Search Results - EGA European Genome-Phenome Archive

T cell receptor repertoire in cell-free DNA as a proxy for tumor infiltrates in patients treated with pembrolizumab

Profiling tumour and systemic T-cell receptor (TCR) repertoires can identify features associated with clinical benefit of cancer patients on immune checkpoint blockade therapy. This study reports on diversity and specificity analysis of TCR sequences from 59 tumor, 306 peripheral blood (PBMC), and 73 cell-free DNA (cfDNA) samples from 81 patients with solid tumors treated with pembrolizumab. This analysis reveals that head and neck carcinomas have significantly lower PBMC diversity and shorter persistence of pembrolizumab-induced diversification compared to other cancers. Using GLIPHII (Grouping Lymphocyte Interactions with Paratope Hotspots), we find that tumor-derived clonotypes form non-microbial specificity signatures that are shared across patients and cancer types. Tumor-derived clonotypes are enriched in cfDNA compared to PBMCs, despite the diversity of cfDNA TCR repertories being two orders of magnitude lower than PBMCs. TCRs shared between tumors and cfDNAs persist in PBMCs beyond 50 weeks of treatment, suggesting cfDNA captures clonotypes contributing to anti-tumor immune surveillance.

Study EGAS50000001306

NEOPREDICT-Lung: Neoadjuvant Immunotherapy for Resectable NSCLC

Links via: DOI: https://doi.org/10.1038/s41591-024-02965-0 PubMed: https://pubmed.ncbi.nlm.nih.gov/38689060/ Journal: https://www.nature.com/articles/s41591-024-02965-0 Abstract Antibodies targeting the immune checkpoint molecules PD-1, PD-L1 and CTLA-4 administered alone or in combination with chemotherapy are standard of care in most patients with metastatic non-small cell lung cancers. When given prior to curative surgery, tumor responses and improved event-free survival are achieved. New antibody combinations may be more efficacious and tolerable. In an ongoing, open-label phase II study, 60 biomarker-unselected, treatment-naïve patients with resectable non-small cell lung cancer were randomized to receive two preoperative doses of nivolumab (anti-PD-1) with or without relatlimab (anti-LAG-3) antibody therapy. The primary study endpoint was feasibility of surgery within 43 days, which was met by all patients. Curative resection was achieved in 95% of patients. Secondary endpoints included pathological and radiographic response rates, pathologically complete resection rates, disease-free and overall survival rates, and safety. Major pathological (≤10% viable tumor cells) and objective radiographic responses were achieved in 27% and 10% (nivolumab), and 30% and 27% (nivolumab and relatlimab) of patients, respectively. In 100% (nivolumab) and 90% (nivolumab and relatlimab) of patients tumors and lymph nodes were pathologically completely resected. With 12 months median duration of follow-up, disease-free survival and overall survival rates at 12 months were 89% and 93% (nivolumab), and 93% and 100% (nivolumab and relatlimab). Both treatments were safe with grade ≥ 3 treatment-emergent adverse events reported in 10% and 13% of patients per study arm. Exploratory analyses provided insights into biological processes triggered by preoperative immunotherapy. This study establishes the feasibility and safety of dual targeting of PD-1 and LAG-3 prior to lung cancer surgery.

Study EGAS00001007753

Developmental Mechanisms of Human Congenital Heart Disease in Subjects with 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome)

The study is designed to identify genetic modifiers of cardiovascular defects in subjects with 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome or velo-cardio-facial syndrome. Affymetrix 6.0 arrays were processed on 1,480 subjects with known cardiovascular anomalies or with normal structures, all with 22q11.2DS. One sample is a duplicate so it was removed. There are 1,472 samples total of unrelated, de-identified, probands. Over 90% have the same sized 3 million base pair deletion flanked by low copy repeats (LCR22) A and D, while approximately 6% have nested A to B deletions. The rest have other nested deletions, that include a deletion in the vicinity of TBX1 (between LCR22 A and B). A subset of the data was used to identify copy number variations serving as modifiers. Some data were previously published by Dr. Emanuel's team at Children's Hospital of Philadelphia in PA, USA (PMID:26742502; PMID:4896312; PMID:25892112; PMID:4570279). The de-identified DNA data from unrelated subjects come from multiple research sites in the US and Europe as part of the International 22q11.2 Consortium and the International 22q11.2 Brain and Behavior Consortium.

