Vitamin D prevents endothelial progenitor cell dysfunction induced by sera from women with preeclampsia or conditioned media from hypoxic placenta

Context: Placenta-derived circulating factors contribute to the maternal endothelial dysfunction underlying preeclampsia. Endothelial colony forming cells (ECFC), a sub-population of endothelial progenitor cells (EPCs), are thought to be involved in vasculogenesis and endothelial repair. Low vitamin D concentrations are associated with an increased risk for preeclampsia. Objective: We hypothesized that the function of human fetal ECFCs in culture would be suppressed by exposure to preeclampsia-related factors-preeclampsia serum or hypoxic placental conditioned medium- in a fashion reversed by vitamin D. Design, Setting, Patients: ECFCs were isolated from cord blood of uncomplicated pregnancies and expanded in culture. Uncomplicated pregnancy villous placenta in explant culture were exposed to either 2% (hypoxic), 8% (normoxic) or 21% (hyperoxic) O2 for 48 h, after which the conditioned media (CM) was collected. Outcome Measures: ECFC tubule formation (Matrigel assay) and migration were examined in the presence of either maternal serum from preeclampsia cases or uncomplicated pregnancy controls, or pooled CM, in the presence or absence of 1,25(OH)2 vitamin D3. Results: 1,25(OH)2 vitamin D3 reversed the adverse effects of preeclampsia serum or CM from hypoxic placenta on ECFCs capillary-tube formation and migration. Silencing of VDR expression by VDR siRNA, VDR blockade, or VEGF pathway blockade reduced ECFC functional abilities. Effects of VDR or VEGF blockade were partially prevented by vitamin D. Conclusion: Vitamin D promotes the capillary-like tubule formation and migration of ECFCs in culture, minimizing the negative effects of exposure to preeclampsia-related factors. Further evaluation of the role of vitamin D in ECFC regulation and preeclampsia is warranted. © 2014 Brodowski et al

Quantification of the relative roles of niche and neutral processes in structuring gastrointestinal microbiomes

The theoretical description of the forces that shape ecological communities focuses around two classes of models. In niche theory, deterministic interactions between species, individuals, and the environment are considered the dominant factor, whereas in neutral theory, stochastic forces, such as demographic noise, speciation, and immigration, are dominant. Species abundance distributions predicted by the two classes of theory are difficult to distinguish empirically, making it problematic to deduce ecological dynamics from typical measures of diversity and community structure. Here, we show that the fusion of species abundance data with genome-derived measures of evolutionary distance can provide a clear indication of ecological dynamics, capable of quantifying the relative roles played by niche and neutral forces. We apply this technique to six gastrointestinal microbiomes drawn from three different domesticated vertebrates, using high-resolution surveys of microbial species abundance obtained from carefully curated deep 16S rRNA hypervariable tag sequencing data. Although the species abundance patterns are seemingly well fit by the neutral theory of metacommunity assembly, we show that this theory cannot account for the evolutionary patterns in the genomic data; moreover, our analyses strongly suggest that these microbiomes have, in fact, been assembled through processes that involve a significant nonneutral (niche) contribution. Our results demonstrate that high-resolution genomics can remove the ambiguities of process inference inherent in classic ecological measures and permits quantification of the forces shaping complex microbial communities

Thyroid cancer: emerging role for targeted therapies

The histology and clinical behavior of thyroid cancer are highly diverse. Although most are indolent tumors with a very favorable outcome with the current standard of care therapy, a small subset of tumors may be among the most lethal malignancies known to man. While surgery and radioactive iodine are the standard of care for differentiated thyroid cancers (DTC) and are effective in curing a majority of such patients, those with iodine-resistant cancers pose a great challenge for clinicians, as these patients have limited treatment options and poor prognoses. Medullary thyroid carcinoma (MTC) has no effective systemic therapy despite the genetic and signaling defects that have been well characterized for the last two decades. Anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors that remains fatal despite conventional multimodality therapy. Increased understanding of the pathogenesis of papillary thyroid carcinoma, the most common type of DTC, as well as ATC, has led to the development of targeted therapies aimed at signaling pathways and angiogenesis that are critical to the development and/or progression of such tumors. Development of tyrosine kinase inhibitors targeting known pathogenetic defects in MTC has led to testing of such agents in the clinic. Numerous clinical trials have been conducted over the last 5 years to examine the effects of these targeted molecular therapies on the outcomes of patients with iodine-refractory DTC, MTC and ATC. Conduction of such trials in the last few years represents a major breakthrough in the field of thyroid cancer. Several trials testing targeted therapies offer promise for setting new standards for the future of patients with progressive thyroid cancer. The purpose of this paper is to outline the recent advances in understanding of the pathogenesis of thyroid cancer and to summarize the results of the clinical trials with these targeted therapies

Ernest L. Mazzaferri, MD, MACP (1936-2013)

