bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study protocol for NCCH1908 (UPFRONT-trial): a prospective clinical trial to evaluate the feasibility and utility of comprehensive genomic profiling prior to the initial systemic treatment in advanced solid tumour patients
Authors: Mizuno Takaaki , Yoshida Tatsuya , Sunami Kuniko , Koyama Takafumi , Okita Natsuko , Kubo Takashi , Sudo Kazuki , Shimoi Tatsunori , Ueno Hideki , Saito Eiko , Katanoda Kota , Shibata Taro , Yonemori Kan , Okusaka Takuji , Boku Narikazu , Ohe Yuichiro , Hiroshima Yukihiko , Ueno Makoto , Kuboki Yasutoshi , Doi Toshihiko , Nakamura Kenichi , Kohno Takashi , Yatabe Yasushi , Yamamoto Noboru 
Published: September 2021

Abstract

Comprehensive genomic profiling has been approved for use in patients with advanced solid tumours; however, it is only indicated in advanced solid tumour patients without available standard chemotherapeutic treatment or those who have completed standard treatments in Japan, and there are no available data on the clinical feasibility and utility of comprehensive genomic profiling in treatment-naive patients. This multicentre, single-arm, prospective study aims to evaluate the feasibility and utility of the OncoGuide NCC Oncopanel System in treatment-naive patients with six advanced major malignancies: non-small cell lung cancer, breast cancer, gastric cancer, colon cancer, pancreatic cancer and biliary tract cancer (NCCH1908). This study (study cohort) will be compared with the other prospective observational study (control cohort), which enrols patients not receiving comprehensive genomic profiling prior to initial systemic treatment. A total of 200 patients will be enrolled in the study over 21 months. This study has been registered in the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) (UMIN000040743).

Clinical trial registration
This study, initiated in June 2020, has been registered in the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) (registration number: UMIN000040743). We plan to enrol a total of 200 patients over a period of 21 months.
Diagnostic Value of Metagenomic Next Generation Sequencing for Ureaplasma urealyticum Infection: A Case Report
Authors: Ruan Xuelian , Li Meng , Qin Xue 
Published: September 2021

Abstract
Ureaplasma urealyticum has high nutritional requirements for culture, and it requires special tools for identification. Theoretically, metagenomic next generation sequencing (mNGS) can be used to detect many pathogens in clinical specimens, especially for complex infectious diseases with rare and atypical causes. Here, our patient developed severe pneumonia caused by U. urealyticum infection after allogeneic hematopoietic stem cell transplantation, and the etiology is unclear. After continuous negative culture, U. urealyticum was detected in the bronchoalveolar lavage fluid by mNGS, and azithromycin was used. Because of the difficulty in its diagnosis, diagnosis and treatment of extragenital U. urealyticum infection is challenging. In addition, many broad-spectrum antibiotics are ineffective against this pathogen because it lacks a cell wall. Therefore, early diagnosis and treatment are key to preventing further complications and deaths.
Excursion set peaks in energy as a model for haloes
Authors: Musso Marcello , Sheth Ravi K 
Published: September 2021

ABSTRACT
The simplest models of dark matter halo formation rely on the heuristic assumption, motivated by spherical collapse, that virialized haloes originate from initial regions that are maxima of the smoothed matter density field. Here, we replace this notion with the dynamical requirement that protohaloes be regions where the local gravitational flow converges to a point. For this purpose, we look for spheres whose acceleration at the boundary – relative to their centre of mass – points towards their geometric centre: that is, spheres with null dipole moment. We show that these configurations are minima of the energy, corresponding to the most energetically bound spheres. Therefore, we study peaks of the smoothed energy overdensity field. This significant conceptual change is technically trivial to implement: to change from density to energy one need only modify the standard top-hat smoothing filter. However, this comes with the important benefit that, for power spectra of cosmological interest, the model is no longer plagued by divergences: improving the physics mends the mathematics. In addition, the ‘excursion set’ requirement that the smoothed matter density crosses a critical value can be naturally replaced by a threshold in energy. Measurements in simulations of haloes more massive than 1013h−1M⊙ show very good agreement with a number of generic predictions of our model.
Bolometric light curves of aspherical shock breakout
Authors: Irwin Christopher M , Linial Itai , Nakar Ehud , Piran Tsvi , Sari Re’em 
Published: September 2021