Study phs001339

Whole transcriptome profiling of liquid biopsies from tumour xenografted mouse models: validation cohort

While cell-free DNA (cfDNA) in liquid biopsies is widely being used and investigated, free circulating RNA (extracellular RNA, exRNA) has the potential to improve therapy response monitoring and cancer detection due to its dynamic nature. A fundamental open question hampering the initiation of large-scale liquid biopsy collections for tumour exRNA analysis is that it remains unclear in which blood subcompartment tumour-derived exRNAs primarily reside. We set out to develop a host-xenograft deconvolution framework, exRNAxeno, with cDNA mapping strategies to either a combined human-mouse reference genome or both species genomes in parallel, that can be applied to exRNA sequencing data from liquid biopsies of human xenograft mouse models, enabling to distinguish (human) tumoural RNA from (murine) host RNA, and as such to specifically analyse tumour-derived exRNA. Subsequently, the preferred exRNAxeno combination pipeline was applied to total exRNA sequencing data from blood platelets and three plasma fractions from a breast cancer patient-derived and neuroblastoma cell line-derived xenograft mouse model. We show that tumoural exRNA concentrations are not determined by plasma platelet levels, while host exRNA concentrations increase with platelet content. Furthermore, a large variability in exRNA levels and gene content across individual mice is observed. In general, the tumoural gene detectability in plasma is correlated with the RNA expression levels in the tumour tissue or cancer cell line. Our results unravel new aspects of tumour-derived exRNA biology in xenograft mouse models.

Study EGAS00001006582

Lactobacillus rhamnosus GG ATCC (LGG) as an immune adjuvant for influenza vaccination in the elderly

Double blind Randomized Controlled trial to evaluate the safety of Lactobacillus rhamnosus GG ATCC 53103 (LGG) vs placebo in elderly receiving Trivalent Inactivated Influenza Vaccine (TIV) (study 1) or Double blind Randomized Controlled trial to evaluate the safety of Lactobacillus rhamnosus GG ATCC 53103 (LGG) vs. placebo in elderly subjects receiving Live Attenuated Influenza vaccine (LAIV) (study 2). Healthy elderly volunteers, ages 65-80 were enrolled as outpatients in two clinical studies in which they received the TIV vaccine (study 1, n=28) or the LAIV vaccine (study 2, n=30). In each of the 2 studies, subjects were randomized to receive either LGG capsules containing 1 x 1010 CFU, twice daily for 28 days, or matching placebo capsules twice daily for the same period of time. The study subjects completed a daily diary, telephone calls, and study visits at the Massachusetts General Hospital Clinical Research Centers at baseline, days 21, 28 and 56 and month 5 for the TIV study and baseline, days 21, 28, and 56 for the LAIV study. During each visit, the subject diary, interim history, potential adverse effects and concomitant medications were reviewed and vital signs and a physical examination were performed. Routine blood tests were obtained to monitor for safety during visits and nasopharyngeal and stool samples were collected for microbiome analysis. Volunteers in both studies who were interested in participating in the effect of LGG probiotic on the Human whole Blood Transcriptome substudy also had blood drawn for DNA and RNA extraction, after signing the substudy consent form. The main objectives of the TIV and LAIV studies were to assess the safety and tolerability of 2 x 1010 CFU LGG administered orally to elderly subjects for 28 days after administration of TIV (study 1) or LAIV (study 2). Secondary objectives were to evaluate the richness and microbial diversity in nasopharyngeal and stool specimens using pyrosequencing, and to compare cytokine production in response to bacterial stimulation by following the kinetics of mRNA expression of pro and anti-inflammatory genes and different signaling pathways, in relation to changes in stool Bifidobacterium and Lactobacillus spp. The studies were reviewed and approved by the Partners Human Research Committee (TIV study IRB # 2010p001694 and LAIV study IRB # 2011p002849) and were registered at ClinicalTrials.gov (NCT01368029 and NCT01545349, respectively).

