Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer.

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.

We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.

Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin.

Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.

spongEffects: ceRNA modules offer patient-specific insights into the miRNA regulatory landscape.

MOTIVATION: Cancer is one of the leading causes of death worldwide. Despite significant improvements in prevention and treatment, mortality remains high for many cancer types. Hence, innovative methods that use molecular data to stratify patients and identify biomarkers are needed. Promising biomarkers can also be inferred from competing endogenous RNA (ceRNA) networks that capture the gene-miRNA gene regulatory landscape. Thus far, the role of these biomarkers could only be studied globally but not in a sample-specific manner. To mitigate this, we introduce spongEffects, a novel method that infers subnetworks (or modules) from ceRNA networks and calculates patient- or sample-specific scores related to their regulatory activity. RESULTS: We show how spongEffects can be used for downstream interpretation and machine learning tasks such as tumor classification and for identifying subtype-specific regulatory interactions. In a concrete example of breast cancer subtype classification, we prioritize modules impacting the biology of the different subtypes. In summary, spongEffects prioritizes ceRNA modules as biomarkers and offers insights into the miRNA regulatory landscape. Notably, these module scores can be inferred from gene expression data alone and can thus be applied to cohorts where miRNA expression information is lacking. AVAILABILITY AND IMPLEMENTATION: https://bioconductor.org/packages/devel/bioc/html/SPONGE.html.

Tibiotalocalcaneal nail and primary closure for the management of open ankle fractures in the elderly patient; results from a major trauma centre.

INTRODUCTION: Open ankle fractures in elderly patients are challenging injuries to manage. The aim of this study was to assess the outcome of elderly patients with open ankle fractures treated with a tibiotalocalcaneal nail and primary wound closure. METHODS: We identified all open ankle fractures in patients over 65 referred to our major trauma centre managed with a tibiotalocalcaneal nail and primary wound closure over 10 years. We recorded patient demographics, comorbidities, injury mechanism, length of stay, operation, weightbearing status, re-operations, infections and mortality. RESULTS: We included 34 patients with an average age of 87 (73-99). We found 56 % of patients' mobility status declined post-operatively and 21 % of patients were discharged directly home. Four patients required further unplanned surgery including two deep infections requiring amputation. We had a 6 % three month mortality rate. CONCLUSION: Use of a tibiotalocalcaneal nail with primary wound closure offers a reasonable treatment option for open fractures of the ankle in the elderly patient.

Carbon availability affects already large species-specific differences in chemical composition of ectomycorrhizal fungal mycelia in pure culture.

Although ectomycorrhizal (ECM) contribution to soil organic matter processes receives increased attention, little is known about fundamental differences in chemical composition among species, and how that may be affected by carbon (C) availability. Here, we study how 16 species (incl. 19 isolates) grown in pure culture at three different C:N ratios (10:1, 20:1, and 40:1) vary in chemical structure, using Fourier transform infrared (FTIR) spectroscopy. We hypothesized that C availability impacts directly on chemical composition, expecting increased C availability to lead to more carbohydrates and less proteins in the mycelia. There were strong and significant effects of ECM species (R2 = 0.873 and P = 0.001) and large species-specific differences in chemical composition. Chemical composition also changed significantly with C availability, and increased C led to more polysaccharides and less proteins for many species, but not all. Understanding how chemical composition change with altered C availability is a first step towards understanding their role in organic matter accumulation and decomposition.

Occupational asthma in teachers.

BACKGROUND: Work-related asthma symptoms are common in teachers and teaching assistants, there are few studies evaluating their causes. AIMS: To identify causes of occupational asthma in teachers and teaching assistants referred to the Birmingham Occupational Lung Disease clinic 2000-20 using evaluation of serial Peak Expiratory Flow (PEF) records. METHODS: Teachers and teaching assistants with possible occupational asthma were asked to record PEF 2-hourly at home and work for 4 weeks. Their records were evaluated with the Oasys programme. Those with a positive score for any of the three scores (area between curves (ABC), timepoint and Oasys score from discriminant analysis) were included. Repeat records were made as indicated to help identify the cause and the effects of remedial actions. RESULTS: Thirty-eight teachers or teaching assistants met the inclusion criteria with all three Oasys scores positive in 24, 2/3 scores in nine and 1/3 in five. The building was the likely cause in 17 (in new builds particularly acrylates from carpet adhesives and in old buildings mould and construction dust), bystander exposure to agents in the schools in 12 (cleaning agents, acrylates from photocopiers and chloramines from indoor pools) and materials used in the classroom in 9 (most commonly MDF in design and technology classes). We illustrate how the PEF records helped identify the cause. CONCLUSIONS: Oasys analysis of PEF records is a useful method of evaluating occupational asthma in teachers and identified difficult to confirm causes where successful remediation or redeployment was achieved.

