Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, ...yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8
T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.
Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical ...cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pollinator communities are more abundant and diverse in agricultural matrices with more natural habitat, although the reasons for these correlations remain unclear. It is possible that forest ...fragments and edges provide resources for pollinators in important early weeks of spring, after which time those insects can then ‘spill over’ into crops such as apple orchards during bloom.
To explore how forest edges may feed and therefore promote flower visitor communities in adjacent agricultural habitats, we sampled springtime pollinators in nine orchards and their adjacent forest edge canopies and understories. We identified pollen consumed by pan‐trapped bees and flower flies to assess if pollinators ate pollen where they were caught, and if their diets similarly ‘spill over’ from forest to orchard. We further explored sex differences in habitat usage.
Our spatially replicated sampling found that bee and flower fly abundance peaks first in the forest understorey, then in the forest canopy and finally in the orchard.
Analysis of digestive tracts showed significant usage of forest canopy pollen throughout the spring, especially before apple bloom. Pollinators had often eaten pollen from a different habitat than the one in which they were caught, suggesting frequent movement between habitats. Digestive tract pollen is an underused but powerful avenue for ecological insight.
In Andrena, which are important orchard pollinators and one of the most abundant wild bee taxa in this study, male bees were primarily found in the woods but not the orchards where conspecific females were later active.
Synthesis and applications: Forested areas, especially forest canopy trees, provide large amounts of early spring resources that facilitate build‐up and spillover of wild pollinator populations into apple orchards during bloom. Forests also provide critical habitat for male bees, which were rarely found in orchards. Despite their importance for bee reproduction, the needs of male bees are usually not considered in conservation planning. Overall, our data indicate that ensuring there is adequate forest habitat adjacent to orchards can improve the long‐term sustainability of pollinator populations that provide essential crop pollination services.
Resumen
Las comunidades de polinizadores son más abundantes y diversas en matrices agrícolas con más hábitat natural, aunque las razones de estas correlaciones no están claras. Es posible que los fragmentos y los bordes del bosque proporcionen recursos para los polinizadores en las primeras semanas importantes de la primavera, después de lo cual esos insectos pueden “spill over” en cultivos como los huertos de manzanos durante la floración.
Para explorar cómo los bordes del bosque pueden alimentar y, por lo tanto, promover las comunidades de visitantes de flores en hábitats agrícolas adyacentes, tomamos muestras de polinizadores primaverales en nueve huertos y los sotobosques y doseles de los bosques adyacentes. Identificamos el polen consumido por las abejas y las moscas de la familia Syrphidae atrapadas para evaluar si los polinizadores comieron el polen donde fueron atrapados y si sus dietas se “spill over” de manera similar del bosque al huerto. Exploramos más a fondo las diferencias sexuales en el uso del hábitat.
Nuestro muestreo replicado espacialmente encontró que la abundancia de abejas y moscas de la familia Syrphidae alcanza su punto máximo primero en el sotobosque, luego en el dosel del bosque y finalmente en el huerto.
El análisis de los tractos digestivos mostró uso significativo del polen del dosel del bosque durante la primavera, especialmente antes de la floración de los manzanos. Los polinizadores frecuentemente habían comido polen de un hábitat diferente al que los atraparon, lo que sugiere un movimiento frecuente entre hábitats. El polen del tracto digestivo es una vía infrautilizada pero poderosa para el conocimiento ecológico.
Con respecto a Andrena, que son importantes polinizadores de huertos y uno de los taxones de abejas silvestres más abundantes en esta investigación, las abejas macho se encontraron principalmente en los bosques, pero no en los huertos donde las hembras conespecíficas estuvieron activas más tarde.
Síntesis e implicaciones: Las áreas boscosas, especialmente los árboles del dosel del bosque, proporcionan grandes cantidades de recursos a principios de la primavera que facilitan la acumulación y el “spill over” de poblaciones de polinizadores silvestres en los huertos de manzanos durante la floración. Los bosques también proporcionan un hábitat crítico para las abejas machos, que rara vez se encuentran en los huertos. A pesar de su importancia para la reproducción de las abejas, las necesidades de las abejas machos generalmente no se consideran en la planificación de la conservación. En general, nuestros datos indican que garantizar que haya un hábitat forestal adecuado junto a los huertos puede mejorar la sostenibilidad a largo plazo de las poblaciones de polinizadores que brindan servicios esenciales de polinización de cultivos.
Forested areas, especially forest canopy trees, provide large amounts of early spring resources that facilitate build‐up and spillover of wild pollinator populations into apple orchards during bloom. Forests also provide critical habitat for male bees, which were rarely found in orchards. Despite their importance for bee reproduction, the needs of male bees are usually not considered in conservation planning. Overall, our data indicate that ensuring there is adequate forest habitat adjacent to orchards can improve the long‐term sustainability of pollinator populations that provide essential crop pollination services.
Inherited predisposition to pancreatic cancer contributes significantly to its incidence and presents an opportunity for the development of early detection strategies. The genetic basis of ...predisposition remains unexplained in a high proportion of patients with familial PC (FPC).
Clinicopathologic features were assessed in a cohort of 766 patients who had been diagnosed with pancreatic ductal adenocarcinoma (PC). Patients were classified with FPC if they had ≥1 affected first-degree relatives; otherwise, they were classified with sporadic PC (SPC).
