ABSTRACT
Dielectric electrostatic capacitors1, because of their ultrafast charge-discharge, are desirable for high-power energy storage applications. Along with ultrafast operation, on-chip integration can enable miniaturized energy storage devices for emerging autonomous microelectronics and microsystems2-5. Moreover, state-of-the-art miniaturized electrochemical energy storage systems-microsupercapacitors and microbatteries-currently face safety, packaging, materials and microfabrication challenges preventing on-chip technological readiness2,3,6, leaving an opportunity for electrostatic microcapacitors. Here we report record-high electrostatic energy storage density (ESD) and power density, to our knowledge, in HfO2-ZrO2-based thin film microcapacitors integrated into silicon, through a three-pronged approach. First, to increase intrinsic energy storage, atomic-layer-deposited antiferroelectric HfO2-ZrO2 films are engineered near a field-driven ferroelectric phase transition to exhibit amplified charge storage by the negative capacitance effect7-12, which enhances volumetric ESD beyond the best-known back-end-of-the-line-compatible dielectrics (115 J cm-3) (ref. 13). Second, to increase total energy storage, antiferroelectric superlattice engineering14 scales the energy storage performance beyond the conventional thickness limitations of HfO2-ZrO2-based (anti)ferroelectricity15 (100-nm regime). Third, to increase the storage per footprint, the superlattices are conformally integrated into three-dimensional capacitors, which boosts the areal ESD nine times and the areal power density 170 times that of the best-known electrostatic capacitors: 80 mJ cm-2 and 300 kW cm-2, respectively. This simultaneous demonstration of ultrahigh energy density and power density overcomes the traditional capacity-speed trade-off across the electrostatic-electrochemical energy storage hierarchy1,16. Furthermore, the integration of ultrahigh-density and ultrafast-charging thin films within a back-end-of-the-line-compatible process enables monolithic integration of on-chip microcapacitors5, which can unlock substantial energy storage and power delivery performance for electronic microsystems17-19.
ABSTRACT
Genetic variants related to colorectal adenoma may help identify those who are at highest risk of colorectal cancer development or illuminate potential chemopreventive strategies. The purpose of this genome-wide association study was to identify genetic variants that are associated with risk of developing a metachronous colorectal adenoma among 1,215 study participants of European descent from the Selenium Trial. Associations of variants were assessed with logistic regression analyses and validated in an independent case-control study population of 1,491 participants from the Colorectal Cancer Study of Austria (CORSA). No statistically significant genome-wide associations between any variant and metachronous adenoma were identified after correction for multiple comparisons. However, an intron variant of FAT3 gene, rs61901554, showed a suggestive association (P = 1.10 × 10-6) and was associated with advanced adenomas in CORSA (P = 0.04). Two intronic variants, rs12728998 and rs6699944 in NLRP3 were also observed to have suggestive associations with metachronous lesions (P = 2.00 × 10-6) in the Selenium Trial and were associated with advanced adenoma in CORSA (P = 0.03). Our results provide new areas of investigation for the genetic basis of the development of metachronous colorectal adenoma and support a role for FAT3 involvement in the Wnt/ß-catenin pathway leading to colorectal neoplasia.Trial Registration number: NCT00078897 (ClinicalTrials.gov).
Subject(s)
Adenoma , Colorectal Neoplasms , Selenium , Humans , Genome-Wide Association Study , Case-Control Studies , Adenoma/genetics , Adenoma/prevention & control , Colorectal Neoplasms/pathology , Risk Factors , ColonoscopyABSTRACT
We present a platform for parallel production of standalone, untethered electronic sensors that are truly microscopic, i.e., smaller than the resolution of the naked eye. This platform heterogeneously integrates silicon electronics and inorganic microlight emitting diodes (LEDs) into a 100-µm-scale package that is powered by and communicates with light. The devices are fabricated, packaged, and released in parallel using photolithographic techniques, resulting in â¼10,000 individual sensors per square inch. To illustrate their use, we show proof-of-concept measurements recording voltage, temperature, pressure, and conductivity in a variety of environments.
