bluuebunny/crossref_metadata_2025 huggingface dataset:
Calibration of polygenic risk scores is required prior to clinical implementation: results of three common cancers in UKB
Authors: Wei Jun , Shi Zhuqing , Na Rong , Resurreccion W Kyle , Wang Chi-Hsiung , Duggan David , Zheng S Lilly , Hulick Peter J , Helfand Brian T , Xu Jianfeng
Published: December 2020

Background

SNP-based polygenic risk scores have recently been adopted in the clinic for risk assessment of some common diseases. Their validity is supported by a consistent trend between their percentile rank and disease risk in populations. However, for clinical use at the individual level, the reliability of score values is necessary considering they are directly used to calculate remaining lifetime risk.

Objectives

We assessed the reliability of polygenic score values to estimate prostate cancer (PCa), breast cancer (BCa) and colorectal cancer (CRC) risk in three incident cohorts from the UK Biobank (n>500 000).

Methods

Cancer-specific Genetic Risk Score (GRS), a well-established population-standardised polygenic risk score, was calculated.

Results

A systematic bias was found between estimated risks (GRS values) and observed risks; β (95% CI) was 0.67 (0.58–0.76), 0.74 (0.65–0.84) and 0.82 (0.75–0.89), respectively, for PCa, BCa and CRC, all significantly lower than 1.00 (perfect calibration), p<0.001. After applying a correction factor derived from a training data set, the β for corrected GRS values in an independent testing data set were 1.09 (1.05–1.13), 1.00 (0.88–1.12) and 1.08 (0.96–1.21), respectively, for PCa, BCa and CRC.

Conclusion

Assessing the calibration of polygenic risk scores is necessary and feasible to ensure their reliability prior to clinical implementation.
Deep exploration of aCDKN1Cmutation causing a mixture of Beckwith-Wiedemann and IMAGe syndromes revealed a novel transcript associated with developmental delay
Authors: Berland Siren , Haukanes Bjørn Ivar , Juliusson Petur Benedikt , Houge Gunnar
Published: December 2020

Background

Loss-of-function mutations inCDKN1Ccause overgrowth, that is, Beckwith-Wiedemann syndrome (BWS), while gain-of-function variants in the gene’s PCNA binding motif cause a growth-restricted condition called IMAGe syndrome. We report on a boy with a remarkable mixture of both syndromes, with developmental delay and microcephaly as additional features.

Methods

Whole-exome DNA sequencing and ultra-deep RNA sequencing of leucocyte-derived and fibroblast-derived mRNA were performed in the family.

Results

We found a maternally inherited variant in the IMAGe hotspot region: NM_000076.2(CDKN1C) c.822_826delinsGAGCTG. The asymptomatic mother had inherited this variant from her mosaic father with mild BWS features. This delins caused tissue-specific frameshifting resulting in at least three novel mRNA transcripts in the boy. First, a splice product causing CDKN1C truncation was the likely cause of BWS. Second, an alternative splice product in fibroblasts encoded IMAGe-associated amino acid substitutions. Third, we speculate that developmental delay is caused by a change in the alternativeCDKN1C-201(ENST00000380725.1) transcript, encoding a novel isoform we call D (UniProtKB: A6NK88). Isoform D is distinguished from isoforms A and B by alternative splicing within exon 1 that changes the reading frame of the last coding exon. Remarkably, this delins changed the reading frame back to the isoform A/B type, resulting in a hybrid D–A/B isoform.

Conclusion

Three different cell-type-dependent RNA products can explain the co-occurrence of both BWS and IMAGe features in the boy. Possibly, brain expression of hybrid isoform D–A/B is the cause of developmental delay and microcephaly, a phenotypic feature not previously reported inCDKN1Cpatients.
Adopted individuals’ interest in elective genomic testing
Authors: Edgar Jessica , Bao Annie , Maga Tara , Schwartz Marci , Yates Carin , Spencer Sara
Published: December 2020

Purpose

Adoptees are a population that could benefit from genetic testing to fill gaps in family health history (FHH). Elective genomic testing (EGT) provides adoptees with clinical genetic testing options to learn about genetic health risks in the absence of FHH. We assessed adoptees’ interests in, motivations for and perceived utility of EGT.

Methods

Adult adoptees and non-adoptees completed an anonymous, online survey regarding their interest and motivations for EGT, perceived utility of potential results and willingness to pay for EGT. A validated measure of social identity was included to measure the effects of social identity on testing interest.