The prevalence of FPC in this cohort was 8.9%. In FPC families with an affected parent-child pair, 71% in the subsequent generation were 12.3 years younger at diagnosis. Patients with FPC had more first-degree relatives who had an extrapancreatic malignancy (EPM) (42.6% vs 21.2; P<.0001), particularly melanoma and endometrial cancer, but not a personal history of EPM. Patients with SPC were more likely to be active smokers, have higher cumulative tobacco exposure, and have fewer multifocal precursor lesions, but these were not associated with differences in survival. Long-standing diabetes mellitus (>2 years) was associated with poor survival in both groups.
FPC represents 9% of PC, and the risk of malignancy in kindred does not appear to be confined to the pancreas. Patients with FPC have more precursor lesions and include fewer active smokers, but other clinicopathologic factors and outcome are similar to those in patients with SPC. Furthermore, some FPC kindreds may exhibit anticipation. A better understanding of the clinical features of PC will facilitate efforts to uncover novel susceptibility genes and the development of early detection strategies.
Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for ...rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies.
HER2 amplification was detected and further analyzed using multiple genomic sequencing approaches. Standardized reference laboratory assays defined HER2 amplification in a large cohort of patients (n = 469) with pancreatic ductal adenocarcinoma (PDAC).
An amplified inversion event (1 MB) was identified at the HER2 locus in a patient with PDAC. Using standardized laboratory assays, we established diagnostic criteria for HER2 amplification in PDAC, and observed a prevalence of 2%. Clinically, HER2- amplified PDAC was characterized by a lack of liver metastases, and a preponderance of lung and brain metastases. Excluding breast and gastric cancer, the incidence of HER2-amplified cancers in the USA is >22,000 per annum.
HER2 amplification occurs in 2% of PDAC, and has distinct features with implications for clinical practice. The molecular heterogeneity of PDAC implies that even an incidence of 2% represents an attractive target for anti-HER2 therapies, as options for PDAC are limited. Recruiting patients based on HER2 amplification, rather than organ of origin, could make trials of anti-HER2 therapies feasible in less common cancer types.
Recent studies have identified germline mutations in TP53, PAX5, ETV6, and IKZF1 in kindreds with familial acute lymphoblastic leukemia (ALL), but the genetic basis of ALL in many kindreds is unknown ...despite mutational analysis of the exome. Here, we report a germline deletion of ETV6 identified by linkage and structural variant analysis of whole-genome sequencing data segregating in a kindred with thrombocytopenia, B-progenitor acute lymphoblastic leukemia, and diffuse large B-cell lymphoma. The 75-nt deletion removed the ETV6 exon 7 splice acceptor, resulting in exon skipping and protein truncation. The ETV6 deletion was also identified by optimal structural variant analysis of exome sequencing data. These findings identify a new mechanism of germline predisposition in ALL and implicate ETV6 germline variation in predisposition to lymphoma. Importantly, these data highlight the importance of germline structural variant analysis in the search for germline variants predisposing to familial leukemia.
•ETV6 germline deletions predispose to familial ALL.•Germline deletions may be detected by analysis of whole genome and exome data that retain soft-clipped (partially mapped) reads.
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Lipoprotein lipase (LPL) catalyses the hydrolysis of the triacylglycerol component of circulating chylomicrons and very low density lipoproteins, thereby providing non-esterified fatty acids and ...2-monoacylglycerol for tissue utilisation. Research carried out over the past two decades have not only established a central role for LPL in the overall lipid metabolism and transport but have also identified additional, non-catalytic functions of the enzyme. Furthermore, abnormalities in LPL function have been found to be associated with a number of pathophysiological conditions, including atherosclerosis, chylomicronaemia, obesity, Alzheimer's disease, and dyslipidaemia associated with diabetes, insulin resistance, and infection. Advances have also been made in relating the various domains in the protein to different functions, and in understanding the mechanisms that are responsible for the changes in LPL expression seen in response to nutritional and other physiological changes, and during disease. This review summarises recent findings in relation to the structure, function, and regulation of LPL along with its important role in disease.
Despite its potential nutritional benefits, consumption of pollen by adult solitary bees has rarely been quantified. Pollen consumption by adult male bees is usually assumed to be negligible, but few ...studies have investigated this assumption. Here, we review existing literature on adult male bee pollen consumption and present new data on female and male pollen consumption by 9 species from 5 subgenera of spring-flying
Andrena
. We dissected and plated full contents of the digestive tract, calculating body-size adjusted pollen volumes for each bee. More females had consumed pollen than males (87% compared to 46%, respectively). Of the bees with pollen, females had consumed over nine times more pollen. However, 10% of males had consumed over 10,000 pollen grains and the highest two exceeded 30,000 grains. Given the large proportion of male bees that consumed pollen, we suggest future work should explore daily/seasonal patterns of consumption and possible fitness implications.
The transcription factor Runx1 is essential for the development of definitive hematopoietic stem cells (HSCs) during vertebrate embryogenesis and is transcribed from 2 promoters, P1 and P2, ...generating 2 major Runx1 isoforms. We have created 2 stable runx1 promoter zebrafish-transgenic lines that provide insight into the roles of the P1 and P2 isoforms during the establishment of definitive hematopoiesis. The Tg(runx1P1:EGFP) line displays fluorescence in the posterior blood island, where definitive erythromyeloid progenitors develop. The Tg(runx1P2:EGFP) line marks definitive HSCs in the aorta-gonad-mesonephros, with enhanced green fluorescent protein–labeled cells later populating the pronephros and thymus. This suggests that a function of runx1 promoter switching is associated with the establishment of discrete definitive blood progenitor compartments. These runx1 promoter–transgenic lines are novel tools for the study of Runx1 regulation and function in normal and malignant hematopoiesis. The ability to visualize and isolate fluorescently labeled HSCs should contribute to further elucidating the complex regulation of HSC development.
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