Subject(s)
Electronics/instrumentation , Equipment Design/methods , Electric Conductivity , Electric Power Supplies , Optical Devices/trends , Silicon/chemistryABSTRACT
BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Microsatellite Instability , Brain Neoplasms , Colorectal Neoplasms , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mismatch Repair/genetics , Humans , Mismatch Repair Endonuclease PMS2/genetics , MutL Protein Homolog 1/genetics , Mutation , Neoplastic Syndromes, HereditaryABSTRACT
NSMCE2 is an E3 SUMO ligase and a subunit of the SMC5/6 complex that associates with the replication fork and protects against genomic instability. Here, we study the fate of collapsed replication forks generated by prolonged hydroxyurea treatment in human NSMCE2-deficient cells. Double strand breaks accumulate during rescue by converging forks in normal cells but not in NSMCE2-deficient cells. Un-rescued forks persist into mitosis, leading to increased mitotic DNA damage. Excess RAD51 accumulates and persists at collapsed forks in NSMCE2-deficient cells, possibly due to lack of BLM recruitment to stalled forks. Despite failure of BLM to accumulate at stalled forks, NSMCE2-deficient cells exhibit lower levels of hydroxyurea-induced sister chromatid exchange. In cells deficient in both NSMCE2 and BLM, hydroxyurea-induced double strand breaks and sister chromatid exchange resembled levels found in NSCME2-deficient cells. We conclude that the rescue of collapsed forks by converging forks is dependent on NSMCE2.
Subject(s)
DNA Damage , Ligases/metabolism , Mitosis , DNA Breaks, Double-Stranded , DNA Repair , DNA Replication , Epistasis, Genetic , Genomic Instability , HEK293 Cells , HeLa Cells , Humans , Hydroxyurea/pharmacology , Ligases/deficiency , Ligases/genetics , Models, Biological , Rad51 Recombinase/genetics , Rad51 Recombinase/metabolism , RecQ Helicases/deficiency , RecQ Helicases/genetics , RecQ Helicases/metabolism , Sister Chromatid Exchange/drug effects , SumoylationABSTRACT
BACKGROUND: Selenium (Se) is a trace element that has been linked to many health conditions. Genome-wide association studies (GWAS) have identified variants for blood and toenail Se levels, but no GWAS has been conducted to date on responses to Se supplementation. OBJECTIVES: A GWAS was performed to identify the single nucleotide polymorphisms (SNPs) associated with changes in Se concentrations after 1 year of supplementation. A GWAS of basal plasma Se concentrations at study entry was conducted to evaluate whether SNPs for Se responses overlap with SNPs for basal Se levels. METHODS: A total of 428 participants aged 40-80 years of European descent from the Selenium and Celecoxib Trial (Sel/Cel Trial) who received daily supplementation with 200 µg of selenized yeast were included for the GWAS of responses to supplementation. Plasma Se concentrations were measured from blood samples collected at the time of recruitment and after 1 year of supplementation. Linear regression analyses were performed to assess the relationship between each SNP and changes in Se concentrations. We further examined whether the identified SNPs overlapped with those related to basal Se concentrations. RESULTS: No SNP was significantly associated with changes in Se concentration at a genome-wide significance level. However, rs56856693, located upstream of the NEK6, was nominally associated with changes in Se concentrations after supplementation (P = 4.41 × 10-7), as were 2 additional SNPs, rs11960388 and rs6887869, located in the dimethylglycine dehydrogenase (DMGDH)/betaine-homocysteine S-methyltransferase (BHMT) region (P = 0.01). Alleles of 2 SNPs in the DMGDH/BHMT region associated with greater increases in Se concentrations after supplementation were also strongly associated with higher basal Se concentrations (P = 8.67 × 10-8). CONCLUSIONS: This first GWAS of responses to Se supplementation in participants of European descent from the Sel/Cel Trial suggests that SNPs in the NEK6 and DMGDH/BHMT regions influence responses to supplementation.
