julilili42/papers huggingface dataset:
Association of clinical/pathological parameters with axillary involvement in early breast cancer in patients with limited sentinel node involvement (< 3 LK) after neoadjuvant chemotherapy (NACT).
2018-05-20

559 Background: The association between pathological complete remission (pCR) in the breast and clinical/pathological parameters is well established, whereas the association of clinical/pathological parameters and residual axillary involvement after NACT is still not sufficiently defined. We used data from the SENTINA trial to analyze this association in a patient population with limited sentinel lymph node (SLN) involvement. Methods: Patients were included if before NACT they presented with a clinically negative axilla but showed involvement of SLNs prior to NACT (Arm B). Analysis was restricted to patients with < 3 involved SLNs before NACT. All patients received SLNB and axillary dissection after NACT. Univariate and multivariate analyses were carried out to evaluate the association between clinical/pathological parameters and axillary involvement after NACT. Results: Arm B of the SENTINA study contained 360 patients, 265 of which were evaluable with respect to the above parameters. After NACT 66/265 (24.9%) patients had involved SLNs or non-SLNs after NACT; 71/265 (26.8%) achieved a pCR in the breast. We observed a significant association between pCR in the breast and ER negativity (p < 0.0001), PR negativity (p < 0.0001) and triple negative (TN) status (p = 0.001). However, no statistically significant association between residual axillary involvement after NACT and clinical/pathological parameters ER (p = 0.381), PR (p = 0.52), HER2 (p = 0.771), TN status (p = 0.937), grade (G) 1 (p = 0.081), G 2 (p = 0.335), G 3 (p = 0.747), age (p = 0.789), tumor size before NACT (p = 0.761) and pCR in the breast (p = 0.136) could be demonstrated. Conclusions: Our analysis demonstrates that patients enrolled in the SENTINA trial with clinically negative axilla but limited SLN involvement show positive axillary nodes in 24.9% of cases after NACT. We found no association between residual axillary involvement after NACT and clinical/pathological parameters. We could not identify a subset of patients in this cohort for whom axillary surgery after NACT could be safely omitted.
Correlating whole blood AR-V7 and AR-V9 with therapy response to AR-targeted therapies in metastatic castrate-resistant prostate cancer (mCRPC).
2018-05-20

e17070 Background: The expression of androgen receptor splice variants (AR-V) in mCRPC patients has widely been regarded as a predictive biomarker for non-response to AR-targeted therapies. However, recent data from our group and others has questioned this association. We report new data from our whole blood assay, correlating baseline and end-of-treatment (EOT) AR-V7 and AR-V9 expression with clinical outcomes in mCRPC patients treated with abiraterone or enzalutamide. Methods: We have previously developed a whole-blood, quantitative polymerase chain reaction assay for detecting circulating AR-V7 and AR-V9. The assay was applied to samples prospectively collected from 48 mCRPC patients immediately prior to commencing abiraterone or enzalutamide, and where available, at treatment cessation. Patients positive for either AR-V7 or AR-V9 were defined as AR-V-positive, and AR-V-negative if neither variant was detected. All AR-V-positive samples underwent confirmatory DNA sequencing to confirm variant expression. AR-V expression was correlated with PSA response rate (chi-square test) and PSA progression-free survival (PSA-PFS) (log-rank test). Results: The median follow-up was 10.6 mo. Twelve out of 48 patients (25%) were AR-V-positive, with no samples positive for both variants at baseline. Similar response rates were observed in AR-V-positive (7/12) and AR-V-negative (23/36) patients (50% vs. 64%, p = 0.7). PSA-PFS did not differ significantly between groups (8.1 mo vs. not reached, p = 0.5). EOT samples were available in nine patients, with four exhibiting AR-V-positivity. Of these, two (50%) patients were AR-V-positive at baseline, and two (50%) patients converted from AR-V-negative to AR-V-positive at treatment cessation (PSA-PFS 3.4 and 2.6 mo respectively). One of the conversion patients transitioned from V7–/V9– to V7+/V9+. Neither AR-V7 nor AR-V9 were detected in any of 13 normal male controls. Conclusions: With extended follow-up, whole blood expression of AR-V7 and AR-9 continues to not correlate with treatment response in mCRPC patients commencing AR-targeted therapies. Dynamic changes in AR-V expression were detectable with this assay.
Rhabdomyosarcoma in the first year of life: outcome data from five trials and one registry of the Cooperative Weichteilsarkom Studiengruppe (CWS).
2018-05-20

