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Introduction: The Covid‐19 pandemic dramatically altered the way cancer care services were accessed and delivered, including for colorectal cancer (CRC). In the United Kingdom, patients were discouraged from presenting in primary care, many consultations took place remotely, investigative procedures and screening programmes were temporarily suspended, and fewer operations and treatments were delivered. People had to face the practical consequences of having cancer during a pandemic and navigate never before seen pathways, often alone. We examined the experience of being diagnosed and treated for CRC during the pandemic, and the implications of this on people's cancer journeys. Methods: Semi‐structured interviews were undertaken with people diagnosed with CRC during the Covid‐19 pandemic (January 2020–May 2021), in the North East of England. An iterative topic guide was used during interviews, which took place remotely (telephone or Zoom), were audio recorded, pseudo‐anonymised and transcribed. Initial transcripts were independently coded by two researchers, and a code 'bank' developed for application across transcripts. Development of themes and overarching analytical constructs was undertaken collaboratively by the research team. Results: Interviews were conducted with 19 participants, analysed and four key themes identified: (1) The relative threats of Covid‐19 and Cancer were not comparable, with cancer seen as posing a far greater risk than Covid‐19; (2) Remote consultations were problematic, affecting patients' abilities to build rapport and trust with clinicians, assess nonverbal communication, and feel able to disclose, comprehend and retain information; (3) Stoma follow‐up care was seen to be lacking, with long wait times for stoma reversal experienced by some; Finally, (4) Being alone during consultations negatively impacted some peoples' abilities to absorb information, and left them without the support of loved ones at an emotionally vulnerable time. However, some participants preferred being alone at certain points in their pathways, including receiving a diagnosis, and most frequently when receiving in‐patient treatment. Conclusion: Being alone brought unexpected benefits, absolving people from undertaking emotions work for others, and instead focus on their recovery, however, remote consultations negatively impacted patients' experiences. This study highlights the complex benefits and burdens of pandemic‐located cancer journeys, including how these shifted at different points across cancer pathways. Patient or Public Contribution: Lorraine Angell, a cancer survivor, has been central to this study from idea conception, contributing to: development of study focus and design; securing funding; production of patient‐facing materials; development of interview topic guides; analysis and interpretation of data; and drafting of key findings and manuscripts. [ABSTRACT FROM AUTHOR]

Ion channels, in particular transient–receptor potential (TRP) channels, are essential genes that play important roles in many physiological processes. Emerging evidence has demonstrated that TRP genes are involved in a number of diseases, including various cancer types. However, we still lack knowledge about the expression alterations landscape of TRP genes across cancer types. In this review, we comprehensively reviewed and summarised the transcriptomes from more than 10 000 samples in 33 cancer types. We found that TRP genes were widespreadly transcriptomic dysregulated in cancer, which was associated with clinical survival of cancer patients. Perturbations of TRP genes were associated with a number of cancer pathways across cancer types. Moreover, we reviewed the functions of TRP family gene alterations in a number of diseases reported in recent studies. Taken together, our study comprehensively reviewed TRP genes with extensive transcriptomic alterations and their functions will directly contribute to cancer therapy and precision medicine. [ABSTRACT FROM AUTHOR]

Transcription factor p53, also known as tumor suppressor protein. Encoded by the TP53 gene, the guardian of genome p53 regulates many gene pathways. Nevertheless, the molecular mechanisms of p53 functioning have been known for a few decades, and the exact role of p53 in cancer therapy is unclear. Also, comprehensive literature on heterocycles as p53‐MDM2 protein‐protein interaction inhibitors is limited. This review covers the molecular mechanism for the p53‐MDM2 interaction and its inhibition by the heterocyclic small molecules. We hope the present comprehensive study will help to develop heterocycles as anticancer drugs that induce apoptosis in tumor cells. [ABSTRACT FROM AUTHOR]

Background: There are delays in the head and neck Urgent Suspicion of Cancer (USOC) pathway. Local anesthetic (LA) biopsy with channeled endoscopes in outpatients can reduce time to diagnosis. Methods: Questionnaire‐based prospective study of LA or general anesthetic (GA) biopsy for investigation of cancer from September 2021 to July 2022. Results: 100% (n = 48) were very satisfied or satisfied with their overall experience. 71% (n = 20) of LA patients reported they would prefer to have a biopsy under LA. LA biopsy was 68% sensitive and 100% specific for cancer diagnosis. 28.6% (8) and 10% (2) of LA and GA patients had palliative MDT outcomes. Median time to diagnosis was 44.5 and 49.0 days for LA and GA biopsy, respectively. Conclusion: LA biopsy had a high satisfaction rate and is sensitive for diagnosing cancer. LA biopsy can expedite treatment pathways. LA biopsy should be considered as an option for first line investigation. [ABSTRACT FROM AUTHOR]

Background: Concern is growing about inequality in cancer treatment, and a call has been made for more knowledge of the underlying causes of this inequality. Studies show that patients with low socioeconomic status in general face a greater risk of inequality than patients with a high socioeconomic status. Aim: The aim of the present study was to uncover how institutional factors may exacerbate inequality in cancer treatment for patients with low socioeconomic status exemplified by patients with head and neck cancer, most of whom have low socioeconomic status. Method: Inspired by Fairclough, we undertook a critical discourse analysis investigating the treatment pathway of patients with head and neck cancer on the basis of policy papers. Results: These papers, which we conceived as formative instruments, harboured a discourse of efficiency and a discourse of participation, together carving out an effective cancer treatment pathway provided patients act in line with the recommendations. Discussion: The discourses of efficiency and participation are not unfamiliar in health care, and prior research shows that they may pose difficulties for patients with low socioeconomic status. Conclusion: The discoursal framing of head and neck cancer treatment may exacerbate inequality because most patients with a low socioeconomic status fail to comprehend and act in accordance with these discourses. [ABSTRACT FROM AUTHOR]

