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• Neural Systems, Inhibitory Control, and Methamphetamine Dependence

  The Neural Systems, Inhibitory Control, and Methamphetamine Dependence study started in 2011 and is currently finishing data collection for its last participants. The study included methamphetamine abusing individuals and healthy control participants aged 18-55 years. Participants who qualified over the telephone were scheduled to visit the London Laboratory at the UCLA Semel Institute for Neuroscience and Human Behavior for the In-Person Screening Phase. The screening procedures, usually scheduled over two visits, determined if participants were eligible to complete the subsequent study visits. Both groups completed identical screening procedures, with the exception of more in-depth drug use questions for the methamphetamine users. After providing written consent, participants completed questionnaires about their mood, medical, psychiatric and drug use history, personality and life experiences. They also provided a urine sample to determine what drugs they recently used and a breath sample to determine the carbon monoxide levels in their system. The drug screen tested for recent methamphetamine, cocaine, opiates/opioids, benzodiazepines, THC and other amphetamines. Methamphetamine participants needed to test positive for methamphetamine at admission. If methamphetamine participants tested positive for any drugs other than methamphetamine or marijuana, and if healthy control participants tested positive for any drugs other than marijuana, they were excluded from the study. Additionally, the urine samples of female participants were tested for pregnancy; pregnant females were also excluded. If no exclusionary criteria were met during the first screening visit, participants completed a second screening visit to ensure they were mentally and physically healthy enough to participate. The second screening visit included a psychiatric diagnostic interview (DSM-IV (SCID-I) for first 500 participants and the MINI International Neuropsychiatric Interview M.I.N.I for the last 50 participants). Additionally, laboratory tests and procedures were completed by the UCLA General Clinical Research Center and interpreted by a study physician. Laboratory tests included vital signs (heart rate--BPM, blood pressure, and respirations), an electrocardiogram (ECG) to record the electrical activity of the heart, and an 18-cc blood sample to perform laboratory tests which included a complete chemistry and metabolic panel, hepatic panel, Hepatitis-C tests, and HIV test. The laboratory tests from this blood sample ensured that participants' liver and kidneys were functioning normally, and that their standard blood counts (red cell, white cell, and salts) were also normal. If a Hepatitis-C (HCV) or HIV test was positive, participants were not allowed to continue in the study and their results were reported to the California State Health Department. Participants deemed eligible to continue in the methamphetamine group participated on an outpatient basis or were admitted to the UCLA Medical Center to participate on an inpatient basis for up to 10 days. Typically, detectable levels of methamphetamine in urinalysis remain for 2-3 days, therefore inpatient days 0-3 served as a "washout period" and the methamphetamine abusing inpatient participants provided daily urine samples to test for recent drug use and pregnancy (female participants only). Outpatient participants were also required to remain abstinent from all drugs except nicotine and marijuana for at least 4 days prior to study sessions. Self-reported abstinence for outpatients was verified by urine toxicology and saliva screening at every visit to UCLA before completion of study procedures. Neurocognitive assessments, about three hours each, typically took place on two separate days. The purpose of the neurocognitive sessions were to assess participants' intellectual and neurocognitive functioning. On either the same day as the neurocognitive testing or on separate days, both methamphetamine abusers and healthy controls were administered a structural MRI to collect information on brain structure.

