Leakage of biodiversity risks under the European Union Biodiversity Strategy 2030.

The European Union Biodiversity Strategy 2030 (EUBDS) aims to regain biodiversity through enhanced forest conservation and protection, which may lead to increased timber harvest in non-EU countries. We aimed to identify the potential leakage of biodiversity risks as induced by the EUBDS. We created an indicator framework that allows one to quantify vulnerability of forest biodiversity. The framework is based on 26 biodiversity indicators for which indicator values were publicly available. We weighted single indicator values with countrywise modeled data on changed timber production under EUBDS implementation. Nearly 80% of the indicators pointed to higher vulnerability in the affected non-EU countries. Roundwood production was transferred to countries with, on average, lower governance quality (p = 0.0001), political awareness (p = 0.548), forest coverage (p = 0.034), and biomass (p = 0.272) and with less sustainable forest management (p = 0.044 and p = 0.028). These countries had more natural habitats (p = 0.039) and intact forest landscapes (p = 0.0001) but higher risk of species extinction (p = 0.006) and less protected area (p = 0.0001) than the EU countries. Only a few indicators pointed to lower vulnerability and biodiversity risks outside the EU. Safeguards are needed to ensure that implementation of EUBDS does not cause harm to ecosystems elsewhere. The EU regulation on deforestation-free supply chains might have limited effects because the sustainable management of existing and even expanding forests is not well considered. Sustained roundwood production in the EU is needed to avoid placing more pressure on more vulnerable ecosystems elsewhere. Decreasing species and habitat indicator values nevertheless call for global conservation and protection schemes. The EUBDS helped pave the way to the Kunming-Montreal Biodiversity Framework. Yet, lower values for the indicators mean governance and biodiversity engagement in non-EU countries suggest that this global framework might not sufficiently prevent leakage of risks to biodiversity. Effective land-use planning is necessary to balance conservation schemes with roundwood production.

Evaluación de la fuga de riesgos para la biodiversidad bajo la Estrategia de la Unión Europea sobre Biodiversidad 2030 Resumen La Estrategia de la Unión Europea sobre Biodiversidad 2030 (EEUSBD) busca recuperar la biodiversidad por medio de mejoras en la conservación y protección forestal, lo que podría derivar en un incremento en la producción maderera en los países que no pertenecen a la UE. Buscamos identificar la posible fuga de riesgos para la biodiversidad inducida por la EEUSBD. Creamos un marco indicador que permita cuantificar la vulnerabilidad de la biodiversidad forestal. El marco se basa en 26 indicadores de biodiversidad cuyos valores están disponibles al público. Ponderamos los valores de los indicadores individuales con datos modelados por países sobre los cambios en la producción maderera tras la aplicación de la EEUSBD. Casi el 80% de los indicadores señalaron un aumento de la vulnerabilidad en los países afectados que no pertenecen a la UE. La extracción forestal se transfirió a países que en promedio tienen menor calidad de gobierno (p = 0.0001), conciencia política (p = 0.548), cobertura forestal (p = 0.034) y biomasa (p = 0.272) y con un manejo forestal menos sustentable (p = 0.044 y p = 0.028). Estos países tienen más hábitats naturales (p = 0.039) y paisajes forestales intactos (p = 0.0001) pero un riesgo más elevado de extinción de especies (p = 0.006) y un área menos protegida (p = 0.0001) que los países de la UE. Sólo unos cuantos indicadores señalaron una reducción en la vulnerabilidad y los riesgos para la biodiversidad fuera de la UE. Se requieren salvaguardas para asegurar que la implementación de la EEUSBD no dañe los ecosistemas en otras partes. La regulación de la UE sobre las cadenas de producción libres de deforestación podría tener efectos limitados pues no se considera correctamente el manejo sustentable del bosque existente o en expansión. También se requiere una extracción forestal sostenida en la UE para evitar una mayor presión sobre otros ecosistemas vulnerables en otras localidades. Sin embargo, la reducción en los valores de los indicadores de especies y hábitat exige esquemas mundiales de conservación y protección. La EEUSBD ayudó a trazar el camino para el Marco Mundial de Biodiversidad de Kunming­Montreal, sin embargo, los valores más bajos de los indicadores de gobernanza y compromiso con la biodiversidad en países no pertenecientes a la UE sugieren que este marco global podría no prevenir efectivamente las fugas de riesgos para la biodiversidad. Es necesario planear eficientemente el uso de suelo para balancear los esquemas de conservación con la extracción forestal.