Background: Cutaneous melanoma is the skin cancer with the highest mutational burden and metastatic rate. Early genetic alterations and biomarkers of distant progression are a point of interest. In addition to germline-susceptibility loci, almost 30% of melanomas arise from precursor benign nevi lesions, providing a source for malignant transformation. Case presentation: Patient#009 developed a cutaneous melanoma over a nevus, followed by progression to regional and distant metastases in months, unresponsive to targeted therapy. To search for the genetic contribution to this rapid progression, a longitudinal analysis was performed through WES of germline, nevi, primary tumor, and a metastatic lymph node. Differential SNP/INDEL and CNV gene alterations, with functional impact on key pathways and cancer hallmarks in each step of evolution, were discerned. Tumor-associated nevus was, for the first time, split into two sections, distant and adjacent to the primary tumor, to study its heterogeneity. Shared SNP alterations, with stable allele fraction from germline to metastasis were detected, mainly affecting DNA repair genes and promoting genome instability. Early somatic alterations, shared by nevi and primary and metastatic tumors, included BRAFV600E and focal copy-loss of several genes, acquiring additional cancer hallmarks. Phylogenetic analyses revealed that these common somatic alterations would provide a "bridge", allowing progression from a benign to a malignant state. Distant and adjacent nevi were rich in alterations, presenting differential SNP and CNV alterations. Upon tumor transformation, a marked increase in CNV over SNP alterations was determined. Both the number of SNP and CNV-affected genes, including known driver genes, increased throughout progression, although TMB levels remained lower than expected for melanoma. Typical alterations in BRAFV600E tumors related to intrinsic resistance to targeted therapy were found, including BRAF amplification and loss of PTEN, CDKN2A/B, and TP53 surveillance genes. Finally, numerous metastatic alterations were detected, further promoting tumor progression. Conclusions: In this patient, longitudinal WES analysis revealed a sequential and cumulative pattern of genetic alterations, where germline and nevi somatic events contributed early to its rapid clinical progression. In this case report, we found tumor-associated nevi as genetically heterogeneous precursor entities, in which potential prognostic biomarkers should be studied prospectively. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial carcinomas (ECs), the most frequent type of uterine body cancer, are highly heterogeneous with overlapping clinical, pathological, and molecular features. This study aimed to gain insights into these cancers' chromosomal and genomic aberration patterns as well as their gene and miRNA expression profiles, all of which are both pathogenetically and clinically important disease features. We found that chromosome 1 was the most frequently rearranged chromosome, mostly leading to gain of 1q, that the genes PTEN, PDGFRA, PIK3CA, and KIT were the most frequent pathogenic variants, and that some other genes and miRNAs of known importance in carcinogenesis and the immune response showed consistent deregulation. This study confirms that a high degree of genetic heterogeneity characterizes EC tumors but highlights the nonrandom involvement of some loci. Endometrial carcinomas (ECs) are histologically classified as endometrioid and nonendometrioid tumors, with each subgroup displaying different molecular profiles and clinical outcomes. Considerable biological and clinical heterogeneity exists within this scheme, however, reflecting its imperfection. We aimed to gather additional data that might help clarify the tumors' pathogenesis and contribute toward a more meaningful classification scheme. In total, 33 ECs were examined for the presence of chromosomal aberrations, genomic imbalances, pathogenic variants, microsatellite instability, and expression profiles at both gene and miRNA levels. Chromosome 1 was the most frequently rearranged chromosome, showing a gain of all or part of the long arm. Pathogenic variants were found for PTEN (53%), PDGFRA (37%), PIK3CA (34%), and KIT (31%). High microsatellite instability was identified in 15 ECs. Comparing tumors and controls, we identified 23 differentially expressed genes of known importance in carcinogenesis, 15 genes involved in innate and adaptative immune responses, and altered expression of 7 miRNAs. miR-32-5p was the most upregulated. Our series showed a high degree of heterogeneity. Tumors were well-separated from controls, but there was no clear-cut separation between endometrioid and nonendometrioid ECs. Whether this means that the current phenotypic classification is of little relevance or if one still has not detected which genomic parameters to enter into correlation analyses remains unknown. [ABSTRACT FROM AUTHOR]

Incidence of cancer in the epididymis is very rare. It is proposed that proteins specific to this organ may contribute to this unique property. We previously demonstrated that siRNA–mediated knockdown of SPAG11A mRNA resulted in increased proliferation of epididymal epithelial cells, whereas overexpression of this gene caused reduced proliferation in immortalized cell lines. In this study, we evaluated the oncogenesis-related anatomical and transcriptome changes in the epididymis of SPAG11A–immunized rats challenged with a low dose of diethyl nitrosamine (DEN). DEN treatment or SPAG11A immunization alone did not cause any histopathological changes in the epididymis. Interestingly, indications of oncogenesis were observed in SPAG11A–immunized + DEN–treated rats. Using high throughput sequencing, we observed that 3549 transcripts that were differentially expressed in the caput epididymis of DEN only–treated rats displayed similar differential expression in the caput epididymis of SPAG11A–immunized rats, indicating that the microenvironment that contributes to oncogenesis sets in when SPAG11A protein is ablated. Differential expression of genes that are involved in 10 major cancer related pathways was also analyzed. Majority of the genes related to these pathways that were differentially expressed in the caput epididymis of DEN only–treated rats also showed similar pattern in the caput epididymis of SPAG11A–immunized rats. For the first time, results of our study demonstrate that ablation of SPAG11A by active immunization renders the epididymis susceptible to oncogenesis and that this protein may be one of the factors that contributes to the rarity of epididymal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: This study integrates the differentially expressed genes and important metabolites found in the transcriptome and metabolome analyses of in vitro acute heat-stressed bovine granulosa cells. Proteins and vitamin B catabolism were the most; tryptophan, proline, pyridoxine, and riboflavin (downregulated metabolites in heat stress) were enriched in many joint pathways. Genes AOX1, PYGM, NOS2, and SLC16A3 (all upregulated metabolites in heat stress) were found to have central roles in metabolic changes in response to heat stress. The negative effects of acute heat stress can be attributed to oxidative stress-driven changes at the inflammation metabolism nexus. Previous studies reported the physical, transcriptome, and metabolome changes in in vitro acute heat-stressed (38 °C versus 43 °C for 2 h) bovine granulosa cells. Granulosa cells exhibited transient proliferation senescence, oxidative stress, an increased rate of apoptosis, and a decline in steroidogenic activity. In this study, we performed a joint integration and network analysis of metabolomic and transcriptomic data to further narrow down and elucidate the role of differentially expressed genes, important metabolites, and relevant cellular and metabolic pathways in acute heat-stressed granulosa cells. Among the significant (raw p-value < 0.05) metabolic pathways where metabolites and genes converged, this study found vitamin B6 metabolism, glycine, serine and threonine metabolism, phenylalanine metabolism, arginine biosynthesis, tryptophan metabolism, arginine and proline metabolism, histidine metabolism, and glyoxylate and dicarboxylate metabolism. Important significant convergent biological pathways included ABC transporters and protein digestion and absorption, while functional signaling pathways included cAMP, mTOR, and AMPK signaling pathways together with the ovarian steroidogenesis pathway. Among the cancer pathways, the most important pathway was the central carbon metabolism in cancer. Through multiple analysis queries, progesterone, serotonin, citric acid, pyridoxal, L-lysine, succinic acid, L-glutamine, L-leucine, L-threonine, L-tyrosine, vitamin B6, choline, and CYP1B1, MAOB, VEGFA, WNT11, AOX1, ADCY2, ICAM1, PYGM, SLC2A4, SLC16A3, HSD11B2, and NOS2 appeared to be important enriched metabolites and genes, respectively. These genes, metabolites, and metabolic, cellular, and cell signaling pathways comprehensively elucidate the mechanisms underlying the intricate fight between death and survival in acute heat-stressed bovine granulosa cells and essentially help further our understanding (and will help the future quest) of research in this direction. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common and the second most fatal cancer. In recent years, more attention has been directed toward the role of gut microbiota in the initiation and development of CRC. Some bacterial species, such as Fusobacterium nucleatum, Escherichia coli, Bacteroides fragilis, Enterococcus faecalis, and Salmonella sp. have been associated with CRC, based upon sequencing studies in CRC patients and functional studies in cell culture and animal models. These bacteria can cause host DNA damage by genotoxic substances, including colibactin secreted by pks + Escherichia coli, B. fragilis toxin (BFT) produced by Bacteroides fragilis, and typhoid toxin (TT) from Salmonella. These bacteria can also indirectly promote CRC by influencing host-signaling pathways, such as E-cadherin/β-catenin, TLR4/MYD88/NF-κB, and SMO/RAS/p38 MAPK. Moreover, some of these bacteria can contribute to CRC progression by helping tumor cells to evade the immune response by suppressing immune cell function, creating a proinflammatory environment, or influencing the autophagy process. Treatments with the classical antibacterial drugs, metronidazole or erythromycin, the antibacterial active ingredients, M13@ Ag (electrostatically assembled from inorganic silver nanoparticles and the protein capsid of bacteriophage M13), berberine, and zerumbone, were found to inhibit tumorigenic bacteria to different degrees. In this review, we described progress in elucidating the tumorigenic mechanisms of several CRC-associated bacteria, as well as progress in developing effective antibacterial therapies. Specific bacteria have been shown to be active in the oncogenesis and progression of CRC, and some antibacterial compounds have shown therapeutic potential in bacteria-induced CRC. These bacteria may be useful as biomarkers or therapeutic targets for CRC. [ABSTRACT FROM AUTHOR]

