Given the high rate of preterm birth (PTB) nationwide and data from RCTs demonstrating risk reduction with vitamin D supplementation, the Medical University of South Carolina (MUSC) implemented a new ...standard of care for pregnant women to receive vitamin D testing and supplementation.
To determine if the reported inverse relationship between maternal 25(OH)D and PTB risk could be replicated at MUSC, an urban medical center treating a large, diverse population.
Medical record data were obtained for pregnant patients aged 18-45 years between September 2015 and December 2016. During this time, a protocol that included 25(OH)D testing at first prenatal visit with recommended follow-up testing was initiated. Free vitamin D supplements were offered and the treatment goal was ≥40 ng/mL. PTB rates (<37 weeks) were calculated, and logistic regression and locally weighted regression (LOESS) were used to explore the association between 25(OH)D and PTB. Subgroup analyses were also conducted.
Among women with a live, singleton birth and at least one 25(OH)D test during pregnancy (N = 1,064), the overall PTB rate was 13%. The LOESS curve showed gestational age rising with increasing 25(OH)D. Women with 25(OH)D ≥40 ng/mL had a 62% lower risk of PTB compared to those <20 ng/mL (p<0.0001). After adjusting for socioeconomic variables, this lower risk remained (OR = 0.41, p = 0.002). Similar decreases in PTB risk were observed for PTB subtypes (spontaneous: 58%, p = 0.02; indicated: 61%, p = 0.006), by race/ethnicity (white: 65%, p = 0.03; non-white: 68%, p = 0.008), and among women with a prior PTB (80%, p = 0.02). Among women with initial 25(OH)D <40 ng/mL, PTB rates were 60% lower for those with ≥40 vs. <40 ng/mL on a follow-up test (p = 0.006); 38% for whites (p = 0.33) and 78% for non-whites (p = 0.01).
Maternal 25(OH)D concentrations ≥40 ng/mL were associated with substantial reduction in PTB risk in a large, diverse population of women.
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The clinical relevancy of the 7-subtype classification of triple-negative breast cancer (TNBC) reported by Lehmann and colleagues is unknown. We investigated the clinical relevancy of TNBC ...heterogeneity by determining pathologic complete response (pCR) rates after neoadjuvant chemotherapy, based on TNBC subtypes.
We revalidated the Lehmann and colleagues experiments using Affymetrix CEL files from public datasets. We applied these methods to 146 patients with TNBC with gene expression microarrays obtained from June 2000 to March 2010 at our institution. Of those, 130 had received standard neoadjuvant chemotherapy and had evaluable pathologic response data. We classified the TNBC samples by subtype and then correlated subtype and pCR status using Fisher exact test and a logistic regression model. We also assessed survival and compared the subtypes with PAM50 intrinsic subtypes and residual cancer burden (RCB) index.
TNBC subtype and pCR status were significantly associated (P = 0.04379). The basal-like 1 (BL1) subtype had the highest pCR rate (52%); basal-like 2 (BL2) and luminal androgen receptor had the lowest (0% and 10%, respectively). TNBC subtype was an independent predictor of pCR status (P = 0.022) by a likelihood ratio test. The subtypes better predicted pCR status than did the PAM50 intrinsic subtypes (basal-like vs. non basal-like).
Classifying TNBC by 7 subtypes predicts high versus low pCR rate. We confirm the clinical relevancy of the 7 subtypes of TNBC. We need to prospectively validate whether the pCR rate differences translate into long-term outcome differences. The 7-subtype classification may spur innovative personalized medicine strategies for patients with TNBC.
High-throughput technologies are widely used, for example to assay genetic variants, gene and protein expression, and epigenetic modifications. One often overlooked complication with such studies is ...batch effects, which occur because measurements are affected by laboratory conditions, reagent lots and personnel differences. This becomes a major problem when batch effects are correlated with an outcome of interest and lead to incorrect conclusions. Using both published studies and our own analyses, we argue that batch effects (as well as other technical and biological artefacts) are widespread and critical to address. We review experimental and computational approaches for doing so.