Study phs000981

Chromatin Accessibility Landscape of Human Pancreatic Ductal Adenocarcinoma (PDAC)

Therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we discovered a signature of 1092 chromatin loci displaying differential accessibility between patients with disease-free survival (DFS) < 1 year and patients with DFS > 1 year. Using this signature, we further develop a chromatin accessibility microarray methodology termed “ATAC-Array”, an easy-to-use platform obviating the time and cost of next-generation sequencing. PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.

Study phs002394

Fragmentomic features of individuals with different cfDNA concentrations

The goal of this study is to explore fragmentomic patterns that vary between individuals of different concentrations of total cell-free DNA in plasma. We have selected a large cohort of individuals (ethnically Chinese men with a median age of 54 years, IQR 49-57) who were part of a screening of a large-scale clinical study to screen for nasopharyngeal carcinoma. Differences in fragmentomic features provided insights into the modulation of cfDNA levels in blood circulation. Fragmentomic and machine learning systems adopted in this study have also been applied to assess the quantity of cfDNA species of clinical interest, including the fraction of circulating fetal and tumor DNA, from pregnancy cases and individuals with hepatocellular carcinoma, respectively.

Study EGAS50000000692

DPY30_ChIP_seq

H9 human embryonic stem cells (hESCs) were cultured in feeder-free chemically-defined conditions in medium containing 10ng/ml Activin A and 12ng/ml FGF2 (Vallier L. 2011, Methods in Molecular Biology, 690: 57–66). Chromatin immunoprecipitation was performed as described in Brown S. et al. 2011. Stem Cells 29: 1176–85 by using 5ug of anti-DPY30 antibody (Sigma, cat. number HPA043761). This protocol was performed in control hESCs (expressing a scrambled shRNA) and in hESCs stably expressing an shRNA against DPY30 (Sigma, clone n. TRCN0000131112).This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Study EGAS00001001132

16 Year Life History and Genomic Evolution of an ER+ HER2- Breast Cancer

We reconstructed the genomic evolution through the sixteen year history of an ER+ HER2- breast cancer patient to investigate molecular mechanisms of disease relapse and treatment resistance after long term exposure to hormonal therapy. Genomic and transcriptomic profiling was performed on primary breast tumor (2002), initial recurrence (2012) and liver metastasis (2015) tumor samples. Cell free DNA analysis was performed at eleven timepoints (2015-2017).This phylogenetic reconstruction of the life history of a single patient's cancer as well as monitoring tumor progression through liquid biopsies with the detection of a resistant clone harboring a de-novo ESR1 E380Q mutation allowed for uncovering the molecular mechanisms leading to initial relapse, metastatic spread and treatment resistance.

Study EGAS00001004624

Peripheral blood DNA methylation of Crohn's disease patients starting treatment with adalimumab, vedolizumab or ustekinumab

In the current study we performed a longitudinal case-control study comparing the peripheral blood DNA methylome of Crohn's disease (CD) patients that were classified as responders and non-responders to adalimumab, vedolizumab, and ustekinumab. Patients with active CD were prospectively recruited and followed up for around 27 weeks into treatment during which response assessment took place. Response was defined as a strict combination of endoscopic- (≥50% reduction in SES-CD score) combined with either corticosteroid-free clinical- (≥3 point drop87 in HBI or HBI ≤4 and no systemic steroids) and/or biochemical response (C-reactive protein (CRP) and fecal calprotectin reduction ≥50% or ≤5 g/mL and fecal calprotectin ≤250 µg/g).

Study EGAS00001007532

Serial assessment of measurable residual disease in medulloblastoma liquid biopsies

Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations (CNVs) in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients decline with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma.