  Study phs001197

• PAK4 inhibition improves PD-1 blockade immunotherapy

  Introduction with rationale and aims for study Immune checkpoint blockade therapies have significantly altered the current landscape of cancer treatment. However, this immunotherapy still fails more often than it succeeds. There are now evidences that the lack of tumour infiltration by immune cells is the main mechanism of primary resistance to PD‐1 blockade therapies for cancer. It has been postulated that cancer cell‐intrinsic mechanisms may actively exclude T cells from tumours, suggesting that the finding of actionable molecules that could be inhibited to increase T cell infiltration may synergize with checkpoint inhibitor immunotherapy. With the idea of finding potential drivers of immune exclusion, we performed RNA sequencing analysis of biopsies from melanoma patients and compared the transcriptomic differences of samples that where infiltrated with those that did not have immune infiltration. Methods RNAseq analysis of gene expressions on biopsies from melanoma patients treated with checkpoint blockade were analysed. We focused on the variable of "infiltration: yes or no,", e.g. tumors that were well infiltrated by immune cells with those that kept immune cells out. Sequencing revealed a list of genes whose expression differed between the infiltrated and noninfiltrated tumors. The kinase PAK4 stood out as a good candidate for inhibition treatment in the future as it was consistently enriched in the samples without immune infiltration. To test whether immunotherapy would work better if we deleted PAK4, we first knocked out PAK4, using CRISPR‐Cas9, in the ‐resistant melanoma cell line, B16. Then they injected the melanoma cells into mice and observed that PAK4 KO tumours now responded to PD‐1 blockade. In order to elucidate whether pharmacological inhibition of PAK4 could recapitulate the results observed in the B16 PAK4 KO tumours, we obtained the PAK4 inhibitor, KPT-9274, from Karyopharm Therapeutics. Indeed, inhibiting PAK4 in combination with anti‐PD‐1 immunotherapy significantly slowed the growth of the B16 melanomas more than either drug alone. Results and Conclusions Transcriptomic analysis of melanoma tumors that were well infiltrated by immune cells with those that kept immune cells out revealed a list of genes whose expression differed between the infiltrated and non-infiltrated tumours. The result suggests that p21 activated kinase 4 (PAK4) is enriched in non-responding tumour biopsies with low T cell and dendritic cell infiltration. In addition, PAK4 decreased WNT activity, a signalling pathway that has previously been involved in immune exclusion. In mouse models, genetic deletion of PAK4 increased T cell infiltration and reversed resistance to PD‐1 blockade in a CD8 T cell-dependent manner. Furthermore, combination of with the PAK4 inhibitor, KPT-9274, improved anti‐tumour responses compared to anti‐PD‐1 alone. Therefore, high PAK4 expression is correlated with low T cell and dendritic cell infiltration and lack of response to PD‐1 blockade, which could be reversed with PAK4 inhibition. The data establish a rationale for targeting this kinase with inhibitors in combination with immune checkpoint inhibitors for patients. Future work and data that we can anticipate for this study Oncogenic signalling pathways and specially the WNT signalling pathway, have been associated with lack of immune infiltration and resistance to PD‐1 blockade therapies. Here, we show that PAK4 overcome resistance to PD‐1 blockade while significantly decreases WNT signalling activity. Therefore, it constitutes the first potential druggable target that is able to reverse oncogenic driven immune cell exclusion. However, the fully mechanism whereby PAK4 sensitizes tumours to immunotherapy remains to be fully elucidated. It is necessary to address whether PAK4 inhibition overcomes resistance through WNT signalling inhibition or if other signalling pathways are involved in the observed phenotype.

  Study phs001919

• Single Cell Analysis Program - Transcriptome (SCAP-T)