ABSTRACT
The shock breakout emission is the first light that emerges from a supernova. In the spherical case, it is characterized by a brief UV flash. In an axisymmetric, non-spherical prolate explosion, the shock first breaches the surface along the symmetry axis, then peels around to larger angles, producing a breakout light curve which may differ substantially from the spherically symmetric case. We study the emergence of a non-relativistic, bipolar shock from a spherical star, and estimate the basic properties of the associated bolometric shock breakout signal. We identify four possible classes of breakout light curves, depending on the degree of asphericity. Compared to spherical breakouts, we find that the main distinguishing features of significantly aspherical breakouts are (1) a longer and fainter initial breakout flash and (2) an extended phase of slowly declining, or even rising, emission which is produced as ejecta flung out by the oblique breakout expand and cool. We find that the breakout flash has a maximum duration of roughly ∼R*/vbo, where R* is the stellar radius and vbo is the velocity of the fastest moving ejecta. For a standard Wolf−Rayet progenitor, the duration of the X-ray flash seen in SN 2008D exceeds this limit, and the same holds true for the prompt X-ray emission of low-luminosity GRBs such as GRB 060218. This suggests that these events cannot be explained by an aspherical explosion within a typical Wolf−Rayet star, implying that they originate from non-standard progenitors with larger breakout radii.
The relative supernovae contribution to the chemical enrichment history of Abell 1837
Authors: Erdim M K , Ezer C , Ünver O , Hazar F , Hudaverdi M 
Published: September 2021

ABSTRACT
In this paper, we report the relative supernovae (SNe) contribution to the metal budget of the intracluster medium (ICM) of the Abell 1837 galaxy cluster at redshift z = 0.069. For this purpose, we analysed the hot ICM of the cluster and obtained radial metal distributions using XMM–Newton archival data with a total exposure of ∼100 ks. These metal measurements consist of Mg, Si, S, Fe and Ni within a radius of 0.7 R500, which is divided into three concentric annuli. In order to explain the observed metal abundance pattern in terms of relative supernova contributions, we used our newly developed code SNeRatio, which utilizes theoretical nucleosynthesis models. This study covers the most recent 3D Type Ia SN and core-collapse SN yield tables. All combinations of these theoretical yields were fitted with our measured abundance ratios, and statistically acceptable ones were selected. Each of these models was found to predict a uniform SNIa percentage contribution to the total SNe from the cluster centre to the outskirts and to form an SNIa ratio distribution with a mean of 39 ± 14${{\ \rm per\ cent}}$. This uniformity is consistent with the early enrichment scenario, which assumes that metal production processes begin in the early phase of cluster formation, namely the proto-cluster phase at epoch z ≥ 2.
Transcriptional Profile of the Industrial Hybrid Saccharomyces pastorianus Reveals Temperature-Dependent Allele Expression Bias and Preferential Orthologous Protein Assemblies
Authors: Timouma Soukaina , Balarezo-Cisneros Laura Natalia , Pinto Javier , De La Cerda Roberto , Bond Ursula , Schwartz Jean-Marc , Delneri Daniela 
Published: September 2021

Abstract
Saccharomyces pastorianus is a natural yeast evolved from different hybridization events between the mesophilic S. cerevisiae and the cold-tolerant S. eubayanus. This complex aneuploid hybrid carries multiple copies of the parental alleles alongside specific hybrid genes and encodes for multiple protein isoforms which impart novel phenotypes, such as the strong ability to ferment at low temperature. These characteristics lead to agonistic competition for substrates and a plethora of biochemical activities, resulting in a unique cellular metabolism. Here, we investigated the transcriptional signature of the different orthologous alleles in S. pastorianus during temperature shifts. We identified temperature-dependent media-independent genes and showed that 35% has their regulation dependent on extracellular leucine uptake, suggesting an interplay between leucine metabolism and temperature response. The analysis of the expression of ortholog parental alleles unveiled that the majority of the genes expresses preferentially one parental allele over the other and that S. eubayanus-like alleles are significantly over-represented among the genes involved in the cold acclimatization. The presence of functionally redundant parental alleles may impact on the nature of protein complexes established in the hybrid, where both parental alleles are competing. Our expression data indicate that the majority of the protein complexes investigated in the hybrid are likely to be either exclusively chimeric or unispecific and that the redundancy is discouraged, a scenario that fits well with the gene balance hypothesis. This study offers the first overview of the transcriptional pattern of S. pastorianus and provides a rationalization for its unique industrial traits at the expression level.
Simultaneous Expression of UV and Violet SWS1 Opsins Expands the Visual Palette in a Group of Freshwater Snakes
Authors: Hauzman Einat , Pierotti Michele E R , Bhattacharyya Nihar , Tashiro Juliana H , Yovanovich Carola A M , Campos Pollyanna F , Ventura Dora F , Chang Belinda S W 
Published: September 2021