Occupational asthma in office workers.

BACKGROUND: Office work has a relative perception of safety for the worker. Data from surveillance schemes and population-based epidemiological studies suggest that office work carries a low risk of occupational asthma (OA). Office workers are frequently used as comparators in studies of occupational exposure and respiratory disease. AIMS: We aimed to describe and illustrate our tertiary clinical experience of diagnosing OA in office workers. METHODS: We searched the Birmingham NHS Occupational Lung Disease Service clinical database for cases of occupational respiratory disease diagnosed between 2002 and 2020, caused by office work or in office workers. For patients with OA, we gathered existing data on demographics, diagnostic tests including Occupational Asthma SYStem (OASYS) analysis of serial peak expiratory flow and specific inhalational challenge, and employment outcome. We summarised data and displayed them alongside illustrative cases. RESULTS: There were 47 cases of OA (5% of all asthma) confirmed using OASYS analysis of PEFs in the majority. Sixty percent of cases occurred in healthcare, education and government sectors. The most frequently implicated causative exposures or agents were: indoor air (9), printing, copying and laminating (7), cleaning chemicals (4), mould and damp (4), and acrylic flooring and adhesives (4). Exposures were grouped into internal office environment, office ventilation-related and adjacent environment. CONCLUSIONS: Clinicians should be vigilant for exposures associated with OA in office workers who present with work-related symptoms, where respiratory sensitizing agents may be present. A structured approach to assessment of the workplace is recommended.

Effect of Planting into a Green Winter Cereal Rye Cover Crop on Growth and Development, Seedling Disease, and Yield of Corn.

Terminating winter cereal rye (Secale cereale L.) cover crops ≥10 days before planting (DBP) corn is recommended to minimize seedling disease and potential yield loss. In Iowa, cold temperatures and frequent precipitation can prevent farmers from following that recommendation and sometimes force them to plant corn while the rye plants are still green, referred to as "planting green" (PG). A field trial was established to evaluate the effect of rye termination shortly before or after corn planting on growth, seedling root disease, and yield of corn. A rye cover crop was terminated 17 and 3 DBP and 6 and 12 days after planting (DAP) corn; corn planted following no rye was included as a control. Rye biomass, C/N ratio, and N accumulation increased when terminated 6 or 12 DAP corn compared with rye terminated 17 or 3 DBP corn. Corn seedlings were taller from the PG treatments. More radicle root rot was observed when rye was terminated 3 DBP, 6 DAP, and 12 DAP corn than for the 17 DBP treatment and the no-rye control. Generally, greater Pythium clade B populations were detected on radicles and seminal roots of corn from the PG treatments. Corn populations, ears, or barren plants were not affected by the treatments. In both years, the no-rye control had the greatest corn yield and the 12 DAP treatment had the lowest yield. Our results suggest that PG increased corn seedling root disease and contributed to reduced corn yield.

Perioperative mortality in bariatric surgery: meta-analysis.

BACKGROUND: Bariatric surgery is an established treatment for severe obesity; however, fewer than 1 per cent of eligible patients undergo surgery. The perceived risk of surgery may contribute to the low uptake. The aim of this study was to determine perioperative mortality associated with bariatric surgery, comparing different operation types and data sources. METHODS: A literature search of Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials was conducted to identify studies published between 1 January 2014 and 31 July 2020. Inclusion criteria were studies of at least 1000 patients reporting short-term mortality after bariatric surgery. Data were collected on RCTs. Meta-analysis was performed to establish overall mortality rates across different study types. The primary outcome measure was perioperative mortality. Different operation types were compared, along with study type, in subgroup analyses. The study was registered at PROSPERO (2019: CRD 42019131632). RESULTS: Some 4356 articles were identified and 58 met the inclusion criteria. Data were available on over 3.6 million patients. There were 4707 deaths. Pooled analysis showed an overall mortality rate of 0.08 (95 per cent c.i. 0.06 to 0.10; 95 per cent prediction interval 0 to 0.21) per cent. In subgroup analysis, there was no statistically significant difference between overall, 30-day, 90-day or in-hospital mortality (P = 0.29). There was no significant difference in reported mortality for RCTs, large studies, national databases or registries (P = 0.60). The pooled mortality rates by procedure type in ascending order were: 0.03 per cent for gastric band, 0.05 per cent for sleeve gastrectomy, 0.09 per cent for one-anastomosis gastric bypass, 0.09 per cent for Roux-en-Y gastric bypass, and 0.41 per cent for duodenal switch (P < 0.001 between operations). CONCLUSION: Bariatric surgery is safe, with low reported perioperative mortality rates.

