julilili42/papers huggingface dataset:
Comparison of therapy benefit from standard anti-HER2 directed approaches in metastatic breast cancer (MBC) between initially HER2-positive patients and patients initially HER2-negative with switch to HER2-positive.
2021-05-20

1040 Background: Metaanalyses have demonstrated that 5% of initially HER2 negative breast cancer patients switch to HER2 positive during the course of the disease. Whether there is a difference in benefit from standard HER2 targeted therapies between patients initially HER2 positive and patients switching from negative to positive is unclear. We used data from the PRAEGNANT registry to compare the outcome of those patients. Methods: PRAEGNANT is a prospective advanced breast cancer registry (NCT02338167) focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis compared progression-free survival (PFS) with standard HER2 targeted therapies between patients with tumors initially HER2 negative and switched to HER2 positive and patients with tumors that were initially HER2 positive adjusted for age and hormone receptor status. Results: At the time of this analysis 4061 patients with MBC were included in the PRAEGNANT registry, 49 of which met the requirements for this analysis. Median age was 56 (IQR 48-64) years and 87.8% of the patients were hormone receptor positive. At first diagnosis 15 patients were HER2 negative and 34 patients were HER2 positive. Within a median observation time of 9 months (95%CI: 3.8, 23.7) 35 PFS events occurred. Median observation time was 9 months (95% CI: 3.8, 23.7). Initially HER2 positive patients had a longer progression-free survival (HR = 0.49, 95% CI (0.24, 1.03), p = 0.07) as compared to initially HER2 negative patients switched to HER2 positive. The 1- and 2-year-PFS rates were also higher for patients initially HER2 positive: 1-year-PFS: 52% (95% CI: 36%, 73%) versus 26 % (95% CI: 12%, 52%); 2-year-PFS: 44% (95% CI: 29%, 67%) versus 19% (95% CI: 7%, 50%). Conclusions: Median PFS and 1- and 2-year PFS rate seem to be better in patients HER2 positive at initial diagnosis receiving standard HER2 directed therapies. Although our result has to be interpreted with caution because of the small cohort and the retrospective nature of our analysis, it justifies prospective research including the group of initially HER2 negative patients switched to HER2 positive as a distinct entity. Clinical trial information: NCT02338167 .
Margaret MacDonald’s scientific common-sense philosophy
2021-05-20

Margaret MacDonald (1907–56) was a central figure in the history of early analytic philosophy in Britain due to both her editorial work as well as her own writings. While her later work on aesthetics and political philosophy has recently received attention, her early writings in the 1930s present a coherent and, for its time, strikingly original blend of common-sense and scientific philosophy. In these papers, MacDonald tackles the central problems of philosophy of her day: verification, the problem of induction, and the relationship between philosophical and scientific method. MacDonald's philosophy of science starts from the principle that we should carefully analyse the elements of scientific practice (particularly its temporal features) and the ways that scientists describe that practice. That is, she applies the techniques of ordinary language philosophy to actual scientific language. MacDonald shows how 'scientific common-sense' is inconsistent with both of the dominant schools of philosophy of her day. Bringing MacDonald back into the story of analytic philosophy corrects the impression that in early analytic philosophy, there are fundamental dichotomies between the style of Moore and Wittgenstein, on the one hand, and the Vienna Circle on the other.
Resting-State Network Alterations Differ between Alzheimer’s Disease Atrophy Subtypes
2021-05-20

Abstract Several Alzheimer’s disease (AD) atrophy subtypes were identified, but their brain network properties are unclear. We analyzed data from two independent datasets, including 166 participants (103 AD/63 controls) from the DZNE-longitudinal cognitive impairment and dementia study and 151 participants (121 AD/30 controls) from the AD neuroimaging initiative cohorts, aiming to identify differences between AD atrophy subtypes in resting-state functional magnetic resonance imaging intra-network connectivity (INC) and global and nodal network properties. Using a data-driven clustering approach, we identified four AD atrophy subtypes with differences in functional connectivity, accompanied by clinical and biomarker alterations, including a medio-temporal-predominant (S-MT), a limbic-predominant (S-L), a diffuse (S-D), and a mild-atrophy (S-MA) subtype. S-MT and S-D showed INC reduction in the default mode, dorsal attention, visual and limbic network, and a pronounced reduction of “global efficiency” and decrease of the “clustering coefficient” in parietal and temporal lobes. Despite severe atrophy in limbic areas, the S-L exhibited only marginal global network but substantial nodal network failure. S-MA, in contrast, showed limited impairment in clinical and cognitive scores but pronounced global network failure. Our results contribute toward a better understanding of heterogeneity in AD with the detection of distinct differences in functional connectivity networks accompanied by CSF biomarker and cognitive differences in AD subtypes.
Search for dark matter annihilation in the Wolf-Lundmark-Melotte dwarf irregular galaxy with H.E.S.S.
2021-05-20