Results

There were 112 adoptees and 229 non-adoptees included in the study. Adoptees reported greater interest in EGT (OR 5.0, 95% CI 2.2 to 11.3) than non-adoptees. They were motivated by curiosity and a desire to learn information about risks to children and grandchildren more than non-adoptees. Adoptees with higher education and non-adoptees with higher incomes were significantly more likely to spend more on EGT. Adoptees with higher incomes and non-adoptees with higher education were not significantly more likely to spend more. Social identity was a significant mediator between adoption and testing motivation.

Conclusion

Understanding adoptees’ unique motivations and interests in EGT will allow healthcare providers to better address the informational needs and desires of this population. Social identity provides a foundation for recognising adoptees’ universal experiences that influence motivations for genetic testing.
Applying futility in psychiatry: a concept whose time has come
Authors: Levitt Sarah , Buchman Daniel Z
Published: December 2020

Since its introduction in the 1980s, futility as a concept has held contested meaning and applications throughout medicine. There has been little discussion within the psychiatric literature about the use of futility in the care of individuals experiencing severe and persistent mental illness (SPMI), despite some tacit acceptance that futility may apply in certain cases of psychiatric illness. In this paper, we explore the literature surrounding futility and argue that its connotation within medicine is to describe situations where patients (or their substitute decision-makers) believe that interventions will almost certainly provide no meaningful benefit. We then provide two arguments in support of the use of futility within the care of individuals experiencing SPMI: that some SPMI can be considered a terminal illness, and that the risk-benefit ratio is a dynamic entity such that futility can help describe what Gillett calls the ‘risk of unacceptable badness’ when it comes to considering how an intervention might impact a patient’s quality of life. We posit that capacity should not pose an obstacle to declaring futility when caring for individuals experiencing SPMI and explain how futility is not antithetical to recovery in mental health. Finally, we describe how using futility within psychiatric practice can allow for a reorientation of care by signalling the need to shift to a palliative approach.
Conflicts of interest in clinical ethics consults
Authors: Weiss Elliott Mark , Wightman Aaron , Webster Laura , Diekema Douglas
Published: December 2020

Although there is wide agreement that ethics consults are at risk for conflicts of interest (COIs), ethics consultants (ECs) have limited guidance with regard to how to identify and approach COIs. We aim to address these concerns and provide practical guidance. We will define and consider four categories of COIs: consult type, team composition, dual clinical roles and other concerns. We will define and consider six actions available for ECs to take in response to COIs: no action, disclosure only, obtaining a second opinion, referring to another EC, referring to an institutional ethics committee or seeking an outside consult. We will then propose a points-based algorithm for ECs to use to determine the appropriate response to COI. Finally, we will discuss the strengths and limitations of our proposed algorithm.
Capturing and promoting the autonomy of capacitous vulnerable adults
Authors: Lewis Jonathan
Published: December 2020

According to the High Court in England and Wales, the primary purpose of legal interventions into the lives of vulnerable adults with mental capacity should be to allow the individuals concerned to regain their autonomy of decision-making. However, recent cases of clinical decision-making involving capacitous vulnerable adults have shown that, when it comes to medical law, medical ethics and clinical practice, vulnerability is typically conceived as opposed to autonomy. The first aim of this paper is to detail the problems that arise when the courts and healthcare practitioners respond to the vulnerability of capacitous adults on the basis of such an opposition. It will be shown that not only does the common law approach to vulnerability fail to adequately capture the autonomy of capacitous vulnerable adults, the conception of vulnerability and autonomy in oppositional terms leads to objectionably paternalistic healthcare responses that undermine the autonomy of vulnerable patients as well as clinical and legal interventions that violate their autonomy. In response, the second aim of this paper is to show that the concepts of autonomy and vulnerability arenecessarilyentwined and, on that basis, the focus should be on promoting the autonomy of capacitous vulnerable adultswhere possible. In order to make this case, the paper explains the limitations of standard approaches to the autonomy of vulnerable adults and, in their place, offers a conception of legitimate, self-authorised autonomy that is fundamentally dependent on intersubjective practices of recognition.
Twin pregnancy, fetal reduction and the 'all or nothing problem’
Authors: Räsänen Joona
Published: December 2020

