tbuckley/cabot-search huggingface dataset:
Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial
Authors: Carmen D. Herling, Florence Cymbalista, Carolin Groß-Ophoff-Müller, Jasmin Bahlo, Sandra Robrecht, Petra Langerbeins, Anna-Maria Fink, Othman Al-Sawaf, Raymonde Busch, Raphael Porcher, Bruno Cazin, Brigitte Dreyfus, Stefan Ibach, Stéphane Leprêtre, Kirsten Fischer, Florian Kaiser, Barbara Eichhorst, Clemens-Martin Wentner, Manuela A. Hoechstetter, Hartmut Döhner, Veronique Leblond, Michael Kneba, Remi Letestu, Sebastian Böttcher, Stephan Stilgenbauer, Michael Hallek, Vincent Levy
Journal: Leukemia (2020)

Abstract We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time &lt;12 months, serum thymidine kinase &gt;10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W&amp;W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0–99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W&amp;W patients (median not reached vs. 18.5 months, p &lt; 0.001). There was no significant overall survival benefit for high-risk patients receiving early FCR therapy (5-year OS 82.9% in Hi-FCR vs. 79.9% in Hi-W&amp;W, p = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care “watch and wait” for these patients.
Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle
Authors: Paola Favuzza, Manuel de Lera Ruiz, Jennifer K. Thompson, Tony Triglia, Anna Ngo, Ryan W.J. Steel, Marissa Vavrek, Janni Christensen, Julie Healer, Christopher Boyce, Zhuyan Guo, Mengwei Hu, Tanweer Khan, Nicholas Murgolo, Lianyun Zhao, Jocelyn Sietsma Penington, Kitsanapong Reaksudsan, Kate Jarman, Melanie H. Dietrich, Lachlan Richardson, Kai-Yuan Guo, Sash Lopaticki, Wai-Hong Tham, Matthias Rottmann, Tony Papenfuss, Jonathan A. Robbins, Justin A. Boddey, Brad E. Sleebs, Hélène Jousset Sabroux, John A. McCauley, David B. Olsen, Alan F. Cowman
Journal: Cell Host & Microbe (2020)

Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets. In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle. We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress. Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver. In addition, WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes. Selection of resistant P. falciparum in vitro was not achievable. Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention.
Abstract 13114: Effects of Aerobic and Inspiratory Training on Skeletal Muscle Microrna-1 and Downstream-Associated Pathways in Patients With Systolic Heart Failure
Authors: Ligia M Antunes-Correa, Patricia Trevizan, Aline V Bacurau, Larissa Ferreira-Santos, João L Gomes, Ursula Urias, Patricia Oliveira, Maria-Janieire N Alves, Dirceu R Almeida, Patricia C Brum, Edilamar M Oliveira, Ludhmila Hajjar, Roberto Kalil Filho, Carlos E Negrao
Journal: Circulation (2019)

Introduction: The exercise intolerance in chronic systolic heart failure (HF) is mostly attributed to alterations in skeletal muscle. However, the mechanisms underlying the skeletal myopathy in HF ...
Tuning C–C sp2/sp3 ratio of DLC films in FCVA system for biomedical application
Authors: Xi Rao, Jihan Yang, Zilin Chen, Yidie Yuan, Qiubing Chen, Xue Feng, Lizhao Qin, Yongping Zhang
Journal: Bioactive Materials (2020)

Diamond like carbon (DLC) films with different C-C sp2/sp3 ratios were prepared by tuning the N2 flow rate in a filtered cathodic vacuum arc (FCVA) system. The increase of N2 flow rate facilitated the increase of C-C sp2/sp3 ratio (1.09-2.66), the growth of particle size (0.78-1.58 nm) and the improvement of surface roughness. The SBF immersion results, as well as WCAs (77.57°~71.71°), hemolysis rate (0.14-1.00%) and cytotoxicity level (0) demonstrated that the as-fabricated DLC film was promising for biomedical application. As a result of surface charge effect, the apatite layers formed in the SBF increased with the increase of C-C sp2/sp3 ratio until 1.74 and then showed a tiny decrease during 1.74-2.66. A raise of hemolysis and cytotoxicity was observed when sp2/sp3 ratio was increased. Moreover, a decrease of friction coefficient of Si surface induced by increasing sp2/sp3 ratio was respectively evidenced in ambient air and SBF lubrication environments.
Elevation of serum ferritin levels for predicting a poor outcome in hospitalized patients with influenza infection
Authors: A. Lalueza, B. Ayuso, E. Arrieta, H. Trujillo, D. Folgueira, C. Cueto, A. Serrano, J. Laureiro, C. Arévalo-Cañas, C. Castillo, C. Díaz-Pedroche, C. Lumbreras
Journal: Clinical Microbiology and Infection (2020)
Associations of Widowhood and β-Amyloid With Cognitive Decline in Cognitively Unimpaired Older Adults
Authors: Kelsey D. Biddle, Heidi I. L. Jacobs, Federico d’Oleire Uquillas, Benjamin S. Zide, Dylan R. Kirn, Michael R. Properzi, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling, Nancy J. Donovan
Journal: JAMA Network Open (2020)

