julilili42/papers huggingface dataset:
1366 B7-H3xCD3 bispecific antibody as novel treatment option in HER2-negative breast cancer
2023-10-31

<h3>Background</h3> Invasive breast cancer is the most common malignant disease in women worldwide. HER2-targeting antibodies like Trastuzumab have achieved notable success in treatment of HER2-positive breast cancer, whereas antibody-based treatment options for HER2-negative patients remain quite limited. B7-H3 (CD276) is overexpressed in various tumor entities on both tumor cells and tumor vessels, the latter facilitating improved infiltration of immune effector cells into the tumor site upon therapeutic targeting. In this study, we investigated the potential of a novel B7-H3xCD3 bispecific antibody termed CC-3 as a therapeutic strategy for HER2-negative breast cancer. <h3>Methods</h3> The efficacy of CC-3 in treatment of HER2-negative breast cancer was evaluated using various <i>in vitro</i> assays including analysis of T cell activation, proliferation, cytokine release and tumor cell lysis. <h3>Results</h3> Our analysis revealed a high expression of B7-H3 on various breast cancer cell lines, regardless of the molecular subtype. Functional analysis using HER2-negative breast cancer cell lines demonstrated that CC-3 induces profound T cell activation and secretion of IL-2, IFNg as well as TNF, and most importantly potent tumor cell lysis. Moreover, CC-3 induced strong T cell proliferation and formation of T cell memory subsets. <h3>Conclusions</h3> These promising results highlight the therapeutic potential of CC-3 for treatment of HER2-negative breast cancer. <h3>Ethics Approval</h3> The studies involving human participants were reviewed and approved by IRB (ethics committee of the Faculty of Medicine of the Eberhard Karls Universität Tübingen) at the University Hospital Tübingen and was conducted in accordance with the Declaration of Helsinki; reference number13/2007V. <h3>Consent</h3> Human material was collected after obtaining informed consent. The patients/participants provided their written informed consent to participate in this study.
1463 The intra-tumoral spatial heterogeneity of T cell antigens in glioblastoma: An integrated multi-omics approach
2023-10-31

<h3>Background</h3> Glioblastoma is the most common primary malignant neoplasm of the central nervous system in adults. Current treatment options comprise maximal surgical resection followed by radiation and/or chemotherapy with temozolomide. These procedures are unable to eliminate all tumor cells, leading to disease recurrence and accounting for the poor prognosis. Glioblastoma is a highly infiltrative tumor with recurrence originating from the unresectable peritumoral infiltration zone (INF). Thus, novel treatment options specifically targeting tumor cells in the INF zone are needed to prevent relapse and enable long-lasting remission. <h3>Methods</h3> In this work, we performed a multi-omics spatial analysis of the necrotic center (NEC), the gadolinium contrast-enhancing region (T1), and the INF zone integrating mass spectrometry-based immunopeptidome analysis with next-generation sequencing methods (whole exome and RNA sequencing) to assess immunologically relevant aspects of tumor heterogeneity. For the multi-omics analysis, HLA-restricted peptides and genetic material from 15 glioblastoma patients were analyzed from the three zones NEC, T1, INF. Additionally, adjacent benign (BEN) brain tissue was analyzed from four patients. <h3>Results</h3> A total of 31,655 unique HLA class I and 10,071 unique HLA class II peptides were identified in 12 of the 15 glioblastoma patients. Comparative profiling of peptides from our study and a benign tissue database (HLA ligand atlas (https://hla-ligand-atlas.org)) identified 38% of HLA class I and 70% of HLA class II peptides as tumor-associated antigens (TAAs) originating from either INF, T1 or NEC zones, respectively. Of these HLA class I TAAs, 17%, 19%, and 17% and of the HLA class II TAAs 16%, 19%, and 43%, were exclusively presented in the INF, T1, or NEC zones, respectively. Five INF-associated HLA class I ligands were frequently presented in 42% of glioblastoma immunopeptidomes, whereas nine INF-associated HLA class II ligands were presented in up to 62% of glioblastoma immunopeptidomes. Of note, the glioblastoma-associated proteins BAALC, NCAN, and SLC20A1A were identified among these INF-associated ligands. Furthermore, integrated RNA/DNA sequencing enabled a greater understanding of spatial tumor antigen presentation. It led to the identification of 1,287 and 923 predicted possible INF-specific HLA class I and HLA class II neoepitopes, respectively, which are derived from tumor-associated mutations. The immunogenicity of these peptides will be further validated in upcoming T cell assays of tumor-infiltrating lymphocytes. <h3>Conclusions</h3> In summary, intra-tumoral regional heterogeneity of tumor antigens was identified, which could be used for specific immunotherapy approaches targeting the INF zone of glioblastoma. <h3>Ethics Approval</h3> Written informed consent was obtained for all patients following the Declaration of Helsinki protocol and the local review board (Kantonale Ethikkomission Zürich; KEK-ZH-Nr.2015–0163)
1390 A Fc-optimized B7-H3 antibody for induction of NK cell reactivity against acute myeloid leukemia
2023-10-31