Introduction: Like many other countries, Norway has seen a shift from inpatient to outpatient cancer care, with pathways aimed at improving the integration and coordination of health services. This study explores the perspectives of seven patients and their family members in light of this change. We focus on one particular phase of the pathway: the first encounter. Our interviews were set in the period from referral until the start of treatment. Methods: Nineteen individual in-depth interviews were conducted in seven families. Seven patients with cancer and 12 family members were interviewed. Results: Three categories of experiences stood out in the empirical material: 'Being in between different health professionals', 'Overwhelmed by written and oral informationʼ and 'Lack of involvement'. Conclusion: This study provides insight into families' experiences with cancer care from referral until the start of treatment. Our findings indicate that families often experience cancer care as fragmented and confusing. Although evaluations have shown that the introduction of cancer pathways seems to have a positive effect on waiting times and standardization of examinations across hospitals and regions, there is still potential for improvement in coordination between services, family involvement, and emotional and practical support. We argue that our findings highlight the tension between two ideals of professional care: standardization and patient-centredness. The study illustrates shortcomings in translating the ideal of patient-centredness into professional practice. [ABSTRACT FROM AUTHOR]

Autoimmune diseases (AiDs) are complex heterogeneous diseases characterized by hyperactive immune responses against self. Genome-wide association studies have identified thousands of single nucleotide polymorphisms (SNPs) associated with several AiDs. While these studies have identified a handful of pleiotropic loci that confer risk to multiple AiDs, they lack the power to detect shared genetic factors residing outside of these loci. Here, we integrated chromatin contact, expression quantitative trait loci and protein-protein interaction (PPI) data to identify genes that are regulated by both pleiotropic and non-pleiotropic SNPs. The PPI analysis revealed complex interactions between the shared and disease-specific genes. Furthermore, pathway enrichment analysis demonstrated that the shared genes co-occur with disease-specific genes within the same biological pathways. In conclusion, our results are consistent with the hypothesis that genetic risk loci associated with multiple AiDs converge on a core set of biological processes that potentially contribute to the emergence of polyautoimmunity. [ABSTRACT FROM AUTHOR]

Cancer is a complex mechanism involving a series of cellular events. The glycoproteins such as hyaluronan (HA) are a significant element of extracellular matrix (ECM), involve in the onset of cancer developmental process. The pivotal roles of HA in cancer progression depend on dysregulated expression in various cancer. HA, also gain attention due to consideration as a primary ligand of CD44 receptor. The CD44, complex transmembrane receptor protein, due to alternative splicing in the transcription process, various CD44 isoforms predominantly exist. The overexpression of distinct CD44 isoforms (CD44v) standard (CD44s) depends on the tumour type and stage. The receptor proteins, CD44 engage in a variety of biological processes, including cell growth, apoptosis, migration, and angiogenesis. HA-CD44 interaction trigger survival pathways that result in cell proliferation, invasion ultimately complex metastasis. The interaction and binding of ligand-receptor HA-CD44 regulate the downstream cytoskeleton pathways involve in cell survival or cell death. Thus, targeting HA, CD44 (variant and standard) isoform, and HA-CD44 binding consider as an attractive and useful approach towards cancer therapeutics. The use of various inhibitors of HA, hyaluronidases (HYALs), and utilizing targeted Nano-delivery of anticancer agents and antibodies against CD44, peptides gives promising results in vitro and in vivo. However, they are in clinical trials with favourable and unfavourable outcomes, which reflects the need for various modifications in targeting agents and a better understanding of potential targets in tumour progression pathways. [ABSTRACT FROM AUTHOR]

Background: Lysine acetylation and deacetylation are posttranslational modifications that are able to link extracellular signals to intracellular responses. However, knowledge regarding the status of lysine regulators in urological cancers is still unknown. Methods: We first systematically analyzed the genetic and expression alterations of 31 lysine acetylation regulators in urological cancers. The correlation between lysine acetylation regulators and activation of cancer pathways was explored. The clinical relevance of lysine acetylation regulators was further analyzed. Results: We identified that there are widespread genetic alterations of lysine acetylation regulators, and that their expression levels are significantly associated with the activity of cancer hallmark-related pathways. Moreover, lysine acetylation regulators were found to be potentially useful for prognostic stratification. HDAC11 may act as a potential oncogene in cell cycle and oxidative phosphorylation of urological cancers. Conclusion: Lysine acetylation regulators are involved in tumorigenesis and progression. Our results provide a valuable resource that will guide both mechanistic and therapeutic analyses of the role of lysine acetylation regulators in urological cancers. [ABSTRACT FROM AUTHOR]