  This initiative is part of the Single Cell Analysis Program (SCAP) and is funded through the NIH Common Fund (See http://nihroadmap.nih.gov/), which supports cross-cutting programs that are expected to have exceptionally high impact. Common Fund initiatives address key roadblocks in biomedical research that impede basic scientific discovery and its translation into improved human health. In addition, these programs capitalize on emerging opportunities to catalyze progress across multiple biomedical fields. Single cell analysis has recently emerged as an important field of research because technologies have improved in sensitivity and throughput sufficiently to begin measuring and understanding heterogeneity in complex biological systems and correlating it with changes in biological function and disease processes. By profiling individual cells it is possible to resolve rare cells, transient cell states, and the influence of organization and environment on such cells and states, which cannot be described by ensemble measurements. The long-term goal of the SCAP is to accelerate this move towards personalizing health to the cellular level by understanding the link between cell heterogeneity, tissue function and emergence of disease through the discovery, development and translation of innovative approaches which will dramatically change the way cells are characterized. The SCAP will focus on research, which will systematically measure, analyze and model cell-to-cell variation, and identify crucial differences and rare biological states, which may have important functional consequences. Under SCAP, there are three studies to evaluate the cellular heterogeneity using transcriptional profiling of single cells (U01): University of Pennsylvania: Role of single cell mRNA variation in systems associated electrically excitable cells University of Southern California: Evaluation of cellular heterogeneity using patchclamp and RNA-seq of single cells University of California at San Diego: Single cell sequencing and in situ mapping of RNA transcripts in human brains The SCAP has been designed as a five-year program with several components: (1) the collection, analysis and sharing of comprehensive expression datasets to understand the role of heterogeneity in tissues and systemically and identify critical parameters and states; (2) the discovery of new, innovative tools for spatiotemporal imaging, manipulation, analysis and modeling of a biologically relevant population of cells with minimal perturbation; (3) milestone-driven validation and translation of technologies for characterizing single cells in situ meeting the needs of end-users; and (4) development and coordination of a multidisciplinary research community through workshops and other collective endeavors. Further details about the NIH SCAP-T program can be found here http://commonfund.nih.gov/singlecell/. The SCAP-T data sets include the detailed phenotype information, experimental protocols, QC information, RNA-sequencing data and NGS results from human heart and human brain cells. The first data release includes 697 single cells from human brain and heart. The second data release includes an additional 978 single cells from human brain and heart. The third data release includes an additional 1631 single cells from human brain and heart. The fourth data release is a correction to this study, but adds no new cells. The fifth data release includes an additional 2984 single cells from human brain and heart. The sixth data release includes an additional 944 single cells from human brain and heart. The seventh data release includes an additional 1977 single cells from human brain and heart. The SCAP-T data portal provides a customized interface for users to quickly identify and retrieve files by phenotypes, and data properties such as sequencing facility or coverage for all of these 9231 single cells. For more information about the SCAP-T study and the data portal, please visit http://www.scap-t.org.

  Study phs000833

• Genomic Diagnosis and Individualized Therapy of Highly Penetrant Genetic Diabetes

  The most common and well-known causes of diabetes are type 1 and type 2 diabetes; however, there are many other etiologies of diabetes. At least 1-2% of diabetes cases result from high penetrance single gene defects, most commonly in a gene encoding either a transcription factor involved in beta cell development and function or the enzyme glucokinase (GCK). Others have mutations in transcription factors necessary for beta cell development and function. This subset of monogenic diabetes cases is autosomal dominant and is known as "Maturity-Onset Diabetes of the Young" (MODY). Patients with type 1 diabetes are insulin dependent, meaning they lack insulin production and therefore require multiple daily injections of insulin, as well as multiple times a day blood glucose monitoring. This can be quite burdensome. Type 2 diabetes is predominantly an insulin resistance problem and can often be managed with pills initially, but there are many who also require insulin either at diagnosis or later on in their disease course. Usually, monogenic diabetes is misdiagnosed as type 1 or type 2 diabetes and thus treated suboptimally. Those with monogenic diabetes, due to a defect in a gene encoding a transcription factor, respond extremely well to a class of oral diabetes medications called sulfonylureas. Those with GCK-MODY often have a mild, stable, fasting, nonprogressive hyperglycemia for which pharmacological treatment is often not necessary. It is important to accurately diagnose our patients with the correct etiology to their diabetes for a multitude of reasons. Accurately diagnosing a patient with MODY, for example, can predict their clinical course and we can tailor treatment accordingly. If diagnosed with a transcription factor MODY, we can try switching the patient from insulin to an oral sulfonylurea, and if diagnosed with a GCK-MODY, we can consider discontinuing pharmacological treatment altogether. With specific tailoring of treatment, we would hope to improve quality of life by discontinuing perhaps multiple daily injections of insulin and glucose checking as these may not be necessary. In addition, we would hope to improve glycemic control with an eventual decreased cost to society by decreasing the complication rate of diabetes, resulting in less specialty referrals, lab tests, supplies and procedures. Further, given MODY is an autosomal dominant condition with a 50% chance of inheritance to first-degree family members, we could offer testing to asymptomatic family members which could lead to prevention and/or early diagnosis and treatment. Overall, testing for monogenic diabetes is underutilized clinically. Testing is being done in the U.K., but in the U.S. we are lagging behind. This is most predominantly due to lack of knowledge and concern over cost. In addition, it is difficult to differentiate the relatively small number of monogenic diabetes cases from the larger number with type 1 and type 2 diabetes as each of these etiologies have overlapping characteristics. In fact, many patients with monogenic diabetes are being misdiagnosed with type 1 and type 2 diabetes. There are recommendations set forth by different societies on who to consider screening for monogenic diabetes. However, these recommendations are difficult to employ clinically as they are general recommendations, there is no specific algorithm, and they are based on varying levels of evidence. The purpose of this study is to implement a personalized diabetes medicine program to enhance the identification of individuals and families affected by highly penetrant diabetes gene mutations through a combination of systematic screening and genetic testing at the University of Maryland Center for Diabetes and Endocrinology, the Baltimore VA Medical Center and additional partner centers at Geisinger Health System and Bay West Endocrinology Associates, and other UM outpatient clinics. Our hope is to develop an approach that can be eventually implemented across the United States so that we can more often uncover the correct etiology to diabetes, tailor treatment accordingly, and test asymptomatic family members.