Subject(s)
Dietary Supplements , Genome-Wide Association Study , Genotype , Selenium/blood , Selenium/pharmacology , White People , Adult , Female , Humans , Male , Middle Aged , Selenium/administration & dosageABSTRACT
Despite improvements over the past 20 years, African Americans continue to have the highest incidence and mortality rates of colorectal cancer (CRC) in the United States. While previous studies have found that copy number variations (CNVs) occur at similar frequency in African American and White CRCs, copy-neutral loss of heterozygosity (cnLOH) has not been investigated. In the present study, we used publicly available data from The Cancer Genome Atlas (TCGA) as well as data from an African American CRC cohort, the Chicago Colorectal Cancer Consortium (CCCC), to compare frequencies of CNVs and cnLOH events in CRCs in the two racial groups. Using genotype microarray data, we analyzed large-scale CNV and cnLOH events from 166 microsatellite stable CRCs-31 and 39 African American CRCs from TCGA and the CCCC, respectively, and 96 White CRCs from TCGA. As reported previously, the frequencies of CNVs were similar between African American and White CRCs; however, there was a significantly lower frequency of cnLOH events in African American CRCs compared to White CRCs, even after adjusting for demographic and clinical covariates. Although larger differences for chromosome 18 were observed, a lower frequency of cnLOH events in African American CRCs was observed for nearly all chromosomes. These results suggest that mechanistic differences, including differences in the frequency of cnLOH, could contribute to clinicopathological disparities between African Americans and Whites. Additionally, we observed a previously uncharacterized phenomenon we refer to as small interstitial cnLOH, in which segments of chromosomes from 1 to 5 Mb long were affected by cnLOH.
Subject(s)
Black or African American/genetics , Colorectal Neoplasms/genetics , Loss of Heterozygosity , Aged , Chromosomes, Human, Pair 18/genetics , Colorectal Neoplasms/ethnology , Colorectal Neoplasms/pathology , DNA Copy Number Variations , Female , Humans , Male , Middle AgedABSTRACT
Adenoid cystic carcinoma (ACC) of the eyelid is a very rare tumor, and only 11 cases have been previously reported in the literature. Here the authors report the 12th case of eyelid ACC that was initially diagnosed as adenoid basal cell carcinoma. This is the first report of local recurrence after wide local excision using the Mohs technique. Additionally, this is the first report that demonstrates that ACC can present clinically and histologically similar to basal cell carcinoma. The authors summarize the previous reports of eyelid ACC to compile a reference for this growing body of literature. It is important for oculoplastic surgeons and dermatopathologists to keep ACC in the differential diagnosis of eyelid tumors and carefully examine histology specimens with this differential in mind.
Subject(s)
Carcinoma, Adenoid Cystic , Carcinoma, Basal Cell , Skin Neoplasms , Carcinoma, Adenoid Cystic/diagnosis , Carcinoma, Adenoid Cystic/surgery , Carcinoma, Basal Cell/diagnosis , Carcinoma, Basal Cell/surgery , Eyelids , Humans , Neoplasm Recurrence, Local , Skin Neoplasms/diagnosisABSTRACT
African Americans have the highest incidence and mortality rates of colorectal cancer (CRC) of any ethnic group in the United States. Although some of these disparities can be explained by differences in access to care, cancer screening, and other socioeconomic factors, disparities remain after adjustment for these factors. Consequently, an examination of recent advances in the understanding of ethnicity-specific factors, including genetic and environmental factors relating to risk of CRC, the biology of CRC progression, and the changes in screening and mortality, is important for evaluating our progress toward eliminating the disparities. An overarching limitation in this field is the number and sample size of studies performed to characterize the etiological bases of CRC incidence and mortality in African Americans. Despite this limitation, significant differences in etiology are manifest in many studies. These differences need validation, and their impacts on disparities need more detailed investigation. Perhaps most heartening, improvements in CRC screening can be attributed to the smallest difference in CRC incidence between African Americans and whites since the late 1980s. Cancer mortality, however, remains a persistent difference.