监测区域保护的治理和管理有效性早已被视为实现国家和全球生物多样性目标和实现适应性管理的重要基础。然而, 保护行动者(包括受治理和管理系统影响的人们)在实施保护活动和计划, 以及收集和利用治理和管理数据为跨时空尺度的决策提供信息的过程中, 仍面临重重阻碍。本文探讨了当前和过去为评估治理和管理有效性所做的努力、行动者在使用产出数据时面临的阻碍, 以及为保护决策提供信息的洞见。为了帮助克服这些阻碍, 我们开发了Elinor这一免费开源监测工具, 该工具以诺贝尔奖获得者Elinor Ostrom的研究成果为基础, 旨在促进不同治理和管理类型区域跨空间尺度的环境治理和管理数据的收集、存储、共享、分析和使用。本文介绍了与保护科学家和实践者共同设计和试用Elinor的过程, 以及其评估和在线数据系统的主要组成部分。我们还考虑了Elinor如何对现有方法进行补充, 包括:在单一评估中高水平地处理不同类型区域保护的治理和管理问题, 为数据收集提供灵活的选择, 以及整合数据系统与评估来支持不同空间尺度的数据使用和共享, 包括对《全球生物多样性框架》的全球监测。虽然挑战持续存在, 但Elinor的开发过程和工具本身为克服系统性收集和使用治理与管理数据中面临的阻碍提供了切实的解决方案。随着Elinor被更广泛地采用, 它将在实现更有效、更包容和更长期的基于区域的保护中发挥宝贵作用。【翻译:胡怡思;审校:聂永刚】.

The availability and type of lesbian, gay, bisexual, transgender, and queer content on sperm, oocyte, and embryo provider websites.

PURPOSE: To evaluate and quantify the character and amount of lesbian, gay, bisexual, transgender, and queer (LGBTQ +) content on sperm, oocyte, and embryo provider websites in the USA. METHODS: Websites with LGBTQ + information were categorized into "minimal," "moderate," and "significant" content. The presence and type (category) of LGBTQ + content were assessed in its relationship to geographic regions, in vitro fertilization (IVF) cycles/year, and website types. Interobserver reliability was assessed for the categorization system created. RESULTS: Out of 373 unique websites, 191 (51.2%) had LGBTQ + content of any kind. Regarding the amount of content, websites were categorized as "none" (48.8%), "minimal" (8.0%), "moderate" (28.4%), and "significant" (14.8%). "Private fertility clinic" websites were more likely to have LGBTQ + content and a significantly increased amount of content compared to other website types ("academic hospital" and "sole sperm, oocyte, and embryo provider" websites) (p < 0.0001). Fertility clinics with more IVF cycles/year were more likely to have increased amount of LGBTQ + content compared to those with fewer IVF cycles/year (OR = 4.280; 95% CI, 1.952-9.388). Northeast, West, South, and Midwest regions showed no statistically significant difference in presence and type of content (p = 0.06 and p = 0.13, respectively). CONCLUSION: Approximately half of websites had LGBTQ + content. Private fertility clinics and fertility clinics with increased IVF cycles/year show a positive relationship to the presence and type of LGBTQ + content, while LGBTQ + website content was similar across four geographic regions.

High-power lasers for directed-energy applications.

