julilili42/papers huggingface dataset:
Testing disformal non-circular deformation of Kerr black holes with LISA
2024-06-01

Abstract There is strong observational evidence that almost every large galaxy has a supermassive black hole at its center. It is of fundamental importance to know whether such black holes are described by the standard Kerr solution in General Relativity (GR) or by another black hole solution. An interesting alternative is the so-called disformal Kerr black holes which exist within the framework of degenerate higher-order scalar-tensor (DHOST) theories of gravity. The departure from the standard Kerr black hole spacetime is parametrized by a parameter D , called disformal parameter . In the present work, we discuss the capability of LISA to detect the disformal parameter. For this purpose, we study Extreme Mass Ratio Inspirals (EMRI's) around disformal Kerr black holes within the framework of the quadrupole hybrid formalism. Even when the disformal parameter is very small, its effect on the globally accumulated phase of the gravitational waveform of an EMRI can be significant due to the large number of cycles in the LISA band made by the small compact object. We show that LISA will in principle be able to detect and measure extremely small values of the disformal parameter which in turn, can be seen as an assessment of LISA's ability to detect very small deviations from the Kerr geometry.
ENLIGHTED phase 3 study: Efficacy and safety of padeliporfin vascular targeted photodynamic therapy (VTP) for treatment of low-grade upper tract urothelial cancer (LG UTUC).
2024-06-01

TPS4622 Background: Padeliporfin VTP has demonstrated safety and efficacy for UTUC treatment in a Phase 1 study (NCT03617003). Padeliporfin VTP is a combination product: a drug, padeliporfin administered IV; a device: a laser light delivery system/laser-source of light emitting near-infrared (NIR) light at 753nm; and an optic fiber delivering the light endoluminally to the vicinity of UTUC tumors within the collecting system. We report the preliminary efficacy and safety outcomes of Padeliporfin VTP for Treatment of LG UTUC in ENLIGHTED, a Phase 3 trial (NCT04620239). Methods: This is an open-label phase 3 study from USA, EU and Israel. Key inclusion criteria is up to 2 biopsy-proven LG UTUC with index tumor ≤15mm in the kidney and≤20mm in the ureter with an absence of high-grade cells on cytology. VTP is performed via retrograde upper tract endoscopy under anesthetic and low light conditions, Padeliporfin is injected IV and a laser light diffuser fiber 20-40 mm is positioned in proximity of the tumor through the scope. After Padeliporfin injection, the laser fiber is illuminated for 10 min. The fiber can be repositioned to provide up to 3 treatments within the upper tract. Patients are treated in two phases: Induction(ITP) and Maintenance Treatment Phases (MTP). ITP consists of 1-3 VTPs provided at 4-week intervals until achieving complete response (CR) or treatment failure. Patients achieving CR will proceed to the MTP and be followed with endoscopic evaluation every 3 months with VTP provided for recurrent tumors only up to 12 months. Patients with high-grade recurrences will be deemed treatment failures and removed from the study to standard of care treatment. Patients completing the MTP, will be followed for an additional 48 months for long-term outcomes. Primary outcome is CR on endoscopic evaluation and selective cytology at the time of primary response evaluation (28 ± 3 days post last treatment) during padeliporfin VTP ITP. A total of 100 patients are to be enrolled. As of 21 Jan 2024, 17 patients have been treated. 13 patients completed ITP and had CR 10/13 (77%) and PR 3/13 (23%). Patients baseline characteristics: age 67±12 years; gender: 9(53%) males and 8(47%) females; tumors location: 5(29%) in ureter, 13(76%) in the kidney; number of tumors: 7(41%) 2 tumors, 10(59%) 1 tumor. The most frequent treatment related adverse events were: flank pain 17%, vomiting 8%, fatigue 8%, nausea 6%, hematuria 6%, all Grade 1-2, resolved within few days. Grade 3 serious adverse events 9% (flank pain, hypertension, renal colic, urinary tract infection) were resolved within 2-7 days. To date Padeliporfin VTP has shown evidence of safety and efficacy with preliminary data that is consistent with prior experience. Recruitment for the ENLIGHTED trial is ongoing with results expected to provide basis for approval of a new therapy that clinically benefits pts. Clinical trial information: NCT04620239 .
Amiloride versus furosemide for the treatment of edema in patients with nephrotic syndrome: A pilot study (AMILOR)
2024-06-01