Background: It is well acknowledged that cancer-related pathways play pivotal roles in the progression of pancreatic cancer (PC). Employing Integrated analysis, we aim to identify the pathway-related ceRNA network associated with PC progression.Methods: We divided eight GEO datasets into three groups according to their platform, and combined TCGA and GTEx databases as a group. Additionally, we screened out the differentially expressed genes (DEGs) and performed functional enrichment analysis in each group, and recognized the top hub genes in the most enriched pathway. Furthermore, the upstream of miRNAs and lncRNAs were predicted and validated according to their expression and prognostic roles. Finally, the co-expression analysis was applied to identify a pathway-related ceRNA network in the progression of PC.Results: A total of 51 significant pathways that common enriched in all groups were spotted. Enrichment analysis indicated that pathway in cancer was greatly linked with tumor formation and progression. Next, the top 20 hug genes in this pathway were recognized, and stepwise prediction and validation from mRNA to lncRNA, including 11 hub genes, 4 key miRNAs, and 2 key lncRNAs, were applied to identify a meaningful ceRNA network according to ceRNA rules. Ultimately, we identified the PVT1/miR-20b/CCND1 axis as a promising pathway-related ceRNA axis in the progression of PC.Conclusion: Overall, we elucidate the pathway-related ceRNA regulatory network of PVT1/miR-20b/CCND1 in the progression of PC, which can be considered as therapeutic targets and encouraging prognostic biomarkers for PC. [ABSTRACT FROM AUTHOR]

Background: This study aims to compare the outcomes of COVID-19-positive disease in patients with a history of cancer to those without. Methods: We retrospectively collected clinical data and outcomes of COVID-19 positive cancer patients treated consecutively in five North London hospitals (cohort A). Outcomes recorded included time interval between most recent anti-cancer treatment and admission, severe outcome [a composite endpoint of intensive care unit (ITU) admission, ventilation and/or death] and mortality. Outcomes were compared with consecutively admitted COVID-19 positive patients, without a history of cancer (cohort B), treated at the primary centre during the same time period (1 March–30 April 2020). Patients were matched for age, gender and comorbidity. Results: The median age in both cohorts was 74 years, with 67% male, and comprised of 30 patients with cancer, and 90 without (1:3 ratio). For cohort B, 579 patients without a history of cancer and consecutively admitted were screened from the primary London hospital, 105 were COVID-19 positive and 90 were matched and included. Excluding cancer, both cohorts had a median of two comorbidities. The odds ratio (OR) for mortality, comparing patients with cancer to those without, was 1.05 [95% confidence interval (CI) 0.4–2.5], and severe outcome (OR 0.89, 95% CI 0.4–2.0) suggesting no increased risk of death or a severe outcome in patients with cancer. Cancer patients who received systemic treatment within 28 days had an OR for mortality of 4.05 (95% CI 0.68–23.95), p = 0.12. On presentation anaemia, hypokalaemia, hypoalbuminaemia and hypoproteinaemia were identified predominantly in cohort A. Median duration of admission was 8 days for cancer patients and 7 days for non-cancer. Conclusion: A diagnosis of cancer does not appear to increase the risk of death or a severe outcome in COVID-19 patients with cancer compared with those without cancer. If a second spike of virus strikes, rational decision making is required to ensure optimal cancer care. [ABSTRACT FROM AUTHOR]

Background: Marine endophytic fungi (MEF) are good sources of structurally unique and biologically active secondary metabolites. Due to the increase in antimicrobial resistance, the secondary metabolites from MEF ought to be fully explored to identify candidates which could serve as lead compounds for novel drug development. These secondary metabolites might also be useful for development of new cancer drugs. In this study, ethyl acetate extracts from marine endophytic fungal cultures were tested for their antifungal activity and anticancer properties against C. albicans and the human liver cancer cell line HepG2, respectively. The highly enriched fractions were also analyzed by high performance liquid chromatography coupled with high resolution mass spectrometry (HPLC-HRMS) and their effect on the HepG2 cells was assessed via transcriptomics and with a proliferation assay. Results: We demonstrated that the fractions could reduce proliferation in HepG2 cells. The detailed transcriptome analysis revealed regulation of several cancer- and metabolism-related pathways and gene ontologies. The down-regulated pathways included, cell cycle, p53 signaling, DNA replication, sphingolipid metabolism and drug metabolism by cytochrome P450. The upregulated pathways included HIF-1 signaling, focal adhesion, necroptosis and transcriptional mis-regulation of cancer. Furthermore, a protein interaction network was constructed based on the 26 proteins distinguishing the three treatment conditions from the untreated cells. This network was composed of central functional components associated with metabolism and cancer such as TNF, MAPK, TRIM21 and one component contained APP. Conclusions: The purified fractions from MEF investigated in this study showed antifungal activity against C. albicans and S. cerevisiae alone or both and reduced proliferation of the human liver cancer cell line HepG2 implicating regulation of several cancer- and metabolism-related pathways. The data from this study could be instrumental in identifying new pathways associated with liver cancer anti-proliferative processes which can be used for the development of novel antifungal and anti-cancer drugs. [ABSTRACT FROM AUTHOR]

Background: Cancer is caused by genetic mutations, but not all somatic mutations in human DNA drive the emergence or growth of cancers. While many frequently-mutated cancer driver genes have already been identified and are being utilized for diagnostic, prognostic, or therapeutic purposes, identifying driver genes that harbor mutations occurring with low frequency in human cancers is an ongoing endeavor. Typically, mutations that do not confer growth advantage to tumors – passenger mutations – dominate the mutation landscape of tumor cell genome, making identification of low-frequency driver mutations a challenge. The leading approach for discovering new putative driver genes involves analyzing patterns of mutations in large cohorts of patients and using statistical methods to discriminate driver from passenger mutations. Results: We propose a novel cancer driver gene detection method, QuaDMutNetEx. QuaDMutNetEx discovers cancer drivers with low mutation frequency by giving preference to genes encoding proteins that are connected in human protein-protein interaction networks, and that at the same time show low deviation from the mutual exclusivity pattern that characterizes driver mutations occurring in the same pathway or functional gene group across a cohort of cancer samples. Conclusions: Evaluation of QuaDMutNetEx on four different tumor sample datasets show that the proposed method finds biologically-connected sets of low-frequency driver genes, including many genes that are not found if the network connectivity information is not considered. Improved quality and interpretability of the discovered putative driver gene sets compared to existing methods shows that QuaDMutNetEx is a valuable new tool for detecting driver genes. QuaDMutNetEx is available for download from https://github.com/bokhariy/QuaDMutNetExunder the GNU GPLv3 license. [ABSTRACT FROM AUTHOR]

