julilili42/papers huggingface dataset:
Hierarchical Development of Early Visual-Spatial Abilities – A Taxonomy Based Assessment Using the MaGrid App
2020-05-20

Visual-spatial abilities (VSA) are considered a building block of early numerical development. They are intuitively acquired in early childhood and differentiate in further development. However, when children enter school, there already are considerable individual differences in children's visual-spatial and numerical abilities. To better understand this diversity, it is necessary to empirically evaluate the development as well as the latent structure of early VSA as proposed by the 2 by 2 taxonomy of Newcombe and Shipley (2015). In the present study, we report on a tablet-based assessment of VSA using the digital application (app) MaGrid in kindergarten children aged 4-6 years. We investigated whether the visual-spatial tasks implemented in MaGrid are sensitive to replicate previously observed age differences in VSA and thus a hierarchical development of VSA. Additionally, we evaluated whether the selected tasks conform to the taxonomy of VSA by Newcombe and Shipley (2015) applying a confirmatory factor analysis (CFA) approach. Our results indicated that the hierarchical development of VSA can be measured using MaGrid. Furthermore, the CFA substantiated the hypothesized factor structure of VSA in line with the dimensions proposed in the taxonomy of Newcombe and Shipley (2015). Taken together, the present results advance our knowledge to the (hierarchical) development as well as the latent structure of early VSA in kindergarten children.
Evidence-Based Decision Aid for Patients With Parkinson Disease: Protocol for Interview Study, Online Survey, and Two Randomized Controlled Trials
2020-05-20

Background Shared decision making is particularly important in situations with different treatment alternatives. For the treatment of idiopathic Parkinson disease, both pharmacological and surgical approaches can be applied. Objective In this research project, a series of studies will be conducted to investigate how decision aids for patients with idiopathic Parkinson disease should be designed in order to support the decision-making process. Methods In Study 1a, qualitative interviews will be conducted to determine which needs frequently occur for patients with idiopathic Parkinson disease. In Study 1b, the identified needs will then be rated for personal relevance by an independent group of patients in an online survey. In Study 2, a randomized controlled trial will be used to pretest different decision aids in a sample group of people who do not have a medical background and who do not have Parkinson disease. In Study 3, a randomized controlled trial will be used to investigate the effect of the decision aids that had been evaluated as positive in Study 2 with patients who have idiopathic Parkinson disease. Results This series of studies received ethical approval in January 2020. As of June 2020, data collection for Study 1a has started, and it is estimated that Studies 1a, 1b, 2, and 3 will take approximately 4, 4, 6, and 6 months to complete, respectively. It is planned to present the results and analyses at international conferences and to submit the results to peer-reviewed journals for publication, once the studies have been completed. The findings will also be shared with clinicians and patients through presentations at information events. Conclusions This series of studies is intended to result in an evidence-based decision aid for patients with idiopathic Parkinson disease in order to support the informed and reflected shared decision-making process. We further intend to contribute to a deeper understanding of the individual preferences of patients with idiopathic Parkinson disease and the impact of those preferences on treatment decisions.
MONARCH 2: Subgroup analysis of patients receiving abemaciclib + fulvestrant as first- and second-line therapy for HR+, HER2- advanced breast cancer.
2020-05-20

