bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term FRII jet evolution in dense environments
Authors: Perucho Manel , Martí José-María , Quilis Vicent
Published: December 2021

We present long-term numerical three-dimensional (3D) simulations of a relativistic outflow propagating through a galactic ambient medium and environment, up to distances ∼100 kpc. Our aim is to study the role of dense media in the global dynamics of the radio source. We use a relativistic gas equation of state, and a basic description of thermal cooling terms. In previous work, we showed that a linear perturbation could enhance the jet propagation during the early phases of evolution, by introducing obliquity to the jet reverse shock. Here, we show that this effect is reduced in denser media. We find that the dentist-drill effect acts earlier, due to slower jet propagation and an increased growth of the helical instability. The global morphology of the jet is less elongated, with more prominent lobes. The fundamental physical parameters of the jet generated structure derived from our simulations fall within the estimated values derived for FRII jets in the 3C sample. In agreement with previous axisymmetric and 3D simulations in lower density media, we conclude that shock heating of the interstellar and intergalactic media is very efficient in the case of powerful, relativistic jets.
Near-infrared spectroscopy of extreme BAL QSOs from the QUBRICS bright quasar survey
Authors: Cupani Guido , Calderone Giorgio , Selvelli Pierluigi , Cristiani Stefano , Boutsia Konstantina , Grazian Andrea , Fontanot Fabio , Guarneri Francesco , D’Odorico Valentina , Giallongo Emanuele , Menci Nicola
Published: December 2021

We report on the spectral confirmation of 18 quasi-stellar object (QSO) candidates from the QUasars as BRIght beacons for Cosmology in the Southern hemisphere (QUBRICS) survey, previously observed in the optical band, for which we acquired new spectroscopic data in the near-infrared band with the Folded-port InfraRed Echellette (FIRE) spectrograph at the Magellan Baade telescope. In most cases, further observations were prompted by the peculiar nature of the targets, whose optical spectra displayed unexpected absorption features. All candidates have been confirmed as bona fide QSOs, with average emission redshift z ≃ 2.1. The analysis of the emission and absorption features in the spectra, performed with astrocook and QSFit, reveals that the large majority of these objects are broad absorption line (BAL) QSOs, with almost half of them displaying strong Fe ii absorption (typical of the so-called FeLoBAL QSOs). The detection of such a large fraction of rare objects (which are estimated to account for less than 1 per cent of the general QSO population) is interpreted as an unexpected (yet favourable) consequence of the particular candidate selection procedure adopted within the QUBRICS survey. The measured properties of FeLoBAL QSOs observed so far provide no evidence that they are a manifestation of a particular stage in active galactic nucleus (AGN) evolution. In this paper, we present an explorative analysis of the individual QSOs, to serve as a basis for a further, more detailed investigation.
L-Galaxies 2020: the formation and chemical evolution of stellar haloes in Milky Way analogues and galaxy clusters
Authors: Murphy Geoff G , Yates Robert M , Mohamed Shazrene S
Published: December 2021

We present an analysis of the formation and chemical evolution of stellar haloes around (a) Milky Way analogue (MWA) galaxies and (b) galaxy clusters in the L-Galaxies 2020 semi-analytic model of galaxy evolution. Observed stellar halo properties are better reproduced when assuming a gradual stripping model for the removal of cold gas and stars from satellites, compared to an instantaneous stripping model. The slope of the stellar mass–metallicity relation for MWA stellar haloes is in good agreement with that observed in the local Universe . This extends the good agreement between L-Galaxies 2020 and metallicity observations from the gas and stars inside galaxies to those outside. Halo stars contribute on average only ∼0.1 per cent of the total circumgalactic medium enrichment by z = 0 in MWAs, ejecting predominantly carbon produced by asymptotic giant branch stars. Around a quarter of MWAs have a single ‘significant progenitor’ with a mean mass of ∼$2.3\times {}10^{9}\, \rm {M}_{\odot }$, similar to that measured for Gaia Enceladus. For galaxy clusters, L-Galaxies 2020 shows good correspondence with observations of stellar halo mass fractions, but slightly overpredicts stellar masses. Assuming a Navarro–Frenk–White profile for the stellar halo mass distribution provides the best agreement. On average, the intracluster stellar component is responsible for 5.4 per cent of the total intracluster medium iron enrichment, exceeding the contribution from the brightest cluster galaxy by z = 0. We find that considering gradual stripping of satellites and realistic radial profiles is crucial for accurately modelling stellar halo formation on all scales in semi-analytic models.
Ancient Human Genomes and Environmental DNA from the Cement Attaching 2,000-Year-Old Head Lice Nits
Authors: Pedersen Mikkel W , Antunes Catia , De Cahsan Binia , Moreno-Mayar J Víctor , Sikora Martin , Vinner Lasse , Mann Darren , Klimov Pavel B , Black Stuart , Michieli Catalina Teresa , Braig Henk R , Perotti M Alejandra
Published: December 2021