Background: Women with ovarian cancer can present with a variety of symptoms and signs, and an increasing range of tests are available for their investigation. A number of international guidelines provide advice for the initial assessment of possible ovarian cancer in symptomatic women. We systematically identified and reviewed the consistency and quality of these documents.Methods: MEDLINE, Embase, guideline-specific databases and professional organisation websites were searched in March 2018 for relevant clinical guidelines, consensus statements and clinical pathways, produced by professional or governmental bodies. Two reviewers independently extracted data and appraised documents using the Appraisal for Guidelines and Research Evaluation 2 (AGREEII) tool.Results: Eighteen documents from 11 countries in six languages met selection criteria. Methodological quality varied with two guidance documents achieving an AGREEII score ≥ 50% in all six domains and 10 documents scoring ≥50% for "Rigour of development" (range: 7-96%). All guidance documents provided advice on possible symptoms of ovarian cancer, although the number of symptoms included in documents ranged from four to 14 with only one symptom (bloating/abdominal distension/increased abdominal size) appearing in all documents. Fourteen documents provided advice on physical examinations but varied in both the examinations they recommended and the physical signs they included. Fifteen documents provided recommendations on initial investigations. Transabdominal/transvaginal ultrasound and the serum biomarker CA125 were the most widely advocated initial tests. Five distinct testing strategies were identified based on the number of tests and the order of testing advocated: 'single test', 'dual testing', 'sequential testing', 'multiple testing options' and 'no testing'.Conclusions: Recommendations on the initial assessment and investigation for ovarian cancer in symptomatic women vary considerably between international guidance documents. This variation could contribute to differences in the way symptomatic women are assessed and investigated between countries. Greater research is needed to evaluate the assessment and testing approaches advocated by different guidelines and their impact on ovarian cancer detection. [ABSTRACT FROM AUTHOR]

Background: The quantity of metastases lesions is an important reference when it comes to making a more informed treatment decision for patients with colorectal cancer liver metastases. However, the molecular alterations in patients with different numbers of lesions have not been systematically studied. Methods: We investigated somatic alterations and microsatellite instability (MSI) of liver metastases from patients with single, multiple or diffuse metastasis lesions. A new algorithm "Pathway Damage Score" was developed to comprehensively assess the functional impact of somatic alterations at the pathway level. Pathogenic pathways of different metastasis were identified and their prognosis effects were evaluated. Furthermore, the subnetworks and affected phenotypes of the altered genes in each pathogenic pathway were analyzed. Results: Somatic alterations and altered genes occurred sporadically as well as in MSI state in different metastasis types, although MSS patients had more metastatic lesions than that of the MSI patients. Every metastasis group has their own pathogenic pathways and damaged "Cargo recognition for clathrin‐mediated endocytosis" is significantly associated with poor prognosis (P < 0.001). Further pathway subnetwork analysis showed that except conventional drivers, other genes could also contribute to metastasis formation. Conclusions: Progression of liver metastasis could be driven by the coefficient of all altered genes belonging to the pathways. Thus, compared to somatic alterations and genes, pathway level analysis is more reasonable for functional interpretations of molecular alterations in clinical samples. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate microRNA (miRNA) differential expression in the two most common equine skin tumours, equine sarcoid (ES) and squamous cell carcinoma (SCC), and its potential influence on the tumour microenvironment at post‐transcriptional level. We investigated miRNA fingerprints in four subgroups: mild (ESM) and aggressive (ESA) ES and ocular SCC (oSCC) and genital SCC (gSCC). Three tumours and three control samples were included in each of the four subgroups. Following next generation sequencing, miRNA differential expression analysis using DESeq2 was carried out. Pathways associated with the human mature homologues of identified dysregulated miRNAs were predicted using DIANA‐ miRPath v3.0. When comparing tumour vs control tissue, 57 miRNAs in ESM, six in ESA, 47 in oSCC and zero in gSCC were found to be differentially expressed and may thus serve as potential diagnostic tissue biomarkers. Whereas, ES lesions in general were associated with downregulation of the miR‐200 family, which may trigger epithelial‐mesenchymal transition, ESM lesions were associated with upregulation of the proposed tumour‐suppressive miRNA cluster on equine chromosome 24. In contrast, the oSCC tumours showed downregulation of this cluster as well as downregulation of the miR‐34 family, which may favour oSCC tumour cell metabolism. To further validate the proposed diagnostic miRNA fingerprints and their suggested biological effects, further miRNA studies need to be carried out in larger study cohorts. [ABSTRACT FROM AUTHOR]

Precision medicine has changed thinking in cancer therapy, highlighting a better understanding of the individual clinical interventions. But what role do the drivers and pathways identified from pan-cancer genome analysis play in the tumor? In this letter, we will highlight the importance of in silico modeling in precision medicine. In the current era of big data, tumor engines and pathways derived from pan-cancer analysis should be integrated into in silico models to understand the mutational tumor status and individual molecular pathway mechanism at a deeper level. This allows to pre-evaluate the potential therapy response and develop optimal patient-tailored treatment strategies which pave the way to support precision medicine in the clinic of the future. [ABSTRACT FROM AUTHOR]

Background: Somatic mutations accumulate in human cells throughout life. Some may have no adverse consequences, but some of them may lead to cancer. A cancer genome is typically unstable, and thus more mutations can accumulate in the DNA of cancer cells. An ongoing problem is to figure out which mutations are drivers - play a role in oncogenesis, and which are passengers - do not play a role. One way of addressing this question is through inspection of somatic mutations in DNA of cancer samples from a cohort of patients and detection of patterns that differentiate driver from passenger mutations. Results: We propose QuaDMutEx, a method that incorporates three novel elements: a new gene set penalty that includes non-linear penalization of multiple mutations in putative sets of driver genes, an ability to adjust the method to handle slow- and fast-evolving tumors, and a computationally efficient method for finding gene sets that minimize the penalty, through a combination of heuristic Monte Carlo optimization and exact binary quadratic programming. Compared to existing methods, the proposed algorithm finds sets of putative driver genes that show higher coverage and lower excess coverage in eight sets of cancer samples coming from brain, ovarian, lung, and breast tumors. Conclusions: Superior ability to improve on both coverage and excess coverage on different types of cancer shows that QuaDMutEx is a tool that should be part of a state-of-the-art toolbox in the driver gene discovery pipeline. It can detect genes harboring rare driver mutations that may be missed by existing methods. QuaDMutEx is available for download from https://github.com/bokhariy/QuaDMutEx under the GNU GPLv3 license. [ABSTRACT FROM AUTHOR]