<h3>Importance</h3> To reduce the rising incidence of clinical impairment due to Alzheimer disease, it is essential to define older adults at highest risk. Widowhood may be an unrecognized factor contributing to accelerated clinical progression along the Alzheimer disease pathway among cognitively unimpaired older adults. <h3>Objective</h3> To determine whether widowhood status and level of brain β-amyloid (ie, the Alzheimer disease pathologic protein) are additively or interactively associated with cognitive decline among cognitively unimpaired older adults. <h3>Design, Setting, and Participants</h3> In this cohort study, 257 married, widowed, and unmarried (ie, never married, divorced, or separated) participants from the Harvard Aging Brain Study longitudinal cohort underwent baseline evaluation of neocortical β-amyloid levels using Pittsburgh compound B positron emission tomography and 4 annual cognitive assessments. Data were collected from September 2010 to February 2017 and analyzed from July 2018 to July 2019. <h3>Main Outcomes and Measures</h3> Cognitive performance was measured using the Preclinical Alzheimer Cognitive Composite. <h3>Results</h3> Of the 257 participants, 153 (59.5%) were women, and the mean (SD) age was 73.5 (6.1) years; 145 participants (56.4%) were married (66 [45.5%] women), 77 (30.0%) were unmarried (56 [72.7%] women), and 35 (13.6%) were widowed (31 [88.6%] women). Compared with married participants, widowed participants demonstrated worsening cognitive performance after adjusting for age, sex, socioeconomic status, depression, and β-amyloid levels (β = −0.11; 95% CI, −0.19 to −0.04;<i>P</i> = .002) with no difference observed between married and unmarried participants. Furthermore, widowed participants with higher baseline β-amyloid levels exhibited steeper cognitive decline (β = −0.22; 95% CI, −0.42 to −0.03;<i>P</i> = .02), indicating both independent and interactive associations of β-amyloid levels and widowhood with cognition. In a secondary model using dichotomous β-amyloid–marital status groupings, the rate of cognitive decline among widowed participants with high β-amyloid was nearly 3 times faster than among married participants with high β-amyloid (widowed, high β-amyloid: β, −0.33; 95% CI, −0.46 to −0.19;<i>P</i> &lt; .001; married, high β-amyloid: β, −0.12; 95% CI, −0.18 to −0.01;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> In a sample of cognitively unimpaired older adults, being widowed was associated with accelerated β-amyloid–related cognitive decline during 3 years. Cognitively unimpaired, widowed older adults were particularly susceptible to Alzheimer disease clinical progression, emphasizing the need for increased research attention and evidenced-based interventions for this high-risk group.
Association of high plasma glutamine levels with outcome in metastatic castration-resistant prostate (mCRPC) patients treated with taxanes.
Authors: Veronica Pereira Diaz, Mercedes Marin, Natalia Jiménez, Oscar Reig, Iván Victoria, Francis Esposito, Aleix Prat, Begona Mellado
Journal: Journal of Clinical Oncology (2020)