AbstractSnakes are known to express a rod visual opsin and two cone opsins, only (SWS1, LWS), a reduced palette resulting from their supposedly fossorial origins. Dipsadid snakes in the genus Helicops are highly visual predators that successfully invaded freshwater habitats from ancestral terrestrial-only habitats. Here, we report the first case of multiple SWS1 visual pigments in a vertebrate, simultaneously expressed in different photoreceptors and conferring both UV and violet sensitivity to Helicops snakes. Molecular analysis and in vitro expression confirmed the presence of two functional SWS1 opsins, likely the result of recent gene duplication. Evolutionary analyses indicate that each sws1 variant has undergone different evolutionary paths with strong purifying selection acting on the UV-sensitive copy and dN/dS ∼1 on the violet-sensitive copy. Site-directed mutagenesis points to the functional role of a single amino acid substitution, Phe86Val, in the large spectral shift between UV and violet opsins. In addition, higher densities of photoreceptors and SWS1 cones in the ventral retina suggest improved acuity in the upper visual field possibly correlated with visually guided behaviors. The expanded visual opsin repertoire and specialized retinal architecture are likely to improve photon uptake in underwater and terrestrial environments, and provide the neural substrate for a gain in chromatic discrimination, potentially conferring unique color vision in the UV–violet range. Our findings highlight the innovative solutions undertaken by a highly specialized lineage to tackle the challenges imposed by the invasion of novel photic environments and the extraordinary diversity of evolutionary trajectories taken by visual opsin-based perception in vertebrates.
Cooperative methylation of human tRNA3Lys at positions A58 and U54 drives the early and late steps of HIV-1 replication
Authors: Fukuda Hiroyuki , Chujo Takeshi , Wei Fan-Yan , Shi Sheng-Lan , Hirayama Mayumi , Kaitsuka Taku , Yamamoto Takahiro , Oshiumi Hiroyuki , Tomizawa Kazuhito 
Published: September 2021

Abstract
Retroviral infection requires reverse transcription, and the reverse transcriptase (RT) uses cellular tRNA as its primer. In humans, the TRMT6-TRMT61A methyltransferase complex incorporates N1-methyladenosine modification at tRNA position 58 (m1A58); however, the role of m1A58 as an RT-stop site during retroviral infection has remained questionable. Here, we constructed TRMT6 mutant cells to determine the roles of m1A in HIV-1 infection. We confirmed that tRNA3Lys m1A58 was required for in vitro plus-strand strong-stop by RT. Accordingly, infectivity of VSV-G pseudotyped HIV-1 decreased when the virus contained m1A58-deficient tRNA3Lys instead of m1A58-modified tRNA3Lys. In TRMT6 mutant cells, the global protein synthesis rate was equivalent to that of wild-type cells. However, unexpectedly, plasmid-derived HIV-1 expression showed that TRMT6 mutant cells decreased accumulation of HIV-1 capsid, integrase, Tat, Gag, and GagPol proteins without reduction of HIV-1 RNAs in cells, and fewer viruses were produced. Moreover, the importance of 5,2′-O-dimethyluridine at U54 of tRNA3Lys as a second RT-stop site was supported by conservation of retroviral genome-tRNALys sequence-complementarity, and TRMT6 was required for efficient 5-methylation of U54. These findings illuminate the fundamental importance of tRNA m1A58 modification in both the early and late steps of HIV-1 replication, as well as in the cellular tRNA modification network.
CLRM-12. HYBRID DESIGNS FOR USING EXTERNAL CONTROLS IN PHASE 3 GLIOBLASTOMA TRIALS
Authors: Polley Mei-Yin , Schwartz Daniel , Dignam James 
Published: September 2021

Abstract
While recent Phase 3 glioblastoma (GBM) trials have failed to establish novel therapies, they potentially provide a high-quality source of external control patients treated with temozolomide. We consider hybrid two-stage adaptive designs that leverage these external controls to safely accelerate Phase 3 GBM trials. The basic strategy is that first patients are randomized 1:1 between the control and experimental arms, then an interim check measures similarity between the trial's control patients and potential external controls, and finally if this interim similarity is high the randomization ratio is changed accordingly and the external controls are used in the final analysis. An extensive simulation study is conducted to assess operating characteristics and we discuss when these hybrid designs can accelerate GBM therapy development while maintaining strict error control.
CLRM-13. INTRAOPERATIVE MICRODIALYSIS: GLIOMA INTELLIGENCE FROM BEHIND ENEMY LINES
Authors: Riviere-Cazaux Cecile , Burns Terry 
Published: September 2021

Abstract

INTRODUCTION
Gliomas present a formidable challenge for translational progress. Heterogeneity within and between tumors may demand empirically individualized and adaptive paradigms requiring rapid mechanistic feedback. We asked if tumor-associated metabolic biomarkers from glioma extracellular fluid could impart mechanistic “intelligence” reflecting intra- and inter-tumoral heterogeneity.