Advances in DNA sequencing technologies have allowed the characterization of somatic mutations in a large number of cancer genomes at an unprecedented level of detail, revealing the extreme genetic heterogeneity of cancer at two different levels: inter-tumor, with different patients of the same cancer type presenting different collections of somatic mutations, and intra-tumor, with different clones coexisting within the same tumor. Both inter-tumor and intra-tumor heterogeneity have crucial implications for clinical practices. Here, we review computational methods that use somatic alterations measured through next-generation DNA sequencing technologies for characterizing tumor heterogeneity and its association with clinical variables. We first review computational methods for studying inter-tumor heterogeneity, focusing on methods that attempt to summarize cancer heterogeneity by discovering pathways that are commonly mutated across different patients of the same cancer type. We then review computational methods for characterizing intra-tumor heterogeneity using information from bulk sequencing data or from single cell sequencing data. Finally, we present some of the recent computational methodologies that have been proposed to identify and assess the association between inter- or intra-tumor heterogeneity with clinical variables. [ABSTRACT FROM AUTHOR]

The central role played by calcium ion in biological systems has generated an interest for its potential implication in human malignancies. Thus, lines of research, on possible association of calcium metabolism regulation with tumorigenesis, implying disruptions and/or alterations of known molecular pathways, have been extensively researched in the recent decades. This paper is a critical synthesis of these findings, based on a functional approach of the calcium signaling toolkit. It provides strong support that this ubiquitous divalent cation is involved in cancer initiation, promotion, and progression. Different pathways have been outlined, involving equally different molecular and cellular structures. However, if the association between calcium and cancer can be described as constant, it is not always linear. We have identified several influencing factors among which the most relevant are ( i) the changes in local or tissular concentrations of free calcium and ( ii) the histological and physiological types of tissue involved. Such versatility at the molecular level may probably account for the conflicting findings reported by the epidemiological literature on calcium dietary intake and the risk to develop certain cancers such as the prostatic or mammary neoplasms. However, it also fuels the hypothesis that behind each cancer, a specific calcium pathway can be evidenced. Identifying such molecular interactions is probably a promising approach for further understanding and treatment options for the disease. [ABSTRACT FROM AUTHOR]

Background/Aims: Ovarian cancer is the most lethal gynecologic malignancy, and there is an unmet clinical need to develop new therapies. Although showing promising anticancer activity, Niclosamide may not be used as a monotherapy. We seek to investigate whether inhibiting IGF signaling potentiates Niclosamide's anticancer efficacy in human ovarian cancer cells. Methods: Cell proliferation and migration are assessed. Cell cycle progression and apoptosis are analyzed by flow cytometry. Inhibition of IGF signaling is accomplished by adenovirus-mediated expression of siRNAs targeting IGF-1R. Cancer-associated pathways are assessed using pathway-specific reporters. Subcutaneous xenograft model is used to determine anticancer activity. Results: We find that Niclosamide is highly effective on inhibiting cell proliferation, cell migration, and cell cycle progression, and inducing apoptosis in human ovarian cancer cells, possibly by targeting multiple signaling pathways involved in ELK1/SRF, AP-1, MYC/MAX and NFкB. Silencing IGF-1R exert a similar but weaker effect than that of Niclosamide's. However, silencing IGF-1R significantly sensitizes ovarian cancer cells to Niclosamide-induced anti-proliferative and anticancer activities both in vitro and in vivo. Conclusion: Niclosamide as a repurposed anticancer agent may be more efficacious when combined with agents that target other signaling pathways such as IGF signaling in the treatment of human cancers including ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Genomic alterations of small bowel cancers remain poorly understood due to the rarity of these diseases. In the current study, the authors report the identification of somatic mutations from patients with duodenal adenocarcinoma by whole-exome sequencing.Methods: Whole-exome sequencing and follow-up analysis were conducted in 12 matched tumor-normal tissue duodenal adenocarcinoma tissue pairs to examine the genetic characteristics of this disease. Somatic mutations (single-nucleotide variants and short insertion/deletions) were obtained and filtered and then searched for recurrently mutated genes and pathways.Results: An excess of C-to-T transitions at the CpG dinucleotide was observed in the substitution of bases. The authors identified recurrent mutations in tumor protein p53 (TP53), KRAS, catenin (cadherin-associated protein) β-1 (CTNNB1), AT-rich interactive domain 2 (ARID2), adenomatous polyposis coli (APC), erb-b2 receptor tyrosine kinase 2 (ERBB2), ARID1A, cadherin-related family member 1 (CDHR1), NRAS, Bcl-2-related ovarian killer (BOK), radial spoke head 14 homolog (chlamydomonas) (RTDR1), cell division cycle 27 (CDC27), catalytic subunit of phosphoinositide-3-kinase (PIK3CA), and SMAD family member 4 (SMAD4). Pathway scan indicated that the Wnt signaling pathway, regulation of the actin cytoskeleton pathway, ErbB signaling pathway, and the pathway of focal adhesion were the most extensively affected pathways.Conclusions: This genomic characterization of duodenal adenocarcinoma provides researchers with insight into its somatic landscape and highlights the vital role of the Wnt/β-catenin signaling pathway. The study data also indicate that duodenal adenocarcinomas have a genetic resemblance to gastric and colorectal cancers. These discoveries may benefit the future development of molecular diagnosis and personalized therapies. Cancer 2016;122:1689-96. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is a major contributor to cancer morbidity and mortality. Tandem repeat instability and its effect on cancer phenotypes remain so far poorly studied on a genome-wide scale. Results: Here we analyze the genomes of 35 colorectal tumors and their matched normal (healthy) tissues for two types of tandem repeat instability, de-novo repeat gain or loss and repeat copy number variation. Specifically, we study for the first time genome-wide repeat instability in the promoters and exons of 18,439 genes, and examine the association of repeat instability with genome-scale gene expression levels. We find that tumors with a microsatellite instable (MSI) phenotype are enriched in genes with repeat instability, and that tumor genomes have significantly more genes with repeat instability compared to healthy tissues. Genes in tumor genomes with repeat instability in their promoters are significantly less expressed and show slightly higher levels of methylation. Genes in well-studied cancer-associated signaling pathways also contain significantly more unstable repeats in tumor genomes. Genes with such unstable repeats in the tumor-suppressor p53 pathway have lower expression levels, whereas genes with repeat instability in the MAPK and Wnt signaling pathways are expressed at higher levels, consistent with the oncogenic role they play in cancer. Conclusions: Our results suggest that repeat instability in gene promoters and associated differential gene expression may play an important role in colorectal tumors, which is a first step towards the development of more effective molecular diagnostic approaches centered on repeat instability. [ABSTRACT FROM AUTHOR]