1061 Background: In MONARCH 2 (M2), abemaciclib (A), an oral selective cyclin dependent kinase 4 &amp; 6 inhibitor, + fulvestrant (F) demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) compared to placebo (P) + F in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC). Numerically more pronounced PFS &amp; OS improvement was noted in subgroups (Sub) with visceral (V) disease and primary endocrine resistance. Here we report efficacy data for M2 with respect to 1L and 2L Sub (last line of endocrine therapy [ET] in (neo)adjuvant and metastatic setting, respectively). Methods: M2 (NCT02107703) was a global, randomized, double-blind Phase 3 trial of A+ F (N = 446) or P + F (N = 223) in women with ET resistant (ETR) HR+, HER2- ABC regardless of menopausal status. Patients (pts) were stratified by site of metastasis (V, bone-only, or other) and resistance to prior ET (primary vs secondary). Exploratory Sub analyses of PFS and OS were conducted among pts in the ITT population with 1L vs 2L. Hazard ratios (HR) were estimated using Cox models with a test of interactions of Sub with treatment performed. Results: At data cut-off (June 20 th , 2019), the effect of A + F vs P + F was consistent across 1L (N = 265/133) and 2L (N = 170/86) Sub, with no statistically significant interaction for PFS (p = 0.341) or OS (p = 0.265). For 1L pts, improvements in PFS (HR: 0.57; 95% CI:0.45, 0.73) and OS (HR: 0.85; 95% CI:0.64, 1.14) were observed. Similar efficacy results were observed for 2L pts (PFS: HR: 0.48; [95% CI: 0.36, 0.64]; OS HR: 0.66 [95% CI: 0.46, 0.94]). The numerically largest effects in the 1L population were noted in pts with less favorable prognostic factors such as primary ETR (PFS: HR 0.40 [95% CI: 0.26, 0.63]; OS: HR 0.58 [95% CI:0.35, 0.97]) and V disease (PFS: HR 0.54 [95% CI: 0.39, 0.73]; OS: HR 0.82 [95% CI: 0.57, 1.17]). Conclusions: The statistically significant benefit observed in the M2 study was observed across 1L and 2L patients. In 1L patients (A+F Arm), improvements were observed for PFS and OS with the most pronounced effects noted in patients with less favorable prognostic factors. Clinical trial information: NCT02107703 .
Nucleophilic RhI Catalyzed Selective Isomerization of Terminal Aziridines to Enamides
2020-05-20

Abstract The selective isomerization of various terminal N ‐Boc protected aziridines to enamides was realized using the highly reactive nucleophilic rhodium catalyst C with the Lewis acid LiNTf 2 as co‐catalyst under moderate conditions. The reaction proceeds smoothly with only 1 mol% catalyst loading and excellent yields were achieved. An intermediate containing an enamide with a non‐conjugated terminal C=C double bond was detected during the course of the reaction, which isomerizes to form the thermodynamically favored 2‐amido styrene. Mechanistic insight is gained based on these observations.
DURTRERAD: A phase II open-label study evaluating feasibility and efficacy of durvalumab (D) and durvalumab and tremelimumab (DT) in combination with radiotherapy (RT) in non-resectable locally advanced HPV-negative HNSCC—Results of the preplanned feasibility interim analysis.
2020-05-20

6574 Background: DURTRERAD is a randomized phase II study evaluating feasibility and efficacy of durvalumab (anti-PD-L1) vs. durvalumab and tremelimumab (anti-CTLA-4) in combination with radiotherapy as primary treatment for locally advanced HPV negative HNSCC. (NCT03624231). Concurrent chemo-RT with a platinum-based regimen is considered the standard treatment, although efficacy and long-term toxicity are not satisfactory. Combining immunotherapy with RT might result in improved efficacy with limited long-term toxicity. Methods: The phase II study planned to enroll 120 pts, 60 pts (1:1) in each treatment arm. Treatment with DT (1500mg/75 mg, arm DT),or D (1500mg, arm D) both in combination with RT (70Gy) was considered to be feasible if less than 10% of the patients treated will discontinue treatment due to on-treatment toxicities. A first interim analysis for feasibility and efficacy was planned after randomisation of 20 patients. Results: So far 23 patients have been screened, 16 patients have been randomised and started their allocated treatment, 10 in arm D and 6 in arm DT. Of 10 patients in arm D 1 patient stopped infusional treatment due to immune related toxicity. Out of 6 patients in the DT arm, however, 5 patients stopped treatment due to treatment related AEs, 2 pts due to immune related toxicity with one Grade 5 AE. Three patients stopped due to non-immune related AE. The grade 5 AE prompted the interim analysis, which revealed non-feasibility as well as safety-issues of the DT+radiotherapy combination . As a result, the DT arm was prematurely terminated. Conclusions: Even though in the recurrent/metastatic setting DT was not associated with increased toxicity, DT in combination with RT was not feasible in our poor prognostic, vulnerable patient cohort of advanced HPV negative unresectable HNSCC, warranting early disclosure of these results. No increase in toxicity was observed in the D monotherapy arm, and the trial continued with D monotherapy in combination with RT. Clinical trial information: NCT03624231 .
Association between complete response and survival in advanced melanoma treated with talimogene laherparepvec (T-VEC) plus ipilimumab (ipi).
2020-05-20

