tbuckley/cabot-search huggingface dataset:
Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial
Authors: Jennifer B. Dwyer, Angeli Landeros-Weisenberger, Jessica A. Johnson, Amalia Londono Tobon, José M. Flores, Madeeha Nasir, Kevin Couloures, Gerard Sanacora, Michael H. Bloch
Journal: American Journal of Psychiatry (2021)

Adolescent depression is prevalent and is associated with significant morbidity and mortality. Although intravenous ketamine has shown efficacy in adult treatment-resistant depression, its efficacy in pediatric populations is unknown. The authors conducted an active-placebo-controlled study of ketamine's safety and efficacy in adolescents.In this proof-of-concept randomized, double-blind, single-dose crossover clinical trial, 17 adolescents (ages 13-17) with a diagnosis of major depressive disorder received a single intravenous infusion of either ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), and the alternate compound 2 weeks later. All participants had previously tried at least one antidepressant medication and met the severity criterion of a score >40 on the Children's Depression Rating Scale-Revised. The primary outcome measure was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment.A single ketamine infusion significantly reduced depressive symptoms 24 hours after infusion compared with midazolam (MADRS score: midazolam, mean=24.13, SD=12.08, 95% CI=18.21, 30.04; ketamine, mean=15.44, SD=10.07, 95% CI=10.51, 20.37; mean difference=-8.69, SD=15.08, 95% CI=-16.72, -0.65, df=15; effect size=0.78). In secondary analyses, the treatment gains associated with ketamine appeared to remain 14 days after treatment, the latest time point assessed, as measured by the MADRS (but not as measured by the Children's Depression Rating Scale-Revised). A significantly greater proportion of participants experienced a response to ketamine during the first 3 days following infusion as compared with midazolam (76% and 35%, respectively). Ketamine was associated with transient, self-limited dissociative symptoms that affected participant blinding, but there were no serious adverse events.In this first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression, the findings suggest that it is well tolerated acutely and has significant short-term (2-week) efficacy in reducing depressive symptoms compared with an active placebo.
Abstract 11543: Comparison of 3 Atherosclerotic Cardiovascular Disease (ASCVD) Risk Score Equations for Predicting Revascularization and Major Adverse Cardiovascular Events (MACE) in Symptomatic Patients Undergoing PET-Stress Testing
Authors: Jeffrey L Anderson, Viet T Le, David B Min, Santanu Biswas, C M Minder, Raymond O McCubrey, Stacey Knight, Benjamin D Horne, Steve Mason, Donald L Lappé, Joseph B Muhlestein, Kirk U Knowlton
Journal: Circulation (2018)

Background: ASCVD continues to be the most important cause of morbidity and mortality nationally and internationally. Improving ASCVD risk prediction is a high clinical research priority. Methods: ...
A Phase 1–2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC
Authors: Jyoti Malhotra, Petros Nikolinakos, Ticiana Leal, Jonathan Lehman, Daniel Morgensztern, Jyoti D. Patel, John M. Wrangle, Giuseppe Curigliano, Laurent Greillier, Melissa L. Johnson, Neal Ready, Gilles Robinet, Satwant Lally, David Maag, Ricardo Valenzuela, Vincent Blot, Benjamin Besse
Journal: Journal of Thoracic Oncology (2021)

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor.This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission.This includes requests for clinical trial data for unlicensed products and indications.These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA).
Hematopoietic stem cell gene therapy targeting TGFβ enhances the efficacy of irradiation therapy in a preclinical glioblastoma model
Authors: Tereza Andreou, Jennifer Williams, Rebecca J Brownlie, Robert J Salmond, Erica Watson, Gary Shaw, Alan Melcher, Heiko Wurdak, Susan C Short, Mihaela Lorger
Journal: Journal for ImmunoTherapy of Cancer (2021)

