julilili42/papers huggingface dataset:
Enzalutamide with androgen deprivation therapy in Japanese men with metastatic hormone‐sensitive prostate cancer: A subgroup analysis of the phase III ARCHES study
2021-05-06

Objective To evaluate the efficacy and safety of enzalutamide plus androgen deprivation therapy in Japanese men with metastatic hormone‐sensitive prostate cancer. Methods A post‐hoc analysis of the Japanese subgroup in the phase III, randomized, multinational ARCHES study (NCT02677896) was carried out. Patients with metastatic hormone‐sensitive prostate cancer were randomized to receive enzalutamide or a placebo, plus androgen deprivation therapy, stratified by disease volume and prior docetaxel therapy. The primary end‐point was radiographic progression‐free survival. Secondary end‐points included time to prostate‐specific antigen progression and overall survival. Results Of 1150 patients, 92 Japanese patients were randomized to enzalutamide ( n = 36) or a placebo ( n = 56), plus androgen deprivation therapy; none received prior docetaxel. Enzalutamide plus androgen deprivation therapy reduced the risk of radiographic progression or death in Japanese patients by 61% versus the placebo, similar to the overall population. Similar results were observed with secondary end‐points, showing clinical benefit of enzalutamide plus androgen deprivation therapy in Japanese patients. Overall survival data were immature. Grade 3–4 adverse events were reported in 47% and 25% of the enzalutamide and placebo groups, respectively. Nasopharyngitis, hypertension and abnormal hepatic function were reported more frequently in Japanese patients versus the overall population. Conclusions Enzalutamide plus androgen deprivation therapy has clinical benefit with a tolerable safety profile in Japanese men with metastatic hormone‐sensitive prostate cancer, consistent with the overall population.
Parenteral high‑dose ascorbate - A possible approach for the treatment of glioblastoma (Review)
2021-05-06

For glioblastoma, the treatment with standard of care therapy comprising resection, radiation, and temozolomide results in overall survival of approximately 14-18 months after initial diagnosis. Even though several new therapy approaches are under investigation, it is difficult to achieve life prolongation and/or improvement of patient's quality of life. The aggressiveness and progression of glioblastoma is initially orchestrated by the biological complexity of its genetic phenotype and ability to respond to cancer therapy via changing its molecular patterns, thereby developing resistance. Recent clinical studies of pharmacological ascorbate have demonstrated its safety and potential efficacy in different cancer entities regarding patient's quality of life and prolongation of survival. In this review article, the actual glioblastoma treatment possibilities are summarized, the evidence for pharmacological ascorbate in glioblastoma treatment is examined and questions are posed to identify current gaps of knowledge regarding accessibility of ascorbate to the tumor area. Experiments with glioblastoma cell lines and tumor xenografts have demonstrated that high‐dose ascorbate induces cytotoxicity and oxidative stress largely selectively in malignant cells compared to normal cells suggesting ascorbate as a potential therapeutic agent. Further investigations in larger cohorts and randomized placebo‐controlled trials should be performed to confirm these findings as well as to improve delivery strategies to the brain, through the inherent barriers and ultimately to the malignant cells.
Theoretical and Experimental Evidence of Two‐Step Tautomerization in Hypericin
2021-05-06

Hypericin has large potential in modern medicine and exhibits fascinating structural dynamics, such as multiple conformations and tautomerization. However, it is difficult to study individual conformers/tautomers, as they cannot be isolated due to the similarity of their chemical and physical properties. An approach to overcome this difficulty is to combine single molecule experiments with theoretical studies. Time‐dependent density functional theory (TD‐DFT) calculations reveal that tautomerization of hypericin occurs via a two‐step proton transfer with an energy barrier of 1.63 eV, whereas a direct single‐step pathway has a large activation energy barrier of 2.42 eV. Tautomerization in hypericin is accompanied by reorientation of the transition dipole moment, which can be directly observed by fluorescence intensity fluctuations. Quantitative tautomerization residence times can be obtained from the autocorrelation of the temporal emission behavior revealing that hypericin stays in the same tautomeric state for several seconds, which can be influenced by the embedding matrix. Furthermore, replacing hydrogen with deuterium further proves that the underlying process is based on tunneling of a proton. In addition, the tautomerization rate can be influenced by a λ /2 Fabry–Pérot microcavity, where the occupation of Raman active vibrations can alter the tunneling rate.
Prevention and treatment of iatrogenic premature ovarian insufficiency: interpretation of the first Chinese guideline on ovarian tissue cryopreservation and transplantation
2021-05-06

