julilili42/papers huggingface dataset:
Basic Gynecologic Ultrasound Examination (Level I): DEGUM, ÖGUM, and SGUM Recommendations
2022-06-15

Abstract Ultrasound has become an essential diagnostic tool in gynecology, and every practicing gynecologist must be able to differentiate normal from pathologic findings, such as benign or malignant pelvic masses, adnexal torsion, pelvic inflammation disease, endometriosis, ectopic pregnancies, and congenital uterine malformations at least on a basic level. A standardized approach to the correct settings of the ultrasound system, the indications for gynecologic ultrasound investigations, and the sonographic appearance of normal anatomy and common pathologic findings in the standard planes are important prerequisites for safe and confident clinical management of gynecologic patients. Based on current publications and different national and international guidelines, updated DEGUM, ÖGUM, and SGUM recommendations for the performance of basic gynecologic ultrasound examinations were established.
Pharmacokinetics, Pharmacodynamics and Antiviral Efficacy of the MEK Inhibitor Zapnometinib in Animal Models and in Humans
2022-06-15

The mitogen-activated protein kinase (MEK) inhibitor zapnometinib is in development to treat acute viral infections like COVID-19 and influenza. While the antiviral efficacy of zapnometinib is well documented, further data on target engagement/pharmacodynamics (PD) and pharmacokinetics (PK) are needed. Here, we report zapnometinib PK and PD parameters in mice, hamsters, dogs, and healthy human volunteers. Mice received 25 mg/kg/day zapnometinib (12.5 mg/kg p. o. twice daily, 8 h interval). Syrian hamsters received 30 mg/kg (15 mg/kg twice daily) or 60 mg/kg/day once daily. Beagle dogs were administered 300 mg/kg/day, and healthy human volunteers were administered 100, 300, 600 and 900 mg zapnometinib (once daily p. o.). Regardless of species or formulation, zapnometinib maximum plasma concentration (C max ) was reached between 2–4 h after administration with an elimination half-life of 4–5 h in dogs, 8 h in mice or hamsters and 19 h in human subjects. Doses were sufficient to cause up to 80% MEK inhibition. Across all species approximately 10 μg/ml zapnometinib was appropriate to inhibit 50% of peripheral blood mononuclear cells (PBMC) MEK activity. In mice, a 50%–80% reduction of MEK activity was sufficient to reduce influenza virus titer in the lungs by more than 90%. In general, while &amp;gt;50% MEK inhibition was reached in vivo at most doses, 80% inhibition in PBMCs required significantly higher doses and appeared to be the practical maximal level obtained in vivo . However, the period of reduced phosphorylated extracellular-signal regulated kinase (pERK), a measure of MEK inhibition, was maintained even after elimination of zapnometinib from plasma, suggesting a sustained effect on MEK consistent with regulatory effects or a slow off-rate. These data suggest a target plasma C max of at least 10 μg/ml zapnometinib in further clinical studies.
Lifetime and Dynamics of Natural Orbits around Titan
2022-06-15

Considering the growing interest in sending probes to the natural satellite Titan, our work aims to investigate and map natural orbits around this moon. For that, we use mathematical models with forces that have symmetry/asymmetry phenomena, depending on the force, applied to orbits around Titan. We evaluated the effects due to the gravitational attraction of the Saturn, together with the perturbative effects coming from the non-sphericity of Titan (the gravitational coefficient J2) and the effects of the atmospheric drag present in the natural satellite. Lifetime maps were generated for different initial configurations of the orbit of the probe, which were analyzed in different scenarios of orbital perturbations. The results showed the existence of orbits surviving at least 20 years and conditions with shorter times, but sufficient to carry out possible missions, including the important polar orbits. Furthermore, the investigation of the oscillation rate of the altitude of the probe, called coefficient Δ, proposed in this work, showed orbital conditions that result in more minor oscillations in the altitude of the spacecraft.
Automated matching of two-time X-ray photon correlation maps from phase-separating proteins with Cahn–Hilliard-type simulations using auto-encoder networks
2022-06-15

Machine learning methods are used for an automated classification of experimental two-time X-ray photon correlation maps from an arrested liquid–liquid phase separation of a protein solution. The correlation maps are matched with correlation maps generated with Cahn–Hilliard-type simulations of liquid–liquid phase separations according to two simulation parameters and in the last step interpreted in the framework of the simulation. The matching routine employs an auto-encoder network and a differential evolution based algorithm. The method presented here is a first step towards handling large amounts of dynamic data measured at high-brilliance synchrotron and X-ray free-electron laser sources, facilitating fast comparison with phase field models of phase separation.
Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease
2022-06-15