Subject(s)
Black or African American/statistics & numerical data , Colorectal Neoplasms/ethnology , Health Status Disparities , Cell Transformation, Neoplastic , Colorectal Neoplasms/etiology , Colorectal Neoplasms/genetics , Genetic Predisposition to Disease , Humans , Incidence , Mutation , Risk Factors , United States/epidemiology , Vitamin D/bloodABSTRACT
African Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared with other US populations. They present with more right-sided, microsatellite stable disease and are diagnosed at earlier ages compared with non-Hispanic Whites (NHWs). To gain insight into these trends, we conducted exome sequencing (n = 45), copy number (n = 33) and methylation analysis (n = 11) of microsatellite stable AA CRCs. Results were compared with data from The Cancer Genome Atlas (TCGA). Two of the 45 tumors contained POLE mutations. In the remaining 43 tumors, only 27 (63%) contained loss-of-function mutations in APC compared with 80% of TCGA NHW CRCs. APC-mutation-negative CRCs were associated with an earlier onset of CRC (P = 0.01). They were also associated with lower overall mutation burden, fewer copy number variants and a DNA methylation signature that was distinct from the CpG island methylator phenotype characterized in microsatellite unstable disease. Three of the APC-mutation-negative CRCs had loss-of-function mutations in BCL9L. Mutations in driver genes identified by TCGA exome analysis were less frequent in AA CRC cases than TCGA NHWs. Genes that regulate the WNT signaling pathway, including SOX9, GATA6, TET1, GLIS1 and FAT1, were differentially hypermethylated in APC-mutation-negative CRCs, suggesting a novel mechanism for cancer development in these tumors. In summary, we have identified a subtype of CRC that is associated with younger age of diagnosis, lack of APC mutation, microsatellite and chromosome stability, lower mutation burden and distinctive methylation changes.
Subject(s)
Adenomatous Polyposis Coli Protein/genetics , Black or African American/genetics , Black or African American/statistics & numerical data , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , DNA Methylation/genetics , Microsatellite Repeats/genetics , Cadherins/genetics , Colorectal Neoplasms/pathology , DNA Copy Number Variations/genetics , DNA-Binding Proteins/genetics , Female , GATA6 Transcription Factor/genetics , Humans , Male , Microsatellite Instability , Middle Aged , Mixed Function Oxygenases/genetics , Proto-Oncogene Proteins/genetics , SOX9 Transcription Factor/genetics , Transcription Factors/genetics , Exome Sequencing , Wnt Signaling Pathway/geneticsABSTRACT
Bloom Syndrome (BSyn) is an autosomal recessive disorder that causes growth deficiency, endocrine abnormalities, photosensitive skin rash, immune abnormalities, and predisposition to early-onset cancer. The available treatments for BSyn are symptomatic, and early identification of complications has the potential to improve outcomes. To accomplish this, standardized recommendations for health supervision are needed for early diagnosis and treatment. The purpose of this report is to use information from the BSyn Registry, published literature, and expertise from clinicians and researchers with experience in BSyn to develop recommendations for diagnosis, screening, and treatment of the clinical manifestations in people with BSyn. These health supervision recommendations can be incorporated into the routine clinical care of people with BSyn and can be revised as more knowledge is gained regarding their clinical utility.
Subject(s)
Bloom Syndrome/epidemiology , Delivery of Health Care , Bloom Syndrome/complications , Bloom Syndrome/diagnosis , Bloom Syndrome/therapy , Child , Child Development , Child, Preschool , Delivery of Health Care/history , Delivery of Health Care/organization & administration , Disease Management , Female , Health Planning Guidelines , History, 20th Century , History, 21st Century , Humans , Incidence , Intelligence , Male , Neoplasms/diagnosis , Neoplasms/epidemiology , Neoplasms/etiology , Neoplasms/therapy , Nutritional Status , Phenotype , Public Health Surveillance , RegistriesABSTRACT
OBJECTIVE: Colorectal cancer (CRC) incidence is higher in African Americans (AAs) compared with non-Hispanic whites (NHWs). A diet high in animal protein and fat is an environmental risk factor for CRC development. The intestinal microbiota is postulated to modulate the effects of diet in promoting or preventing CRC. Hydrogen sulfide, produced by autochthonous sulfidogenic bacteria, triggers proinflammatory pathways and hyperproliferation, and is genotoxic. We hypothesised that sulfidogenic bacterial abundance in colonic mucosa may be an environmental CRC risk factor that distinguishes AA and NHW. DESIGN: Colonic biopsies from uninvolved or healthy mucosa from CRC cases and tumour-free controls were collected prospectively from five medical centres in Chicago for association studies. Sulfidogenic bacterial abundance in uninvolved colonic mucosa of AA and NHW CRC cases was compared with normal mucosa of AA and NHW controls. In addition, 16S rDNA sequencing was performed in AA cases and controls. Correlations were examined among bacterial targets, race, disease status and dietary intake. RESULTS: AAs harboured a greater abundance of sulfidogenic bacteria compared with NHWs regardless of disease status. Bilophila wadsworthia-specific dsrA was more abundant in AA cases than controls. Linear discriminant analysis of 16S rRNA gene sequences revealed five sulfidogenic genera that were more abundant in AA cases. Fat and protein intake and daily servings of meat were significantly higher in AAs compared with NHWs, and multiple dietary components correlated with a higher abundance of sulfidogenic bacteria. CONCLUSIONS: These results implicate sulfidogenic bacteria as a potential environmental risk factor contributing to CRC development in AAs.
