julilili42/papers huggingface dataset:
Abstract 2864: A CLEC12A immunocytokine with target cell-restricted IL-15 activity shows a favorable toxicity profile and high potency in AML
2022-06-15

Abstract IL-15, often referred to as the “anti-cancer cytokine”, potently stimulates proliferation and activation of NK and T cells, but unlike its close relative IL-2, does neither promote activation-induced death of lymphocytes nor activity of immunoinhibitory Tregs. So far, short half-life, poor accumulation at the tumor site and severe toxicity upon systemic application limit IL-15 efficacy in patients. Fusion of IL-15 to antibodies directed to tumor antigens (classical immunocytokines, ICs) improves on accumulation at the tumor site and pharmacokinetics. However, since the activity of the cytokine moiety within classical ICs does not depend on antigen binding, the application of clinically effective doses is still prevented by toxicity due to unspecific immune activation. To overcome this problem, we took advantage of the unique mechanism of action of IL-15 which stimulates IL-15Rβ/γ on NK and T cells as a membrane-bound complex with IL-15Rα on monocytes and DCs (trans-presentation). We used an Fc-optimized antibody directed to CLEC12A, a surface antigen abundantly expressed on AML cells and leukemic stem cells but not on healthy stem cells. This antibody termed 33C2-SDIE was fused to an IL-15E46K mutant with abolished binding to IL-15Rα, allowing to substitute physiological trans-presentation of IL-15 by binding of the construct to its tumor-expressed target. Antigen-specific binding of the resulting modified immunocytokine (MIC12) was confirmed using multiple CLEC12A-expressing cell lines and primary AML samples from patients. Functional analysis of activation, cytokine release, and target cell lysis demonstrated that MIC proteins, in contrast to classical IC, stimulate cytotoxic lymphocytes in a highly target cell-restricted manner, allowing for the desired reduction of unspecific immune activation. At the same time, significantly superior NK cell reactivity against AML cells as compared to even the Fc-optimized antibody was observed. Both, IL-15 signaling and engagement of Fc-receptors by the optimized Fc-domain were found to be essential for optimal activity of our MIC constructs. Importantly, only treatment with MIC12 was capable to induce NK cell proliferation, which is required to overcome unfavorable target to effector ratios that prevail in overt cancer disease. In summary, our novel CLEC12A-targeting immunocytokine allows for tumor-restricted stimulation of cytotoxic lymphocytes and reduced toxicity while displaying superior anti-leukemic activity and constitutes a promising compound for the treatment of AML. Citation Format: Boris Klimovich, Leonard Anton, Yangmi Lim, Jonghwa Won, Anna Chashchina, Martin Pflügler, Latifa Zekri, Gundram Jung, Helmut R. Salih. A CLEC12A immunocytokine with target cell-restricted IL-15 activity shows a favorable toxicity profile and high potency in AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2864.
Optimized planning of self-sufficient microgrids
2022-06-15

The paper describes a methodology for an optimized planning of a microgrid considering multiple objec-tives. The developed methodology generates a pareto set of optimized planning solutions by means of an iterative procedure, which allows to systematically analyze and explore different prioritizations of the objectives as well as their dependencies and trade-offs, and therefore to identify an optimized planning solution for a concrete constel-lation of boundary conditions and objectives. A proposed planning solution covers both the technological design of the microgrids' virtual power plant (in terms of the composition and dimensioning of power plant types) and the energy storage system (in terms of the dimensioning of the storage units used in the microgrid). The energy storage system includes both stationary storages and mobile storages in electric vehicles, which are actively integrated into the energy storage system via a vehicle-to-grid approach. In the following, the degree of self-sufficiency of the microgrid, the total CO2 emissions and the mobility requirements of the electric vehicles integrated in the microgrids' energy storage system are considered as objectives. To build up the pareto set of optimized proposed solutions, various metaheuristics, including Artificial Bee Colony, Particle Swarm Optimization, and Simulated Annealing, were investigated and evaluated.
European Respiratory Society guidelines on transbronchial lung cryobiopsy in the diagnosis of interstitial lung diseases
2022-06-16