Abstract Aim In rodent models of nephrotic syndrome (NS), edema formation was prevented by blockade of the epithelial sodium channel ENaC with amiloride. However, apart from case reports, there is no evidence favoring ENaC blockade in patients with NS. Methods The monocentric randomized controlled AMILOR study investigated the antiedematous effect of amiloride (starting dose 5 mg/day, max. 15 mg/day) in comparison to standard therapy with the loop diuretic furosemide (40 mg/day, max. 120 mg/day) over 16 days. Overhydration (OH) was measured by bioimpedance spectroscopy (BCM, Fresenius). Depending on the OH response, diuretic dose was adjusted on days 2, 5, 8 and 12, and if necessary, hydrochlorothiazide (HCT) was added from d8 (12.5 mg/day, max. 25 mg/day). The primary endpoint was the decrease in OH on d8. The study was terminated prematurely due to insufficient recruitment and a low statistical power due to a low actual effect size. Results Median baseline OH was +26.4 (interquartile range 15.5–35.1)% extracellular water (ECW) in the amiloride arm and + 27.9 (24.1–29.4)% ECW in the furosemide arm and decreased by 1.95 (0.80–6.40) and 5.15 (0.90–8.30)% ECW after 8 days, respectively, and by 10.10 (1.30–14.40) and 7.40 (2.80–10.10)% ECW after 16 days, respectively. OH decrease on d8 and d16 was not significantly different between both arms. Conclusion The AMILOR study is the first randomized controlled pilot study suggesting a similar antiedematous effect as furosemide. Further studies are required to better define the role of amiloride in NS (EudraCT 2019‐002607‐18).
Updated results on the bispecific PSMAxCD3 antibody CC-1 for treatment of prostate cancer.
2024-06-01

2536 Background: While being efficient in hematological malignancies, bispecific antibodies (bsAbs), like CAR T cells, are not yet established in solid tumors. Moreover, all T cell-mobilizing strategies cause side effects that endanger patients and may limit applicable doses and thus efficacy. We report on the clinical development of CC-1, a PSMAxCD3 bsAb in an IgG-based format that induces fully target cell-restricted T cell activity against prostate cancer (1). Targeting PSMA, which is expressed on both the malignant cells and the neovasculature, improves accessibility of the tumor site for immune effector cells as critical prerequisite for therapeutic success in solid tumors. Methods: A FIH trial evaluating CC-1 included patients with metastatic castration resistant prostate carcinoma (mCRPC) (NCT04104607) and consisted of two parts: Dose escalation (n=10-66) using a novel intra-individual dose escalation design to rapidly reach the target dose of 826μg to determine safety, tolerability and maximum tolerated dose (MTD) (2), and Dose expansion, which exposed patients to CC-1 at MTD and explored efficacy to define RP2D (n=14). Currently, subcutaneous (SC) application as different application mode is being evaluated. Based on very favorable safety and preliminary efficacy data, another phase I trial was initiated where CC-1 is evaluated as first line treatment in patients with hormone sensitive biochemical recurrence (BCR) of PC (NCT05646550), where tumor burden is low and accordingly lower side effects and long-lasting efficacy are expected. Results: Recruitment in the FIH trial in mCRPC has been completed. 28 patients completed treatment with the most frequently observed (86%) toxicity being cytokine release syndrome (CRS, max. 2°). Other adverse events (all ≤2°) included hematologic events (93%) as well as elevated liver enzymes (61%), hypertension (18%) and xerostomia (7%). A rapid and profound decline of PSA levels with up to 62% reduction compared to baseline was documented in all but one of the heavily pretreated patients that received the target dose. Twelve patients received multiple treatment cycles. Recruitment of patients to receive SC application of CC-1 is currently ongoing. In the phase I trial in BCR of PC, the first four dose cohorts have so far been completed. CC-1 application was well tolerated in all patients. In all but one of so far treated patients, mild CRS (transiently elevated temperature) that ceased within 24h upon dosing with antipyretics was observed. No other CC-1 related toxicities were observed and recruitment is ongoing. Conclusions: CC-1 is a promising compound with a favourable toxicity profile and promising clinical activity. Details on study designs and updated data from the clinical trials will be presented at the meeting. 1. Zekri et al, EMBO Mol Med, 2020. 2. Labrenz et al, Pharm Stat, 2022. Clinical trial information: NCT04104607 .
Role of Metacognitive Confidence Judgments in Curiosity: Different Effects of Confidence on Curiosity Across Epistemic and Perceptual Domains
2024-06-01

