Projected shortages of global phosphate have prompted investigation of methods that could be employed to capture and recycle phosphate, rather than continue to allow the resource to be essentially ...irreversibly lost through dilution in surface waters. Hydrothermal carbonization of animal manures from large farms was investigated as a scenario for the reclamation of phosphate for agricultural use and mitigation of the negative environmental impact of phosphate pollution. Hydrothermal reaction conditions were identified for poultry, swine, and cattle manures that resulted in hydrochar yields of 50–60% for all three manures, and >90% of the total phosphorus present in these systems was contained in the hydrochars as precipitated phosphate salts. Phosphate recovery was achieved in yields of 80–90% by subsequent acid treatment of the hydrochars, addition of base to acid extracts to achieve a pH of 9, and filtration of principally calcium phosphate. Phosphate recovery was achieved in yields of 81−87% based on starting manures by subsequent acid treatment of the hydrochars, addition of base to acid extracts to achieve a pH of 9, and filtration of principally calcium phosphate. Swine and cattle manures produced hydrochars with combustion energy contents comparable to those of high-end sub-bituminous coals.
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IJS, KILJ, NUK, PNG, UL, UM
ARID1A (AT-rich interactive domain-containing protein 1A) is a subunit of the BAF chromatin remodeling complex and plays roles in transcriptional regulation and DNA damage response. Mutations in ...ARID1A that lead to inactivation or loss of expression are frequent and widespread across many cancer types including colorectal cancer (CRC). A tumor suppressor role of ARID1A has been established in a number of tumor types including CRC where the genetic inactivation of Arid1a alone led to the formation of invasive colorectal adenocarcinomas in mice. Mechanistically, ARID1A has been described to largely function through the regulation of enhancer activity.
To mimic ARID1A-deficient colorectal cancer, we used CRISPR/Cas9-mediated gene editing to inactivate the ARID1A gene in established colorectal cancer cell lines. We integrated gene expression analyses with genome-wide ARID1A occupancy and epigenomic mapping data to decipher ARID1A-dependent transcriptional regulatory mechanisms.
Interestingly, we found that CRC cell lines harboring KRAS mutations are critically dependent on ARID1A function. In the absence of ARID1A, proliferation of these cell lines is severely impaired, suggesting an essential role for ARID1A in this context. Mechanistically, we showed that ARID1A acts as a co-factor at enhancers occupied by AP1 transcription factors acting downstream of the MEK/ERK pathway. Consistently, loss of ARID1A led to a disruption of KRAS/AP1-dependent enhancer activity, accompanied by a downregulation of expression of the associated target genes.
We identify a previously unknown context-dependent tumor-supporting function of ARID1A in CRC downstream of KRAS signaling. Upon the loss of ARID1A in KRAS-mutated cells, enhancers that are co-occupied by ARID1A and the AP1 transcription factors become inactive, thereby leading to decreased target gene expression. Thus, targeting of the BAF complex in KRAS-mutated CRC may offer a unique, previously unknown, context-dependent therapeutic option in CRC.
Purpose
Data on childhood intensive care unit (ICU) deaths are needed to identify changing patterns of intensive care resource utilization. We sought to determine the epidemiology and mode of ...pediatric ICU deaths in Australia and New Zealand (ANZ).
Methods
This was a retrospective, descriptive study of multicenter data from pediatric and mixed ICUs reported to the ANZ Pediatric Intensive Care Registry and binational Government census. All patients < 16 years admitted to an ICU between 1 January 2006 and 31 December 2016 were included. Primary outcome was ICU mortality. Subject characteristics and trends over time were evaluated.
Results
Of 103,367 ICU admissions, there were 2672 (2.6%) deaths, with 87.6% of deaths occurring in specialized pediatric ICUs. The proportion of ANZ childhood deaths occurring in ICU was 12%, increasing by 43% over the study period. Unadjusted (0.1% per year, 95% CI 0.096–0.104;
p
< 0.001) and risk-adjusted (0.1%/year, 95% CI 0.07–0.13;
p
< 0.001) ICU mortality rates fell. Across all admission sources and diagnostic groups, mortality declined except following pre-ICU cardiopulmonary arrest where increased mortality was observed. Half of the deaths followed withdrawal of life-sustaining therapy (51%), remaining constant throughout the study. Deaths despite maximal resuscitation declined (0.92%/year, 95% CI 0.89–0.95%;
p
< 0.001) and brain death diagnoses increased (0.72%/year, 95% CI 0.69–0.75%;
p
= 0.001).