Subject(s)
Adenocarcinoma/microbiology , Black or African American , Colon/microbiology , Colorectal Neoplasms/microbiology , Intestinal Mucosa/microbiology , Sulfur-Reducing Bacteria/isolation & purification , White People , Adenocarcinoma/ethnology , Adenocarcinoma/etiology , Adult , Aged , Case-Control Studies , Chicago , Colorectal Neoplasms/ethnology , Colorectal Neoplasms/etiology , Diet/adverse effects , Dietary Fats/adverse effects , Dietary Proteins/adverse effects , Female , Health Status Disparities , Humans , Male , Middle Aged , Prospective Studies , Real-Time Polymerase Chain Reaction , Risk FactorsABSTRACT
OBJECTIVE: ATG16L1 is an autophagy gene known to control host immune responses to viruses and bacteria. Recently, a non-synonymous single-nucleotide polymorphism in ATG16L1 (Thr300Ala), previously identified as a risk factor in Crohn's disease (CD), was associated with more favourable clinical outcomes in thyroid cancer. Mechanisms underlying this observation have not been proposed, nor is it clear whether an association between Thr300Ala and clinical outcomes will be observed in other cancers. We hypothesised that Thr300Ala influences clinical outcome in human colorectal cancer (CRC) and controls innate antiviral pathways in colon cancer cells. DESIGN: We genotyped 460 patients with CRC and assessed for an association between ATG16L1 Thr300Ala and overall survival and clinical stage. Human CRC cell lines were targeted by homologous recombination to examine the functional consequence of loss of ATG16L1, or introduction of the Thr300Ala variant. RESULTS: We found an association between longer overall survival, reduced metastasis and the ATG16L1 Ala/Ala genotype. Tumour sections from ATG16L1 Ala/Ala patients expressed elevated type I interferons (IFN-I)-inducible, MxA, suggesting that differences in cytokine production may influence disease progression. When introduced into human CRC cells by homologous recombination, the Thr300Ala variant did not affect bulk autophagy, but increased basal production of type I IFN. Introduction of Thr300Ala resulted in increased sensitivity to the dsRNA mimic poly(I:C) through a mitochondrial antiviral signalling (MAVS)-dependent pathway. CONCLUSIONS: The CD-risk allele, Thr300Ala, in ATG16L1 is associated with improved overall survival in human CRC, generating a rationale to genotype ATG16L1 Thr300Ala in patients with CRC. We found that Thr300A alters production of MAVS-dependent type I IFN in CRC cells, providing a mechanism that may influence clinical outcomes.