10534 Background: Infantile soft tissue sarcoma (STS) has been associated with worse survival than STS in older children. Age, histology, molecular phenotype and treatment adjustment according to age may affect the outcome of patients with rhabdomyosarcoma (RMS) diagnosed during the first year of life. Methods: The records of 5 trials and one registry, conducted by the Cooperative Studiengruppe (CWS) between 1981–2016, were reviewed to identify children diagnosed with RMS during the first year of life. Patient characteristics, treatment data and outcome were evaluated. Results: A total of 155 infants ≤ 12 months with histological diagnosis of RMS were identified, including 115 cases of embryonal RMS (RME), 38 cases of alveolar RMS (21/25 PAX7/3:FOXO1-positive (PF+)), 1 case of botryoid RMS and 1 case of spindle-cell RMS. 144 infants presented with localized disease (LD); 11 with metastatic disease (MD). 150 children received age- and weight-adapted chemotherapy (1/3 dose reduction in infants ≤6 months): VAIA/VACA/CEVAIE (n = 100), IVA/VA/VAC/other (n = 50). Resections were achieved R0 (n = 64), R1 (n = 37), R2 (n = 37) and biopsies (n = 17). Adjuvant radiotherapy (RT) was administered to 37 children. After a median follow-up of 7.55 years [0.24- 30], the 5-year overall survival (OS) and event-free survival (EFS) rates were 66% and 49% for the whole group. Significant prognostic factors were LD (OS 69% vs 12% in MD, p = 0.000), tumor size and resection status. For patients with LD, tumor size and best resection (R0/R1/R2) were no prognostic factors and RT did not improve survival. 2nd malignancy occurred in 6 infants. OS and EFS rates of newborns (≤1 month, n = 15) were significantly worse (31% and 17%, respectively) compared to those > 1 month and ≤ 12 months (n = 140, OS 69% and EFS 52%, p = 0.001 and 0.001). Children with RMA (41% and 24%) and/or PF+-RMS achieved significantly worse regarding OS and EFS (36% and 19%) than those diagnosed with RME (72% and 56%; p = 0.018 and 0.003). Conclusions: Survival of infants with RMS is comparable to older children. Metastatic disease, RMA histology/ PF+ status and age below 1 month are factors relevant for inferior outcome. RT did not improve survival in LD.
Addressing unmet medical needs in maintenance treatment for newly diagnosed multiple myeloma (NDMM).
2018-05-20

e20049 Background: In NDMM, following response to primary therapy, maintenance may delay progression and prolong OS; however, maintenance is not an established treatment option worldwide; lenalidomide (R) is the only approved agent, and only post-ASCT. Methods: We reviewed published/ongoing phase 3 trials of current/emerging maintenance treatments to identify unmet needs and how these may be addressed. Results: Maintenance with R, bortezomib (V), or thalidomide (T) has been well-studied and offers differential benefit, leaving unmet needs in some populations. R post-ASCT prolongs PFS/OS but increases the risk of SPMs and shows a less pronounced benefit in some subgroups, e.g high-risk (HR) cytogenetics, high ISS stage. R has improved PFS but not OS in the non-ASCT setting. T prolongs PFS/OS but not in HR cytogenetics, and with notable toxicity. V has activity post-ASCT, including in HR cytogenetics, and in the non-ASCT setting, but has not been studied in a placebo-controlled setting. Long-term use of these agents may be limited by short- and long-term toxicity and the treatment burden of repeated IV/SC administration. There is a need for a therapy that can be dosed for an extended time without cumulative/late-onset toxicity or emergence of resistant clones and that can offer benefit in all patients, including HR subgroups. Ongoing studies of ixazomib (I), carfilzomib (K), and daratumumab (D) (Table) may address some of these needs. Long-term I/K/D-based treatment results in deepening responses and improved outcomes, including in HR subgroups; oral ixazomib potentially offers convenient, feasible long-term proteasome inhibitor therapy with a manageable toxicity profile. Conclusions: Current maintenance therapies improve patient outcomes, with some limitations. Emerging therapies may offer a feasible approach due to manageable long-term toxicity profiles and convenience, especially oral agents. Ongoing phase 3 maintenance trials Agent Study Design NCT number I TOURMALINE-MM3 I vs placebo, post-ASCT NCT02181413 TOURMALINE-MM4 I vs placebo, non-ASCT NCT02312258 GEM2014MAIN I-R vs R, post-ASCT NCT02406144 K Uni of Chicago KRd vs R, post-ASCT NCT02659293 D Cassiopeia D vs observation, post-ASCT NCT02541383
Community-based benchmarking improves spike rate inference from two-photon calcium imaging data
2018-05-21