10029 Background: This is the first randomized trial testing the addition of an oncolytic virus to an immune checkpoint inhibitor for advanced melanoma. At the 3-year (yr) follow-up, the combination (combo) of T-VEC and ipi demonstrated durable and statistically superior objective response rate (ORR) over ipi alone (36.7% vs. 16.0%; odds ratio, 3.0; 95% Cl, 1.6–6.0; P = 0.002). Complete response (CR) rate was 21.4% with the combo and 6.0% with ipi. Median overall survival (OS) was not reached in either arm. In this post hoc analysis, we utilized the 3-yr landmark data to explore the relationship between CR and OS in the combo arm. Methods: Pts with unresectable, stage IIIB-IV melanoma were randomized 1:1 to receive combo or ipi alone. T-VEC was administered intratumorally on day 1 of week (wk) 1 at 10 6 plaque-forming units (PFU)/mL followed by subsequent doses at 10 8 PFU/mL on day 1 of wk 4, and every 2 wks thereafter. Ipi (3 mg/kg) was given every 3 wks starting on day 1 of wk 6 for up to 4 doses. Response was assessed by investigators per immune-related response criteria every 12 wks until disease progression. The primary endpoint was ORR; key secondary endpoints were OS, progression-free survival, and safety. Results: 198 pts were randomized (98 to combo; 100 to ipi). As of February 25, 2019, the median follow-up time was 40.0 mos (range: 0.2–63.7) for the combo arm. Among 98 pts who received combo, 21 (21.4%) had a best overall response of CR including 8 who converted from an initial partial response (PR), 15 (15.3%) had PR, 19 (19.4%) had stable disease, 30 (30.6%) had progressive disease, and 13 (13.2%) were unevaluable. Of 21 pts achieving CR, 17 (81%) had ECOG status of 0, 16 (76.2%) had stage IIIB-IVM1a disease, and 16 (76.2%) had no visceral metastases. Median duration of CR was not reached (range: 5.4[+]–58.2[+] mos); 19 of 21 CRs lasted more than 6 months. The baseline tumor burden was lower in pts with CR than in those with non-CR. Median OS was not reached in pts with CR (range: 25.1[+]–63.7[+] mos) and was 47.6 mos (range: 0.2[+]– 63.7[+] mos) in pts with non-CR (Log-rank P = 0.0005). The Kaplan–Meier estimated 3-year OS rate was 100.0% for patients with CR and 52.3% for those with non-CR. Conclusions: CR rate was higher with T-VEC plus ipi than with ipi alone in pts with advanced melanoma (21.4% vs. 6.0%). In the combo arm, CR was associated with prolonged OS, and pts with CR tended to have better ECOG performance status, earlier-stage disease, and lower baseline tumor burden, as compared with those with non-CR. Clinical trial information: NCT01740297.
The HLA Ligand Atlas: A novel immuno-oncology resource for T-cell antigen discovery.
2020-05-20

3128 Background: The human leukocyte antigen (HLA) complex regulates the adaptive immune response by showcasing the intracellular and extracellular protein content to the immune system, which is the basis for T cell-dependent tumor rejection. Therefore, a comprehensive map of the entirety of both HLA class I- and class II-presented peptides from various benign tissues is a highly sought after resource, as it enables the definition of tumor-association on the immunologically pivotal level of the HLA ligandome. Methods: Human tissue samples were snap frozen post mortem during autopsy. The study was approved by the local IRB. HLA ligands were immunopurified and characterized using an Orbitrap Fusion Lumos mass spectrometer coupled to an Ultimate 3000 RSLC Nano UHPLC System. Data acquisition was performed as technical triplicates in data-dependent mode, and data were analyzed using the containerized, computational pipeline MHCquant. Results: In this work, we describe the HLA Ligand Atlas, a comprehensive collection of matched HLA class I and class II ligandomes from 29 non-malignant tissues and 13 human subjects (208 samples in total), covering 38 HLA class I, and 17 HLA*DRB alleles and comprising 48,381 HLA class I and 16,146 HLA class II peptides. Nearly 50% of HLA ligands have not been previously described. The HLA Ligand Atlas is publicly available as a raw data resource, but also in the form of a user-friendly web interface that allows users to quickly formulate complex queries against the data set. Both downloadable data and the query interface are available at www.hla-ligand-atlas.org. Conclusions: This data set provides a valuable tool for research in diverse fields such as systems biology, general immunology, autoimmune disease and organ transplantation. Most importantly, the HLA Ligand Atlas provides essential information for translational applications in immuno-oncology. The knowledge of HLA ligands from benign tissues strongly supports the informed design of proteogenomic HLA-dependent target discovery approaches.
Entropic Identification of the First Order Freezing Transition of a Suspension of Hard Sphere Particles
2020-05-20