Patients with glioblastoma (GBM) have a poor prognosis, and inefficient delivery of drugs to tumors represents a major therapeutic hurdle. Hematopoietic stem cell (HSC)-derived myeloid cells efficiently home to GBM and constitute up to 50% of intratumoral cells, making them highly appropriate therapeutic delivery vehicles. Because myeloid cells are ubiquitously present in the body, we recently established a lentiviral vector containing matrix metalloproteinase 14 (MMP14) promoter, which is active specifically in tumor-infiltrating myeloid cells as opposed to myeloid cells in other tissues, and resulted in a specific delivery of transgenes to brain metastases in HSC gene therapy. Here, we used this novel approach to target transforming growth factor beta (TGFβ) as a key tumor-promoting factor in GBM. Transplantation of HSCs transduced with lentiviral vector expressing green fluorescent protein (GFP) into lethally irradiated recipient mice was followed by intracranial implantation of GBM cells. Tumor-infiltrating HSC progeny was characterized by flow cytometry. In therapy studies, mice were transplanted with HSCs transduced with lentiviral vector expressing soluble TGFβ receptor II-Fc fusion protein under MMP14 promoter. This TGFβ-blocking therapy was compared with the targeted tumor irradiation, the combination of the two therapies, and control. Tumor growth and survival were quantified (statistical significance determined by t-test and log-rank test). T cell memory response was probed through a repeated tumor challenge. Myeloid cells were the most abundant HSC-derived population infiltrating GBM. TGFβ-blocking HSC gene therapy in combination with irradiation significantly reduced tumor burden as compared with monotherapies and the control, and significantly prolonged survival as compared with the control and TGFβ-blocking monotherapy. Long-term protection from GBM was achieved only with the combination treatment (25% of the mice) and was accompanied by a significant increase in CD8+ T cells at the tumor implantation site following tumor rechallenge. We demonstrated a preclinical proof-of-principle for tumor myeloid cell-specific HSC gene therapy in GBM. In the clinic, HSC gene therapy is being successfully used in non-cancerous brain disorders and the feasibility of HSC gene therapy in patients with glioma has been demonstrated in the context of bone marrow protection. This indicates an opportunity for clinical translation of our therapeutic approach.
68Ga-FAPI PET/CT in Thyroid Cancer With Thyroglobulin Elevation and Negative Iodine Scintigraphy
Authors: Hao Fu, Jie Fu, Jingxiong Huang, Xinyi Su, Haojun Chen
Journal: Clinical Nuclear Medicine (2021)

Differentiated thyroid cancer with thyroglobulin elevation and negative iodine scintigraphy (TENIS) syndrome is a diagnostic and therapy dilemma. In this study, we present a case of TENIS with detectable metastases in the larynx and lung on the CT scan. 68Ga-fibroblast activation protein inhibitor (FAPI) PET/CT was performed for further detection of tumor recurrence and metastases, which showed intense 68Ga-FAPI activity in the metastatic lesions. To the best of our knowledge, this is the first case of TENIS presenting with FAPI-avid metastatic lesions, demonstrating its usefulness for localizing recurrent or metastatic lesions in patients with TENIS.
Crizotinib in Patients With MET-Amplified NSCLC
Authors: D. Ross Camidge, Gregory A. Otterson, Jeffrey W. Clark, Sai-Hong Ignatius Ou, Jared Weiss, Steven Ades, Geoffrey I. Shapiro, Mark A. Socinski, Danielle A. Murphy, Umberto Conte, Yiyun Tang, Sherry C. Wang, Keith D. Wilner, Liza C. Villaruz
Journal: Journal of Thoracic Oncology (2021)

MET amplification is a rare, potentially actionable, primary oncogenic driver in patients with NSCLC.The influence of MET amplification on the clinical activity of the ALK, ROS1, and MET inhibitor, crizotinib (250 mg twice daily), was examined in patients with NSCLC (NCT00585195) who were enrolled into high (≥4 MET-to-CEP7 ratio), medium (>2.2 to <4 MET-to-CEP7 ratio), or low (≥1.8 to ≤2.2 MET-to-CEP7 ratio) amplification categories. Retrospective next-generation sequencing profiling was performed on archival tumor tissue. End points included objective response rate (ORR), duration of response, and progression-free survival.A total of 38 patients with a MET-to-CEP7 ratio greater than or equal to 1.8 by local fluorescence in situ hybridization testing received crizotinib. All patients were response-assessable, among whom 21, 14, and 3 had high, medium, and low MET amplification, respectively. ORRs of 8 of 21 (38.1%), 2 of 14 (14.3%), and 1 of 3 (33.3%), median duration of response of 5.2, 3.8, and 12.2 months, and median progression-free survival values of 6.7, 1.9, and 1.8 months were observed for those with high, medium, and low MET amplification, respectively. MET amplification gene copy number greater than or equal to 6 was detected by next-generation sequencing in 15 of 19 (78.9%) analyzable patients. Of these 15 patients, objective responses were observed in six (40%), two of whom had concurrent MET exon 14 alterations. No responses were observed among five patients with concurrent KRAS, BRAF, or EGFR mutations.Patients with high-level, MET-amplified NSCLC responded to crizotinib with the highest ORR. Use of combined diagnostics for MET and other oncogenes may potentially identify patients most likely to respond to crizotinib.
The complex advanced endoscopic approach in the treatment of choledocholitiasis and empyema of gallbladder
Authors: Artur Raiter, Joanna Szełemej, Katarzyna Kozłowska-Petriczko, Jan Petriczko, Katarzyna M. Pawlak
Journal: Endoscopy (2021)

