Mast cells (MCs) are critical components of the innate immune system and important for host defense, allergy, autoimmunity, tissue regeneration and tumor progression. Dysregulated MC development ...leads to systemic mastocytosis (SM), a clinically variable but often devastating family of hematologic disorders. Here we report that induced expression of Lin28, a heterochronic gene and pluripotency factor implicated in driving a fetal hematopoietic program, caused MC accumulation in adult mice in target organs such as the skin and peritoneal cavity. In vitro assays revealed a skewing of myeloid commitment in LIN28B-expressing hematopoietic progenitors, with increased levels of LIN28B in common myeloid and basophil-MC progenitors altering gene expression patterns to favor cell fate choices that enhanced MC specification. In addition, LIN28B-induced MCs appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of MC terminal differentiation in the context of LIN28B upregulation. Finally, interrogation of human MC leukemia samples revealed upregulation of LIN28B in abnormal MCs from patients with SM. This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in MC disease.
Abstract
Observations with the Chandra
X-ray Observatory are used to examine the hot gas properties within a sample of 10 galaxy groups selected from the Galaxy And Mass Assembly survey's optical ...Friends-of-Friends group catalogue. Our groups have been screened to eliminate spurious and unrelaxed systems, and the effectiveness of this procedure is demonstrated by the detection of intergalactic hot gas in 80 per cent of our sample. However, we find that 9 of the 10 are X-ray underluminous by a mean factor of ∼4 compared to typical X-ray-selected samples. Consistent with this, the majority of our groups have gas fractions that are lower and gas entropies somewhat higher than those seen in typical X-ray-selected samples. Two groups, which have high 2σ lower limits on their gas entropy, are candidates for the population of high-entropy groups predicted by some active galactic nucleus feedback models.
REASONS FOR PERFORMING STUDY: Survey data on equine tumours are sparse compared with other species and may have changed over time. OBJECTIVES: To describe the most frequently diagnosed equine tumours ...recorded by a diagnostic pathology laboratory over 29 years, to identify background factors associated with tumour type, and to identify any changes in the tumours diagnosed or the background of cases submitted during the study period. STUDY DESIGN: Observational; cross‐sectional analysis of records of a diagnostic pathology laboratory. METHODS: The records of all neoplastic equine histology submissions to the University of Bristol (January 1982–December 2010) were accessed from a database, and a list of diagnoses compiled. The 6 most commonly diagnosed tumour types were analysed using logistic regression to identify background factors associated with tumour type. The overall population of equine tumour submissions and the relative frequency of diagnosis of the most common tumour types were compared between decades. RESULTS: There were 964 cases included. The most frequently diagnosed tumours were: sarcoid (24% cases), squamous cell carcinoma (SCC) (19%), lymphoma (14%), melanoma (6%), gonadal stromal tumour (6%) and mast cell tumour (MCT) (4%). With sarcoid, Thoroughbred/Thoroughbred cross and gelding as reference categories: increasing age was significantly associated with the odds of each of the other tumour types, mares were at reduced risk of SCC, Arab/Arab cross had a higher risk of MCT, Cob/Cob cross had an increased risk of SCC and MCT, and ponies had an increased risk of melanoma. The mean age of submissions increased in each successive decade and the breed composition became broader. Sarcoids and lymphoma formed a smaller proportion of diagnoses in later decades. CONCLUSIONS: The types of tumours submitted to this laboratory have changed over the last 3 decades. Current data inform clinicians and researchers and further studies are warranted to follow trends. The Summary is available in Chinese – see Supporting information.
Summary
1. Macroinvertebrates were collected in dry and wet seasons from riffles and pools in two streams in tropical north Queensland. Total biomass, abundance and species richness were higher in ...riffles than in pools but did not differ between streams or seasons.
2. Gut contents of all species were identified. Cluster analysis based on gut contents identified five dietary groups: I, generalist collectors; II, generalist shredders and generalist predators; III, generalist scrapers; IV, specialist shredders; and V, specialist predators. Species were allocated to functional feeding groups (FFGs) based on these dietary groups.