Background In patients with interstitial lung diseases (ILD), histopathological input is often required to obtain a diagnosis. Surgical lung biopsy (SLB) is considered the reference standard, but many patients are clinically unfit to undergo this invasive procedure, and adverse events, length of hospitalisation and costs are considerable. This European Respiratory Society (ERS) guideline provides evidence-based clinical practice recommendations for the role of transbronchial lung cryobiopsy (TBLC) in obtaining tissue-based diagnosis in patients with undiagnosed ILD. Methods The ERS Task Force consisted of clinical experts in the field of ILD and/or TBLC and methodological experts. Four PICO (Patient, Intervention, Comparator, Outcomes) questions and two narrative questions were formulated. Systematic literature searches were performed in MEDLINE and Embase (up to June 2021). GRADE (Grading, Recommendation, Assessment, Development and Evaluation) methodology was applied. Results In patients with undiagnosed ILD and an indication to obtain histopathological data: 1) TBLC is suggested as a replacement test in patients considered eligible to undergo SLB, 2) TBLC is suggested in patients not considered eligible to undergo SLB, 3) SLB is suggested as an add-on test in patients with a non-informative TBLC, 4) no recommendation is made for or against a second TBLC in patients with a non-informative TBLC and 5) TBLC operators should undergo training, but no recommendation is made for the type of training required. Conclusions TBLC provides important diagnostic information in patients with undiagnosed ILD. Diagnostic yield is lower compared to SLB, at reduced serious adverse events and length of hospitalisation. Certainty of the evidence is mostly “very low”.
Prognosis of Patients With Primary Melanoma Stage I and II According to American Joint Committee on Cancer Version 8 Validated in Two Independent Cohorts: Implications for Adjuvant Treatment
2022-06-16

PURPOSE The first randomized trial of adjuvant treatment with checkpoint inhibitor in stage II melanoma reported a significant reduction in risk of tumor recurrence. This study evaluates two independent data sets to further document survival probabilities for patients with primary stage I and II melanoma. PATIENTS AND METHODS The Central Malignant Melanoma Registry (CMMR) in Germany evaluated 17,544 patients with a primary diagnosis of stage I and II melanoma from 2000 to 2015. The exploratory cohort consisted of 6,725 patients from the Center for Dermato-Oncology at the University of Tübingen, and the confirmatory cohort consisted of 10,819 patients from 11 other German centers. Survival outcomes were compared with published American Joint Committee on Cancer version 8 (AJCCv8) stage I and II survival data. RESULTS For the two CMMR cohorts in stage IA compared with the AJCCv8 cohort, melanoma-specific survival rates at 10 years were 95.1%-95.6% versus 98%; 89.7%-90.9% versus 94% in stage IB; 80.7%-83.1% versus 88% in stage IIA; 72.0%-79.9% versus 82% in stage IIB; and 57.6%-64.7% versus 75% in stage IIC, respectively. Recurrence rates were approximately twice as high as melanoma-specific mortality rates in stages IA-IIA. CONCLUSION The melanoma-specific survival rates in the two CMMR cohorts across stages I and II are less favorable than published in AJCCv8. This has important implications for the consideration of adjuvant treatment in this population.
Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure–Activity Relationships, Antiviral Activity, and X-ray Structure Determination
2022-06-16

The main protease (M<sup>pro</sup>, 3CL<sup>pro</sup>) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure-activity relationships of novel small-molecule thioesters as SARS-CoV-2 M<sup>pro</sup> inhibitors. Compounds <b>3w</b> and <b>3x</b> exhibited excellent SARS-CoV-2 M<sup>pro</sup> inhibition with <i>k</i><sub>inac</sub>/<i>K</i><sub>i</sub> of 58,700 M<sup>-1</sup> s<sup>-1</sup> (<i>K<sub>i</sub></i> = 0.0141 μM) and 27,200 M<sup>-1</sup> s<sup>-1</sup> (<i>K</i><sub>i</sub> = 0.0332 μM), respectively. In Calu-3 and Vero76 cells, compounds <b>3h</b>, <b>3i, 3l</b>, <b>3r</b>, <b>3v</b>, <b>3w</b>, and <b>3x</b> displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of <b>3w</b> and <b>3af</b> with SARS-CoV-2 M<sup>pro</sup> was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the M<sup>pro</sup> of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections.
Monomorphic epitheliotropic intestinal T-cell lymphoma comprises morphologic and genomic heterogeneity impacting outcome
2022-06-16