Conclusions
Unadjusted and risk-adjusted mortality for children admitted to ANZ ICUs is declining. Half of pediatric ICU deaths follow withdrawal of life-sustaining therapy. Epidemiology and mode of pediatric ICU death are changing. Further investigation at an international level will inform benchmarking, resource allocation and training requirements for pediatric critical care.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Recent genome- and exome-wide sequencing studies have revealed a close association between the epigenome and the pathogenesis of cancer. Not only were chromatin regulators found to be ...commonly mutated in a wide range of cancers, but a class of these regulators, the ATP-dependent chromatin remodelers, especially subunits of the mammalian BAF complex, were among the most frequently mutated group of genes across cancer types, mutated in over 20% of cancers. Among these subunits, loss of function mutations in ARID1A (AT-rich interactive domain-containing protein 1A) are most frequent across cancer types including 10% of colorectal cancer (CRC). Very interestingly, a recent publication described the pivotal role of the loss of ARID1A in driving CRC wherein its inactivation alone led to the formation of invasive adenocarcinomas in mice. However, surprisingly, in contrast to the expected tumor suppressive role of ARID1A in CRC, we observe that the knockout (KO) of ARID1A in CRC cell lines leads to impaired proliferation. Moreover, subcutaneous xenografts in SCID/SHO mice using ARID1A KO CRC cells did not form more aggressive tumors than their wild type counterparts. One of the most commonly occurring mutations in CRC is in the APC gene, which leads to hyperactive Wnt signaling. Thus CRC progression is typically highly dependent on this pathway. Notably, it is reported that loss of ARID1A in the context of APC mutations results in diminished tumor formation in mice and increased differentiation. This led us to hypothesize that ARID1A is required for Wnt signaling-mediated transcriptional (de)regulation in CRC. To uncover this further, we utilized several publically available ChIP-seq, RNA-seq and ATAC-seq datasets as well as our own ChIP-seq data for ARID1A in the HCT116 cell line. We observe a substantial co-localization of the BAF complex with TCF7L2, a downstream effector of the Wnt signaling pathway, suggesting cooperation between these factors. Further, these sites are also co-occupied by AP1 transcription factors. A crosstalk between the TCF7L2 and AP1 factors has been reported in intestinal tumors. From data available in the ARID1A KO system, we observe a downregulation of potential target genes which are co-occupied at neighboring sites by these factors. Therefore, we suggest that ARID1A plays an important role in the regulation of colorectal cancer relevant genes that are targets of TCF7L2/AP1, thus facilitating a pathway that is most commonly hijacked in colorectal cancer.
Citation Format: Madhobi Sen, Feda H. Hamdan, Xin Wang, Jacobe Rapp, Steven A. Johnsen. The role of the BAF complex in Wnt signaling-mediated transcriptional regulation in colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1472.
A genome-wide association study (GWAS) suggested inherited genetic single-nucleotide polymorphisms (SNPs) affecting overall survival (OS) in advanced pancreatic cancer. To identify robust clinical ...biomarkers, we tested the strongest reported candidate loci in an independent patient cohort, assessed cellular drug sensitivity, and evaluated molecular effects.
This study comprised 381 patients with histologically verified pancreatic ductal adenocarcinoma treated with gemcitabine-based chemotherapy. The primary outcome was the relationship between germline polymorphisms and OS. Functional assays addressed pharmacological dose-response effects in lymphoblastoid cell lines (LCLs) and pancreatic cancer cell lines (including upon RNAi), gene expression analyses, and allele-specific transcription factor binding. All statistical tests were two-sided.
The A allele (26% in Caucasians) at SNP rs11644322 in the putative tumor suppressor gene WWOX conferred worse prognosis. Median OS was 14 months (95% confidence interval CI = 12 to 15 months), 13 months (95% CI = 11 to 15 months), and nine months (95% CI = 7 to 12 months) for the GG, GA, and AA genotypes, respectively (P trend < .001 for trend in univariate log-rank assuming a codominant mode of inheritance; advanced disease subgroup P trend < .001). Mean OS was 25 months (95% CI = 21 to 29 months), 19 months (95% CI = 15 to 22 months), and 13 months (95% CI = 10 to 16 months), respectively. This effect held true after adjustment for age, performance status according to Eastern Cooperative Oncology Group classification, TNM, grading, and resection status and was comparable with the strongest established prognostic factors in multivariable analysis. Consistently, reduced responsiveness to gemcitabine, but not 5-fluorouracil, along with lower WWOX expression was demonstrated in LCLs harboring the AA genotype. Likewise, RNAi-mediated WWOX knockdown in pancreatic cancer cells confirmed differential cytostatic drug sensitivity. In electrophoretic mobility shift assays, the A allele exhibited weaker binding of Sp family members Sp1/Sp3.
WWOX rs11644322 represents a major predictive factor in gemcitabine-treated pancreatic cancer. Decreased WWOX expression may interfere with gemcitabine sensitivity, and allele-specific binding at rs11644332 might be a causative molecular mechanism behind the observed clinical associations.