  Study phs001771

• Natural Killer Cell Therapies for Hematologic Malignancies

  The "Natural Killer Cell Therapies for Hematologic Malignancies" study is an umbrella repository for data pertaining to multiple related clinical trials that aim to assess NK cell therapies as part of treatment strategies for a range of hematologic malignancies. Here, data from two trials, NCT03068819 and NCT02782546, are presented.Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML after Allogeneic Hematopoietic Cell Transplant in Children and Adults (NCT03068819)Pediatric and young adult (YA) patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic cell transplantation (HCT) have extremely poor prognosis. Standard salvage chemotherapy and donor lymphocyte infusions (DLI) have little curative potential. Previous studies showed that natural killer (NK) cells can be stimulated ex vivo with interleukin-12 (IL-12), IL-15, and IL-18 to generate memory-like (ML) NK cells with enhanced anti-leukemia responses. We treated nine pediatric/YA patients with post-HCT relapsed AML with donor ML NK cells on a phase I trial. Patients received fludarabine, cytarabine, and filgrastim followed two weeks later by infusion of DLI and ML NK cells from the original HCT donor. ML NK cells were successfully generated from haploidentical, matched-related and matched-unrelated donors. Following infusion, donor-derived ML NK cells expanded and maintained ML multidimensional mass cytometry phenotype for over 3 months. Furthermore, ML NK cells exhibited persistent functional responses as evidenced by leukemia-triggered IFN-gamma production. Following DLI and ML NK cell adoptive transfer, 4 of 8 evaluable patients achieved complete remission at day 28. Two patients maintained a durable remission for over 3 months with one patient in remission for greater than two years. No significant toxicity was experienced. This study demonstrates that in a compatible immune environment post-HCT, donor ML NK cells robustly expand and persist with potent anti-leukemic activity in the absence of exogenous cytokines. ML NK cells in combination with DLI present a novel immunotherapy platform for AML that has relapsed after allogeneic HCT. This trial was registered at https://www.clinicaltrials.gov/study/NCT03068819.A Phase II Study of Cytokine Induced Memory-like NK Cell Adoptive Therapy after Haploidentical Donor Hematopoietic Cell Transplantation (NCT02782546)Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced anti-tumor function following stimulation with IL-12, IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for HLA-haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on Day 7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in the clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well-tolerated and 87% of patients achieved a composite complete response at Day 28, which corresponded with clearing high-risk mutations, including TP53 variants. NK cells were the major blood lymphocytes for two months post-HCT with prolific expansion (1104-fold) over 1-2 weeks. Multidimensional mass cytometry and CITE-seq identified donor ML NK cells as distinct from conventional NK cells and persisting for over two months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patient and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML, with ML NK cells demonstrating enhanced in vivo persistence and functionality, overcoming barriers in the field.