In this article, we review and discuss the research programs at the Naval Research Laboratory (NRL) on high-power lasers for directed-energy (DE) applications in the atmosphere. Physical processes affecting propagation include absorption/scattering, turbulence, and thermal blooming. The power levels needed for DE applications require combining a number of lasers. In atmospheric turbulence, there is a maximum intensity that can be placed on a target that is independent of the initial beam spot size and laser beam quality. By combining a number of kW-class fiber lasers, scientists at the NRL have successfully demonstrated high-power laser propagation in a turbulent atmosphere and wireless recharging. In the NRL experiments, four incoherently combined fiber lasers having a total power of 5 kW were propagated to a target 3.2 km away. These successful high-power experiments in a realistic atmosphere formed the basis of the Navy's Laser Weapon System. We compare the propagation characteristics of coherently and incoherently combined beams without adaptive optics. There is little difference in the energy on target between coherently and incoherently combined laser beams for multi-km propagation ranges and moderate to high levels of turbulence. Unlike incoherent combining, coherent combining places severe constraints on the individual lasers. These include the requirement of narrow power spectral linewidths in order to have long coherence times as well as polarization alignment of all the lasers. These requirements are extremely difficult for high-power lasers.

Wintering Bald Eagle Count Trends in the Conterminous United States, 1986-2010.

We analyzed counts from the annual Midwinter Bald Eagle Survey to examine state, regional, and national trends in counts of wintering Bald Eagles (Haliaeetusleucocephalus) within the conterminous 48 United States from 1986 to 2010. Using hierarchical mixed model methods, we report trends in counts from 11,729 surveys along 844 routes in 44 states. Nationwide Bald Eagle counts increased 0.6% per yr over the 25-yr period, compared to an estimate of 1.9% per yr from 1986 to 2000. Trend estimates for Bald Eagles were significant (P≤0.05) and positive in the northeastern and northwestern U.S. (3.9% and 1.1%, respectively), while trend estimates for Bald Eagles were negative (P≤0.05) in the southwestern U.S. (-2.2%). After accounting for potential biases resulting from temporal and regional differences in surveys, we believe trends reflect post-DDT recovery and subsequent early effects of density-dependent population regulation.

Exploring continental-scale stand health - N : P ratio relationships for European forests.

Understanding the relationship between nitrogen (N) availability and stand health in forest ecosystems is crucial, because a large proportion of European forests is subjected to N-deposition levels beyond their retention capacity. We used data from a long-term forest monitoring programme (ICP Forests) to test the relationship between an index of N availability, foliar nitrogen : phosphorus (N : P) ratios, tree defoliation and discoloration. We hypothesized a segmented response of stand health to N : P ratios and an improved model-fit after correcting for climatic covariates. In accordance with the hypothesis, we found a segmented response with a breakpoint for conifer defoliation at N : P ratios as low as 7.3. Inclusion of climatic variables improved the fit of the models, but there was significant collinearity with N : P. Increases in N availability appear, at least for conifers, to have a negative effect on tree health even under N-limiting conditions. Regulation of N-deposition levels is consequently as timely as ever. We propose that increases in tree defoliation, other than resulting in serious plant fitness issues, may represent early diagnostic symptoms of N-addition related imbalances.

CD40 inhibits replication of hepatitis C virus in primary human hepatocytes by c-Jun N terminal kinase activation independent from the interferon pathway.

UNLABELLED: CD40, a member of the tumor necrosis factor receptor family, and its ligand, CD40L (CD154), are important regulators of the antiviral immune response. CD40L is up-regulated on lymphocytes and CD40 on hepatocytes during infection with hepatitis C virus (HCV); we investigated the role of CD40 signaling during HCV replication in hepatocytes. Viral replication was studied in primary human hepatocytes (PHH) and Huh7.5 cells using the infectious HCV Japanese fulminate hepatitis 1 isolate (JFH1) culture system, and in coculture with HCV antigen-specific CD8+ T cells. CD40L rapidly and transiently inhibits expression of the HCV nonstructural proteins NS3 and NS5A as well as HCV structural proteins core and E2 in Huh7.5 cells. Similarly, CD40L prevented replication of HCV in PHH, in synergy with interferon (IFN)-alpha. In Huh7.5 cells with replicating HCV, CD40L prevented production of infectious viral particles. When HCV antigen-specific CD8+ T cells were cocultured with HLA-A2-expressing Huh7 cells that had replicating virus, the T cells became activated, up-regulated CD40L, and inhibited HCV replication. Inhibition of CD40L partially prevented the antiviral activity of the CD8+ T cells. The antiviral effect of CD40L required activation of c-Jun N terminal kinases (JNK)1/2, but not induction of apoptosis or the JAK/STAT pathway that is necessary for the antiviral effects of IFNs. CONCLUSION: CD40 inhibits HCV replication by a novel, innate immune mechanism. This pathway might mediate viral clearance, and disruptions might be involved in the pathogenesis of HCV infection.