<h3>Background</h3> Acute myeloid leukemia (AML) is the most frequent acute leukemia in adults. Although treatment options of AML have improved during the last decade, so far, no anti-tumor antibodies are clinically approved for AML therapy. The crucially important factor for the therapeutic success of monoclonal antibodies (mAbs) in cancer treatment is their ability to mediate antibody-dependent cellular cytotoxicity (ADCC) through natural killer (NK) cells. Recently, the coreceptor of immune-checkpoint B7 family B7-H3 (CD276) has emerged as a promising target for AML immunotherapy, due to its profound expression on leukemic blasts of AML patients. <h3>Methods</h3> Here we provide preclinical characterization of our previously developed B7-H3 mAb 8H8 in AML. By introduction of amino acid substitutions (S239D/I332E) in the Fc part, 8H8-SDIE provides enhanced affinity to the activating Fc receptor CD16 on NK cells. We characterized B7-H3 expression and binding of 8H8 on AML cell lines (n=12) and patient samples (n=64) and employed 8H8-SDIE in various in vitro assays. <h3>Results</h3> Flow cytometric analyses showed that 8H8-SDIE bound specifically to the target antigen at saturating doses of approximately 1 μg/mL on primary AML patients' samples. Co-cultures of allogeneic peripheral blood mononuclear cells (PBMC) with B7-H3-positive primary AML cells, revealed that B7-H3-SDIE induced significant NK cell activation measured by CD69 and CD25 expression. In line, determination of CD107a upregulation confirmed significant induction of NK cell degranulation by our construct. Additional analysis of the supernatants by LegendPlex showed 8H8-SDIE treatment-induced secretion of immunomodulatory IFNγ and TNF as well es enhanced levels of Granzyme B, Granulysin, and Perforin mediating NK cell effector functions. No effects were observed in the presence of the corresponding iso-SDIE control. Target cell-restricted lysis of AML cell lines and primary AML patients' samples by 8H8-SDIE was potently induced in Europium and FACS-based cytotoxicity assays, while iso-SDIE treatment did not induce lysis of leukemic cells. <h3>Conclusions</h3> Taken together, we here introduce a novel attractive immunotherapeutic compound potently inducing NK cell anti-leukemic reactivity as a beneficial treatment option for AML.
1133 Characterization of CD4+ T cell responses against Rho C, a metastasis associated tumor antigen
2023-10-31

