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The statistical properties are presented for the direct numerical simulation of a self-similar adverse pressure gradient (APG) turbulent boundary layer (TBL) at the verge of separation. The APG TBL has a momentum thickness-based Reynolds number range from $Re_{\\unicode[STIX]{x1D6FF}_{2}}=570$ to 13 800, with a self-similar region from $Re_{\\unicode[STIX]{x1D6FF}_{2}}=10\\,000$ to 12 300. Within this domain the average non-dimensional pressure gradient parameter $\\unicode[STIX]{x1D6FD}=39$ , where for a unit density $\\unicode[STIX]{x1D6FD}=\\unicode[STIX]{x1D6FF}_{1}P_{\\!e}^{\\prime }/\\unicode[STIX]{x1D70F}_{w}$ , with $\\unicode[STIX]{x1D6FF}_{1}$ the displacement thickness, $\\unicode[STIX]{x1D70F}_{w}$ the mean shear stress at the wall and $P_{\\!e}^{\\prime }$ the far-field pressure gradient. This flow is compared with previous zero pressure gradient and mild APG TBL ( $\\unicode[STIX]{x1D6FD}=1$ ) results of similar Reynolds number. All flows are generated via the direct numerical simulation of a TBL on a flat surface with far-field boundary conditions tailored to apply the desired pressure gradient. The conditions for self-similarity, and the appropriate length and velocity scales, are derived. The mean and Reynolds stress profiles are shown to collapse when non-dimensionalised on the basis of these length and velocity scales. As the pressure gradient increases, the extent of the wake region in the mean streamwise velocity profiles increases, whilst the extent of the log-layer and viscous sublayer decreases. The Reynolds stress, production and dissipation profiles of the APG TBL cases exhibit a second outer peak, which becomes more pronounced and more spatially localised with increasing pressure gradient. This outer peak is located at the point of inflection of the mean velocity profiles, and is suggestive of the presence of a shear flow instability. The maximum streamwise velocity variance is located at a wall normal position of $\\unicode[STIX]{x1D6FF}_{1}$ of spanwise wavelength of $2\\unicode[STIX]{x1D6FF}_{1}$ . In summary as the pressure gradient increases the flow has properties less like a zero pressure gradient TBL and more akin to a free shear layer.

Background: Circulating tumour cells (CTC) have a crucial role in metastasis formation and can consistently provide information on patient prognosis. Epithelial-mesenchymal transition (EMT) is considered as an essential process in the metastatic cascade, but there is currently very few data demonstrating directly the existence of the EMT process in CTCs. Methods: CTCs were enriched by blood filtration using ISET (isolation by size of epithelial tumour cells), triply labelled with fluorescent anti-vimentin, anti-pan-keratin antibodies and SYTOX orange nuclear dye, and examined by confocal microscopy in six patients with metastatic non-small cell lung cancer (NSCLC). In parallel, CTCs were morphocytologically identified by an experienced cytopathologist. Results: Isolated or clusters of dual CTCs strongly co-expressing vimentin and keratin were evidenced in all patients (range 5–88/5 ml). CTCs expressing only vimentin were detected in three patients, but were less frequent (range 3–15/5 ml). No CTC expressing only keratin was detected. Conclusion: We showed for the first time the existence of hybrid CTCs with an epithelial/mesenchymal phenotype in patients with NSCLC. Their characterisation should provide further insight on the significance of EMT in CTCs and on the mechanism of metastasis in patients with NSCLC.

Studying soil hydrological processes requires the determination of soil hydraulic parameters whose assessment using traditional methods is expensive and time-consuming. A specific method, Beerkan estimation of soil transfer parameters referred to as BEST was developed to facilitate the determination of both the water retention curve, theta(h), and the hydraulic conductivity curve, K(theta), defined by their shape and scale parameters. BEST estimates shape parameters from particle-size distribution analysis and scale parameters from infiltration experiments at null pressure head. Saturated water content is measured directly at the end of infiltration. Hydraulic conductivity and water pressure scale parameters are calculated from the steady-state infiltration rate and prior estimation of sorptivity (S). This is provided by fitting transient infiltration data on the classical two-term equations with values from zero to a maximum corresponding to null hydraulic conductivity and using a data subset for which the two-term infiltration equations are verified as valid. BEST was compared with other fitting methods to estimate sorptivity and hydraulic conductivity from infiltration modeling data on the basis of the same infiltration equations for three contrasting soils: agricultural soil, sandy soil, and a coarser fluvioglacial deposit. The other methods failed sometimes to model accurately experimental data and to provide values in agreement with physical principles of water infiltration (negative values for hydraulic conductivity, too high steady-state infiltration rate). None of these anomalies was encountered when modeling cumulative infiltration with BEST. BEST appears to be a promising, easy, robust, and inexpensive way of characterizing the hydraulic behavior of soil.

