bluuebunny/crossref_metadata_2025_split huggingface dataset:
New evaluation of the tumor immune microenvironment of non-small cell lung cancer and its association with prognosis
Authors: Shinohara Shuichi , Takahashi Yusuke , Komuro Hiroyasu , Matsui Takuya , Sugita Yusuke , Demachi-Okamura Ayako , Muraoka Daisuke , Takahara Hirotomo , Nakada Takeo , Sakakura Noriaki , Masago Katsuhiro , Miyai Manami , Nishida Reina , Shomura Shin , Shigematsu Yoshiki , Hatooka Shunzo , Sasano Hajime , Watanabe Fumiaki , Adachi Katsutoshi , Fujinaga Kazuya , Kaneda Shinji , Takao Motoshi , Ohtsuka Takashi , Yamaguchi Rui , Kuroda Hiroaki , Matsushita Hirokazu 
Published: April 2022

BackgroundA better understanding of the tumor immune microenvironment (TIME) will facilitate the development of prognostic biomarkers and more effective therapeutic strategies in patients with lung cancer. However, little has been reported on the comprehensive evaluation of complex interactions among cancer cells, immune cells, and local immunosuppressive elements in the TIME.MethodsWhole-exome sequencing and RNA sequencing were carried out on 113 lung cancers. We performed single sample gene set enrichment analysis on TIME-related gene sets to develop a new scoring system (TIME score), consisting of T-score (tumor proliferation), I-score (antitumor immunity) and S-score (immunosuppression). Lung cancers were classified according to a combination of high or low T-score, I-score, and S-scores (eight groups; G1-8). Clinical and genomic features, and immune landscape were investigated among eight groups. The external data sets of 990 lung cancers from The Cancer Genome Atlas and 76 melanomas treated with immune checkpoint inhibitors (ICI) were utilized to evaluate TIME scoring and explore prognostic and predictive accuracy.ResultsThe representative histological type including adenocarcinoma and squamous cell carcinoma, and driver mutations such as epidermal growth factor receptor and TP53 mutations were different according to the T-score. The numbers of somatic mutations and predicted neoantigens were higher in Thi (G5-8) than Tlo (G1-4) tumors. Immune selection pressure against neoantigen expression occurred only in Thi and was dampened in Thi/Ilo (G5-6), possibly due to a reduced number of T cells with a high proportion of tumor specific but exhausted cells. Thi/Ilo/Shi (G5) displayed the lowest immune responses by additional immune suppressive mechanisms. The T-score, I-score and S-scores were independent prognostic factors, with survival curves well separated into eight groups with G5 displaying the worst overall survival, while the opposite group Tlo/Ihi/Slo (G4) had the best prognosis. Several oncogenic signaling pathways influenced on T-score and I-scores but not S-score, and PI3K pathway alteration correlated with poor prognosis in accordance with higher T-score and lower I-score. Moreover, the TIME score predicted the efficacy of ICI in patients with melanoma.ConclusionThe TIME score capturing complex interactions among tumor proliferation, antitumor immunity and immunosuppression could be useful for prognostic predictions or selection of treatment strategies in patients with lung cancer.
Contribution of large genomic rearrangements inPALB2to familial breast cancer: implications for genetic testing
Authors: Li Na , Zethoven Magnus , McInerny Simone , Healey Eliza , DeSilva Dilanka , Devereux Lisa , Scott Rodney J , James Paul A , Campbell Ian G 
Published: April 2022

BackgroundPALB2is the most important contributor to familial breast cancer afterBRCA1andBRCA2. Large genomic rearrangements (LGRs) inBRCA1andBRCA2are routinely assessed in clinical testing and are a significant contributor to the yield of actionable findings. In contrast, the contribution of LGRs inPALB2has not been systematically studied.MethodsWe performed targeted sequencing and real-time qPCR validation to identify LGRs inPALB2in 5770 unrelated patients with familial breast cancer and 5741 cancer-free control women from the same Australian population.ResultsSeven large deletions ranging in size from 0.96 kbp to 18.07 kbp involvingPALB2were identified in seven cases, while no LGRs were identified in any of the controls. Six LGRs were considered pathogenic as they included one or more exons ofPALB2and disrupted the WD40 domain at the C terminal end of the PALB2 protein while one LGR only involved a partial region of intron 10 and was considered a variant of unknown significance. Altogether, pathogenic LGRs identified in this study accounted for 10.3% (6 of 58) of the pathogenicPALB2variants detected among the 5770 families with familial breast cancer.ConclusionsOur data show that a clinically important proportion ofPALB2pathogenic mutations in Australian patients with familial breast cancer are LGRs. Such observations have provided strong support for inclusion ofPALB2LGRs in routine clinical genetic testing.
Ethical implications of the widespread use of informal mHealth methods in Ghana
Authors: Owusu Samuel Asiedu 
Published: April 2022

