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Perianal fistulas on18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) can be an incidental site of FDG uptake in patients undergoing PET for other indications. There are no longitudinal studies describing FDG uptake patterns in perianal fistulas. Therefore, we aimed to analyze changes in FDG uptake over time in patients with incidental perianal fistulas. Patients who underwent at least two FDG-PET/CTs between January 2011 and May 2023, with incidental perianal fistula, were retrospectively identified. We analyzed all sequential PET/CTs to determine the presence of a perianal fistula and recorded the fistula's maximum standardized uptake value (SUV max). Statistical analysis compared fistula FDG-avidity in the initial versus final PET/CT examinations and assessed the correlation between initial fistula SUV max and percent change over time. The study included 15 fistulas in 14 patients, with an average of 5 PET/CT examinations per patient. The average interval between the first and last PET/CT was 24 months (range: 6–64). The average initial fistula SUV max (11.28 ± 3.81) was significantly higher than the final fistula SUV max (7.22 ± 3.99) (p = 0.0067). The fistula SUV max declined by an average of 32.01 ± 35.33% with no significant correlation between initial fistula SUV max and percent change over time (r = −0.213, p = 0.443, 95% CI −0.66–0.35). FDG uptake in perianal fistulas shows temporal fluctuations but follows a decreasing SUV max trend, possibly indicating a relationship with inflammatory activity. Further studies with larger cohorts paired with perianal fistula pelvic MR imaging are needed to validate these observations and their utility in guiding further management. [ABSTRACT FROM AUTHOR]

The use of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) in assessing inflammatory diseases has shown significant promise. Uptake patterns in perianal fistulas, which may be an incidental finding on PET/CT, have not been purposefully studied. Our aim was to compare FDG uptake of perianal fistulas to that of the liver and anal canal in patients who underwent PET/CT for hematologic/oncologic diagnosis or staging. We retrospectively identified patients who underwent FDG-PET/CT imaging between January 2011 and May 2023, where the report described a perianal fistula or abscess. PET/CTs of patients included in the study were retrospectively analyzed to record the maximum standardized uptake value (SUV max) of the fistula, abscess, anal canal, rectum, and liver. Fistula-to-liver and Fistula-to-anus SUV max ratios were calculated. We statistically compared FDG activity among the fistula, liver, and anal canal. We also assessed FDG activity in patients with vs. without anorectal cancer, as well as across different St. James fistula grades. The study included 24 patients with identifiable fistulas. Fistula SUV max (mean = 10.8 ± 5.28) was significantly higher than both the liver (mean = 3.09 ± 0.584, p < 0.0001) and the anal canal (mean = 5.98 ± 2.63, p = 0.0005). Abscess fistula SUV max was 15.8 ± 4.91. St. James grade 1 fistulas had significantly lower SUV max compared to grades 2 and 4 (p = 0.0224 and p = 0.0295, respectively). No significant differences existed in SUV max ratios between anorectal and non-anorectal cancer groups. Perianal fistulas have increased FDG avidity with fistula SUV max values that are significantly higher than the anal canal. [ABSTRACT FROM AUTHOR]

Transcriptional activators bind DNA and recruit cofactors to modify chromatin. The extent to which these two events are separable is unclear. Here, using a custom ChIP tiling array to map chromatin modifications, we show that interferon-γ-induced DNA binding of signal transducer and activator of transcription 1 (STAT1), typically associated with the transcription factor interferon regulatory factor 1 (IRF1), causes histone acetylation (H3ac, H4ac). In contrast, among IRF1 sites lacking concomitant STAT1 recruitment, only 25% underwent inducible histone acetylation, 31% exhibited constitutive histone acetylation, and 44% had no histone acetylation. These latter “orphan sites” also lacked other activating modifications (e.g. H3K4me1, H3K4me2) and were typically remote from transcription start sites. In these cases the closest gene was typically an IFNγ-inducible locus that did not respond to IFNγ in this setting. Orphan sites were detected in different cell types, suggesting broad relevance. Despite an atypical downstream response (i.e. no histone modifications), IRF1 binding depended on SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4 or BRG1), as is typical of active IRF1 enhancers. Although SMARCA4 permitted IRF1 access to the orphan sites, there was no corecruitment of the histone acetyltransferases CREB-binding protein (CBP) and p300. Orphan sites were constitutively unacetylated, and several were marked with repressive chromatin modifications (e.g. H3K27me3). In conclusion, although IRF1 can trigger enhanceosome formation independently of STAT1, its ability to do so depends on local chromatin cues. [ABSTRACT FROM AUTHOR]

