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Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all 3 World Health Organization (WHO) grades (I through III) using clinical, gene expression, and sequencing data. Unsupervised clustering analysis identified 3 molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which classifies more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell-cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.

BackgroundThe existence of immunologically ‘cold tumors’ frequently found across a wide spectrum of tumor types represents a significant challenge for cancer immunotherapy. Cold tumors have poor baseline pan-leukocyte infiltration, including a low prevalence of cytotoxic lymphocytes, and not surprisingly respond unfavorably to immune checkpoint (IC) inhibitors. We hypothesized that cold tumors harbor a mechanism of immune escape upstream and independent of ICs that may be driven by tumor biology rather than differences in mutational neoantigen burden.MethodsUsing a bioinformatic approach to analyze TCGA (The Cancer Genome Atlas) RNA sequencing data we identified genes upregulated in cold versus hot tumors across four different smoking-related cancers, including squamous carcinomas from the oral cavity (OCSCC) and lung (LUSC), and adenocarcinomas of the bladder (BLCA) and lung (LUAD). Biological significance of the gene most robustly associated with a cold tumor phenotype across all four tumor types, glutathione peroxidase 2 (GPX2), was further evaluated using a combination of in silico analyses and functional genomic experiments performed both in vitro and in in vivo with preclinical models of oral cancer.ResultsElevated RNA expression of five metabolic enzymes including GPX2, aldo-keto reductase family 1 members AKR1C1, AKR1C3, and cytochrome monoxygenases (CP4F11 and CYP4F3) co-occurred in cold tumors across all four smoking-related cancers. These genes have all been linked to negative regulation of arachidonic acid metabolism—a well-established inflammatory pathway—and are also known downstream targets of the redox sensitive Nrf2 transcription factor pathway. In OCSCC, LUSC, and LUAD, GPX2 expression was highly correlated with Nrf2 activation signatures, also elevated in cold tumors. In BLCA, however, GPX2 correlated more strongly than Nrf2 signatures with decreased infiltration of multiple leukocyte subtypes. GPX2 inversely correlated with expression of multiple pro- inflammatory cytokines/chemokines and NF-kB activation in cell lines and knockdown of GPX2 led to increased secretion of prostaglandin E2 (PGE2) and interleukin-6. Conversely, GPX2 overexpression led to reduced PGE2 production in a murine OCSCC model (MOC1). GPX2 overexpressing MOC1 tumors had a more suppressive tumor immune microenvironment and responded less favorably to anti-cytotoxic T-lymphocytes-associated protein 4 IC therapy in mice.ConclusionGPX2 overexpression represents a novel potentially targetable effector of immune escape in cold tumors.

Gliomas are a major cause of cancer-related death among children, adolescents, and young adults (age 0–40 years). Primary mismatch repair deficiency (MMRD) is a pan-cancer mechanism with unique biology and therapeutic opportunities. We aimed to determine the extent and impact of primary MMRD in gliomas among children, adolescents, and young adults. Clinical and molecular data were collected from a population-based cohort of children, adolescents, and young adults with gliomas from Toronto (TOR-Ped, age 0–18 years, collected Jan 1, 2000, to Dec 31, 2021; and TOR-AYA, age 18–40 years, collected Jan 1, 2000, to June 30, 2019). Additional validation paediatric cohorts from St Jude Children's Research Hospital (0–18 years, 2015–21) and the Children's Brain Tumor Network (0–18 years, 1981–2021) were used. Functional genomic tools were applied with the primary aim of assessing primary MMRD prevalence among glioma subgroups and germline impact. To evaluate the effect of primary MMRD on therapy and overall survival, Kaplan–Meier estimates were used on an additional cohort of patients with primary MMRD gliomas treated with immunotherapy. 1389 gliomas were included in the study. The prevalence of primary MMRD ranged between 3·7% and 12·4% in high-grade gliomas (overall 30 of 483; 6·2%, 95% CI 4·2–8·7) and less than 1% in low-grade gliomas (four of 899; 0·4%, 0·1–1·1; p<0·0001 by χ2 test). Specific molecular analysis for all gliomas showed that primary MMRD was absent among oligodendrogliomas (none of 67) and uncommon in BRAFV600E gliomas (one of 110) and histone mutant-driven gliomas (one of 150). In the paediatric age group (<18 years), primary MMRD was common in IDHWT and H3WT gliomas harbouring pathogenic TP53 variants (21 of 61; 34·4%, 22·7–47·7) and in malignant IDHmut gliomas (five of eight; 62·5%, 24·5–91·5). Germline aetiology accounted for 33 (94·3%) of 35 primary MMRD gliomas, including children, adolescents, and young adults with previously unrecognised Lynch syndrome. Survival was poor for patients with primary MMRD gliomas. Particularly poor survival was observed for those with IDHmut astrocytomas with primary MMRD when compared with those with mismatch repair-proficient gliomas (HR 12·6, 95% CI 2·8–57·5; p=0·0011 by multivariable Cox regression). Immune checkpoint blockade was associated with improved survival for patients with primary MMRD gliomas compared with conventional chemoradiotherapy regimens (HR 0·4, 0·3–0·7; p=0·0017 by multivariable Cox regression), regardless of age or germline status. Primary MMRD is more common than previously reported in gliomas in children, adolescents, and young adults, is enriched in specific molecular subgroups, and is associated with poor outcomes. Accurate detection, genetic testing, early diagnosis through surveillance, and implementation of immunotherapy might improve survival for these patients. The Canadian Institutes for Health Research, Stand Up to Cancer—Bristol Myers Squibb Catalyst, US National Institutes of Health, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Canada's Immunotherapy Network, Harry and Agnieszka Hall, Meagan's Hug, BRAINchild Canada, and the LivWise Foundation.