In recent years, two-photon calcium imaging has become a standard tool to probe the function of neural circuits and to study computations in neuronal populations. However, the acquired signal is only an indirect measurement of neural activity due to the comparatively slow dynamics of fluorescent calcium indicators. Different algorithms for estimating spike rates from noisy calcium measurements have been proposed in the past, but it is an open question how far performance can be improved. Here, we report the results of the spikefinder challenge, launched to catalyze the development of new spike rate inference algorithms through crowd-sourcing. We present ten of the submitted algorithms which show improved performance compared to previously evaluated methods. Interestingly, the top-performing algorithms are based on a wide range of principles from deep neural networks to generative models, yet provide highly correlated estimates of the neural activity. The competition shows that benchmark challenges can drive algorithmic developments in neuroscience.
Identification of key lipids critical for platelet activation by comprehensive analysis of the platelet lipidome
2018-05-21

Key Points First quantitative analysis of dynamic platelet lipidome modulation reveals key lipids altered in platelet activation. Lipidomics in a knockout approach unravel SMPD1 as a powerful modulator of platelet lipidome and activation via regulation of SPC.
Estimating mechanical properties of cloth from videos using dense motion trajectories: Human psychophysics and machine learning
2018-05-21

Humans can visually estimate the mechanical properties of deformable objects (e.g., cloth stiffness). While much of the recent work on material perception has focused on static image cues (e.g., textures and shape), little is known about whether humans can integrate information over time to make a judgment. Here we investigated the effect of spatiotemporal information across multiple frames (multiframe motion) on estimating the bending stiffness of cloth. Using high-fidelity cloth animations, we first examined how the perceived bending stiffness changed as a function of the physical bending stiffness defined in the simulation model. Using maximum-likelihood difference-scaling methods, we found that the perceived stiffness and physical bending stiffness were highly correlated. A second experiment in which we scrambled the frame sequences diminished this correlation. This suggests that multiframe motion plays an important role. To provide further evidence for this finding, we extracted dense motion trajectories from the videos across 15 consecutive frames and used the trajectory descriptors to train a machine-learning model with the measured perceptual scales. The model can predict human perceptual scales in new videos with varied winds, optical properties of cloth, and scene setups. When the correct multiframe was removed (using either scrambled videos or two-frame optical flow to train the model), the predictions significantly worsened. Our findings demonstrate that multiframe motion information is important for both humans and machines to estimate the mechanical properties. In addition, we show that dense motion trajectories are effective features to build a successful automatic cloth-estimation system.
Serum neurofilament light chain is increased in hereditary spastic paraplegias
2018-05-21

Abstract Blood biomarkers are still largely missing in hereditary spastic paraplegias (HSPs). We here explored Neurofilament light chain (NfL) as a biomarker in HSP. Serum NfL was assessed in 96 HSP (63 genetically confirmed), 96 healthy control, and 33 ALS subjects by single molecule array (Simoa). Compared to controls, NfL was increased in HSP ( P &lt; 0.001), correlating with cross‐sectional disease progression ( ρ = 0.28). Levels were lower than in ALS ( P &lt; 0.001), allowing to differentiate HSP from ALS (AUC = 0.91). Serum NfL might serve as a biomarker in HSP indicating neuronal damage and, if confirmed longitudinally, disease progression. It might also support differentiating HSP from ALS.
Brief Report: Smoking in Systemic Sclerosis: A Longitudinal European Scleroderma Trials and Research Group Study
2018-05-21

