Distinct karyotypic and mutational landscape in trisomy AML.

Trisomy karyotype occurs in 5%-10% of AML. Its mutational landscape and prognostic significance are not well defined. A cohort of 156 trisomy AML patients was analysed, with reference to 615 cytogenetically normal (CN) AML patients. Trisomy AML showed distinct mutational landscape with more prevalent SMC1A, N/KRAS, ASXL1 and BCOR but fewer CEBPAbZIP and NPM1 mutations in patients ≤60, and fewer NPM1 mutations in those >60. NRAS mutations were associated with poor outcome in trisomy AML, whereas DNMT3A and FLT3-ITD mutations had neutral effect. Trisomy AML appeared biologically distinct from CN-AML.

Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice.

BACKGROUND: Acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transplantation of immunosuppressive human mesenchymal stromal cells (hMSCs) can protect against aGvHD post-HSCT; however, their efficacy is limited by poor engraftment and survival. Moreover, infused MSCs can be damaged by activated complement, yet strategies to minimise complement injury of hMSCs and improve their survival are limited. METHODS: Human MSCs were derived from bone marrow (BM), adipose tissue (AT) and umbilical cord (UC). In vitro immunomodulatory potential was determined by co-culture experiments between hMSCs and immune cells implicated in aGvHD disease progression. BM-, AT- and UC-hMSCs were tested for their abilities to protect aGvHD in a mouse model of this disease. Survival and clinical symptoms were monitored, and target tissues of aGvHD were examined by histopathology and qPCR. Transplanted cell survival was evaluated by cell tracing and by qPCR. The transcriptome of BM-, AT- and UC-hMSCs was profiled by RNA-sequencing. Focused experiments were performed to compare the expression of complement inhibitors and the abilities of hMSCs to resist complement lysis. RESULTS: Human MSCs derived from three tissues divergently protected against aGvHD in vivo. AT-hMSCs preferentially suppressed complement in vitro and in vivo, resisted complement lysis and survived better after transplantation when compared to BM- and UC-hMSCs. AT-hMSCs also prolonged survival and improved the symptoms and pathological features of aGvHD. We found that complement-decay accelerating factor (CD55), an inhibitor of complement, is elevated in AT-hMSCs and contributed to reduced complement activation. We further report that atorvastatin and erlotinib could upregulate CD55 and suppress complement in all three types of hMSCs. CONCLUSION: CD55, by suppressing complement, contributes to the improved protection of AT-hMSCs against aGvHD. The use of AT-hMSCs or the upregulation of CD55 by small molecules thus represents promising new strategies to promote hMSC survival to improve the efficacy of transplantation therapy. As complement injury is a barrier to all types of hMSC therapy, our findings are of broad significance to enhance the use of hMSCs for the treatment of a wide range of disorders.

Chronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8+ T cell exhaustion and curtails anti-PD-1 efficacy.

Identifying signals that govern the differentiation of tumor-infiltrating CD8+ T cells (CD8+ TILs) toward exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues, enhancing terminal CD8+ T cell exhaustion in tumors. We find enrichment of IFN-I-stimulated genes (ISGs) within exhausted CD8+ T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8+ TILs devoid of IFN-I signaling develop less exhaustion features, provide better tumor control, and show greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-I stimulation perturbs lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promote lipid peroxidation, which potentiates metabolic and functional exhaustion of Tex cells. Thus, cell-intrinsic IFN-I signaling regulates the extent of CD8+ TIL exhaustion and has important implications for immunotherapy.

Occurrence of various viruses and recent evidence of SARS-CoV-2 in wastewater systems.

Viruses are omnipresent and persistent in wastewater, which poses a risk to human health. In this review, we summarise the different qualitative and quantitative methods for virus analysis in wastewater and systematically discuss the spatial distribution and temporal patterns of various viruses (i.e., enteric viruses, Caliciviridae (Noroviruses (NoVs)), Picornaviridae (Enteroviruses (EVs)), Hepatitis A virus (HAV)), and Adenoviridae (Adenoviruses (AdVs))) in wastewater systems. Then we critically review recent SARS-CoV-2 studies to understand the ongoing COVID-19 pandemic through wastewater surveillance. SARS-CoV-2 genetic material has been detected in wastewater from France, the Netherlands, Australia, Italy, Japan, Spain, Turkey, India, Pakistan, China, and the USA. We then discuss the utility of wastewater-based epidemiology (WBE) to estimate the occurrence, distribution, and genetic diversity of these viruses and generate human health risk assessment. Finally, we not only promote the prevention of viral infectious disease transmission through wastewater but also highlight the potential use of WBE as an early warning system for public health assessment.

Experimental and bioinformatics considerations in cancer application of single cell genomics.