METHODS
Five live human gliomas (2 oligos; 2 IDH-WT GBMs; 1 IDH-mutant GBM), were evaluated in situ with high molecular weight (100kDA) intraoperative microdialysis using 3 disparately placed catheters. Isotonic 3% dextran perfusate was collected in 20 min (40mL) aliquots. CSF samples (n=21) were additionally evaluated from these and other patients with diverse brain tumors. The IDH-mutant glioma-associated oncometabolite D2-hydroxyglutarate (D2-HG) was quantified with targeted Liquid Chromotography-Mass Spectrometry (LC-MS). Over 200 metabolites were further evaluated via untargeted LC-MS using the Metabolon platform. Correlation, clustering, ROC and enrichment analyses were employed to identify correlations within and between patient samples.

RESULTS
CSF samples from patients with IDH-mutant gliomas contained over twenty-fold higher levels of D2-HG (median 4.1 mM, range 1.6-13.2, n=7) compared to those from IDH-wild type tumors (median 0.19 mM; range 0.89-0.35, n=14). Microdialysate from IDH-mutant gliomas contained 10-953mM D2-HG, 9-63x higher than paired CSF samples. Interestingly, IDH status failed to predict the global metabolic signature of microdialysate. Microdialysate samples clustered into 2 major metabolic phenotype clusters with IDH-WT and IDH-mutant gliomas in each cluster. A superimposed metabolic signature distinguishing enhancing from non-enhancing tumor, was conserved in both patient clusters. Amino acid and carnitine metabolism predominated in microdialysate signatures. TCA cycle and Warburg-associated metabolites were differentially enriched in CSF samples after prior therapy independent of tumor burden.

CONCLUSIONS
Intra-operative micro-dialysis may complement currently available “intelligence” regarding the phenotype, burden, and metabolism of live human gliomas and is feasible within standard-of-care surgical procedures. Future work will evaluate utility for pharmacodynamic feedback following novel early phase candidate therapies.
IMMU-04. VACCINATING AGAINST NOVEL CYTOMEGALOVIRUS ANTIGENS IN GLIOBLASTOMA USING A PEPTIDE VACCINE IN COMBINATION WITH TEMOZOLOMIDE
Authors: Hotchkiss Kelly , Singh Kirit , Batich Kristen , Archer Gerald , Norberg Pamela , Desjardins Annick , Friedman Henry , Johnson Margaret , Peters Katherine , Khasraw Mustafa , Ashley David , Reap Elizabeth , Sampson John 
Published: September 2021

Abstract

INTRODUCTION
Cytomegalovirus (CMV) antigens are excellent anti-tumor immunotherapeutic targets in glioblastoma (GBM). The PERFORMANCE trial (IRB-pro34208, IND-15846) assessed the feasibility, safety and optimal adjuvant temozolomide (TMZ) regimen to be used with PEP-CMV vaccination in adults with newly-diagnosed GBM.

METHODS
Seropositive CMV patients (n=16) were randomized into two arms and treated with standard of care RT-TMZ (SOC) (150-200 mg/m2/day on days 1-5 per 28-day cycle) or dose-intensive TMZ (DI) (75-100 mg/m2/day on days 1-21 per 28-day cycle). Patients received intradermal PEP-CMV vaccines (500μg of CMVpp65 synthetic long peptide (SLP) mixed with Montanide ISA-51) on days 23, 37 and 51 following TMZ. All patients received tetanus/diphtheria toxoid (Td) preconditioning at the vaccination site on day 22. Serum cytokine levels were measured pre-vaccination, 1-hour and 2-hours post vaccination. PEP-CMV specific circulating PBMCs were quantified at baseline and after each vaccine.

RESULTS
Of the 16 trial patients, 7 experienced site-reactions, 4 had grade-II Immune Related Adverse Events (IRAEs), and 4 experienced flu-like grade-III IRAEs. Inflammatory cytokines (IL-2, IFNγ, MIP-1a, IL-8, TNFα, and IL-10) were elevated in patients with grade-III responses 2-hours post vaccine 1. Td p2/p30 specific PBMC levels were similar between IRAEs. However, pp65 responsive PBMCs were elevated at baseline in patients with grade-III reactions compared to site-reaction suggesting pre-existing peptide specific responses may lead to increased vaccine immunogenicity. PBMCs specific for pp65 increased with number of consecutive vaccines. No difference in progression free survival (PFS) or overall survival (OS) was observed between TMZ regimens.

