Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct ...from those in the initial tumor. To explore this hypothesis, we sequenced the exornes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.
We present an overview of the National Science Foundation’s
Daniel K. Inouye Solar Telescope
(DKIST), its instruments, and support facilities. The 4 m aperture DKIST provides the highest-resolution ...observations of the Sun ever achieved. The large aperture of DKIST combined with state-of-the-art instrumentation provide the sensitivity to measure the vector magnetic field in the chromosphere and in the faint corona, i.e. for the first time with DKIST we will be able to measure and study the most important free-energy source in the outer solar atmosphere – the coronal magnetic field. Over its operational lifetime DKIST will advance our knowledge of fundamental astronomical processes, including highly dynamic solar eruptions that are at the source of space-weather events that impact our technological society. Design and construction of DKIST took over two decades. DKIST implements a fast (f/2), off-axis Gregorian optical design. The maximum available field-of-view is 5 arcmin. A complex thermal-control system was implemented in order to remove at prime focus the majority of the 13 kW collected by the primary mirror and to keep optical surfaces and structures at ambient temperature, thus avoiding self-induced local seeing. A high-order adaptive-optics system with 1600 actuators corrects atmospheric seeing enabling diffraction limited imaging and spectroscopy. Five instruments, four of which are polarimeters, provide powerful diagnostic capability over a broad wavelength range covering the visible, near-infrared, and mid-infrared spectrum. New polarization-calibration strategies were developed to achieve the stringent polarization accuracy requirement of 5×10
−4
. Instruments can be combined and operated simultaneously in order to obtain a maximum of observational information. Observing time on DKIST is allocated through an open, merit-based proposal process. DKIST will be operated primarily in “service mode” and is expected to on average produce 3 PB of raw data per year. A newly developed data center located at the NSO Headquarters in Boulder will initially serve fully calibrated data to the international users community. Higher-level data products, such as physical parameters obtained from inversions of spectro-polarimetric data will be added as resources allow.
Although it is known that the methylation of DNA in 5' promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear. In mammals, tissue- and cell type-specific ...methylation is present in a small percentage of 5' CpG island (CGI) promoters, whereas a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences. Tissue-specific intragenic methylation might reduce, or, paradoxically, enhance transcription elongation efficiency. Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes. To investigate the role of intragenic methylation, we generated a map of DNA methylation from the human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were shown to be in intragenic and intergenic regions, whereas less than 3% of CpG islands in 5' promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters. The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue- and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.
The evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to stable genetic events, epigenetic states are reversible and sensitive to ...the microenvironment, prompting the question whether epigenetic information can similarly be used to discover tumor phylogeny. We examined the spatial and temporal dynamics of DNA methylation in a cohort of low-grade gliomas and their patient-matched recurrences. Genes transcriptionally upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint. Moreover, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations. These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution.
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•Dramatic loss of DNA methylation during the progression of low-grade gliomas to GBM•Phenotypic convergence of genomic and epigenomic evolution on cell cycle defects•Phyloepigenetics recapitulates the phylogenetics of tumor evolution•Robust model of gliomagenesis from tumor initiation through malignant progression
Mazor et al. show that spatial and temporal patterns of DNA methylation and somatic mutations during the progression of low-grade gliomas to high-grade tumors produce remarkably similar evolutionary histories and both converge to deregulate the cell cycle.
Background
The COVID‐19 pandemic has disrupted routine hospital services globally. This study estimated the total number of adult elective operations that would be cancelled worldwide during the 12 ...weeks of peak disruption due to COVID‐19.
Methods
A global expert response study was conducted to elicit projections for the proportion of elective surgery that would be cancelled or postponed during the 12 weeks of peak disruption. A Bayesian β‐regression model was used to estimate 12‐week cancellation rates for 190 countries. Elective surgical case‐mix data, stratified by specialty and indication (surgery for cancer versus benign disease), were determined. This case mix was applied to country‐level surgical volumes. The 12‐week cancellation rates were then applied to these figures to calculate the total number of cancelled operations.
Results
The best estimate was that 28 404 603 operations would be cancelled or postponed during the peak 12 weeks of disruption due to COVID‐19 (2 367 050 operations per week). Most would be operations for benign disease (90·2 per cent, 25 638 922 of 28 404 603). The overall 12‐week cancellation rate would be 72·3 per cent. Globally, 81·7 per cent of operations for benign conditions (25 638 922 of 31 378 062), 37·7 per cent of cancer operations (2 324 070 of 6 162 311) and 25·4 per cent of elective caesarean sections (441 611 of 1 735 483) would be cancelled or postponed. If countries increased their normal surgical volume by 20 per cent after the pandemic, it would take a median of 45 weeks to clear the backlog of operations resulting from COVID‐19 disruption.
Conclusion
A very large number of operations will be cancelled or postponed owing to disruption caused by COVID‐19. Governments should mitigate against this major burden on patients by developing recovery plans and implementing strategies to restore surgical activity safely.
Antecedentes
La pandemia de COVID‐19 ha interrumpido los servicios hospitalarios habituales a nivel mundial. En este estudio se calculó el número total de operaciones electivas para adultos que se cancelarían en todo el mundo durante las 12 semanas de interrupción máxima debido a COVID’19.
Métodos
Se realizó un estudio global de respuestas de expertos para obtener proyecciones sobre la proporción de cirugía electiva que se cancelaría o pospondría durante las 12 semanas del pico máximo de disrupción. Se usó un modelo bayesiano de regresión beta para estimar las tasas de cancelación durante 12 semanas en 190 países. Se determinaron los datos de la casuística de casos quirúrgicos electivos, estratificados por especialidad e indicación (cáncer versus cirugía benigna). Esta casuística de casos se aplicó a volúmenes quirúrgicos a nivel de país. Las tasas de cancelación de las 12 semanas se aplicaron a estas cifras para calcular el total de operaciones suspendidas.
