julilili42/papers huggingface dataset:
ProtEGOnist: Visual Analysis of Interactions in Small World Networks Using Ego‐graphs
2024-06-01

Abstract Visualizing small‐world networks such as protein‐protein interaction networks or social networks often leads to visual clutter and limited interpretability. To overcome these problems, we present ProtEGOnist , a visualization approach designed to explore small‐world networks. ProtEGOnist visualizes networks using ego‐graphs that represent local neighborhoods. Ego‐graphs are visualized in an aggregated state as a glyph where the size encodes the size of the neighborhood and in a detailed version where the original network nodes can be explored. The ego‐graphs are arranged in an ego‐graph network, where edges encode similarity using the Jaccard index. Our design aims to reduce visual complexity and clutter while enabling detailed exploration and facilitating the discovery of meaningful patterns. To achieve this, our approach offers a network overview using ego‐graphs, a radar chart for a one‐to‐many ego‐graph comparison and meta‐data integration, and detailed ego‐graph subnetworks for interactive exploration. We demonstrate the applicability of our approach on a co‐author network and two different protein‐protein interaction networks. A web‐based prototype of ProtEGOnist can be accessed online at https://protegonist-tuevis.cs.uni-tuebingen.de/ .
N2M2/NOA-20: Phase I/IIa umbrella trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation.
2024-06-01

2000 Background: Patients with glioblastoma without MGMT promoter hypermethylation are unlikely to benefit from temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed. Methods: This phase I/IIa umbrella trial aimed at showing safety, feasibility, and preliminary efficacy of targeted compounds in addition to standard radiotherapy initiated within 42 days postoperatively. Molecular diagnostics and bioinformatic evaluation are performed within 28 days after surgery. Stratification for treatment takes place in five subtrials, including alectinib, idasanutlin, palbociclib, vismogedib and temsirolimus, according to the best matching molecular alteration. Patients without matching alterations are randomized between subtrials without strong biomarkers using atezolizumab and asunercept and TMZ as standard of care. Primary objective of the phase I parts of the trial was dose finding or dose validation. In the phase IIa trials, centrally determined progression-free survival at six months (PFS-6) is used as endpoint for efficacy with interim analyses for futility ( H 0 : p=0.231). Results: From May 2018 through July 2022, 301 patients were enrolled and 228 treated in 13 German NOA sites. The alectinib and vismodegib subtrials were closed since no molecularly matching patients were accrued; the idasanutlin subtrial was closed prior to the optimal dose at nine patients at discretion of the company providing the drug. The TMZ subtrial showed a PFS-6 of 18.52% (10/54 patients) (p=0.831) and a median overall survival (OS) of 12.1 months. Asunercept: PFS-6 of 15.4% (4/26) (p=0.8825) and OS of 12.8 months. Atezolizumab: PFS-6 of 21.4% (9/42) (p=0.660) and OS of 11.7 months. Palbociclib with patients demonstrating CDK4 amplification or CDKN2A/B codeletion: PFS-6 of 24.4% (10/41) (p=0.4823) and OS of 12.6 months. Temsirolimus with patients demonstrating mTOR activation: PFS-6 of 39.1% (18/46) (p=0.0109) and OS of 15.4 months. The regimen-limiting toxicity (RLT)-rate is 34.8%, which is insignificantly above the predefined unacceptable rate for RLTs of 30%. Most RLTs had severity grade 3, one RLT had severity grade 4. No RLTs resulted in death. Conclusions: N 2 M 2 allows for elaborate molecular testing being integrated into the treatment decision and efficient determination of treatment activity for patients with newly diagnosed glioblastoma. There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients and also palbociclib in molecularly selected patients. Clinical trial information: NCT03158389 .
The causal involvement of the visual cortex in visual working memory remains uncertain
2024-06-01