  Study phs002681

• Detroit Research on Cancer Survivors (ROCS) and Disparities and Cancer Epidemiology - Colorectal Cancer (DANCE)

  The goals for this study were as follows:1. Enroll a total of 5,060 African Americans newly diagnosed with cancer into the Detroit Research on Cancer Survivors (Detroit ROCS) Cohort. These population-based cases will be ascertained through the Detroit Metropolitan Detroit Cancer Surveillance System (MDCSS), a founding member of the NCI SEER Program. Participation at baseline will include a written, web-based, or telephone interview, saliva and/or blood collection, and tumor block retrieval, with detailed cancer-related information coming from the MDCSS registry and medical records.2. Enroll a subgroup of colorectal cancer patients identified through the Louisiana Tumor Registry (LTR). An additional 500 colorectal cancer patients, approximately half non-Hispanic white and half African American, will be identified through the LTR and enrolled into the ROCS protocol. The survey is the same survey administered to the ROCS cohort. The Louisiana (“DANCE-CRC”) cohort will not be followed beyond baseline, and blood will not be collected (tumor tissue, however, will be collected, deidentified, and sent for processing through Dr. Rozek's laboratory at Georgetown University).The proposed cohorts will provide for a broad research agenda evaluating cancer outcomes in African Americans across a variety of factors from individual, provider, health care system and community perspectives. These factors include tumor characteristics driving individualized treatment planning, quality of life after a diagnosis and recurrence. Utilizing the MDCSS registry, we will enroll a large population-based sample of African-American cases with lung, breast, colorectal, and prostate cancers and their caregivers resulting in a cohort that will provide substantial benefit to the cancer research community. KCI has a strong history of research in the African-American community and the faculty represents a breadth of experience that includes clinical oncology, genetic epidemiology, environmental exposures, quality of life, treatment decision making, racism/discrimination, and health behaviors. Drs. Schwartz and Beebe-Dimmer have been and will continue to be generous collaborators with other institutions to ensure that this resource will be extensively utilized. The proposed overall cohort will be the only one of its kind, to our knowledge, filling a substantial gap in our understanding of the determinants driving cancer outcomes in African Americans. In addition to registry data detailing cancer specifics, yearly surveys have collected information about individualized treatment experiences, heath histories, family histories, quality of life after a diagnosis, recurrence and caregiving. Population: Adult cancer survivors (see inclusion criteria in next section) Molecular Technologies: Genotyping: Infinium Expanded Multi-Ethnic Genotyping Array (MEGAEX) DNA Sequencing: Illumina NovaSeq X Plus using XLEAP-SBS (sequencing by synthesis) Whole genome sequencingPrincipal Findings: The preliminary data collected reinforces differences by race in factors affecting cancer outcomes. Variants in DNA damage repair genes and HOXB13 may be important cancer risk factors for Black men diagnosed with prostate cancer, and are more frequently observed in men with a family history of cancer. ROCS participants reported high rates of a family history of cancer. The high rate of eligibility for Cancer genetic counseling among ROCS participants supports the need for interventions to increase referrals and uptake of genetic counseling among African Americans 60% of ROCS participants reported participating in regular physical activity (PA), with 24% reporting ≥150 min/wk. There were no differences by sex, but prostate cancer survivors were the most likely to report participating in regular PA, whereas lung cancer survivors were the least likely. Survivors who reported participating in regular PA reported higher health-related quality of life and lower depression. More African American than White survivors reported financial hardship and limiting care. More White than African American survivors reported utilizing assets, while more African American survivors reported cancer-related debt. Data available in dbGaP: Individual phenotype data Individual genotype data Individual sequencing dataSample types: Germline DNA