Single cell genomics offers an unprecedented resolution to interrogate genetic heterogeneity in a patient's tumour at the intercellular level. However, the DNA yield per cell is insufficient for today's sequencing library preparation protocols. This necessitates DNA amplification which is a key source of experimental noise. We provide an evaluation of two protocols using micro-fluidics based amplification for whole exome sequencing, which is an experimental scenario commonly used in single cell genomics. The results highlight their respective biases and relative strengths in identification of single nucleotide variations. Towards this end, we introduce a workflow SoVaTSiC, which allows for quality evaluation and somatic variant identification of single cell data. As proof of concept, the framework was applied to study a lung adenocarcinoma tumour. The analysis provides insights into tumour phylogeny by identifying key mutational events in lung adenocarcinoma evolution. The consequence of this inference is supported by the histology of the tumour and demonstrates usefulness of the approach.

An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia.

Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.

Cancer-associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17.

The functional consequences of cancer-associated missense mutations are unclear for the majority of proteins. We have previously demonstrated that the activity of SOX and Pit-Oct-Unc (POU) family factors during pluripotency reprogramming can be switched and enhanced with rationally placed point mutations. Here, we interrogated cancer mutation databases and identified recurrently mutated positions at critical structural interfaces of the DNA-binding domains of paralogous SOX and POU family transcription factors. Using the conversion of mouse embryonic fibroblasts to induced pluripotent stem cells as functional readout, we identified several gain-of-function mutations that enhance pluripotency reprogramming by SOX2 and OCT4. Wild-type SOX17 cannot support reprogramming but the recurrent missense mutation SOX17-V118M is capable of inducing pluripotency. Furthermore, SOX17-V118M promotes oncogenic transformation, enhances thermostability and elevates cellular protein levels of SOX17. We conclude that the mutational profile of SOX and POU family factors in cancer can guide the design of high-performance reprogramming factors. Furthermore, we propose cellular reprogramming as a suitable assay to study the functional impact of cancer-associated mutations.

Isolation and 3D expansion of multipotent Sox9+ mouse lung progenitors.

Multiple adult tissues are maintained by stem cells of restricted developmental potential which can only form a subset of lineages within the tissue. For instance, the two adult lung epithelial compartments (airways and alveoli) are separately maintained by distinct lineage-restricted stem cells. A challenge has been to obtain multipotent stem cells and/or progenitors that can generate all epithelial cell types of a given tissue. Here we show that mouse Sox9+ multipotent embryonic lung progenitors can be isolated and expanded long term in 3D culture. Cultured Sox9+ progenitors transcriptionally resemble their in vivo counterparts and generate both airway and alveolar cell types in vitro. Sox9+ progenitors that were transplanted into injured adult mouse lungs differentiated into all major airway and alveolar lineages in vivo in a region-appropriate fashion. We propose that a single expandable embryonic lung progenitor population with broader developmental competence may eventually be used as an alternative for region-restricted adult tissue stem cells in regenerative medicine.

Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness.

Male-pattern baldness (MPB) is a common and highly heritable trait characterized by androgen-dependent, progressive hair loss from the scalp. Here, we carry out the largest GWAS meta-analysis of MPB to date, comprising 10,846 early-onset cases and 11,672 controls from eight independent cohorts. We identify 63 MPB-associated loci (P<5 × 10-8, METAL) of which 23 have not been reported previously. The 63 loci explain ∼39% of the phenotypic variance in MPB and highlight several plausible candidate genes (FGF5, IRF4, DKK2) and pathways (melatonin signalling, adipogenesis) that are likely to be implicated in the key-pathophysiological features of MPB and may represent promising targets for the development of novel therapeutic options. The data provide molecular evidence that rather than being an isolated trait, MPB shares a substantial biological basis with numerous other human phenotypes and may deserve evaluation as an early prognostic marker, for example, for prostate cancer, sudden cardiac arrest and neurodegenerative disorders.

Distribution, enrichment, and source identification of selected heavy metals in surface sediments of the Siran River, Mansehra, Pakistan.

To assess the trace metal pollution in the Siran River, sediments were collected from 12 sites, from the left and right banks of the river in 2013. The concentrations, accumulation, distribution pattern, and pollution status of heavy metals in sediments were investigated using geoaccumulation index (I geo) and enrichment factor (EF). The toxic risk of heavy metals was assessed using interim sediment quality guidelines (ISQGs), portable effect level (PEL), threshold effect level (TEL), and toxic effect threshold (TET). I geo and EF values showed that sediments were loaded with Ni, Cd, Pb, and Co and no obvious variations were found among the left and right banks of the river. The EF and I geo values were found in order of Co > Pb > Ni > As > Cd > Cu > Zn > Fe and Cd > Co > Pb > Ni > As > Fe > Zn > Cu > Mn, respectively. Furthermore, multivariate statistical analysis like inter-metal correlation, cluster analysis (CA), and principal component analysis (PCA) results revealed that geogenic and anthropogenic activities were major sources of sediment contamination in the study area. These results indicated that more attention should be paid to the inner loads of sediment in order to achieve improvements in reservoir water quality after the control of external pollution.