BackgroundInformal mHealth is widely used by community health nurses in Ghana to extend healthcare delivery services to clients who otherwise might have been excluded from formal health systems or would experience significant barriers in their quest to access formal health services. The nurses use their private mobile phones or devices to make calls to their clients, health volunteers, colleagues or superiors. These phone calls are also reciprocal in nature. Besides, the parties exchange or share other health data and information through text messages, pictures, videos or voice clips. There are some ethical dimensions that are inherent in these practices that ought to be critically scrutinised by bioethicists.ObjectiveThe author has argued in this paper that informal mHealth at large scale adoption in Ghana is associated with some bioethical challenges.MethodsThis essay was largely based on an analysis of an empirical study published by Hampshireet alin 2021 on the use of informal mHealth methods in Ghana.ResultsWidespread adoption of Informal mHealth in Ghana is associated with privacy invasion of both the nurses and their clients, breaches confidentiality of the parties, discredits the validity of informed consent processes and may predispose the nurses to some other significant aggregated harms.ConclusionThe author affirms his partial support for a formalised adoption process of informal mHealth in Ghana but has reiterated that the current ethical challenges associated with informal mHealth in Ghana cannot escape all the debilitating bioethical challenges, even if it is formalised.
p-Chloro-diphenyl diselenide modulates Nrf2/Keap1 signaling and counteracts renal oxidative stress in mice exposed to repeated dexamethasone administrations
Authors: Müller Sabrina G. , Heck Suélen O. , Marques Luiza S. , Zborowski Vanessa A. , Nogueira Cristina W. 
Published: April 2022

Dexamethasone is a synthetic glucocorticoid that has been associated with oxidative stress in central and peripheral tissues. p-Chloro-diphenyl diselenide (( p-ClPhSe)2) is an antioxidant organoselenium compound. The present study evaluated whether nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap-1) signaling contributes to the ( p-ClPhSe)2antioxidant effects in the kidney of mice exposed to dexamethasone. Adult Swiss mice received dexamethasone (intraperitoneal) at a dose of 2 mg/kg or its vehicle for 21 days. After that, mice were treated with ( p-ClPhSe)2(intragastric) (1, 5, or 10 mg/kg) for 7 days. Samples of kidneys were collected for biochemical assays. ( p-ClPhSe)2at a dose of 1 mg/kg reversed the renal reactive oxygen species (ROS) and carbonyl protein (CP) levels increased by dexamethasone. ( p-ClPhSe)2at doses of 5 and 10 mg/kg was effective against the increase of thiobarbituric acid reactive substances, ROS, and CP, as well as the decrease of δ-aminolevulinic acid dehydratase activity and nonprotein sulfhydryl levels induced by dexamethasone. At 5 mg/kg, ( p-ClPhSe)2reduced the renal levels of 4-OH-2-HNE and heme oxygenase (HO-1), as well as modulated the Nrf2/Keap-1 signaling in mice exposed to dexamethasone. The present findings revealed that ( p-ClPhSe)2antioxidant effects were associated with the modulation of Nrf2/Keap-1 signaling pathway in the kidney of mice exposed to dexamethasone.
RGE effects on the LFV scale from meson decays
Authors: González Marcela , Kovalenko Sergey , Neill Nicolás A. , Vignatti Jonatan 
Published: April 2022

AbstractWe consider the lepton-flavor violating (LFV) lepton-quark dimension-6 operators and analyze their contributions to the LFV leptonic decays of vector, pseudoscalar, and scalar neutral mesons $$M\rightarrow \ell _1 \ell _2$$