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microRNAs (miRNAs/miRs) belong to a class of small noncoding RNAs that can negatively regulate messenger RNA (mRNA) expression of target genes. miRNAs are involved in multiple aspects of ovarian ...cancer cell dysfunction and the phenotype of ovarian cancer cells can be modified by targeting miRNA expression. miRNA profiling has detected a number of candidate miRNAs with the potential to regulate many important biologic functions in ovarian cancer, but their role still needs to be clarified, given the remarkable heterogeneity among ovarian cancers and the context-dependent role of miRNAs. This review summarizes the data collected from The Cancer Genome Atlas (TCGA) and several other genome-wide projects to identify dysregulated miRNAs in ovarian cancers. Copy number variations (CNVs), epigenetic alterations, and oncogenic mutations are also discussed that affect miRNA levels in ovarian disease. Emphasis is given to the role of particular miRNAs in altering expression of genes in human ovarian cancers with the potential to provide diagnostic, prognostic, and therapeutic targets. Particular attention has been given to TP53, BRCA1/2, CA125 (MUC16), HE4 (WFDC2), and imprinted genes such as ARHI (DIRAS3). A better understanding of the abnormalities in miRNA expression and downstream transcriptional and biologic consequences will provide leads for more effective biomarkers and translational approaches in the management of ovarian cancer.
Abstract Background Progression of conventional urothelial carcinoma of the bladder to a tumor with unique microscopic features referred to as micropapillary carcinoma is coupled with aggressive ...clinical behavior signified by a high propensity for metastasis to regional lymph nodes and distant organs resulting in shorter survival. Objective To analyze the expression profile of micropapillary cancer and define its molecular features relevant to clinical behavior. Design, setting, and participants We retrospectively identified 43 patients with micropapillary bladder cancers and a reference set of 89 patients with conventional urothelial carcinomas and performed whole-genome expression messenger RNA profiling. Outcome measurements and statistical analysis The tumors were segregated into distinct groups according to hierarchical clustering analyses. They were also classified according to luminal, p53-like, and basal categories using a previously described algorithm. We applied Ingenuity Pathway Analysis software (Qiagen, Redwood City, CA, USA) and gene set enrichment analysis for pathway analyses. Cox proportional hazards models and Kaplan-Meier methods were used to assess the relationship between survival and molecular subtypes. The expression profile of micropapillary cancer was validated for selected markers by immunohistochemistry on parallel tissue microarrays. Results and limitations We show that the striking features of micropapillary cancer are downregulation of miR-296 and activation of chromatin-remodeling complex RUVBL1. In contrast to conventional urothelial carcinomas that based on their expression can be equally divided into luminal and basal subtypes, micropapillary cancer is almost exclusively luminal, displaying enrichment of active peroxisome proliferator-activated receptor γ and suppression of p63 target genes. As with conventional luminal urothelial carcinomas, a subset of micropapillary cancers exhibit activation of wild-type p53 downstream genes and represent the most aggressive molecular subtype of the disease with the shortest survival. The involvement of miR-296 and RUVBL1 in the development of micropapillary bladder cancer was identified by the analyses of correlative associations of genome expression profiles and requires mechanistic validation. Conclusions Micropapillary cancer evolves through the luminal pathway and is characterized by the activation of miR-296 and RUVBL1 target genes. Patient summary Our observations have important implications for prognosis and for possible future development of more effective therapies for micropapillary bladder cancer.
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Considerable controversy has erupted in recent years regarding whether genotyping should be part of standard care for patients with age-related macular degeneration (AMD) who are being considered for ...treatment with antioxidants and zinc. We aimed to determine whether genotype predicts response to supplements in AMD.
Three separate statistical teams reanalyzed data derived from the Age-Related Eye Disease Study (AREDS), receiving data prepared by the AREDS investigators and, separately, data from investigators reporting findings that support the use of genotyping.
The population of interest was AREDS participants with AMD worse than category 1 and genotyping data available. Data from the 2 groups overlap imperfectly with respect to measurements made: the largest common set involved 879 participants for whom the same CFH and ARMS2 single nucleotide polymorphisms were measured by both groups.
Each team took a separate but complementary approach. One team focused on data concordance between conflicting studies. A second team focused on replicating the key claim of an interaction between genotype and treatment. The third team took a blank slate approach in attempting to find baseline predictors of treatment response.
Progression to advanced AMD.
We found errors in the data used to support the initial claim of genotype-treatment interaction. Although we found evidence that high-risk patients had more to gain from treatment, we were unable to replicate any genotype-treatment interactions after adjusting for multiple testing. We tested 1 genotype claim on an independent set of data, with negative results. Even if we assumed that interactions in fact did exist, we did not find evidence to support the claim that supplementation leads to a large increase in the risk of advanced AMD in some genotype subgroups.
Patients who meet criteria for supplements to prevent AMD progression should be offered zinc and antioxidants without consideration of genotype.