In recent years, with the rapid development of medical research, cancer diagnosis and treatment technology have significantly improved young cancer patient's survival rate. Anticancer therapy such as chemotherapy, radiotherapy, or hematopoietic stem cell transplantation can lead to premature ovarian insufficiency. The endocrine and reproductive function of the ovary is critical to women's physical and mental health. Ovarian tissue cryopreservation and transplantation can protect not only female fertility but also preserve ovarian endocrine function. This paper interprets the guidelines for ovarian tissue cryopreservation and transplantation issued by the Chinese Society of Gynecological Endocrinology affiliated to the International Society of Gynecological Endocrinology. The purpose of this guideline's interpretation is to promote more medical workers to understand the technology of ovarian tissue cryopreservation and transplantation, which can provide patients with more choices of fertility protection methods and improve their quality of life.
Reviews and Syntheses: Composition and Characteristics ofBurrowing Animals along a Climate and Ecological Gradient,Chile
2021-05-06

Abstract. Although the burrowing activity of some species (e.g. gophers) is well studied, a comprehensive inventory of burrowing animals in adjacent biomes is not yet known, despite the potential importance of burrowing activity on the physical and chemical evolution of Earth’s surface. In this study, we review the available information with a focus on: a) an inventory of burrowing vertebrates and invertebrates along the climate and ecological gradient in Chile; b) the dimensions and characteristics of burrows; and c) calculation of excavation rates by local species compositions. Methods used include a literature compilation (&gt; 1000 studies) of Chilean burrowing animal species integrated with global, species-specific excavation rates. A field study augments literature findings with quantification of the zoogeomorphic effects on hillslope mass transport at the animal community level and along the arid to humid-temperate climate gradient within the Chilean Coastal Cordillera (27–38° S latitude). The literature review indicates 45 vertebrate and 345 invertebrate burrowing species distributed across Chile in different biomes. Burrowing depths for Chilean mammals range between 3 m (e.g. for skunks, Conepatus) to 0.25 m (for rock rats, Aconaemys). For invertebrates, burrowing depths in Chile range between 1 m for scorpions to 0.3 m for spiders. In comparison, globally documented maximum burrow depths reach up to more than 6 m for vertebrates (gopher tortoises and aardvarks) and 4 m for invertebrates (ants). Minimum excavation rates of local animal communities observed from field sites in Chile are 0.34 m3 ha−1 yr−1 for the arid site, 0.56 m3 ha−1 yr−1 for the semi-arid site, 0.93 m3 ha−1 yr−1 for the mediterranean site and 0.09 m3 ha−1 yr−1 for the humid-temperate site, with the latter likely an underestimation. The calculated minimum Chilean excavation rates are within the large range of globally observed single species rates ranging between 0.01 and 146.20 m3 ha−1 yr−1 for vertebrates and from 0.01 to 53.33 m3 ha−1 yr−1 for invertebrates. Taken together, results highlight not only the diverse and latitudinally varying number of burrowing vertebrates and invertebrates present in different biomes, but also fosters the understanding of how burrowing activity changes over a gradient and is influenced by mean annual temperature, mean annual precipitation, slope aspect and latitudinal related incoming solar energy.
Pulseq‐CEST: Towards multi‐site multi‐vendor compatibility and reproducibility of CEST experiments using an open‐source sequence standard
2021-05-07