Advanced endoscopic procedures using a cholangioscope and performed under the endoscopic ultrasound (EUS) guidance for minimally invasive therapy of complex biliary diseases has become a promising treatment modality in selected cases [1] [2] [3].
Abstract P334: The Effects of Inadequate Sleep on Blood Pressure and Endothelial Inflammation in Women: Findings From the American Heart Association Go Red for Women Strategically Focused Research Network
Authors: Brooke Aggarwal, Nour Makarem, Riddhi Shah, Memet Emin, Ying Wei, Marie-Pierre St-Onge, Sanja Jelic
Journal: Circulation (2018)

Background: Insufficient sleep impairs blood pressure regulation. However, the effects of milder, highly prevalent but frequently neglected sleep disturbances, including poor sleep quality and insomnia, on vascular health in women are unclear. We investigated whether poor sleep patterns are associated with blood pressure and endothelial inflammation in a diverse sample of women. Methods: Women who participated in the ongoing AHA Go Red for Women Strategically Focused Research Network population project were studied (n=323, 57% minority, mean age=39 + 17 y, range=20-79 y). Sleep duration, sleep quality, and time to sleep onset were assessed using the Pittsburgh Sleep Quality Index (score &gt; 5=poor sleep quality). Risk for obstructive sleep apnea (OSA) was evaluated using the Berlin questionnaire, and insomnia was assessed using the Insomnia Severity Index (ISI). In a subset of women who participated in the basic study (n=28), sleep duration was assessed objectively using actigraphy and endothelial inflammation was assessed directly in harvested endothelial cells by measuring nuclear translocation of nuclear factor kappa B (NFκB). Vascular reactivity was measured by brachial artery flow-mediated dilation (FMD). Systolic and diastolic blood pressure (SBP and DPB) were measured by trained personnel. Multivariate linear regressions were used to evaluate associations between sleep patterns and blood pressure, NFκB and FMD. Results: Mean sleep duration was 6.8 ± 1.3 h/night in the population study and 7.5 ± 1.1 h/night in the basic study. In the population study sample, 50% had poor sleep quality (25% in the basic study), and 37% had some level of insomnia (15% in the basic study). SBP was associated directly with poor sleep quality, and DBP with OSA risk after adjusting for confounders (p=0.04 and p=0.08, respectively). Poor sleep quality was associated with endothelial NFκB activation (β=30.6; p=0.03). Insomnia and longer time to sleep onset were also associated with endothelial NFκB activation (β=27.6; p=0.002 and β=8.26; p=0.02, respectively). Sleep patterns were not associated with FMD. Conclusions: These findings provide direct evidence that common but frequently neglected sleep disturbances such as poor sleep quality and insomnia are associated with increased blood pressure and vascular inflammation even in the absence of sleep deprivation in women.
Clinically significant events associated with metastatic castration-resistant prostate cancer (mCRPC) treatments.
Authors: Kelvin A. Moses, Katrine L Wallace, Adrienne Landsteiner, Scott H Bunner, Nicole Engel-Nitz, Lincy S. Lal, Tony Golsorkhi
Journal: Journal of Clinical Oncology (2021)