  Study phs003116

• Trial of Late Surfactant for Prevention of Bronchopulmonary Dysplasia: A Study in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide (TOLSURF-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To assess whether late surfactant treatment in extremely low gestational age newborn (ELGAN, ≤28 week gestation) infants requiring ventilation at 7-14 days safely improves survival without bronchopulmonary dysplasia.Background: Bronchopulmonary dysplasia (BPD) is the most common form of chronic lung disease in children with an estimated 15,000 new cases annually in the United States. BPD affects infants born prematurely, is a major contributor to the cost of prematurity each year, and is associated with long-term pulmonary disability, neurodevelopmental abnormalities and death.Increases in the survival of ELGAN infants have resulted in another form of BPD, which is characterized by impaired alveolar and microvascular development with excess tone and reactivity of airway smooth muscle. Despite treatments to enhance lung maturation, premature infants often need prolonged intubation and mechanical ventilation and/or oxygen support. When mechanical ventilation is required longer than 7 days, BPD results in 70% of surviving ELGAN infants. Most of these infants experience clinical episodes of increased requirement for ventilatory support that are associated with dysfunctional surfactant, which is primarily due to low surfactant protein B (SP-B). In pilot studies of late surfactant treatment in premature infants, there was short-term improvement in SP-B content. These prior studies provided the rationale for a larger clinical trial for later doses of surfactant treatment to prevent episodes of respiratory decompensation and BPD. Participants: 511 infants were eligible for randomization of the 2693 infants screened. Of the 511 infants eligible for randomization, there were 252 infants allocated to the treatment arm and 259 infants allocated to the placebo arm.Design: The study was designed to assess the effect of late doses of surfactant on survival without BPD at 36 weeks post menstrual age (PMA) in ELGAN infants who required intubation and mechanical ventilation between 7 and 14 days of age and were receiving Inhaled nitric oxide (iNO). Infants were stratified within clinical centers and gestational age groups and randomized to treatment with calfactant, a natural surfactant extracted from bovine lung lavage fluid, or a sham procedure.All infants received iNO according to the protocol used in the Nitric Oxide Chronic Lung Disease (NOCLD) trial. A masked syringe containing either a standard dose of calfactant for the treatment group, or air for the placebo group, was administered to the infant behind a screen by staff not involved in providing the infant's clinical care. Monitor and ventilator alarms were turned off during dosing to avoid unblinding of clinical staff. To accommodate research staff availability and infant instability, the dosing interval was not strictly set but could be repeated every 24 – 72 hours up to 5 doses if the infant still required intubation. Dosing could be discontinued by physician request or parental withdrawal from the study. Due to parental preference, the first infant in a multiple birth was randomized according to the randomization schedule and subsequent infants were assigned to the same treatment group. Follow-up to assess pulmonary and neurologic development continued until 2 years of age, with treatment group blinding maintained. The primary outcome was survival without BPD at 36 weeks PMA. Secondary outcomes included BPD at 40 weeks PMA, pulmonary outcome at 12–24 months of age, and neurodevelopmental outcome at 2 years of age. Conclusions: There were no significant differences observed between the treatment group and the control group for survival without BPD at 36 weeks or 40 weeks.

