not NOXA.
BH3 mimetics are promising novel anticancer therapeutics. By selectively inhibiting BCL-2, BCL-xL, or MCL-1 (i.e. ABT-199, A-1331852, S63845) they shift the balance of pro- and anti-apoptotic proteins in favor of apoptosis. As Bromodomain and Extra Terminal (BET) protein inhibitors promote pro-apoptotic rebalancing, we evaluated the potential of the BET inhibitor JQ1 in combination with ABT-199, A-1331852 or S63845 in rhabdomyosarcoma (RMS) cells. The strongest synergistic interaction was identified for JQ1/A-1331852 and JQ1/S63845 co-treatment, which reduced cell viability and long-term clonogenic survival. Mechanistic studies revealed that JQ1 upregulated BIM and NOXA accompanied by downregulation of BCL-xL, promoting pro-apoptotic rebalancing of BCL-2 proteins. JQ1/A-1331852 and JQ1/S63845 co-treatment enhanced this pro-apoptotic rebalancing and triggered BAK- and BAX-dependent apoptosis since a) genetic silencing of BIM, BAK or BAX, b) inhibition of caspase activity with zVAD.fmk and c) overexpression of BCL-2 all rescued JQ1/A-1331852- and JQ1/S63845-induced cell death. Interestingly, NOXA played a different role in both treatments, as genetic silencing of NOXA significantly rescued from JQ1/A-1331852-mediated apoptosis but not from JQ1/S63845-mediated apoptosis. In summary, JQ1/A-1331852 and JQ1/S63845 co-treatment represent new promising therapeutic strategies to synergistically trigger mitochondrial apoptosis in RMS.
Non‐small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on ...identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)‐based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non‐malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non‐malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D‐imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D‐imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development.
What's new?
Cellular membranes are subject to extensive modification in cancer, often with marked alterations in phospholipid metabolism. The extent and nature of those changes are not fully known, however, particularly for non‐small cell lung cancer (NSCLC). In this study, lipidomics analysis of phospholipid profiles uncovered dramatic differences between NSCLC and normal lung tissue. The differences were confirmed via 2D‐imaging lipidomics in tissue sections. Lipid markers capable of discriminating between tumor and normal tissue and between different NSCLC subtypes were identified. The observed alterations in NSCLC phospholipid profiles may be biologically significant.
In order to identify anaplastic lymphoma kinase‐driven non‐small cell lung cancer (ALK+ NSCLC) patients with a worse outcome, who might require alternative therapeutic approaches, we retrospectively ...analyzed all stage IV cases treated at our institutions with one of the main echinoderm microtubule‐associated protein‐like 4 (EML4)‐ALK fusion variants V1, V2 and V3 as detected by next‐generation sequencing or reverse transcription‐polymerase chain reaction (n = 67). Progression under tyrosine kinase inhibitor (TKI) treatment was evaluated both according to Response Evaluation Criteria in Solid Tumors (RECIST) and by the need to change systemic therapy. EML4‐ALK fusion variants V1, V2 and V3 were found in 39%, 10% and 51% of cases, respectively. Patients with V3‐driven tumors had more metastatic sites at diagnosis than cases with the V1 and V2 variants (mean 3.3 vs. 1.9 and 1.6, p = 0.005), which suggests increased disease aggressiveness. Furthermore, V3‐positive status was associated with earlier failure after treatment with first and second‐generation ALK TKI (median progression‐free survival PFS by RECIST in the first line 7.3 vs. 39.3 months, p = 0.01), platinum‐based combination chemotherapy (median PFS 5.4 vs. 15.2 months for the first line, p = 0.008) and cerebral radiotherapy (median brain PFS 6.1 months vs. not reached for cerebral radiotherapy during first‐line treatment, p = 0.028), and with inferior overall survival (39.8 vs. 59.6 months in median, p = 0.017). Thus, EML4‐ALK fusion variant V3 is a high‐risk feature for ALK+ NSCLC. Determination of V3 status should be considered as part of the initial workup for this entity in order to select patients for more aggressive surveillance and treatment strategies.
What's new?
EML4‐ALK fusions are driving 5% of non‐small cell lung cancers (NSCLC). The present study shows for the first time that a specific fusion variant, namely V3 (E6;A20), is associated with more aggressive disease and worse overall survival due to earlier failure of several therapeutic modalities. This will necessitate inclusion of molecular assays beyond FISH in future diagnostic guidelines for ALK+ NSCLC and prompt development of more efficient strategies for the management of higher‐risk, V3‐positive cases.
The dependence of the thin film morphology and excited-state dynamics for the low-bandgap donor–acceptor copolymer ...poly2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta2,1-b;3,4-b′-dithiophene)-alt-4,7-(2,1,3-benzothiadiazole) (PCPDTBT) in pristine films and in blends (1:2) with 6,6-phenyl-C61-butyric acid methyl ester (PCBM) on the use of the solvent additive 1,8-octanedithiol (ODT) is studied by solid-state nuclear magnetic resonance (NMR) spectroscopy and broadband visible and near-infrared pump–probe transient absorption spectroscopy (TAS) covering a spectral range from 500–2000 nm. The latter allows monitoring of the dynamics of excitons, bound interfacial charge-transfer (CT) states, and free charge carriers over a time range from femto- to microseconds. The broadband pump–probe experiments reveal that excitons are not only generated in the polymer but also in PCBM-rich domains. Depending on the morphology controlled by the use of solvent additives, polymer excitons undergo mainly ultrafast dissociation (<100 fs) in blends prepared without ODT or diffusion-limited dissociation in samples prepared with ODT. Excitons generated in PCBM diffuse slowly to the interface in both samples and undergo dissociation on a time scale of several tens of picoseconds up to hundreds of picoseconds. In both samples a significant fraction of the excitons creates strongly bound interfacial CT states, which exhibit subnanosecond geminate recombination. The total internal quantum efficiency loss due to geminate recombination is estimated to be 50% in samples prepared without ODT and is found to be reduced to 30% with ODT, indicating that more free charges are generated in samples prepared with solvent additives. In samples prepared with ODT, the free charges exhibit clear intensity-dependent recombination dynamics, which can be modeled by Langevin-type recombination with a bimolecular recombination coefficient of 6.3 × 10–11 cm3 s–1. In samples prepared without ODT, an additional nanosecond recombination of polaron pairs is observed in conjunction with an increased intensity-independent trap-assisted nongeminate recombination of charges. Furthermore, a comparison of the triplet-induced absorption spectra of PCPDTBT with the charge-induced absorption in PCPDTBT:PCBM blends reveals that triplets have a very similar excited-state absorption spectrum compared to the free charge carriers, however, in contrast have a distinct intensity-independent lifetime. Overall, our results suggest that whether free charges or strongly bound CT states are created upon dissociation of excitons at the PCPDTBT:PCBM interface is determined instantaneously upon exciton dissociation and that once formed strongly bound CT states rapidly recombine and thus are unlikely to dissociate into free charges. The observation of a significantly larger bimolecular recombination coefficient than previously determined for poly(3-hexylthiophen-2,5-diyl):PCBM (P3HT:PCBM) and PCDTBT:PCBM samples indicates that nongeminate recombination of free charges considerably competes with charge extraction in PCPDTBT:PCBM photovoltaic devices.
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