Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer.

Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in Aim2-deficient mice; however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with healthy wild-type mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.

Dietary modulation of the microbiome affects autoinflammatory disease.

The incidences of chronic inflammatory disorders have increased considerably over the past three decades. Recent shifts in dietary consumption may have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2(cmo) mice, which express a homozygous Leu98Pro missense mutation in the Pombe Cdc15 homology family protein PSTPIP2 (proline-serine-threonine phosphatase interacting protein 2), spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis in humans. Recent reports demonstrated a crucial role for interleukin-1ß (IL-1ß) in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2(cmo) mice from inflammatory bone disease. Thus, the upstream mechanisms controlling IL-1ß production in Pstpip2(cmo) mice remain to be identified. In addition, the environmental factors driving IL-1ß-dependent inflammatory bone erosion are unknown. Here we show that the intestinal microbiota of diseased Pstpip2(cmo) mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2(cmo) mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced pro-IL-1ß expression in distant neutrophils. Furthermore, pro-IL-1ß expression was also decreased in Pstpip2(cmo) mice treated with antibiotics, and in wild-type mice that were kept under germ-free conditions. We further demonstrate that combined deletion of caspases 1 and 8 was required for protection against IL-1ß-dependent inflammatory bone disease, whereas the deletion of either caspase alone or of elastase or neutrophil proteinase 3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a crucial factor regulating inflammasome- and caspase-8-mediated maturation of IL-1ß and osteomyelitis in Pstpip2(cmo) mice.

The genetic basis of early T-cell precursor acute lymphoblastic leukaemia.

Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

Genome-wide and single-cell analyses reveal a context dependent relationship between CBP recruitment and gene expression.

Genome-wide distribution of histone H3K18 and H3K27 acetyltransferases, CBP (CREBBP) and p300 (EP300), is used to map enhancers and promoters, but whether these elements functionally require CBP/p300 remains largely uncertain. Here we compared global CBP recruitment with gene expression in wild-type and CBP/p300 double-knockout (dKO) fibroblasts. ChIP-seq using CBP-null cells as a control revealed nearby CBP recruitment for 20% of constitutively-expressed genes, but surprisingly, three-quarters of these genes were unaffected or slightly activated in dKO cells. Computationally defined enhancer-promoter-units (EPUs) having a CBP peak near the enhancer-like element were more predictive, with CBP/p300 deletion attenuating expression of 40% of such constitutively-expressed genes. Examining signal-responsive (Hypoxia Inducible Factor) genes showed that 97% were within 50 kilobases of an inducible CBP peak, and 70% of these required CBP/p300 for full induction. Unexpectedly, most inducible CBP peaks occurred near signal-nonresponsive genes. Finally, single-cell expression analysis revealed additional context dependence where some signal-responsive genes were not uniformly dependent on CBP/p300 in individual cells. While CBP/p300 was needed for full induction of some genes in single-cells, for other genes CBP/p300 increased the probability of maximal expression. Thus, target gene context influences the transcriptional requirement for CBP/p300, possibly by multiple mechanisms.

Control of virulence by small RNAs in Streptococcus pneumoniae.

Small noncoding RNAs (sRNAs) play important roles in gene regulation in both prokaryotes and eukaryotes. Thus far, no sRNA has been assigned a definitive role in virulence in the major human pathogen Streptococcus pneumoniae. Based on the potential coding capacity of intergenic regions, we hypothesized that the pneumococcus produces many sRNAs and that they would play an important role in pathogenesis. We describe the application of whole-genome transcriptional sequencing to systematically identify the sRNAs of Streptococcus pneumoniae. Using this approach, we have identified 89 putative sRNAs, 56 of which are newly identified. Furthermore, using targeted genetic approaches and Tn-seq transposon screening, we demonstrate that many of the identified sRNAs have important global and niche-specific roles in virulence. These data constitute the most comprehensive analysis of pneumococcal sRNAs and provide the first evidence of the extensive roles of sRNAs in pneumococcal pathogenesis.

Social Interest Data as a Proxy for Off-Label Performance-Enhancing Drug Use: Implications and Clinical Considerations.

Performance-enhancing drugs (PEDs) can be categorized into various classes based on the physiological mechanism of the compound, with the most popular being anabolic steroids, selective androgen receptor modulators, and growth hormones. Ancillary compounds, such as selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders, are commonly utilized alongside a PED to counterbalance any potential undesired side effects. With little clinically relevant data to support the use of these ancillary compounds, medical education and evidence-based approaches aimed at monitoring the potential adverse effects of PED use are sparse.This study aims to identify emerging trends in the interest of PEDs and related ancillary compounds, hypothesize the physiological effects of the continued respective behavior, and propose a proxy for use by clinicians to approximate off-label drug use and subsequently modify their practices accordingly. Several significant trends were identified for non-FDA-regulated compounds (i.e., selective androgen receptor modulators such as RAD-140) and off-label indications for FDA-regulated drugs (i.e., SERMs such as tamoxifen). A significant increase in interest regarding selective androgen receptor modulators, mirrored by anecdotal reports in clinical settings and online forums, is coupled with stagnant or decreasing interest in both post-cycle therapies and anabolic steroids. Ultimately, we propose a call to action for utilizing social data and/or prescription data as a proxy for clinicians to better understand trends in these compounds and thus refine their treatment protocols in a concordant manner.

Social Data: An Underutilized Metric for Determining Participation in COVID-19 Vaccinations.

Many measures have been taken since late 2019 to combat the coronavirus disease (COVID-19) pandemic. National, state, and local governments employed precautions, including mask mandates, stay-at-home orders, and social distancing policies, to alleviate the burden on healthcare workers and slow the spread of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) virus until an efficacious vaccine was made widely available. By early spring of 2021, three effective and well-tolerated SARS-CoV-2 vaccines emerged and underwent broad distribution. Throughout the course of the COVID-19 vaccination campaign, several key logistical and psychological issues surfaced. Of these, access to vaccines and vaccination hesitancy are cited as two substantial hindrances towards vaccination. Noting the demand for the SARS-CoV-2 vaccine and its highly sensitive storage requirements, accurate dose allocation is critical for vaccinating the population quickly and successfully. Here, we propose the use of social data as a tool to predict vaccination participation by correlating Google searches with state-level daily vaccination. We identified a temporal and regionally-ubiquitous Google search syntax that broadly captures daily vaccination trends. By correlating trends in the search syntax with daily vaccination rates, we were able to quantify the correlation and identify optimal lag periods between Google searches and daily vaccination. This work highlights the importance of analyzing social data as a metric to effectively arrange vaccination roll-outs, identify voluntary vaccination participation, and identify inflection points in vaccination participation. In addition, social data assessments can help direct dose allocation, identify geographic areas that may seek, but lack, access to the vaccines, and actively prepare for fluctuations in vaccination demands.