Nowadays, legal regulations and social environmental concerns are converging towards the promotion of more sustainable agriculture based on organic compounds and soil preservation. These trends are fuelling the growth of the biofertilizers, which are beneficial preparations containing microorganisms able to enhance a plant’s ability to uptake essential nutrients. Their production and commercialization encompass a multitude of critical steps deeply reviewed in this manuscript through an exhaustive overview of the key stages, such as microorganism selection, new environmental sources, upscaling to field trials, encapsulation, current application systems and regulatory considerations. However, although the economical expectations are promising, several methodological, environmental, and legal concerns are undermining their advancement. The redefinition of international legal frameworks, their enhancement based on trending technologies, and the fostering of multidisciplinary collaboration across sectors are key players to promote biofertilizers as eco-friendly and cost-effective alternatives to chemical fertilizers.

Chronic kidney disease is commonly diagnosed in dogs, and clinical signs may be aggravated when infected agents are involved. In this case report, 33 dogs with chronic kidney disease were clinically evaluated and serologically tested for Leptospira spp., Ehrlichia canis, and Anaplasma phagocytophilum . The seroprevalence for Leptospira spp. was 39.4%. The most frequent serovars found were Pyrogenes, Canicola, Bratislava and Australis, with serological titers between 1:100 to 1:800. Clinical signs included fever, depression, decreased body condition, vomiting and hematuria. Significant laboratory findings were anemia, leukocytosis, thrombocytopenia, increased liver enzymes, urea and creatinine, hyperbilirubinemia and hyperphosphatemia. All leptospira seronegative dogs were positive for one or both monitored homoparasites (i.e., E. canis and A. phagocytophilum ); only three leptospira seropositive dogs were positive for one or both hemoparasites. Findings also suggest that endemic hemoparasites of dogs should be monitored in dogs with a kidney condition for a better clinical picture of the patients and therapeutic approach.