3. Many species were generalist in their diets, but specialist predators and shredders were particularly prominent components of the invertebrate assemblages in terms of biomass and species richness.
4. Community composition (proportions of biomass, abundance and species richness of the different FFGs) varied between habitat types, but not between streams or seasons, although differences between riffles and pools varied with season.
5. Comparison of the fauna of 20 streams showed that our study sites were similar to, or not atypical of, low‐order streams in the Queensland wet tropics.
Recent studies have suggested that C-MYC may be an excellent therapeutic cancer target and a number of new agents targeting C-MYC are in preclinical development. Given most therapeutic regimes would ...combine C-MYC inhibition with genotoxic damage, it is important to assess the importance of C-MYC function for DNA damage signalling in vivo. In this study, we have conditionally deleted the c-Myc gene in the adult murine intestine and investigated the apoptotic response of intestinal enterocytes to DNA damage. Remarkably, c-Myc deletion completely abrogated the immediate wave of apoptosis following both ionizing irradiation and cisplatin treatment, recapitulating the phenotype of p53 deficiency in the intestine. Consistent with this, c-Myc-deficient intestinal enterocytes did not upregulate p53. Mechanistically, this was linked to an upregulation of the E3 Ubiquitin ligase Mdm2, which targets p53 for degradation in c-Myc-deficient intestinal enterocytes. Further, low level overexpression of c-Myc, which does not impact on basal levels of apoptosis, elicited sustained apoptosis in response to DNA damage, suggesting c-Myc activity acts as a crucial cell survival rheostat following DNA damage. We also identify the importance of MYC during DNA damage-induced apoptosis in several other tissues, including the thymus and spleen, using systemic deletion of c-Myc throughout the adult mouse. Together, we have elucidated for the first time in vivo an essential role for endogenous c-Myc in signalling DNA damage-induced apoptosis through the control of the p53 tumour suppressor protein.
Summary
1. The dry tropics are characterised by episodic summer rainfall such that the majority of annual river flow occurs in a short period of time. This dryland hydrological cycle leads to ...variably connected channels and waterholes along the length of a river bed.
2. We investigated the seasonal changes in biophysical characteristics and macroinvertebrate assemblage composition in dry‐tropics rivers at 15 sites on four rivers, each sampled five times (representing one annual hydrological cycle), in the Burdekin catchment, north Queensland, Australia.
3. Assemblages and their temporal trajectories differed among seasons, sites and habitats, even within the same habitat and/or river. Wet season flooding did not appear to ‘reset’ assemblages, with post‐wet season assemblages differing between years.
4. We found no consistent pattern in taxonomic richness over time, and sites within rivers showed no consistent convergence or divergence (i.e. turnover) in macroinvertebrate assemblage composition. However, biophysical variables associated with the rigours of the late dry season had significant effects on macroinvertebrate assemblages, highlighting the variable and often harsh conditions of dry‐tropics rivers. Underlying these patterns were different resistance and resilience traits of invertebrates (such as colonisation and establishment abilities), as well as the local‐scale effects of biophysical variables.
5. The dynamic nature of dryland rivers presents major challenges to monitoring programmes, and our results suggest a more complex scenario for monitoring and management than previously described.
Summary
Background
The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) is a reliable outcome measure for cutaneous lupus erythematosus (CLE) in adults used in clinical trials. ...However, it has not been validated in children, limiting clinical trials for paediatric CLE.
Objectives
This study aimed to validate the CLASI in paediatrics.
Methods
Eleven paediatric patients with CLE, six dermatologists and six rheumatologists participated. The physicians were trained to use the CLASI and Physician's Global Assessment (PGA), and individually rated all patients using both tools. Each physician reassessed two randomly selected patients. Within each physician group, the intraclass correlation coefficient (ICC) was calculated to assess the reliability of each measure.
Results
CLASI activity scores demonstrated excellent inter‐ and intrarater reliability (ICC > 0·90), while the PGA activity scores had good inter‐rater reliability (ICC 0·73–0·77) among both specialties. PGA activity scores showed excellent (ICC 0·89) and good intrarater reliability (ICC 0·76) for dermatologists and rheumatologists, respectively. Limitations of this study include the small sample size of patients and potential recall bias during the physician rerating session.