  Study phs003899

• Pomalidomide for the Treatment of Bleeding in HHT (PATH-HHT)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To determine efficacy (reduction in severity of epistaxis), tolerability, and improvement in quality of life of pomalidomide compared to placebo after 24 weeks of treatment.Background: This study addresses the efficacy of pomalidomide in the treatment of epistaxis in patients with Hereditary Hemorrhagic Telangiectasia (HHT) who have anemia and/or require blood transfusion or iron infusion for treatment of bleeding-induced anemia and iron deficiency. HHT (also known as Osler-Weber-Rendu disease) is an inherited bleeding disorder. Over 95% of patients develop recurrent epistaxis, which may be severe and result in chronic anemia, need for iron infusions and blood transfusions, substantial psychiatric comorbidity (including depression and post-traumatic stress disorder) and reduction in health-related quality of life (HRQoL). HHT is clinically diagnosed using the Curacao criteria, which consists of 1) spontaneous and recurrent epistaxis, 2) telangiectasias at characteristic sites, 3) visceral arteriovenous malformations (AVMs) or telangiectasias, and 4) a first degree relative with HHT (inheritance is usually autosomal dominant). Patients with three criteria are considered to have definite HHT, and those with 2 criteria probable HHT. HHT affects approximately 1 in 3,800 individuals. Significant manifestations of HHT often do not appear until the third or fourth decades, sometimes later.Participants: 144 patients from 11 clinical centers were enrolled.Design: This is a multi-center, double blind, randomized placebo-controlled trial that investigated the efficacy and safety of pomalidomide in patients with HHT and chronic epistaxis leading to iron-deficiency anemia or requiring intravenous iron infusions or blood transfusion.Screening evaluation included the Epistaxis Severity Score (ESS) with three-month recall, which reflected the patient's history of epistaxis and bleeding over the prior three months, as well as detailed review of iron infusion and red cell transfusion over the preceding six months. Eligible patients were provided a diary to record the duration of each epistaxis event that occurred during the 4 weeks prior to the baseline visit, and then returned for the baseline randomization visit, at which time patients underwent genetic testing, if this had not been previously performed, and completed an ESS with 4-week recall and quality of life assessments. Patients were randomized 2:1, stratified by study site, to either pomalidomide 4 mg/day or matching placebo during each of six 28 day cycles (24 weeks). Patients were seen every four weeks during treatment, and at a 4-week post-treatment follow-up visit to measure the ESS (with 4-week recall), laboratory assessments including iron stores and need for iron infusion, CBC, and metabolic profile. Patients were assessed for adverse events (AE) throughout the study. Treatment dosage could be reduced, or temporarily or permanently discontinued following AE-specific guidelines related to fatigue, cytopenias or other toxicities.Quality of life assessments were completed at baseline, and the 12- and 24-week visits, and the 4-week post-treatment follow-up visit using validated NIH instruments of 1) Neuro-QOL satisfaction with social roles and activities, 2) PROMIS emotional distress – depression, and 3) PROMIS fatigue, and the HHT-specific quality of life instrument developed specifically for this study. The effect of pomalidomide on duration of epistaxis was assessed via diary between weeks 8-12, 20-24 and the 4-week post-treatment period.Conclusions: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified (Al-Samkari et al., 2024; PMID: 39292928)