Morphologically heterogeneous prostate cancers that behave clinically like small-cell prostate cancers (SCPC) share their chemotherapy responsiveness. We asked whether these clinically defined, ...morphologically diverse, "aggressive variant prostate cancer (AVPC)" also share molecular features with SCPC.
Fifty-nine prostate cancer samples from 40 clinical trial participants meeting AVPC criteria, and 8 patient-tumor derived xenografts (PDX) from 6 of them, were stained for markers aberrantly expressed in SCPC. DNA from 36 and 8 PDX was analyzed by Oncoscan for copy number gains (CNG) and losses (CNL). We used the AVPC PDX to expand observations and referenced publicly available datasets to arrive at a candidate molecular signature for the AVPC.
Irrespective of morphology, Ki67 and Tp53 stained ≥10% cells in 80% and 41% of samples, respectively. RB1 stained <10% cells in 61% of samples and AR in 36%. MYC (surrogate for 8q) CNG and RB1 CNL showed in 54% of 44 samples each and PTEN CNL in 48%. All but 1 of 8 PDX bore Tp53 missense mutations. RB1 CNL was the strongest discriminator between unselected castration-resistant prostate cancer (CRPC) and the AVPC. Combined alterations in RB1, Tp53, and/or PTEN were more frequent in the AVPC than in unselected CRPC and in The Cancer Genome Atlas samples.
Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in RB1, Tp53, and/or PTEN.
Loss of genome-wide methylation is a common feature of cancer, and the degree of hypomethylation has been correlated with genomic instability. Global methylation of repetitive elements possibly arose ...as a defense mechanism against parasitic DNA elements, including retrotransposons and viral pathogens. Given the alterations of global methylation in both viral infection and cancer, we examined genome-wide methylation levels in head and neck squamous cell carcinoma (HNSCC), a cancer causally associated with human papilloma virus (HPV). We assayed global hypomethylation levels in 26 HNSCC samples, compared with their matched normal adjacent tissue, using Pyrosequencing-based methylation assays for LINE repeats. In addition, we examined cell lines derived from a variety of solid tumors for LINE and SINE (Alu) repeats. The degree of LINE and Alu hypomethylation varied among different cancer cell lines. There was only moderate correlation between LINE and Alu methylation levels, with the range of variation in methylation levels being greater for the LINE elements. LINE hypomethylation was more pronounced in HPV-negative than in HPV-positive tumors. Moreover, genomic instability, as measured by genome-wide loss-of-heterozygosity (LOH) single nucleotide polymorphism (SNP) analysis, was greater in HNSCC samples with more pronounced LINE hypomethylation. Global hypomethylation was variable in HNSCC. Its correlation with both HPV status and degree of LOH as a surrogate for genomic instability may reflect alternative oncogenic pathways in HPV-positive versus HPV-negative tumors.
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The standard treatment for high-grade serous ovarian cancer is primary debulking surgery followed by chemotherapy. The extent of metastasis and invasive potential of lesions can influence the outcome ...of these primary surgeries. Here, we explored the underlying mechanisms that could increase metastatic potential in ovarian cancer. We discovered that FABP4 (fatty acid binding protein) can substantially increase the metastatic potential of cancer cells. We also found that miR-409-3p regulates FABP4 in ovarian cancer cells and that hypoxia decreases miR-409-3p levels. Treatment with DOPC nanoliposomes containing either miR-409-3p mimic or FABP4 siRNA inhibited tumor progression in mouse models. With RPPA and metabolite arrays, we found that FABP4 regulates pathways associated with metastasis and affects metabolic pathways in ovarian cancer cells. Collectively, these findings demonstrate that FABP4 is functionally responsible for aggressive patterns of disease that likely contribute to poor prognosis in ovarian cancer.
High-throughput biological assays such as microarrays let us ask very detailed questions about how diseases operate, and promise to let us personalize therapy. Data processing, however, is often not ...described well enough to allow for exact reproduction of the results, leading to exercises in "forensic bioinformatics" where aspects of raw data and reported results are used to infer what methods must have been employed. Unfortunately, poor documentation can shift from an inconvenience to an active danger when it obscures not just methods but errors. In this report we examine several related papers purporting to use microarray-based signatures of drug sensitivity derived from cell lines to predict patient response. Patients in clinical trials are currently being allocated to treatment arms on the basis of these results. However, we show in five case studies that the results incorporate several simple errors that may be putting patients at risk. One theme that emerges is that the most common errors are simple (e.g., row or column offsets); conversely, it is our experience that the most simple errors are common. We then discuss steps we are taking to avoid such errors in our own investigations.
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