61 Background: We describe the association between clinically significant events (CSEs) and mCRPC treatments in US-insured patients using an administrative claims database. Methods: Adult men in a large administrative claims database from Jan 2008 to Mar 2019 with ≥1 claim for prostate cancer, codes for pharmacologic or surgical castration, and incident metastatic disease during the identification period were included in the study. Patients who had ≥6 months of continuous enrollment before and after the index date (first metastatic claim) were included. Patients were followed until death, end of study, or disenrollment. Claims-based algorithms were used to identify patients with mCRPC, lines of therapy (LOTs), and CSEs of interest. CSEs were assessed in the first LOT in which an mCRPC regimen was used. Time on treatment was used as a person-time denominator to assess rates of CSEs per 365 days (treatment year) to control for differing times on treatment regimens. Results: Overall, we identified 3690 patients with mCRPC, of which 3150 (85%) received ≥1 LOT, among whom 1680/3150 (53%) received a regimen indicated for mCRPC. Average follow-up time was 705 days. CSEs occurred in 664/1680 (40%) patients, an average of 1.15 CSE per treatment year (Table). Patients had an average of 2 CSEs. The most common CSEs were anemia (14%), fatigue (15%), and back pain (10%). CSE rates per treatment year were highest among patients who received a taxane (1.7 per treatment year), taxane + gonadotropin-releasing hormone (GnRH) modulator (1.6 per treatment year), and other chemotherapy (1.6 per treatment year). Conclusions: Among treatments for patients with mCRPC, chemotherapy-based regimens showed the highest CSE rates per treatment year. These data indicate the burden of treatment for patients and can inform treatment decisions. [Table: see text]
Post-radical prostatectomy (RP) outcome for patients with high-risk prostate cancer treated with intense neoadjuvant hormone therapy (NHT): Results of a pooled analysis of contemporary clinical trials.
Authors: Rana R. McKay, Jacob E Berchuck, Lucia Kwak, Wanling Xie, Rebecca Silver, Glenn Bubley, Peter K. Chang, Andrew Wagner, Zhenwei Zhang, Adam S. Kibel, Mary-Ellen Taplin
Journal: Journal of Clinical Oncology (2021)

238 Background: Patients with high-risk prostate cancer have an increased risk of recurrence and death from prostate cancer. Intense NHT prior to RP has been associated with favorable pathologic responses in a subset of patients with high-risk disease. We conducted a pooled analysis of post-RP outcomes of four, multicenter, randomized, clinical trials of intense NHT prior to RP. Methods: All patients included were enrolled on trials evaluating intense NHT followed by RP. The primary endpoint was time to biochemical recurrence (BCR), defined as the time from RP to prostate specific antigen (PSA) &gt;0.1 ng/mL or start of first post-RP therapy. Secondary endpoints included metastasis-free survival (MFS), overall survival (OS), and time to testosterone recovery. We evaluated outcomes in the overall population, favorable responders (defined as a pathologic complete response or minimum residual disease ≤ 5 mm at RP), and non-responders. We correlated pathologic parameters, including RP pathologic response, PTEN status, ERG status, and presence of intraductal carcinoma with BCR. Results: 121 patients were included of whom 78.5% (n=95) had high-risk disease by NCCN risk categories. Following NHT, 20.7% (n=25) had 0-5 mm of residual tumor (including 9.1%, n=11, with pathologic complete response). Overall, 52 patients (43.0%) experienced BCR, of whom two were exceptional responders (Table). Testosterone recovery was observed in 94.0% of patients (n=109/116). PTEN loss and presence of intraductal carcinoma were associated with shorter time to BCR. Conclusions: In this pooled analysis of clinical trials, we demonstrate that patients who achieve a favorable pathologic response to NHT prior to RP experienced a decreased PSA relapse rate and prolonged time to BCR. Larger residual tumor volumes and tissue-based parameters, including PTEN loss and intraductal carcinoma, were associated with BCR. Additional follow-up is warranted to evaluate the impact on long-term outcomes. Clinical trial information: NCT00298155; NCT00924469; NCT01547299; NCT02268175 . [Table: see text]
Impact of treatment and frailty on elder-relevant physical function outcomes in older adults with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Helen Yang, Henriette Breunis, Narhari Timilshina, Seungyeon Kim, Shabbir M.H. Alibhai
Journal: Journal of Clinical Oncology (2021)

76 Background: Maintenance of physical function is a key consideration in treatment decision-making for older adults with metastatic cancer, many of whom are frail. However, physical function outcomes with treatment, and effects of frailty, have not been adequately explored in the mCRPC setting. We evaluated the effects of frailty status and treatment with docetaxel (CHEMO), abiraterone (ABI), enzalutamide (ENZA), and radium 223 (RAD) on elder-relevant physical function outcomes in older men with mCRPC. Methods: Men aged 65+ were enrolled in this multicenter prospective observational cohort study. Daily function was evaluated with the OARS instrumental activities of daily living (IADL). Objective physical function was assessed by grip strength and the Short Physical Performance Battery (SPPB). Falls were documented during interviews. We also collected FACT-G physical well-being (PWB) and functional well-being (FWB) subscales. Assessments were performed at baseline, 3 months, and 6 months. We identified frailty status with a validated frailty index. Mixed effects regression models were used to examine the difference in primary outcomes over time by treatment group or frailty status adjusted for baseline characteristics. Factors associated with falls within 6 months of treatment initiation were determined with logistic regression. Results: A total of 70, 38, 67, and 23 men starting CHEMO, ABI, ENZA, and RAD were included. Mean age, education, race, number of medications, and BMI were similar at baseline between treatment groups. In treatment-stratified analyses without considering frailty, no significant changes over time were reported for any physical function outcome. Frailty was significantly associated with lower IADL function (p &lt; 0.0001), worse grip strength (p &lt; 0.0001), worse SPPB score (p &lt; 0.0001), worse PWB (p &lt; 0.0001), and worse FWB (p &lt; 0.0001) at baseline. In frailty-stratified analyses, grip strength (p = 0.0345) worsened, but SPPB (p = 0.0147) improved significantly over time. Also, changes in SPPB (p = 0.0394) and PWB scores (p = 0.0269) over time differed by frailty status, where frail cohorts had greater improvement over time in both scores. Frailty and treatment type were not predictors of falls whereas prior falls history (OR: 3.52, 95% CI: 1.40-8.86) and age (OR: 1.07, 95% CI: 1.01-1.14) were significant predictors. Conclusions: Frail older men receiving treatment for mCRPC have worse IADL function, grip strength, SPPB scores, PWB, and FWB at baseline. Although grip strength worsened over time, they had greater improvement in SPPB scores and PWB over time than fit patients. Contrary to our hypothesis, most older adults do not experience significant worsening in elder-relevant physical function outcomes over time regardless of treatment. The impact of frailty requires further study.
Abstract 12443: Different Histopathologic Diagnoses in Clinically Diagnosed Hypertrophic Cardiomyopathy Patients Following Surgical Myectomy to Relieve Dynamic Left Ventricular Outflow Tract Obstruction
Authors: Alaa Alashi, Ria M Desai, Tamanna Khullar, Kevin Hodges, E R Rodriguez, Carmela Tan, Zoran B Popovic, Maran Thamilarasan, Per Wierup, Milind Y Desai, Harry M Lever, Nicholas G Smedira
Journal: Circulation (2018)

Background: Dynamic left ventricular outflow tract obstruction (LVOTO), which is typically relieved by surgical myectomy (SM), is the hallmark of obstructive hypertrophic cardiomyopathy (HCM). Howe...
Structural and Functional Analyses of Hub MicroRNAs in An Integrated Gene Regulatory Network of <i>Arabidopsis</i>
Authors: Zhaoxu Gao, Jun Li, Li Li, Yanzhi Yang, Jian Li, Chunxiang Fu, Danmeng Zhu, Hang He, Huaqing Cai, Lei Li
Journal: Genomics Proteomics & Bioinformatics (2021)

MicroRNAs (miRNAs) are trans-acting small regulatory RNAs that work coordinately with transcription factors (TFs) to shape the repertoire of cellular mRNAs available for translation. Despite our growing knowledge of individual plant miRNAs, their global roles in gene regulatory networks remain mostly unassessed. Based on interactions obtained from public databases and curated from the literature, we reconstructed an integrated miRNA network in Arabidopsis that includes 66 core TFs, 318 miRNAs, and 1712 downstream genes. We found that miRNAs occupy distinct niches and enrich miRNA-containing feed-forward loops (FFLs), particularly those with miRNAs as intermediate nodes. Further analyses revealed that miRNA-containing FFLs coordinate TFs located in different hierarchical layers and that intertwined miRNA-containing FFLs are associated with party and date miRNA hubs. Using the date hub MIR858A as an example, we performed detailed molecular and genetic analyses of three interconnected miRNA-containing FFLs. These analyses revealed individual functions of the selected miRNA-containing FFLs and elucidated how the date hub miRNA fulfills multiple regulatory roles. Collectively, our findings highlight the prevalence and importance of miRNA-containing FFLs, and provide new insights into the design principles and control logics of miRNA regulatory networks governing gene expression programs in plants.