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Prostate cancer (PCa) is the most diagnosed non-cutaneous cancer in men. Despite therapies such as radical prostatectomy, which is considered curative, distant metastases may form, resulting in biochemical recurrence (BCR). This study used radiomic features calculated from multi-parametric magnetic resonance imaging (MP-MRI) to evaluate their ability to predict BCR and PCa presence. Data from a total of 279 patients, of which 46 experienced BCR, undergoing MP-MRI prior to surgery were assessed for this study. After surgery, the prostate was sectioned using patient-specific 3D-printed slicing jigs modeled using the T2-weighted imaging (T2WI). Sectioned tissue was stained, digitized, and annotated by a GU-fellowship trained pathologist for cancer presence. Digitized slides and annotations were co-registered to the T2WI and radiomic features were calculated across the whole prostate and cancerous lesions. A tree regression model was fitted to assess the ability of radiomic features to predict BCR, and a tree classification model was fitted with the same radiomic features to classify regions of cancer. We found that 10 radiomic features predicted eventual BCR with an AUC of 0.97 and classified cancer at an accuracy of 89.9%. This study showcases the application of a radiomic feature-based tool to screen for the presence of prostate cancer and assess patient prognosis, as determined by biochemical recurrence.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.

Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion-positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer. SIGNIFICANCE: These data provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this dismal cancer.

Oral anticancer medications (OAMs) are increasingly utilized. We evaluated the representativeness and completeness of IQVIA, a large aggregator of pharmacy data, for breast cancer, colon cancer, chronic myeloid leukemia, and myeloma cases diagnosed in six Surveillance, Epidemiology, and End Results Program (SEER) registries between 2007 and 2011. Patient's SEER and SEER-Medicare data were linked and compared with IQVIA pharmacy data from 2006 to 2012 for specific OAMs. Overall, 67.6% of SEER cases had a pharmacy claim in IQVIA during the treatment assessment window. This varied by location, race and ethnicity, and insurance status. IQVIA consistently identified fewer cases who received an OAM of interest than SEER-Medicare. The difference was least pronounced for breast cancer agents and most pronounced for myeloma agents. The IQVIA pharmacy database included a large portion of persons in the SEER areas. Future studies should assess receipt of OAMs for other cancer sites and in different SEER registries.

PurposeEnd-of-life (EOL) cancer care is costly, with challenges regarding intensity and place of care. We described EOL care and costs for patients with colorectal cancer (CRC) in the United States and the province of Ontario, Canada, to inform better care delivery.MethodsPatients diagnosed with CRC from 2007 to 2013, who died of any cancer from 2007 to 2013 at age ≥ 66 years, were selected from the US SEER cancer registries linked to Medicare claims (n = 16,565) and the Ontario Cancer Registry linked to administrative health data (n = 6,587). We estimated total and resource-specific costs (2015 US dollars) from public payer perspectives over the last 360 days of life by 30-day periods, by stage at diagnosis (0-II, III, IV).ResultsIn all months, especially 30 days before death, higher percentages of SEER-Medicare than Ontario patients received chemotherapy (15.7% v 8.0%), and imaging tests (39.4% v 31.1%). A higher percentage of Ontario patients were hospitalized (62.5% v 51.0%), but 43.2% of hospitalized SEER-Medicare patients had intensive care unit (ICU) admissions versus 17.9% of hospitalized Ontario patients. Cost differences between cohorts were greater for patients with stage IV disease. In the last 30 days, mean total costs for patients with stage IV disease were $15,881 (SEER-Medicare) and $12,034 (Ontario) versus $19,354 and $17,312 for stage 0-II. Hospitalization costs were higher for SEER-Medicare patients ($11,180 v $9,434), with lower daily hospital costs in Ontario ($1,067 v $2,004).ConclusionThese findings suggest opportunities for reducing chemotherapy and ICU use in the United States and hospitalizations in Ontario.

