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Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors. 65% of somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating a higher mutation rate in metastases. Tumor- and metastasis-specific mutations harbor elevated levels of BRCAness. We confirm multistage progression with new components ARHGEF7/ARHGEF33 . Recurrently mutated non-coding elements include ncRNAs RP11-594N15.3, AC010091, SNHG14 , 3’ UTRs of FOXP2, DACH2, TRPM3, XKR4, ANO5, CBL, CBLB , the latter four potentially dual protagonists in metastasis and efferocytosis-/ PD-L1 mediated immunosuppression. Actionable metastasis-specific lesions include FAT1, FGF1, BRCA2, KDR , and AKT2 -, AKT3 -, and PDGFRA -3’ UTRs. Metastasis specific mutations are enriched in PI3K-Akt signaling, cell adhesion, ECM and hepatic stellate activation genes, suggesting genetic programs for site-specific colonization. Our results put forward hypotheses on tumor and metastasis evolution, and evidence for metastasis-specific events relevant for personalized therapy. The evolution and genetic nature of metastatic lesions is not completely characterized. Here the authors perform a comprehensive whole-genome study of colorectal metastases in comparison to matched primary tumors and define a multistage progression model and metastasis-specific changes that, in part, are therapeutically actionable.

The paucity of microbiome studies at intestinal tissues has contributed to a yet limited understanding of potential viral and bacterial cofactors of colorectal cancer (CRC) carcinogenesis or progression. We analysed whole‐genome sequences of CRC primary tumours, their corresponding metastases and matched normal tissue for sequences of viral, phage and bacterial species. Bacteriome analysis showed Fusobacterium nucleatum, Streptococcus sanguinis, F. Hwasookii, Anaerococcus mediterraneensis and further species enriched in primary CRCs. The primary CRC of one patient was enriched for F. alocis, S. anginosus, Parvimonas micra and Gemella sp. 948. Enrichment of Escherichia coli strains IAI1, SE11, K‐12 and M8 was observed in metastases together with coliphages enterobacteria phage φ80 and Escherichia phage VT2φ_272. Virome analysis showed that phages were the most preponderant viral species (46%), the main families being Myoviridae, Siphoviridae and Podoviridae. Primary CRCs were enriched for bacteriophages, showing five phages (Enterobacteria, Bacillus, Proteus, Streptococcus phages) together with their pathogenic hosts in contrast to normal tissues. The most frequently detected, and Blast‐confirmed, viruses included human endogenous retrovirus K113, human herpesviruses 7 and 6B, Megavirus chilensis, cytomegalovirus (CMV) and Epstein–Barr virus (EBV), with one patient showing EBV enrichment in primary tumour and metastases. EBV was PCR‐validated in 80 pairs of CRC primary tumour and their corresponding normal tissues; in 21 of these pairs (26.3%), it was detectable in primary tumours only. The number of viral species was increased and bacterial species decreased in CRCs compared with normal tissues, and we could discriminate primary CRCs from metastases and normal tissues by applying the Hutcheson t‐test on the Shannon indices based on viral and bacterial species. Taken together, our results descriptively support hypotheses on microorganisms as potential (co)risk factors of CRC and extend putative suggestions on critical microbiome species in CRC metastasis. This work analysed the presence of sequences of bacteria and viruses in primary colorectal cancer (CRC) tissues, compared with corresponding normal colorectal tissues and metastases. We observed a higher viral species diversity and lower bacterial species diversity in primary CRCs than in matched normal tissues. Some microbial species were enriched in primary CRCs and some metastases, particularly phages.

Growth factor receptor signalling plays a central and critical role in colorectal cancer. Most importantly, the EGFR signalling cascade involving PI3K/AKT/mTOR and Raf/MEK/ERK pathways are particularly relevant, since they are commonly activated in several cancer entities, including colorectal cancer. In this study, we show that miRs-134 and -370 are both capable of regulating these pathways by targeting EGFR and PIK3CA. In three different colorectal cancer cell lines (DLD1, HCT-116 and RKO), suppression of EGFR and PIK3CA through the enhanced expression of miR-134 or -370 led to a suppression of the key molecules of the PI3K/AKT/mTOR pathway. Furthermore, overexpression of miR-134 or -370 resulted in a significant reduction of cell proliferation, colony formation, migration, invasion and in-vivo tumor growth and metastasis. Concurrent experiments with small interfering RNAs targeting the prime targets show that our selected miRNAs exert a greater functional influence and affect more downstream molecules than is seen with silencing of the individual proteins. Taken together, these data indicate that miRs-134 and -370 are potential tumour suppressor miRNAs and could play a fundamental role in suppressing colorectal cancer tumorigenesis through their ability to co-ordinately regulate EGFR signalling cascade by independently targeting EGFR and PIK3CA.

