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Understanding the lateral distribution of carbonate facies is essential to understand reservoir continuity, geometry and quality, and, as a consequence, can help improving development strategies as reservoir characteristics vary between dif- ferent types of depositional environments. This study focuses on three outcrops of Zechstein-2-Carbonates (second cycle, Stassfurt, Ca2) along the SW margin of the Harz Mountains. The carbonates were deposited on the Eichsfeld-Altmark Swell, a NNE–SSW striking palaeohigh at the southern margin of the Southern Permian Basin. For each outcrop, different gross depositional environments (GDE) from slope to platform margin to inner platform deposition are interpreted and correlated over a lateral distance of 25 km. Reservoir characteristics are analysed with regard to the interpreted type of depositional environment and exemplarily compared to subsurface data of a gas-producing Ca2 field, representing one interpreted GDE type, at a distance of approximately 130 km to the NW in the Lower Saxony Basin. Porosity values of the slope carbonates in outcrop are in good accordance with the provided subsurface slope data. Both show a similar range of values and average porosities of approximately 6 % (outcrop) and 4 % (reservoir). In contrast, per- meability values of the subsurface samples are increased compared to outcrop values which may be due to micro-fracturing. Platform-related grainstone facies show best matrix porosities and permeabilities, and highest proportions of those outcrop carbonates are located in the centre of the studied Eichsfeld-Altmark Swell. Porosity-permeability relationships are derived for the interpreted gross depositional environments. In combination with the presented lateral GDE correlation lengths of 25 km, they can be incorporated into models of Ca2 reservoirs in NW Germany. Subsurface information about the depositional environment distribution potentially derived from core descriptions are the basis to choose the correct outcrop analogue for future studies of the structural inventory and lateral reservoir quality variations. Kurzfassung:Die Reservoireigenschaften in Karbonatgesteinen sind verschiedenen Ablagerungstypen zugeordnet. Ein Verständnis der lateralen Faziesverteilung der Karbonate kann somit der Schlüssel zu einem besseren Verständnis der Lager- stättenkontinuität, -geometrie und -qualität darstellen. Im Fokus dieser Arbeit stehen drei Zechstein-Karbonat-Aufschlüsse (Zweiter Zyklus, Stassfurt, Ca2) am SW-Rand des Harzes. Diese Karbonate wurden am Südrand des Südpermischen Beck- ens auf der Eichsfeld-Altmark-Schwelle, einem NNE–SSW streichendem Paläohochgebiet, abgelagert. Es werden Ablagerungsgebiete des Plattformhanges, des Plattformrandes und der inneren Plattform in jedem Aufschluss unterschieden. Basierend auf dieser Interpretation können die untersuchten Aufschlüsse über den Verlauf der Schwelle über eine Entfernung von 25 km korreliert werden. Die erhobenen Daten werden mit Reservoirdaten eines 130 km in NW-Rich- tung liegenden Feldes, welches eines der untersuchten Ablagerungsgebiete widerspiegelt, verglichen. Porositäten der Platt- formhang-Karbonate im Aufschluss (ca. 6 %) und Reservoir (ca. 4 %) sind vergleichbar, jedoch sind die Permeabilitäten in den Aufschlussgesteinen reduziert. Die erhöhten Permeabilitäten der Reservoirgesteine können möglicherweise durch Mi- krorissbildung erklärt werden. Beste Reservoirqualitäten zeigen die Karbonate des Plattformrandes, die im Bereich des Zentrums der untersuchten Schwelle die größten Mächtigkeiten aufweisen. Zusammen mit der Korrelation der untersuchten Ablagerungsgebiete über eine Länge von 25 km können diese Informationen in Untergrundmodelle der Zechstein-2-Kar- bonate in NW Deutschland eingefügt werden. Um ein mögliches Aufschlussanalog, welches wichtige zusätzliche Informationen über laterale Reservoirheterogenitäten liefern kann, zu definieren, werden Untergrunddaten über die Verteilung der Ablagerungsräume des jeweiligen Feldes benötigt.

