Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity.

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance1,2. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity3-6. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8+ T cell function by enhancing JAK-STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.

Author Correction: Global status and conservation potential of reef sharks.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Global status and conservation potential of reef sharks.

Decades of overexploitation have devastated shark populations, leaving considerable doubt as to their ecological status1,2. Yet much of what is known about sharks has been inferred from catch records in industrial fisheries, whereas far less information is available about sharks that live in coastal habitats3. Here we address this knowledge gap using data from more than 15,000 standardized baited remote underwater video stations that were deployed on 371 reefs in 58 nations to estimate the conservation status of reef sharks globally. Our results reveal the profound impact that fishing has had on reef shark populations: we observed no sharks on almost 20% of the surveyed reefs. Reef sharks were almost completely absent from reefs in several nations, and shark depletion was strongly related to socio-economic conditions such as the size and proximity of the nearest market, poor governance and the density of the human population. However, opportunities for the conservation of reef sharks remain: shark sanctuaries, closed areas, catch limits and an absence of gillnets and longlines were associated with a substantially higher relative abundance of reef sharks. These results reveal several policy pathways for the restoration and management of reef shark populations, from direct top-down management of fishing to indirect improvement of governance conditions. Reef shark populations will only have a high chance of recovery by engaging key socio-economic aspects of tropical fisheries.

Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death.

Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A-SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A-SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.

Targeting ROS production through inhibition of NADPH oxidases.

NADPH oxidases (NOXs) are transmembrane enzymes that are devoted to the production of reactive oxygen species (ROS). In cancers, dysregulation of NOX enzymes affects ROS production, leading to redox unbalance and tumor progression. Consequently, NOXs are a drug target for cancer therapeutics, although current therapies have off-target effects: there is a need for isoenzyme-selective inhibitors. Here, we describe fully validated human NOX inhibitors, obtained from an in silico screen, targeting the active site of Cylindrospermum stagnale NOX5 (csNOX5). The hits are validated by in vitro and in cellulo enzymatic and binding assays, and their binding modes to the dehydrogenase domain of csNOX5 studied via high-resolution crystal structures. A high-throughput screen in a panel of cancer cells shows activity in selected cancer cell lines and synergistic effects with KRAS modulators. Our work lays the foundation for the development of inhibitor-based methods for controlling the tightly regulated and highly localized ROS sources.

Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers.

Aberrant DNA repair is a hallmark of cancer, and many tumors display reduced DNA repair capacities that sensitize them to genotoxins. Here, we demonstrate that the differential DNA repair capacities of healthy and transformed tissue may be exploited to obtain highly selective chemotherapies. We show that the novel N3-(2-fluoroethyl)imidazotetrazine "KL-50" is a selective toxin toward tumors that lack the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT), which reverses the formation of O6-alkylguanine lesions. We establish that KL-50 generates DNA interstrand cross-links (ICLs) by a multistep process comprising DNA alkylation to generate an O6-(2-fluoroethyl)guanine (O6FEtG) lesion, slow unimolecular displacement of fluoride to form an N1,O6-ethanoguanine (N1,O6EtG) intermediate, and ring-opening by the adjacent cytidine. The slow rate of N1,O6EtG formation allows healthy cells expressing MGMT to reverse the initial O6FEtG lesion before it evolves to N1,O6EtG, thereby suppressing the formation of toxic DNA-MGMT cross-links and reducing the amount of DNA ICLs generated in healthy cells. In contrast, O6-(2-chloroethyl)guanine lesions produced by agents such as lomustine and the N3-(2-chloroethyl)imidazotetrazine mitozolomide rapidly evolve to N1,O6EtG, resulting in the formation of DNA-MGMT cross-links and DNA ICLs in healthy tissue. These studies suggest that careful consideration of the rates of chemical DNA modification and biochemical DNA repair may lead to the identification of other tumor-specific genotoxic agents.

Systematic identification of biomarker-driven drug combinations to overcome resistance.