164 Background: Cancer cells may metabolize glutamine to fulfill their metabolic needs. In prostate cancer it has been shown that androgen receptor signaling promotes glutamine metabolism by increasing the expression of the glutamine transporters, and that stromal glutamine may promote tumor growth. Methods: We retrospectively tested glutamine levels in frozen plasma samples from mCRPC patients treated with taxanes, which were included in a prospective biomarker study in our institution. Glutamine levels were determined by a bioluminescent assay. Optimal cut-offs for glutamine levels were assessed using maximally selected log-rank statistics to determine low and high level groups. Pre-treatment glutamine level was correlated with taxanes response and clinical outcome. Independent association with survival was evaluated by multivariate Cox modeling. Results: Seventy eight mCRPC patients treated with taxanes were included. Median age was 70.3 (55.8-83.5) years and median follow-up was 13.1 (0.2-53.9) months. Glutamine was tested in 88 plasma samples: 69 from pre-docetaxel and 19 pre-cabazitaxel treatment (10 patients had both samples). High glutamine levels significantly correlated with worst PSA-progression-free survival (PFS) (median 2.8 vs 4.7 months, hazard ratio [HR] 1.8, 95%CI 1.1-2.7, P= 0.012) and overall survival (OS) (median 12.4 vs 20.4, HR 2, 95%CI 1.2-3.3, P= 0.006). In a multivariate analysis, high plasma glutamine levels were independently associated with shorter PSA-PFS (HR 2.3, 95%CI 1.4-3.7, P&lt; 0.001) and OS (HR 2.2, 95%CI 1.3-3.7, P= 0.003). Patients with high glutamine levels were more likely to present PSA progression to taxanes than those with low levels (odds ratio [OR] 3, 95%CI 1.2-7.7, P= 0.016). Moreover, samples from patients treated with abiraterone or enzalutamide before taxanes (51 samples from 43 patients) had significantly higher glutamine levels (T-test, P= 0.014) than those without these prior therapies. Conclusions: Glutamine can be detected in plasma of mCRPC patients and higher levels are associated with adverse clinical outcome, supporting the relevance of metabolism in prostate cancer progression.
Monocytes from IgE- and IgE+ Adults with Allergies and Asthma Continue to Express Inducible Nitric Oxide Synthase (iNOS) after Frozen Storage
Authors: Maja Nowakowski, Liang XUE, Nicholas Tan, Rohan Goyal, Venkatesh Gangadharappa, Stephen McCormick, Seto Chice, Helen Durkin
Journal: Journal of Allergy and Clinical Immunology (2020)
Formononetin Isolated from Ku Shen (Radix Sophorae Flavescentis) Inhibits B cell IgE Production by Inhibiting STAT 6 and NF-κB phosphorylation and XBP1 and IgE heavy chain expression
Authors: Ibrahim Musa, Nan Yang, Xiu-Min Li
Journal: Journal of Allergy and Clinical Immunology (2020)
A phase I study to evaluate PSCA-targeting chimeric antigen receptor (CAR)-T cells for patients with PSCA+ metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tanya B. Dorff, Suzette Blanchard, Patti Carruth, Jamie Wagner, Peter Kuhn, Ammar Chaudhry, Lauren Adkins, Sandra Thomas, Hripsime Martirosyan, Peiguo Chu, Sumanta K. Pal, Stephen J. Forman, Saul Priceman
Journal: Journal of Clinical Oncology (2020)

TPS250 Background: Although treatment options have improved, mCRPC remains highly lethal. Immunotherapy holds potential for durable remissions but not yet in mCRPC. CAR-T cell therapy has yielded cure for patients with refractory hematologic malignancies, and shows promise in solid tumors. Identifying and targeting the optimal antigen will be key to successful translation in solid tumors. Prostate stem cell antigen (PSCA) is highly expressed on prostate cancer cells, especially metastatic foci, and has limited expression on normal tissues. City of Hope has developed a second-generation PSCA CAR-T cell therapy containing an intracellular 4-1BB co-stimulatory domain (PSCA-BBζ) for first-in-human testing in men with mCRPC refractory to standard therapy (NCT03873805). Methods: The toxicity equivalence range (TEQR) design of Blanchard and Longmate will be used to evaluate select doses of PSCA-BBζ cells and determine the maximum tolerated dose (MTD). Doses include Cohort 1 = 100 million (M) CAR-T x 1 alone; Cohort 1b = 100M CAR-T x1 after lymphodepletion; Cohort 2 = 300M after lymphodepletion; Cohort 3 = 600M after lymphodepletion. 12 subjects will be accrued at the MTD. Eligibility: mCRPC treated with either abiraterone, enzalutamide or both; prior chemotherapy and/or radium223 allowed but not mandated. Tumor tissue, primary or metastatic, must stain positive for PSCA by IHC (Abcam 15168) and biopsy is repeated 28 days post infusion. Endpoints: Primary: all toxicities and dose-limiting toxicities defined as grade 3+ toxicity with attribution of possibly related or above, except CRS grade 3 resolved to &lt; grade 2 within 72 hours or grade 3 encephalopathy resolved to baseline within 28 days. Secondary: persistence/expansion of CAR-T, response (soft tissue by RECIST, bone by PCWG3 criteria). Correlative studies include blood (immunophenotyping, cytokines, circulating tumor cell enumeration and PSCA expression), MRI (enhancement/diffusion changes in target lesions) and metastatic core biopsies (PSCA expression and local immune phenotype changes). Progress: 4 subjects have successfully manufactured PSCA-BBζ T cells; 1 completed treatment. Clinical trial information: NCT03873805.
Comparative cost-effectiveness analysis of avelumab plus axitinib versus pembrolizumab plus axitinib, ipilimumab plus nivolumab, and sunitnib for advanced renal cell carcinoma in the U.K. Perspective.
Authors: Ramon Andrade De Mello, Emili Ayoub, Pedro Castelo-Branco, Victor Andre De Almeida Zia, Andre Savio, Daniel Humberto Pozza, Hakaru Tadokoro, Nelson Teich
Journal: Journal of Clinical Oncology (2020)