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma most reported in Asia. We performed a comprehensive clinical, pathological and genomic study of 71 European MEITL patients (36 males, 35 females, median age 67 years). The majority presented with gastrointestinal involvement and had emergency surgery, and 40% had stage IV disease. The tumors were morphologically classified into two groups: typical (58%) and atypical (i.e., non-monomorphic or with necrosis, angiotropism or starry-sky pattern) (42%), sharing a homogeneous immunophenotypic profile (CD3+ [98%] CD4- [94%] CD5- [97%] CD7+ [97%] CD8+ [90%] CD56+ [86%] CD103+ [80%] cytotoxic marker+ [98%]) with more frequent expression of TCRgd (50%) than TCRab (32%). MYC expression (30% of cases) partly reflecting MYC gene locus alterations, correlated with non-monomorphic cytology. Almost all cases (97%) harbored deleterious mutation(s) and/or deletion of the SETD2 gene and 90% had defective H3K36 trimethylation. Other frequently mutated genes were STAT5B (57%), JAK3 (50%), TP53 (35%), JAK1 (12.5%), BCOR and ATM (11%). Both TP53 mutations and MYC expression correlated with atypical morphology. The median overall survival (OS) of 63 patients (43/63 only received chemotherapy after initial surgery) was 7.8 months. Multivariate analysis found a strong negative impact on outcome of MYC expression, TP53 mutation, STAT5B mutation and poor performance status while aberrant B-cell marker expression (20% of cases) correlated with better survival. In conclusion, MEITL is an aggressive disease with resistance to conventional therapy, predominantly characterized by driver gene alterations deregulating histone methylation and JAK/STAT signaling and encompasses genetic and morphologic variants associated with very high clinical risk.
Prevalence of non-Plasmodium falciparum species in southern districts of Brazzaville in The Republic of the Congo
2022-06-16

Abstract Background Although Plasmodium falciparum infection is largely documented and this parasite is the main target for malaria eradication, other Plasmodium species persist, and these require more attention in Africa. Information on the epidemiological situation of non- P. falciparum species infections is scarce in many countries, including in the Democratic Republic of the Congo (hereafter Republic of the Congo) where malaria is highly endemic. The aim of this study was to determine the prevalence and distribution of non- P. falciparum species infections in the region south of Brazzaville. Methods A cross-sectional survey was conducted in volunteers living in rural and urban settings during the dry and rainy seasons in 2021. Socio-demographic and clinical parameters were recorded. Plasmodium infection in blood samples was detected by microscopic analysis and nested PCR (sub-microscopic analysis). Results Of the 773 participants enrolled in the study, 93.7% were from the rural area, of whom 97% were afebrile. The prevalence of microscopic and sub-microscopic Plasmodium spp. infection was 31.2% and 63.7%, respectively. Microscopic Plasmodium malariae infection was found in 1.3% of participants, while sub-microscopic studies detected a prevalence of 14.9% for P. malariae and 5.3% for Plasmodium ovale . The rate of co-infection of P. malariae or P. ovale with P. falciparum was 8.3% and 2.6%, respectively. Higher rates of sub-microscopic infection were reported for the urban area without seasonal fluctuation. In contrast, non- P. falciparum species infection was more pronounced in the rural area, with the associated risk of the prevalence of sub-microscopic P. malariae infection increasing during the dry season. Conclusion There is a need to include non- P. falciparum species in malaria control programs, surveillance measures and eradication strategies in the Republic of the Congo. Graphical Abstract
A MeerKAT, e-MERLIN, H.E.S.S., and Swift search for persistent and transient emission associated with three localized FRBs
2022-06-16