Study EGAS00001005592

Tissue-specific cell-free DNA degradation quantifies circulating tumor DNA burden

Profiling of circulating tumor DNA (ctDNA) may offer a non-invasive approach to monitor disease progression. Here, we developed a quantitative method, exploiting local tissue-specific cell-free DNA (cfDNA) degradation patterns, that accurately estimates ctDNA burden independent of genomic aberrations. Nucleosome-dependent cfDNA degradation at promoters and first exon-intron junctions was strongly associated with differential transcriptional activity in tumors and blood. A quantitative model, based on just 6 regulatory regions, could accurately predict ctDNA levels in colorectal cancer patients. Strikingly, a model restricted to blood-specific regulatory regions could predict ctDNA levels across both colorectal and breast cancer patients.

Study EGAS00001004657

Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics

The human placenta is a dynamic and cellular heterogeneous organ, which is critical in fetomaternal homeostasis and the development of preeclampsia. Previous work has shown that placenta-derived cell-free RNA increases during pregnancy. We applied large-scale microfluidic single-cell transcriptomic technology to comprehensively characterize cellular heterogeneity of the human placentas and identified multiple placental cell-type–specific gene signatures. Analysis of the cellular signature expression in maternal plasma enabled noninvasive delineation of the cellular dynamics of the placenta during pregnancy and the elucidation of extravillous trophoblastic dysfunction in early preeclampsia.

Study EGAS00001002449

Characterization of the oral and gut microbiome of melanoma patients before initiation of ant-PD-1 therapy, and confirmation of the phenotype in germ-free mice

The oral and gut microbiomes of melanoma patients were characterized before the initiation of ant-PD1 immunotherapy, and compared to treatment response. Validation studies were performed in germ-free mice using stool from patients who responded/did not respond to ant-PD1 immunotherapy. All baseline oral(n=86) and gut (n=43) microbiome samples were subject to 16S sequencing - V4 region ( merged fastq files have been made available through this portal). Whole genome shotgun sequencing (WGS) was performed on a subset of fecal samples (n=25)- these files are also available( paired end reads). Also available are 16S sequencing results of stool samples from donors (n=2) used in fecal microbiota transplant and murine samples (n=12) from germ-free mice transplanted with stool from responder/non-responder patients. The fastq files associated with this dataset are stored at ENA under the following links: Fecal 16S – PRJEB22894 https://www.ebi.ac.uk/ena/browser/view/PRJEB22894 Oral 16S – PRJEB22874 https://www.ebi.ac.uk/ena/browser/view/PRJEB22874 Murine 16S – PRJEB22895 https://www.ebi.ac.uk/ena/browser/view/PRJEB22895 Fecal WGS – PRJEB22893 https://www.ebi.ac.uk/ena/browser/view/PRJEB22893

Dataset EGAD00001003943

Differential Presence of Exons in Cell-Free DNA Reveals Different Patterns in Colorectal Cancer Between Metastatic and Non-Metastatic Patients

Tumor genotyping during disease follow-up is gaining an increasing interest for monitoring and clinical management in colorectal cancer (CRC). Growing evidences suggest that single biopsies are inefficient for molecular profiling, due to clonal evolution and intratumoral heterogeneity of primary tumors and/or metastasis. Circulating free DNA (cfDNA) has emerged as an alternative source of genetic material that seems to be representative of the continuously changing tumor molecular features. Thus, the so-called 'liquid biopsy' also offers the additional advantages of accessibility and non-invasiveness for the patient. Novel strategies based on next-generation sequencing (NGS) of cfDNA are being currently developed, with most studies focusing on targeted deep sequencing panels of potential clinically actionable genes. Here we describe an alternative approach, consisting of exome-sequencing in cfDNA at a relatively shallower depth to provide a more general overview of the circulating genome. In this study, two groups of colorectal cancer patients, with either disseminated (M) or localized disease (N), were compared using whole-exome sequencing and a RNA-seq bioinformatics analysis pipeline. Thus, a set of 379 exons present at different levels in cfDNA from both groups were identified, giving rise to a completely new concept in this field, termed as 'Differential Presence of Exons'. Differentially present exons (DPEs) were subsequently used for M and N patients clustering and classification, allowing for the design of a predictive algorithm with encouraging preliminary results in a small subset of patients that could not be initially classified attending to the selection criteria (U group, unassignable).