Knowledge of mobile genetic elements that capture and disseminate antimicrobial resistance genes between diverse environments, particularly across human-animal boundaries, is key to understanding the ...role anthropogenic activities have in the evolution of antimicrobial resistance. Plasmids that circulate within the
and the Proteobacteria more broadly are well placed to acquire resistance genes sourced from separate niche environments and provide a platform for smaller mobile elements such as IS
to assemble these genes into large, complex genomic structures. Here, we characterised two atypical Z/I1 hybrid plasmids, pSTM32-108 and pSTM37-118, hosting antimicrobial resistance and virulence associated genes within endemic pathogen
serovar Typhimurium 1,4,5,12:i:-, sourced from Australian swine production facilities during 2013. We showed that the plasmids found in
Typhimurium 1,4,5,12:i:- are close relatives of two plasmids identified from
of human and bovine origin in Australia circa 1998. The older plasmids, pO26-CRL
and pO111-CRL
, encoded a putative serine protease autotransporter and were host to a complex resistance region composed of a hybrid Tn
-Tn
mercury resistance transposon and composite IS
transposon Tn
. This gave a broad antimicrobial resistance profile keyed towards first generation antimicrobials used in Australian agriculture but also included a class 1 integron hosting the trimethoprim resistance gene
. Genes encoding resistance to ampicillin, trimethoprim, sulphonamides, streptomycin, aminoglycosides, tetracyclines and mercury were a feature of these plasmids. Phylogenetic analyses showed very little genetic drift in the sequences of these plasmids over the past 15 years; however, some alterations within the complex resistance regions present on each plasmid have led to the loss of various resistance genes, presumably as a result of the activity of IS
. These alterations may reflect the specific selective pressures placed on the host strains over time. Our studies suggest that these plasmids and variants of them are endemic in Australian food production systems.
Loss of AT-rich interactive domain-containing protein 1A (ARID1A) fosters acinar-to-ductal metaplasia (ADM) and pancreatic carcinogenesis by down-regulating transcription programs controlling acinar ...cell identity. However, how ARID1A reacts to metaplasia-triggering environmental cues remains elusive. Here, we aimed to elucidate the role of ARID1A in controlling ductal pancreatic gene signatures and deciphering hierarchical signaling cues determining ARID1A-dependent chromatin regulation during acinar cell reprogramming.
Acinar cell explants with differential ARID1A status were subjected to genome-wide expression analyses. The impact of epidermal growth factor receptor (EGFR) signaling, NFATc1 activity, and ARID1A status on acinar reprogramming processes were characterized by ex vivo ADM assays and transgenic mouse models. EGFR-dependent ARID1A chromatin binding was studied by chromatin immunoprecipitation sequencing analysis and cellular fractionation.
EGFR signaling interferes with ARID1A-dependent transcription by inducing genome-wide ARID1A displacement, thereby phenocopying ARID1A loss-of-function mutations and inducing a shift toward ADM permissive ductal transcription programs. Moreover, we show that EGFR signaling is required to push ARID1A-deficient acinar cells toward a metaplastic phenotype. Mechanistically, we identified the transcription factor nuclear factor of activated T cells 1 (NFATc1) as the central regulatory hub mediating both EGFR signaling-induced genomic ARID1A displacement and the induction of ADM-promoting gene signatures in the absence of ARID1A. Consequently, pharmacologic inhibition of NFATc1 or its depletion in transgenic mice not only preserves genome-wide ARID1A occupancy, but also attenuates acinar metaplasia led by ARID1A loss.
Our data describe an intimate relationship between environmental signaling and chromatin remodeling in orchestrating cell fate decisions in the pancreas, and illustrate how ARID1A loss influences transcriptional regulation in acinar cell reprogramming.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background & Aims: Loss of AT-rich interactive domain-containing protein 1A (ARID1A) fosters acinar-to-ductal metaplasia (ADM) and pancreatic carcinogenesis by down-regulating transcription programs ...controlling acinar cell identity. However, how ARID1A reacts to metaplasia-triggering environmental cues remains elusive. Here, we aimed to elucidate the role of ARID1A in controlling ductal pancreatic gene signatures and deciphering hierarchical signaling cues determining ARID1A-dependent chromatin regulation during acinar cell reprogramming. Methods: Acinar cell explants with differential ARID1A status were subjected to genome-wide expression analyses. The impact of epidermal growth factor receptor (EGFR) signaling, NFATc1 activity, and ARID1A status on acinar reprogramming processes were characterized by ex vivo ADM assays and transgenic mouse models. EGFR-dependent ARID1A chromatin binding was studied by chromatin immunoprecipitation sequencing analysis and cellular fractionation. Results: EGFR signaling interferes with ARID1A-dependent transcription by inducing genome-wide ARID1A displacement, thereby phenocopying ARID1A loss-of-function mutations and inducing a shift toward ADM permissive ductal transcription programs. Moreover, we show that EGFR signaling is required to push ARID1A-deficient acinar cells toward a metaplastic phenotype. Mechanistically, we identified the transcription factor nuclear factor of activated T cells 1 (NFATc1) as the central regulatory hub mediating both EGFR signaling-induced genomic ARID1A displacement and the induction of ADM-promoting gene signatures in the absence of ARID1A. Consequently, pharmacologic inhibition of NFATc1 or its depletion in transgenic mice not only preserves genome-wide ARID1A occupancy, but also attenuates acinar metaplasia led by ARID1A loss. Conclusions: Our data describe an intimate relationship between environmental signaling and chromatin remodeling in orchestrating cell fate decisions in the pancreas, and illustrate how ARID1A loss influences transcriptional regulation in acinar cell reprogramming.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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