ABSTRACT Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models that faithfully recapitulate different subtypes of the human disease. To close this gap, we developed methods to somatically introduce different oncogenic lesions directly into the stomach epithelium and show that genotypic configurations observed in patients produce metastatic gastric cancers that recapitulate the histological, molecular, and clinical features of all non-viral molecular subtypes of the human disease. Applying this platform to both wild-type and immune-deficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells that produced distinct patterns of metastasis that were mirrored in patients. Our results establish and credential a highly portable platform for producing autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts aimed at improving outcomes in gastric cancer patients.
Zamites (Bennettitales) from the Minjur Formation (Norian) of Saudi Arabia – a unique record from the Late Triassic palaeotropics of Gondwana
2022-06-15

Late Triassic plant macro-remains are extremely rare in an equatorial belt stretching across the North of Gondwana from northern South America to Arabia. Located between the Laurussian floral province to the North and the Gondwana floral province to the South, this large area, is almost entirely lacking palaeobotanical data. Thus, this region is of special interest to our knowledge of Late Triassic floral provincialism and plant distribution. Based on impressions from ferruginous crusts, the first record of identifiable plant macro-remains from the Late Triassic (Norian-Rhaetian) Minjur Formation is described, as belonging to the bennettitalean taxon Zamites aff. persicus. This new finding at least tentatively supports palynological data, which indicated similarities between the Late Triassic (Norian) palynoflora of the Minjur Formation of the Arabian Peninsula on the southern shores of the Tethys and the Norian palynoflora of Iran, during this time located in the northern part of the Tethys.
The effect of exercise interventions on inflammatory markers in major depressive disorder: protocol for a systematic review and meta-analysis
2022-06-15

<ns4:p><ns4:bold>Background:</ns4:bold> Depression currently affects 4.4% of the global population, and 93.7% of this population suffer from major depressive disorder (MDD) according to 2017 statistics. MDD patients are more likely to suffer from co-morbidities such as cardiovascular disease and high body mass index (BMI), thus contributing to its large cost to society. Throughout the literature, there are known links between inflammation and MDD. Interestingly, while exercise is considered a promising intervention for MDD, the mechanism(s) of action remain unclear, thereby preventing the creation of optimal, cost-saving, exercise “prescriptions” for those with MDD. Thus, the aim of this review and meta-analysis is to summarize and analyse the current literature exploring how quantified exercise interventions modulate inflammatory molecules in MDD patients.</ns4:p><ns4:p> <ns4:bold>Methods:</ns4:bold> Electronic databases (APA PsycINFO, and PubMed/MEDLINE (EBSCO interface), EMBASE) will be searched using a detailed search strategy comprised of three search term themes: exercise, depression/MDD, and inflammation/inflammatory molecules. Only quantified exercise interventions performed in adult humans with MDD validated via a recognized diagnostic criterion will be included. Studies should also include a MDD control group and explore changes in inflammatory molecules. Examples of these molecules include: C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1 beta (IL-1b), tumour necrosis factor-alpha (TNF-a), homocysteine, d-dimer and myeloperoxidase (MPO). After eligible studies are identified, standardized data extraction will be employed and the risk of bias in each study will be appraised using the Cochrane handbook checklists. In the event of two or more homogenous studies exploring exercise effects over a similar time period, raw mean differences or standardized mean differences will be pooled using random effects analysis. This systematic review and meta-analysis will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.</ns4:p><ns4:p> <ns4:bold>Dissemination:</ns4:bold> This systematic review and meta-analysis will be disseminated in peer-reviewed journals.</ns4:p><ns4:p> <ns4:bold>PROSPERO registration: </ns4:bold>CRD42020186006 (31/08/2020)</ns4:p>
An interpretable semantic similarity for predicting eye movements in reading: Approach comparison
2022-06-15

Expectations or predictions about upcoming content play an important role during language comprehension and processing. Semantic similarity as a metric has been used to predict the experimental data on language comprehension and processing. Some approaches have been proposed to compute contextual semantic similarity to predict how words in a context are processed. However, these approaches can be improved. This study uses a massive and naturalistic discourse as stimuli for collecting data on eye-movement in reading. It proposes asimple but effective approach to computing contextual semantic similarity. In order to test the efficiency of the new approach, we compare it to the recently developed cosine method and the Euclidean method. This comparison reveals that our approach can make good predictions about fixation durations on reading and that it outperforms the two aforementioned approaches. To our knowledge, this is the first study to compare a number of approaches on contextual semantic similarity that are used to process naturalistic discourse in the fields of cogni-tion, psycholinguistics and neuroscience. The findings of this study aretherefore of significance to the acquisition of a better understanding ofhow humans process words in a real-world context and how they makepredictions in language comprehension and processing. This study creates an interpretable but more effective approach for computing contextual semantic similarity, which allows further explorations of the data on naturalistic discourse reading, language comprehension and neuroscience.
Abstract 2865: CC-3, an IgG-based B7-H3xCD3 bispecific antibody for targeting of gastrointestinal cancers
2022-06-15