Over the past few decades, there has been a growing demand for genome analysis of ancient human remains. Destructive sampling is increasingly difficult to obtain for ethical reasons, and standard methods of breaking the skull to access the petrous bone or sampling remaining teeth are often forbidden for curatorial reasons. However, most ancient humans carried head lice and their eggs abound in historical hair specimens. Here we show that host DNA is protected by the cement that glues head lice nits to the hair of ancient Argentinian mummies, 1,500–2,000 years old. The genetic affinities deciphered from genome-wide analyses of this DNA inform that this population migrated from north-west Amazonia to the Andes of central-west Argentina; a result confirmed using the mitochondria of the host lice. The cement preserves ancient environmental DNA of the skin, including the earliest recorded case of Merkel cell polyomavirus. We found that the percentage of human DNA obtained from nit cement equals human DNA obtained from the tooth, yield 2-fold compared with a petrous bone, and 4-fold to a bloodmeal of adult lice a millennium younger. In metric studies of sheaths, the length of the cement negatively correlates with the age of the specimens, whereas hair linear distance between nit and scalp informs about the environmental conditions at the time before death. Ectoparasitic lice sheaths can offer an alternative, nondestructive source of high-quality ancient DNA from a variety of host taxa where bones and teeth are not available and reveal complementary details of their history.
Tissue-specific regulation of translational readthrough tunes functions of the traffic jam transcription factor
Authors: Karki Prajwal , Carney Travis D , Maracci Cristina , Yatsenko Andriy S , Shcherbata Halyna R , Rodnina Marina V
Published: December 2021

Translational readthrough (TR) occurs when the ribosome decodes a stop codon as a sense codon, resulting in two protein isoforms synthesized from the same mRNA. TR has been identified in several eukaryotic organisms; however, its biological significance and mechanism remain unclear. Here, we quantify TR of several candidate genes in Drosophila melanogaster and characterize the regulation of TR in the large Maf transcription factor Traffic jam (Tj). Using CRISPR/Cas9-generated mutant flies, we show that the TR-generated Tj isoform is expressed in a subset of neural cells of the central nervous system and is excluded from the somatic cells of gonads. Control of TR in Tj is critical for preservation of neuronal integrity and maintenance of reproductive health. The tissue-specific distribution of a release factor splice variant, eRF1H, plays a critical role in modulating differential TR of leaky stop codon contexts. Fine-tuning of gene regulatory functions of transcription factors by TR provides a potential mechanism for cell-specific regulation of gene expression.
Computational investigation of the impact of core sequence on immobile DNA four-way junction structure and dynamics
Authors: Adendorff Matthew R , Tang Guo Qing , Millar David P , Bathe Mark , Bricker William P
Published: December 2021

Immobile four-way junctions (4WJs) are core structural motifs employed in the design of programmed DNA assemblies. Understanding the impact of sequence on their equilibrium structure and flexibility is important to informing the design of complex DNA architectures. While core junction sequence is known to impact the preferences for the two possible isomeric states that junctions reside in, previous investigations have not quantified these preferences based on molecular-level interactions. Here, we use all-atom molecular dynamics simulations to investigate base-pair level structure and dynamics of four-way junctions, using the canonical Seeman J1 junction as a reference. Comparison of J1 with equivalent single-crossover topologies and isolated nicked duplexes reveal conformational impact of the double-crossover motif. We additionally contrast J1 with a second junction core sequence termed J24, with equal thermodynamic preference for each isomeric configuration. Analyses of the base-pair degrees of freedom for each system, free energy calculations, and reduced-coordinate sampling of the 4WJ isomers reveal the significant impact base sequence has on local structure, isomer bias, and global junction dynamics.
Reexamining assumptions about miRNA-guided gene silencing
Authors: Kilikevicius Audrius , Meister Gunter , Corey David R
Published: December 2021

MicroRNAs (miRNAs) are short endogenously expressed RNAs that have the potential to regulate the expression of any RNA. This potential has led to the publication of several thousand papers each year connecting miRNAs to many different genes and human diseases. By contrast, relatively few papers appear that investigate the molecular mechanism used by miRNAs. There is a disconnect between rigorous understanding of mechanism and the extraordinary diversity of reported roles for miRNAs. Consequences of this disconnect include confusion about the assumptions underlying the basic science of human miRNAs and slow development of therapeutics that target miRNAs. Here, we present an overview of investigations into miRNAs and their impact on gene expression. Progress in our understanding of miRNAs would be aided by a greater focus on the mechanism of miRNAs and a higher burden of evidence on researchers who seek to link expression of a particular miRNA to a biological phenotype.
Stimulation of adaptive gene amplification by origin firing under replication fork constraint
Authors: Whale Alex J , King Michelle , Hull Ryan M , Krueger Felix , Houseley Jonathan
Published: December 2021

Adaptive mutations can cause drug resistance in cancers and pathogens, and increase the tolerance of agricultural pests and diseases to chemical treatment. When and how adaptive mutations form is often hard to discern, but we have shown that adaptive copy number amplification of the copper resistance gene CUP1 occurs in response to environmental copper due to CUP1 transcriptional activation. Here we dissect the mechanism by which CUP1 transcription in budding yeast stimulates copy number variation (CNV). We show that transcriptionally stimulated CNV requires TREX-2 and Mediator, such that cells lacking TREX-2 or Mediator respond normally to copper but cannot acquire increased resistance. Mediator and TREX-2 can cause replication stress by tethering transcribed loci to nuclear pores, a process known as gene gating, and transcription at the CUP1 locus causes a TREX-2-dependent accumulation of replication forks indicative of replication fork stalling. TREX-2-dependent CUP1 gene amplification occurs by a Rad52 and Rad51-mediated homologous recombination mechanism that is enhanced by histone H3K56 acetylation and repressed by Pol32 and Pif1. CUP1 amplification is also critically dependent on late-firing replication origins present in the CUP1 repeats, and mutations that remove or inactivate these origins strongly suppress the acquisition of copper resistance. We propose that replicative stress imposed by nuclear pore association causes replication bubbles from these origins to collapse soon after activation, leaving a tract of H3K56-acetylated chromatin that promotes secondary recombination events during elongation after replication fork re-start events. The capacity for inefficient replication origins to promote copy number variation renders certain genomic regions more fragile than others, and therefore more likely to undergo adaptive evolution through de novo gene amplification.
Clinical utility of targeted next-generation sequencing assay in IDH-wildtype glioblastoma for therapy decision-making
Authors: Lim-Fat Mary Jane , Youssef Gilbert C , Touat Mehdi , Iorgulescu J Bryan , Whorral Sydney , Allen Marie , Rahman Rifaquat , Chukwueke Ugonma , McFaline-Figueroa J Ricardo , Nayak Lakshmi , Lee Eudocia Q , Batchelor Tracy T , Arnaout Omar , Peruzzi Pier Paolo , Chiocca E Antonio , Reardon David A , Meredith David , Santagata Sandro , Beroukhim Rameen , Bi Wenya Linda , Ligon Keith L , Wen Patrick Y
Published: December 2021