Background: Cancer is characterized by the accumulation of large numbers of genetic variations and alterations of multiple biological phenomena. Cancer genomics has largely focused on the identification of such genetic alterations and the genes containing them, known as 'cancer genes'. However, the non-functional somatic variations out-number functional variations and remain as a major challenge. Recurrent somatic variations are thought to be cancer drivers but they are present in only a small fraction of patients. Methods: We performed an extensive analysis of amino acid substitutions (AASs) from 6,861 cancer samples (whole genome or exome sequences) classified into 30 cancer types and performed pathway enrichment analysis. We also studied the overlap between the cancers based on proteins containing harmful AASs and pathways affected by them. Results: We found that only a fraction of AASs (39.88 %) are harmful even in known cancer genes. In addition, we found that proteins containing harmful AASs in cancers are often centrally located in protein interaction networks. Based on the proteins containing harmful AASs, we identified significantly affected pathways in 28 cancer types and indicate that proteins containing harmful AASs can affect pathways despite the frequency of AASs in them. Our cross-cancer overlap analysis showed that it would be more beneficial to identify affected pathways in cancers rather than individual genes and variations. Conclusion: Pathways affected by harmful AASs reveal key processes involved in cancer development. Our approach filters out the putative benign AASs thus reducing the list of cancer variations allowing reliable identification of affected pathways. The pathways identified in individual cancer and overlap between cancer types open avenues for further experimental research and for developing targeted therapies and interventions. [ABSTRACT FROM AUTHOR]

Background: Cancer is characterized by the accumulation of large numbers of genetic variations and alterations of multiple biological phenomena. Cancer genomics has largely focused on the identification of such genetic alterations and the genes containing them, known as ‘cancer genes’. However, the non-functional somatic variations out-number functional variations and remain as a major challenge. Recurrent somatic variations are thought to be cancer drivers but they are present in only a small fraction of patients. Methods: We performed an extensive analysis of amino acid substitutions (AASs) from 6,861 cancer samples (whole genome or exome sequences) classified into 30 cancer types and performed pathway enrichment analysis. We also studied the overlap between the cancers based on proteins containing harmful AASs and pathways affected by them. Results: We found that only a fraction of AASs (39.88 %) are harmful even in known cancer genes. In addition, we found that proteins containing harmful AASs in cancers are often centrally located in protein interaction networks. Based on the proteins containing harmful AASs, we identified significantly affected pathways in 28 cancer types and indicate that proteins containing harmful AASs can affect pathways despite the frequency of AASs in them. Our cross-cancer overlap analysis showed that it would be more beneficial to identify affected pathways in cancers rather than individual genes and variations. Conclusion: Pathways affected by harmful AASs reveal key processes involved in cancer development. Our approach filters out the putative benign AASs thus reducing the list of cancer variations allowing reliable identification of affected pathways. The pathways identified in individual cancer and overlap between cancer types open avenues for further experimental research and for developing targeted therapies and interventions. [ABSTRACT FROM AUTHOR]

BACKGROUND: The purpose of this study was to identify genome‐wide single nucleotide variants and mutations in African American patients with colorectal cancer (CRC). There is a need of such studies in African Americans, because they display a higher incidence of aggressive CRC tumors. METHODS: We performed whole exome sequencing (WES) on DNA from 12 normal/tumor pairs of African American CRC patient tissues. Data analysis was performed using the software package GATK (Genome Analysis Tool Kit). Normative population databases (eg, 1000 Genomes SNP database, dbSNP, and HapMap) were used for comparison. Variants were annotated using analysis of variance and were validated via Sanger sequencing. RESULTS: We identified somatic mutations in genes that are known targets in CRC such as APC, BRAF, KRAS, and PIK3CA. We detected novel alterations in the Wnt pathway gene, APC, within its exon 15, of which mutations are highly associated with CRC. CONCLUSIONS: This WES study in African American patients with CRC provides insight into the identification of novel somatic mutations in APC. Our data suggest an association between specific mutations in the Wnt signaling pathway and an increased risk of CRC. The analysis of the pathogenicity of these novel variants may shed light on the aggressive nature of CRC in African Americans. Cancer 2015;121:34–42. © 2014 American Cancer Society. We have little knowledge of the phenotypic genetic changes of colorectal cancer in African Americans and their correlation with the DNA changes found in the majority of cancers in this population. Identifying biomarkers in colorectal cancer in African Americans is likely to help determine the key genes involved in the progression of this disease and identify biomarkers for targeted therapy and management in African Americans with colorectal cancer. [ABSTRACT FROM AUTHOR]

Background Lung cancer stage at diagnosis predicts possible curative treatment. In Denmark and the UK, lung cancer patients have lower survival rates than citizens in most other European countries, which may partly be explained by a comparatively longer diagnostic interval in these two countries. In Denmark, a pathway was introduced in 2008 allowing general practitioners (GPs) to refer patients suspected of having lung cancer directly to fast-track diagnostics. However, symptom presentation of lung cancer in general practice is known to be diverse and complex, and systematic knowledge of the routes to diagnosis is needed to enable earlier lung cancer diagnosis in Denmark. This study aims to describe the routes to diagnosis, the diagnostic activity preceding diagnosis and the diagnostic intervals for lung cancer in the Danish setting. Methods We conducted a national registry-based cohort study on 971 consecutive incident lung cancer patients in 2010 using data from national registries and GP questionnaires. Results GPs were involved in 68.3% of cancer patients' diagnostic pathways, and 27.4% of lung cancer patients were referred from the GP to fast-track diagnostic work-up. A minimum of one X-ray was performed in 85.6% of all cases before diagnosis. Patients referred through a fast-track route more often had diagnostic X-rays (66.0%) than patients who did not go through fast-track (49.4%). Overall, 33.6% of all patients had two or more X-rays performed during the 90 days before diagnosis. Patients whose symptoms were interpreted as non-alarm symptoms or who were not referred to fast-track were more likely to experience a long diagnostic interval than patients whose symptoms were interpreted as alarm symptoms or who were referred to fast-track. Conclusions Lung cancer patients followed several diagnostic pathways. The existing fast-track pathway must be supplemented to ensure earlier detection of lung cancer. The high incidence of multiple X-rays warrants a continued effort to develop more accurate lung cancer tests for use in primary care. [ABSTRACT FROM AUTHOR]