Environmental drivers of ectomycorrhizal communities in Europe's temperate oak forests.

Ectomycorrhizal fungi are major ecological players in temperate forests, but they are rarely used in measures of forest condition because large-scale, high-resolution, standardized and replicated belowground data are scarce. We carried out an analysis of ectomycorrhizas at 22 intensively monitored long-term oak plots, across nine European countries, covering complex natural and anthropogenic environmental gradients. We found that at large scales, mycorrhizal richness and evenness declined with decreasing soil pH and root density, and with increasing atmospheric nitrogen deposition. Shifts in mycorrhizas with different functional traits were detected; mycorrhizas with structures specialized for long-distance transport related differently to most environmental variables than those without. The dominant oak-specialist Lactarius quietus, with limited soil exploration abilities, responds positively to increasing nitrogen inputs and decreasing pH. In contrast, Tricholoma, Cortinarius and Piloderma species, with medium-distance soil exploration abilities, show a consistently negative response. We also determined nitrogen critical loads for moderate (9.5-13.5 kg N/ha/year) and drastic (17 kg N/ha/year) changes in belowground mycorrhizal root communities in temperate oak forests. Overall, we generated the first baseline data for ectomycorrhizal fungi in the oak forests sampled, identified nitrogen pollution as one of their major drivers at large scales and revealed fungi that individually and/or in combination with others can be used as belowground indicators of environmental characteristics.

Cesarean section prior to 28 weeks' gestation: which type of uterine incision is optimal?

OBJECTIVE: The purpose of this study was to determine the factors that influence physician preference for type of hysterotomy incisions in gravidas with a singleton or twin pregnancy undergoing cesarean section under 28 weeks, and to assess factors that result in delivery complications, defined as either intraoperative dystocia or hysterotomy extension. We hypothesized that compared to those with non-cephalic presentations, gravidas with a presenting fetus in cephalic presentation would have higher rates of low-transverse cesarean section, and reduced rates of delivery complications with low-transverse hysterotomy. METHODS: This was a retrospective cohort chart analysis of 128 gravidas between 23 0/7 and 27 6/7 weeks undergoing cesarean section at a single academic institution between August 2010 and December 2022. Data was abstracted for factors that might influence the decision for hysterotomy incision type, as well as for documentation of difficulty with delivery of the fetus or need for hysterotomy extension to affect delivery. RESULTS: There was a total of 128 subjects, 113 with a singleton gestation and 15 with twins. The presenting fetus was in cephalic presentation in 43 (33.6%), breech presentation in 71 (55.5%), transverse/oblique lie in 13 (10.2%), and not documented in 1 (0.8%). Sixty-eight (53.1%) had a low-transverse cesarean section (LTCS), 53 (41.4%) had a Classical, 5 (3.9%) had a low-vertical hysterotomy and 2 (1.6%) had a mid-transverse incision. There was a significantly higher rate of LTCS among gravidas with the presenting fetus in cephalic presentation (30/43, 69.8%) compared to those with breech (31/71, 43.7%) or transverse/oblique presentations (7/13, 53.8%), p = .03. No other significant associations were related to hysterotomy incision, including nulliparity, racially or ethnically minoritized status, plurality, indication for cesarean delivery, or pre-cesarean labor. Twenty (15.6%) subjects experienced either an intraoperative dystocia or hysterotomy extension. For the entire cohort, there was a greater median cervical dilatation in those with delivery complications (4.0 cm, IQR .5 - 10 cm) compared to those without complications (1.5, IQR 0 - 4.0), p = .03, but no significant association between delivery complications and fetal presentation, hysterotomy type, plurality, or other demographic/obstetrical factors. However, among gravidas undergoing low-transverse cesarean section, only 2/30 (6.7%) with cephalic presentations had a delivery complication, compared to 9/31 (29.0%) with breech presentations and 3/7 (42.9%) with a transverse/oblique lie, p = .03. CONCLUSION: In pregnancies under 28 weeks, the performance of a low-transverse cesarean section was significantly associated only with presentation of the presenting fetus. Among those with cephalic presentations, the rate of intrapartum dystocia or hysterotomy extension was low after a low-transverse hysterotomy, suggesting that in this subgroup, a low-transverse cesarean section should be considered.