689 Background: Avelulmab plus axitinib showed to improve clinical outcomes for patients with advanced renal cell carcinoma (aRCC) in the JAVELIN RENAL 101 trial. Several other immunocheckpints inihibitos (ICIs) options acquired a main role in the aRCC treatment, such as nivolumab plus ipilimumab and pembrolizumab plus axitinib. Our aim is to evaluate the cost effectiveness of avelumab/axitinib versus other FDA approved options for previously untreated patients with aRCC. Methods: A Markov model was used to estimate the costs and health outcomes of treatment of aRCC with sunitinib, or avelumab plus axitinib. Univariable and probabilistic sensitivity analyses were performed to determine the robustness of the model outcomes. The primary outputs of the model included the total cost, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER). Results: Avelumab plus axitinib provided and 4.77 additional QALY benefit. Total cost per patient was US$ 174,725 for avelumab/axitinib, US$ 178,725 for pembrolizumab/axitinib, US$ 169,390 for ipilimumab/nivolumab and US$ 97,846 for sunitnib. Avelumab/axitinib showed to be more cost-effective (ICER US$ 28,011/QALY) when compared to pembrolizumab/axitinib (ICER US$ 47,916/QALY) and ipilumumab/nivolumab (ICER US$ 95,392/QALY). Conclusions: Avelumab/axitinib is likely to be more cost-effective than ipilimumab/nivolumab, pembrolizumab/axitinib and sunitinib in the UK perspective. However further models, market discounts and stakeholders price negotiations could lead to variations of this scenario across the globe.
A microarray platform designed for high-throughput screening the reaction conditions for the synthesis of micro/nanosized biomedical materials
Authors: Xiaoyu Li, Xiran Yang, Lei Liu, Peipei Zhou, Jianhua Zhou, Xuetao Shi, Yingjun Wang
Journal: Bioactive Materials (2020)

Materials research usually relies on lengthy and largely trial-and-error methods, high-throughput technology has thereby emerged as an alternative method which is proven to be a simple, rapid, accurate and sensitive technique. Here, we presented a microfluidic platform with a set of 6 × 6 microarray chips for high-throughput synthesis and rapid screening the reaction conditions of biomedical materials. The core design of this platform is to generate concentration gradient inside microarray chips. Considering that calcium phosphates (CaP) are the most important inorganic constituents of biological hard tissues, different phases of calcium phosphates particles were synthesized with various morphogenesis when the reaction conditions such as Ca/P concentration ratio, NaOH concentration were screened using our platform. And this platform is universal and expected to apply to other systems for high-throughput screening and synthesis.
A Randomized Phase II Study of OGX-427 Plus Prednisone (P) Vs. P Alone in Patients (PTS) with Metastatic Castration Resistant Prostate Cancer (CRPC)
Authors: K. Chi, E.Y. Yu, S. Ellard, S.J. Hotte, J.R. Gingerich, A.M. Joshua, M.E. Gleave
Journal: Annals of Oncology (2012)
The Modern Epidemic of Syphilis
Authors: Khalil G. Ghanem, Sanjay Ram, Peter A. Rice
Journal: New England Journal of Medicine (2020)

Over the past two decades, the incidence of syphilis has increased sharply. The courses of both untreated and treated disease can be unpredictable. This review presents guidance on clinical recognition of syphilis, diagnostic-test algorithms, and recommended treatment regimens.
Pathogenic FBN1 Genetic Variation and Aortic Dissection in Patients With Marfan Syndrome
Authors: Olivier Milleron, Florence Arnoult, Gabriel Delorme, Delphine Detaint, Quentin Pellenc, Richard Raffoul, Maria Tchitchinadze, Maud Langeois, Celine Guien, Christophe Beroud, Jacques Ropers, Nadine Hanna, Pauline Arnaud, Laurent Gouya, Catherine Boileau, Guillaume Jondeau
Journal: Journal of the American College of Cardiology (2020)
Immunosuppressive milieu of high-risk localized prostate cancer.
Authors: Victor Ricardo Adorno Febles, Dennis Adeegbe, Aarif Ahsan, Jiansheng Wu, Alireza Khodadad-Jamayran, Herbert Lepor, James Wysock, Samir Taneja, William C. Huang, Arjun Vasant Balar, Jonathan Melamed, Fang-Ming Deng, Qinghu Ren, Aristotelis Tsirigos, Donald W. Kufe, Adriana Heguy, Kwok-Kin Wong, David R. Wise
Journal: Journal of Clinical Oncology (2020)