A leptospirosis clinical-epidemiological study was made in humans and reservoirs in the state of Yucatán, México. Interviews and serological analyses were made on 400 persons from an open population, 439 probable cases of leptospirosis and 1060 animal reservoirs (cows, pigs, dogs, rats and opossums). IgM Leptospira DipstickTM and Microscopic Agglutination Test (MAT) was used to detect human antibodies to leptospiras and serovar respectively. Leptospirosis incidence in humans was 2.2/100,000 inhab. in 1998, 0.7/100,000 in 1999 and 0.9/100,000 in 2000. Overall seroprevalence was 14.2%, relatively unchanged from seroprevalences observed 20 years ago. Highest seropositivity was found in people over 56 years of age, predominating males over females. Predominant serovars in the open population were tarassovi, hardjo, pomona and panama. Leptospirosis cases were most frequent in rural areas, and the anicteric course predominated over the icteric. The panama, icterohaemorrhagiae and pomona serovars predominated in both anicteric and icteric courses. Dogs, pigs and rodents had the highest seropositivity among the reservoirs. Contact with rodents and natural water sources were significant factors (p £ 0.05). Human cases (74%) occurred during the rainy season. It is concluded that leptospirosis is still a serious illness with important clinical and epidemiological implications in the state of Yucatán, Mexico. Un estudio clínico-epidemiológico de leptospirosis fue realizado en humanos y reservorios en el estado de Yucatán, México. Se entrevistaron y analizaron mediante serología 400 personas en población abierta, 439 pacientes sospechosos y 1060 reservorios (bovinos, cerdos, perros, roedores y zarigüeyas). En humanos para la detección de anticuerpos se utilizó IgM Dipstick LeptospiraTM y la prueba de aglutinación microscópica (MAT) para detectar serovar. La incidencia en humanos fue de 2.2/100,000, 0.7/100,000 y 0.9/100,000 habitantes para los años 1998, 1999 y 2000 respectivamente y la seroprevalencia de 14.2%. La frecuencia más alta de seropositivos se encontró en mayores de 56 años, predominando el sexo masculino sobre el femenino. Predominó en población abierta el serovar tarassovi siguiendo en importancia hardjo, pomona y panamá. Los casos fueron más frecuentes en el área rural y el curso anictérico predominó sobre el ictérico. Panamá, icterohaemorrhagiae y pomona predominaron en ambos cursos de la enfermedad. Los perros cerdos y roedores tuvieron mayor positividad. El contacto con roedores y depósitos naturales de agua fue significativo (p £ 0.05). El 74.3% de los casos se presentaron en época de lluvia. En conclusión la leptospirosis en Yucatán, México, sigue siendo una entidad patológica de importancia tanto clínica como epidemiológica.

Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system, there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all three WHO grades (I-III) using clinical, gene expression and sequencing data. Unsupervised clustering analysis identified three molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which would classify more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors. Footnotes * Throughout the paper we revised minor details. These include a more detailed description of methods and statistical analysis, which the readers will appreciate. The paper will be published in the form submitted today in PNAS. The overall paper and results did not change.

Cities are the result of complex relationships within various actors in a territory. Understanding and predicting their growth can be challenging, but prospective techniques, and long-term planning, may help mitigate uncertainty. This article analyzes the factors that determine urban growth in Montería, Colombia, and proposes prospective scenarios by the year 2033. Geographic information and secondary data were used to identify transformations, along with expert analysis and structural equation techniques, which helped consolidate growth factors. The results show that there are factors that trigger and drive urban growth, often unexpected or less intuitive. They also offer a new perspective on the articulation of territorial foresight techniques, since structural equations made it possible to identify the significance and direction of the variables' influences within and between macrocategories. This facilitates expert consultation and the construction of prospective scenarios. Understanding the factors of urban growth and prospective scenarios, which do not always coincide with the desired and planned scenarios, provides decision-makers with tools to correct and reorient urban development. Las ciudades son el resultado de relaciones complejas entre diferentes actores en un territorio. Comprender su crecimiento y proyectarlo es un desafío, pero las técnicas de prospectiva y planificación a largo plazo pueden ayudar a reducir la incertidumbre. Este artículo analiza los factores que determinan el crecimiento urbano en Montería, Colombia, y propone escenarios prospectivos para el año 2033. Se utilizó información geográfica y datos secundarios para identificar las transformaciones, junto con análisis de expertos y técnicas de ecuaciones estructurales, que permitieron consolidar los factores de crecimiento. Los resultados muestran que hay factores que detonan e impulsan el crecimiento urbano, muchas veces inesperados o menos intuitivos. También ofrecen una nueva perspectiva de articulación de técnicas de prospectiva territorial, ya que las ecuaciones estructurales permitieron identificar la significancia y la dirección de las influencias de las variables dentro y entre las macrocategorías, lo cual facilita el ejercicio de consulta a expertos y la construcción de escenarios prospectivos. Conocer los factores del crecimiento urbano y los escenarios prospectivos, que no siempre coinciden con los escenarios deseados y planeados, brinda a los tomadores de decisiones herramientas para corregir y reorientar el desarrollo urbano. Les villes sont le résultat de relations complexes entre différents acteurs d'un territoire. Comprendre et projeter votre croissance est un défi, mais les techniques de planification et de prospective à long terme peuvent contribuer à réduire l’incertitude. Cet article analyse les facteurs qui déterminent la croissance urbaine à Montería, en Colombie, et propose des scénarios prospectifs pour l'année 2033. Pour identifier les transformations, des informations géographiques et des données secondaires ont été utilisées, ainsi que des techniques d'analyse experte et d'équations structurelles, qui ont permis de consolider les facteurs de croissance. Les résultats montrent qu’il existe des facteurs qui déclenchent et stimulent la croissance urbaine, souvent inattendus ou moins intuitifs. Elles offrent également une nouvelle perspective sur l’articulation des techniques de prospective territoriale, puisque les équations structurelles ont permis d’identifier la signification et la direction des influences des variables au sein et entre les macrocatégories, ce qui facilite la consultation d’experts et la construction de scénarios prospectifs. Comprendre les moteurs de la croissance urbaine et les scénarios prospectifs, qui ne coïncident pas toujours avec les scénarios souhaités et planifiés, fournit aux décideurs des outils pour corriger et réorienter le développement urbain. As cidades são o resultado de relações complexas entre diferentes atores de um território. Compreender e projetar o seu crescimento é um desafio, mas técnicas de planejamento e previsão de longo prazo podem ajudar a reduzir a incerteza. Este artigo analisa os fatores que determinam o crescimento urbano em Montería, Colômbia, e propõe cenários prospectivos para o ano 2033. Foram utilizadas informações geográficas e dados secundários para identificar as transformações, juntamente com análises especializadas e técnicas de equações estruturais, que permitiram consolidar os fatores de crescimento. Os resultados mostram que há fatores que desencadeiam e impulsionam o crescimento urbano, muitas vezes inesperados ou menos intuitivos. Oferecem também uma nova perspectiva sobre a articulação de técnicas de prospecção territorial, uma vez que as equações estruturais permitiram identificar a significância e a direção das influências das variáveis ​​dentro e entre as macrocategorias, o que facilita a consulta a especialistas e a construção de cenários prospectivos. Compreender os impulsionadores do crescimento urbano e os cenários prospectivos, que nem sempre coincidem com os cenários desejados e planejados, fornece aos tomadores de decisão ferramentas para corrigir e redirecionar o desenvolvimento urbano.