Objective Data on the role of tobacco exposure in systemic sclerosis ( SS c; scleroderma) severity and progression are scarce. We aimed to assess the effects of smoking on the evolution of pulmonary and skin manifestations, based on the European Scleroderma Trials and Research group database. Methods Adult SS c patients with data on smoking history and a 12–24‐month follow‐up visit were included. Associations of severity and progression of organ involvement with smoking history and the Comprehensive Smoking Index were assessed using multivariable regression analyses. Results A total of 3,319 patients were included (mean age 57 years, 85% female); 66% were never smokers, 23% were ex‐smokers, and 11% were current smokers. Current smokers had a lower percentage of antitopoisomerase autoantibodies than previous or never smokers (31% versus 40% and 45%, respectively). Never smokers had a higher baseline forced expiratory volume in 1 second/forced vital capacity ( FEV 1 / FVC ) ratio than previous and current smokers ( P &lt; 0.001). The FEV 1 / FVC ratio declined faster in current smokers than in never smokers ( P = 0.05) or ex‐smokers ( P = 0.01). The baseline modified Rodnan skin thickness score ( MRSS ) and the MRSS decline were comparable across smoking groups. Although heavy smoking (&gt;25 pack‐years) increased the odds of digital ulcers by almost 50%, there was no robust adverse association of smoking with digital ulcer development. Conclusion The known adverse effect of smoking on bronchial airways and alveoli is also observed in SS c patients; however, robust adverse effects of smoking on the progression of SS c‐specific pulmonary or cutaneous manifestations were not observed.
The EVcouplings Python framework for coevolutionary sequence analysis
2018-05-21

Abstract Summary Coevolutionary sequence analysis has become a commonly used technique for de novo prediction of the structure and function of proteins, RNA, and protein complexes. This approach requires extensive computational pipelines that integrate multiple tools, databases, and data processing steps. We present the EVcouplings framework, a fully integrated open-source application and Python package for coevolutionary analysis. The framework enables generation of sequence alignments, calculation and evaluation of evolutionary couplings (ECs), and de novo prediction of structure and mutation effects. The application has an easy to use command line interface to run workflows with user control over all analysis parameters, while the underlying modular Python package allows interactive data analysis and rapid development of new workflows. Through this multi-layered approach, the EVcouplings framework makes the full power of coevolutionary analyses available to entry-level and advanced users. Availability https://github.com/debbiemarkslab/evcouplings Contact sander.research@gmail.com , debbie@hms.harvard.edu
Influence of Enzyme Quantity and Distribution on the Self-Propulsion of Non-Janus Urease-Powered Micromotors
2018-05-22

The use of enzyme catalysis to power micro- and nanomachines offers unique features such as biocompatibility, versatility, and fuel bioavailability. Yet, the key parameters underlying the motion behavior of enzyme-powered motors are not completely understood. Here, we investigate the role of enzyme distribution and quantity on the generation of active motion. Two different micromotor architectures based on either polystyrene (PS) or polystyrene coated with a rough silicon dioxide shell (PS@SiO<sub>2</sub>) were explored. A directional propulsion with higher speed was observed for PS@SiO<sub>2</sub> motors when compared to their PS counterparts. We made use of stochastically optical reconstruction microscopy (STORM) to precisely detect single urease molecules conjugated to the micromotors surface with a high spatial resolution. An asymmetric distribution of enzymes around the micromotor surface was observed for both PS and PS@SiO<sub>2</sub> architectures, indicating that the enzyme distribution was not the only parameter affecting the motion behavior. We quantified the number of enzymes present on the micromotor surface and observed a 10-fold increase in the number of urease molecules for PS@SiO<sub>2</sub> motors compared to PS-based micromotors. To further investigate the number of enzymes required to generate a self-propulsion, PS@SiO<sub>2</sub> particles were functionalized with varying amounts of urease molecules and the resulting speed and propulsive force were measured by optical tracking and optical tweezers, respectively. Surprisingly, both speed and force depended in a nonlinear fashion on the enzyme coverage. To break symmetry for active propulsion, we found that a certain threshold number of enzymes molecules per micromotor was necessary, indicating that activity may be due to a critical phenomenon. Taken together, these results provide new insights into the design features of micro/nanomotors to ensure an efficient development.
Mapping the HLA Ligandome of Colorectal Cancer Reveals an Imprint of Malignant Cell Transformation
2018-05-22