Subject(s)
Adenocarcinoma/genetics , Biomarkers, Tumor/genetics , Carrier Proteins/genetics , Colorectal Neoplasms/genetics , Interferon Type I/metabolism , Polymorphism, Single Nucleotide , Adenocarcinoma/metabolism , Adenocarcinoma/mortality , Adult , Aged , Aged, 80 and over , Autophagy-Related Proteins , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/mortality , Female , Follow-Up Studies , Humans , Male , Middle Aged , Survival AnalysisABSTRACT
The purpose of this study was to identify novel colorectal cancer (CRC)-causing alleles in unexplained familial CRC cases. In order to do so, coding regions in five candidate genes (MGMT, AXIN2, CTNNB1, TGFBR1 and TGFBR2) were sequenced in 11 unrelated microsatellite-stable hereditary non-polyposis CRC (MSS HNPCC) cases. Selected genetic variants were genotyped in a discovery set of 27 MSS HNPCC cases and 85 controls. One genetic variant, rs67687202, in TGFBR1 emerged as significant (P = 0.002), and it was genotyped in a replication set of 87 additional MSS HNPCC-like cases and 338 controls where it was also significantly associated with MSS HNPCC cases (P = 0.041). In the combined genotype data, rs67687202 was associated with a moderate increase in CRC risk (OR = 1.68; 95% CI = 1.13-2.50; P = 0.010). We tested a highly correlated SNP rs868 in 723 non-familial CRC cases compared with 629 controls, and it was not significantly associated with CRC risk (P = 0.370). rs868 is contained in a let-7 miRNA binding site in the 3'UTR of TGFBR1, which might provide a functional basis for the association in MSS HNPCC. In luciferase assays, the risk-associated allele for rs868 was associated with half the luciferase expression in the presence of miRNA let-7b-5p compared with protective allele, suggesting more binding of let-7b-5p and less TGFBR1 expression. Thus, rs868 potentially is a CRC risk-causing allele. Our results support the concept that rs868 is associated with lower TGFBR1 expression thereby increasing CRC risk.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mismatch Repair/genetics , Protein Serine-Threonine Kinases/genetics , Receptors, Transforming Growth Factor beta/genetics , Adult , Aged , Alleles , Axin Protein/genetics , Binding Sites , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Female , Gene Expression Regulation, Neoplastic , Genotype , Humans , Male , Microsatellite Instability , Middle Aged , Protein Serine-Threonine Kinases/biosynthesis , Receptor, Transforming Growth Factor-beta Type I , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/biosynthesis , Tumor Suppressor Proteins/genetics , beta Catenin/geneticsABSTRACT
BACKGROUND: Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with diseases of the colon including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). However, the functional role of many of these SNPs is largely unknown and tissue-specific resources are lacking. Expression quantitative trait loci (eQTL) mapping identifies target genes of disease-associated SNPs. This study provides a comprehensive eQTL map of distal colonic samples obtained from 40 healthy African Americans and demonstrates their relevance for GWAS of colonic diseases. RESULTS: 8.4 million imputed SNPs were tested for their associations with 16,252 expression probes representing 12,363 unique genes. 1,941 significant cis-eQTL, corresponding to 122 independent signals, were identified at a false discovery rate (FDR) of 0.01. Overall, among colon cis-eQTL, there was significant enrichment for GWAS variants for IBD (Crohn's disease [CD] and ulcerative colitis [UC]) and CRC as well as type 2 diabetes and body mass index. ERAP2, ADCY3, INPP5E, UBA7, SFMBT1, NXPE1 and REXO2 were identified as target genes for IBD-associated variants. The CRC-associated eQTL rs3802842 was associated with the expression of C11orf93 (COLCA2). Enrichment of colon eQTL near transcription start sites and for active histone marks was demonstrated, and eQTL with high population differentiation were identified. CONCLUSIONS: Through the comprehensive study of eQTL in the human colon, this study identified novel target genes for IBD- and CRC-associated genetic variants. Moreover, bioinformatic characterization of colon eQTL provides a tissue-specific tool to improve understanding of biological differences in diseases between different ethnic groups.