We analyze the experimental particle current autocorrelation function of suspensions of hard spheres. Interactions between the particles are mediated by thermally activated acoustic excitations in the solvent. Those acoustic modes are tantamount to the system's (energy) microstates and by their orthogonality, each of those modes can be identified with an independent Brownian particle current. Accordingly, partitioning of the system's energy states is impressed on the current autocorrelation function. This impression provides a novel measure of the entropy and location of a partitioning or entropy limit at a packing fraction that coincides with that of the observed suspension's first order freezing transition.
Genome Sequences of Two Putative Streptogramin Producers, Streptomyces sp. Strains TÜ 2975 and TÜ 3180, from the Tübingen Strain Collection
2020-05-20

Streptomyces sp. TÜ 2975 and TÜ 3180 are two strains from the Tübingen Actinomycetes strain collection. Here, we present the draft genome sequences of TÜ 2975 and TÜ 3180, with sizes of 7.62 Mb and 8.63 Mb, respectively.
Factors associated with axillary conversion after neoadjuvant chemotherapy in initially node positive breast cancer patients: A transSENTINA analysis.
2020-05-20

567 Background: Current study concepts in early breast cancer after neoadjuvant chemotherapy (NAT) are aiming at reducing morbidity by omission of axillary surgery in selected patients. Selection criteria for this strategy have to include the probability of conversion from cN1 to ycN0. We analyzed the association of clinical/pathological parameters and axillary conversion with data from arms C and D of the SENTINA trial (Kühn T et al., Lancet Oncol 2013). Methods: Patients were recruited to Arms C/D of the SENTINA trial in case they presented with clinically positive nodes before NAT. Based on their response to NAT they were then assigned to either arm C (clinically conversion to ycN0) or arm D (no clinical conversion (ycN+). In both the pre- and post-NAT scenarios, clinically involved lymph nodes were defined as palpable and/or suspect by ultrasound. Univariate logistic regression analyses were carried out to evaluate the association between clinical/pathological parameters and axillary conversion after NAT. Results: Of the 892 patients in arms C and D of the SENTINA trial 716 were evaluable for this analysis. After NAT, 593 patients converted to ycN0 and were therefore assigned to arm C; in contrast, 123 patients still had involved lymph nodes after NAT (ycN+) and were assigned to Arm D. Arms C and D were compared regarding the clinical/pathological parameters tumor diameter by ultrasound before and after NAT, grading, multifocality, ER status, PR status, HER2 status, pathological complete remission in the breast (breast pCR), morphology, lymphovascular invasion (LVI) and hemangiosis. Only small tumor diameter after NAT (p = 0.0038), achievement of breast pCR (p = 0.0001) and lack of LVI (p = 0.0009) were positively associated with axillary conversion from cN1 to ycN0 after NAT. Conclusions: Because of the small patient number in arm D, we were not able to identify an association between parameters of tumor biology (ER, PR, HER2 and TN status) and axillary conversion. However, favorable response of the primary tumor (represented both clinically by tumor diameter after NAT and pathologically by pCR in the breast) were positively associated with conversion from cN1 to ycN0. These results justify including patients with clinical and pathological response of the primary tumor in trials investigating de-escalation of axillary surgery after NAT.
Efficacy of enzalutamide (ENZA) + androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) by pattern of metastatic spread: ARCHES post hoc analyses.
2020-05-20