M
→

ℓ
1

ℓ
2

as well as to $$\mu (\tau ) \rightarrow \ell ee, \ell \gamma \gamma $$

μ
(
τ
)
→
ℓ
e
e
,
ℓ
γ
γ

decays. These operators contribute to the purely leptonic processes via quark loop. On the basis of quark-hadron duality, we relate these loops to the appropriate meson-exchange contributions. In this way, we extract lower bounds on the individual scales of the studied LFV operators from the experimental and phenomenological limits on the leptonic decays of mesons and leptons. As a byproduct, we shall obtain new limits on the LFV leptonic decays of flavored mesons from the experimental bounds on the three-body lepton decays. We study the effects of QED and QCD radiative corrections to the LFV lepton-quark operators in question. We derive for them the one-loop matrix of the RGE evolution and examine its effect on the previously derived tree-level limits on these operators. We show that the QED corrections are particularly relevant due to operator mixing. Specifically, for some of them the limits on their individual LFV scales improve by up to 3 orders of magnitude.
Wave propagation in phononic materials based on the reduced micromorphic model by one-sided Fourier transform
Authors: Dhaba A. R. El , Abou-Dina M. S. , Ghaleb A. F. 
Published: April 2022

AbstractA one-dimensional problem of wave propagation in phononic materials is solved under the reduced micromorphic model introduced recently. An efficient technique is used for the solution, based on one-sided Fourier transform. This allows obtaining an exact solution in closed form, which can be utilized to check approximate solutions obtained by other methods. The results are confirmed numerically by the method of finite differences. They illustrate the existence of frequency band gaps.
Prediction of the capillary pressure of fluid surrounding a cylinder representing an idealized rock structure in porous media
Authors: Davarpanah Afshin , Cox Simon 
Published: April 2022

AbstractLiquids in oil-bearing porous media assume complex shapes that depend on the reservoir characteristics and the wetting properties of the liquid. The wide variation in the geometry of rock formations makes it difficult to accurately predict the capillary pressure of small volumes of liquid and hence the likelihood of being able to move it. Here, we consider the situation in which a small volume of liquid surrounds an upright cylinder on a flat substrate and predict the shape that the liquid takes and its capillary pressure. We validate our predictions by comparing with Surface Evolver simulations for a range of contact angles and cylinder radii.
Broadband diffuse optical spectroscopy of two-layered scattering media containing oxyhemoglobin, deoxyhemoglobin, water, and lipids
Authors: Blaney Giles , Bottoni Martina , Sassaroli Angelo , Fernandez Cristianne , Fantini Sergio 
Published: April 2022

We investigated the relationship between chromophore concentrations in two-layered scattering media and the apparent chromophore concentrations measured with broadband optical spectroscopy in conjunction with commonly used homogeneous medium inverse models. We used diffusion theory to generate optical data from a two-layered distribution of relevant tissue absorbers, namely, oxyhemoglobin, deoxyhemoglobin, water, and lipids, with a top-layer thickness in the range 1–15[Formula: see text]mm. The generated data consisted of broadband continuous-wave (CW) diffuse reflectance in the wavelength range 650–1024[Formula: see text]nm, and frequency-domain (FD) diffuse reflectance at 690 and 830[Formula: see text]nm; two source-detector distances of 25 and 35[Formula: see text]mm were used to simulate a dual-slope technique. The data were inverted using diffusion theory for a semi-infinite homogeneous medium to generate reduced scattering coefficients at 690 and 830[Formula: see text]nm (from FD data) and effective absorption spectra in the range 650–1024[Formula: see text]nm (from CW data). The absorption spectra were then converted into effective total concentration and oxygen saturation of hemoglobin, as well as water and lipid concentrations. For absolute values, it was found that the effective hemoglobin parameters are typically representative of the bottom layer, whereas water and lipid represent some average of the respective concentrations in the two layers. For concentration changes, lipid showed a significant cross-talk with other absorber concentrations, thus indicating that lipid dynamics obtained in these conditions may not be reliable. These systematic simulations of broadband spectroscopy of two-layered media provide guidance on how to interpret effective optical properties measured with similar instrumental setups under the assumption of medium homogeneity.
The Polysaccharides from the Aerial Parts of Bupleurum chinense DC Attenuate Epilepsy-Like Behavior through Oxidative Stress Signaling Pathways
Authors: Li Xiaomao , Liu Yan , Wang Siyi , Jiang Yikai , Algradi Adnan Mohammed , Zhou Yuanyuan , Guan Wei , Pan Juan , Kuang Haixue , Yang Bingyou 
Published: April 2022