Fetal reduction is the practice of reducing the number of fetuses in a multiple pregnancy, such as quadruplets, to a twin or singleton pregnancy. Use of assisted reproductive technologies increases the likelihood of multiple pregnancies, and many fetal reductions are done after in vitro fertilisation and embryo transfer, either because of social or health-related reasons. In this paper, I apply Joe Horton’s all or nothing problem to the ethics of fetal reduction in the case of a twin pregnancy. I argue that in the case of a twin pregnancy, there are two intuitively plausible claims: (1) abortion is morally permissible, and (2) it is morally wrong to abort just one of the fetuses. But since we should choose morally permissible acts rather than impermissible ones, the two claims lead to another highly implausible claim: the woman ought to abort both fetuses rather than only one. Yet, this does not seem right. A plausible moral theory cannot advocate such a pro-death view. Or can it? I suggest ways to solve this problem and draw implications for each solution.
The long term effect of pulmonary tuberculosis on income and employment in a low income, urban setting
Authors: Meghji Jamilah , Gregorius Stefanie , Madan Jason , Chitimbe Fatima , Thomson Rachael , Rylance Jamie , Banda Ndaziona PK , Gordon Stephen B , Corbett Elizabeth L , Mortimer Kevin , Squire Stephen Bertel
Published: December 2020

Background

Mitigating the socioeconomic impact of tuberculosis (TB) is key to the WHO End TB Strategy. However, little known about socioeconomic well-being beyond TB-treatment completion. In this mixed-methods study, we describe socioeconomic outcomes after TB-disease in urban Blantyre, Malawi, and explore pathways and barriers to financial recovery.

Methods

Adults ≥15 years successfully completing treatment for a first episode of pulmonary TB under the National TB Control Programme were prospectively followed up for 12 months. Socioeconomic, income, occupation, health seeking and cost data were collected. Determinants and impacts of ongoing financial hardship were explored through illness narrative interviews with purposively selected participants.

Results

405 participants were recruited from February 2016 to April 2017. Median age was 35 years (IQR: 28–41), 67.9% (275/405) were male, and 60.6% (244/405) were HIV-positive. Employment and incomes were lowest at TB-treatment completion, with limited recovery in the following year: fewer people were in paid work (63.0% (232/368) vs 72.4% (293/405), p=0.006), median incomes were lower (US$44.13 (IQR: US$0–US$106.15) vs US$72.20 (IQR: US$26.71–US$173.29), p<0.001), and more patients were living in poverty (earning <US$1.90/day: 57.7% (211/366) vs 41.6% (166/399), p<0.001) 1 year after TB-treatment completion compared with before TB-disease onset. Half of the participants (50.5%, 184/368) reported ongoing dissaving (use of savings, selling assets, borrowing money) and 9.5% (35/368) reported school interruptions in the year after TB-treatment completion. Twenty-one participants completed in-depth interviews. Reported barriers to economic recovery included financial insecurity, challenges rebuilding business relationships, residual physical morbidity and stigma.

Conclusions

TB-affected households remain economically vulnerable even after TB-treatment completion, with limited recovery in income and employment, persistent financial strain requiring dissaving, and ongoing school interruptions. Measures of the economic impact of TB disease should include the post-TB period. Interventions to protect the long-term health and livelihoods of TB survivors must be explored.
Increased advanced glycation end product and meat consumption is associated with childhood wheeze: analysis of the National Health and Nutrition Examination Survey
Authors: Wang Jing Gennie , Liu Bian , Kroll Francesca , Hanson Corrine , Vicencio Alfin , Coca Steven , Uribarri Jaime , Bose Sonali
Published: December 2020

We examined 4388 children from the 2003 to 2006 National Health and Nutrition Examination Survey and used survey-design-adjusted multivariable logistic regression to evaluate associations between dietary advanced glycation end product (AGE) and meat consumption frequencies and respiratory symptoms. Higher AGE intake was significantly associated with increased odds of wheezing (adjusted OR 1.18; 95% CI 1.02 to 1.36), wheeze-disrupted sleep (1.26; 95% CI 1.05 to 1.51) and exercise (1.34; 95% CI 1.08 to 1.67) and wheezing requiring prescription medication (1.35; 95% CI 1.13 to 1.63). Higher intake of non-seafood meats was associated with wheeze-disrupted sleep (2.32; 95% CI 1.11 to 4.82) and wheezing requiring prescription medication (2.23; 95% CI 1.10 to 4.54).
Deaths of weaned lambs with visceral Listeria ivanovii i nfections
Authors: Dunnett Elizabeth , Florea Laura , Thurston Lisa , Floyd Tobias , Collins Rachael , Otter Arthur
Published: December 2020