The role of the early visual cortex in visual working memory (VWM) is a matter of current debate. Neuroimaging studies have consistently shown that visual areas encode the content of working memory, while transcranial magnetic stimulation (TMS) studies have presented incongruent results. Thus, we lack conclusive evidence supporting the causal role of early visual areas in VWM. In a recent registered report, Phylactou et al . (Phylactou P, Shimi A, Konstantinou N 2023 R. Soc. Open Sci . 10, 230321 (doi:10.1098/rsos.230321)) sought to tackle this controversy via two well-powered TMS experiments, designed to correct possible methodological issues of previous attempts identified in a preceding systematic review and meta-analysis (Phylactou P, Traikapi A, Papadatou-Pastou M, Konstantinou N 2022 Psychon. Bull. Rev. 29, 1594–1624 (doi:10.3758/s13423-022-02107-y)). However, a key part of their critique and experimental design was based on a misunderstanding of the visual system. They disregarded two important anatomical facts, namely that early visual areas of each hemisphere represent the contralateral visual hemifield, and that each hemisphere receives equally strong input from each eye—both leading to confounded conditions and artefactual effects in their studies. Here, we explain the correct anatomy, describe why their experiments failed to address current issues in the literature and perform a thorough reanalysis of their TMS data revealing important null results. We conclude that the causal role of the visual cortex in VWM remains uncertain.
Adaption of neurosurgical resection patterns for pediatric low‐grade glioma spanning two decades—Report from the German LGG‐studies 1996–2018
2024-06-01

Abstract Introduction Neurosurgery is considered the mainstay of treatment for pediatric low‐grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long‐term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. Patients and Methods Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1‐5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1‐status, sex, and age. Results The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends ( p &lt; 0.001) and the link with tumor site for each extent of resection ( p &lt; 0.001). Higher age is related to more complete resections in the cerebellum and cerebral hemispheres. Conclusions The declining extent of surgical resections over time was unrelated to patient characteristics. It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1‐status integrated as such into current treatment guidelines. Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals.
Identification of patients at high risk for relapse using the Merlin Assay (CP-GEP) in an independent cohort of 451 patients (pts) with stage I/II melanoma who did not undergo sentinel lymph node biopsy.
2024-06-01

9574 Background: Sentinel lymph node biopsy (SLNB) is the gold standard for nodal assessment in staging cutaneous melanoma (CM) according to AJCC v8 guideline. 80-85% of pts are negative for nodal metastasis, but most pts who relapse or die from melanoma are initially diagnosed as ‘low risk’ early-stage. Previously we showed that the clinicopathological-gene expression profiling (CP-GEP) model is able to stratify SLNB negative pts for their risk of recurrence (1). Later we showed in a small cohort (n=80) that CP-GEP also has the potential to stratify pts who did not undergo SLNB in low and high-risk of recurrence (2). Here we investigate CP-GEP ability to stratify pts who did not undergo SLNB for their risk of recurrence in an expanded cohort. Methods: We analysedformalin-fixed paraffin-embedded primary tumor samples of 451 pts with stage I/II CM diagnosed between 2000-2017, included in the Central Malignant Melanoma Registry, who did not receive SLNB. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome. The CP-GEP model used combines the expression of 8 genes ( SERPINE2, GDF15, ITGB3, CXCL8, LOXL4, TGFBR1, PLAT and MLANA) by quantitative reverse transcription polymerase chain reaction with age and Breslow thickness to obtain a binary output: CP-GEP Low- or High-Risk. Relapse-free survival (RFS), distant metastasis free survival (DMFS) and Melanoma Specific Survival (MSS) were evaluated using Kaplan-Meier curves. Results: We included 451 pts (stage IA-IIC). 40% were females, median age was 63-year-old, median Breslow thickness was 0.5 mm, and the majority were not ulcerated (96%). An interim analysis was performed on samples from 159 pts and showed the following survival: 5-year RFS 85.8%; DMFS 94.1; MSS 95.7%. The median follow-up time of 57 months (RFS). CP-GEP identified 149 pts as Low-Risk and 10 pts as High-Risk. The 5-year RFS rate was 90.5% and 0% (HR 23.85; p &lt; 0.001), 5-year DMFS was 97.2% and 27% (HR 43.14; p &lt; 0.001), respectively for CP-GEP Low-Risk and High-Risk pts. The 5-year MSS was 99.1% for Low-Risk pts and 25.7% for High-Risk patients (HR 112.96; p &lt; 0.001), capturing 4 out of 5 melanoma specific deaths in the CP-GEP High-Risk group. The final survival analysis of the whole cohort will be presented at the congress. Conclusions: This study shows that CP-GEP has the potential to stratify pts with early-stage melanoma who did not undergo SLNB based on their risk of recurrence. Pts with CP-GEP Low-Risk have a good long-term survival. Contrary, pts with CP-GEP High-Risk have a high risk of recurrence. CP-GEP may have the potential to stratify pts beyond SLNB. 1. Amaral et al, ASCO 2022. 2. Amaral et al, EJC 2023.
KozhukhovaE.I., MustafinKh.Kh., SemenovV.A., UchanevaE.N. Reconstructing Ethnocultural Processes in the Sausken Valley (Tuva) during the Later Half of the 1st Millennium BC
2024-06-01