Background

Targeted gene NGS testing is available through many academic institutions and commercial entities and is increasingly incorporated in practice guidelines for glioblastoma (GBM). This single-center retrospective study aimed to evaluate the clinical utility of incorporating NGS results in the management of GBM patients at a clinical trials-focused academic center.

Methods

We identified 1011 consecutive adult patients with pathologically confirmed GBM (IDHwt or IDHmut) who had somatic tumor sequencing (Oncopanel, ~500 cancer gene panel) at DFCI from 2013–2019. Clinical records of all IDHwt GBM patients were reviewed to capture clinical trial enrollment and off-label targeted therapy use based on NGS results.

Results

Of the 557 IDHwt GBM patients with sequencing, 182 entered clinical trials at diagnosis (32.7%) and 213 (38.2%) entered after recurrence. Sequencing results for 130 patients (23.3%) were utilized for clinical trial enrollment for either targeted therapy indications (6.9 % upfront and 27.7% at recurrent clinical trials and 3.1% for off-label targeted therapy) or exploratory studies (55.4% upfront and 6.9% recurrent clinical trials). Median overall survival was 20.1 months with no survival difference seen between patients enrolled in clinical trials compared to those who were not, in a posthoc analysis.

Conclusions

While NGS testing has become essential for improved molecular diagnostics, our study illustrates that targeted gene panels remain underutilized for selecting therapy in GBM-IDHwt. Targeted therapy and clinical trial design remain to be improved to help leverage the potential of NGS in clinical care.
SPDR-1 HSP90 inhibition overcomes resistant to molecular targeted therapy in BRAFV600E mutant glioblastoma
Authors: Sasame Jo , Ikegaya Naoki , Miyake Yohei , Hayashi Takahiro , Oshima Akito , Homma Hirokuni , Isoda Masataka , Takabayashi Katsuhiro , Yamamoto Tetsuya , Tateishi Kensuke
Published: December 2021

The BRAFV600E mutation results in the constitutive activation of downstream mitogen activated protein kinase (MAPK) pathway that promotes tumor growth. Recently, molecular targeted therapy using BRAF/MEK inhibitor has been reported for BRAFV600E mutant high-grade glioma, but the therapeutic effect is limited by the emergence of drug resistance. Herein, we established paired BRAFV600E mutant glioblastoma (GBM) patient-derived xenograft (PDX) models, which were derived from tumors at prior to and recurrence after molecular targeted therapy. These PDX models were found to extensively recapitulate the histology, genetic abnormalities, and even the clinical course of the patients. Furthermore, BRAF/MEK inhibitor gradually caused resistance in cell lines derived from specimens that initially responded to molecular targeted therapy. In this study, genomic and epigenomic changes had little effect on the resistance mechanism. On the other hand, we found that hyperactivation of the MAPK pathway through c-Raf and the AKT/mTOR pathway primarily caused resistance to molecular targeted therapy in BRAFV600E mutant GBM. Through a high throughput drug screening, we find that HSP90 inhibitor with BRAF/MEK inhibitor coordinately deactivates MAPK pathway and AKT/mTOR pathway, and mediates potent toxicity in vitro and in vivo in refractory and acquired resistant models. These findings support that this therapeutic approach can overcome the limitation of current molecular targeted therapy in BRAFV600E mutant GBM.
STMO-5 Utilization of intraoperative multimodal technologies [PET and 5-ALA] for treating glioblastoma
Authors: Miyake Keisuke , Ogawa Daisuke , Hatakeyama Tetsuhiro
Published: December 2021

Background: We can improve prognosis of glioblastoma by using positron emission tomography (PET) scans to guide them in removing tumors, and intraoperative magnetic resonance imaging (IoMRI) and 5-aminolevulinic acid (5-ALA) for identifying residual tumors. Tau proteins are reported to accumulate in glioblastomas, so we compared the efficacy of their PET tracer, THK5351, against that of 11C-MET, 18F-FLT, and 18F-FMISO. Methods: Patients (n = 11) underwent scans between February 2020 and July 2021 for glioblastoma resection. Tumor-to-normal tissue accumulation ratio (TNR) and accumulation volumes of 4 PET tracers were evaluated. Following excisions, 5-ALA fluorescent evaluation was classified as strong, vague, or none. Residual tumor volumes and removal rates were determined using T1Gd assessments and PET tracers. IoMRI confirmed presence of residual tumors.Results: THK5351 had a TNR of 5.20, and its accumulated volume was greater than that of other tracers: 1.80 for 11C-MET, 1.72 for 18F-FLT, and 2.82 for 18F-FMISO. 5-ALA fluorescent evaluation was vague (n = 7) or none (n = 4); respective residual tumor volumes (mL) were 2.3 and 0.2 (T1Gd), 5.7 and 0.9 (11C-MET), 5.6 and 0.6 (18F-FLT), 1.3 and 0.4 (18F-FMISO), and 7 and 1.4 (THK5351); respective tumor removal rates (%) were 90.4 and 99.6 (T1Gd), 79.2 and 86.4 (11C-MET), 84.4 and 89.2 (18F-FLT), 94.3 and 94.4 (18F-FMISO), and 72.3 and 83.4 (THK5351). The excised tumor tissue was found in the area where only THK5351 was accumulated.Conclusions: THK5351 accumulated in glioblastomas to a greater degree than that of other tracers, making it useful for discriminating between healthy and malignant tissues.
RT-1 Treatment results of salvage gamma knife stereotactic radiosurgery and bevacizumab (AVAgamma therapy) for recurrent malignant glioma
Authors: Sato Kenichi , Asanome Taku , Ishida Yuuki , Sugio Hironori , Nakamura Hirohiko
Published: December 2021

Purpose: We report the treatment results of AVAgamma therapy combining gamma knife (GK) and bevacizumab for recurrent malignant glioma. Subjects: From August 2013 to January 2021, 71 patients (Grade 2:8 patients, Grade3:16 patients, Grade 4:47 patients) with recurrent malignant glioma treated with AVAgamma therapy as salvage therapy at the time of relapse after initial treatment. The average age is 55.7 years, with 44 men and 27 women. The tumor volume is 150 ml or less, and KPS is 40% or more as the indication of AVAgamma therapy. When the irradiation volume of the gamma knife was 15 ml or less, the marginal dose was 20 to 26 Gy, and when the irradiation volume was 15 ml or more, the marginal dose was 12 to 15 Gy in two divided doses.The mean therapeutic borderline dose was 24 Gy. Bevacizumab was administered 10 mg / kg or 15 mg / kg 1 to 10 times after GK. Methods: Median progression-free survival (mPFS) from AVAgamma treatment, median survival (mOS), and mOS from initial treatment were examined and compared with mOS in the RPA classification of recurrent glioma. Results: In relapsing glioma RPA classification, NABTT CNC class 2 mOS is 17.2 months, class 3 mOS is 3.8 months, class 5 mOS is 5.6 months, class 6 mOS is 6.4 months, but mOS from AVAgamma therapy is 18 months in class 3, 11 months in class 5, 9 months in class 6. The survival time has been extended in class3, class5, class6. Discussion: By AVAgamma therapy, it was thought that recurrent lesions were locally controlled and life prognosis was prolonged. Conclusion: AVAgamma therapy is thought to prolong the survival of recurrent malignant glioma and play an important role as salvage treatment.
MPC-2 Clinical course and prognosis of lower-grade glioma, IDH wildtype and pTERT mutant
Authors: Takahashi Yoshinobu , Takeuchi Hayato , Tanigawa Seisuke , Okamoto Takanari , Hashimoto Naoya
Published: December 2021

Background and Purpose: In the cIMPACT-Now update 3, it was proposed that grade 2 astrocytic gliomas without IDH-mutations and grade 3 astrocytic gliomas with TERT promoter mutations should be designated as diffuse IDH wildtype astrocytic glioma with molecular features of WHO grade IV glioblastoma. Therefore, we investigated whether this group of tumors actually corresponds to grade IV prognostically in cases that we encountered ourselves. Cases and Methods: Among the 65 patients having primary astrocytic glioma who were operated in our hospital from January 2016 to March 2021, the prognostic values of seven patients with lower-grade glioma, IDH wildtype, and pTERT mutant were investigated. Results: Among the seven patients, the median age was 59 years (50–66 years). Four of them had anaplastic astrocytoma, two had diffuse astrocytoma, and no tumor lesion could be identified upon histological examination for one patient. The male-to-female ratio was 1:6. MGMT methylation was observed in two patients (29%). The median survival was 20 months, with a significantly worse prognosis when compared with lower-grade glioma without the TERT promoter mutation (13 patients: median survival 40 months), but a better prognosis when compared with glioblastoma (45 patients: median survival 13 months) (Log-rank p = 0.0051). Conclusion: Although EGFR amplification, combined whole chromosome 7 gain, and whole chromosome 10 loss were not examined, the prognostic value of lower-grade glioma, IDH wildtype, and pTERT mutant was not as poor as that of glioblastoma. Further investigation is required to confirm whether these groups of tumors should be treated in the same way as grade IV glioblastoma.
MPC-13 The evaluation of the shift of trend in lower grade glioma diagnoses based on each era`s criteria
Authors: Pareira Eriel Sandika , Shibuya Makoto , Ohara Kentaro , Nakagawa Yu , Kanazawa Tokunori , Kamamoto Dai , Yoshida Kazunari , Sasaki Hikaru
Published: December 2021

It is found that molecular characteristics in lower grade gliomas (LrGGs) such as codeletion of 1p/19q and IDH mutation was found to be more accurate to predict the patient`s clinical outcome compared to morphological diagnoses alone. Since the revision WHO2016 classification of LrGGs, molecular characteristics were implemented as diagnostic standard for LrGGs diagnoses. In the other hand, morphological diagnostic standard before WHO2016 classification era was determined by different considerations and therapeutic strategies. The malignancy grades were also majorly determined by morphological diagnoses only. This study re-evaluated 20 years of LrGG cases in single institution based on WHO2007 morphological criteria and compared them to the original institutional diagnoses from each era. The study samples were originally grade II-III diffuse glioma-diagnosed cases resected from 1990 to 2016. Biopsy cases were excluded. IDH mutation was analyzed by Sanger sequence and 1p/19 codeletion status was analyzed by Comparative Genome Hybridization (CGH). As the result 93 cases were collected and based on original diagnoses, more than 50% cases are astrocytomas. Compared to re-assessment by morphological diagnoses (WHO 2007), case numbers of astrocytoma diagnoses are decreased whereas oligodendroglioma and oligoastrocytoma case numbers are increased. But, based on WHO2016 criteria, the case number of astrocytomas is again found to be increased. From comparison between original institutional diagnoses and re-assessment results, it is found that there is a shift of trend from astrocytoma to oligodendroglioma and from grade II to grade III. Comparison between morphological diagnoses (WHO2007) and molecular (WHO2016) found that astrocytoma diagnoses remain unchanged meanwhile 45% of oligodendroglioma diagnoses were shifted into astrocytomas. There is a probability that there are high frequency of morphologically diagnosed oligodendroglioma tumors which are having molecular characteristics of astrocytoma. There is a trend that diagnosed grade II LrGGs are actually grade III based on re-assessment diagnosis.
NI-10 Reclassification of diffuse gliomas based on molecular diagnosis -evaluation of methionine uptake and treatment outcome-
Authors: Tamura Kaoru , Inaji Motoki , Kobayashi Daisuke , Hara Shoko , Karakama Jun , Sugawara Takashi , Tanaka Yoji , Nariai Tadashi , Ishii Kenji , Maehara Taketoshi
Published: December 2021

Object: The revised 2016 WHO Classification of Tumours of the Central Nervous System incorporates genetic alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. In this study, we reclassified diffuse gliomas with molecular diagnosis and examined for 11C-methionine uptake and prognosis. Methods. 182 diffuse glioma patients (Grade II in 42 patients, Grade III in 61 patients, Grade IV in 77 patients) treated at Tokyo Medical and Dental University Hospital from 2000 to 2018 were included in this study. The IDH1/2, ATRX and 1p19q status were analyzed using tumor samples. The tumor-to-normal ratio (T/N) of 11 C-methionine uptake was calculated by dividing the mean standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. Result. By molecular diagnosis, 11 diffuse astrocytomas and 17 anaplastic astrocytomas were diagnosed as “IDH-mutant”, while 14 diffuse astrocytomas and 29 anaplastic astrocytomas were diagnosed as “IDH-wild”. 5 out of 77 grade IV tumors had IDH mutation. 4 tumors were diagnosed as “Diffuse midline glioma, H3 K27M-mutant”. In the 32 oligodendroglial tumors, 12 oligodendrogliomas and 9 anaplastic oligodendrogliomas were diagnosed as “IDH-mutant and 1p/19q-codeleted”. The median T/N ratios in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” were significantly higher than those in astrocytic tumors with “IDH-mutant”. On the other hand, in tumors with the same genetic background, higher grade tumor has significant higher T/N ratio. Kaplan-Meier survival analysis revealed that oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” had significantly better outcomes regardless of WHO grade. Overall survival was 90.9% at 5 years and 77.9% at 10 years in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted”. IDH wild tumors had significantly worse outcomes.Conclusions. The results indicated that diffuse glioma categories reclassified with molecular classification correlate with the T/N ratio of methionine and the prognosis.
NQPC-5 Does high-dose methotrexate-based chemotherapy for relapsed primary CNS lymphoma increase a risk of leukoencephalopathy with prior whole brain radiotherapy?
Authors: Kobayashi Keiichi , Sasaki Nobuyoshi , Saito Kuniaki , Yamagishi Yuki , Hanayama Naomi , Nakatomi Hirofumi , Shiokawa Yoshiaki , Nagane Motoo
Published: December 2021

Backgrounds: Standard care for primary central nervous system lymphoma (PCNSL) comprises high-dose (HD) methotrexate (MTX) -based chemotherapy with or without consolidation whole brain radiotherapy (WBRT). HD-MTX administration following WBRT has been suggested to increase a risk of leukoencephalopathy. However, given that there are no other agents with efficacy similar to or better than MTX, patients with relapsed PCNSL may often be treated with regimens containing HD-MTX if the initial MTX treatment achieved a long-term complete remission. Here, we retrospectively analyzed prevalence and an extent of white mater damages in association with prior WBRT in patients with relapsed PCNSL treated with HD-MTX based therapy. Patients & methods: Among 79 patients with relapsed/refractory PCNSL in a total of 162 patients with newly-diagnosed PCNSL treated in our institution from April, 2000 to February, 2021, 35 patients were identified with evaluable KPS, MMSE, and Fazekas scale data at both baseline and follow-up periods. Of the 35 patients, 22 were treated with chemotherapy at a relapse (10 with prior WBRT, while 12 without WBRT), and were included in this preliminary study. Results: In the WBRT group (male/female: 5/5), median age was 65 years (range, 45–73), initial median KPS was 70 (40–90), and median WBRT dose was 27 Gy (23.4–40). Median progression-free survival (mPFS) was 11.8 months, and median overall survival (mOS) was not reached. In the non-WBRT group (M/F 8/4), median age 75 (62–84), initial mKPS 80 (50–90), mPFS 16.2 m, and mOS not reached. Initial KPS and MMSE score tended to be worse in WBRT group, presumably due to enrichment of patients with poorer performance status and more comorbidities. A decline in the Fazekas score was not associated with MMSE deterioration.Conclusions: The preliminary analysis was not informative enough, and further extensive imaging analysis will be exploited.
COT-6 Body mass index and height in relation to brain tumor risk in a Japanese population
Authors: Ogawa Takahiro , Sawada Norie , Iwasaki Motoki , Sanjeev Budhatoki , Yamaji Taiki , Shimazu Taichi , Narita Yoshitaka
Published: December 2021

Purpose: Because the prognosis of the malignant brain tumor including glioblastoma is extremely worse than other cancer, it is important to clarify the preventive factors of the brain tumor in the prospective cohort study. In the Japanese epidemiologic study of the brain tumor, the report of the prospective cohort study has not been accomplished. Therefore, we have reported the study in recent years from a multipurpose cohort study (Japan Public Health Center-based Prospective Study: JPHC study) that the national cancer center was mainly conducted. This prospective study investigated the association between height and BMI (Body mass index) and brain tumor risk in an Asian population, whose distribution of anthropometric data differs from Westerners. Methods: A total of 106,324 subjects (50,438 men and 55,886 women) enrolled in JPHC Study, was followed from 1990. We divided participants into 5 categories based on the distribution of BMI as <18.5, 18.5- <23, 23- <25, 25- <27.5, and >-27.5 Kg/m2. We used the Cox proportional hazards regression model and estimated brain tumor incidence by gender and tumor subtype, with adjustment for potential confounding variables; age, sex, pack-years of cigarette smoking, alcohol intake, coffee intake, green tea intake, past history of allergy and past history of diabetes mellitus.Results: During an average follow-up of 18.1 years, 157 incident cases of brain tumor were newly identified, included glioma (n=60), meningioma (n =51), lymphoma(n=9), schwannoma(n=3), pituitary adenoma(n=2), and others(n=32). Higher BMI was significantly positively associated with the risk of brain tumor. This positive association of BMI was stronger in men and for meningioma in subgroup analyses. In contrast, height showed no clear association with brain tumor risk. Conclusion: Higher BMI was associated with an increased risk of brain tumor, in particular of meningioma, and among men.Full article has been published annals of epidemiology.
Incidence and Risk Factors for Inappropriate Use of Non-Culture-Based Fungal Assays: Implication for Diagnostic Stewardship
Authors: Ito Hiroshi , Okamoto Koh , Yamamoto Shinya , Yamashita Marie , Kanno Yoshiaki , Jubishi Daisuke , Ikeda Mahoko , Harada Sohei , Okugawa Shu , Moriya Kyoji
Published: December 2021

Background

Non-culture-based fungal assays (NCBFAs) have been used increasingly to help diagnose invasive fungal diseases. However, little is known about inappropriate use of NCBFAs. We aimed to investigate inappropriate use of NCBFAs in a tertiary academic hospital.

Methods

This retrospective cohort study included patients who underwent testing with beta-D glucan (BDG) between January and March 2018 or with galactomannan antigen (GMA) or cryptococcal antigen (CRAG) between January and June 2018. Testing was deemed appropriate if the clinical presentation was compatible with a fungal infection and there was a predisposing host factor at the time of ordering. We compared patients with appropriate and inappropriate use of NCBFAs using multivariate logistic regression analysis.

Results

Four hundred seventy patients (BDG, 394; GMA, 138; CRAG, 164) met inclusion criteria and were evaluated. About 80% of NCBFAs were deemed inappropriate. Ordering by transplant medicine physicians, repetitions of the test, the absence of predisposing factors for fungal infections, and the absence of recommendations from infectious diseases consultants were associated with an increased risk of inappropriate NCBFA use.

Conclusions

We found that a large proportion of NCBFAs were deemed inappropriate. There is an opportunity for diagnostic stewardship to reduce avoidable fungal testing among patients at low risk for fungal infection.
Copepods key traits in diverse habitats of tropical waters
Authors: Doan-Nhu Hai , Nguyen Tam-Vinh , Do-Huu Hoang , Montoya Joseph P , Nguyen-Ngoc Lam
Published: December 2021

Copepods are the dominant marine zooplankton and perform important functions in the marine food web. However, copepod traits have not been studied in many waters. We studied the copepod community under influence of the Mekong River and the Southern Vietnamese coastal upwelling, based on their functional traits, during the southwest monsoon period in 2016. Fourteen trait categories of four key functional traits (trophic-groups, feeding-types, reproductive-strategies and diel migration) of copepod data were analyzed to investigate how environmental gradients impact on their distribution and abundance among the four defined habitats: Mekong River (MKW), upwelling (UpW), nearshore (OnSW) and offshore waters (OSW). There were seven functional groups identified in the study waters based on multiple correspondence analysis of distribution, abundance and traits of 139 copepod species. Herbivorous, current-feeding and sac-spawning copepods were dominant in all habitats with the highest abundance in OSW. Specifically, herbivorous species dominated in MKW and UpW, whereas omnivorous species dominated in OnSW and OSW. Sac-spawners dominated in all habitats, but decreased from MKW and UpW to OnSW and lowest in OSW. Cruise feeders were 2-fold higher than ambush feeders in the UpW, but the opposite was observed in the other habitats. The results suggest that impacts of Mekong River and coastal upwelling led to distinctive copepod assemblages with specific functional traits.
Why Do People Stay Poor?
Authors: Balboni Clare , Bandiera Oriana , Burgess Robin , Ghatak Maitreesh , Heil Anton
Published: December 2021

There are two broad views as to why people stay poor. One emphasizes differences in fundamentals, such as ability, talent, or motivation. The poverty traps view emphasizes differences in opportunities that stem from access to wealth. To test these views, we exploit a large-scale, randomized asset transfer and an 11-year panel of 6,000 households who begin in extreme poverty. The setting is rural Bangladesh, and the assets are cows. The data support the poverty traps view—we identify a threshold level of initial assets above which households accumulate assets, take on better occupations (from casual labor in agriculture or domestic services to running small livestock businesses), and grow out of poverty. The reverse happens for those below the threshold. Structural estimation of an occupational choice model reveals that almost all beneficiaries are misallocated in the work they do at baseline and that the gains arising from eliminating misallocation would far exceed the program costs. Our findings imply that large transfers, which create better jobs for the poor, are an effective means of getting people out of poverty traps and reducing global poverty.
Somatic mutations in rheumatological diseases: VEXAS syndrome and beyond
Authors: Sikora Keith A , Wells Kristina V , Bolek Ertugrul Cagri , Jones Adrianna I , Grayson Peter C
Published: December 2021

Discovery of the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome demonstrates that somatic mutations in haematological precursor cells can cause adult-onset, complex inflammatory disease. Unlike germline mutations, somatic mutations occur throughout the lifespan, are restricted to specific tissue types, and may play a causal role in non-heritable rheumatological diseases, especially conditions that start in later life. Improvements in sequencing technology have enabled researchers and clinicians to detect somatic mutations in various tissue types, especially blood. Understanding the relationships between cell-specific acquired mutations and inflammation is likely to yield key insights into causal factors that underlie many rheumatological diseases. The objective of this review is to detail how somatic mutations are likely to be relevant to clinicians who care for patients with rheumatological diseases, with particular focus on the pathogenetic mechanisms of the VEXAS syndrome.
Mechanism of DNA methylation-mediated downregulation of O6-methylguanine-DNA methyltransferase in cartilage injury of Kashin–Beck disease
Authors: Zhang Dandan , Zhang Di , Wang Chen , Zhang Rongqiang , Li Qiang , Xiong Yongmin
Published: December 2021

Objective

Kashin–Beck disease (KBD) is an endemic osteoarthropathy, in which excessive apoptosis of chondrocytes occurs. O6-methylguanine-DNA methyltransferase (MGMT), a DNA damage repair gene, plays an important role in apoptosis, but the mechanism is unclear in KBD cartilage injury. This study was to investigate the expression and promoter methylation of MGMT in KBD patients and its role in DNA damage and apoptosis of chondrocytes.

Methods

MGMT mRNA and protein level were detected by quantitative real-time PCR and immunohistochemistry. Demethylation of MGMT was carried out using 5-Aza-2′-deoxycytidine, and the methylation level of MGMT promoter was measured by quantitative methylation specific PCR. Next, small hairpin RNA was used to knockdown the expression of MGMT. Cell viability, apoptosis and DNA damage were determined by MTT assay, flow cytometry, Hoechst 33342 staining and alkaline comet assay following T-2 toxin and selenium treatment.

Results

MGMT protein expression and mRNA levels were decreased (P = 0.02, P = 0.007) and promoter methylation was increased (P = 0.008) in KBD patients. Meanwhile, MGMT level was upregulated by 5-Aza-2′-deoxycytidine in chondrocytes (P = 0.0002). DNA damage and apoptosis rates were increased in MGMT-silenced chondrocytes (all P < 0.0001). Furthermore, DNA damage and apoptosis were increased in chondrocytes treated with T-2 toxin (all P < 0.0001), but were decreased after selenium treatment (P < 0.0001, P = 0.01). Decreased mRNA level and increased methylation of MGMT were found in the T-2 toxin group (P = 0.005, P = 0.002), while selenium reversed it (P = 0.02, P = 0.004).

Conclusions

MGMT might play a crucial part in the pathogenesis of KBD cartilage injury, which could provide a therapeutic target for KBD.
ULTRA-LOW-DOSE COMPUTED TOMOGRAPHY IN UROLITHIASIS—EFFECT OF AN ADDITIONAL TIN FILTER ON IMAGE QUALITY AND RADIATION DOSE
Authors: Haubold Johannes , Zensen Sebastian , Erfanian Youssef , Guberina Nika , Opitz Marcel , Sawicki Lino Morris , Forsting Michael , Umutlu Lale , Theysohn Jens M
Published: December 2021

To compare radiation dose and image quality of three CT-scanners using optimal dose protocols in patients with suspected urolithiasis regarding additional hardware (tin filter) and software (iterative reconstruction). Examinations from a single-source CT-scanner (A2) and a dual-source CT-scanner (DSCT) (A1) were compared to a tin filter DSCT (B) regarding dose-length product (DLP) and volume-weighted CT dose-index (CTDIvol). DLP of B was 51 and 53% lower in comparison to A1 and A2 (78.62, 159.20 and 165.80 mGy·cm, respectively; P < 0.0001). CTDIvol of B was 53% and 56% significantly lower compared to A1 and A2, respectively (1.52 vs. 3.22 vs. 3.46 mGy; P < 0.0001). Image quality in B proved to be similar to A1 and A2 (3.57, 3.51 and 3.60, respectively; P > 0.05). Inter-rater agreement regarding image quality was good for all CT-scanners (κ = 0.62). Modern CTs with a built-in tin filter allow a significant reduction of radiation exposure in patients with suspected urolithiasis by optimizing the X-ray spectrum.
The Speciality of Public Health Medicine in South Africa: 1974–2021
Authors: Zweigenthal Virginia E M , Pick William M , London Leslie
Published: December 2021

The speciality, Public Health Medicine (PHM), was developed in response to political and health realities in pre-apartheid South Africa (SA), following the lead of the discipline in Britain, SA’s previous coloniser. This article describes a 47-year journey from its origins as Community Health through to current practice, based on reviews of archival material, databases of institutional stakeholders involved in trainee education and our own experiences. Embedded throughout PHM’s history are tensions between colonial forms of public health education and practice and resistance to these. As found in complementary SA research, and globally, this review shows that concerns about unclear roles, inadequate career paths and professional boundaries have preoccupied and are innate to the speciality. To be institutionalised more definitively in SA, PHM needs to demonstrate its value as a key resource for the functioning of SA’s health system and thus improve the health status of her population.
Perceptions of animal welfare and animal welfare curricula offered for undergraduate and graduate students in animal science departments in the United States
Authors: Mijares Sage , Sullivan Paxton , Cramer Catie , Román-Muñiz Noa , Edwards-Callaway Lily
Published: December 2021

While perceptions of animal welfare have been assessed in veterinary students and students internationally, there remains a gap in research concerning undergraduate and graduate student perspectives of animal welfare in animal science programs at colleges and universities across the United States. A survey was developed to assess current animal science student perspectives of the importance of animal welfare as part of their education, their knowledge of available educational opportunities, and resources they think should be included in animal welfare curricula. An online survey was distributed to a national listserv of university administrators of animal science programs in the United States. A total of 624 survey responses were statistically summarized. Most respondents were undergraduate students (78.0%, n = 487), between the ages of 18 and 24 (85.9%, n = 536), and female (86.1%, n = 537). Results indicated that despite most respondents not taking an animal welfare course previously (60.7%, n = 379), most students strongly agreed that the inclusion of an animal welfare course is an important part of the animal science curriculum (72.0%, n = 449), that animal welfare is an important component of their education (63.1%, n = 394), and that animal welfare courses would be helpful for their future careers (70.0%, n = 437). When asked what attributes would be most important in an animal welfare class, students identified many different types of information and resources. The majority of respondents answered that discussing current hot topics in animal welfare (76.1%, n = 475), ethical discussions (76.0%, n = 474), and practical, applied questions (75.3%, n = 470) were important course components. Suggestions for future research include investigating how animal science student perceptions change before and after taking an animal welfare course and exploring opportunities to expand formal welfare education in animal science departments. Inclusion of animal welfare into the curriculum is critical as many of the students currently enrolled in animal science departments will become the future stakeholders in animal-focused industries.
Investigation of developmental and reproductive effects of resveratrol in Drosophila melanogaster
Authors: Atli Emel , Tamtürk Erkut
Published: December 2021

Resveratrol is a chemical that attracts attention due to its antioxidative, anti-inflammatory, and estrogenic/antiestrogenic properties. In the present study, it was aimed to investigate developmental and reproductive effects (developmental periods, average numbers of offspring, sex ratios) of resveratrol in Drosophila melanogaster. Their larvae were exposed to 50, 100, and 200 μM of resveratrol. Resveratrol treatments did not affect pupation and maturation rate (P ˃ 0.05) statistically. But the pupation and maturation times were significantly extended at all doses (P ˂ 0.05). Also, 100 and 200 μM resveratrol treatments resulted in a significant decrease in the number of offspring (P ˂ 0.05). The results reveal that resveratrol, which is generally known for its positive effects, may have negative effects on the development and reproduction of invertebrates. The results of this study support the idea that resveratrol may act as an endocrine disruptor, as it is a phytoestrogen.
COVID-19 in Pediatric Patients: A Systematic Review
Authors: Jackson William M. , Price Jerri C. , Eisler Lisa , Sun Lena S. , Lee Jennifer J.
Published: December 2021

Introduction:

The coronavirus disease (COVID)-19 pandemic has been an enormous global health burden, resulting in hundreds of millions of documented infections and more than 3 million deaths. Increasing reports characterizing the effects of COVID-19 in pediatric populations have been published during the course of the pandemic. We performed a systematic review to assess the scope of diagnosis, treatment, and management of COVID-19 in pediatric patients.

Materials and Methods:

We searched the Cochrane Database of Systematic Reviews, PubMed, CINAHL, and Embase for studies published between January 1, 2020, and May 1, 2021. Each result was screened by 2 authors independently, and discordant findings were adjudicated by a third party. Data extracted included demographic data, symptom data, and clinical data including mortality, severe illness, laboratory data, radiologic data, and treatment. Bias assessment was performed using the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies.

Results:

We found a total of 16,266 search results, and we accepted 63 manuscripts into the review. The quality of evidence was low. It was difficult to estimate the risk of mortality in pediatric patients with COVID-19 given the quality of the evidence, but overall it is likely below 1%. The most common symptoms in symptomatic pediatric COVID-19 patients were fever (58%) and cough (50%). There was a high proportion of asymptomatic infection (65%).

Discussion:

Pediatric COVID-19 infection is mild and frequently asymptomatic. There is a low risk of severe illness or death in children who contract COVID-19. High-quality studies should be conducted to develop best practices for prevention, diagnosis, and management of symptomatic illness.