The ability to understand and predict variable responses to therapeutic agents may improve outcomes in patients with cancer. We hypothesized that the basal gene-transcription state of cancer cell lines, coupled with cell viability profiles of small molecules, might be leveraged to nominate specific mechanisms of intrinsic resistance and to predict drug combinations that overcome resistance. We analyzed 564,424 sensitivity profiles to identify candidate gene-compound pairs, and validated nine such relationships. We determined the mechanism of a novel relationship, in which expression of the serine hydrolase enzymes monoacylglycerol lipase (MGLL) or carboxylesterase 1 (CES1) confers resistance to the histone lysine demethylase inhibitor GSK-J4 by direct enzymatic modification. Insensitive cell lines could be sensitized to GSK-J4 by inhibition or gene knockout. These analytical and mechanistic studies highlight the potential of integrating gene-expression features with small-molecule response to identify patient populations that are likely to benefit from treatment, to nominate rational candidates for combinations and to provide insights into mechanisms of action.

Non-viral pathogens of infectious diarrhoea post-allogeneic stem cell transplantation are associated with graft-versus-host disease.

Infectious diarrhoea is common post-allogeneic haematopoietic stem-cell transplantation (alloHSCT). While the epidemiology of Clostridioides difficile infection (CDI) post-alloHSCT has been described, the impact of other diarrhoeal pathogens is uncertain. We reviewed all alloHSCT between 2017 and 2022 at a single large transplant centre; 374 patients were identified and included. The 1-year incidence of infectious diarrhoea was 23%, divided into viral (13/374, 3%), CDI (65/374, 17%) and other bacterial infections (16/374, 4%). There was a significant association between infectious diarrhoea within 1 year post-transplant and the occurrence of severe acute lower gastrointestinal graft-versus-host disease (GVHD, OR = 4.64, 95% CI 2.57-8.38, p < 0.001) and inferior GVHD-free, relapse-free survival on analysis adjusted for age, donor type, stem cell source and T-cell depletion (aHR = 1.64, 95% CI = 1.18-2.27, p = 0.003). When the classes of infectious diarrhoea were compared to no infection, bacterial (OR = 6.38, 95% CI 1.90-21.40, p = 0.003), CDI (OR = 3.80, 95% CI 1.91-7.53, p < 0.001) and multiple infections (OR = 11.16, 95% CI 2.84-43.92, p < 0.001) were all independently associated with a higher risk of severe GI GVHD. Conversely, viral infections were not (OR = 2.98, 95% CI 0.57-15.43, p = 0.20). Non-viral infectious diarrhoea is significantly associated with the development of GVHD. Research to examine whether the prevention of infectious diarrhoea via infection control measures or modulation of the microbiome reduces the incidence of GVHD is needed.

High-risk multiple myeloma: Redefining genetic, clinical, and functional high-risk disease in the era of molecular medicine and immunotherapy.

Multiple myeloma (MM) exhibits significant heterogeneity in its presentation, genetics, and treatment response. Despite therapeutic advances, some patients continue to relapse early (ER, <18-months) and rapidly cycle through therapies. Myriad prognostic factors have been identified and incorporated into risk stratification models; however, these produce discordant, often three-tiered outputs that fail to identify many patients destined for ER. Treatment strategies are increasingly focused on disease biology and trials enriched for high-risk (HR)MM, but consensus on the minimum required testing and a succinct, specific, and clinically meaningful definition for HRMM remains elusive. We review the risk-factors, definitions, and future directions for HRMM.

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.

Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFß-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.

Targeting the BRAF pathway in haematological diseases.

Since the recognition of BRAF V600E mutations in the majority of cases of hairy cell leukaemia, Erdheim-Chester disease and Langerhans cell histiocytosis, the targeted oral kinase inhibitors dabrafenib and vemurafenib have been adapted for their treatment. Like other targeted agents, these drugs produce high response rates and predictable but unique side effects. Physician familiarity is essential for the effective use of these agents. We review the Australian experience of BRAF/MEK inhibitor therapy in these rare haematological cancers.

Effects of human footprint and biophysical factors on the body-size structure of fished marine species.