Abstract Despite substantial improvements over the last decades, survival rates in metastatic gastrointestinal cancer are still far from satisfactory, with an accordingly high medical need for new treatment strategies. B7-H3 (CD276) is a member of the B7 immune checkpoint family. Initially thought to act as co-stimulator, recent studies revealed that B7-H3 rather has an inhibitory role for T cells and contributes to tumor immune evasion. Clinically, its overexpression has been linked to invasive and metastatic potential as well as poor prognosis. Due to its expression on both, tumor cells and tumor vasculature, in a variety of cancer entities including colorectal cancer, B7-H3 attracted our interest as therapeutic target for T cell-recruiting bispecific antibodies (bsAbs). We postulate that “dual targeting” of both, the cancer cells and the tumor vasculature may support the influx of T cells into the tumor site, a critical prerequisite for successful immunotherapy of solid tumors allowing for subsequent destruction of antigen-positive malignant cells. We generated a panel of monoclonal antibodies directed to different epitopes of the B7-H3 molecule. After biochemical characterization, we selected two antibodies with distinct binding proprieties and subsequently used them for the construction of Tcell-recruiting B7-H3xCD3 bsAbs in an IgG-based (IgGsc) format. To reduce side effects, constructs were cloned using a UCHT-1 derived low affinity anti-CD3 sequence. In vitro characterization using colorectal and other carcinoma cells allowed for selection of a construct with optimal functional properties (thereafter termed CC-3) as revealed by target cell-restricted induction of T cell activation, proliferation and tumor cell killing. In vivo, potent efficacy of CC-3 was documented in a lung metastasis model and by its ability to eliminate large established flank tumors using immunocompromised NSG mice adoptively transferred with human effector cells. Despite the high therapeutic efficacy of CC-3, no toxicity was observed in the absence of target cells. In summary, CC-3 is a bsAb with promising therapeutic activity against B7-H3 positive tumors. GMP compliant production of CC-3 is presently ongoing to enable evaluation in a clinical “first in human” study in patients with colorectal cancer. Citation Format: Latifa Zekri, Martina S. Lutz, Ilona Hagelstein, Timo Manz, Monika Engel, Boris Klimovich, Nisha Prakash, Anna Chashchina, Sebastian Hörner, Stefanie Müller, Melanie Märklin, Martin Pflügler, Gundram Jung, Helmut R. Salih. CC-3, an IgG-based B7-H3xCD3 bispecific antibody for targeting of gastrointestinal cancers [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 2865.
Real world data on IO-based therapy for metastatic renal cell carcinoma
2022-06-15

Abstract Purpose: Immune-based (IO)-combinations are the backbone in the systemic therapy of metastatic renal cell carcinoma (mRCC). Despite phase III clinical trial data, real world data are of special importance to reflect clinical practice. Methods: This retrospective study included 201 mRCC patients receiving first-line systemic therapy from January 2006. Clinicopathological and treatment-related data were recorded. Progression-free (PFS) and overall survival (OS) were analyzed using descriptive statistics and Kaplan-Meier analysis. Results: Over the years, IO-based therapies have increased significantly. The collective comprises 76 patients with first-line IO-based therapy (IO-IO:55, TKI-IO:21) and 125 patients with TKI-monotherapy. PFS was significantly improved with TKI-IO combinations if compared to both TKI-monotherapy (23.9 vs. 10.3 months, HR 0.48, p=0.034) and IO-IO combination (23.9 vs. 6.1 months, HR 0.37, p=0.012). OS for TKI-IO treated patients was longer compared to TKI-monotherapy (HR 0.37, p=0.050) at median follow-up of 24.1 versus 29.9 months. In a subanalysis of nivolumab treated patients, starting from second-line (n=40), PFS was 5.5 months. The addition of nivolumab either in second-or later lines improved OS compared to repeated TKI- or mTOR-therapies alone (6.13 vs. 2.61 years, HR 0.46, p=0.003). Conclusion: Both first-line IO-based combinations and nivolumab after first-line TKI-monotherapy prolong OS in a real-world setting.
Abstract 3710: Synergistic cell death induction in ovarian cancer by cisplatin and ABT-199 is mediated by expression of NOXA
2022-06-15