344 Background: The immune factors that modulate the aggressiveness of localized treatment-naïve prostate cancer remain poorly understood. Methods: Fresh tumor and peripheral blood were collected at the time of radical prostatectomy in patients with localized prostate cancer. We evaluated the immune cell composition of 22 patient samples employing multi-parametric flow cytometry. Samples were grouped by histological grade into intermediate (INTPCA) and high-grade (HIGHPCA) prostate cancers based on standard NCCN criteria and immune cell abundances were quantified by mean +/- SEM. Statistical significance was assessed using the Mann-Whitney test. Results: INTPCA and HIGHPCA tumors harbored a similar increase in CD8+ T cells ( p &lt; 0.0005 and p &lt; 0.05, respectively) and CD11b+CD68-CD16+ myeloid-derived cells (p &lt; 0.05) relative to the peripheral blood. Other cell types were similarly decreased in both INTPCA and HIGHPCA, including CD11b+CD68+CD14+ ( p &lt; 0.005 and p &lt; 0.05, respectively). By contrast, regulatory T cells were the only cell type in our analysis to be uniquely enriched in HIGHPCA rather than INTPCA ( p &lt; 0.05). The most unique feature found in phenotypic profiling of the immune repertoire of HIGHPCA relative to INTPCA was an increase in the immune inhibitory receptor ligand, PD-L1, in the tumor associated macrophages (CD11b+CD68+CD14+) compared to the periphery (p &lt; 0.05). Conclusions: Collectively, our findings reveal that HIGHPCA harbors a distinct immunological landscape. Although effector CD8+ T cells are preferentially expressed in the tumor, these are met with an increased proportion of regulatory T cells as well as PD-L1 expressing macrophages that contribute to the inert tumor microenvironment. These are key features of aggressive prostate cancer that may serve as potential biomarkers and therapeutic targets.
Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence (STOMP): Five-year results of a randomized phase II trial.
Authors: Piet Ost, Dries Reynders, Karel Decaestecker, Valerie Fonteyne, Nicolaas Lumen, Aurélie De Bruycker, Bieke Lambert, Louke Delrue, Renée Bultijnck, Els Goetghebeur, Geert Villeirs, Kathia De Man, Filip Ameye, Ignace Billiet, Steven Joniau, Friedl Vanhaverbeke, Gert de Meerleer
Journal: Journal of Clinical Oncology (2020)

10 Background: Multiple randomized phase II trials suggest that metastasis-directed therapy (MDT) for oligometastatic prostate cancer (PCa) improves progression-free survival, but the majority of trials lack longer follow-up. We present the updated 5-year results from the STOMP-trial. Methods: In this multicentre, randomised, phase II study, asymptomatic PCa patients were eligible in case of a biochemical recurrence following primary PCa treatment with curative intent and presenting with up to 3 extracranial on choline PET-CT and a serum testosterone levels &gt; 50 ng/ml. Patients were randomly assigned (1:1) to either surveillance or MDT of all detected lesions. Randomisation was balanced dynamically on two factors: PSA doubling time (≤3 vs. &gt; 3 months) and nodal vs non-nodal metastases. The primary endpoint was androgen deprivation therapy (ADT)-free survival. Castrate resistant prostate cancer-free survival (CRPC) was a secondary endpoint. Tests were performed two-sided; p values less than 0.20 were deemed significant. Results: The 5-year ADT-free survival was 8% for the surveillance group and 34% for the MDT group (Figure 1, hazard ratio 0.57 [80% CI: 0.38-0.84], log-rank p = 0.06). There was no significant difference in effect for the different stratification factors (interaction test). The 5-year CRPC-free survival was 53% for the surveillance group and 76% for the MDT group (hazard ratio 0.62 [80% CI: 0.35−1.09]; log−rank p = 0.27). At a median follow for survival of 5.3 years (IQR 4.3-6.3), the 5-year overall survival was 85%, with 6 out of 14 deaths attributed to prostate cancer. Conclusions: The updated STOMP trial outcomes confirm the earlier reported significant difference in ADT free survival in favor of the MDT group compared to surveillance. Prostate-cancer related mortality is low within the first 5 years of diagnosis of oligorecurrent prostate cancer. Clinical trial information: NCT01558427.