Marine fisheries in coastal ecosystems in many areas of the world have historically removed large-bodied individuals, potentially impairing ecosystem functioning and the long-term sustainability of fish populations. Reporting on size-based indicators that link to food-web structure can contribute to ecosystem-based management, but the application of these indicators over large (cross-ecosystem) geographical scales has been limited to either fisheries-dependent catch data or diver-based methods restricted to shallow waters (<20 m) that can misrepresent the abundance of large-bodied fished species. We obtained data on the body-size structure of 82 recreationally or commercially targeted marine demersal teleosts from 2904 deployments of baited remote underwater stereo-video (stereo-BRUV). Sampling was at up to 50 m depth and covered approximately 10,000 km of the continental shelf of Australia. Seascape relief, water depth, and human gravity (i.e., a proxy of human impacts) were the strongest predictors of the probability of occurrence of large fishes and the abundance of fishes above the minimum legal size of capture. No-take marine reserves had a positive effect on the abundance of fishes above legal size, although the effect varied across species groups. In contrast, sublegal fishes were best predicted by gradients in sea surface temperature (mean and variance). In areas of low human impact, large fishes were about three times more likely to be encountered and fishes of legal size were approximately five times more abundant. For conspicuous species groups with contrasting habitat, environmental, and biogeographic affinities, abundance of legal-size fishes typically declined as human impact increased. Our large-scale quantitative analyses highlight the combined importance of seascape complexity, regions with low human footprint, and no-take marine reserves in protecting large-bodied fishes across a broad range of species and ecosystem configurations.

Las pesquerías marinas de los ecosistemas costeros en muchas áreas del mundo históricamente han removido a individuos de gran tamaño, potencialmente perjudicando el funcionamiento ambiental y la sostenibilidad a largo plazo de las poblaciones de peces. Los reportes sobre los indicadores basados en el tamaño que se vinculan con la estructura de la red alimenticia pueden contribuir al manejo basado en el ecosistema, aunque la aplicación de estos indicadores a grandes (inter-ecosistemas) escalas geográficas ha estado limitada a datos de captura dependientes de las pesquerías o métodos basados en el buceo restringidos a aguas someras (<20 m), lo cual puede representar erróneamente la abundancia de peces de gran tamaño capturados para la pesca. Obtuvimos los datos de la estructura del tamaño corporal de 82 teleósteos marinos demersales focalizados por razones recreativas o comerciales tomados de 2,904 despliegues de video estéreo subacuático remoto con cebo (stereo-BRUV, en inglés). El muestreo se realizó hasta los 50 metros de profundidad y abarcó aproximadamente 10,000 km del talud continental de Australia. El relieve marino, la profundidad del agua y la gravedad humana (es decir, un indicador de los impactos humanos) fueron los pronosticadores más sólidos de la probabilidad de incidencia de los peces de gran tamaño y de la abundancia de peces por encima del tamaño legal mínimo de captura. Las reservas marinas de protección total tienen un efecto positivo sobre la abundancia de los peces que están por encima del tamaño legal, aunque el efecto varió según el grupo de especies. Como contraste, los peces de tamaño sublegal fueron pronosticados de mejor manera usando gradientes de la temperatura de la superficie marina (media y varianza). En las áreas con un impacto humano reducido, los peces de gran tamaño corporal tenían hasta tres veces mayor probabilidad de aparecer y los peces de tamaño legal eran aproximadamente cinco veces más abundantes. Para los grupos de especies conspicuas con afinidades contrastantes de hábitat, ambiente y biogeografía, la abundancia de peces de tamaño legal normalmente declinó conforme aumentó el impacto humano. Nuestros análisis cuantitativos a gran escala resaltan la importancia conjunta que tienen la complejidad marina, las regiones con una huella humana reducida y las reservas marinas de protección total para la protección de los peces de gran tamaño corporal en una extensa gama de especies y configuraciones ecosistémicas. Efectos de la Huella Humana y los Factores Biofísicos sobre la Estructura del Tamaño Corporal de Especies Marinas Capturadas para la Pesca.

Increased connectivity and depth improve the effectiveness of marine reserves.