Listeriosis in humans and ruminants is most frequently associated with Listeria monocytogenes, with Listeria ivanovii only occasionally identified, mostly causing abortion in sheep. Between September 2018 and January 2019, visceral L ivanovii infection was identified in seven weaned lambs from five farms examined postmortem at APHA VICs. In each of the lambs, there was gastrointestinal pathology which was confirmed to be caused by parasitic gastroenteritis (PGE) in six of the lambs and suspected in the seventh. The findings described in this case series demonstrate the benefits of including abdominal viscera bacteriology in diarrhoeic lambs where concurrent bacterial infections are possible, in addition to parasitological examinations. As PGE was found as an underlying debilitating condition on four of the five farms, these cases also highlight the importance of having a sustainable parasite control programme in place as part of a flock health plan.
Hermitian separability of BFKL eigenvalue in Bethe–Salpeter approach
Authors: Joubat Mohammad , Prygarin Alexander
Published: December 2020

We consider the Bethe–Salpeter approach to the BFKL evolution in order to naturally incorporate the property of the Hermitian separability in the BFKL approach. We combine the resulting all order ansatz for the BFKL eigenvalue together with reflection identities for harmonic sums and derive the most complicated term of the next-to-next-to-leading order BFKL eigenvalue in SUSY $$N=4$$

N
=
4

. We also suggest a numerical technique for reconstructing the unknown functions in our ansatz from the known results for specific values of confomal spin.
Searches for new phenomena with the ATLAS detector
Authors: Guescini Francesco
Published: December 2020

Many theories beyond the Standard Model predict new phenomena accessible by the Lhc. Searches for new physics are performed using the Atlas experiment at the Lhc focusing on exotic signatures that are predicted in several theories, excluding supersymmetry. The results of recent searches using 13 TeV data, with the exception of those for Dark Matter signatures, and their interplay and interpretation are presented. Prospects for searches at the High Luminosity Lhc are also discussed.
Measurement of the weak mixing phase ϕs through time-dependent CP-violation in Bs0 → J/ψϕ decays in the ATLAS detector
Authors: Nikolaenko Vladimir
Published: December 2020

A measurement of [Formula: see text] decay parameters using data collected by the ATLAS detector in [Formula: see text] collisions at 13 TeV in 2015–2017 is performed. Integrated luminosity of this sample is 80.5 fb[Formula: see text]. The measurement of physical parameters are statistically combined with results obtained from Run 1 data at 7 and 8 TeV. The measured value of CP-violating phase [Formula: see text] is obtained, which has significantly better precision in comparison with Run 1 result. Precision of other physical parameters is also improved, including the decay width difference [Formula: see text]. Further improvement is expected from the use of full Run 2 statistics, as well as from modifications in the analysis.
Precision electroweak measurements with the CMS detector
Authors: Ciulli V.
Published: December 2020

Recent results by the CMS experiment on Drell–Yan, W and multiboson events are presented, including in particular the measurement of the electroweak mixing angle, the differential distributions in Drell–Yan events, and the electroweak production of one and two vector bosons in association with two jets. No deviations from the Standard Model predictions are found and stringent bounds are set on anomalous triple and quartic gauge couplings.
Design of the barrel and endcap DIRC detectors for particle identification in PANDA
Authors: Köseoglu I.
Published: December 2020

The PANDA experiment at the future Facility for Antiproton and Ion Research (FAIR) in Darmstadt/Germany aims to investigate fundamental questions of hadron physics. PANDA is designed as a fixed-target experiment for an antiproton beam with a momentum range of 1.5 GeV/[Formula: see text] to 15 GeV/[Formula: see text]. In order to obtain an excellent particle identification of pions and kaons, two independent DIRC detectors have been developed for two adjacent spatial regions. The Barrel DIRC covers polar angles from [Formula: see text]–[Formula: see text] and performs [Formula: see text] separation with [Formula: see text] or more for momenta from 0.5 to 3.5 GeV/[Formula: see text]. The novel Endcap Disc DIRC (EDD) detector will cover the forward polar angles between [Formula: see text] and [Formula: see text] and will provide a [Formula: see text] separation from 0.5 GeV/[Formula: see text] up to 4 GeV/[Formula: see text] with a separation power at least [Formula: see text]. The design of the Barrel DIRC is based on the successful BaBar DIRC and the SuperB FDIRC R&D with several improvements to optimize the performance for PANDA. Both PANDA DIRC detectors use synthetic fused silica as material for radiators and light guides and lifetime-enhance Microchannel Plate PMTs (MCP-PMTs) as sensors. The Barrel DIRC uses narrow bars as a radiator, a prism-shaped expansion volume and a complex multi-layer spherical lens as focusing system. The Cherenkov radiator for the EDD is a large, 2 cm thick fused silica plate that is divided into four identical quadrants. A combination of bars and cylindrical elements with aluminum coating focus the Cherenkov light on the MCP-PMTs with segmented anode plates.