  Study phs003948

• Highlights from 2025: Our top 10 requested studies

  In 2025, as in previous years, EGA has facilitated the reuse of numerous datasets spanning a broad range of research and healthcare topics. To reflect on this activity, we would like to highlight the top 10 studies behind the most requested datasets of last year. Notably, the vast majority of these highly requested datasets are cancer-focused, particularly involving the study of immune checkpoint inhibitor therapies. Immune checkpoint inhibitors (ICIs) have become one of the most transformative advances in modern cancer therapy. These monoclonal antibodies enhance antitumor immune responses by targeting inhibitory immune checkpoint molecules. While ICIs have led to remarkably favorable and durable responses in some patients, treatment outcomes vary widely. This variability has fueled intense research efforts aimed at understanding resistance mechanisms, exploring combination therapies, and discovering predictive biomarkers to better stratify patients and guide treatment decisions. Study Title Disease 1 EGAS00001005503 Integrated genomic analyses reveal molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma Liver Cancer 2 EGAS00001005013 Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell lung cancer Lung Cancer 3 EGAS00001004809 BIOKEY: A single-cell catalogue of the dynamic changes underlying Checkpoint Immunotherapy response in Early Breast Cancer Breast Cancer 4 EGAS50000000138 BIOKEY: Immune heterogeneity in small cell lung cancer and vulnerability to immune checkpoint blockade Lung Cancer 5 EGAS50000000497 Bladder cancer subtyping study across 4 atezo clinical trials Bladder Cancer 6 EGAS50000000689 MOSAIC - Multi-Omics Spatial Atlas In Cancer Cancer Atlas 7 EGAS00000000083 METABRIC (Breast cancer - genome and transcriptome) Breast Cancer 8 EGAS00001005702 Human genomic and phenotypic synthetic data for the study of rare diseases Synthetic data 9 EGAS00001002556 TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells Bladder Cancer 10 EGAS00001004353 Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade Renal Cancer The most requested dataset of the year was EGAD00001008128. It belongs to a study that analyzed 358 liver cancer patients enrolled in clinical trials and treated with the combination of atezolizumab (anti–PD-L1) and bevacizumab (anti-VEGF), atezolizumab alone, or sorafenib. The study highlights how bevacizumab enhances anti-PD-L1 effect and identifies candidate biomarkers to predict treatment response. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer-related death worldwide [1]. Because symptoms often appear late, many patients are diagnosed at advanced stages, when curative options are no longer viable. For many years, sorafenib—a multikinase inhibitor approved in 2007—was the only systemic treatment available. Although numerous clinical trials followed, it was not until a decade later that additional therapies showed meaningful clinical benefit. Among these advances, immunotherapy emerged as a promising first-line option [2]. In particular, the combination of atezolizumab and bevacizumab demonstrated improved survival in patients with advanced HCC, reshaping the treatment landscape. However, treatment efficacy remains limited by the complex and diverse hepatic microenvironments that influence immune responses, as well as by high intratumoral heterogeneity. Identifying robust predictors of treatment response is critical to enable effective patient stratification and maximize the benefits of these therapies [2]. The continued demand for these datasets highlights the interest and critical role of data reuse in deepening our understanding of cancer, accelerating the development of more effective therapies, and improving patient outcomes. By providing secure access to high-quality genomic and clinical data, EGA acts as a catalyst for biomedical progress. References Sung, Hyuna, et al. "Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries."CA: a cancer journal for clinicians 71.3 (2021): 209-249. Ladd, Alexandra D, et al.“Mechanisms of drug resistance in HCC.” Hepatology 79(4) (2024): 926-940

  Blog top-10-studies-2025

• Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells

  Human Induced Pluripotent Stem Cells (hiPSC) are an established patient-specific model system where opportunities are emerging for cell-based therapies. We compared and contrasted hiPSCs derived from different tissues, skin and blood, in the same individual. We show extensive single-nucleotide mutagenesis in all hiPSC lines, although fibroblast-derived hiPSCs (F-hiPSCs) are particularly heavily mutagenized by ultraviolet (UV)-related damage. We utilized genome sequencing data on 454 F-hiPSCs and 44 blood-derived hiPSCs (B-hiPSCs) to gain further insights. Across 324 whole genome sequenced (WGS) F-hiPSCs derived by the Human Induced Pluripotent Stem Cell Initiative (HipSci), UV-related damage is present in ~72% of cell lines, sometimes causing substantial mutagenesis (range 0.25-15 per Mb). Furthermore, we find remarkable genomic heterogeneity between independent F-hiPSC clones derived from the same reprogramming process in the same donor, due to oligoclonal populations within fibroblasts. Combining WGS and exome-sequencing data of 452 HipSci F-hiPSCs, we identify 272 predicted pathogenic mutations in cancer-related genes, of which 21 genes were hit recurrently three or more times, involving 77 (17%) lines. Notably, 151 of 272 mutations were present in starting fibroblast populations suggesting that more than half of putative driver events in F-hiPSCs were acquired in vivo. In contrast, B-hiPSCs reprogrammed from erythroblasts show lower levels of genome-wide mutations (range 0.28-1.4 per Mb), no UV damage, but a strikingly high prevalence of acquired BCOR mutations in ~57% of lines, indicative of strong selection pressure. All hiPSCs had otherwise stable, diploid genomes on karyotypic pre-screening, highlighting how copy-number-based approaches do not have the required resolution to detect widespread nucleotide mutagenesis. This work strongly suggests that models for cell-based therapies require detailed nucleotide-resolution characterization prior to clinical application.

  Dataset EGAD00001007029