Epithelial to mesenchymal transition (EMT) is a central regulatory program that is similar in many aspects to several steps of embryonic morphogenesis. In addition to its physiological role in tissue repair and wound healing, EMT contributes to chemo resistance, metastatic dissemination and fibrosis, amongst others. Classically, the morphological change from epithelial to mesenchymal phenotype is characterized by the appearance or loss of a group of proteins which have come to be recognized as markers of the EMT process. As with all proteins, these molecules are controlled at the transcriptional and translational level by transcription factors and microRNAs, respectively. A group of developmental transcription factors form the backbone of the EMT cascade and a large body of evidence shows that microRNAs are heavily involved in the successful coordination of mesenchymal transformation and vice versa, either by suppressing the expression of different groups of transcription factors, or otherwise acting as their functional mediators in orchestrating EMT. This article dissects the contribution of microRNAs to EMT and analyzes the molecular basis for their roles in this cellular process. Here, we emphasize their interaction with core transcription factors like the zinc finger enhancer (E)-box binding homeobox (ZEB), Snail and Twist families as well as some pluripotency transcription factors.

MiRs are important players in cancer and primarily genetic/transcriptional means of regulating their gene expression are known. However, epigenetic changes modify gene expression significantly. Here, we evaluated genome-wide methylation changes focusing on miR genes from primary CRC and corresponding normal tissues. Differentially methylated CpGs spanning CpG islands, open seas, and north and south shore regions were evaluated, with the largest number of changes observed within open seas and islands. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed several of these miRs to act in important cancer-related pathways, including phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) pathways. We found 18 miR genes to be significantly differentially methylated, with MIR124-2, MIR124-3, MIR129-2, MIR137, MIR34B, MIR34C, MIR548G, MIR762, and MIR9-3 hypermethylated and MIR1204, MIR17, MIR17HG, MIR18A, MIR19A, MIR19B1, MIR20A, MIR548F5, and MIR548I4 hypomethylated in CRC tumor compared with normal tissue, most of these miRs having been shown to regulate steps of metastasis. Generally, methylation changes were distributed evenly across all chromosomes with predominance for chromosomes 1/2 and protein-coding genes. Interestingly, chromosomes abundantly affected by methylation changes globally were rarely affected by methylation changes within miR genes. Our findings support additional mechanisms of methylation changes affecting (miR) genes that orchestrate CRC progression and metastasis.

Seawater intrusion (SWI) is the main threat to fresh groundwater (GW) resources in coastal regions worldwide. Early identification and delineation of such threats can help decision-makers plan for suitable management measures to protect water resources for coastal communities. This study assesses seawater intrusion (SWI) and GW salinization of the shallow and deep coastal aquifers in the Al-Qatif area, in the eastern region of Saudi Arabia. Field hydrogeological and hydrochemical investigations coupled with laboratory-based hydrochemical and isotopic analyses (18O and 2H) were used in this integrated study. Hydrochemical facies diagrams, ionic ratio diagrams, and spatial distribution maps of GW physical and chemical parameters (EC, TDS, Cl−, Br−), and seawater fraction (fsw) were generated to depict the lateral extent of SWI. Hydrochemical facies diagrams were mainly used for GW salinization source identification. The results show that the shallow GW is of brackish and saline types with EC, TDS, Cl−, Br− concentration, and an increasing fsw trend seaward, indicating more influence of SWI on shallow GW wells located close to the shoreline. On the contrary, deep GW shows low fsw and EC, TDS, Cl−, and Br−, indicating less influence of SWI on GW chemistry. Moreover, the shallow GW is enriched in 18O and 2H isotopes compared with the deep GW, which reveals mixing with recent water. In conclusion, the reduction in GW abstraction in the central part of the study area raised the average GW level by three meters. Therefore, to protect the deep GW from SWI and salinity pollution, it is recommended to implement such management practices in the entire region. In addition, continuous monitoring of deep GW is recommended to provide decision-makers with sufficient data to plan for the protection of coastal freshwater resources.

The increases in extreme rainfall could increase the probable maximum flood (PMF) and pose a severe threat to the critical hydraulic infrastructure such as dams and flood protection structures. This study is conducted to assess the impact of climate change on PMF in a tropical catchment. Climate and inflow data of the Tenmengor reservoir, located in the state of Perak in Malaysia, have been used to calibrate and validate the hydrological model. The projected rainfall from regional climate model is used to generate probable maximum precipitation (PMP) for future periods. A hydrological model was used to simulate PMF from PMP estimated for the historical and two future periods, early (2031 − 2045) and late (2060 − 2075). The results revealed good performance of the hydrological model with Nash–Sutcliffe efficiency, 0.74, and the relative standard error, 0.51, during validation. The estimated rainfall depths were 89.5 mm, 106.3 mm, and 143.3 mm, respectively, for 5, 10, and 50 years of the return period. The study indicated an increase in PMP by 162% to 507% and 259% to 487% during early and late periods for different return periods ranging from 5 to 1000 years. This would cause an increase in PMF by 48.9% and 122.6% during early and late periods. A large increase in PMF indicates the possibility of devastating floods in the future in his tropical catchment due to climate change.