The article represents findings of the group research devoted to reconstructing ethnocultural processes of the second half of the 1st millennium BC (Sausken Terrain Feature, Tuva). The research comprehensively studies local population groups who left behind their burial monuments in Eerbek River Valley. The study engages geneticist, ancient technologies experts, anthropologists and archaeologists. Kurgans of the middle and late Uyuk-Sagly Culture (5th–2nd century BC) were excavated in 2011–2016 by Tuva archaeological expedition arranged by the Russian Academy of Sciences Institute for the History of Material Culture. Nearly all burials in the kurgans had been robbed back in the ancient days. The study analyses above-ground structures and internal layouts of the kurgans, the burial ritual and tools (weapons, mirrors, belt accessories, bone items, embellishments). It allows to conclude that the kurgans have varying cultural attributions. The research also implies instrumental process analysis of glass and stone beads, chromatography of fabrics and proteomic analysis of archaeological leather. The paper reveals radiocarbon dating (14C) and correlations with other burial monuments of the Scythian Tuva. Craniological materials analysed allow to determine populations that could have been related to the aliens who arrived at the Eerbek River Valley in the Uyuk times. The Ozen-Ala-Belig groups differ from their peers from other territories in Tuva. It might be explained through the Uyuyk migrants mixing with the Eerbek Valley people who had been living there since the late Bronze Age. The paleogenetic study of 19 items especially focuses on researching the Y-chromosome DNA. For many researched samples the study determines haplogroups Q1b1a3-L330 and R1a1a1b2-Z93 (or its subgroups). The area of spread for these haplogroups is Soviet Central Asia, Central Asia, West and South Siberia. One samples is assigned to I2a1b1-M223 haplogroups with the area of spread in the Balkans and South-Eastern Europe. The obtained findings may indicate that the Western and Eastern nomads kept in touch during the researched period. The archaeological, anthropological and genetic data lead to a conclusion that the Scythian cultures in the given region is complex and multi-faceted.
Clinical validation of a prognostic 7-marker IHC assay (7-IHC) in 382 patients (pts) with stage IB/IIA cutaneous melanoma (CM; MELARISK-001).
2024-06-01

9572 Background: For pts with resected CM, adjuvant anti-PD1 is approved for AJCC v8 stage IIB–IV and BRAFi/MEKi for stage III–IV disease. Nonetheless, there remains a subgroup of pts within stages IB/IIA, which is at high risk of relapse and death, accounts for a considerable share of overall CM mortality (1), and lacks access to such therapy. Thus, adjuvant clinical trials in this “early”-stage setting may be merited. However, this subgroup is not detectable via AJCC staging alone. A prognostic 7-IHC assay that was developed (2), and analytically (3) and prospectively clinically validated (4) to identify stage IB/IIA pts at high risk of relapse and death, may be useful in selecting pts for adjuvant trials (2,4). Here, we report results from the MELARISK-001 multicenter study of that assay. Methods: MELARISK-001 enrolled consecutive pts diagnosed with stage IB/IIA CM from 2000–16, with available formalin-fixed paraffin-embedded primary melanoma. Specimens were analyzed by 7-IHC and pts classified as either high-risk or low-risk. Kaplan-Meier survival analysis and multivariate Cox regression analysis (MVA) against Breslow thickness, ulceration, age, and sex were performed. Results: MELARISK-001 included 382 pts; 247 (65%) pts in stage IB, 135 (35%) in stage IIA, all sentinel node-negative. Median Breslow thickness was 1.6 mm, median age 60Y. 212 pts (55%) were classified as 7-IHC high-risk, 170 pts (45%) as 7-IHC low-risk. Median follow-up for recurrence-free survival (RFS) was 90 mos, for melanoma-specific survival (MSS) 98 mos. Comparing 7-IHC high-risk vs low-risk pts, 5Y RFS was 79% vs 100%, 10Y RFS, 72% vs 99%, 5Y MSS, 92% vs 100%, and 10Y MSS 82% vs 100% (Table; logrank p&lt;0.001). In MVA, 7-IHC risk class (hazard ratio [HR] 22.3; 95% CI 7.0–70.9), Breslow thickness (1.5; 1.1–1.9), and age (1.61; 1.0–2.5) were significant independent prognosticators of RFS. 7-IHC HR for MSS could not be computed due to 7-IHC's 100% sensitivity. Prognostic performance variables (95% CI) for RFS were: sensitivity 98% (91%–100%), positive predictive value 26% (20%–33%), negative predictive value 99% (97%–100%). Conclusions: 7-IHC risk categorization identified 98% of relapses and 100% of CM-related deaths in stage IB/IIA pts. In MVA, 7-IHC risk class was the strongest independent prognosticator of survival endpoints. 7-IHC high-risk pts have a relapse rate comparable to that of later-stage pts for whom adjuvant therapy is approved. MELARISK-001 provides further evidence supporting use of 7-IHC to identify early-stage pts at high risk of relapse and death who may benefit from adjuvant therapy trials. 1. Whiteman et al J Invest Dermatol 2015. 2. Meyer et al PloS ONE 2012. 3. Ziemer et al Diagnostics2023. 4. Meyer et al Eur J Cancer 2023. [Table: see text]
A hemispheric dome setup for naturalistic visual stimulation in head-fixed mice
2024-06-01