5547 Background: ENZA + ADT significantly reduced the risk of radiographic progression or death in men with mHSPC (NCT02677896). Here, we assess how pattern of metastatic spread impacts the efficacy of ENZA + ADT in patients enrolled in ARCHES. Methods: Patients with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or placebo (PBO) + ADT, stratified by disease volume and prior docetaxel treatment. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints included time to prostate-specific antigen (PSA) progression, time to first symptomatic skeletal event (SSE), time to castration resistance, and time to initiation of new antineoplastic therapy. Post hoc analyses were performed by pattern of metastatic spread at study entry. Results: Of the overall population with known metastases at screening (n=1146), the largest patient subgroups were those with bone metastases only (n=513) and those with bone and soft-tissue metastases only (n=351); there were fewer M0 patients or patients with soft-tissue metastases only (n=154) and patients with visceral ± bone metastases (n=128). ENZA + ADT reduced the risk of rPFS and other secondary endpoint measures versus PBO + ADT across all subgroups, with greater relative efficacy observed in patients without visceral metastases (Table). Conclusions: ENZA + ADT provides improvements in rPFS and other secondary endpoints versus PBO + ADT in patients with mHSPC regardless of pattern of metastatic spread, particularly in patients without visceral metastases. These results highlight the importance of patient/physician discussion regarding the use of ENZA in the treatment of mHSPC. Clinical trial information: NCT02677896 . [Table: see text]
CYCLONE 2: A phase II, randomized, placebo-controlled study of abiraterone acetate plus prednisone with or without abemaciclib in patients with metastatic castration-resistant prostate cancer.
2020-05-20

TPS5591 Background: Despite recent advances, nearly all patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) experience disease progression and cancer-specific mortality. Persistent or reactivated androgen receptor (AR) signaling and/or activation of pathways in cross-talk with AR signaling are key drivers of mCRPC progression. Evidence suggests that AR signaling promotes translation of D-type cyclins resulting in cyclin-dependent kinase 4 and 6 (CDK4&amp;6) activation and cell cycle progression. Abemaciclib is an oral selective inhibitor of CDK4&amp;6 dosed on a continuous schedule, that is FDA-approved in combination with endocrine therapy or as monotherapy to treat HR+, HER2- metastatic breast cancer pts. Preclinical studies with prostate cancer cell lines and xenograft models showed that abemaciclib induces cell cycle arrest and tumor growth inhibition. The hypothesis is that addition of abemaciclib to AR targeted therapy may be an effective treatment for mCRPC pts. Methods: CYCLONE 2 (NCT03706365) is a phase II, randomized, double-blind, multicenter, placebo-controlled study to assess the safety and efficacy of abemaciclib in combination with abiraterone acetate plus prednisone (AA+P) as first-line treatment of pts with mCRPC. The study is designed in two parts. Part 1 is a 30-patient safety lead-in to determine the recommended phase II dose (RP2D; 150 mg or 200 mg, twice daily) of abemaciclib in combination with AA (1000 mg, once daily) + P (5 mg, twice daily). In part 2, 150 pts are randomized 1:1 to abemaciclib at the RP2D with AA+P or placebo with AA+P. Pts who received prior AA+P, enzalutamide, apalutamide, darolutamide, radiopharmaceuticals, or sipuleucel-T are excluded. Prior docetaxel for metastatic hormone-sensitive prostate cancer, but not for mCRPC, is allowed. Pts must have progressive mCRPC (by PSA and/or imaging) and an accessible metastatic lesion for tumor biopsy. The co-primary objectives are radiographic PFS (per RECIST1.1 for soft tissue and PCWG3 for bone) and time to PSA progression. Secondary objectives include safety, objective response rate, duration of response, OS, time to symptomatic progression, and pharmacokinetics. Assuming hazard ratios of 0.64 (rPFS) and 0.6 (PSA progression), the study is powered to 80% and 85%, respectively, to test the superiority of abemaciclib plus AA+P vs. placebo plus AA+P at one-sided α=0.1 using stratified log-rank tests. Part 1 is completed and part 2 is enrolling in 70 sites worldwide. Clinical trial information: NCT03706365 .
Density-dependence tips the change of plant–plant interactions under environmental stress
2020-05-21

Abstract Facilitation studies typically compare plants under differential stress levels with and without neighbors, while the density of neighbors has rarely been addressed. However, recent empirical studies indicate that facilitation may be density-dependent too and peak at intermediate neighbor densities. Here, we propose a conceptual model to incorporate density-dependence into theory about changes of plant–plant interactions under stress. To test our predictions, we combine an individual-based model incorporating both facilitative response and effect, with an experiment using salt stress and Arabidopsis thaliana . Theoretical and experimental results are strikingly consistent: (1) the intensity of facilitation peaks at intermediate density, and this peak shifts to higher densities with increasing stress; (2) this shift further modifies the balance between facilitation and competition such that the stress-gradient hypothesis applies only at high densities. Our model suggests that density-dependence must be considered for predicting plant–plant interactions under environmental change.