CONCLUSION
PEP-CMV vaccination with Td preconditioning is feasible and generates immune responses specific to pp65 in patients with newly diagnosed GBM. Importantly, IRAEs were associated with antitumor efficacy. The mild IRAEs in PERFORMANCE are likely indicative of vaccine potency and can be managed through standard premedication as has been used in other trials with similar IRAEs.
SYST-03. A PHASE I/II STUDY TO EVALUATE SAFETY AND PRELIMINARY ACTIVITY OF THE TUMOR-TARGETING ANTIBODY-CYTOKINE FUSION PROTEIN L19TNF IN PATIENTS WITH GLIOBLASTOMA AT FIRST RELAPSE
Authors: Weiss Tobias , Hemmerle Teresa , Roth Patrick , Neri Dario , Weller Michael 
Published: September 2021

Abstract
Treatment options for recurrent glioblastoma are limited and there is a need for novel effective therapies. We previously demonstrated encouraging anti-tumor activity with the targeted delivery of tumor necrosis factor a (TNF) in preclinical orthotopic glioma models. TNF- a is a potent pro-inflammatory cytokine which may trigger strong anti-tumor immunity. However, its systemic administration at therapeutically active doses is hampered by toxic side effects. L19TNF is a fully human antibody-cytokine fusion protein, comprising TNF- a fused to the antibody L19 that binds a tumor-specific epitope of the extracellular matrix protein fibronectin. This allows a targeted delivery of therapeutically relevant doses of TNF to the tumor site upon intravenous administration while sparing healthy tissues. In this phase I/II open label, non-randomized, monocentric study, we investigated the safety and preliminary activity of L19TNF for patients with isocitrate dehydrogenase (IDH) wildtype World Health Organization (WHO) grade III / IV glioma at first relapse. Twenty patients were enrolled from 2019-2020 and treated with intravenous infusions of L19TNF. In the phase I part of the study, 6 patients were assigned to two different dose levels of L19TNF and a dose of 13 µg/kg was established as the recommended dose. In the phase II part 14 patients were treated at the recommended dose. No dose-limiting toxicities were observed and survival follow-up is ongoing. In almost all patients, we observed treatment-associated emerging tumor necrosis. For patients that had re-surgery at progression on or after treatment with L19TNF, we demonstrated increased numbers of tumor-infiltrating lymphocytes compared to the tumor tissue obtained at primary diagnosis. Translational studies to better understand the effects of L19TNF on a molecular and immunophenotypic level are ongoing. ClinicalTrials.gov Identifier: NCT 03779230
Shift rotation scheme, sleepiness and sleep quality in night-shift workers
Authors: Lecca R , Puligheddu M , Acar G M , Figorilli M , Congiu P , Gioi G , Loscerbo R , Meloni F , De Matteis S , Cocco P 
Published: September 2021

Abstract

Background
Shift rotation schemes can influence workers’ tolerance of night-shift work and its impact on health.

Aims
This study was aimed to assess the influence of shift work rotation schemes on sleepiness and sleep quality.

Methods
We conducted a cross-sectional study of 145 male workers, 77 from a ceramic tile factory on a fixed, forward-rotating shift work scheme, and 68 from a dockyard company, working on-call night shifts. Participants self-administered the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI) questionnaires and provided data on demographic and lifestyle variables. We set two logistic regression models to predict the risk of daytime sleepiness and poor sleep quality as a function of night-shift work and on-call night shifts, adjusting for personal and lifestyle covariates.

Results
Marital status, body mass index, smoking and alcohol intake did not affect ESS and PSQI scores, nor did they differ between the two cohorts. Night-shift workers from both cohorts were more likely to have a PSQI score ≥6, suggestive of poor sleep quality, with no variation between the two cohorts. ESS scores suggestive of daytime sleepiness were strongly associated with on-call night shifts among dockyard workers for (odds ratio = 13.4; 95% confidence interval 2.9–63.9), in respect the regular, forward-rotating night-shift work among ceramic tile factory workers.

Discussion
Daytime sleepiness occurred more frequently among dockyard workers working on-call night shifts. Poor sleep quality occurred more frequently among night-shift workers, but it did not differ between the two companies.