Abstract The visual system of any animal species is adapted to its ecological niche. Thus, investigating visual function and behavior using naturalistic stimuli holds significant potential. In mice, these adaptations include a field of view of ∼280° and cone opsins sensitive to UV and green wavelengths. Such adaptations, however, cannot be probed with standard consumer displays. To present naturalistic visual stimuli to mice, we built a hemispheric dome setup, enabling the controlled projection of wide-field movies with UV-green spectral content. For our UV-green projection, we used a customized light engine with external high-power LEDs. We mitigated spatial distortions introduced by the projection through a geometry-independent calibration procedure. Additionally, we adapted a head-mounted eye tracking system to capture behavioral responses of head-fixed mice viewing these stimuli. We validated our setup by quantifying the pupillary light reflex to uniform stimuli and the optokinetic reflex to drifting gratings. Finally, in experiments with naturalistic movies, we investigated whether mice showed differential saccades and eye positions based on visual input. Comparing naturalistic movies to a uniform screen control condition, we observed that although head-fixed mice did not make targeted saccades during movies, their overall eye position consistently shifted towards more frontal regions of visual space. This indicates that mice adjust their eye position in a stimulus-dependent way, potentially to optimize visual processing of information ahead in the visual field. Together, our results highlight the utility of our setup for in vivo studies of the mouse visual system with more naturalistic visual stimulation. Significance Statement Over the past decades, mice have emerged as a prominent model for vision. Nonetheless, compared to primates, mice inhabit a different visual niche, featuring several species-specific adaptations, including a wide field of view and sensitivity to UV light. Both adaptations cannot be adequately studied using consumer displays commonly employed in vision research. We therefore built a hemispheric dome setup allowing the presentation of wide field movies with appropriate spectral content and tracking eye movements and pupil dynamics in head-fixed mice with minimal shadows. We provide a baseline assessment of the setup leveraging two well-established eye reflexes. We also showcase the setup’s utility by reporting adjustments in eye movements when mice viewed the naturalistic movies.
A Mimicry-Based Strategy Between Human and Commensal Antigens for the Development of a New Family of Immune Therapies for Cancer
2024-06-01