Subject(s)
Colorectal Neoplasms/genetics , Gene Expression Regulation/genetics , Inflammatory Bowel Diseases/genetics , Quantitative Trait Loci/genetics , Black or African American/genetics , Aged , Colorectal Neoplasms/pathology , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Inflammatory Bowel Diseases/pathology , Male , Middle Aged , Organ Specificity , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
Genome-wide association studies (GWAS) in colorectal cancer (CRC) identified five regions near transforming growth factor ß-related genes BMP4, GREM1, CDH1, SMAD7 and RPHN2. The true risk alleles remain to be identified in these regions, and their role in CRC risk in non-European populations has been understudied. Our previous work noted significant genetic heterogeneity between African Americans (AAs) and European Americans (EAs) for single nucleotide polymorphisms (SNPs) identified in GWAS. We hypothesized that associations may not have been replicated in AAs due to differential or independent genetic structures. In order to test this hypothesis, we genotyped 195 tagging SNPs across these five gene regions in 1194 CRC cases (795 AAs and 399 EAs) and 1352 controls (985 AAs and 367 EAs). Imputation was performed, and association testing of genotyped and imputed SNPs included ancestry, age and sex as covariates. In two of the five genes originally associated with CRC, we found evidence for association in AAs including rs1862748 in CDH1 (OR(Add) = 0.82, P = 0.02) and in GREM1 the SNPs rs10318 (OR(Rec) = 60.1, P = 0.01), rs11632715 (OR(Rec) = 2.36; P = 0.004) and rs12902616 (OR(Rec) = 1.28, P = 0.005), the latter which is in linkage disequilibrium with the previously identified SNP rs4779584. Testing more broadly for associations in these gene regions in AAs, we noted three statistically significant association peaks in GREM1 and RHPN2 that were not identified in EAs. We conclude that some CRC risk alleles are shared between EAs and AAs and others are population specific.
Subject(s)
Bone Morphogenetic Protein 4/genetics , Colorectal Neoplasms/genetics , Adaptor Proteins, Signal Transducing/genetics , Black or African American , Aged , Alleles , Antigens, CD , Cadherins/genetics , Case-Control Studies , Colorectal Neoplasms/ethnology , Female , Gene Frequency , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Intercellular Signaling Peptides and Proteins/genetics , Linkage Disequilibrium , Male , Middle Aged , Polymorphism, Single Nucleotide , Smad7 Protein/genetics , White PeopleABSTRACT
PURPOSE: Disparities in both colorectal cancer (CRC) incidence and survival impact African Americans (AAs) more than other US ethnic groups. Because vitamin D is thought to protect against CRC and AAs have lower serum vitamin D levels, genetic variants that modulate the levels of active hormone in the tissues could explain some of the cancer health disparity. Consequently, we hypothesized that genetic variants in vitamin D-related genes are associated with CRC risk. METHODS: To test this hypothesis, we studied 39 potentially functional single-nucleotide polymorphisms (SNPs) in eight genes (CYP2R1, CYP3A4, CYP24A1, CYP27A1, CYP27B1, GC, DHCR7, and VDR) in 961 AA CRC cases and 838 healthy AA controls from Chicago and North Carolina. We tested whether SNPs are associated with CRC incidence using logistic regression models to calculate p values, odds ratios, and 95 % confidence intervals. In the logistic regression, we used a log-additive genetic model and used age, gender, and percent West African ancestry, which we estimated with the program STRUCTURE, as covariates in the models. RESULTS: A nominally significant association was detected between CRC and the SNP rs12794714 in the vitamin D 25-hydroxylase gene CYP2R1 (p = 0.019), a SNP that has previously been associated with serum vitamin D levels. Two SNPs, rs16847024 in the GC gene and rs6022990 in the CYP24A1 gene, were nominally associated with left-sided CRC (p = 0.015 and p = 0.018, respectively). CONCLUSIONS: Our results strongly suggest that genetic variation in vitamin D-related genes could affect CRC susceptibility in AAs.
Subject(s)
Black or African American/genetics , Colorectal Neoplasms/ethnology , Colorectal Neoplasms/genetics , Vitamin D/genetics , Aged , Case-Control Studies , Cholestanetriol 26-Monooxygenase/genetics , Colorectal Neoplasms/blood , Cytochrome P450 Family 2 , Female , Genetic Predisposition to Disease , Genetic Variation , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , Vitamin D/bloodABSTRACT
Although there is a large amount of literature indicating the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depressive disorder (trMDD), the authors did not find any literature supporting rTMS for MDD with the comorbid condition of posttraumatic stress disorder (PTSD). Here, we report an original case of a patient whose trMDD and PTSD remitted using rTMS at the left dorsolateral prefrontal cortex.