We search for an indirect signal of dark matter through very high-energy γ rays from the Wolf-Lundmark-Melotte (WLM) dwarf irregular galaxy. The pair annihilation of dark matter particles would produce Standard Model particles in the final state such as γ rays, which might be detected by ground-based Cherenkov telescopes. Dwarf irregular galaxies represent promising targets as they are dark matter dominated objects with well-measured kinematics and small uncertainties on their dark matter distribution profiles. In 2018, the five-telescopes of the high energy stereoscopic system observed the dwarf irregular galaxy WLM for 18 hours. We present the first analysis based on data obtained from an imaging atmospheric Cherenkov telescope for this subclass of dwarf galaxy. As we do not observe any significant excess in the direction of WLM, we interpret the result in terms of constraints on the velocity-weighted cross section for dark matter pair annihilation ⟨σv⟩ as a function of the dark matter particle mass for various continuum channels, as well as the prompt γγ emission. For the τ+τ- channel, the limits reach a ⟨σv⟩ value of about 4×10-22 cm3 s-1 for a dark matter particle mass of 1 TeV. For the prompt γγ channel, the upper limit reaches a ⟨σv⟩ value of about 5×10-24 cm3 s-1 for a mass of 370 GeV. These limits represent an improvement of up to a factor 200, with respect to previous results for the dwarf irregular galaxies for TeV dark matter search.
Quality of life, functioning, and symptoms in patients with previously treated locally advanced or metastatic urothelial carcinoma from EV-301: A randomized phase 3 trial of enfortumab vedotin versus chemotherapy.
2021-05-20

4539 Background: In EV-301, a randomized, open-label phase 3 study (NCT03474107), enfortumab vedotin (EV), a Nectin-4–directed therapy, significantly prolonged median overall survival by ̃3.9 months and reduced the risk of death by 30% compared with standard chemotherapy (SC; docetaxel, paclitaxel, or vinflunine) in patients with previously treated locally advanced/metastatic urothelial carcinoma. Understanding patient perspectives and experiences is important to further contextualize the benefits/risks of EV. Here, we report key prespecified quality-of-life (QoL) endpoints, a secondary objective of EV-301. Methods: Patients completed the validated European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, on Day 1 of each week for the first 12 weeks, and then every 12 weeks until discontinuation. The QLQ-C30 assessed functional domains, symptom scales/items, financial impact, and overall health/QoL. Descriptive statistics were used to summarize instrument compliance rates and scores; mixed model repeated measures were used to evaluate changes from baseline over time. Logistic regressions were conducted to assess confirmed improvement rates, defined as clinically meaningful improvement (predefined per domain) over two subsequent visits. Results: Of the 608 randomized patients (EV, n = 301; SC, n = 307), 77.3% were male, median age was 68 (range: 30-88), and 30.9% had liver metastasis. Questionnaire compliance rates at baseline were ̃90% in both groups; during the study, average rates were 70.2% (EV) and 66.9% (SC). Baseline QLQ-C30 scores were similar between groups. At Week 12, scores on the global health status (GHS) scale were similar between groups (EV: -2.8, SC: -5.0; P=.2429), but SC was associated with numerically greater deterioration and more variability in QoL over the first 12 weeks. Patients receiving EV had significant reduction in pain symptoms (EV: -5.62, SC: +0.11; adjusted difference: -5.73, P&lt;.05), but significant worsening of appetite loss (EV: +8.55, SC: +1.26; adjusted difference: 7.29, P&lt;.05) compared with SC. Other symptom scores were not significantly different between groups. Higher proportions of patients on EV vs SC had significant confirmed improvements across all functioning domains (role, physical, emotional, social, cognitive), GHS, and several symptom scales (pain, fatigue, dyspnea, constipation). The greatest difference in improvement was reported for pain (EV: 51.6%, SC: 28.8%; OR = 2.76[1.81, 4.22]). Conclusions: Compared with SC, patients receiving EV had numerically less deterioration and variability in QoL during the first 12 weeks of treatment. More patients in the EV group had improvements over SC in 10 of 15 QLQ-C30 domains; improvement in pain showed the largest benefit. Clinical trial information: NCT03474107.
Halogen (F, Cl, Br, I) contents in silt and clay fractions of a Cambisol from a temperate forest
2021-05-20