Purpose As the field of CEST grows, various novel preparation periods using different parameters are being introduced. At the same time, large, multisite clinical studies require clearly defined protocols, especially across different vendors. Here, we propose a CEST definition standard using the open Pulseq format for a shareable, simple, and exact definition of CEST protocols. Methods We present the benefits of such a standard in three ways: (1) an open database on GitHub, where fully defined, human‐readable CEST protocols can be shared; (2) an open‐source Bloch‐McConnell simulation to test and optimize CEST preparation periods in silico; and (3) a hybrid MR sequence that plays out the CEST preparation period and can be combined with any existing readout module. Results The exact definition of the CEST preparation period, in combination with the flexible simulation, leads to a good match between simulations and measurements. The standard allowed finding consensus on three amide proton transfer–weighted protocols that could be compared in healthy subjects and a tumor patient. In addition, we could show coherent multisite results for a sophisticated CEST method, highlighting the benefits regarding protocol sharing and reproducibility. Conclusion With Pulseq‐ CEST, we provide a straightforward approach to standardize, share, simulate, and measure different CEST preparation schemes, which are inherently completely defined.
CYP2D6 in the Brain: Potential Impact on Adverse Drug Reactions in the Central Nervous System—Results From the ADRED Study
2021-05-07

Cytochrome P450 (CYP) 2D6 is a polymorphic enzyme expressed in the central nervous system (CNS), important in drug metabolism and with a potentially constitutive role in CNS function such as vigilance. This study aimed to analyze variability in CYP2D6 activity linked to vigilance-related adverse drug reactions (ADRs) in the CNS. A dataset of N = 2939 ADR cases of the prospective multicenter observational trial in emergency departments (EDs) (ADRED; trial registration: DRKS-ID: DRKS00008979) was analyzed. Dizziness as the most frequent reported CNS ADR symptom (12.7% of patients, n = 372) related to vigilance was chosen as the outcome. The association of dizziness with CYP2D6 activity markers was analyzed. The number of CYP2D6 substrates taken, a CYP2D6 saturation score (no, moderate, and strong saturation), a CYP2D6 saturation/inhibition score (no, weak, moderate, and strong), and composed CYP2D6 activity using a genotyped subsample ( n = 740) calculating additive effects of genotype and CYP2D6 saturation by drug exposure were used as CYP2D6 activity markers. Effects were compared to other frequent nonvigilance-related CNS ADR symptoms (syncope and headache). Secondary analyses were conducted to control for other ADR symptoms frequently associated with dizziness (syncope, nausea, and falls). The majority of all patients (64.5%, n = 1895) took at least one drug metabolized by CYP2D6. Around a third took a CNS drug (32.5%, n = 955). The chance to present with drug-related dizziness to the ED increased with each CYP2D6 substrate taken by OR 1.11 [1.01–1.23]. Presenting with drug-related dizziness was more likely with CYP2D6 saturation and saturation/inhibition (both OR 1.27 [1.00–1.60]). The composed CYP2D6 activity was positively associated with dizziness ( p = 0.028), while poorer activity affected patients more often with dizziness as an ADR. In contrast, nonvigilance-related ADR symptoms such as syncope and nausea were not consistently significantly associated with CYP2D6 activity markers. This study shows an association between the number of CYP2D6 substrates, the predicted CYP2D6 activity, and the occurrence of dizziness as a CNS ADR symptom. As dizziness is a vigilance-related CNS symptom, patients with low CYP2D6 activity might be more vulnerable to drug-related dizziness. This study underlines the need for understanding individual drug metabolism activity and individual risks for ADRs.
Characterization of a Plant Nuclear Matrix Constituent Protein in Liverwort
2021-05-07