The technical design of the two DIRC detectors and the performance of prototypes, tested in a mixed hadron beam at CERN, will be discussed.
Unknotting numbers and crossing numbers of spatial embeddings of a planar graph
Authors: Akimoto Yuta , Taniyama Kouki
Published: December 2020

It is known that the unknotting number [Formula: see text] of a link [Formula: see text] is less than or equal to half the crossing number [Formula: see text] of [Formula: see text]. We show that there are a planar graph [Formula: see text] and its spatial embedding [Formula: see text] such that the unknotting number [Formula: see text] of [Formula: see text] is greater than half the crossing number [Formula: see text] of [Formula: see text]. We study relations between unknotting number and crossing number of spatial embedding of a planar graph in general.
Multi-Unionism at the Firm Level: The Impact of Asymmetric Nash Bargaining Solutions on Labor Unions’ Merger Incentives
Authors: Cords Dario
Published: December 2020

This paper investigates the incentives of labor unions to merge in a right-to-manage model for several bargaining regimes. It is assumed that the worker groups produce different goods, and that the products are either substitutable in consumption (tariff competition), complementary (tariff plurality), or are independent of one another. The already existing merger results can be replicated in a right-to-manage model when joint bargaining is compared to simultaneous and sequential bargaining: labor unions have strict incentives to merge if the two products are substitutes in consumption, while they bargain independently if the products are complements in consumption. Further, there exists a first-mover advantage for unions under sequential bargaining for complementary products. Workers, on the other hand, benefit from a first-mover advantage in terms of their wage for the entire degree of product differentiation under sequential bargaining.
On warped product of Hermitian and Kählerian manifolds
Authors: Rezaei Abbas , Haji-Badali Ali , Faghfouri Morteza
Published: December 2020

In this paper, warped product in Hermitian and Kählerian manifolds was considered, and almost complex structure on the warped product is defined. Also, warped product almost Hermitian manifolds were defined. According to the holomorphic sectional curvature of Kählerian manifolds, the Einstein condition for constructed warped product Kählerian manifolds is obtained.
Syn-rift carbonate platforms in space and time: testing and refining conceptual models using stratigraphic and seismic numerical forward modelling
Authors: Masiero Isabella , Burgess Peter , Hollis Cathy , Manifold Lucy , Gawthorpe Rob , Lecomte Isabelle , Marshall Jim , Rotevatn Atle
Published: December 2020

Understanding and predicting architecture and facies distribution of syn-rift carbonates is challenging owing to complex control by climatic, tectonic, biological and sedimentological factors. CarboCAT is a three-dimensional stratigraphic forward model of carbonate and mixed carbonate–siliciclastic systems that has recently been developed to include processes controlling carbonate platform development in extensional settings. CarboCAT has been used here to perform numerical experiment investigations of the various processes and factors hypothesized to control syn-rift carbonates sedimentation. Models representing three tectonic scenarios have been calculated and investigated, to characterize facies distribution and architecture of carbonate platforms developed on half-grabens, horsts and transfer zones. For each forward stratigraphic model, forward seismic models have also been calculated, so that modelled stratal geometries presented as synthetic seismic images can be directly compared with seismic images of subsurface carbonate strata. The CarboCAT models and synthetic seismic images corroborate many elements of the existing syn-rift and early-post-rift conceptual model, but also expand these models by describing how platform architecture and spatial facies distributions vary along-strike between hanging-wall, footwall and transfer zone settings. Synthetic seismic images show how platform margins may appear in seismic data, showing significant differences in overall seismic character between prograding and backstepping stacking patterns.
Tofacitinib inhibits inflammatory cytokines from ulcerative colitis and healthy mucosal explants and is associated with pSTAT1/3 reduction in T-cells
Authors: Brand Rhonda M. , Moore Beverley A. , Zyhowski Ashley , Siegel Aaron , Uttam Shikhar , Metter E. Jeffrey , Engstrom Jarret , Brand Randall E. , Biswas Nabanita , Whitcomb David C. , Binion David G. , Schwartz Marc , McGowan Ian
Published: December 2020