Abstract In spite of considerable efforts to understand the role of halogens (F, Cl, Br, I) in soil, concentration data for different soil size fractions is still sparse and information on the sorption behavior of halogens in natural soils is limited. We determined total halogen concentrations in different soil horizons and particle size fractions (i.e., coarse silt with 20–63 μm, medium and fine silt with 2–20 μm, coarse clay with 0.2 to &amp;lt;2 μm and medium clay with 0.02–0.2 μm) of a Cambisol from a temperate forest ecosystem in SW Germany. Furthermore, we estimated the minimum proportions of sorbed halogens onto clay minerals and pedogenic oxides for different soil horizons and different particle size fractions. Vertical depth profiles of halogens in the individual soil particle size fractions matched with the bulk soil vertical patterns. The lack of vertical differences of total halogens concentrations (Ftot, Brtot, and Itot) in the mineral soil during soil development may be due to steady state or equilibrium conditions between weathering, sorption processes, and surface input. In contrast, the vertical depth pattern of Cltot tended to decrease, suggesting the process of Cl accumulation in the topsoil and nutrient uplift. While F was likely mainly incorporated into the crystal lattice of clay minerals and gibbsite occupying OH-sites, significant amounts of the halogens with larger ionic radii (Cl, Br, and I) were sorbed. The largest amounts (around 90% Cl and 70% Br and I, respectively) were sorbed on the smallest particle size fraction investigated (medium clay fraction; 0.02–0.2 μm), although this fraction only contributed about 1 wt% to the bulk soil. This is probably related to the highest sorption capacity of small particles due to their large surface area. Our study provides new data on sorption behavior of the various halogens in soils of forest ecosystems, which is different between F and the heavier halogens (Cl, Br, I) and further depends on soil particle sizes. The understanding of the chemical behavior of halogens in soils has implications for the retention processes of pollutants in landfills or radioactive waste disposal.
Synthesis of the [11]Cyclacene Framework by Repetitive Diels–Alder Cycloadditions
2021-05-20

The Diels–Alder cycloaddition between bisdienes and bisdienophile incorporating the 7-oxa-bicyclo[2.2.1]heptane unit are well known to show high diastereoselectivity that can be exploited for the synthesis of molecular belts. The related bisdiene 5,6,7,8-tetramethylidene-2-bicyclo[2.2.2]octene is a valuable building block for the synthesis of photoprecursors for acenes, but it has not been employed for the synthesis of molecular belts. The present work investigates by computational means the Diels–Alder reaction between these bisdiene building blocks with syn-1,4,5,8-tetrahydro-1,4:5,8-diepoxyanthracene, which shows that the diastereoselectivity of the Diels–Alder reaction of the etheno-bridged bisdiene is lower than that of the epoxy-bridged bisdiene. The reaction of the etheno-bridged bisdiene and syn-1,4,5,8-tetrahydro-1,4:5,8-diepoxyanthracene in 2:1 ratio yields two diastereomers that differ in the orientation of the oxa and etheno bridges based on NMR and X-ray crystallography. The all-syn diastereomer can be transformed into a molecular belt by inter- and intramolecular Diels–Alder reactions with a bifunctional building block. The molecular belt could function as a synthetic intermediate en route to a [11]cyclacene photoprecursor.
Prognostic impact of recurrence score, endocrine response and clinical-pathological factors in high-risk luminal breast cancer: Results from the WSG-ADAPT HR+/HER2- chemotherapy trial.
2021-05-20

504 Background: In HR+/HER2- N0-1 early BC, postmenopausal patients (pts) with RSTM &gt; 25 and a substantial proportion of premenopausal pts seem to benefit from addition of adjuvant chemotherapy (CT) to endocrine therapy (ET). However, the magnitude of absolute benefit from this treatment intensification seems to depend on clinical-pathological and biological prognostic factors. For the first time, we present outcome from the CT part of the prospective phase III WSG-ADAPT HR+/HER- trial combining both static (RS in baseline core biopsy (CB) and dynamic (Ki67 response) biomarkers to optimize adjuvant therapy in luminal EBC. Methods: Pts with clinically high-risk HR+/HER2- EBC (cT2-4 OR clinically N+ OR G3 OR Ki67&gt;15%) were initially treated by 3 (+/-1) weeks of standard ET (postmenopausal: mostly AI; premenopausal: TAM) before surgery or sequential CB. Pts with cN2-3 or G3/Ki67&gt;40% were randomized directly to the CT trial. pN0-1 pts with RS0-11 OR RS12-25/ET-response (central Ki67 postendocrine &lt;10%) received ET alone; the remaining high-risk cohort was randomized to the CT trial: (neo)adjuvant dose-dense CT (4xPaclitaxelà4xEC q2w vs. 8xNab-Paclitaxel q1wà4xEC q2w) followed by ET. Primary endpoint is efficacy comparison of CT schedules for survival; secondary endpoints reported here involve impacts of key prognostic factors on survival. Kaplan-Meier and Cox proportional hazard models were used to estimate survival curves and hazard ratios. For this analysis, subgroups free of selection bias by RS/ET-response were defined. Results: 5625 pts were screened and 4621 (ITT) entered the trial. After 4.9y median follow-up, higher baseline and post-endocrine Ki-67 levels were associated with poorer iDFS (both p &lt; 0.001). In the CT cohort (n = 2331), higher RS, nodal status, and tumor size were generally associated with poorer iDFS. However, iDFS differed between N1 and N0 status only among younger pts (&lt;50 years). In pts with &gt;4 positive LN (n = 390), lower RS was associated with improved iDFS (RS0-11 vs RS &gt; 25: p log-rank = 0.016, 5y-iDFS 90% vs. 64%). In pts with RS &gt; 25 (n = 965), low Ki67 postendocrine , N0 status, and c/pT1 status were associated with improved iDFS. In particular, ET-responders had higher 5y-iDFS (84%) than ET-non-responders (77%; p log-rank = 0.040). Younger patients (&lt;50 years old) with N0-1 RS 12-25/ ET-non-responders treated by CT had non-significantly poorer 5-year iDFS (89%) compared to those with ET-response treated by ET only (92%) (p log-rank = 0.249). Conclusion: First results from the prospective high risk cohort from a large prospective phase III ADAPT trial provide evidence for good prognosis in some pts with &gt;4 positive LN and e.g. low RS. Moreover combination of lower post-endocrine Ki-67 and limited tumor burden may be a promising criterion for CT de-escalation strategies even in patients with high RS. Clinical trial information: NCT01779206.
The truly advantaged: racial inequalities of educational opportunities among the privileged in the United States
2021-05-20