Abstract Immune cell infiltrates have proven highly relevant for colorectal carcinoma prognosis, making colorectal cancer a promising candidate for immunotherapy. Because tumors interact with the immune system via HLA-presented peptide ligands, exact knowledge of the peptidome constitution is fundamental for understanding this relationship. Here, we comprehensively describe the naturally presented HLA ligandome of colorectal carcinoma and corresponding nonmalignant colon (NMC) tissue. Mass spectrometry identified 35,367 and 28,132 HLA class I ligands on colorectal carcinoma and NMC, attributable to 7,684 and 6,312 distinct source proteins, respectively. Cancer-exclusive peptides were assessed on source protein level using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER), revealing pathognomonic colorectal carcinoma–associated pathways, including Wnt, TGFβ, PI3K, p53, and RTK-RAS. Relative quantitation of peptide presentation on paired colorectal carcinoma and NMC tissue further identified source proteins from cancer- and infection-associated pathways to be overrepresented merely within the colorectal carcinoma ligandome. From the pool of tumor-exclusive peptides, a selected HLA-ligand subset was assessed for immunogenicity, with the majority exhibiting an existing T-cell repertoire. Overall, these data show that the HLA ligandome reflects cancer-associated pathways implicated in colorectal carcinoma oncogenesis, suggesting that alterations in tumor cell metabolism could result in cancer-specific, albeit not mutation-derived, tumor antigens. Hence, a defined pool of unique tumor peptides, attributable to complex cellular alterations that are exclusive to malignant cells, might comprise promising candidates for immunotherapeutic applications. Significance: Cancer-associated pathways are reflected in the antigenic landscape of colorectal cancer, suggesting that tumor-specific antigens do not necessarily have to be mutation-derived but may also originate from other alterations in cancer cells. Cancer Res; 78(16); 4627–41. ©2018 AACR.
First observations of speed of light tracks by a fluorescence detector looking down on the atmosphere
2018-05-22

EUSO-Balloon is a pathfinder mission for the Extreme Universe Space\\nObservatory onboard the Japanese Experiment Module (JEM-EUSO). It was launched\\non the moonless night of the 25 of August 2014 from Timmins, Canada. The\\nflight ended successfully after maintaining the target altitude of 38 km for\\nfive hours. One part of the mission was a 2.5 hour underflight using a\\nhelicopter equipped with three UV light sources (LED, xenon flasher and laser)\\nto perform an inflight calibration and examine the detectors capability to\\nmeasure tracks moving at the speed of light. We describe the helicopter laser\\nsystem and details of the underflight as well as how the laser tracks were\\nrecorded and found in the data. These are the first recorded laser tracks\\nmeasured from a fluorescence detector looking down on the atmosphere. Finally,\\nwe present a first reconstruction of the direction of the laser tracks relative\\nto the detector.\\n
Chlorosis as a developmental program in cyanobacteria: the proteomic fundament for survival and awakening
2018-05-22

Summary Cyanobacteria that do not fix atmospheric nitrogen gas survive prolonged periods of nitrogen starvation in a chlorotic, dormant state where cell growth and metabolism are arrested. Upon nutrient availability, these dormant cells return to vegetative growth within 2–3 days. This resuscitation process is highly orchestrated and relies on the stepwise re-installation and activation of essential cellular structures and functions. We have been investigating the transition to chlorosis and the return to vegetative growth as a simple model of a cellular developmental process and a fundamental survival strategy in biology. In the present study, we used quantitative proteomics and phosphoproteomics to describe the proteomic landscape of a dormant cyanobacterium and its dynamics during the transition to vegetative growth. We identified intriguing alterations in the set of ribosomal proteins, in RuBisCO components, in the abundance of central regulators and predicted metabolic enzymes. We found O-phosphorylation as an abundant protein modification in the chlorotic state, specifically of metabolic enzymes and proteins involved in photosynthesis. Non-degraded phycobiliproteins were hyperphosphorylated in the chlorotic state. We provide evidence that hyperphosphorylation of the terminal rod linker CpcD increases the lifespan of phycobiliproteins during chlorosis.