Liposomal amphotericin B is an important frontline drug for the treatment of visceral leishmaniasis, a neglected disease of poverty. The mechanism of action of amphotericin B (AmB) is thought to involve interaction with ergosterol and other ergostane sterols, resulting in disruption of the integrity and key functions of the plasma membrane. Emergence of clinically refractory isolates of L. donovani and L. infantum is an ongoing issue and knowledge of potential resistance mechanisms can help to alleviate this problem. Here we report the characterisation of four independently selected L. donovani clones that are resistant to AmB. Whole genome sequencing revealed that in three of the moderately resistant clones, resistance was due solely to the deletion of a gene encoding C24-sterol methyltransferase (SMT1). The fourth, hyper-resistant resistant clone (>60-fold) was found to have a 24 bp deletion in both alleles of a gene encoding a putative cytochrome P450 reductase (P450R1). Metabolic profiling indicated these parasites were virtually devoid of ergosterol (0.2% versus 18% of total sterols in wild-type) and had a marked accumulation of 14-methylfecosterol (75% versus 0.1% of total sterols in wild-type) and other 14-alpha methylcholestanes. These are substrates for sterol 14-alpha demethylase (CYP51) suggesting that this enzyme may be a bona fide P450R specifically involved in electron transfer from NADPH to CYP51 during catalysis. Deletion of P450R1 in wild-type cells phenocopied the metabolic changes observed in our AmB hyper-resistant clone as well as in CYP51 nulls. Likewise, addition of a wild type P450R1 gene restored sterol profiles to wild type. Our studies indicate that P450R1 is essential for L. donovani amastigote viability, thus loss of this gene is unlikely to be a driver of clinical resistance. Nevertheless, investigating the mechanisms underpinning AmB resistance in these cells provided insights that refine our understanding of the L. donovani sterol biosynthetic pathway. Author summary: The antifungal drug, amphotericin B, is also used in the treatment of visceral leishmaniasis, a potentially lethal parasitic disease infecting the specialised immune cells (macrophages) in the liver, spleen, and bone marrow. Treatment failures due to emerging drug resistance are a significant concern. Using a combination of genetic and biochemical approaches, we have confirmed the mechanisms by which these parasites become less sensitive to treatment with amphotericin B. In addition, we have identified a novel mechanism involving loss of a key enzyme (cytochrome P450 reductase 1) in the biosynthetic pathway to ergosterol, an important lipid component of the parasite's plasma membrane. These studies increase our fundamental understanding of this important metabolic pathway and provide information that may be exploited to develop novel therapeutic strategies to combat this killer disease. [ABSTRACT FROM AUTHOR]

The X-ray crystal structure of an arginase-like protein from the parasitic protozoan Trypanosoma brucei, designated TbARG, is reported at 1.80 and 2.38 Å resolution in its reduced and oxidized forms, respectively. The oxidized form of TbARG is a disulfide-linked hexamer that retains the overall architecture of a dimer of trimers in the reduced form. Intriguingly, TbARG does not contain metal ions in its putative active site, and amino acid sequence comparisons indicate that all but one of the residues required for coordination to the catalytically obligatory binuclear manganese cluster in other arginases are substituted here with residues incapable of metal ion coordination. Therefore, the structure of TbARG is the first of a member of the arginase/deacetylase superfamily that is not a metalloprotein. Although we show that metal binding activity is easily reconstituted in TbARG by site-directed mutagenesis and confirmed in X-ray crystal structures, it is curious that this protein and its parasitic orthologues evolved away from metal binding function. Knockout of the TbARG gene from the genome demonstrated that its function is not essential to cultured bloodstream-form T. brucei, and metabolomics analysis confirmed that the enzyme has no role in the conversion of l-arginine to l-ornithine in these cells. While the molecular function of TbARG remains enigmatic, the fact that the T. brucei genome encodes only this protein and not a functional arginase indicates that the parasite must import l-ornithine from its host to provide a source of substrate for ornithine decarboxylase in the polyamine biosynthetic pathway, an active target for the development of antiparasitic drugs.