Abstract: Transplants of culture-expanded bone marrow stromal cells (BMSCs) combined with hydroxyapatite/tricalcium phosphate (HA/TCP) scaffolds successfully form cortico-cancellous bone to reconstruct the dog craniofacial skeleton. Yet, these transplants'' long-term stability in large animal models has not been evaluated. This study''s purpose was the evaluation of long-term BMSC transplant stability when used to augment the mandible. Here, autologous BMSC–HA/TCP transplants were introduced onto the unilateral dog mandible as onlay grafts, while contralateral control mandibles received HA/TCP onlays alone. Quantitative CT (qCT) scans were obtained both early and late after transplantation. Transplants were harvested up to 19 months later for histologic and mechanical analyses. In all dogs, BMSC transplants formed significantly greater amounts of bone over their control counterparts. The new bone formed an extensive union with the underlying mandible. BMSC transplants retained the majority of their initial volume, while control (HA/TCP only) transplants were nearly completely resorbed. By qCT, the extent of newly formed bone could be determined non-invasively. In summary, HA/TCP particles alone undergo a high degree of resorption, while autologous cultured BMSC–HA/TCP transplants provide long-term bony augmentation of the mandible. [Copyright &y& Elsevier]

Abstract: The intensity of biogenic sediment mixing is often expressed as a “biodiffusion coefficient” (D b ), quantified by fitting a diffusive model of bioturbation to vertical profiles of particle-bound radioisotopes. The biodiffusion coefficient often exhibits a dependence on tracer half-life: short-lived radioisotopes (e.g. 234Th) tend to yield notably larger D b values than longer-lived radioisotopes (e.g. 210Pb). It has been hypothesized that this is a result of differential mixing of tracers by particle-selective benthos. This study employs a lattice-automaton model of bioturbation to explore how steady-state tracers with different half-lives are mixed in typical marine settings. Every particle in the model is tagged with the same array of radioisotopes, so that all tracers experienced exactly the same degree of mixing. Two different estimates of the mixing intensity are calculated: a tracer-derived D b , obtained in the standard way by fitting the biodiffusion model to resulting tracer profiles, and a particle-tracking D b , derived from the statistics of particle movements. The latter provides a tracer-independent measure of mixing for use as a reference. Our simulations demonstrate that an apparent D b tracer-dependence results from violating the underlying assumptions of the biodiffusion model. Breakdown of the model is rarely apparent from tracer profiles, emphasizing the need to evaluate the model’s criteria from biological and ecological parameters, rather than relying on obvious indications of model breakdown, e.g., subsurface maxima. Simulations of various marine environments (coastal, slope, abyssal) suggest that the time scales of short-lived radioisotopes, such as 234Th and 7Be, are insufficient for the tracers to be used with the biodiffusion model. 210Pb appears an appropriate tracer for abyssal sediments, while 210Pb and 228Th are suitable for slope and coastal sediments. [Copyright &y& Elsevier]