Study EGAS00001002687

Detection and characterization of lung cancer using cell-free DNA fragmentomes

Lung cancer remains the leading cause of cancer death world-wide, largely due to its late diagnosis. Non-invasive approaches for assessment of cell-free DNA (cfDNA) provide an opportunity for detection and intervention that may have broader accessibility than current imaging approaches. Using a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation, we examined a prospective study of 365 individuals at risk for lung cancer (Lung Cancer Diagnostic Study, LUCAS), including 129 individuals ultimately diagnosed with lung cancer and 236 individuals determined to not have lung cancer. We externally validated the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 predominantly early stage lung cancer patients. Combining fragmentation features with clinical risk factors and CEA levels followed by CT imaging detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites could be used to distinguish individuals with small cell lung cancer (SCLC) from those with non-small cell lung cancer (NSCLC) with high accuracy (AUC=0.98). Among individuals with lung cancer, a higher cfDNA fragmentation score was associated with tumor size and invasion, and represented an independent prognostic indicator of survival. These studies provide a facile approach for non-invasive detection of lung cancer and clinical management of this disease.

Study EGAS00001005340

Genetic Epidemiology Network of Arteriopathy (GENOA)

The Genetic Epidemiology Network of Arteriopathy (GENOA) is one of four networks in the NHLBI Family-Blood Pressure Program (FBPP). GENOA's long-term objective is to elucidate the genetics of target organ complications of hypertension, including both atherosclerotic and arteriolosclerotic complications involving the heart, brain, kidneys, and peripheral arteries. The longitudinal GENOA Study recruited European-American and African-American sibships with at least 2 individuals with clinically diagnosed essential hypertension before age 60 years. All other members of the sibship were invited to participate regardless of their hypertension status. Participants were diagnosed with hypertension if they had either 1) a previous clinical diagnosis of hypertension by a physician with current anti-hypertensive treatment, or 2) an average systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg based on the second and third readings at the time of their clinic visit. The Family Blood Pressure Program (FBPP), GENOA's parent program, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators created a single confederation with program-wide and network-specific goals.

Study phs001238

Molecular Analysis of Alliance A031201 Study

This is the first study examining the relationship between clonal hematopoiesis and clinical outcomes in prostate cancer patients. We used a targeted gene sequencing panel to identify patients in the A031201 clinical trial with and without clonal hematopoiesis. We found that clonal hematopoiesis did not affect overall or progression free survival in A031201 but was associated more adverse cardiac events.

Study phs003717

Circulating RNAs prior to endometrial cancer diagnosis

We analyzed circulating RNA levels using small RNA sequencing, targeting RNA in the size range 17 to 47 nucleotides, in samples collected prior to endometrial cancer diagnosis compared to cancer-free controls. The analysis included 316 cases with samples collected 1-11 years prior to diagnosis , and 316 matched controls, both from the Janus Serum Bank Cohort in Norway.

Study EGAS50000000267

The Genomic Map of Poland in Open Access

The main goal is to prepare and share WGS/WES of Polish population In this project NGS (next generation sequencing) was performed using Illumina NOVASEQ 6000 and Illumina DRAGEN aligner was used. Shared BAM and BAM.BAI files Library Construction Protocol: Illumina DNA PCR-Free Prep, Tagmentation. Reference Genome: GRCh37.

Study EGAS50000000091

The Berlin (BLN) panel of glioblastoma cell lines: RNAseq of human gliomasphere cell lines and matched parental tumors

We generated a panel of nine glioma stem-like cell lines under serum-free cell culture conditions from human glioblastoma samples. In addition to clinical annotation, MR imaging and histological characterization of the parental tumor, as well as xenograft studies of tumorigenecity, transcriptomic profiling of tumor/cell line pairs by RNA sequencing has been performed.

Study EGAS00001001167

Nuclease deficiencies alter plasma cell-free DNA methylation profiles (Mouse samples)

The dataset contains sequencing data in wildtype, Dnase1-deficient and Dnase1l3-deficient mice. We performed 2 x 75bp paired-end whole genome bisulfite sequencing of pooled plasma cell-free DNA (cfDNA) and buffy coat genomic DNA. The effects of DNASE1L3 or DNASE1 deficiency on cfDNA methylation was explored in plasma of mice deficient in these nucleases.