Conclusions
CLASI activity measurement showed excellent inter‐ and intrarater reliability in paediatric CLE and superiority over the PGA. These results demonstrate that the CLASI is a reliable and valid outcome instrument for paediatric CLE.
What's already known about this topic?
The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) has been established as a reliable outcome measure for CLE in adults and is used in clinical trials.
What does this study add?
This study validates the reliability of the CLASI in the paediatric population with CLE, which can manifest differently from CLE in adults.
This validation will allow clinical trials to assess treatment efficacy reliably in CLE.
Linked Comment: Chong. Br J Dermatol 2019; 180:20–21.
Plain language summary available online
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Summary Objective To determine the reliability, reproducibility, variability and validity of the Osteoarthritis Cartilage Histopathology (OACH) assessment system and Mankin Histological–Histochemical ...Grading System (HHGS) when applied to the characterisation of the osteoarthritic human knee. Method Osteoarthritic knees of 10 patients undergoing unilateral knee arthroplasty were assessed, and assigned Kellgren–Lawrence and Line Drawing Atlas (LDA) radiology scores. The tibial plateaux were scored using the Modified Collins (MC) and Société Française d’Arthroscopie (SFA). Three observers twice scored both the OACH and HHGS across a single complete medial and lateral tibial plateau transect taken to include the region with the most severe osteoarthritis (OA) lesion. Intra- and inter-observer reliability, reproducibility, variability and validity were assessed, and the correlation between the two histopathology scoring systems was calculated. Result Both histopathology scoring systems were determined to be reliable and reproducible exhibiting similar variability, when applied to characterise OA specimens sampled from a well defined patient group with knee OA. A strong correlation between the mean OACH and mean HHGS scores was identified (Spearman’s ρ 0.980, P < 0.0001). Conclusion Both scoring systems implemented provide useful measures in the characterisation of knee osteoarthritis. It is of note that an additional parameter within the OACH score over the HHGS defines the extent of the disease, where the HHGS is a grade attributed to the most representative level of the biological aggression within the OA lesions. This study has confirmed the OACH system’s utility in human knee OA and is supported by a significant correlation with the established HHGS.
Transcription factors are often regarded as having two separable components: a DNA-binding domain (DBD) and a functional domain (FD), with the DBD thought to determine target gene recognition. While ...this holds true for DNA bindingin vitro, it appears thatin vivoFDs can also influence genomic targeting. We fused the FD from the well-characterized transcription factor Krüppel-like Factor 3 (KLF3) to an artificial zinc finger (AZF) protein originally designed to target the Vascular Endothelial Growth Factor-A (VEGF-A) gene promoter. We compared genome-wide occupancy of the KLF3FD-AZF fusion to that observed with AZF. AZF bound to theVEGF-Apromoter as predicted, but was also found to occupy approximately 25,000 other sites, a large number of which contained the expected AZF recognition sequence, GCTGGGGGC. Interestingly, addition of the KLF3 FD re-distributes the fusion protein to new sites, with total DNA occupancy detected at around 50,000 sites. A portion of these sites correspond to known KLF3-bound regions, while others contained sequences similar but not identical to the expected AZF recognition sequence. These results show that FDs can influence and may be useful in directing AZF DNA-binding proteins to specific targets and provide insights into how natural transcription factors operate.
Abstract
TP53
, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target ...mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of
SLC7A11
, a component of the cystine/glutamate antiporter, system x
C
−
, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage. System x
C
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inhibitors specifically exploit this vulnerability to preferentially kill cancer cells with stabilized mutant-p53 protein. Moreover, we demonstrate that
SLC7A11
expression is a novel and robust predictive biomarker for APR-246, a first-in-class mutant-p53 reactivator that also binds and depletes glutathione in tumours, triggering lipid peroxidative cell death. Importantly, system x
C
−
antagonism strongly synergizes with APR-246 to induce apoptosis in mutant-p53 tumours. We propose a new paradigm for targeting cancers that accumulate mutant-p53 protein by inhibiting the SLC7A11–glutathione axis.
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