Performance improvement of nanocatalysts by promoter-induced defects in the support material: methanol synthesis over Cu/ZnO:Al.

Addition of small amounts of promoters to solid catalysts can cause pronounced improvement in the catalytic properties. For the complex catalysts employed in industrial processes, the fate and mode of operation of promoters is often not well understood, which hinders a more rational optimization of these important materials. Herein we show for the example of the industrial Cu/ZnO/Al2O3 catalyst for methanol synthesis how structure-performance relationships can deliver such insights and shed light on the role of the Al promoter in this system. We were able to discriminate a structural effect and an electronic promoting effect, identify the relevant Al species as a dopant in ZnO, and determine the optimal Al content of improved Cu/ZnO:Al catalysts. By analogy to Ga- and Cr-promoted samples, we conclude that there is a general effect of promoter-induced defects in ZnO on the metal-support interactions and propose the relevance of this promotion mechanism for other metal/oxide catalysts also.

Reconciling policy instruments with drivers of deforestation and forest degradation: cross-scale analysis of stakeholder perceptions in tropical countries.

Cross-scale studies combining information on policy instruments and on drivers of deforestation and forest degradation are key to design and implement effective forest protection measures. We investigated the scale and country dependency of stakeholder perceptions about future threats to tropical forests (e.g. agriculture, logging, woodfuel) and preferred policy instruments (e.g. reforestation, protected areas, combat illegal logging), by interviewing 224 representatives of forest-related institutions. We conducted analysis of variance and principal component analysis for eighteen variables across three countries (Zambia, Ecuador and the Philippines) and four spatial levels (from international to local). We found that the overall alertness about commercial drivers and the confidence in policy instruments are significantly lower at subnational levels and also in Zambia. Stakeholder expectations about the most important drivers and the most effective policies in the coming decade follow regional narratives, suggesting that there are no one-size-fits-all solutions in international forest policy. However, we found an unexpected consensus across scales, indicating potential for collaboration between institutions operating at different geographical levels. Overall, agriculture remains the driver with the highest expected influence (43%), while a strong favoritism for reforestation and forest restoration (38%) suggests a paradigm shift from protected areas to a stronger focus on integrative approaches.

Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.

Pitt-Hopkins syndrome (PTHS), characterized by severe intellectual disability and typical facial gestalt, is part of the clinical spectrum of Rett-like syndromes. TCF4, encoding a basic helix-loop-helix (bHLH) transcription factor, was identified as the disease-causing gene with de novo molecular defects. While PTHS appears to be a recognizable clinical entity, it seems to remain underdiagnosed, especially when facial gestalt is less typical. With the aim to facilitate the diagnosis of PTHS and to increase its rate and specificity, we have investigated 33 novel patients and defined a Clinical Diagnosis Score. Analysis of 112 individuals (79 previously reported and 33 novel patients) allowed us to delineate the TCF4 mutational spectrum, with 40% point mutations, 30% small deletions/insertions, and 30% deletions. Most of these were private mutations and generated premature stop codons. Missense mutations were localized in the bHLH domain, which is a mutational hotspot. No obvious difference was observed between patients harboring truncating, missense mutations, or deletions, further supporting TCF4 haploinsufficiency as the molecular mechanism underlying PTHS. In this study, we have summarized the current knowledge of TCF4 molecular pathology, reported all the mutations in the TCF4 database (http://www.LOVD.nl/TCF4), and present a novel and comprehensive diagnostic strategy for PTHS.

Low perforin expression of early differentiated HCV-specific CD8+ T cells limits their hepatotoxic potential.