Abstract Ovarian cancer is among the top ten leading causes of cancer death in women worldwide with a mortality rate of roughly 5% among all cancer deaths. So far, there are no recommended screening tests for the early detection of ovarian cancer. Therefore, patients are frequently diagnosed at late stages of ovarian cancer, which is associated with unfavorable 5-year survival. Patients suffering from ovarian cancer often show a good response to initial therapy with platinum-based compounds and/or taxanes subsequent to resection of the affected tissue. Unfortunately, ovarian cancer shows a high frequency of relapse and after chemotherapy persistent tumor cells re-expand and successively evolve into therapy-resistant tumors. We recently reported that cisplatin (cisPt) treatment of ovarian cancer cells enhances mitochondrial content and mitochondrial reactive oxygen species (Kleih et al. 2019). We therefore speculated that the enhanced mitochondrial content primes cisPt-treated cells for apoptosis induced by BH3 mimetic drugs, such as Venetoclax (ABT-199), that act on anti-apoptotic Bcl-2 proteins at the outer mitochondrial membrane. To explore this hypothesis, we investigated whether the combined administration of cisPt and ABT-199 leads to a synergistic cell death induction in ovarian cancer cells with different cisPt resistance and mitochondrial content. Detection of cell death by flow cytometric measurements of the mitochondrial membrane potential and exposure of phosphatidylserine demonstrated a synergistic cell death induction by cisPt and ABT-199 in OVCAR4 and OVCAR8 cells, irrespective of the cisPt resistance. Interestingly, Western blot analysis revealed that ABT-199 induced the accumulation of the BH3-only protein NOXA in both cancer cell lines. Accumulation of NOXA was dependent on ABT-199-mediated activation of the stress-responsive transcription factor ATF4. Knock-down experiments showed that apoptosis of cisPt-resistant OVCAR8 cells by the combined treatment with ABT-199 and cisPt was entirely dependent on NOXA. Moreover, also cisPt-sensitive OVCAR4 cells revealed an initially reduced apoptosis induction by the NOXA knock-down. Our data therefore elucidate the molecular mechanism of the synergistic efficacy of cisPt/ABT-199 combination therapies, which should be promising especially for the treatment of recurrent tumors developing reduced sensitivity to cisPt-based treatments. Citation Format: Benjamin Schaefer, Sandra Weller, Tobias B. Beigl, Klaus Schulze-Osthoff, Hans-Georg Kopp, Walter E. Aulitzky, Frank Essmann. Synergistic cell death induction in ovarian cancer by cisplatin and ABT-199 is mediated by expression of NOXA [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 3710.
Abstract 2859: Platelet-derived TGFβ undermines treatment efficacy of t cell recruiting bispecific antibodies
2022-06-15

Abstract Immunotherapeutic strategies such as T cell-recruiting bispecific antibodies (bsAb), chimeric antigen receptor (CAR) T cells, and immune checkpoint inhibition have revolutionized oncological treatment. However, many patients do not respond to treatment with the so far available therapeutics, others for limited time only. Various tumor immune evasion mechanisms have been reported to counteract efficiency of T cell engaging therapeutics. Thrombocytes have recently been described to affect cancer biology by mediating epithelial-mesenchymal transition, tumor invasion, metastasis and notably also immune evasion. Here we report that, upon treatment of prostate cancer patients within a clinical trial evaluating a novel PSMAxCD3 bsAb (NCT04104607), we observed profound treatment-associated platelet activation, mirrored by a decrease of total platelet count. Upon modelling the treatment setting, we found that platelet activation significantly reduced bsAb-mediated CD4+ and CD8+ T cell reactivity as revealed by impaired T cell activation, reduced secretion of perforin and ultimately inhibition of target cell lysis. The immunosuppressive effect mediated by platelets occurred in a TGFβ-dependent manner and was not restricted to the PSMAxCD3 bsAb, but was also observed with various other CD3-directed bispecific constructs including the clinically approved CD19xCD13 bsAb Blinatumomab. BsAb-mediated T cell reactivity could generally be restored by inhibiting platelets using dabigatran, but also specifically by blocking the TGFβ axis. Together, our findings unravel that platelets undermine the efficacy of T cell-recruiting bsAb and identify modulation of platelet function and TGFβ as means to reinforce the effectiveness of bsAb treatment. Citation Format: Martina S. Lutz, Boris Klimovich, Stefanie Maurer, Jonas S. Heitmann, Melanie Maerklin, Latifa Zekri, Gundram Jung, Helmut R. Salih, Clemens Hinterleitner. Platelet-derived TGFβ undermines treatment efficacy of t cell recruiting bispecific antibodies [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 2859.