<h3>Background</h3> CD4+ T cells are conventionally thought of as mainly 'help providers' in anti-cancer immune responses, supporting the generation of robust CD8+ T cell responses. However, more recently CD4+ T cells and their role in anti-cancer responses have gained new interest based on data suggesting that CD4+ T cells are often induced in high frequency in therapeutic vaccination against cancer. Recently, vaccination with a RhoC derived long-synthetic peptide (RV001) induced a long-lasting CD4+ T cell response in prostate cancer patients.<sup>1</sup> Nonetheless, it is not known whether endogenous RhoC protein is processed and presented as peptides in the context of HLA Class II molecules for recognition by CD4+ T cells. Similarly, it remains unclear whether the CD4+ T cells induced by the vaccine have the ability to directly kill cancer cells. To address these questions, we mimicked vaccine-induced RV001 specific CD4+ T cells <i>in vitro</i> and tested their capacity to kill cancer cells expressing their cognate antigen. <h3>Methods</h3> T cells were isolated from the peripheral blood of a healthy donor and stimulated with peptide-pulsed autologous dendritic cells or PBMCs for five rounds. After each stimulation round, peptide reactivity was evaluated using EliSpot and intracellular cytokine staining (ICS). Peptide specific CD4+ T cells were sorted based on cytokine secretion and subsequently cloned by limiting dilution. Expanded clones were tested for cytotoxicity against FM3 cancer cells using xCELLigence Real-Time Cell Analysis and T cell receptor (TCR) assessment was performed using flow cytometry and polymerase chain reaction (PCR). <h3>Results</h3> After multiple rounds of stimulation, we successfully generated RV001-specific CD4+ T cells from a healthy donor. These reactive CD4+ T cells exhibited production of TNFα and IFNγ, along with the surface expression of the degranulation marker CD107a. Upon restimulation with the peptide, the generated CD4+ T cell clones demonstrated robust production of TNFα and IFNγ, as well as the synthesis of the cytotoxic molecules granzyme B and granulysin. Next, all clones showed cytotoxic activity upon peptide-pulsed FM3 cancer cells. For two of the clones, killing of unpulsed FM3, which express endogenous RhoC, was seen. Notably, the same TCR beta variable chain was found across the generated clones. <h3>Conclusions</h3> We showed that peptide-specific CD4+ T cells can produce cytotoxic molecules and mediate tumor cell killing. These findings offer a glimpse of the possible benefits of targeting CD4+ T responses in therapeutic cancer vaccination. <h3>Reference</h3> Schuhmacher J, Heidu S, Balchen T. Vaccination against RhoC induces long-lasting immune responses in patients with prostate cancer: results from a phase I/II clinical trial. <i>J Immunother Cancer</i>. 2020;<b>8</b>:e001157
1353 An Fc-optimized B7-H3-targeting antibody for treatment of ovarian cancer
2023-10-31

<h3>Background</h3> Ovarian cancer remains the most lethal gynecologic malignancy to date and thus represents a substantial health challenge. The introduction of monoclonal antibodies (mAbs) has revolutionized treatment of various types of cancer, but patients with ovarian cancer have yet not benefitted. Natural killer (NK) cells contribute significantly to antibody-dependent cellular cytotoxicity (ADCC), a key factor for success of mAb treatment, and many efforts presently aim to enhance this important antibody function by modifying the Fc moiety. B7-H3 (CD276) is highly expressed in many tumor entities whereas expression on healthy tissue is rather limited, making it a promising target for immunotherapy. Here, we report on an Fc-optimized B7-H3 antibody for treatment of ovarian cancer. <h3>Methods</h3> We generated a chimeric B7-H3-mAb containing a Fc part with amino acid substitutions (S239D/I332E) to increase affinity for CD16-expressing NK cells (8H8-SDIE). The efficacy of 8H8-SDIE against ovarian cancer cells was tested in various in vitro assays, including analysis of NK cell activation, degranulation, cytokine release and cytotoxicity. <h3>Results</h3> Our analyses demonstrate that various ovarian cancer cell lines exhibit high B7-H3 expression levels. Furthermore, functional analysis revealed that 8H8-SDIE triggers profound NK cell functions such as activation, degranulation and secretion of IFNg, resulting in potent tumor cell lysis. <h3>Conclusions</h3> Our data emphasize the potential of 8H8-SDIE as a novel immunotherapeutic option for treatment of ovarian cancer. <h3>Ethics Approval</h3> The study was approved by IRB (ethics committee of the Faculty of Medicine of the Eberhard Karls Universitaet Tuebingen and of the University Hospital Tuebingen) and was conducted in accordance with the Declaration of Helsinki; reference number 13/2007V. <h3>Consent</h3> Human material was collected after obtaining written informed consent of patients/participants.
A power law solution for FRLW Universe with observational constraints
2023-10-31