Professor and physician Dr. Ernest L. Mazzaferri Sr. passed away on May 14, 2013, at 76 years of age ( 1 , 2 ). Ernie is remembered as a caring and talented physician, an accomplished scholar and educator, as well as a loving husband, father, and grandfather. He was a luminary figure, and few people have had a greater impact in thyroidology in recent decades. Here we include reflections from a few of us that knew him, as well as commentaries from people who did not. Ernie's passion was caring for patients and how to improve their care. Our goal is to pay tribute and memorialize the person we knew and the impact that he had on patients around the world through his dedication to research, lecturing, and writing that achieved remarkable global influence

Do Ultrasound Patterns and Clinical Parameters Inform the Probability of Thyroid Cancer Predicted by Molecular Testing in Nodules with Indeterminate Cytology?

Background: Molecular testing (MT) is commonly used to refine cancer probability in thyroid nodules with indeterminate cytology. Whether or not ultrasound (US) patterns and clinical parameters can further inform the risk of thyroid cancer in nodules predicted to be positive or negative by MT remains unknown. The aim of this study was to test if clinical parameters, including patient age, sex, nodule size (by US), Bethesda category (III, IV, V), US pattern (American Thyroid Association [ATA] vs. American College of Radiology Thyroid Image Reporting and Data System [TI-RADS] systems), radiation exposure, or family history of thyroid cancer can modify the probability of thyroid cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) predicted by MT. Methods: We studied 257 thyroid nodules in 232 patients from 10 study centers with indeterminate fine needle aspiration cytology and informative MT results using the ThyroSeq v3 genomic classifier (TSv3). Univariate and multivariate logistic regression was used for data analysis. Results: The presence of cancer/NIFTP was associated with positive TSv3 results (odds ratio 61.39, p < 0.0001). On univariate regression, patient sex, age, and Bethesda category were associated with cancer/NIFTP probability (p < 0.05 for each). Although ATA (p = 0.1211) and TI-RADS (p = 0.1359) US categories demonstrated positive trends, neither was significantly associated with cancer/NIFTP probability. A multivariate regression model incorporating the four most informative non-MT covariates (sex, age, Bethesda category, and ATA US pattern; Model No. 1) yielded a C index of 0.653; R2 = 0.108. When TSv3 was added to Model number 1, the C index increased to 0.888; R2 = 0.572. However, age (p = 0.341), Bethesda category (p = 0.272), and ATA US pattern (p = 0.264) were nonsignificant, and other than TSv3 (p < 0.0001), male sex was the only non-MT parameter that potentially contributed to cancer/NIFTP risk (p = 0.095). The simplest and most efficient clinical model (No. 3) incorporated TSv3 and sex (C index = 0.889; R2 = 0.588). Conclusions: In this multicenter study of thyroid nodules with indeterminate cytology and MT, neither the ATA nor TI-RADS US scoring systems further informed the risk of cancer/NIFTP beyond that predicted by TSv3. Although age and Bethesda category were associated with cancer/NIFTP probability on univariate analysis, in sequential nomograms they provided limited incremental value above the high predictive ability of TSv3. Patient sex may contribute to cancer/NIFTP risk in thyroid nodules with indeterminate cytology

Performance of a Multigene Genomic Classifier in Thyroid Nodules with Indeterminate Cytology: A Prospective Blinded Multicenter Study

© 2019 American Medical Association. All rights reserved. Importance: Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients if the nodules are reliably diagnosed as benign without surgery. Objective: To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules. Design, Setting, and Participants: Prospective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules. Interventions: A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3). Main Outcomes and Measures: The primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules. Results: Of the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%. Conclusions and Relevance: In this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result.

SMIM1 underlies the Vel blood group and influences red blood cell traits

<p>The blood group Vel was discovered 60 years ago(1), but the underlying gene is unknown. Individuals negative for the Vel antigen are rare and are required for the safe transfusion of patients with antibodies to Vel(2). To identify the responsible gene, we sequenced the exomes of five individuals negative for the Vel antigen and found that four were homozygous and one was heterozygous for a low-frequency 17-nucleotide frameshift deletion in the gene encoding the 78-amino-acid transmembrane protein SMIM1. A follow-up study showing that 59 of 64 Vel-negative individuals were homozygous for the same deletion and expression of the Vel antigen on SMIM1-transfected cells confirm SMIM1 as the gene underlying the Vel blood group. An expression quantitative trait locus (eQTL), the common SNP rs1175550 contributes to variable expression of the Vel antigen (P = 0.003) and influences the mean hemoglobin concentration of red blood cells (RBCs; P = 8.6 x 10(-15))(3). In vivo, zebrafish with smim1 knockdown showed a mild reduction in the number of RBCs, identifying SMIM1 as a new regulator of RBC formation. Our findings are of immediate relevance, as the homozygous presence of the deletion allows the unequivocal identification of Vel-negative blood donors.</p>