Bupleurum chinense DC. is a traditional Chinese medicine with a long medicinal history and is often used as the main ingredient in prescription drugs for epilepsy. The aerial parts of B. chinense DC. have similar efficacy and composition to B. chinense DC. Therefore, we speculated that the aerial parts of B. chinense DC. could be used in the treatment of epilepsy. Polysaccharides from the aerial parts of B. chinense DC. were selected to explore their therapeutic effects on epilepsy and their potential mechanism of action. The study is aimed at clarifying the antiepileptic effects of the polysaccharides from the aerial parts of B. chinense DC. and their potential underlying mechanisms. The chemical profile of the aerial parts of B. chinense DC. polysaccharides (ABP) was characterized by FT-IR spectrum and HPLC chromatogram. To determine the therapeutic effects of ABPs on epilepsy, we established a kainic acid- (KA-) induced rat model of epilepsy, and through H&E staining, Nissl staining, immunohistochemistry, biochemical analysis, ELISA, and Western blot analysis, we explored the mechanisms underlying the therapeutic effects of ABPs on epilepsy. The monosaccharide content of ABP included galacturonic acid (45.19%), galactose (36.63%), arabinose rhamnose (12.13%), and mannose (6.05%). Moreover, the average molecular weight of ABP was

1.38
×

10

3

kDa

. ABP could improve hippocampal injuries and neuronal function in the KA-induced epilepsy rat model. ABP significantly inhibited oxidative stress in the hippocampus of KA-induced rats. More importantly, ABP could regulate TREM2 activation in the PI3K/Akt/GSK-3β pathway to inhibit neuronal apoptosis, including increasing the expression of superoxide dismutase and lactate dehydrogenase and decreasing the expression of malondialdehyde. The current study defined the potential role of ABP in inhibiting the development of epilepsy, indicating that ABP could upregulate TREM2 to alleviate neuronal apoptosis, by activating the PI3K/Akt/GSK-3β pathway and oxidative stress in epilepsy.
Effect of Aspirin on Melanoma Incidence in Older Persons: Extended Follow-up of a Large Randomized Double-blind Placebo-controlled Trial
Authors: Yan Mabel K. , Orchard Suzanne G. , Adler Nikki R. , Wolfe Rory , McLean Catriona , Rodriguez Luz María. , Woods Robyn L. , Gibbs Peter , Chan Andrew T. , Haydon Andrew , Mar Victoria J. 
Published: April 2022

Abstract

The effects of aspirin on melanoma are unclear, with studies reporting conflicting results. Data from two periods of the ASPirin in Reducing Events in the Elderly (ASPREE) study; the randomized placebo-controlled trial period examining daily 100 mg aspirin in older adults with a median follow-up of 4.7 years, and the second period, an additional 2 years of observational follow-up, were utilized in this secondary analysis to examine whether aspirin exposure is associated with a reduced cutaneous melanoma incidence. All melanoma cases were adjudicated and Cox proportional hazards models were used to compare incidence between randomized treatment groups. ASPREE recruited 19,114 participants with a median age of 74 years. During the trial period, 170 individuals (76 aspirin, 94 placebo) developed an invasive melanoma, and no significant effect of aspirin was observed on incident melanoma [HR = 0.81; 95% confidence interval (CI), 0.60–1.10]. Including the additional 2 years of observational follow-up (median follow-up of 6.3 years), 268 individuals (119 aspirin, 149 placebo) developed an invasive melanoma, and similar results were observed (HR = 0.81; 95% CI, 0.63–1.03). A reduced number of events was observed with aspirin among females in a subgroup analysis (HR = 0.65; 95% CI, 0.44–0.92); however, the interaction effect with males (HR = 0.92; 95% CI, 0.68–1.25) was nonsignificant (P = 0.17). Our findings from this randomized trial do not provide strong support that aspirin is associated with a reduced risk of invasive melanoma in older individuals. Additional studies are required to further explore this relationship.

Prevention Relevance:
Melanoma prevention is an important strategy to improve outcomes and while preventive efforts have largely focused on sun protection, the role of potential chemopreventive agents such as aspirin warrants investigation.
Tumor Immune Microenvironment of Brain Metastases: Toward Unlocking Antitumor Immunity
Authors: Strickland Matthew R. , Alvarez-Breckenridge Christopher , Gainor Justin F. , Brastianos Priscilla K. 
Published: April 2022