Abstract Previous research suggests that curiosity is sometimes induced by novel information one has no relevant knowledge about, but it is sometimes induced by new information about something that one is familiar with and has prior knowledge about. However, the conditions under which novelty or familiarity triggers curiosity remain unclear. Using metacognitive confidence judgments as a proxy to quantify the amount of knowledge, this study evaluates the relationship between the amount of relevant knowledge and curiosity. We reviewed previous studies on the relationship between subjective curiosity and confidence and reanalyzed existing large‐sample data. The findings indicate that the relationship between curiosity and confidence differs depending on the nature of the stimuli: epistemic versus perceptual. Regarding perceptual stimuli, curiosity is stronger when individuals have lower confidence levels. By contrast, for epistemic stimuli, curiosity is stronger when individuals have higher confidence levels. These results suggest that curiosity triggered by perceptual stimuli is based on perceived novelty, whereas that triggered by epistemic stimuli is based on familiarity with prior knowledge.
Subanesthetic Ketamine Suppresses Locus Coeruleus–Mediated Alertness Effects: A 7T fMRI Study
2024-06-01

Abstract Background The NMDA antagonist S-ketamine is gaining increasing use as a rapid-acting antidepressant, although its exact mechanisms of action are still unknown. In this study, we investigated ketamine in respect to its properties toward central noradrenergic mechanisms and how they influence alertness behavior. Methods We investigated the influence of S-ketamine on the locus coeruleus (LC) brain network in a placebo-controlled, cross-over, 7T functional, pharmacological MRI study in 35 healthy male participants (25.1 ± 4.2 years) in conjunction with the attention network task to measure LC-related alertness behavioral changes. Results We could show that acute disruption of the LC alertness network to the thalamus by ketamine is related to a behavioral alertness reduction. Conclusion The results shed new light on the neural correlates of ketamine beyond the glutamatergic system and underpin a new concept of how it may unfold its antidepressant effects.
DEAD box RNA helicases are pervasive protein kinase interactors and activators
2024-06-01

DEAD box (DDX) RNA helicases are a large family of ATPases, many of which have unknown functions. There is emerging evidence that besides their role in RNA biology, DDX proteins may stimulate protein kinases. To investigate if protein kinase–DDX interaction is a more widespread phenomenon, we conducted three orthogonal large-scale screens, including proteomics analysis with 32 RNA helicases, protein array profiling, and kinome-wide in vitro kinase assays. We retrieved Ser/Thr protein kinases as prominent interactors of RNA helicases and report hundreds of binary interactions. We identified members of ten protein kinase families, which bind to, and are stimulated by, DDX proteins, including CDK, CK1, CK2, DYRK, MARK, NEK, PRKC, SRPK, STE7/MAP2K, and STE20/PAK family members. We identified MARK1 in all screens and validated that DDX proteins accelerate the MARK1 catalytic rate. These findings indicate pervasive interactions between protein kinases and DEAD box RNA helicases, and provide a rich resource to explore their regulatory relationships.
Cyanobacteria-ferrihydrite aggregates, BIF sedimentation and implications for Archaean- Palaeoproterozoic seawater geochemistry
2024-06-01

Abstract Precambrian banded iron formations (BIFs) are iron- and silica-rich (bio)chemical sediments that are widely believed to have been precipitated by microbial oxidation of dissolved Fe(II). The by-product of these metabolisms – insoluble ferric iron – would have settled through the water column, often as aggregates with the cell biomass. While the mineralogy, composition and physical properties of cell-iron mineral aggregates formed by anaerobic Fe(II)-oxidising photoferrotrophic bacteria have been extensively studied, there are limited studies that characterise cyanobacteria-iron mineral aggregates that formed during oxygenic photosynthesis. This gap in knowledge is important because it impacts sedimentation velocities and the Fe(III) to organic carbon (Corg) ratios in the marine sediment pile. Here, we used a recently introduced approach to precisely measure the sedimentation velocity of cyanobacteria-ferrihydrite aggregates and the Fe(III):Corg ratios of the cyanobacteria-ferrihydrite aggregates over a wide range of pH and initial Fe(II) concentrations under predicted Palaeoproterozoic atmospheric conditions. Our results indicate that it was highly unlikely BIFs formed at pH &amp;lt;7 via chemical oxidation due to the insufficient sedimentation velocity, even at the maximum predicted Fe(II) concentration of 1800 μM with excess oxygen. Instead, large Banded Iron Formation (BIF) deposits, such as those associated with the ca. 2.47 Ga Kuruman Formation in South Africa, would only had been deposited at minimum Fe(II) concentrations of 500 μM at pH 7 or 250 μM at pH 8. The Fe:Corg ratios in cyanobacteria-ferrihydrite sediments formed during initially anoxic Fe(II) oxidation experiments represent the maximum values under each condition because we specifically extracted samples after all Fe(II) was oxidised. The Fe(III) to organic carbon ratio was consistently below 4, which is also the ratio required for dissimilatory Fe(III) reduction (DIR). This result indicates that biomass in this case was in excess, which contradicts the low organic carbon content seen in most BIFs. Thus, we suggest that biomass was either physically separated from ferrihydrite aggregates during sedimentation under the influence of ocean currents and waves, or it was degraded prior to DIR. The mineralogical and geochemical evidences of both oxide and carbonate facies from the Kuruman Iron Formation (IF) suggest that ferrihydrite was most likely the precursor along with a significant initial organic carbon input, supporting the proposed cyanobacterially-mediated BIF depositional model and experimental results.
Implementation and Evaluation of IEEE 802.11ax Target Wake Time Feature in ns-3
2024-06-01