Marine reserves are a key tool for the conservation of marine biodiversity, yet only ~2.5% of the world's oceans are protected. The integration of marine reserves into connected networks representing all habitats has been encouraged by international agreements, yet the benefits of this design has not been tested empirically. Australia has one of the largest systems of marine reserves, providing a rare opportunity to assess how connectivity influences conservation success. An Australia-wide dataset was collected using baited remote underwater video systems deployed across a depth range from 0 to 100 m to assess the effectiveness of marine reserves for protecting teleosts subject to commercial and recreational fishing. A meta-analytical comparison of 73 fished species within 91 marine reserves found that, on average, marine reserves had 28% greater abundance and 53% greater biomass of fished species compared to adjacent areas open to fishing. However, benefits of protection were not observed across all reserves (heterogeneity), so full subsets generalized additive modelling was used to consider factors that influence marine reserve effectiveness, including distance-based and ecological metrics of connectivity among reserves. Our results suggest that increased connectivity and depth improve the aforementioned marine reserve benefits and that these factors should be considered to optimize such benefits over time. We provide important guidance on factors to consider when implementing marine reserves for the purpose of increasing the abundance and size of fished species, given the expected increase in coverage globally. We show that marine reserves that are highly protected (no-take) and designed to optimize connectivity, size and depth range can provide an effective conservation strategy for fished species in temperate and tropical waters within an overarching marine biodiversity conservation framework.

Rapidly assessing cobenefits to advance threat-management alliances.

Conservation strategies aimed at reducing threats to biodiversity can have significant implications for multiple sectors in a socioeconomic system, but these cobenefits are often poorly understood. For example, many of the threats to native species also impede agricultural production, yet agriculture is typically perceived as in competition with conservation objectives. Although a comprehensive, multiobjective decision analysis is usually beyond the scope and capacity of conservation decision makers, failing to incorporate key socioeconomic costs and benefits into conservation decision-making processes can result in missed opportunities for diversifying outcomes and creating cost-sharing multisectoral partnerships. We devised a straightforward and readily interpretable approach to incorporate cobenefits into a threat-management prioritization approach. We used it to analyze the agricultural cobenefits of implementing 9 invasive animal management strategies designed to ensure the persistence of 148 threatened species across Australia's Lake Eyre Basin over 50 years. A structured elicitation process with 24 participants (scientists, land managers, agriculturalists, and other stakeholders) was used to collect information on each strategy, including costs, technical and social feasibility, benefits to native threatened species, and cobenefits to agricultural production systems. The costs of targeted invasive animal management to save threatened species across the basin (AU$33 million/year) outweighed the overall benefits to the agricultural industry (estimated AU$226 million/year). The return on investment for these management strategies varied substantially when agricultural cobenefits were considered alongside threatened species benefits and showed synergies and challenges. Our approach demonstrates the value of incorporating cobenefits of conservation actions into cost-effectiveness analyses to guide potential investment and partnerships and to diversify implementation pathways.

Evaluación Rápida de los Cobeneficios para Promover Alianzas de Manejo de Amenazas Resumen Las estrategias de conservación enfocadas en la reducción de las amenazas para la biodiversidad pueden tener implicaciones importantes para muchos sectores de un sistema socioeconómico, pero existe un entendimiento reducido de estos cobeneficios. Por ejemplo, muchas de las amenazas para las especies nativas también impiden la producción agrícola y a pesar de esto, comúnmente se percibe a la agricultura como una competencia para los objetivos de conservación. Aunque un análisis completo de decisiones con objetivos múltiples está usualmente más allá del enfoque y la capacidad del órgano decisorio, no incluir costos y beneficios socioeconómicos importantes dentro del proceso de toma de decisiones puede resultar en oportunidades perdidas para la diversificación de resultados y la creación de colaboraciones multisectoriales con reparto de costes. Diseñamos una estrategia directa y de fácil interpretación para incorporar los cobeneficios dentro de una estrategia de priorización de manejo de amenazas. Usamos esta estrategia para analizar los cobeneficios agrícolas de la implementación de nueve estrategias de manejo de animales invasores diseñadas para asegurar la persistencia de 148 especies amenazadas en la cuenca del Lago Eyre en Australia durante 50 años. Usamos un proceso estructurado de extracción con 24 participantes (científicos, administradores de tierras, agricultores y otros actores) para recolectar información sobre cada estrategia, incluyendo los costos, viabilidad técnica y social, beneficios para las especies nativas amenazadas y los cobeneficios para los sistemas de producción agrícola. Los costos del manejo enfocado en animales invasores para salvar a las especies amenazadas de la cuenca (AU$33 millones al año) superaron a los beneficios generales para la industria agrícola (estimados en AU$226 millones al año). El rendimiento de la inversión para estas estrategias de manejo varió sustancialmente cuando los cobeneficios agrícolas estuvieron considerados junto con los beneficios para las especies amenazadas y mostró retos y sinergias. Nuestra estrategia demuestra la importancia de la incorporación de los cobeneficios de las acciones de conservación dentro de los análisis de rentabilidad para guiar la inversión potencial y las alianzas y para diversificar las vías de implementación.