This paper examines a power law solution under gravity for an isotropic and homogeneous universe by considering its functional form as , where is a positive constant. In gravity, we have built the field equation for homogeneous and isotropic spacetime. The developed model's solution is . We have used the redshift in the range and obtained the model parameters , , by using the Markov Chain Monte Carlo (MCMC) method. The constrained values of the model parameter are as follows: km s Mpc , km s Mpc , km s Mpc , km s Mpc , km s Mpc which have been achieved by bounding the model with the Hubble parameter ( ) dataset, Baryon Acoustic Oscillations (BAO) dataset, Pantheon dataset, joint + Pantheon dataset and collective + BAO + Pantheon dataset, respectively. These computed observational values agree well with the outcomes from the Plank collaboration group. Through an analysis of the energy conditions' behaviour on our obtained solution, the model has been examined and analysed. Using the Om diagnostic as the state finder diagnostic tool and the jerk parameter, we have also investigated the model's validity. Our results show that, within a certain range of restrictions, the proposed model agrees with the observed signatures.
About the ability of agnostic X-ray tests of the Kerr Hypothesis to discover new physics
2023-10-31

In the past decade, we have seen an unprecedented progress in our ability of testing general relativity in the strong field regime with black hole observations. Most studies have focused on the so-called tests of the Kerr hypothesis: they have tried to verify whether the spacetime geometry around black holes is described by the Kerr solution as expected in general relativity. One can follow either a theory-specific analysis or an agnostic approach. Each strategy has its advantages and disadvantages. In this work, we study the ability of agnostic X-ray tests of the Kerr hypothesis to discover new physics. We simulate X-ray observations of bright Galactic black holes of specific theories of gravity and we analyze the simulated data with a reflection model employing the correct theory of gravity and another reflection model for agnostic tests of the Kerr hypothesis. Our results suggest that agnostic X-ray tests are valid tools to discover new physics, but their constraining power may be lower than a theory-specific analysis.
Discovery of X-Ray Polarization from the Black Hole Transient Swift J1727.8−1613
2023-11-01

Abstract We report the first detection of the X-ray polarization of the bright transient Swift J1727.8−1613 with the Imaging X-ray Polarimetry Explorer. The observation was performed at the beginning of the 2023 discovery outburst, when the source resided in the bright hard state. We find a time- and energy-averaged polarization degree of 4.1% ± 0.2% and a polarization angle of 2.°2 ± 1.°3 (errors at 68% confidence level; this translates to ∼20 σ significance of the polarization detection). This finding suggests that the hot corona emitting the bulk of the detected X-rays is elongated, rather than spherical. The X-ray polarization angle is consistent with that found in submillimeter wavelengths. Since the submillimeter polarization was found to be aligned with the jet direction in other X-ray binaries, this indicates that the corona is elongated orthogonal to the jet.
Regional but not global temperature variability underestimated by climate models at supradecadal timescales
2023-11-01

Knowledge of the characteristics of natural climate variability is vital when assessing the range of plausible future climate trajectories in the next decades to centuries. The reliable detection of climate fluctuations on multidecadal to centennial timescales depends on proxy reconstructions and model simulations, as the instrumental record extends back only a few decades in most parts of the world. Systematic comparisons between model-simulated and proxy-based inferences of natural variability, however, often seem contradictory. Locally, simulated temperature variability is consistently smaller on multidecadal and longer timescales than is indicated by proxy-based reconstructions, implying that climate models or proxy interpretations might have deficiencies. In contrast, at global scales, studies found agreement between simulated and proxy reconstructed temperature variations. Here we review the evidence regarding the scale of natural temperature variability during recent millennia. We identify systematic reconstruction deficiencies that may contribute to differing local and global model–proxy agreement but conclude that they are probably insufficient to resolve such discrepancies. Instead, we argue that regional climate variations persisted for longer timescales than climate models simulating past climate states are able to reproduce. This would imply an underestimation of the regional variability on multidecadal and longer timescales and would bias climate projections and attribution studies. Thus, efforts are needed to improve the simulation of natural variability in climate models accompanied by further refining proxy-based inferences of variability.
30 years of nanobodies – an ongoing success story of small binders in biological research
2023-11-01