Abstract Peptide vaccines have emerged as a promising strategy for cancer immunotherapy, yet often lack of strong, specific and sustained immune responses against tumor antigens. To achieve a robust immune response, the effective selection of tumour antigens is crucial. While neoantigens trigger potent immune responses, their use suffers from patient specificity and their rarity in low-mutational tumors. Alternatively, the immunogenic potential of tumor-associated antigens (TAAs) is limited by central immune tolerance. Molecular mimicry and T cell cross-reactivity is a proposed mechanism to trigger a robust T cell-mediated antitumor response. Although molecular mimicry between pathogens and tumor antigens has been described, the potential benefits of exploiting this molecular mimicry with commensal bacterial antigens in antitumor immunity have not been thoroughly investigated despite strong evidence that the composition of the human microbiota significantly influences immune competency. Our new approach called OncoMimicsTM, which uses molecular mimicry between commensal bacterial and tumoral antigens to induce cross-reactive cytotoxic T cells against tumor cells. In preclinical studies, vaccination with OncoMimicTM peptides (OMPs) led to the expansion of CD8 + T cells reacting against homologous tumor-associated antigen peptides and elicits cytotoxic activity against tumor cells. OMPs are efficiently recognized by a prevalent T cell population within the peripheral blood mononuclear cells of healthy individuals. An ongoing clinical trial ( NCT04116658 ) using OncoMimicsTM in patients with glioblastoma demonstrates early, durable, and cross-reactive tumor antigen CD8 + T cell responses with pronounced memory persistence. By overcoming the current vaccine limitations, OncoMimicsTM constitutes a promising strategy for enhancing cancer immunity and improving patient outcomes. Statement of Significance This study introduces OncoMimicsTM, a peptide-based immunotherapy leveraging molecular mimicry to induce robust, cross-reactive T cell responses against tumor antigens, showing promising early results in an ongoing glioblastoma clinical trial ( NCT04116658 )
Subgroup analysis of real-world efficacy of enfortumab vedotin in patients with metastatic/locally advanced urothelial carcinoma from a European database.
2024-06-01

e16562 Background: Enfortumab vedotin (EV) is an antibody drug conjugate targeting Nectin-4. It was approved by EMA/FDA in patients (pts) with metastatic/ locally advanced urothelial cancer post platinum and immune check point inhibitors (ICI) following the results of the EV-301 trial. We report updated efficacy data of EV in a large European cohort of real-world pts (GUARDIANS consortium) treated in hospitals and private practices. Methods: Retrospective data were collected from 25 German and Swiss hospitals and private practices for pts who received EV. Objective responses were evaluated by local investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Cox proportional hazard model was used to analyze risk patterns. Correlation was assessed using spearmen’s rank correlation coefficient. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: We identified 188 pts (32.4% female) with a median age of 66 yrs (range 31-89; 22.3% ≥ 75 yrs). Median OS (mOS) was 12.0 months (mo) (95% CI 9.65-14.35) and median PFS (mPFS) was 7.0 mo (95% CI 5.43-8.57). Overall response rate was 46.3% (partial remission: 42.0%, complete response 4.3%). Median follow up was 11 mo (IQR: 6.0-17.0 mo). Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1/ 2-4/ unknown in 75/14/11%. With decreasing ECOG-PS ≥2, there was also a decrease in OS 4.95 (95 CI 3.0-8.3; p&lt;0.001) and PFS 2.1 (95 CI 1.14-3.92), resulting in a significant Spearman coefficant for death 0.31, OS -0.36 and PFS -0.31 (p&lt;0.001). Median EV line was 3 (IQR: 3-4). Bellmunt Risk Score (BRS) &gt;1 prior to EV initiation significantly predicts poorer OS and PFS with 3.3 (95 CI 1.82-5.72, p&lt;0.001) and 1.9 (65 CI 1.15-3.25, p=0.013), respectively. Regarding metastases localization, liver and bone involvement correlated with poorer OS with 1.3 (95 CI 0.9-2.1; p=0.01) and 1.5 (95 CI 1.01-2.36; p=0.04). In addition cancer of the Upper Urinary Tract showed a poorer OS 1.4 (95 CI 0.89-2.19; p=0.027). Prior definitive local intervention demonstrated improvement in OS 0.6 (95 CI 0.32-1; p=0.048). Response to ICI-therapy, IC or CPS did influence neither OS nor PFS. Limitations are retrospective design and short follow-up. Conclusions: Anti-tumor activity of EV in real-world pts including difficult-to-treat subgroups is comparable to the results of the pivotal EV-301 trial. Frail pts. have a significant higher risk for death and progression. BRS is a predictive indicator for treatment with EV in heavily pretreated patients. Liver and bone metastases have a poorer OS. The improvement in prognosis after local definitive therapy in connection with EV therapy should be investigated further in the future.