ABSTRACT We report on a search for persistent radio emission from the one-off fast radio burst (FRB) 20190714A, as well as from two repeating FRBs, 20190711A and 20171019A, using the MeerKAT radio telescope. For FRB 20171019A, we also conducted simultaneous observations with the High-Energy Stereoscopic System (H.E.S.S.) in very high-energy gamma rays and searched for signals in the ultraviolet, optical, and X-ray bands. For this FRB, we obtain a UV flux upper limit of Å−1, X-ray limit of and a limit on the very high energy gamma-ray flux . We obtain a radio upper limit of ∼15 Jy beam−1 for persistent emission at the locations of both FRBs 20190711A and 20171019A with MeerKAT. However, we detected an almost unresolved (ratio of integrated flux to peak flux is ∼1.7 beam) radio emission, where the synthesized beam size was ∼ 8 arcsec size with a peak brightness of Jy beam−1 at MeerKAT and Jy beam−1 at e-MERLIN, possibly associated with FRB 20190714A at z = 0.2365. This represents the first detection of persistent continuum radio emission potentially associated with a (as-yet) non-repeating FRB. If the association is confirmed, one of the strongest remaining distinction between repeaters and non-repeaters would no longer be applicable. A parallel search for repeat bursts from these FRBs revealed no new detections down to a fluence of 0.08 Jy ms for a 1 ms duration burst.
Quantitatively improved finite-size criteria for spectral gaps
2022-06-16

Abstract Finite-size criteria have emerged as an effective tool for deriving spectral gaps in higher-dimensional frustration-free quantum spin systems. We quantitatively improve the existing finite-size criteria by introducing a novel subsystem weighting scheme. The approach applies to Euclidean lattices of any dimension, the honeycomb lattice, and the triangular lattice.
The amnestic syndrome of posterior cerebral artery infarction
2022-06-16

Abstract Background and purpose Little is known about the character and underlying lesions of ischaemic amnesia. Episodic memory functions and brain lesions were therefore studied in 84 patients with acute ischaemic infarcts in the supply territory of the posterior cerebral artery. The aim was also to learn how the neural memory systems are organized. Methods Standard neuropsychological tests were used to assess verbal and figural memory. Patients were split into memory‐impaired and memory‐intact groups. Lesions were demarcated, normalized and anatomically labelled, using standard mapping procedures. Results Of the 84 patients more than 80% had an amnestic syndrome, mostly with combined memory impairment, less often with figural or verbal memory impairment. Amnesia in subjects with left hemispheric lesions was more frequent and more severe, with significantly lower scores on the verbal memory test. Normal performance or figural amnesia were prevalent after right hemispheric lesions. However, no amnesia subtype was strictly tied to left‐ or right‐sided brain damage. Hippocampal and thalamic lesions were common, but 30% of lesions were extrahippocampal located in the ventral occipito‐temporal cortex and long occipital white matter tracts. Most amnestic patients lacked awareness for their memory impairment. Conclusions Memory impairment is a key clinical manifestation of acute posterior cerebral artery stroke. Amnesia is more frequent and more severe after left stroke, suggesting a left hemisphere dominance of the two memory systems. Domain specific memory appears not to be strictly lateralized, since deficits in verbal and figural memory were found after lesions of both sides. Extrahippocampal lesions may also cause memory impairment.
B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens
2022-06-16

Abstract Burkitt lymphoma (BL) represents the most aggressive B‐cell‐lymphoma. Beside the hallmark of IG‐MYC ‐translocation, surface B‐cell receptor (BCR) is expressed, and mutations in the BCR pathway are frequent. Coincidental infections in endemic BL, and specific extra‐nodal sites suggest antigenic triggers. To explore this hypothesis, BCRs of BL cell lines and cases were screened for reactivities against a panel of bacterial lysates, lysates of Plasmodium falciparum , a custom‐made virome array and against self‐antigens, including post‐translationally modified antigens. An atypically modified, SUMOylated isoform of Bystin, that is, SUMO1‐BYSL was identified as the antigen of the BCR of cell line CA46. SUMO1‐BYSL was exclusively expressed in CA46 cells with K139 as site of the SUMOylation. Secondly, an atypically acetylated isoform of HSP40 was identified as the antigen of the BCR of cell line BL41. K104 and K179 were the sites of immunogenic acetylation, and the acetylated HSP40 isoform was solely present in BL41 cells. Functionally, addition of SUMO1‐BYSL and acetylated HSP40 induced BCR pathway activation in CA46 and BL41 cells, respectively. Accordingly, SUMO1‐BYSL‐ETA’ immunotoxin, produced by a two‐step intein‐based conjugation, led to the specific killing of CA46 cells. Autoantibodies directed against SUMO1‐BYSL were found in 3 of 14 (21.4%), and autoantibodies against acetylated HSP40 in 1/14(7.1%) patients with sporadic Burkitt‐lymphoma. No reactivities against antigens of the infectious agent spectrum could be observed. These results indicate a pathogenic role of autoreactivity evoked by immunogenic post‐translational modifications in a subgroup of sporadic BL including two EBV‐negative BL cell lines.
Multi-task learning for activity detection in neovascular age-related macular degeneration
2022-06-16