The Target Wake Time (TWT) feature has been introduced in Wi-Fi technology in 802.11ah and has been extended by IEEE 802.11ax as an optional feature. It allows stations (STAs) to sleep for some intervals and wake up at a Target Wake Time to send and receive their traffic. This feature reduces energy consumption of devices. While the standards are completed, there is no publicly available implementation of Target Wake Time (TWT) in a simulation framework.
Temperature-dependence of beam-driven dynamics in graphene-fullerene sandwiches
2024-06-01

C<sub>60</sub> fullerenes encapsulated between graphene sheets were investigated by aberration-corrected high-resolution transmission electron microscopy at different temperatures, namely about 93 K, 293 K and 733 K, and by molecular dynamics simulations. We studied beam-induced dynamics of the C<sub>60</sub> fullerenes and the encapsulating graphene, measured the critical doses for the initial damage to the fullerenes and followed the beam-induced polymerization. We find that, while the doses for the initial damage do not strongly depend on temperature, the clusters formed by the subsequent polymerization are more tubular at lower temperatures, while sheet-like structures are generated at higher temperatures. The experimental findings are supported by the results of first-principles and analytical potential molecular dynamics simulations. The merging of curved carbon sheets is clearly promoted at higher temperatures and proceeds at once over few-nm segments.
Surgical Technique and Preliminary Outcomes of Double-Level Osteotomy for Valgus Deformity
2024-06-01

Background: Data are limited regarding the surgical technique or outcomes of double-level osteotomy (DLO) combining medial closing-wedge distal femoral osteotomy and medial closing-wedge high tibial osteotomy in patients with moderate-to-severe valgus deformity. Purpose/Hypothesis: To describe the surgical technique and assess the short-term outcomes and surgical accuracy of DLO in patients with a moderate or severe valgus deformity. It was hypothesized that this technique would result in good clinical outcomes with precise deformity correction. Study Design: Case series; Level of evidence, 4. Methods: Eight patients (mean age, 44.2 ± 10.9 years) with a moderate or severe valgus knee treated with DLO (9 knees; mechanical tibiofemoral angle [mTFA], 10.3°± 3.5°) were included. The mean follow-up was 25.1 ± 11.1 months. Preoperative to postoperative changes in radiographic parameters (mTFA, mechanical lateral distal femoral angle, mechanical medial proximal tibial angle, joint line convergence angle) and clinical scores (Hospital for Special Surgery score, Oxford Knee Score, Lysholm score) were assessed. Surgical accuracy was calculated by subtracting the achieved postoperative correction from the preoperatively planned targeted correction. Results: The mTFA changed significantly from 10.3°± 3.5° preoperatively to –1.8°± 3.4° postoperatively ( P &lt; .001); the mechanical lateral distal femoral angle and mechanical medial proximal tibial angle changed significantly by 5.1°± 2.7° and 5.9°± 2.2°, respectively ( P &lt; .001 for both); and the posterior distal femoral angle decreased significantly from 85.9°± 3.1° to 84.2°± 2.4° ( P &lt; .01). There was no significant difference between pre- and postoperative joint line convergence angles (3.3°± 2.3° to 2.6°± 2.1°). The accuracy of the correction was high: the mTFA achieved postoperatively differed from the mTFA planned preoperatively by a mean of 2.7°± 1.9° (range, 0.6°-6.6°). Significant pre- to postoperative improvement was seen for all outcome scores (Hospital for Special Surgery, from 67 ± 11 to 93 ± 4; Oxford Knee Score, from 29 ± 7 to 43 ± 3; Lysholm, from 41 ± 24 to 89 ± 8; P &lt; .001 for all). Conclusion: High surgical accuracy was achieved, and patients who underwent varus DLO for valgus knees showed improved knee function at short-term follow-up. Varus DLO can be a surgical option to restore the optimal alignment and joint line obliquity in patients with moderate or severe valgus malalignment.
Re-irradiation in recurrent glioblastoma: PET- or MRI-based? Results of a prospective randomized clinical trial.
2024-06-01