B-cell acute lymphoblastic leukemia (B-ALL) is characterized by a multitude of recurrent genetic alterations, which drive malignant transformation. Besides their essential role in leukemia biology these aberrations also serve as predictors of treatment response and survival, making their reliable detection a prerequisite for risk stratification in state-of-the-art clinical trials. Currently, the genetic characterization of B-ALL in most diagnostic laboratories still relies on an integrative approach combining conventional cytogenetics, reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) assays as well as single nucleotide polymorphism (SNP) array analysis. However, these conventional diagnostic tools fail to identify a considerable number of genetic alterations, particularly cryptic rearrangements such as IGH::DUX4, IGH::EPORor MEF2Dinvolving fusions. Although next generation DNA- and RNA-based sequencing (NGS) assays have significantly improved the reliable detection of fusion genes, the need for large sample numbers to achieve acceptable turnaround times and cost effectiveness impairs their application in small- to medium-sized diagnostic laboratories.

Understanding natural fracture networks in the subsurface is highly challenging, as direct one-dimensional borehole data are unable to reflect their spatial complexity, and three-dimensional seismic data are limited in spatial resolution to resolve individual meter-scale fractures. Here, we present a prototype workflow for automated fracture detection along horizontal scan lines using terrestrial light detection and ranging (t-LIDAR). Data are derived from a kilometer-scale Pennsylvanian (locally upper Carboniferous) reservoir outcrop analog in the Lower Saxony Basin, northwestern Germany. The workflow allows the t-LIDAR data to be integrated into conventional reservoir-modeling software for characterizing natural fracture networks with regard to orientation and spatial distribution. The analysis outlines the lateral reorientation of fractures from a west-southwest/east-northeast strike, near a normal fault with approximately 600 m (~1970 ft) displacement, toward an east-west strike away from the fault. Fracture corridors, 10-20 m (33-66 ft) wide, are present in unfaulted rocks with an average fracture density of 3.4-3.9 m-1 (11.2-12.8 ft-1). A reservoir-scale digital outcrop model was constructed as a basis for data integration. The fracture detection and analysis serve as input for a stochastically modeled discrete fracture network, demonstrating the transferability of the derived data into standard hydrocarbon exploration-and-production-industry approaches. The presented t-LIDAR workflow provides a powerful tool for quantitative spatial analysis of outcrop analogs, in terms of natural fracture network characterization, and enriches classical outcrop investigation techniques. This study may contribute to a better application of outcrop analog data to naturally fractured reservoirs in the subsurface, reducing uncertainties in the characterization of this reservoir type at depth. [ABSTRACT FROM AUTHOR]

Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR+ B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR+ ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations. In pre-BCR+ ALL, ibrutinib thwarted autonomous and induced pre-BCR signaling, resulting in deactivation of PI3K/Akt signaling. Ibrutinib modulated the expression of pre-BCR regulators (PTPN6, CD22, CD72, and PKCβ) and substantially reduced BCL6 levels. Ibrutinib inhibited ALL cell migration toward CXCL12 and beneath marrow stromal cells and reduced CD44 expression. CRISPR-Cas9 gene editing revealed that both BTK and B lymphocyte kinase (BLK) are relevant targets of ibrutinib in pre-BCR+ ALL. Consequently, in mouse xenograft models of pre-BCR+ ALL, ibrutinib treatment significantly prolonged survival. Combination treatment of ibrutinib with dexamethasone or vincristine demonstrated synergistic activity against pre-BCR+ ALL. These data corroborate ibrutinib as a promising targeted agent for pre-BCR+ ALL and highlight the importance of ibrutinib effects on alternative kinase targets.

Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR+B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR+ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations. In pre-BCR+ALL, ibrutinib thwarted autonomous and induced pre-BCR signaling, resulting in deactivation of PI3K/Akt signaling. Ibrutinib modulated the expression of pre-BCR regulators (PTPN6, CD22, CD72, and PKCβ) and substantially reduced BCL6 levels. Ibrutinib inhibited ALL cell migration toward CXCL12 and beneath marrow stromal cells and reduced CD44 expression. CRISPR-Cas9 gene editing revealed that both BTK and B lymphocyte kinase (BLK) are relevant targets of ibrutinib in pre-BCR+ALL. Consequently, in mouse xenograft models of pre-BCR+ALL, ibrutinib treatment significantly prolonged survival. Combination treatment of ibrutinib with dexamethasone or vincristine demonstrated synergistic activity against pre-BCR+ALL. These data corroborate ibrutinib as a promising targeted agent for pre-BCR+ALL and highlight the importance of ibrutinib effects on alternative kinase targets.