Background During the initial phase of the Coronavirus Disease 2019 (COVID-19) pandemic, reduced numbers of acutely ill or injured children presented to emergency departments (EDs). Concerns were raised about the potential for delayed and more severe presentations and an increase in diagnoses such as diabetic ketoacidosis and mental health issues. This multinational observational study aimed to study the number of children presenting to EDs across Europe during the early COVID-19 pandemic and factors influencing this and to investigate changes in severity of illness and diagnoses. Methods and findings Routine health data were extracted retrospectively from electronic patient records of children aged 18 years and under, presenting to 38 EDs in 16 European countries for the period January 2018 to May 2020, using predefined and standardized data domains. Observed and predicted numbers of ED attendances were calculated for the period February 2020 to May 2020. Poisson models and incidence rate ratios (IRRs), using predicted counts for each site as offset to adjust for case-mix differences, were used to compare age groups, diagnoses, and outcomes. Reductions in pediatric ED attendances, hospital admissions, and high triage urgencies were seen in all participating sites. ED attendances were relatively higher in countries with lower SARS-CoV-2 prevalence (IRR 2·26, 95% CI 1·90 to 2·70, p < 0.001) and in children aged Conclusions Reductions in ED attendances were seen across Europe during the first COVID-19 lockdown period. More severely ill children continued to attend hospital more frequently compared to those with minor injuries and illnesses, although absolute numbers fell. Trial registration ISRCTN91495258 https://www.isrctn.com/ISRCTN91495258., Author(s): Ruud G. Nijman 1,2,3,*, Kate Honeyford 4, Ruth Farrugia 5, Katy Rose 1,6, Zsolt Bognar 7, Danilo Buonsenso 8,9, Liviana Da Dalt 10, Tisham De 2, Ian K. Maconochie [...]

Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.

Background: A previous phase IB/II study of nab‐paclitaxel + cisplatin + gemcitabine (NABPLAGEM) in 25 patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC) demonstrated favorable results. This phase II study was conducted to further evaluate the safety, efficacy, and impact on quality of life (QOL) of NABPLAGEM in a multi‐center setting. Methods: Participants were ≥18 years; had measurable PDAC; Karnofsky performance status of ≥70%; life expectancy ≥12 weeks;

Incorporation of red clover (Trifolium pratense L.) into grass pastures can reduce the need for nitrogen fertilizer applications and increase the nutritional value of the forage. However, red clover cultivars available for Kentucky producers are highly susceptible to herbicides, such as 2,4-D (2,4-dichlorophenoxy acetic acid), used for pasture broadleaf weed control. To overcome this problem, 'UK2014' red clover was selected for increased tolerance to 2,4-D. We employed a transcriptome analysis approach to compare the gene expression response following 2,4-D treatment of 'UK2014' to that of 'Kenland', a 2,4-D sensitive red clover and one of the parents of 'UK2014'. The objectives were to first determine if the increased 2,4-D tolerance in 'UK2014' is reflected in a change of transcription response and/or a quicker recovery of a transcriptional response following 2,4-D treatment, and second, to identify genes, whether constitutively expressed or induced by 2,4-D, which could be the basis for the increased 2,4-D tolerance. Leaf tissue from the two red clovers grown in the field was collected at 4, 24, and 72 h after 2,4-D (1.12 kg 2,4-amine a.e. ha−1) treatment from both untreated and treated plants. Global gene expression was determined with reads from Illumina Hiseq 2500 mapped against the red clover draft genome, Tpv2.1 (GenBank Accession GCA_900079335.1). Genes that displayed differential expression (DEGs) following 2,4-D treatment were selected for further analysis. The number of DEGs was higher for 'Kenland' than for 'UK2014', suggesting that a lower transcriptional response corresponds with the higher 2,4-D tolerance in the 'UK2014' line. Similarly, gene ontology enrichment analysis revealed that expression of photosynthesis-related genes was less affected by 2,4-D in the 'UK2014' line than 'Kenland'. Although we were not able to identify any specific genes that are the basis for the increased 2,4-D tolerance of 'UK2014', we concluded that the increased 2,4-D tolerance of 'UK2014' correlates with a decreased transcription response to 2,4-D. Additionally, expression of several cytochrome P450 genes that had different isoforms between 'UK2014' and 'Kenland' increased significantly in both following 2,4-D treatment, one or more of these P450s could be mediators of 2,4-D metabolism and tolerance in red clover. [ABSTRACT FROM AUTHOR]