Accelerating cures for children with cancer remains an immediate challenge due to extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs) from high-risk childhood cancers, many refractory to current standard-of-care treatments. Here, we genomically characterize 261 PDX models from 29 unique pediatric cancer malignancies and demonstrate faithful recapitulation of histologies, subtypes, and refine our understanding of relapsed disease. Expression and mutational signatures are used to classify tumors for TP53 and NF1 inactivation, as well as impaired DNA repair. We anticipate that these data will serve as a resource for pediatric oncology drug development and guide rational clinical trial design for children with cancer. Footnotes * Figure 2 revised * https://pedcbioportal.org/study?id=pptc#summary * https://figshare.com/projects/Genomic_landscape_of_childhood_cancer_patient-derived_xenograft_models/38147 * https://figshare.com/articles/PPTC_RNAseq_and_Genomic_Alterations/7127726

Pelliciera rhizophorae es una especie neotropical de mangle, la única especie representante de su género, cuya distribución actual está casi restringida a la costa del Pacífico americano. Como una contribución al conocimiento de la ecogenética de P. rhizophorae se realizó un análisis de su variabilidad genética y morfológica en el Pacífico colombiano y los factores ambientales asociados en seis localidades: Virudó, Charambirá, Isla La Plata, Tumaco, Milagros y Chontal (Colombia). El análisis de diversidad genética realizado mediante marcadores moleculares AFLP, produjo 225 fragmentos amplificados con 155 (69%) polimórficos en 57 individuos de P. rhizophorae colectados en las seis zonas del Pacífico colombiano. La diversidad genética dentro de poblaciones reveló niveles de variación más bajos en Isla La Plata y Tumaco y el más alto en Chontal (Hep = 0,187). Esta especie en el Pacífico colombiano resultó estar significativamente estructurada (fst = 0,2654), con un 73,5% de variación dentro de poblaciones. La diferenciación genética no mostró correlación con la distancia geográfica entre zonas. Esto sugiere que la dinámica poblacional de la especie está asociada con procesos históricos influenciados por factores ecológicos y ambientales. El estudio de la variabilidad morfológica, reveló un óptimo desarrollo de los árboles en la localidad de Virudó, una zona constituida por manglar de ribera; en contraste, Tumaco, Milagros y Charambirá, mostraron un fenotipo disminuido, a pesar de ser también manglares de ribera. El análisis de suelo determinó que el sustrato de anclaje de la especie está compuesto en su mayoría por arenas muy finas y arcillas y, aunque la salinidad medida en agua intersticial mostró una ligera variación entre las zonas de estudio, estas características parecen ser adecuadas para la sobrevivencia de la especie.