BACKGROUND & AIMS: Perforin plays a central role in the immunopathogenesis of different viral infections. However, its role in hepatitis C virus (HCV) infection has not been fully understood. Here, we analyzed two closely related questions: first, is CD8+ T cell-mediated killing of HCV-replicating human hepatoma cells mediated by perforin? Second, if so, do HCV-specific CD8+ T cells obtained from chronically HCV infected patients express and upregulate perforin? METHODS: Susceptibility of HCV-replicating human hepatoma cells to the cytotoxic pathway was tested in vitro by addition of perforin substitute streptolysin O and granzyme B and by co-culture experiments with a perforin-expressing HCV-specific CD8+ T cell clone in the presence of perforin or caspase inhibitors. HCV-specific CD8+ T cells were obtained and analyzed for perforin expression and differentiation markers ex vivo from 12 chronically infected patients and 12 patients with resolved HCV infection. RESULTS: HCV-replicating human hepatoma cells were susceptible to cytotoxic killing in vitro and a dominant role of perforin in HCV-specific CD8+ T cell-mediated cytolysis was observed. However, HCV-specific CD8+ T cells obtained ex vivo from chronically HCV infected patients expressed only low levels of perforin and showed an impaired ability to upregulate perforin. This was tightly linked to the distinct differentiation stage of HCV-specific CD8+ T cell differentiation ex vivo since early and intermediate differentiated HCV-specific CD8+ T cells only showed weak perforin expression in contrast to late differentiated CD8+ T cells that displayed strong perforin expression. CONCLUSIONS: Our results suggest that perforin plays a dominant role in CD8+ T cell-mediated lysis of HCV-replicating human hepatoma cells but that lysis may be limited in human chronic viral infection by the low perforin expression of early/intermediate differentiated HCV-specific CD8+ T cells.

Preterm prelabor rupture of membranes prior to 33 0/7 weeks: when should rescue corticosteroids be given?

OBJECTIVE: To determine an optimal timing strategy for rescue corticosteroids in gravidas with preterm prelabor rupture of membranes (PPROM) prior to 33 0/7 weeks. METHODS: This was a retrospective cohort analysis of 109 gravidas with a singleton gestation and PPROM between 23 0/7 and 32 6/7 weeks who delivered at a single inner city tertiary care center. The time of the actual first dose of corticosteroids was chosen as Time 0. The date and time of labor onset, chorioamnionitis, heavy bleeding, cord prolapse, or fetal heart rate decelerations warranting delivery were recorded, as well as the date and time of delivery. We then compared hypothetical timing strategies for administration of the rescue course of corticosteroids at either 1, 2, or 3 weeks after the first course if still undelivered, compared to a strategy of withholding the rescue course until the recognition of spontaneous labor or the need for delivery. For each strategy, we calculated the percentage of gravidas who would have delivered within the optimal window after rescue course corticosteroids, defined as delivery at 24 h to 7 days from the first rescue dose. RESULTS: The median time from PPROM to delivery among the 109 gravidas was 8.9 days (interquartile range 4.4-17.9 days). Forty-eight (44%) gravidas delivered within the first week after initial corticosteroid administration, leaving 61 (56%) eligible for a rescue dose. In our hypothetical models, the strategy of giving rescue corticosteroids at either 1, 2, or 3 weeks from the first course would have resulted in 34.4%, 23.0%, and 19.7% of infants being born at 24 h to 7 days after the first rescue dose, respectively. These differences among the three groups or between any two groups were not statistically significant. However, all fixed interval strategies were statistically superior to the strategy of waiting for spontaneous labor or the need for delivery, in which only 4.9% would have delivered within the optimal window. CONCLUSION: In gravidas with PPROM prior to 33 0/7 weeks, giving rescue corticosteroids at a fixed interval of either 1, 2, or 3 weeks after the first course would result in a greater percentage of infants being born within the optimal 24 h to 7 day window compared to administering the rescue course at the onset of labor, infection, bleeding, or abnormal fetal heart rate tracing.

Nanometallurgy in solution: organometallic synthesis of intermetallic Pd-Ga colloids and their activity in semi-hydrogenation catalysis.