Excision repair cross-complementation group 1 (ERCC1) is a DNA repair enzyme that is frequently defective in non-small cell lung cancer (NSCLC). Although low ERCC1 expression correlates with platinum sensitivity, the clinical effectiveness of platinum therapy is limited, highlighting the need for alternative treatment strategies. To discover new mechanism-based therapeutic strategies for ERCC1-defective tumours, we performed high-throughput drug screens in an isogenic NSCLC model of ERCC1 deficiency and dissected the mechanism underlying ERCC1-selective effects by studying molecular biomarkers of tumour cell response. The high-throughput screens identified multiple clinical poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors, such as olaparib (AZD-2281), niraparib (MK-4827) and BMN 673, as being selective for ERCC1 deficiency. We observed that ERCC1-deficient cells displayed a significant delay in double-strand break repair associated with a profound and prolonged G 2 /M arrest following PARP1/2 inhibitor treatment. Importantly, we found that ERCC1 isoform 202, which has recently been shown to mediate platinum sensitivity, also modulated PARP1/2 sensitivity. A PARP1/2 inhibitor-synthetic lethal siRNA screen revealed that ERCC1 deficiency was epistatic with homologous recombination deficiency. However, ERCC1-deficient cells did not display a defect in RAD51 foci formation, suggesting that ERCC1 might be required to process PARP1/2 inhibitor-induced DNA lesions before DNA strand invasion. PARP1 silencing restored PARP1/2 inhibitor resistance in ERCC1-deficient cells but had no effect in ERCC1-proficient cells, supporting the hypothesis that PARP1 might be required for the ERCC1 selectivity of PARP1/2 inhibitors. This study suggests that PARP1/2 inhibitors as a monotherapy could represent a novel therapeutic strategy for NSCLC patients with ERCC1-deficient tumours.

Background: Circulating tumour cells (CTCs) can provide information on patient prognosis and treatment efficacy. However, there is no universal method to detect CTC currently available. Here, we compared the performance of two CTC detection systems based on the expression of the EpCAM antigen (CellSearch assay) or on cell size (ISET assay). Methods: Circulating tumour cells were enumerated in 60 patients with metastatic carcinomas of breast, prostate and lung origins using CellSearch according to the manufacturer's protocol and ISET by studying cytomorphology and immunolabelling with anti-cytokeratin or lineage-specific antibodies. Results: Concordant results were obtained in 55% (11 out of 20) of the patients with breast cancer, in 60% (12 out of 20) of the patients with prostate cancer and in only 20% (4 out of 20) of lung cancer patients. Conclusion: Our results highlight important discrepancies between the numbers of CTC enumerated by both techniques. These differences depend mostly on the tumour type. These results suggest that technologies limiting CTC capture to EpCAM-positive cells, may present important limitations, especially in patients with metastatic lung carcinoma.

SummaryBackground Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911–17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC.

Pazopanib and lapatinib are two tyrosine kinase inhibitors that have been designed to inhibit the VEGF tyrosine kinase receptors 1, 2 and 3 (pazopanib), and the HER1 and HER2 receptors in a dual manner (lapatinib). Pazopanib has also been reported to mediate inhibitory effect on a selected panel of additional tyrosine kinases such as PDGFR and c-kit. Here, we report that pazopanib and lapatinib act synergistically to induce apoptosis of A549 non-small-cell lung cancer cells. Systematic assessment of the kinome revealed that both pazopanib and lapatinib inhibited dozens of different tyrosine kinases and that their combination could suppress the activity of some tyrosine kinases (such as c-Met) that were not or only partially affected by either of the two agents alone. We also found that pazopanib and lapatinib induced selective changes in the transcriptome of A549 cells, some of which were specific for the combination of both agents. Analysis of a panel of unrelated human carcinoma cell lines revealed a signature of 52 genes whose up- or downregulation reflected the combined action of pazopanib and lapatinib. Indeed, pazopanib and lapatinib exerted synergistic cytotoxic effects on several distinct non-small-cell lung cancer cells as well as on unrelated carcinomas. Altogether, these results support the contention that combinations of tyrosine kinase inhibitors should be evaluated for synergistic antitumor effects. Such combinations may lead to a ‘collapse’ of pro-survival signal transduction pathways that leads to apoptotic cell death.