Unconsolidated earthen surface materials can retain heavy metals originating from different sources. These metals are dangerous to humans as well as the immediate environment. This danger leads to the need to assess various geochemical conditions of the materials. In this study, the assessment of topsoil materials’ contamination with heavy metals (HMs) was conducted. The material’s representative spatial samples were taken from various sources: agricultural, industrial, and residential areas. The materials include topsoil, eolian deposits, and other unconsolidated earthen materials. The samples were analyzed using the ICP-OES. The obtained results based on the experimental procedure indicated that the average levels of the heavy metals were: As (1.21 ± 0.69 mg/kg), Ba (110.62 ± 262 mg/kg), Hg (0.08 ± 0.18 mg/kg), Pb (6.34 ± 14.55 mg/kg), Ni (8.95 ± 5.66 mg/kg), V (9.98 ± 6.08 mg/kg), Cd (1.18 ± 4.33 mg/kg), Cr (31.79 ± 37.9 mg/kg), Cu (6.76 ± 12.54 mg/kg), and Zn (23.44 ± 84.43 mg/kg). Subsequently, chemometrics modeling and a prediction of Cr concentration (mg/kg) were performed using three different modeling techniques, including two artificial intelligence (AI) techniques, namely, generalized neural network (GRNN) and Elman neural network (Elm NN) models, as well as a classical multivariate statistical technique (MST). The results indicated that the AI-based models have a superior ability in estimating the Cr concentration (mg/kg) than MST, whereby GRNN can enhance the performance of MST up to 94.6% in the validation step. The concentration levels of most metals were found to be within the acceptable range. The findings indicate that AI-based models are cost-effective and efficient tools for trace metal estimations from soil.

There have been insufficient data for African patients with COVID-19 who are critically ill. The African COVID-19 Critical Care Outcomes Study (ACCCOS) aimed to determine which resources, comorbidities, and critical care interventions are associated with mortality in this patient population. The ACCCOS study was a multicentre, prospective, observational cohort study in adults (aged 18 years or older) with suspected or confirmed COVID-19 infection who were referred to intensive care or high-care units in 64 hospitals in ten African countries (ie, Egypt, Ethiopia, Ghana, Kenya, Libya, Malawi, Mozambique, Niger, Nigeria, and South Africa). The primary outcome was in-hospital mortality censored at 30 days. We studied the factors (ie, human and facility resources, patient comorbidities, and critical care interventions) that were associated with mortality in these adult patients. This study is registered on ClinicalTrials.gov, NCT04367207. From May to December, 2020, 6779 patients were referred to critical care. Of these, 3752 (55·3%) patients were admitted and 3140 (83·7%) patients from 64 hospitals in ten countries participated (mean age 55·6 years; 1890 [60·6%] of 3118 participants were male). The hospitals had a median of two intensivists (IQR 1–4) and pulse oximetry was available to all patients in 49 (86%) of 57 sites. In-hospital mortality within 30 days of admission was 48·2% (95% CI 46·4–50·0; 1483 of 3077 patients). Factors that were independently associated with mortality were increasing age per year (odds ratio 1·03; 1·02–1·04); HIV/AIDS (1·91; 1·31–2·79); diabetes (1·25; 1·01–1·56); chronic liver disease (3·48; 1·48–8·18); chronic kidney disease (1·89; 1·28–2·78); delay in admission due to a shortage of resources (2·14; 1·42–3·22); quick sequential organ failure assessment score at admission (for one factor [1·44; 1·01–2·04], for two factors [2·0; 1·33–2·99], and for three factors [3·66, 2·12–6·33]); respiratory support (high flow oxygenation [2·72; 1·46–5·08]; continuous positive airway pressure [3·93; 2·13–7·26]; invasive mechanical ventilation [15·27; 8·51–27·37]); cardiorespiratory arrest within 24 h of admission (4·43; 2·25–8·73); and vasopressor requirements (3·67; 2·77–4·86). Steroid therapy was associated with survival (0·55; 0·37–0·81). There was no difference in outcome associated with female sex (0·86; 0·69–1·06). Mortality in critically ill patients with COVID-19 is higher in African countries than reported from studies done in Asia, Europe, North America, and South America. Increased mortality was associated with insufficient critical care resources, as well as the comorbidities of HIV/AIDS, diabetes, chronic liver disease, and kidney disease, and severity of organ dysfunction at admission. The ACCCOS was partially supported by a grant from the Critical Care Society of Southern Africa.