The occurrence of more than 200 diseases, including cancer, can be attributed to alcohol drinking. The global cancer deaths attributed to alcohol-consumption rose from 243,000 in 1990 to 337,400 in ...2010. In 2010, cancer deaths due to alcohol consumption accounted for 4.2% of all cancer deaths. Strong epidemiological evidence has established the causal role of alcohol in the development of various cancers, including esophageal cancer, head and neck cancer, liver cancer, breast cancer, and colorectal cancer. The evidence for the association between alcohol and other cancers is inconclusive. Because of the high prevalence of ALDH2*2 allele among East Asian populations, East Asians may be more susceptible to the carcinogenic effect of alcohol, with most evidence coming from studies of esophageal cancer and head and neck cancer, while data for other cancers are more limited. The high prevalence of ALDH2*2 allele in East Asian populations may have important public health implications and may be utilized to reduce the occurrence of alcohol-related cancers among East Asians, including: 1) Identification of individuals at high risk of developing alcohol-related cancers by screening for ALDH2 polymorphism; 2) Incorporation of ALDH2 polymorphism screening into behavioral intervention program for promoting alcohol abstinence or reducing alcohol consumption; 3) Using ALDH2 polymorphism as a prognostic indicator for alcohol-related cancers; 4) Targeting ALDH2 for chemoprevention; and 5) Setting guidelines for alcohol consumption among ALDH2 deficient individuals. Future studies should evaluate whether these strategies are effective for preventing the occurrence of alcohol-related cancers.
Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for ...cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors.
Abstract
5-Methylcytosine (m5C) is a base modification broadly found on various RNAs in the human transcriptome. In eukaryotes, m5C is catalyzed by enzymes of the NSUN family composed of seven human ...members (NSUN1-7). NOP2/NSUN1 has been primarily characterized in budding yeast as an essential ribosome biogenesis factor required for the deposition of m5C on the 25S ribosomal RNA (rRNA). Although human NOP2/NSUN1 has been known to be an oncogene overexpressed in several types of cancer, its functions and substrates remain poorly characterized. Here, we used a miCLIP-seq approach to identify human NOP2/NSUN1 RNA substrates. Our analysis revealed that NOP2/NSUN1 catalyzes the deposition of m5C at position 4447 on the 28S rRNA. We also find that NOP2/NSUN1 binds to the 5′ETS region of the pre-rRNA transcript and regulates pre-rRNA processing through non-catalytic complex formation with box C/D snoRNAs. We provide evidence that NOP2/NSUN1 facilitates the recruitment of U3 and U8 snoRNAs to pre-90S ribosomal particles and their stable assembly into snoRNP complexes. Remarkably, expression of both WT and catalytically inactive NOP2/NSUN1 in knockdown background rescues the rRNA processing defects and the stable assembly of box C/D snoRNP complexes, suggesting that NOP2/NSUN1-mediated deposition of m5C on rRNA is not required for ribosome synthesis.
The epidemiology of neuroendocrine tumors (NETs) is not well illustrated, particularly for Asian countries.
The age-standardized incidence rates and observed survival rates of NETs diagnosed in ...Taiwan from January 1, 1996 to December 31, 2008 were calculated using data of the Taiwan Cancer Registry (TCR) and compared to those of the Norwegian Registry of Cancer (NRC) and the US Surveillance, Epidemiology, and End Results (SEER) program.
During the study period, a total of 2,187 NET cases were diagnosed in Taiwan, with 62% males and a mean age of 57.9 years-old. The age-standardized incidence rate of NETs increased from 0.30 per 100,000 in 1996 to 1.51 per 100,000 in 2008. The most common primary sites were rectum (25.4%), lung and bronchus (20%) and stomach (7.4%). The 5-year observed survival was 50.4% for all NETs (43.4% for men and 61.8% for women, P<0.0001). The best 5-year observed survivals for NETs by sites were rectum (80.9%), appendix (75.7%), and breast (64.8%).
Compared to the data of Norway and the US, the age-standardized incidence rate of NETs in Taiwan is lower and the major primary sites are different, whereas the long-term outcome is similar. More studies on the pathogenesis of NETs are warranted to devise preventive strategies and improve treatment outcomes for NETs.
Lipid membranes are ubiquitous biological organizers, required for structural and functional compartmentalization of the cell and sub-cellular organelles. Membranes in living cells are ...compositionally complex, comprising hundreds of dynamically regulated, distinct lipid species. Cellular physiology requires tight regulation of these lipidomic profiles to achieve proper membrane functionality. While some general features of tissue- and organelle-specific lipid complements have been identified, less is known about detailed lipidomic variations caused by cell-intrinsic or extrinsic factors. Here, we use shotgun lipidomics to report detailed, comprehensive lipidomes of a variety of cultured and primary mammalian membrane preparations to identify trends and sources of variation. Unbiased principle component analysis (PCA) shows clear separation between cultured and primary cells, with primary erythrocytes, synaptic membranes, and other mammalian tissue lipidomes sharply diverging from all cultured cell lines and also from one other. Most broadly, cultured cell membrane preparations were distinguished by their paucity of polyunsaturated lipids. Cultured mammalian cell lines were comparatively similar to one another, although we detected clear, highly reproducible lipidomic signatures of individual cell lines and plasma membrane (PM) isolations thereof. These measurements begin to establish a comprehensive lipidomic atlas of mammalian cells and tissues, identifying some major sources of variation. These observations will allow investigation of the regulation and functional significance of mammalian lipidomes in various contexts.