Nanoparticles (NPs) of Pd1--xGax (x = 0.67, 0.5, 0.33), stabilized in non-aqueous colloidal solution, were obtained via an organometallic approach under mild conditions using [Pd2(dvds)3] and GaCp* as all-hydrocarbon ligated metal-precursor compounds (dvds = 1,1,3,3-tetramethyl-1,3-divinyl-disiloxane; Cp* = η5-C5Me5; Me = CH3). The reaction of the two precursors involves the formation of a library of molecular clusters [PdnGamCp*y(dvds)z], as shown by liquid injection field desorption ionization mass spectrometry (LIFDI-MS). Full characterization of the catalytic system (HR-TEM, EDX, DLS, PXRD, XPS, NMR, IR, Raman) confirmed the formation of ultra-small, spherical NPs with narrow size distributions ranging from 1.2 ± 0.2 nm to 2.1 ± 0.4 nm (depending on the Pd : Ga ratio). The catalytic performance of the Pd1--xGax NPs in the semi-hydrogenation of terminal and internal alkynes and the influence of the gallium content on product selectivity were investigated. The highest activities (65%) and selectivities (81%) are achieved using colloids with a "stoichiometric" Pd/Ga ratio of 1 : 1 at 0 °C and 2.0 bar H2 pressure. While lower Ga ratios lead to an increase in activity, higher Ga contents increase the olefin selectivity but are detrimental to the activity.

Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program.

INTRODUCTION: We report on the results of the German early access program (EAP) with the third-generation ALK- and ROS1-inhibitor lorlatinib. PATIENTS AND METHODS: Patients with documented treatment failure of all approved ALK/ROS1-specific therapies or with resistance mutations not covered by approved inhibitors or leptomeningeal carcinomatosis were enrolled and analyzed. RESULTS: In total, 52 patients were included [median age 57 years (range 32-81), 54% female, 62% never smokers, 98% adenocarcinoma]; 71% and 29% were ALK- and ROS1-positive, respectively. G1202R and G2032R resistance mutations prior to treatment with lorlatinib were observed in 10 of 26 evaluable patients (39%), 11 of 39 patients showed TP53 mutations (28%). Thirty-six patients (69%) had active brain metastases (BM) and nine (17%) leptomeningeal carcinomatosis when entering the EAP. Median number of prior specific TKIs was 3 (range 1-4). Median duration of treatment, progression-free survival (PFS), response rate and time to treatment failure were 10.4 months, 8.0 months, 54% and 13.0 months. Calculated 12-, 18- and 24-months survival rates were 65, 54 and 47%, overall survival since primary diagnosis (OS2) reached 79.6 months. TP53 mutations were associated with a substantially reduced PFS (3.7 versus 10.8 month, HR 3.3, p = 0.003) and were also identified as a strong prognostic biomarker (HR for OS2 3.0 p = 0.02). Neither prior treatments with second-generation TKIs nor BM had a significant influence on PFS and OS. CONCLUSIONS: Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis.

Hepatitis C virus infection sensitizes human hepatocytes to TRAIL-induced apoptosis in a caspase 9-dependent manner.

Apoptosis of infected cells represents a key host defense mechanism against viral infections. The impact of apoptosis on the elimination of hepatitis C virus (HCV)-infected cells is poorly understood. The TRAIL has been implicated in the death of liver cells in hepatitis-infected but not in normal liver cells. To determine the impact of TRAIL on apoptosis of virus-infected host cells, we studied TRAIL-induced apoptosis in a tissue culture model system for HCV infection. We demonstrated that HCV infection sensitizes primary human hepatocytes and Huh7.5 hepatoma cells to TRAIL induced apoptosis in a dose- and time-dependent manner. Mapping studies identified the HCV nonstructural proteins as key mediators of sensitization to TRAIL. Using a panel of inhibitors targeting different apoptosis pathways, we demonstrate that sensitization to TRAIL is caspase-9 dependent and mediated in part via the mitochondrial pathway. Sensitization of hepatocytes to TRAIL-induced apoptosis by HCV infection represents a novel antiviral host defense mechanism that may have important implications for the pathogenesis of HCV infection and may contribute to the elimination of virus-infected hepatocytes.