Weight loss surgery helps patients with severe obesity. This study looked at the risk of dying after weight loss surgery in over 3.6 million patients. The risk was less than 1 in 1000 (0.08 per cent). The risk was lowest for gastric band and sleeve gastrectomy, then for gastric bypasses and highest for the duodenal switch operation. This shows that weight loss surgery is safe, with a low risk of dying similar to that of other common operations.

Effect of 6-Methoxy-2-Benzoxazolinone (MBOA) on Pythium Species and Corn Seedling Growth and Disease.

Corn yield reduction following a cereal rye cover crop has been attributed to, among other factors, allelochemicals released from decomposing cereal rye residue. The allelopathic effect of 6-methoxy-2-benzoxazolinone (MBOA) was evaluated on corn seedling growth, mycelial growth of seven pathogenic species of Pythium, and root rot of corn seedlings caused by Pythium spp. at 13, 16, and 22 to 23°C (room temperature) using a plate assay. Mycelial growth of all Pythium spp. tested was slower with MBOA at 0.25 mg/ml compared with MBOA at 0.125 and 0.0625 mg/ml and the check (4% V8 juice medium containing neomycin sulfate and chloramphenicol with 0.5% dimethyl sulfoxide). Therefore, no further tests were done with MBOA at 0.25 mg/ml. In general, MBOA reduced corn radicle length and did not cause root rot across all temperatures. However, greater root rot severity in corn was observed on corn seedlings grown in the presence of Pythium lutarium and P. oopapillum on media amended with MBOA compared with the check at all temperatures. Similarly, more root rot caused by P. torulosum and P. spinosum was observed when MBOA was present at 16°C compared with the check with no MBOA. These data suggest that corn seedling disease caused by Pythium spp. could be more severe when corn is planted following a cover crop of winter cereal rye due to the presence of allelochemicals that are released from the cover crop.

Effect of macro-calcification on the failure mechanics of intracranial aneurysmal wall tissue.

BACKGROUND: Calcification was recently found to be present in the majority of cerebral aneurysms, though how calcification and the presence or absence of co-localized lipid pools affect failure properties is still unknown. OBJECTIVE: The primary objective is to quantify the biomechanical effect of a macro-calcification with surrounding Near-Calcification Region (NCR) of varying mechanical properties on tissue failure behavior. METHODS: We utilized a structurally informed finite element model to simulate pre-failure and failure behavior of a human cerebral tissue specimen modeled as a composite containing a macro-calcification and surrounding NCR, embedded in a fiber matrix composite. Data from multiple imaging modalities was combined to quantify the collagen organization and calcification geometry. An idealized parametric model utilizing the calibrated model was used to explore the impact of NCR properties on tissue failure. RESULTS: Compared to tissue without calcification, peak stress was reduced by 82% and 49% for low modulus (representing lipid pool) and high modulus (simulating increase in calcification size) of the NCR, respectively. Failure process strongly depended on NCR properties with lipid pools blunting the onset of complete failure. When the NCR was calcified, the sample was able to sustain larger overall stress, however the failure process was abrupt with nearly simultaneous failure of the loaded fibers. CONCLUSIONS: Failure of calcified vascular tissue is strongly influenced by the ultrastructure in the vicinity of the calcification. Computational modeling of failure in fibrous soft tissues can be used to understand how pathological changes impact the tissue failure process, with potentially important clinical implications.

Adaptive Remodeling in the Elastase-induced Rabbit Aneurysms.

BACKGROUND: Rupture of brain aneurysms is associated with high fatality and morbidity rates. Through remodeling of the collagen matrix, many aneurysms can remain unruptured for decades, despite an enlarging and evolving geometry. OBJECTIVE: Our objective was to explore this adaptive remodeling for the first time in an elastase induced aneurysm model in rabbits. METHODS: Saccular aneurysms were created in 22 New Zealand white rabbits and remodeling was assessed in tissue harvested 2, 4, 8 and 12 weeks after creation. RESULTS: The intramural principal stress ratio doubled after aneurysm creation due to increased longitudinal loads, triggering a remodeling response. A distinct wall layer with multi-directional collagen fibers developed between the media and adventitia as early as 2 weeks, and in all cases by 4 weeks with an average thickness of 50.6 ± 14.3 µm. Collagen fibers in this layer were multi-directional (AI = 0.56 ± 0.15) with low tortuosity (1.08 ± 0.02) compared with adjacent circumferentially aligned medial fibers (AI = 0.78 ± 0.12) and highly tortuous adventitial fibers (1.22 ± 0.03). A second phase of remodeling replaced circumferentially aligned fibers in the inner media with longitudinal fibers. A structurally motivated constitutive model with both remodeling modes was introduced along with methodology for determining material parameters from mechanical testing and multiphoton imaging. CONCLUSIONS: A new mechanism was identified by which aneurysm walls can rapidly adapt to changes in load, ensuring the structural integrity of the aneurysm until a slower process of medial reorganization occurs. The rabbit model can be used to evaluate therapies to increase aneurysm wall stability.