Anthropized environments often fragment native habitats and alter the movement of individuals across the modified landscape mosaic, which is significantly challenging for wild species. Deciphering the environmental factors associated with population genetic patterns in modified habitats is essential to understand functional connectivity and for the conservation of wild populations inhabiting increasingly modified habitats. We used ddRAD-seq genomic data to study the genetic diversity, genetic structure and functional connectivity of the Giant Toad, Rhinella horribilis populations across two landscapes with distinct levels of habitat modification. We also applied a landscape genetics approach to identify landscape variables (climatic, vegetation, water bodies, land use) associated with the toad’s functional connectivity in both landscapes. Structure analysis between the two landscapes show that they are genetically differentiated given their distinct degree of habitat modification. Within landscapes, our results identified lower genetic diversity, higher genetic structure and lower functional connectivity among R. horribilis populations in the landscape with higher habitat modification. Results also demonstrate that structure and functional connectivity are significantly influenced by barriers like rivers and roads. Furthermore, water bodies availability was the most important landscape feature for R. horribilis connectivity, whereas vegetation cover, solar radiation and relative humidity also played a significant role. Our study illustrates how landscape features in modified habitats can differently determine genetic diversity and functional connectivity patterns, and highlights the importance of working with often-disregarded common species like the Giant Toad. Prioritizing the management of water bodies in our study sites and elsewhere would be essential to sustain amphibian population dynamics, enhancing individual movement and genetic exchange.

A statistical description of flow regions with negative streamwise velocity is provided based on simulations of turbulent plane channels in the Reynolds number range$547\\leqslant Re_{\\unicode[STIX]{x1D70F}}\\leqslant 2003$. It is found that regions of backflow are attached and their density per surface area – in wall units – is an increasing function of$Re_{\\unicode[STIX]{x1D70F}}$. Their size distribution along the three coordinates reveals that, even though in the mean they appear to be circular in the wall-parallel plane, they tend to become more elongated in the spanwise direction after reaching a certain height. Time-tracking of backflow regions in a$Re_{\\unicode[STIX]{x1D70F}}=934$simulation showed they convect downstream at the mean velocity corresponding to$y^{+}\\approx 12$, they seldom interact with other backflow events, their statistical signature extends in the streamwise direction for at least$300$wall units, and they result from a complex interaction between regions of high and low spanwise vorticity far beyond the viscous sublayer. This could explain why some statistical aspects of these near-wall events do not scale in viscous units; they are dependent on the$Re_{\\unicode[STIX]{x1D70F}}$-dependent dynamics further away from the wall.

hTERT is the catalytic subunit of the telomerase and is hence required for telomerase maintenance activity and cancer cell immortalization. Here, we show that acute hTERT depletion has no adverse effects on the viability or proliferation of cervical and colon carcinoma cell lines, as evaluated within 72 h after transfection with hTERT-specific small interfering RNAs (siRNAs). Within the same time frame, hTERT depletion facilitated the induction of apoptotic cell death by cisplatin, etoposide, mitomycin C and reactive oxygen species, yet failed to sensitize cells to death induction via the CD95 death receptor. Experiments performed with p53 knockout cells or chemical p53 inhibitors revealed that p53 was not involved in the chemosensitizing effect of hTERT knockdown. However, the proapoptotic Bcl-2 family protein Bax was involved in cell death induction by hTERT siRNAs. Depletion of hTERT facilitated the conformational activation of Bax induced by genotoxic agents. Moreover, Bax knockout abolished the chemosensitizing effect of hTERT siRNAs. Inhibition of mitochondrial membrane permeabilization by overexpression of Bcl-2 or expression of the cytomegalovirus-encoded protein vMIA (viral mitochondrial inhibitor of apoptosis), which acts as a specific Bax inhibitor, prevented the induction of cell death by the combination of hTERT depletion and chemotherapeutic agents. Altogether, our data indicate that hTERT inhibition may constitute a promising strategy for facilitating the induction of the mitochondrial pathway of apoptosis.