The nuclear lamina (NL) is a complex network of nuclear lamins and lamina-associated nuclear membrane proteins, which scaffold the nucleus to maintain structural integrity. In animals, type V intermediate filaments are the main constituents of NL. Plant genomes do not encode any homologs of these intermediate filaments, yet plant nuclei contain lamina-like structures that are present in their nuclei. In Arabidopsis thaliana , CROWDED NUCLEI (CRWN), which are required for maintaining structural integrity of the nucleus and specific perinuclear chromatin anchoring, are strong candidates for plant lamin proteins. Recent studies revealed additional roles of Arabidopsis Nuclear Matrix Constituent Proteins (NMCPs) in modulating plants’ response to pathogen and abiotic stresses. However, detailed analyses of Arabidopsis NMCP activities are challenging due to the presence of multiple homologs and their functional redundancy. In this study, we investigated the sole NMCP gene in the liverwort Marchantia polymorpha ( MpNMCP ). We found that MpNMCP proteins preferentially were localized to the nuclear periphery. Using CRISPR/Cas9 techniques, we generated an MpNMCP loss-of-function mutant, which displayed reduced growth rate and curly thallus lobes. At an organelle level, MpNMCP mutants did not show any alteration in nuclear morphology. Transcriptome analyses indicated that MpNMCP was involved in regulating biotic and abiotic stress responses. Additionally, a highly repetitive genomic region on the male sex chromosome, which was preferentially tethered at the nuclear periphery in wild-type thalli, decondensed in the MpNMCP mutants and located in the nuclear interior. This perinuclear chromatin anchoring, however, was not directly controlled by MpNMCP. Altogether, our results unveiled that NMCP in plants have conserved functions in modulating stress responses.
3D Spheroids Versus 3D Tumor‐Like Microcapsules: Confinement and Mechanical Stress May Lead to the Expression of Malignant Responses in Cancer Cells
2021-05-07

Abstract As 2D surfaces fail to resemble the tumoral milieu, current discussions are focused on which 3D cell culture strategy may better lead the cells to express in vitro most of the malignant hints described in vivo. In this study, this question is assessed by analyzing the full genetic profile of MCF7 cells cultured either as 3D spheroids‐considered as “gold standard” for in vitro cancer research‐ or immobilized in 3D tumor‐like microcapsules, by RNA‐Seq and transcriptomic methods, allowing to discriminate at big‐data scale, which in vitro strategy can better resemble most of the malignant features described in neoplastic diseases. The results clearly show that mechanical stress, rather than 3D morphology only, stimulates most of the biological processes involved in cancer pathogenicity, such as cytoskeletal organization, migration, and stemness. Furthermore, cells entrapped in hydrogel‐based scaffolds are likely expressing other physiological hints described in malignancy, such as the upregulated expression of metalloproteinases or the resistance to anticancer drugs, among others. According to the knowledge, this study represents the first attempt to answer which 3D experimental system can better mimic the neoplastic architecture in vitro, emphasizing the relevance of confinement in cancer pathogenicity, which can be easily achieved by using hydrogel‐based matrices.
RGD-Peptide Functionalization Affects the In Vivo Diffusion of a Responsive Trimeric MRI Contrast Agent through Interactions with Integrins
2021-05-07

The relevance of MRI as a diagnostic methodology has been expanding significantly with the development of molecular imaging. Partially, the credit for this advancement is due to the increasing potential and performance of targeted MRI contrast agents, which are able to specifically bind distinct receptors or biomarkers. Consequently, these allow for the identification of tissues undergoing a disease, resulting in the over- or underexpression of the particular molecular targets. Here we report a multimeric molecular probe, which combines the established targeting properties of the Arg-Gly-Asp (RGD) peptide sequence toward the integrins with three calcium-responsive, Gd-based paramagnetic moieties. The bifunctional probe showed excellent <sup>1</sup>H MRI contrast enhancement upon Ca<sup>2+</sup> coordination and demonstrated a longer retention time in the tissue due to the presence of the RGD moiety. The obtained results testify to the potential of combining bioresponsive contrast agents with targeting vectors to develop novel functional molecular imaging methods.
Negative social jetlag – Special consideration of leisure activities and evidence from birdwatchers
2021-05-07