Cancer heterogeneity impacts therapeutic response, driving efforts to discover over-arching rules that supersede variability. Here, we define pan-cancer binary classes based on distinct expression of YAP and YAP-responsive adhesion regulators. Combining informatics with in vivo and in vitro gain- and loss-of-function studies across multiple murine and human tumor types, we show that opposite pro- or anti-cancer YAP activity functionally defines binary YAPon or YAPoff cancer classes that express or silence YAP, respectively. YAPoff solid cancers are neural/neuroendocrine and frequently RB1 −/−, such as retinoblastoma, small cell lung cancer, and neuroendocrine prostate cancer. YAP silencing is intrinsic to the cell of origin, or acquired with lineage switching and drug resistance. The binary cancer groups exhibit distinct YAP-dependent adhesive behavior and pharmaceutical vulnerabilities, underscoring clinical relevance. Mechanistically, distinct YAP/TEAD enhancers in YAPoff or YAPon cancers deploy anti-cancer integrin or pro-cancer proliferative programs, respectively. YAP is thus pivotal across cancer, but in opposite ways, with therapeutic implications. [Display omitted] • YAP/TAZ silencing in multiple cancers reflects their tumor suppressor activity • Cancers can be parsed into binary YAPon and YAPoff classes • Binary transcriptomes drive distinct adhesive, metabolic, genetic, and drug profiles • Alternate YAP enhancers explain anti-cancer integrin-αVβ5 program in YAPoff cancers Pearson et al. demonstrate that YAP/TAZ, well-known oncogenes, are tumor suppressors in a large group of cancers. Pan-cancer analyses reveal that opposite YAP/TAZ expression, adhesive behavior, and oncogenic versus tumor suppressor YAP/TAZ activity functionally stratify binary cancer classes, which interchange to drive drug resistance. Contrasting YAPoff/YAPon classes exhibit unique vulnerabilities, facilitating therapeutic selection. [ABSTRACT FROM AUTHOR]

Co-contamination with complex mixtures of carcinogenic metals, such as chromium, and polycyclic aromatic hydrocarbons is a common environmental problem with multiple biological consequences. Chromium exposure alters inducible gene expression; forms chromium-DNA adducts and chromium-DNA cross-links, and disrupts transcriptional activator-co-activator complexes. We have shown previously that exposure of mouse hepatoma Hepa-1 cells to chromate inhibits the induction of the Cyp1a1 and Nqo1 genes by dioxin. Here we have tested the hypothesis that chromium blocks gene expression by interfering with the assembly of productive transcriptional complexes at the promoter of inducible genes. To this end, we have studied the effects of chromium on the expression of genes induced by benzo[a]pyrene (B[a]P), another aryl hydrocarbon receptor agonist, and characterized the disruption of Cyp1a1 transcriptional induction by chromium. Gene expression profiling by using high density microarray analysis revealed that the inhibitory effect of chromium on B[a]Pdependent gene induction was generalized, affecting the induction of over 50 different genes involved in a variety of signaling transduction pathways. The inhibitory effect of chromium on Cyp1a1 transcription was found to depend on the presence of promoter-proximal sequences and not on the cis-acting enhancer sequences that bind the aryl hydrocarbon receptor-aryl hydrocarbon receptor nuclear translocator complex. By using transient reporter assays and chromatin immunoprecipitation analyses, we found that chromium prevented the B[a]P-dependent release of HDAC-1 from Cyp1a1 chromatin and blocked p300 recruitment. These results provide a mechanistic explanation for the observation that chromium inhibits inducible but not constitutive gene expression. [ABSTRACT FROM AUTHOR]

• Wastewater viral titers precede clinical COVID-19 surveillance data across the U.S. • SARS-CoV-2 detection rate in wastewater is 80% when incidence is 13 per 100k people. • SARS-CoV-2 detection rate in wastewater positively associates with catchment size. • Wastewater surveillance shows a 62.7% consistency to clinical reported data. Wastewater-based disease surveillance is a promising approach for monitoring community outbreaks. Here we describe a nationwide campaign to monitor SARS-CoV-2 in the wastewater of 159 counties in 40 U.S. states, covering 13% of the U.S. population from February 18 to June 2, 2020. Out of 1,751 total samples analyzed, 846 samples were positive for SARS-CoV-2 RNA, with overall viral concentrations declining from April to May. Wastewater viral titers were consistent with, and appeared to precede, clinical COVID-19 surveillance indicators, including daily new cases. Wastewater surveillance had a high detection rate (>80%) of SARS-CoV-2 when the daily incidence exceeded 13 per 100,000 people. Detection rates were positively associated with wastewater treatment plant catchment size. To our knowledge, this work represents the largest-scale wastewater-based SARS-CoV-2 monitoring campaign to date, encompassing a wide diversity of wastewater treatment facilities and geographic locations. Our findings demonstrate that a national wastewater-based approach to disease surveillance may be feasible and effective. [Display omitted] [ABSTRACT FROM AUTHOR]