AbstractBrain metastasis (BrM) is a devastating complication of solid tumors associated with poor outcomes. Immune-checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, but determinants of response are incompletely understood. Given the rising incidence of BrM, improved understanding of immunobiologic principles unique to the central nervous system (CNS) and dissection of those that govern the activity of ICIs are paramount toward unlocking BrM-specific antitumor immunity. In this review, we seek to discuss the current clinical landscape of ICI activity in the CNS and CNS immunobiology, and we focus, in particular, on the role of glial cells in the CNS immune response to BrM.Significance:There is an urgent need to improve patient selection for and clinical activity of ICIs in patients with cancer with concomitant BrM. Increased understanding of the unique immunobiologic principles that govern response to ICIs in the CNS is critical toward identifying targets in the tumor microenvironment that may potentiate antitumor immunity.
Txnip Enhances Fitness of Dnmt3a-Mutant Hematopoietic Stem Cells via p21
Authors: Zhang Christine R. , Ostrander Elizabeth L. , Kukhar Ostap , Mallaney Cates , Sun Jiameng , Haussler Emily , Celik Hamza , Koh Won Kyun , King Katherine Y. , Gontarz Paul , Challen Grant A. 
Published: April 2022

Abstract

Clonal hematopoiesis (CH) refers to the age-related expansion of specific clones in the blood system, and manifests from somatic mutations acquired in hematopoietic stem cells (HSCs). Most CH variants occur in the gene DNMT3A, but while DNMT3A-mutant CH becomes almost ubiquitous in aging humans, a unifying molecular mechanism to illuminate how DNMT3A-mutant HSCs outcompete their counterparts is lacking. Here, we used interferon gamma (IFNγ) as a model to study the mechanisms by which Dnmt3a mutations increase HSC fitness under hematopoietic stress. We found Dnmt3a-mutant HSCs resist IFNγ-mediated depletion, and IFNγ-signaling is required for clonal expansion of Dnmt3a-mutant HSCs in vivo. Mechanistically, DNA hypomethylation–associated overexpression of Txnip in Dnmt3a-mutant HSCs leads to p53 stabilization and upregulation of p21. This preserves the functional potential of Dnmt3a-mutant HSCs through increased quiescence and resistance to IFNγ-induced apoptosis. These data identify a previously undescribed mechanism to explain increased fitness of DNMT3A-mutant clones under hematopoietic stress.

Significance:
DNMT3A mutations are common variants in clonal hematopoiesis, and recurrent events in blood cancers. Yet the mechanisms by which these mutations provide hematopoietic stem cells a competitive advantage as a precursor to malignant transformation remain unclear. Here, we use inflammatory stress to uncover molecular mechanisms leading to this fitness advantage.
See related commentary by De Dominici and DeGregori, p. 178.
This article is highlighted in the In This Issue feature, p. 171
Addressing Cognitive Vulnerabilities through Genome and Epigenome Editing: Techno-Legal Adaptations for Persons with Intellectual Disabilities
Authors: Lau Pin Lean 
Published: April 2022

Abstract
The key aim of this paper is to highlight the oft-under-represented narrative of how persons with disabilities (specifically, those with intellectual disabilities) may access the benefits that genome editing may offer. Firstly, this paper reflects on the critical need for a paradigm shift in how we view intellectual disabilities, and centering the rights of persons with disabilities to allow them to access the broad scope of their right to health under various international law instruments (including the complementary right to habilitation under Article 26 of the CRPD). Secondly, the paper evaluates the legal provisions in the CRPD and other international instruments relating to the rights of persons with intellectual disabilities, and their access to genome editing technologies. This analysis intends to demonstrate that human rights in disability discourse be complemented with emancipatory, participatory, and transformative research. Finally, the paper argues for a reinvigorated line of thinking that expands on the social model of disability: to align with inclusive, contemporary disability discourse that embodies greater responsibility and innovation in perpetuating better access to genome editing technologies for persons with intellectual disabilities.
Stanislas Breton
Authors: Hackett William C. 
Published: April 2022

Abstract
The name Stanislas Breton likely drums up a few interesting facts: chum of Louis Althusser or Michel de Certeau, author of an obscure spiritual classic (The Word and the Cross) or bewildering treatises on Nothing, the Imaginary, and the “poetics of the sensible” – an idiosyncratic figure at the margins, writing on St. Paul or Proclus well before it was mainstream. Coming across his name can be like discovering a great record that none of your friends are talking about or taking a chance on Netflix to find an arthouse ‘hidden gem’. To facilitate that experience (perhaps why you got into Continental philosophy and into religion in the first place), I offer a brief introductory essay sounding some of the major notes in his thought and life, followed by a translation of his “Examen particulier,” written in 1988 as a late-stage critical self-interrogation. The reader should find here that Breton’s oeuvre develops a coherent and penetrating philosophy of conceptual rigor and thematic range that is as deeply indebted to its modern engagements as it is to its medieval and late antique sources of inspiration.