Summary Birdwatching (birding) is a nature‐based recreational activity, often including arising early in the morning. In the present study, we tested the effect of a negative social jetlag (SJL) in birders. Negative SJL implies that people have an even earlier sleep–wake rhythm on free days or weekends. As birds’ activities start before or shortly after sunrise, especially during spring and early summer, birdwatchers follow this diurnal pattern. Further, birders are not homogeneous and vary greatly in recreational specialisation. The study was based on an online survey with 2,404 birdwatchers (55% male) who responded to questions about their sleep–wake times and about their birding activities. Birders show the same differences between weekdays and weekends/free days sleep like most other people. However, birdwatching days started earlier than weekdays (14 min) and lasted longer. Thus, birdwatching days are shifted towards an earlier sleep–wake rhythm in total. Birdwatchers experience a sleep curtailment during birding. Instead of sleeping ~30 min longer on weekends, they arise ~15 min earlier, summing up to a sleep reduction of about ~45 min compared to a regular weekend. The more psychologically committed birders are, the less they sleep, the earlier they arise, and the earlier is their midpoint of sleep on birdwatching days; meaning that highly specialised birders shift their sleep–wake rhythm to an earlier time compared to their regular weekend, and even their weekday sleep. Thus, birders may suffer more from the short‐ and long‐term consequences of negative SJL. The results might stand representatively for other nature‐related leisure activities.
Scalable 18F Processing Conditions for Copper-Mediated Radiofluorination Chemistry Facilitate "Design of Experiments" (DoE) Optimization Studies and Afford an Improved Synthesis of [18F]Olaparib.
2021-05-07

A convenient, scalable, and azeotropic drying free method for processing [18F]fluoride as base free [18F]TBAF is reported and applied to copper-mediated radiofluorination (CMRF) radiosyntheses. A central feature of this method is that a single production of [18F]TBAF can be divided into small aliquots that can be used to perform multiple small-scale reactions in DoE optimization studies. The results of these studies can then be reliably translated to full batch tracer productions using automated synthesizers. This processing technique was successfully applied to the manual DoE optimization, DoE study validation, and subsequent full-batch automation of the PARP-1 tracer [18F]olaparib. After DoE optimization, we were able to produce [18F]olaparib in high radiochemical yields via both manual (%RCY (CMRF step only) = 78 ± 6 %, n = 4) and automated (up to 80% radiochemical yield (%RCY); 41% activity yield (%AY)) radiosynthesis procedures. This work further demonstrates the power of the DoE approach for improving the radiochemical yields and radiosynthesis performance of clinically relevant tracer productions
Proximate historiographies in Jennifer Nansubuga Makumbi’s Kintu
2021-05-07

Jennifer Nansubuga Makumbi’s novel Kintu (2014) places alongside forms of historical fiction familiar to European readers, a form of historical causality that obeys a different logic, namely, one governed by the long-term efficacity of a curse uttered in pre-colonial Buganda. The novel can be read as a historiographical experiment. It sets in a relationship of ‘proximity’ linear historical narration as understood within the framework of European historicism and the genre of the historical novel theorised by Lukács, and notions of magical ‘verbal-incantatory’ and ‘somatic’ history that elude the logic of hegemonic European historicism but nonetheless cohabit the same fictional space. Makumbi’s novel thus sketches an ‘entanglement’ of various historical temporalities that are articulated upon one another within the capacious realm of fiction, thereby reinforcing a cosmic ontology and axiology of reciprocity and fluid duality whose infringement in fact triggers the curse at the origin of the narrative.
Laplace Matching for fast Approximate Inference in Generalized Linear Models.
2021-05-07

Bayesian inference in generalized linear models (GLMs), i.e.~Gaussian regression with non-Gaussian likelihoods, is generally non-analytic and requires computationally expensive approximations, such as sampling or variational inference. We propose an approximate inference framework primarily designed to be computationally cheap while still achieving high approximation quality. The concept, which we call \\emph{Laplace Matching}, involves closed-form, approximate, bi-directional transformations between the parameter spaces of exponential families. These are constructed from Laplace approximations under custom-designed basis transformations. The mappings can then be leveraged to effectively turn a latent Gaussian distribution into a conjugate prior for a rich class of observable variables. This effectively turns inference in GLMs into conjugate inference (with small approximation errors). We empirically evaluate the method in two different GLMs, showing approximation quality comparable to state-of-the-art approximate inference techniques at a drastic reduction in computational cost. More specifically, our method has a cost comparable to the \\emph{very first} step of the iterative optimization usually employed in standard GLM inference.