Abstract Purpose Comparison of performance and explainability of a multi-task convolutional deep neuronal network to single-task networks for activity detection in neovascular age-dependent macular degeneration. Methods From n = 70 patients (46 female, 24 male) who attended the University Eye Hospital Tübingen 3762 optical coherence tomography B-scans (right eye: 2011, left eye: 1751) were acquired with Heidelberg Spectralis, Heidelberg, Germany. B-scans were graded by a retina specialist and an ophthalmology resident, and then used to develop a multi-task deep learning model to predict disease activity in neovascular age-related macular degeneration along with the presence of sub- and intraretinal fluid. We used performance metrics for comparison to single-task networks and visualized the DNN-based decision with t-distributed stochastic neighbor embedding and clinically validated saliency mapping techniques. Results The multi-task model surpassed single-task networks in accuracy for activity detection (94.2). Further-more, compared to single-task networks, visualizations via t-distributed stochastic neighbor embedding and saliency maps highlighted that multi-task networks’ decisions for activity detection in neovascular age-related macular degeneration were highly consistent with the presence of both sub- and intraretinal fluid. Conclusions Multi-task learning increases the performance of neuronal networks for predicting disease activity, while providing clinicians with an easily accessible decision control, which resembles human reasoning. Translational Relevance By improving nAMD activity detection performance and transparency of automated decisions, multi-task DNNs can support the translation of machine learning research into clinical decision support systems for nAMD activity detection.
ISMIP-HOM benchmark experiments using Underworld
2022-06-16

Abstract. Numerical models have become an indispensable tool for understanding and predicting the flow of ice sheets and glaciers. Here we present the full-Stokes software package Underworld to the glaciological community. The code is already well established in simulating complex geodynamic systems. Advantages for glaciology are that it provides a full-Stokes solution for elasto-visco-plastic materials and includes mechanical anisotropy. Underworld uses a material point method to track the full history information of Lagrangian material points, of stratigraphic layers and of free surfaces. We show that Underworld successfully reproduces the results of other full-Stokes models for the benchmark experiments of the ISMIP-HOM project. Furthermore, we test FE meshes with different geometries and highlight the need to be able to adapt the finite-element grid to discontinuous interfaces between materials with strongly different properties, such as the ice-bedrock boundary.
Prenatal arsenic exposure stymies gut butyrate production and enhances gut permeability in post natal life even in absence of arsenic deftly through miR122-Occludin pathway
2022-06-16

Abstract This discourse attempts to capture a few important dimensions of gut physiology like microbial homeostasis, short chain fatty acid (SCFA) production, occludin expression and gut permeability in post-natal life of mice those received arsenic only during pre-natal life (pAs-mice). The pAs-mice showed a striking reduction in Firmicutes to Bacteroidetes (F/B) ratio coupled with decrease in tight junction protein, occludin resulting in increase in gut permeability, increased infiltration of inflammatory cells in the colon and decrease in common SCFAs in which butyrate reduction was quite prominent in fecal samples as compared to normal control. The above phenotypes of pAs-mice were mostly reversed by supplementing butyrate with food. The talismanic ability of butyrate in enhancing occludin expression, in particular, was dissected further. As miR122 causes degradation of Occludin mRNA, we transiently overexpressed miR122 by injecting appropriate plasmids and showed reversal of butyrate effects in pAs-mice. Thus, pre-natal arsenic exposure orchestrates variety of effects by decreasing in butyrate in pAs-mice leading to increased permeability due to reduced occludin expression. Our research adds a new dimension to our understanding that pre-natal arsenic exposure imprints in post-natal life while there was no further arsenic exposure. Highlights Prenatal Arsenic exposure decreases prevalence of butyrate producing bacteria and butyrate production in gut. Lack of butyrate production in the gut is responsible for increased permeability and decreased occludin expression. Oral supplementation with butyrate reverses the prenatal arsenic induced changes in the gut. Butyrate increases Occludin gene expression by downregulating miR122 in the gut.