Resultados
La mejor estimación fue que 28.404.603 operaciones hubieran sido canceladas o pospuestas durante las 12 semanas del pico de disrupción por COVID‐19 (2.367.050 operaciones por semana). La mayoría hubieran sido operaciones por enfermedad benigna (90,2%, 25.638.922/28. 404. 603). La tasa de cancelación general en 12 semanas sería del 72,3%. A nivel mundial, el 81,7% (25.638.921/31.378.062) de la cirugía benigna, el 37,7% (2. 324.069/6.162.311) de la cirugía por cáncer y el 25,4% (441.611/1.735.483) de las cesáreas electivas hubieran sido canceladas o pospuestas. Si los países aumentan su volumen quirúrgico normal en un 20% después de la pandemia, se tardaría una mediana de 45 semanas para eliminar la acumulación de operaciones resultantes de la disrupción por COVID’19.
Conclusión
Se cancelará o pospondrá un número muy grande de operaciones debido a la disrupción causada por COVID‐19. Los gobiernos deberían mitigar esta importante carga para los pacientes mediante el desarrollo de planes de recuperación e implementando estrategias para reiniciar de manera segura la actividad quirúrgica.
A very large number of operations will be cancelled or postponed owing to disruption caused by COVID‐19. Governments should mitigate against this major burden on patients by developing recovery plans and implementing strategies to restore surgical activity safely.
A mountain to climb
Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA ...hypermethylation of the
O
6
-
methylguanine
-
DNA methyltransferase
(
MGMT)
promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT–mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of
MGMT
methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased
MGMT
methylation compared to their untreated initial tumors and higher overall
MGMT
methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing
MGMT
, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated
MGMT
may undergo positive selection during TMZ treatment in the context of MMR deficiency.
To compare secondary outcomes after ablation (AB), surgical resection (SR), and liver transplant (LT) for small hepatocellular carcinomas (HCCs), including resource utilization and adverse event (AE) ...rates.
Using Surveillance, Epidemiology, and End Results Program (SEER)-Medicare, HCCs <5 cm that were treated with AB, SR, or LT in 2009-2016 (n = 1,067) were identified using Healthcare Common Procedure Coding System codes through Medicare claims. Index procedure length of stay, need for intensive care unit (ICU) level care, readmission rates, and AE rates at 30 and 90 days were compared using chi-square tests or Fisher exact tests. Examined AEs included hemorrhage, abscess formation, biliary injury, pneumonia, sepsis, liver disease-related AEs, liver failure, and anesthesia-related AEs, identified by International Classification of Diseases, Ninth/10th Revision, codes.
The median length of stay for initial treatment was 1 day, 6 days, and 7 days for AB, SR, and LT, respectively (P < .001). During initial hospital stay, 5.0%, 40.8%, and 63.4% of AB, SR, and LT cohorts, respectively, received ICU-level care (P < .001). By 30 and 90 days, there were significant differences among the AB, SR, and LT cohorts in the rate of postprocedural hemorrhage, abscess formation, biliary injury, pneumonia, sepsis, liver disease-related AEs, and anesthesia-related AEs (P < .05). By 90 days, the readmission rates after AB, SR, and LT were 18.6%, 28.2%, and 40.6% (P < .001), respectively.
AB results in significantly less healthcare utilization during the initial 90 days after procedure compared with that after SR and LT due to shorter length of stay, lower intensity care, fewer readmissions, and fewer AEs.
Spatially-resolved molecular profiling by immunostaining tissue sections is a key feature in cancer diagnosis, subtyping, and treatment, where it complements routine histopathological evaluation by ...clarifying tumor phenotypes. In this work, we present a deep learning-based method called speedy histological-to-immunofluorescent translation (SHIFT) which takes histologic images of hematoxylin and eosin (H&E)-stained tissue as input, then in near-real time returns inferred virtual immunofluorescence (IF) images that estimate the underlying distribution of the tumor cell marker pan-cytokeratin (panCK). To build a dataset suitable for learning this task, we developed a serial staining protocol which allows IF and H&E images from the same tissue to be spatially registered. We show that deep learning-extracted morphological feature representations of histological images can guide representative sample selection, which improved SHIFT generalizability in a small but heterogenous set of human pancreatic cancer samples. With validation in larger cohorts, SHIFT could serve as an efficient preliminary, auxiliary, or substitute for panCK IF by delivering virtual panCK IF images for a fraction of the cost and in a fraction of the time required by traditional IF.
Analysis of DNA methylation patterns relies increasingly on sequencing-based profiling methods. The four most frequently used sequencing-based technologies are the bisulfite-based methods MethylC-seq ...and reduced representation bisulfite sequencing (RRBS), and the enrichment-based techniques methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA binding domain sequencing (MBD-seq). We applied all four methods to biological replicates of human embryonic stem cells to assess their genome-wide CpG coverage, resolution, cost, concordance and the influence of CpG density and genomic context. The methylation levels assessed by the two bisulfite methods were concordant (their difference did not exceed a given threshold) for 82% for CpGs and 99% of the non-CpG cytosines. Using binary methylation calls, the two enrichment methods were 99% concordant and regions assessed by all four methods were 97% concordant. We combined MeDIP-seq with methylation-sensitive restriction enzyme (MRE-seq) sequencing for comprehensive methylome coverage at lower cost. This, along with RNA-seq and ChIP-seq of the ES cells enabled us to detect regions with allele-specific epigenetic states, identifying most known imprinted regions and new loci with monoallelic epigenetic marks and monoallelic expression.
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