Pediatric to Adult Transition in Sickle Cell Disease: Survey Results from Young Adult Patients.

BACKGROUND/AIMS: We surveyed sickle cell disease (SCD) patients who transitioned from pediatric care at Texas Children's Hematology Center (TCHC) to adult care to determine the characteristics of patients with an adult SCD provider, continuation rates of pre-transition therapies, and patient perceptions of the transition process. METHODS: A cross-sectional study was conducted by telephone survey of 44 young adults with SCD, aged 19-29 years, who transitioned from TCHC to adult care within the last 15 years. RESULTS: Findings of the 23-item questionnaire revealed that transitioned patients with current adult providers (68.2%) were more likely to have seen a provider within 6 months of transition (p = 0.023) and to have been on hydroxyurea and/or monthly blood transfusions pre-transition (p = 0.021) than transitioned patients without a provider; 83% of patients on pre-transition hydroxyurea reported continuing hydroxyurea after transition. Transition challenges included inadequate preparation, difficulty finding knowledgeable adult providers, and lack of healthcare insurance/coverage. CONCLUSION: Transition to adult providers is predicted by establishing care with an adult SCD provider within 6 months of transition and being on pre-transition disease-modifying therapy. Transition may be improved if pediatric hematology centers assist and verify adult provider contact within 6 months of transition and engage patients of all disease severity during transition.

Voltammetry at Hexamethyl-P-Terphenyl Poly(Benzimidazolium) (HMT-PMBI)-Coated Glassy Carbon Electrodes: Charge Transport Properties and Detection of Uric and Ascorbic Acid.

We describe the voltammetric behavior of an anion-exchange membrane, hexamethyl-p-terphenyl poly(benzimidazolium) (HMT-PMBI). The anion-exchange properties of HMT-PMBI chemically modified electrodes were investigated using K4Fe(CN)6 and K2IrCl6 as redox probes. The permselectivity properties of HMT-PMBI chemically modified electrodes were ascertained using tris(2-2')bipyridyl-ruthenium(II) chloride Ru(bpy)32+. Cyclic voltammetry and chronoamperometry were utilized to extract parameters such as the concentration of the redox mediators inside the films and the apparent diffusion coefficients. We found the concentration of K4Fe(CN)6 and K2IrCl6 redox species within HMT-PMBI-coated films to be on the order of 0.04-0.1 mol·dm-3, and values of Dapp ca. 10-10-10-9 cm2·s-1. To evaluate the possibility of using such a polymer coating in electroanalysis, HMT-PMBI-modified electrodes were utilized for the voltammetric detection of uric acid in artificial urine, Surine® and ascorbic acid in Vitamin C samples. The results showed that HMT-PMBI-coated electrodes can detect uric acid in Surine® with a limit of detection (LoD) of 7.7 µM, sensitivity of 0.14 µA·µM-1·cm-2, and linear range between 5 µM and 200 µM, whereas for Vitamin C tablets, the LoD is 41.4 µM, the sensitivity is 0.08 µA·µM-1·cm-2, and the linear range is between 25 µM and 450 µM.

Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics.

High cancer death rates indicate the need for new anticancer therapeutic agents. Approaches to discovering new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds through phenotypic compound library screening and target deconvolution by predictive chemogenomics. We found that sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, across 766 cancer cell lines correlates with expression of the gene PDE3A, encoding phosphodiesterase 3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells, whereas others do not. Furthermore, PDE3A depletion leads to DNMDP resistance. We demonstrated that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), suggestive of a neomorphic activity. Coexpression of SLFN12 with PDE3A correlates with DNMDP sensitivity, whereas depletion of SLFN12 results in decreased DNMDP sensitivity. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery.