tbuckley/cabot-search huggingface dataset:
Adeno-associated virus vectored immunoprophylaxis to prevent HIV in healthy adults: a phase 1 randomised controlled trial
Authors: Frances H Priddy, David J M Lewis, Huub C Gelderblom, Hana Hassanin, Claire Streatfield, Celia LaBranche, Jonathan Hare, Josephine H Cox, Len Dally, Daryl Bendel, David Montefiori, Eddy Sayeed, Jim Ackland, Jill Gilmour, Bruce C Schnepp, J Fraser Wright, Philip Johnson
Journal: The Lancet HIV (2019)

BackgroundA preventive vaccine for HIV is a crucial public health need; adeno-associated virus (AAV)-mediated antibody gene delivery could be an alternative to immunisation to induce sustained expression of neutralising antibodies to prevent HIV. We assessed safety and tolerability of rAAV1-PG9DP, a recombinant AAV1 vector encoding the gene for PG9, a broadly neutralising antibody against HIV.MethodsThis first-in-human, proof-of-concept, double-blind, phase 1, randomised, placebo-controlled, dose-escalation trial was done at one clinical research centre in the UK. Healthy men aged 18–45 years without HIV infection were randomly assigned to receive intramuscular injection with rAAV1-PG9DP or placebo in the deltoid or quadriceps in one of four dose-escalating cohorts (group A, 4 × 1012 vector genomes; group B, 4 × 1013 vector genomes; group C, 8 × 1013 vector genomes; and group D, 1·2 × 1014 vector genomes). Volunteers were followed up for 48 weeks. The primary objective was to assess safety and tolerability. A secondary objective was to assess PG9 expression in serum and related HIV neutralisation activity. All volunteers were included in primary and safety analyses. The trial is complete and is registered with ClinicalTrials.gov, number NCT01937455.FindingsBetween Jan 30, 2014, and Feb 28, 2017, 111 volunteers were screened for eligibility. 21 volunteers were eligible and provided consent, and all 21 completed 48 weeks of follow-up. Reactogenicity was generally mild or moderate and resolved without intervention. No probably or definitely related adverse events or serious adverse events were recorded. We detected PG9 by HIV neutralisation in the serum of four volunteers, and by RT-PCR in muscle biopsy samples from four volunteers. We did not detect PG9 by ELISA in serum. PG9 anti-drug antibody was present in ten volunteers in the higher dose groups. Both anti-AAV1 antibodies and AAV1-specific T-cell responses were detected.InterpretationFuture studies should explore higher doses of AAV, alternative AAV serotypes and gene expression cassettes, or other broadly neutralising HIV antibodies.FundingInternational AIDS Vaccine Initiative, United States Agency for International Development, Bill & Melinda Gates Foundation, US National Institutes of Health.
Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and Treatment Strategies: A Scientific Statement From the American Heart Association
Authors: Janani Rangaswami, Vivek Bhalla, John E.A. Blair, Tara I. Chang, Salvatore Costa, Krista L. Lentine, Edgar V. Lerma, Kenechukwu Mezue, Mark Molitch, Wilfried Mullens, Claudio Ronco, W.H. Wilson Tang, Peter A. McCullough
Journal: Circulation (2019)

Cardiorenal syndrome encompasses a spectrum of disorders involving both the heart and kidneys in which acute or chronic dysfunction in 1 organ may induce acute or chronic dysfunction in the other organ. It represents the confluence of heart-kidney interactions across several interfaces. These include the hemodynamic cross-talk between the failing heart and the response of the kidneys and vice versa, as well as alterations in neurohormonal markers and inflammatory molecular signatures characteristic of its clinical phenotypes. The mission of this scientific statement is to describe the epidemiology and pathogenesis of cardiorenal syndrome in the context of the continuously evolving nature of its clinicopathological description over the past decade. It also describes diagnostic and therapeutic strategies applicable to cardiorenal syndrome, summarizes cardiac-kidney interactions in special populations such as patients with diabetes mellitus and kidney transplant recipients, and emphasizes the role of palliative care in patients with cardiorenal syndrome. Finally, it outlines the need for a cardiorenal education track that will guide future cardiorenal trials and integrate the clinical and research needs of this important field in the future.
Abstract 12396: Elevated Myocardial Oxidative Stress Induced by Catecholamines Related to Transient Left Ventricular Dysfunction in Patients With Takotsubo Cardiomyopathy
Authors: Wakako Murakami, Shigeki Kobayashi, Tadamitsu Nakashima, Hiroki Tateishi, Shinichi Okuda, Masahiro Doi, Yasuaki Wada, Tomoko Nao, Jutaro Yamada, Takayuki Okamura, Masafumi Yano, Masunori Matsuzaki
Journal: Circulation (2012)

Background: The pathophysiology of takotsubo cardiomyopathy (TC) remains elusive. Here, we investigated how myocardial oxidative stress influenced myocardial dysfunction in patients with TC compare...
Characterization of actionable genetic alterations to guide targeted therapy for metastatic urothelial carcinoma.
Authors: Nima Almassi, Eugene J. Pietzak, Samuel Aaron Funt, Nikolaus Schultz, Guido Dalbagni, Bernard H. Bochner, Hikmat Al-Ahmadie, Dean F. Bajorin, Jonathan E. Rosenberg, Gopa Iyer, David B. Solit
Journal: Journal of Clinical Oncology (2019)

407 Background: Genetic alterations predicting response to targeted therapy are an area of active interest in developing novel therapies for patients with metastatic urothelial carcinoma (mUC). With the objective of characterizing the frequency of actionable alterations (AA) and the evidence supporting targeted therapy for these AAs, we report our experience with next-generation sequencing in mUC. Methods: Patients with sequenced mUC lesions were identified from our prospectively-maintained database. All AAs with clinical or biologic evidence supporting the alteration as predicting response to targeted therapy were identified and stratified by Oncology Knowledge Base (OncoKB) level of evidence (table). The relationship between strength of evidence and administration of targeted therapy was examined. Results: Ninety-nine of 134 patients (74%) harbored at least one AA, with 162 total AAs identified. Twenty level 2B AAs were identified, reflecting the highest level evidence in this cohort, with ERBB2 amplification (9), TSC1/TSC2 (6), and BRCA1/BRCA2 mutations (3) most common. Twenty-eight level 3A, 51 level 3B, and 62 level 4 AAs were also identified. Seventeen patients received targeted therapy, which was administered with greater frequency among patients with level 3B or higher AAs (21% vs 3%). Conclusions: Most patients with mUC harbor at least one AA, suggesting multiple targeted therapeutic opportunities in mUC. These findings highlight the need for additional clinical trials and the role of genetic testing in identifying candidates for targeted therapy. [Table: see text]
Pancreatic neuroendocrine tumors (pNET) in adolescent and young adult (AYA) population: A multi-institutional study of characteristics and outcomes.
Authors: Marine Gilabert, Young soo Rho, Vera Georgieva Megdanova, Zhasmina Mihaylova Milanova, Jean Luc Raoul, Patrice Viens, Gerald Batist, Petr Kavan
Journal: Journal of Clinical Oncology (2015)

e15173 Background: Pancreatic neuroendocrine tumors (pNETS) are rare entity that represents 5-10% of all pancreatic tumors. To date, limited studies detail characteristics and outcomes of pNET in AYA pts (AYAp). A multi-institutional retrospective study was conducted to elucidate the aforementioned. Methods: AYAp (18-44 years old), diagnosed with pNETs at the Institut Paoli-Calmettes France, Segal Cancer Centre Canada and Military Medical Academy Bulgaria between Aug 2002 to Dec 2013. Pts characteristics and outcomes were pooled for analysis. Survival data used Kaplan Meier methodology. Results: 28 AYAp (median 37 yo, range 19-44, 19 female) diagnosed with pNETS were identified. 3 VHL disease or 1 MNN were reported. The most frequent presenting symptoms were: abdominal cramps (46%), weight loss (25%), diarrhea (10%) and flushing (3%). Seven pts (25%) had a functioning tumor and 1 secreting. 53% were already metastatic (met) at the diagnosis with liver predominance (70%). Tumors were well differentiated (D)(60%), moderately-D (4%) and poorly-D (7%) with 25% unknown; 75% grade 1 or 2, 65% Ki-67 rate between 3-20%. Primary tumor was resected in 17 pts (61%) with 4 further undergoing liver resection. Seven pts received adjuvant or neoadjuvant chemotherapy. 13 pts went on to receive palliative chemotherapy, mainly platinum-based, with 30% receiving it in combination with Sandostatine LR. Only 1 pt everolimus. 46% and 10% went on to receive 2nd and 3d line respectively. The median follow-up was 28.2 months (mo) (0.2-185). Survival data are presented in the Table. Conclusions: pNETs in AYAp are a heterogeneous and poorly understood disease with prognosis dependent on tumor biology, extensiveness of surgery and response to systemic treatments. Half of pts in our cohort had met disease at the diagnosis and were associated with poorer outcomes. With approval of tyrosine kinase inhibitors in 2011, their role in AYAp remain to be answered. Further international collaboration will be required. Median OS survival (mo) OS 1 year 2 year 5year Median DFS mo (range) Median PFS mo (range) Total n = 28 170 72% 58% 52% - - Non Met disease n = 13 ongoing - 42 (4-131) - Met disease n = 15 34.4 - - 13 (0.4-35)
Interferon-λ enhances adaptive mucosal immunity by boosting release of thymic stromal lymphopoietin
Authors: Liang Ye, Daniel Schnepf, Jan Becker, Karolina Ebert, Yakup Tanriver, Valentina Bernasconi, Hans Henrik Gad, Rune Hartmann, Nils Lycke, Peter Staeheli
Journal: Nature Immunology (2019)
Brain specific progression free survival (bsPFS) according to breast cancer subtypes in patients with brain metastases.
Authors: Cagatay Arslan, Ozan Yazici, Sercan Aksoy, Kadri Altundag
Journal: Journal of Clinical Oncology (2015)

e13040 Background: Whole brain external radiotherapy (WBRT) of 30Gy is the most frequently used palliative treatment for brain metastases (BM). Disease control in brain with palliative RT might alter between different subtypes of breast cancer (BC). We aimed to investigate bsPFS among BC subtypes treated with palliative WBRT. Methods: Data of brain metastatic breast cancer patients (BMBCP) treated with WBRT between years 1998 to 2014 at Hacettepe University Oncology Institute were retrospectively analyzed. Patients treated with brain surgery were excluded. bsPFS was defined as the time from the occurrence of BM until progression at brain in months. Results: There were 56 patients, groupped in to four subtypes as; hormone receptor (HR) positive-HER2 negative (HR+HER2-, N = 23;41%), HR+HER2+ (N = 13;23.2% ), HR-HER2+ (N = 6;10.7%) and triple negative (TN, N = 14;25%). Median age of diagnosis was 42.9±11.1 (22-72). Twelve patients (21.4%) were metastatic and 6(10.7%) of them had BM at the time of diagnosis. All but one patient received adjuvant chemotherapy(CT) with anthracycline and/or taxanes. All HR+ patients received tamoxifen or aromatase inhibitors for adjuvant treatment. All HER2+ patients received adjuvant trastuzumab treatment. Patients who were metastatic at the diagnosis recevied both anthracycline and taxane including regimens. CT regimens given after the diagnosis of BM were similar between groups. Median time to occurrence of BM was 18.5 (13.4-23.6), 13.5 (6.1-20.9), 14.0 (10.1-17.9) and 8.9 (1.0-16.8) months in HR+, HR-HER2+, HR+HER2+ and TN subgroups; respectively (p = 0.181). bsPFS was 9.1 (3.7-14.5), 8.2 (4.7-11.7), 7.1 (6.2-8.1) and 3.6 (1.2-6) months in HR+HER2-, HR+HER2-, HR-HER2+ and HR+HER2+ subgroups, respectively (p = 0.014). Conclusions: bsPFS was shortest in TN and longest in HR+ subgroup. TN breast cancer patients developed BM earlier compared to other subtypes. But the difference was not at the statstical significance level. HR+, BC patients developed BM later than the HER2+ives. Median bsPFS was 3.6 months in TN subgroup. Planning frontline alternative treatment approaches might be needed beyond standard palliative WBRT in this poor prognostic TN subgroup of BCPBM.
Abstract P372: Association of Cardiovascular Disease Family History With Major Cardiovascular Risk Factors in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Authors: Christina G Hutten, Shruti Sachdeva, Molly Scannell Bryan, Ramon A Durazo-Arvizu, Krista M Perreira, Gregory A Talavera, Linda C Gallo, Sheila F Castaneda, Robert J Ostfeld, Sylvia Smoller, Maria M Llabre, Neil Schneiderman, James P Lash, Martha L Daviglus, Maria Argos
Journal: Circulation (2019)

Introduction: Family history (FH) is a well-known risk factor for cardiovascular disease (CVD); however, the association of FH with CVD in Hispanic/Latino populations has not been well investigated. We examined the cross-sectional association of FH of CVD or CVD risk factors with individual CVD risk factors (hypertension, hypercholesterolemia, obesity, diabetes mellitus, and smoking), CVD risk profile, and prevalence of CHD or stroke in the HCHS/SOL. Methods: Baseline data on FH and CVD risk factors from 15,104 HCHS/SOL participants were analyzed. Self-reported first-degree FH of high blood pressure (BP), high cholesterol, diabetes, angina, heart attack, heart failure, rheumatic heart disease, angioplasty/bypass, stroke, aortic aneurysm, and peripheral artery disease was ascertained and categorized as any first-degree FH vs. no FH of each condition. Hypertension, high cholesterol, obesity and diabetes mellitus were ascertained by objective measures and/or medication use; smoking was self-reported. The CVD risk profile was calculated by assigning a score of 0 to 5 based on the number of adverse CVD risk factors. Analysis of CVD risk factors was dichotomized as low (0 and 1 risk factor) vs. high (2+ risk factors). Odds ratios and 95% confidence intervals were derived from logistic regression models, accounting for the complex study design and controlling for multiple covariates. Results: Prevalence of CVD risk factors and risk profile were associated with self-reported FH (see Table). Furthermore, prevalence of CHD was associated with FH of high BP, high cholesterol, diabetes, angina, heart attack, heart failure, and rheumatic heart disease. Personal history of stroke was associated with FH of high BP, angina, and aortic aneurysm. Conclusions: First-degree FH of CVD factors and diseases was associated with hypertension, high cholesterol, obesity, diabetes, CHD and stroke among Hispanics/Latinos in HCHS/SOL. Ascertainment of FH should be an integral part of CVD risk assessment in Hispanics/Latinos in the US.
Feasibility of progressive resistance training in patients undergoing concurrent chemoradiotherapy for head and neck cancer.
Authors: Camilla Loenkvist, Anders Vinther, Bo Zerahn, Eva Rosenbom, Pernille Hojman, Elo Andersen, Julie Gehl
Journal: Journal of Clinical Oncology (2015)

e17015 Background: Weight loss (WL) is common in head and neck cancer (HNCa) patients undergoing concurrent chemoradiotherapy (CCR). Loss of lean body mass (LBM) is associated with reduced muscle strength, functional performance, and survival. This feasibility project investigates progressive resistance training (PRT) for reduction of LBM loss (LBML). Methods: From March to July 2014, twelve HNCa patients receiving curatively intended radiotherapy (66–68 Gy), concurrent weekly Cisplatin (40mg/m2) and nimorazole (1200 mg/m2) were included and attended a 12-week supervised PRT program at the hospital during and after CCR. Primary endpoint was feasibility as measured by adherence to PRT. Results: All patients had p16-positive stage 3-4a oropharyngeal cancer, median age was 56, 58% men, 25% never smokers, and 25% current smokers. Patients completed 77% of training sessions on average. Two months post-CCR both LBML and fat mass loss (FML) was significant, but most pronounced was FML. Muscle strength in legs was maintained, but reduced in chest, whilst muscle power and functional performance were significantly improved. (See table). No serious adverse events were related to training. Conclusions: The primary endpoint was met in terms of completion of training sessions. Progressive resistance training during CCR may preserve lean body mass and physical function, which should be further investigated in a randomized study. Clinical trial information: NCT02068950.Changes in body composition, strength and functional performance after concomitant chemoradiotherapy with concurrent progressive resistance training. Baseline (SD) Change at 2-months follow-up (SD) p-value Measured by DXA-scans Total body LBM kg 49.4 (10.3) -3.6 (2.3) < 0.001 % 62.2 (11.0) -6.8 (3.3) Total body FM kg 28.2 (12.0) -5.4 (3.4) < 0.001 % 34.5 (11.4) -18.5 (13.6) Total body mass kg 80.2 (14.7) -9.0 (4.6) < 0.001 % 100 (0.0) -10.8 (4.9) Muscle strength (1 Repetition Maximum) Chest % 100 (0.0) -10.8 (14.8) 0.03 Leg % 100 (0.0) -3.4 (16.1) 0.5 Functional performance Arm curl % 100 (0.0) 16.8 (17.8) 0.01 Sit-to-stand % 100 (0.0) 16.9 (18.1) 0.01 Stairclimbing time % 100 (0.0) 0.5 (8.7) 0.85 Leg muscle power
Positron emission tomography with <sup>18</sup>F-fluciclovine to predict recurrence in post-treatment recurrent prostate cancer and its role in altering treatment plans.
Authors: Julio Chong, Mitchel Muhleman, Rollin Say, Lale Kostakoglu, Jalal Ahmed, Ashutosh Tewari, Richard Stock, William K. Oh
Journal: Journal of Clinical Oncology (2019)

214 Background: 18 F-fluciclovine PET/CT can improve the detection of post-treatment recurrent prostate cancer (PCa). We quantified factors which increase the likelihood of a positive scan, assessed the ability of 18 F-fluciclovine to alter treatment plans and identified an optimal PSA cut-off to identify radiographic recurrence. Methods: Patients who received 18 F-fluciclovine PET/CT for recurrent PCa (n=78) were analyzed. Treatment changes based on positive scans were tracked. A receiver-operator characteristic (ROC) curve was used to estimate the optimal PSA cut-off for a positive scan. Results: 18 F-fluciclovine predicted radiographic recurrence in 67.9% of patients. PSA at scan (p = 0.010), salvage therapy (p = 0.03), any use of ADT (p = 0.016) and number of studies (p = 0.042) were all associated with a positive scan. Alteration of treatment plans occurred in 34/58 (58.6%) patients. Recurrence sites are: 79/120 (65.8%) lymph nodes, 27/120 (22.5%) bone, 11/120 (9.2%) prostatic bed, and 3/120 (2.5%) elsewhere. The most common treatment alteration was directed stereotactic body radiation therapy (SBRT) (16/34, 47%), followed by salvage surgical therapy (4/34, 11.7%) and ADT (3/34, 8.7%).The optimal PSA cut-off was 0.5 with sensitivity of 81.13% and specificity of 78.38% (ROC=0.7880). Conclusions: 18 F-fluciclovine PET/CT detected radiographic disease in 67.9% of patients, resulting in alterations in treatment plans in 58.6% of cases. SBRT was the most common alteration in treatment plan. Previous use of salvage therapy or ADT are risk factors and when combined with a PSA &gt;0.5, may be associated with radiographic recurrence. [Table: see text]
Two-stage hepatectomy for extensive colorectal liver metastases: How to predict the failure to complete both sequential procedures?
Authors: Katsunori Imai, Carlos Castro Benitez, Marc Antoine Allard, Eric Vibert, Antonio Sa Cunha, Daniel Cherqui, Denis Castaing, Hideo Baba, Rene Adam
Journal: Journal of Clinical Oncology (2015)

3559 Background: Two-stage hepatectomy (TSH) has been adopted as a treatment strategy for extensive bilateral colorectal liver metastases (CRLM) unable to be resected by a single hepatectomy. However, one of the most critical problems is the risk of failure to achieve both two sequential procedures. The aims of this study were to identify the predictive factors and develop a predictive model for failure of TSH for the optimal selection of patients who could benefit from this strategy. Methods: Among a total of 845 patients who underwent hepatectomy for CRLM Between 2000 and 2012, 125 patients (14.8%) with extensive bilateral CRLM were scheduled to perform TSH and were enrolled in this study. Based on the result of multivariate logistic analysis, a predictive model for failure of TSH was developed. Results: The median number and size of liver metastases was 9 and 37 mm, respectively. Concomitant extrahepatic disease was present in 34 patients (27.2%). On an intention-to-treat basis, the 5-year overall survival (OS) rate was 33.2%. Among the 125 patients who were planned for TSH, 44 patients (35.2%) could not proceed to the second-stage mainly because of tumor progression, and their OS were significantly worse than those who completed (5-year OS: 0% and 44.2%, P< 0.0001). Multivariate logistic analysis revealed that carcinoembryonic antigen > 30 ng/dL (relative risk (RR) 2.73, P= 0.034), tumor size > 40 mm (RR: 2.89, P= 0.036), chemotherapy cycles > 12 (RR: 3.46, P= 0.0098), and tumor progression during first-line chemotherapy (RR: 6.56, P= 0.01) were the independent predictive factors for failure of TSH. For patients without any factors, the probability of failure was 10.5% with 5-year OS of 41.9%. The addition of subsequent factors increased the probability to 43.5% for one (5-year OS 38.8%), 72.7% for two (29.2%), 88.5% for three (0%), and 95.5% for four factors (not reached). The OS for patients with predictive score of 3-4 was significantly worth than that of 0-2 (5-year OS; 0% and 36.8%, P< 0.0001). Conclusions: TSH in patients with more than 3 risk factors should be contraindicated. Avoidance of these risk factors significantly reduces the risk of failure and is crucial for the long-term survival.
Oligodepsipeptide (nano)carriers: Computational design and analysis of enhanced drug loading
Authors: Nadia Brunacci, Axel T. Neffe, Christian Wischke, Toufik Naolou, Ulrich Nöchel, Andreas Lendlein
Journal: Journal of Controlled Release (2019)

High drug loads of nanoparticles are essential to efficiently provide a desired dosage in the required timeframe, however, these conditions may not be reached with so far established degradable matrices. Our conceptual approach for increasing the drug load is based on strengthening the affinity between drug and matrix in combination with stabilizing drug-matrix-hybrids through strong intermolecular matrix interactions. Here, a method for designing such complex drug-matrix hybrids is introduced employing computational methods (molecular dynamics and docking) as well as experimental studies (affinity, drug loading and distribution, drug release from films and nanoparticles). As model system, dexamethasone (DXM), relevant for the treatment of inflammatory diseases, in combination with poly[(rac-lactide)-co-glycolide] (PLGA) as standard degradable matrix or oligo[(3-(S)-sec-butyl)morpholine-2,5-dione]diol (OBMD) as matrix with hypothesized stronger interaction with DXM were investigated. Docking studies predicted higher affinity of DXM to OBMD than PLGA and displayed amide bond participation in hydrogen bonding with OBMD. Experimental investigations on films and nanoparticles, i.e. matrices of different shapes and sizes, confirmed this phenomenon as shown e.g. by a ~10 times higher solid state solubility of DXM in OBMD than in PLGA. DXM-loaded particles of ~ 150 nm prepared by nanoprecipitation in aqueous environment had a drug loading (DL) up to 16 times higher when employing OBMD as matrix compared to PLGA carriers due to enhanced drug retention in the OBMD phase. Importantly, drug relase periods were not altered as the release from films and particles was mainly ruled by the diffusion length as well as matrix degradation rather than the matrix type, which can be assigned to water diffusing into the matrix and breaking up of drug-matrix hydrogen bonds. Overall, the presented design and fabrication scheme showed predictive power and might universally enable the screening of drug/matrix interactions particularly to expand the oligodepsipeptide platform technology, e.g. by varying the depsipeptide side chains, for drug carrier and release systems.