In the last few decades,technological and experimental advancement shave enabled amorepreciseunderstandingofthemodeofactionofdrugswithrespecttohumancellsignangpathwaysandhavepositivelyinfluencedthedesignofnewdrugcompounds.However,asthedesignofcompoundshasbecomeincreasinglytarget-specific,theoveralleffectsofadrugonadjacentcellularsignalingpathwaysremaindifficulttopredictbecauseofthecomplexityoftheinteractionsinvold.Off-targeteffectsofdrugsareknowntoinfluencetheirefficacyandsafety.Similarly,drugswhicharemoretarget-specificalsosufferfromlackofefficacybecausetheirscopemightbetoolimitedinthecontextofcellularsignaling.Eveninsituationswherethesignalingpathwaystargetedbyadrugareknown,thepresenceofpointmutationsinsomeofthecomponentsofthepathwayscanrenderatherapyineffectiveinaconsiderabletargetsubpopulation.SomeoftheseissuescanbeaddressedbypredictingMinimalInterventionSets(MIS)ofelementsofthesignalingpathwaysthatwhenperturbedgiverisetoapre-definedcellularphenotype.Theseminimalgeneperturbationsetscanthenbefurtherusedtoscreenalibraryofdrugcompoundsinordertodiscovereffectivedrugtherapies.ThismanuscriptdescribesalgorithmsthatcanbeusedtodiscoverMISinageneregulatorynetworkthatcanleadtoadefinedcellularphenotype.AlgorithmsareimplementedinourBooleanmodelingtoolbox,GenYsis.ThesoftwarebinariesofGenYsisareavailablefordownloadfromhttp://www.vital-it.ch/software/genYsis/. [ABSTRACT FROM AUTHOR]

The proteins MDM2 and MDM4 are key negative regulators of the tumor suppressor protein p53, which are frequently upregulated in cancer cells. They inhibit the transactivation activity of p53 by binding separately or in concert to its transactivation domain. MDM2 is also a ubiquitin ligase that leads to the degradation of p53. Accordingly, MDM2 and MDM4 are important targets for drugs to inhibit their binding to p53. We found from in silico screening and confirmed by experiment that lithocholic acid (LCA) binds to the p53 binding sites of both MDM2 and MDM4 with a fivefold preference for MDM4. LCA is an endogenous steroidal bile acid, variously reported to have both carcinogenic and apoptotic activities. The comparison of LCA effects on apoptosis in HCT116 p53-/+ vs. p53 -/- cells shows a predominantly p53-mediated induction of caspase-3/7. The dissociation constants are in the |iM region, but only modest inhibition of binding of MDM2 and MDM4 is required to negate their upregulation because they have to compete with transcriptional coactivator p300 for binding to p53. Binding was weakened by structural changes in LCA, and so it may be a natural ligand of MDM2 and MDM4, raising the possibility that MDM proteins may be sensors for specific steroids. [ABSTRACT FROM AUTHOR]

Background: Pathways with members that have known relevance to a disease are used to support hypotheses generated from analyses of gene expression and proteomic studies. Using cancer as an example, the pitfalls of searching pathways databases as support for genes and proteins that could represent false discoveries are explored. Findings: The frequency with which networks could be generated from 100 instances each of randomly selected five and ten genes sets as input to MetaCore, a commercial pathways database, was measured. A PubMed search enumerated cancer-related literature published for any gene in the networks. Using three, two, and one maximum intervening step between input genes to populate the network, networks were generated with frequencies of 97%, 77%, and 7% using ten gene sets and 73%, 27%, and 1% using five gene sets. PubMed reported an average of 4225 cancer-related articles per network gene. Discussion: This can be attributed to the richly populated pathways databases and the interest in the molecular basis of cancer. As information sources become enriched, they are more likely to generate plausible mechanisms for false discoveries. [ABSTRACT FROM AUTHOR]

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare malignancy of the serosal membranes of the abdominal cavity. This cancer is ultimately fatal in almost all afflicted individuals; however, there is marked variability in its clinical behavior: Some patients die rapidly, and others survive for many years. In the current study, the authors investigated the molecular nature of MPM to obtain insights into the heterogeneity of its clinical behavior and to identify new therapeutic targets for intervention. METHODS: Fresh pretreatment tumor samples were collected from 41 patients with MPM who underwent surgical cytoreduction and received regional intraoperative chemotherapy perfusion. From those samples, gene expression analyses were performed. The major cellular pathways that were identified in this cancer were inhibited using a pathway-specific inhibitor. RESULTS: Unsupervised clustering of genes identified 2 distinct groups of patients with significantly different survivals (Group A; median survival, 24 months; Group B: median survival, 69.5 months; P = .035). Phosphoinositide-3-kinase (PI3K) and the closely interacting mammalian target of rapamycin (mTOR) signaling pathways were overexpressed predominantly in the poor survival group; and the genes of these pathways, phosphoinositide-3-kinase, catalytic, a polypeptide (PIK3CA) and rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR), were highly significantly predictive of shortened patient survival in Group A. The role of these pathways in MPM tumor progression was also investigated by treating 2 MPM cell lines with BEZ235, a dual-class PI3K and mTOR inhibitor, and the authors observed significant inhibition of downstream cell signaling and cell proliferation. CONCLUSIONS: Taken together, the results from this study revealed that, based on gene expression profiles, there were 2 distinct patient groups with significantly different survival and that targeting the PI3K and mTOR signaling pathways may have significant therapeutic value in patients with MPM. [ABSTRACT FROM AUTHOR]

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• Introduction • From metabolic adaptation to stem cell signalling • HIF-1α regulates Notch effects on cellular differentiation • Stem cell pluripotency requires HIF target gene function • O2 regulation of Wnt signalling is differentiation-stage specific • HIFs, stem cell pathways and disease • HIF and cMyc • HIF and p53 Cellular properties are influenced by complex factors inherent to their microenvironments. While oxygen deprivation (hypoxia) occurs in tumours because of rapid cell proliferation and aberrant blood vessel formation, embryonic cells develop in a naturally occurring hypoxic environment. Cells respond to hypoxia by stabilizing hypoxia-inducible factors (HIFs), which are traditionally viewed to function by altering cellular metabolism and blood vessel architecture. Recently, HIFs have been shown to modulate specific stem cell effectors, such as Notch, Wnt and Oct4 that control stem cell proliferation, differentiation and pluripotency. Direct molecular links have also been established between HIFs and critical cell signalling pathways such as cMyc and p53. These novel links suggest a new role for HIFs in stem cell and tumour regulation. [ABSTRACT FROM AUTHOR]

The methylation of N6 adenosine (m6A) plays a critical role in diverse biological processes. However, knowledge regarding the reconstitution of m6A across cancer types is still lacking. Here, we systematically analyzed the molecular alterations and clinical relevance of m6A regulators across > 10,000 subjects representing 33 cancer types. We found that there are widespread genetic alterations to m6A regulators, and that their expression levels are significantly correlated with the activity of cancer hallmark-related pathways. Moreover, m6A regulators were found to be potentially useful for prognostic stratification, and we identified IGF2BP3 as a potential oncogene across multiple cancer types. Our results provide a valuable resource that will guide both mechanistic and therapeutic analyses of the role of m6A regulators in cancer. [ABSTRACT FROM AUTHOR]