ABSTRACT A milestone in the field of recombinant binding molecules was achieved 30 years ago with the discovery of single-domain antibodies from which antigen-binding variable domains, better known as nanobodies (Nbs), can be derived. Being only one tenth the size of conventional antibodies, Nbs feature high affinity and specificity, while being highly stable and soluble. In addition, they display accessibility to cryptic sites, low off-target accumulation and deep tissue penetration. Efficient selection methods, such as (semi-)synthetic/naïve or immunized cDNA libraries and display technologies, have facilitated the isolation of Nbs against diverse targets, and their single-gene format enables easy functionalization and high-yield production. This Review highlights recent advances in Nb applications in various areas of biological research, including structural biology, proteomics and high-resolution and in vivo imaging. In addition, we provide insights into intracellular applications of Nbs, such as live-cell imaging, biosensors and targeted protein degradation.
The First X-Ray Polarization Observation of the Black Hole X-Ray Binary 4U 1630–47 in the Steep Power-law State
2023-11-01

Abstract The Imaging X-ray Polarimetry Explorer (IXPE) observed the black hole X-ray binary 4U 1630–47 in the steep power-law (or very high) state. The observations reveal a linear polarization degree of the 2–8 keV X-rays of 6.8% ± 0.2% at a position angle of 21.°3 ± 0.°9 east of north (all errors at 1 σ confidence level). Whereas the polarization degree increases with energy, the polarization angle stays constant within the accuracy of our measurements. We compare the polarization of the source in the steep power-law state with the previous IXPE measurement of the source in the high soft state. We find that, even though the source flux and spectral shape are significantly different between the high soft state and the steep power-law state, their polarization signatures are similar. Assuming that the polarization of both the thermal and power-law emission components are constant over time, we estimate the power-law component polarization to be 6.8%–7.0% and note that the polarization angle of the thermal and power-law components must be approximately aligned. We discuss the implications for the origin of the power-law component and the properties of the emitting plasma.
Microfluidic-based nanoplatforms for cancer theranostic applications: A mini-review on recent advancements
2023-11-01

Cancer is amongst the foremost causes of death worldwide, and the field of nanotechnology presents promising prospects in terms of diagnostic and therapeutic approaches. Theranostics are nanoparticles (NPs) that possess the ability to combine therapeutic and diagnostic capabilities into a single agent. Nonetheless, the synthesis, characterization, and delivery of NPs for theranostics against cancer present obstacles. By providing swift, responsive, and economical platforms for cancer detection and treatment, microfluidic systems based on nanomaterials can overcome these obstacles. A synopsis of recent developments in microfluidic-assisted theranostic nanosystems for the treatment of various malignancies is provided in this mini-review. In addition to microfluidic system-based cancer sensing methods (optical, electrochemical, mechanical, and thermal), efficacious treatment approaches (gene therapy, drug delivery, sonodynamic therapy, etc.) are examined. Further, the potential and limitations of this innovative technique are analyzed, and its potential clinical applications in the future are proposed.
The Hitchhiker’s Guide to Statistical Analysis of Feature-based Molecular Networks from Non-Targeted Metabolomics Data
2023-11-01

Feature-Based Molecular Networking (FBMN) is a popular analysis approach for LC-MS/MS-based non-targeted metabolomics data. While processing LC-MS/MS data through FBMN is fairly streamlined, downstream data handling and statistical interrogation is often a key bottleneck. Especially, users new to statistical analysis struggle to effectively handle and analyze complex data matrices. In this protocol, we provide a comprehensive guide for the statistical analysis of FBMN results. We explain the data structure and principles of data clean-up and normalization, as well as uni- and multivariate statistical analysis of FBMN results. We provide explanations and code in two scripting languages (R and Python) as well as the QIIME2 framework for all protocol steps, from data clean-up to statistical analysis. Additionally, the protocol is accompanied by a web application with a graphical user interface (https://fbmn-statsguide.gnps2.org/), to lower the barrier of entry for new users. Together, the protocol, code, and web app provide a complete guide and toolbox for FBMN data integration, clean-up, and advanced statistical analysis, enabling new users to uncover molecular insights from their non-targeted metabolomics data. Our protocol is tailored for the seamless analysis of FBMN results from Global Natural Products Social Molecular Networking (GNPS and GNPS2) and can be adapted to other MS feature detection, annotation, and networking tools.