Inhibition of VEGF signaling leads to a proinvasive phenotype in mouse models of glioblastoma multiforme (GBM) and in a subset of GBM patients treated with bevacizumab. Here, we demonstrate that ...vascular endothelial growth factor (VEGF) directly and negatively regulates tumor cell invasion through enhanced recruitment of the protein tyrosine phosphatase 1B (PTP1B) to a MET/VEGFR2 heterocomplex, thereby suppressing HGF-dependent MET phosphorylation and tumor cell migration. Consequently, VEGF blockade restores and increases MET activity in GBM cells in a hypoxia-independent manner, while inducing a program reminiscent of epithelial-to-mesenchymal transition highlighted by a T-cadherin to N-cadherin switch and enhanced mesenchymal features. Inhibition of MET in GBM mouse models blocks mesenchymal transition and invasion provoked by VEGF ablation, resulting in substantial survival benefit.
► VEGF blocks HGF-induced tumor invasion by recruiting PTP1B to a MET/VEGFR2 complex ► VEGF inhibition enhances MET activity, mesenchymal transformation, and invasion in GBM ► Combined VEGF and MET inhibition blocks invasion and prolongs survival in GBM
Eradicating triple-negative breast cancer (TNBC) resistant to neoadjuvant chemotherapy (NACT) is a critical unmet clinical need. In this study, patient-derived xenograft (PDX) models of ...treatment-naïve TNBC and serial biopsies from TNBC patients undergoing NACT were used to elucidate mechanisms of chemoresistance in the neoadjuvant setting. Barcode-mediated clonal tracking and genomic sequencing of PDX tumors revealed that residual tumors remaining after treatment with standard frontline chemotherapies, doxorubicin (Adriamycin) combined with cyclophosphamide (AC), maintained the subclonal architecture of untreated tumors, yet their transcriptomes, proteomes, and histologic features were distinct from those of untreated tumors. Once treatment was halted, residual tumors gave rise to AC-sensitive tumors with similar transcriptomes, proteomes, and histological features to those of untreated tumors. Together, these results demonstrated that tumors can adopt a reversible drug-tolerant state that does not involve clonal selection as an AC resistance mechanism. Serial biopsies obtained from patients with TNBC undergoing NACT revealed similar histologic changes and maintenance of stable subclonal architecture, demonstrating that AC-treated PDXs capture molecular features characteristic of human TNBC chemoresistance. Last, pharmacologic inhibition of oxidative phosphorylation using an inhibitor currently in phase 1 clinical development delayed residual tumor regrowth. Thus, AC resistance in treatment-naïve TNBC can be mediated by nonselective mechanisms that confer a reversible chemotherapy-tolerant state with targetable vulnerabilities.
The epithelial-mesenchymal transition (EMT) enables dissociation of tumour cells from the primary tumour mass, invasion through the extracellular matrix, intravasation into blood vessels and ...colonisation of distant organs. Cells that revert to the epithelial state via the mesenchymal-epithelial transition cause metastases, the primary cause of death in cancer patients. EMT also empowers cancer cells with stem-cell properties and induces resistance to chemotherapeutic drugs. Understanding the driving factors of EMT is critical for the development of effective therapeutic interventions.
This manuscript describes the generation of a database containing EMT gene signatures derived from cell lines, patient-derived xenografts and patient studies across cancer types and multiomics data and the creation of a web-based portal to provide a comprehensive analysis resource.
EMTome incorporates (i) EMT gene signatures; (ii) EMT-related genes with multiomics features across different cancer types; (iii) interactomes of EMT-related genes (miRNAs, transcription factors, and proteins); (iv) immune profiles identified from The Cancer Genome Atlas (TCGA) cohorts by exploring transcriptomics, epigenomics, and proteomics, and drug sensitivity and (iv) clinical outcomes of cancer cohorts linked to EMT gene signatures.
The web-based EMTome portal is a resource for primary and metastatic tumour research publicly available at www.emtome.org .
This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming ...to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)1. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Müllerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents.
This study showed an interaction between oral bacteria, lifestyle factors and genetic polymorphisms on the risk of oral cancer. The results also provided biological support for the established ...association between poor oral hygiene and oral cancer risk.
Abstract
Poor oral hygiene may lead to overgrowth of pathogenic oral bacteria, which may induce chronic inflammation to promote the oncogenesis of oral squamous cell carcinoma (OSCC). This study investigated the association between oral bacterial profile and OSCC risk in a case-control study of 138 OSCC cases and 151 controls (88 cases and 90 controls for the discovery group and 50 cases and 61 controls for the validation group). Oral bacterial profiles were characterized by targeted sequencing of the 16S rRNA gene. Three species of periodontopathogenic bacteria, Prevotella tannerae, Fusobacterium nucleatum, and Prevotella intermedia, were associated with an increased OSCC risk. This association was modified by the genetic polymorphisms of TLR2 and TLR4. Use of alcohol, betel quids and cigarettes and poor oral hygiene were associated with a higher percentage of oral periodontopathogenic bacteria. The association between alcohol and periodontopathogenic bacteria was modified by the genetic polymorphism of ALDH2, with a stronger positive association observed among the ALDH2-deficient individuals. The percentage of periodontopathogenic bacteria was positively correlated with the level of salivary IL1β, an inflammatory cytokine. Overall, our results showed a positive association between periodontopathogenic bacteria and OSCC risk and this relationship may be influenced by lifestyle and genetic factors. Our results provided further biological support for the established association between poor oral hygiene and OSCC risk. This suggested that improving oral hygiene may reduce OSCC risk and should be part of a public health campaign to prevent the occurrence of OSCC.
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