Subject(s)
Depressive Disorder, Treatment-Resistant/therapy , Stress Disorders, Post-Traumatic/therapy , Transcranial Magnetic Stimulation/methods , Antidepressive Agents, Second-Generation/therapeutic use , Combat Disorders/psychology , Combined Modality Therapy , Cyclohexanols/therapeutic use , Depressive Disorder, Major/complications , Depressive Disorder, Major/psychology , Depressive Disorder, Major/therapy , Depressive Disorder, Treatment-Resistant/complications , Depressive Disorder, Treatment-Resistant/psychology , Diagnostic and Statistical Manual of Mental Disorders , Humans , Male , Military Personnel , Stress Disorders, Post-Traumatic/complications , Stress Disorders, Post-Traumatic/psychology , Venlafaxine Hydrochloride , Young AdultABSTRACT
Dynamic changes in the endoplasmic reticulum (ER) morphology are central to maintaining cellular homeostasis. Microtubules (MT) facilitate the continuous remodeling of the ER network into sheets and tubules by coordinating with many ER-shaping protein complexes, although how this process is controlled by extracellular signals remains unknown. Here we report that TAK1, a kinase responsive to various growth factors and cytokines including TGF-ß and TNF-α, triggers ER tubulation by activating αTAT1, an MT-acetylating enzyme that enhances ER-sliding. We show that this TAK1/αTAT1-dependent ER remodeling promotes cell survival by actively downregulating BOK, an ER membrane-associated proapoptotic effector. While BOK is normally protected from degradation when complexed with IP3R, it is rapidly degraded upon their dissociation during the ER sheets-to-tubules conversion. These findings demonstrate a distinct mechanism of ligand-induced ER remodeling and suggest that the TAK1/αTAT1 pathway may be a key target in ER stress and dysfunction.
Subject(s)
Endoplasmic Reticulum , MAP Kinase Kinase Kinases , Microtubules , Signal Transduction , Microtubules/metabolism , Endoplasmic Reticulum/metabolism , Humans , MAP Kinase Kinase Kinases/metabolism , MAP Kinase Kinase Kinases/genetics , Acetylation , Animals , Microtubule-Associated Proteins/metabolism , Microtubule-Associated Proteins/genetics , Acetyltransferases/metabolism , Acetyltransferases/genetics , Endoplasmic Reticulum Stress , Mice , Microtubule ProteinsABSTRACT
BACKGROUND: The United States is becoming increasingly diverse, but few molecular studies have assessed the progression of clear cell renal cell carcinoma (ccRCC) in diverse patient populations. This study examined ccRCC molecular variations in non-Hispanic White (NHW) and Hispanic patients and their effect on the association of gene expression with high-grade (Grade 3 or 4) ccRCC and overall mortality. METHODS: A total of 156 patients were included in VHL sequencing and/or TempO-Seq analysis. DESeq2 was used to identify the genes associated with high-grade ccRCC. Logistic regression analysis was performed to assess whether race and ethnicity was associated with high/moderate impact VHL somatic mutations and the ccA/ccB subtype. Cox regression analysis was performed to assess association of molecular subtype and gene expression with overall mortality. RESULTS: NHWs had moderate or high impact mutations in the VHL gene at a higher frequency than Hispanics (40.2% vs. 27.4%), while Hispanics had a higher frequency of the ccA subtype than NHWs (61.9% vs. 45.8%). ccA was more common in patients with BMI≥35 (65.2%) than in those with BMI < 25 (45.0%). There were 11 differentially expressed genes between high- and low-grade tumors. The Haptoglobin (HP) gene was most significantly overexpressed in high- compared to low-grade ccRCC in all samples (p-adj = 1.7 × 10-12 ). When stratified by subtype, the 11 genes were significantly differentially expressed in the ccB subtype, but none of them were significant after adjusting for multiple testing in ccA. Finally, patients with the ccB subtype had a significantly increased risk of overall mortality (HR 4.87; p = 0.01) compared to patients with ccA, and patients with high HP expression and ccB, had a significantly increased risk of mortality compared to those with low HP expression and ccA (HR 6.45, p = 0.04). CONCLUSION: This study reports ccRCC molecular variations in Hispanic patients who were previously underrepresented.