To compare early versus delayed intravitreal betamethasone as an adjuvant in the treatment of presumed acute postoperative endophthalmitis after phacoemulsification.

La DMLA exsudative est caractérisée par la formation de néovaisseaux choroïdiens, médiée par le facteur de croissance endothélial vasculaire (VEGF) responsable d’une baisse d’acuité visuelle et de métamorphopsies d’apparition brutale. L’injection intravitréenne d’anti-VEGF permet de stabiliser, voire d’améliorer, l’acuité visuelle. Si la question de la phase d’induction par injection d’anti-VEGF fait consensus chez les ophtalmologues, il existerait des divergences en pratique quant aux modalités de prise en charge thérapeutique. L’objectif de ce travail était d’explorer cette hypothèse et de mieux comprendre les pratiques en vie réelle.

The vascular endothelial growth factor (VEGF) is a central mediator of tumor-induced angiogenesis. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, decreases VEGF-secretion of cancer cells. Vatalanib is a selective inhibitor of VEGF receptors 1-3. In the present study it was hypothesized that dual inhibition of VEGF signaling by inhibition of VEGF production and VEGF receptor signaling leads to synergistic anti-tumor effects. In vitro, effects of vatalanib and everolimus on cell proliferation, cell cycle, apoptosis and signal transduction were examined in three gastric cancer cell lines. Effects on angiogenesis were assessed using tube formation assays of cultured human umbilical vein endothelial cells (HUVECs). In vivo, the anti-tumor effect of compounds was studied using a gastric cancer xenograft nude mouse model. VEGF of murine origin (mVEGF) and human cancer cell-derived VEGF (hVEGF) were studied separately by specific ELISAs. Tumor vascularization and proliferation were quantified by immunohistochemistry. In vitro, everolimus but not vatalanib decreased gastric cancer proliferation without inducing apoptosis. Vatalanib abolished endothelial cell tube formation, whereas inhibition of tube formation by everolimus was incomplete. In vivo, the combination of vatalanib with everolimus was superior to single agent treatments and reduced tumor size by about 50% relative to everolimus monotherapy (p

Le traitement de la DMLA fait appel aux injections intravitréennes d’anti-VEGF comme l’aflibercept (Eylea®, laboratoire Bayer Healthcare). Ces injections nécessitent une antiseptie et des collyres anesthésiques et antibiotiques parfois allergisants.

Burger: Pharmacyclics: Research Funding. Westin:Chugai: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; ProNAi: Membership on an entity's Board of Directors or advisory committees.

Westin: Spectrum: Research Funding.

La maladie de Vogt-Koyanagi-Harada (VKH) est une pathologie auto-immune rare affectant les yeux, les oreilles, les méninges et la peau. La cible semble être les antigènes associés aux mélanocytes.

No relevant conflicts of interest to declare.

Coffey: Portola Pharmaceuticals: Employment, Equity Ownership.

A pivotal step during B-cell development is the expression of the precursor B-cell receptor (pre-BCR) by pre-B lymphocytes (cyto-Igµ+, surface-IgM-). The pre-BCR represents an immature form of the BCR and consists of two immunoglobulin heavy chains (IgH), two surrogate light chains (SLC) and the signal transducing adapter proteins Igα and Igβ. A functional pre-BCR drives proliferation of pre-B-cells, ensuring their further differentiation into mature B-cells. By immunophenotype, ~20% of B-cell acute lymphoblastic leukemia (B-ALL) cases originate from the pre-B-cell stage (pre-B-ALL) of lymphocyte development and might therefore also express the pre-BCR. In view of the importance of pre-BCR signaling for normal pre-B-cell development, we hypothesize that it is exploited by pre-B-ALL for malignant growth and proliferation.

Phosphoinositide-3-kinases (PI3K) play an important role in transmitting signals from surface receptors such as the B-cell receptor (BCR), cytokine receptors and receptor tyrosine kinases, that result in survival and growth of normal and malignant B cells. In mature B-cell malignancies such as CLL and indolent B-NHL, the PI3K pathway is constitutively upregulated and is dependent on PI3Kδ. Idelalisib is a p110δ-isoform-specific PI3K inhibitor that is highly active in patients with CLL and indolent NHL. In contrast to mature B cell malignancies, expression and function of PI3Kδ in B-ALL has not been well characterized.

