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• Spatial transcriptomic data of breast cancer

  Fastq files from spatial transcriptomic of breast cancer coming from 8 Breast cancer sections. Sample preparation: frozen BC samples were chosen based on tissue structure and RNA quality (RIN > 8). The “Visium Spatial Tissue Optimization Slide and Reagent Kit” (10X Genomics; #PN-1000193) was then used to optimize permeabilization conditions for BC tissues. Briefly, sections were fixed, stained and then permeabilized at different time points to capture mRNA, and the reverse transcription was performed to generate fluorescently labeled cDNA. The permeabilization time that resulted in the highest fluorescence signal with the lowest background diffusion was chosen. The best permeabilization time for BC tissue was 18 min. Cryostat sections of 10 μm of thickness were cut and placed on Visium Spatial Gene Expression slides (10X Genomics, PN-1000184). The slide was incubated for 1 min at 37°C, then fixed with methanol for 30 min at -20°C followed by Hematoxylin and Eosin (H&E) staining and images were taken under a high-resolution microscope. After imaging, the coverslip was detached by holding the slide in water and the slide was mounted in a plastic slide cassette. The spatial gene expression process, including tissue permeabilization, second strand synthesis and cDNA amplification, was performed according to the manufacturer’s instructions (10X Genomics; #CG000239). cDNA quality was next assessed using Agilent High sensitivity DNA Kit (Agilent, #5067-4626). The spatial gene libraries were constructed using Visium Spatial Library Construction Kit (10X Genomics, PN-1000184).

  Dataset EGAD50000000322

• 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

• FASTQ Files from Breast Tumor Biopsies Collected Across Five Timepoints in the PROMETEO Phase II Trial

  The dataset contains RNA sequencing raw data from tumor biopsies collected at five time points during the SOLTI-1503 PROMETEO trial: baseline (pre-NAC), post-NAC screening, Cycle 2 Day 1, Cycle 3 Day 1, and surgery. The study intervention consisted of intratumoral injections of T-VEC followed by intravenous administrations of atezolizumab prior to surgery. The data is obtained from tumor samples of patients included in the study: female breast cancer patients with residual disease after neoadjuvant chemotherapy, including both triple-negative and Luminal B-like subtypes. Each sample includes raw paired-end RNAseq reads (~110 million reads per library) aligned to the GRCh38/hg38 reference genome

  Dataset EGAD50000002165

• T-VEC CBCL scRNA

  We are presenting raw and processed data of our study where we analyze fine-needle aspirate (FNA) samples of primary cutaneous B-cell lymphoma patients undergoing oncolytic virotherapy (https://clinicaltrials.gov/ct2/show/NCT03458117). We are uploading single cell RNA-sequencing and immune repertoire profiling data of 29 FNA samples from four pCBCL patients. The four patients have three different subtypes of primary cutaneous B-cell lymphoma: pCDLBCL-LT, pCFCL and pCMZL. The samples are taken at different time points following T-VEC injection (from baseline up to 91 days after injection). We are uploading the sequences in BAM format and the outputs of the cellranger pipeline (count matrices and filtered VDJ contigs) in CSV format.

  Dataset EGAD00001006829

• 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

• Genetics of 24 hour urine composition

  Genetic and environmental factors play an important role in the etiology of nephrolithiasis. This project will build on and extend our previous efforts (examining environmental risk factors for stone formation) by allowing us to study the risk of stone formation associated with specific genes and gene-environment interactions. We will take advantage of previously collected data in three large cohort studies: Nurses' Health Study I (n=121,000 women), Nurses' Health Study II (n=116,000 women), and Health Professionals Follow-up Study (n=51,000 men). Over a period of 17 to 26 years, information has been collected prospectively on important exposures including diet, family history, body size measures, past medical history, and medications. We have confirmed over 2000 incident cases of kidney stones in each cohort (DK59583, PI Curhan). Further, we have collected 24-hour urine samples from over 4100 stone formers and non-stone formers; the majority of participants have performed two collections. The primary objective of this project is to examine the association between single nucleotide polymorphisms and the 24-hour urinary excretion of stone promoters (calcium and oxalate) and a stone inhibitor (citrate). The secondary objective is to explore the impact of interactions between the genetic factors and dietary factors on 24-hour urinary excretion of relevant lithogenic factors. These findings should provide new insight into regulation of these important factors and also into novel approaches for prevention of stone formation.