This article pinpoints the mathematic performance gaps among high-socioeconomic background (SES) students from different racial groups in the United States. By doing so, it sheds light on how racial and socioeconomic privilege intersects thus creating different educational outcomes among high-SES children. In short, it illuminates who are the truly advantaged in the American educational system. Taken together, the results suggest that there are substantial racial performance gaps among high-SES children. First, white and Asian privileged children outperform their black and Hispanic counterparts. Second, black high-SES children appear to be the least advantaged among the privileged, and their mathematic performance lags over two years behind that of whites and Asians. What is more, low-SES Asians and whites are more likely to be high achievers than high-SES blacks are. Finally, Hispanics appear to perform better than their black counterparts, nonetheless, they lag about one year behind their Asian and white high-SES peers.
‘All We Have to Decide Is What to Do with the Time That Is Given to Us’ a Photovoice Study on Physical Activity in Nursing Homes
2021-05-20

(1) Background: Despite high prevalence of physical inactivity and sedentariness among nursing home residents, research on the influence of environments on this topic remains scarce. This Photovoice study explores how structural and social environments relate to residents’ everyday physical activity (PA). (2) Methods: 27 residents, staff, and significant others conducted Photovoice in eight nursing homes in Germany to document factors facilitating or hindering PA. Photographs were discussed with the participants in eight focus groups and analysed using thematic analysis. (3) Results: 169 photographs (between 8 and 42per home) were categorized into three thematic groups: (1) ‘architectural challenges for PA promotion in nursing homes’; (2) ‘opportunities and limitations of using daily work equipment for PA promotion’; (3) ‘social incentives for PA promotion’. Photographs’ foci in the homes differed considerably between participant groups. Staff primarily chose environmental constructions and aids that they perceived to enable residents’ PA. Residents were more likely to express affections and emotions that would encourage them to be active. (4) Conclusions: PA promotion research in this setting should be sensitive to diverse perceptions of different stakeholder groups and existing power imbalances. Interventions are needed that integrate residents’ needs and train staff on how to consider residents’ perspectives.
A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST).
2021-05-20

TPS4597 Background: Non-clear cell renal cell carcinomas (nccRCC) account for approximately 25% of RCC patients (pts.). Data on treatment strategies for this heterogenous group of RCC are still limited, since most clinical trials focus on clear-cell RCC (ccRCC) histology. Recently combination therapies with immune checkpoint inhibitors (IO, avelumab or pembrolizumab) and tyrosinekinaseinhibitors (TKI) (axitinib) have been approved for treatment in RCC in all International Metastatic RCC Database Consortium (IMDC) risk groups. Additionally nivolumab and ipilimumab (IO/IO) has been approved for treatment in intermediate and high risk pts. showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) compared to sunitinib. Moreover retrospective analysis in nccRCC pts. have shown promising results for IO-based therapies as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky &gt;70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ̃306 pts. stratified for papillary or non-papillary non-clear cell histology and by the IMDC risk score. Pts. will be randomized 1:1 to either i) nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by nivolumab fixed dose 240mg IV every 2 weeks or fixed dose 480mg IV every 4 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 214 patients (132 pts with papillary, 76 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423.