RTNsurvival: an R/Bioconductor package for regulatory network survival analysis.

MOTIVATION: Transcriptional networks are models that allow the biological state of cells or tumours to be described. Such networks consist of connected regulatory units known as regulons, each comprised of a regulator and its targets. Inferring a transcriptional network can be a helpful initial step in characterizing the different phenotypes within a cohort. While the network itself provides no information on molecular differences between samples, the per-sample state of each regulon, i.e. the regulon activity, can be used for describing subtypes in a cohort. Integrating regulon activities with clinical data and outcomes would extend this characterization of differences between subtypes. RESULTS: We describe RTNsurvival, an R/Bioconductor package that calculates regulon activity profiles using transcriptional networks reconstructed by the RTN package, gene expression data, and a two-tailed Gene Set Enrichment Analysis. Given regulon activity profiles across a cohort, RTNsurvival can perform Kaplan-Meier analyses and Cox Proportional Hazards regressions, while also considering confounding variables. The Supplementary Information provides two case studies that use data from breast and liver cancer cohorts and features uni- and multivariate regulon survival analysis. AVAILABILITY AND IMPLEMENTATION: RTNsurvival is written in the R language, and is available from the Bioconductor project at http://bioconductor.org/packages/RTNsurvival/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

RTNduals: an R/Bioconductor package for analysis of co-regulation and inference of dual regulons.

MOTIVATION: Transcription factors (TFs) are key regulators of gene expression, and can activate or repress multiple target genes, forming regulatory units, or regulons. Understanding downstream effects of these regulators includes evaluating how TFs cooperate or compete within regulatory networks. Here we present RTNduals, an R/Bioconductor package that implements a general method for analyzing pairs of regulons. RESULTS: RTNduals identifies a dual regulon when the number of targets shared between a pair of regulators is statistically significant. The package extends the RTN (Reconstruction of Transcriptional Networks) package, and uses RTN transcriptional networks to identify significant co-regulatory associations between regulons. The Supplementary Information reports two case studies for TFs using the METABRIC and TCGA breast cancer cohorts. AVAILABILITY AND IMPLEMENTATION: RTNduals is written in the R language, and is available from the Bioconductor project at http://bioconductor.org/packages/RTNduals/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Tar Spot: An Understudied Disease Threatening Corn Production in the Americas.

Tar spot of corn has been a major foliar disease in several Latin American countries since 1904. In 2015, tar spot was first documented in the United States and has led to significant yield losses of approximately 4.5 million t. Tar spot is caused by an obligate pathogen, Phyllachora maydis, and thus requires a living host to grow and reproduce. Due to its obligate nature, biological and epidemiological studies are limited and impact of disease in corn production has been understudied. Here we present the current literature and gaps in knowledge of tar spot of corn in the Americas, its etiology, distribution, impact and known management strategies as a resource for understanding the pathosystem. This will in tern guide current and future research and aid in the development of effective management strategies for this disease.

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

BACKGROUND: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist. METHODS: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis. RESULTS: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH). CONCLUSIONS: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).

Repeat capsule endoscopy in suspected gastrointestinal bleeding.

Objectives: This study aims to review the utility of repeat capsule endoscopy (CE) with on-going concern of small bowel (SB) bleeding following initial SB investigation with CE. Materials and methods: A specifically designed database of CE examinations performed over 13 years, with hospital records, was retrospectively interrogated for patients undergoing multiple CEs to investigate iron deficiency anaemia (IDA) or suspected SB bleeding. Results: 1335/2276 (58.7%) of CEs were performed to investigate IDA or SB bleeding; 92 were repeat CEs carried out for ongoing clinical concern. The median time interval between initial and repeat CE procedures was 466.5 (range 1-3066) days. Twenty-four patients had initially normal CE; on repeat examination, abnormalities were detected in 11/24 (45.8%). 3/21 (14.2%) of patients with angioectasia on first CE had alternative causes for IDA or GI bleeding detected on repeat CE. Six patients with active bleeding, without an identifiable source on initial CE, undergoing repeat CE had a cause isolated in 5/6 (83.3%). Changing CE device did not affect diagnostic yield (DY) compared to repeat CE using the same device (27.5% to 26.8%). Conclusions: It is known that CE can miss clinically relevant and serious lesions. Our results suggest that patients with an initially negative or inconclusive CE frequently have a cause of SB bleeding detected on repeat CE. The DY of repeat CE is highest in those with bleeding on their initial CE (83.3%) and lower in those with initially normal examinations (45.8%) or when an alternative cause, such as angioectasia is seen (14.2%).

Integrated genomic characterization of endometrial carcinoma.

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.