  Study phs000460

• Neoadjuvant combination PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable urothelial carcinoma

  Immune checkpoint therapy (ICT) is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma (UC), with one study reporting data in cisplatin-ineligible patients who received anti PD-L1 monotherapy. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathologic complete response (pCR) rate of 17%. Here, we report on the first pilot combination neoadjuvant trial (NCT02812420) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high risk features (N=28). Primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (N=4), hepatitis and colitis (N=2). We also observed pCR of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (N=24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized UC, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment. Publication: Gao et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nature Medicine volume 26, pages1845–1851(2020)

  Study EGAS00001004074

• The clinical utility of genomics in childhood cancer extends beyond targetable mutations

  Survival of children with relapsed cancer remains unacceptably low. Cancer genomic profiling may identify new therapeutic options, enhance diagnostic accuracy, and improve understanding of tumors’ origins and continued evolution. We deeply sequenced 864 cancer-associated genes and the complete genomes and transcriptomes for 300 pediatric and adolescent/young adult (AYA) patients with poor prognosis or rare tumors. Using integrative somatic-germline analyses, we assessed the clinical utility of cancer genomics in this population. We analyzed tumor mutational signatures and burden to interrogate the relevance of germline variants in DNA repair genes and the impact of therapeutic exposures on tumor evolution. We also evaluated the frequency of changes to tumor drivers and therapeutic targets at relapse in those with serial samples. Integrative analysis yielded clinically actionable variants in a majority of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants were of unanticipated timing and type, with many of these derived from the germline. Enrichment in corroborating mutational signature 3 (‘BRCAness’) in patients with germline homologous recombination defects suggests they are drivers of pediatric cancers and potential targets for PARP inhibition. We show that mutation burden, which may in part be driven by prior therapeutic exposures, was significantly elevated in a minority of patients. Over one-third of patients with sequential samples analyzed showed a change in therapeutically-targetable drivers. Comprehensive somatic-germline cancer genomic profiling is useful at multiple points in the care trajectory for pediatric/AYA patients, supporting its integration into early clinical management. Re-biopsy at the time of relapse should be considered, and specific attention to mutational burden is indicated. Defective DNA repair genes in the germline may represent important targetable drivers.

  Study EGAS00001006034

• Effects of Metformin on Transcriptomic and Metabolomic Profiles in Breast Cancer Survivors Enrolled in the Randomized Placebo-Controlled MetBreCS Trial

  RNA from snap-frozen breast tissue biopsies were purified after lysing by tissuelyser (Qiagen) and using RNA Purification Plus Kit (Norgen biotek CORP, 47700) with additional on-column DNase-I treatment (Qiagen, 79254) at 27 °C. RNA purity and integrity (RIN) were quantified using RNA 6000 Nano kit (Agilent Technologies, 5067-1511) on the 4200 TapeStation (Agilent, Santa Clara, USA). Library preparation and 2x75bp paired-end of 160 ng total RNA input was performed using Illumina Stranded Total RNA Prep Ligation kit and Illumina HiSeq4000 system (Illumina, Sand Diego, CA, USA). RNA sequencing data from HiSeq4000 were quality checked and aligned to GRCh38 (GCA_000001405.15) reference genome using HISAT2 2.0.5 and submitted to subread v.1.5.2 for feature counts calculation. Finally, 36 paired biopsies samples (metformin n=26 and placebo n=12) were sequenced and included in the final analyses.

  Dataset EGAD50000001274

• Tremelimumab +/- durvalumab in combination with paclitaxel as immune induction in metastatic urothelial cancer: clinical and translational results of the ICRA trial

  DESCRIPTION: New therapeutic strategies for therapy-refractory metastatic urothelial carcinoma (mUC) patients are still needed. In the phase I-II ICRA trial, we evaluated whether paclitaxel plus tremelimumab (T; anti-CTLA-4), with or without durvalumab (D; anti-PD-L1), could induce a tumor response in mUC patients who had already received platinum chemotherapy and immune checkpoint inhibition (ICI). After a dose-escalation safety phase, patients were randomized between three arms: A (n=20 after expansion) paclitaxel plus T750mg (cycles 2-8); B (n=12) paclitaxel plus T300mg (cycle 2) plus D1500mg (cycles 2-13); C (n=12) T750mg (cycles 1-7). The objective response rate in arm A was 26% (88% confidence interval (CI) = [14,36%]) versus 17% (88% CI = [3,42%]) in arm B and 8% (88% CI = [0.3,33%]) in arm C. Grade 3-4 treatment-related adverse events occurred in (A) 45%, (B) 75%, and (C) 25% of patients. Murine experiments showed attenuated tumor outgrowth for paclitaxel plus anti-CTLA-4 compared to monotherapy with either agent. Transcriptomic analyses showed upregulation of inflammation signatures in on-treatment tumor tissue biopsies. This study demonstrated encouraging antitumor activity in therapy-refractory mUC treated with paclitaxel plus high-dose anti-CTLA-4 and suggests immune induction may still be possible after failure to anti-PD-(L)1 therapy. PROJECT GOAL: We aimed to explore both potential biomarkers for response to combination ICB, as well as treatment dynamics to gain a better understanding of the effects of ICB on the urothelial cancer tumor microenvironment (TME).

  Study EGAS50000001574