2021 Background: Re-irradiation is an important treatment option for recurrent glioblastoma (rGBM). Here, we aimed to compare the oncological outcome of a re-irradiation target volume delineation based on O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) with the one of a treatment based on contrast enhanced T1-weighted magnetic resonance imaging (T1Gd-MRI). Methods: GLIAA was a prospective, multicenter, randomized trial (NOA 10/ARO 2013-1, DKTK-a.). Patients with rGBM recurrence of 1-6 cm following initial radiotherapy were recruited at 14 centers in Germany and randomized 1:1 between a FET-PET- (arm A) and a T1Gd-MRI-based target volume delineation (arm B). The treatment consisted in a high-precision stereotactic re-irradiation with 39 Gy in 13 fractions. The primary endpoint was progression-free survival (PFS) from randomization. Secondary endpoints included overall survival (OS), local tumor control, and toxicity. Results: From November 26, 2013, to September 2, 2021, 271 patients were assessed for eligibility and 200 were randomized. 98 patients in the FET-PET arm and 97 patients in the T1Gd-MRI arm were treated per protocol. Median PFS was 4.0 months (95% confidence interval [CI] 3.7-5.2) in the FET-PET arm and 4.9 months (95% CI 3.7-6.0) in the GdT1-MRI arm (one-sided stratified log-rank test p=0.98; adjusted HR for the experimental versus the control arm 1.14 [95% CI 0.85-1.52], p=0.39). Median OS was 9.4 months (95% CI 7.8-11.1) in arm A and 9.0 months (95% CI 7.6-10.5) in arm B (HR 1.01 [95% CI 0.75-1.37], p=0.92). Local control rate at 12 months was 22% in the FET-PET arm (95% CI 14%-31%) and 20% in the GdT1-MRI arm (95% CI 12%-29%). Radiation necrosis as adverse event was documented in 25.5% of cases in arm A and in 21.6% in arm B. Of the 239 patients who received the FET tracer, 3 reported 5 severe adverse events in the timespan of 7 days after PET. No event was related to the application of the tracer. Conclusions: In this trial, FET-PET-based re-irradiation of rGBM was not superior to the GdT1-MRI-based treatment. Consequently, both options remain valid in this setting. Stereotactic re-irradiation with 39 Gy in 3 Gy fractions was shown to be safe and the FET-PET investigation was well tolerated in all cases. Due to the inclusion of FET-PET-positive patients only, our results do not impact the known diagnostic role of FET-PET in differentiating rGBM progression from post-therapeutic changes. Clinical trial information: NCT01252459 .
A β-catenin chromobody-based probe highlights endothelial maturation during vascular morphogenesis in vivo
2024-06-01

ABSTRACT Visualization of protein dynamics is a crucial step in understanding cellular processes. Chromobodies, fluorescently labelled single-domain antibodies, have emerged as versatile probes for live cell imaging of endogenous proteins. However, how these chromobodies behave in vivo and how accurately they monitor tissue changes remain poorly explored. Here, we generated an endothelial-specific β-catenin chromobody-derived probe and analyzed its expression pattern during cardiovascular development in zebrafish. Using high-resolution confocal imaging, we show that the chromobody signal correlates with the localization of β-catenin in the nucleus and at cell-cell junctions, and thereby can be used to assess endothelial maturation. Loss of Cadherin 5 strongly affects the localization of the chromobody at the cell membrane, confirming the cadherin-based adherens junction role of β-catenin. Furthermore, using a genetic model to block blood flow, we observed that cell junctions are compromised in most endothelial cells but not in the endocardium, highlighting the heterogeneous response of the endothelium to the lack of blood flow. Overall, our data further expand the use of chromobodies for in vivo applications and illustrate their potential to monitor tissue morphogenesis at high resolution.