Coffey: Portola Pharmaceuticals: Employment.

Bruton′s tyrosine kinase (BTK) is a member of TEC family of non-receptor tyrosine kinases. BTK is mostly expressed in hematopoietic cell lineages, except in T cells. It plays a particularly important role in B cell development and is present at almost all stages of their maturation, disappearing only in plasma cells. BTK is an essential kinase downstream of pre-B cell (pre-BCR) and B cell receptors (BCR) promoting proliferation, differentiation and survival of B cells.Surface protein expression in B-cell acute lymphoblastic leukemia (B-ALL) cell lines was assessed by flow cytometry using PE conjugated anti-CD179a, anti-CD179b (BioLegend) and anti-CD22 (BD Pharmingen). To investigate effects of the BTK inhibitor ibrutinib (PCI-32765) on constitutive pre-BCR signaling RCH-ACV cells were pretreated with 0.1% DMSO or increasing concentrations of the drug (0.0001, 0.001, 0.01, 0.1, 1.0 μM) for 1 hour and lysed in RIPA buffer. To induce pre-BCR signaling in pretreated cells they were incubated with 10 μg/ml of anti-Igμ for 30 minutes. Intracellular calcium mobilization was measured by using the fluorogenic probe Fluo3-AM (Invitrogen). RCH-ACV cells pretreated with 1 μM ibrutinib for 72 hours were subjected to gene expression profile analysis on HT-12 v4 Expression BeadChip (Illumina).Previously we explored the effects of ibrutinib in B-ALL cell lines and primary samples. Ibrutinib induced only low levels of apoptosis in B-ALL cell lines, but significantly inhibited their proliferation. RCH-ACV and SMS-SB were the most sensitive cell lines with half maximal inhibitory concentrations of ibrutinib of 0.6 and 0.4 μM found in XTT cell proliferation assay. Interestingly, both cell lines expressed a pre-B cell immunophenotype with pre-BCR surface expression. Next, we explored the effect of BTK inhibition on constitutive and induced pre-BCR signaling. Treatment of RCH-ACV cells with varying concentrations of ibrutinib resulted in decreased levels of pBTK, pAKT, pS6 and pSYK. The lowest concentration of ibrutinib needed to observe complete disappearance of pBTK (Y223) and any reduction of other phospho-proteins was 10 nM, however the maximum effect was achieved with 1 μM ibrutinib. Upon pre-BCR crosslinking with anti-Igμ elevated levels of pSYK, pBTK, pAKT, pS6 and pERK were detected in RCH-ACV. Pretreatment of the cells with ibrutinib greatly reduced this effect. As calcium mobilization is another important indicator of B cell activation upon pre-BCR stimulation, we evaluated ibrutinib in calcium flux assays. Pretreatment with 1 μM ibrutinib effectively abrogated anti-Igμ induced calcium flux in pre-B ALL cell lines. Gene expression profile analysis of RCH-ACV cells after 72 hours of incubation with 1 μM ibrutinib showed down-regulation of pre-BCR related genes such as PTPN6 (SHP-1), Bcl6 and CD22. Flow cytometry analysis confirmed the down-regulation of the inhibitory co-receptor CD22 in pre-B ALL cell lines after incubation with ibrutinib. The down-regulation of SHP-1 protein was verified by western blotting.The results indicate that ibrutinib reduces the pre-B ALL cell proliferation by inhibiting constitutive and/or induced pre-BCR signaling. Observed down-regulation of CD22 and SHP-1, known negative regulators of BCR signaling, suggests a possible mechanism of cell adaptation to the presence of the BTK inhibitor. Taken together, these data provide a rationale for clinical testing of ibrutinib in B-ALL with active pre-BCR signaling.O'Brien: Pharmacyclics: Research Funding. Buggy:Pharmacyclics: Employment. Burger:Pharmacyclics: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

O'Brien: Pharmacyclics: Research support Other. Buggy:Pharmacyclics: Employment, Equity Ownership. Burger:Pharmacyclics: Consultancy, Research Funding.

Lannutti: Gilead Sciences Inc: Employment.