Dataset EGAD00001007751

Elucidating the heterogeneity of immunotherapy response and immune-related toxicities by longitudinal ctDNA and immune cell compartment tracking in lung cancer

The dataset for the study Elucidating the heterogeneity of immunotherapy response and immune-related toxicities by longitudinal ctDNA and immune cell compartment tracking in lung cancer includes 207 bam files from hybrid capture targeted error-correction next-generation sequencing (TEC-Seq) from plasma cell-free DNA and matched white blood cell DNA from 30 individuals with non-small cell lung cancer, alongside 46 bam files from whole exome sequencing of tumor and matched normal DNA for 21 individuals with non-small cell lung cancer who received immunotherapy-containing regimens.

Dataset EGAD00001011991

Single-nucleus RNA-sequencing data of kidney biopsies from patients with primary FSGS, maladaptive FSGS, proteinuric controls and healthy controls

This dataset includes FASTQ files of single-nucleus RNA sequencing of cryopreserved kidney biopsy cores from adult patients with diagnosed primary FSGS (n = 9, all nephrotic), maladaptive FSGS (n = 9, not nephrotic), proteinuric controls (PLA2R-positive membranous nephropathy, n = 3), and healthy controls (n = 4). A total of 120,751 high-quality nuclei were identified, including 2,471 podocytes and 1,574 parietal epithelial cells (PECs). In addition to the raw FASTQ files, the dataset includes processed data files from all 25 samples, generated using Seurat in R: barcode files, features, count matrices, and associated metadata. Details regarding the bioinformatics pipeline can be found at https://github.com/lambrechtslab/FSGS_Deleersnijder_et_al

Dataset EGAD50000001557

Transcriptomic Profile of Whole Blood Cells from Elderly Subjects fed Probiotic Bacteria Lactobacillus rhamnosus GG ATCC 53103 (LGG) in a Phase I Open Label Study

Open label study to evaluate the safety of Lactobacillus rhamnosus GG ATCC 53103 (LGG) in elderly subjects. Fifteen healthy elderly volunteers, ages 65-80 were enrolled in a study in which they received LGG capsules containing 1 x 1010 CFU, twice daily for 28 days and were followed through day 56. The study subjects completed a daily diary, a telephone call on study days 3, 7 and 14 and study visits at the Massachusetts General Hospital Clinical Research Center at baseline, day 28 and day 56. During each visit, the subject diary, interim history, potential adverse effects and concomitant medications were reviewed and vital signs and a physical examination were performed. Routine blood tests were obtained to monitor for safety during visits and nasopharyngeal and stool samples were collected for microbiome analysis. Volunteers interested in participating in the effect of LGG probiotic on the Human whole Blood Transcriptome substudy also had blood drawn for DNA and RNA extraction, after signing the substudy consent form. The main objective of the study was to assess the safety and tolerability of 2 x 1010 CFU LGG administered orally to elderly subjects for 28 days. Secondary objectives were to evaluate the richness and microbial diversity in nasopharyngeal and stool specimens using pyrosequencing, and to compare cytokine production in response to bacterial stimulation by following the kinetics of mRNA expression of pro and anti-inflammatory genes and different signaling pathways, in relation to changes in stool Bifidobacterium and Lactobacillus spp. The study was reviewed and approved by the Partners Human Research Committee (IRB # 2010P001695) and was registered at ClinicalTrials.gov (NCT01274598). The main results regarding the clinical signs and safety of intervention is published in PLoS One. 2014 Dec 1;9(12):e113456. doi: 10.1371/journal.pone.0113456. eCollection 2014. PMID: 25438151. RNA sequencing for transcriptome analysis was only done in 11 of the 15 subjects as RNA integrity and quantity had to be optimal for the three times where blood was collected in order for a subject to be included in the study. The information regarding the microbiome data associated with this study is presented in a separate paper, which can be found at dbGaP study accession, phs000896, and PMID: 25873374.

Study phs000928

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