Using colorectal biopsy material from healthy volunteers and patients with clinically defined IBD supports translational research by informing the evaluation of therapeutic efficacy and target engagement for the development of new therapeutic entities. Combining experimental readouts from intact and dissociated tissue permits understanding of elements of the tissue-resident immune system that contribute to disease pathology. Bayesian logistic regression modeling is an effective tool for predicting ex vivo explant biomarker release patterns.
Addiction history moderates the effect of prefrontal 10-Hz transcranial alternating current stimulation on habitual action selection
Authors: McKim Theresa H. , Dove Samantha J. , Robinson Donita L. , Fröhlich Flavio , Boettiger Charlotte A.
Published: December 2020

Treating the executive dysfunction associated with addiction is hampered by redundancies in pharmacological regulation of different behavioral control circuits. Thus, nonpharmacological interventions hold promise for addiction treatment. Here, we show that, among people with an addiction history, 10-Hz transcranial alternating current stimulation (10Hz-tACS) of the dorsolateral prefrontal cortex can reduce habitual actions. The fact that 10Hz-tACS can regulate behavioral flexibility suggests its possible utility in reducing harmful habitual actions.
Confidence in predicted position error explains saccadic decisions during pursuit
Authors: Coutinho Jonathan D. , Lefèvre Philippe , Blohm Gunnar
Published: December 2020

This is the first stochastic dynamical systems model of pursuit-saccade coordination accounting for noise and delays in the sensorimotor system. The model uses Bayesian inference to predictively estimate visual motion, triggering saccades when confidence in predicted position error accumulates to a threshold. This model explains saccade frequency and trigger time distributions across target trajectories and makes novel predictions about the influence of sensory uncertainty in saccade decisions during pursuit.
The influence of temporal predictability on express visuomotor responses
Authors: Contemori Samuele , Loeb Gerald E. , Corneil Brian D. , Wallis Guy , Carroll Timothy J.
Published: December 2020

Express stimulus-driven responses in humans have been proposed to be originated subcortically via the superior colliculus. These short-latency responses are facilitated by the presentation of dynamic visual stimuli. Here, we show that this facilitation is related to the predictable target timing, regardless of its kinematic attributes. We propose that the superior colliculus can be primed to generate express stimulus-driven motor responses via cortical top-down projection.
The execution of movement: a spinal affair
Authors: Grillner Sten
Published: December 2020

In this tribute to Reggie Edgerton, I briefly review the spinal mechanisms that coordinate locomotion and the interaction between the different sensory mechanisms that help coordinate the locomotor movements and the central locomotor network. The step cycle has four distinct parts, the support phase, the lift off, the flexion phase, and, the most complex, the touch down, when the limb makes a smooth contact with ground again. Each of these phases is affected by different sensory mechanisms, which interact with the central network [central pattern generator (CPG)] generating the basic movements with its four components. Conversely, the CPG also gates the sensory reflex pathways, so that they are active only in a given phase of the step cycle, or even produces opposite effects in different parts of the step cycle. These different examples from mammals are most likely important also to consider for human locomotion and, in particular, in patients with spinal cord injury, partial or complete.
STAP Based on Toeplitz Covariance Matrix Reconstruction for Airborne Radar
Authors: Liu Mingxin , Zou Lin , Yu Xuelian , Zhou Yun , Wang Xuegang
Published: December 2020

We consider the problem of clutter covariance matrix (CCM) estimation for space-time adaptive processing (STAP) radar in the small sample. In this paper, a fast efficient algorithm for CCM reconstruction is proposed to overcome this shortcoming for the linear structure. Particularly, we present a low-rank matrix recovery (LRMR) question about CCM estimation based on the Toeplitz structure of CCM and the prior knowledge of the noise. The closed-form solution is obtained by relaxing the nonconvex LRMR problem that the trace norm replaces the rank norm. The target can then be efficiently detected by using the recovered CCM according to the STAP theorem. We also analyze the algorithm model under the linear structure in the presence of unknown mutual coupling. It is shown that our method can obtain accurate CCM in the small sample, with even higher accuracy than the traditional algorithms in the same number of samples. It also can reduce the coupling effect and obtain more degrees of freedom (DOF) with limited sensors and pulses by utilizing sparse linear structure (SLS) and improve angle and Doppler resolutions. Finally, numerical simulations have verified the effectiveness of the proposed method in comparison with some of the existing methods.
Targeting p300/CBP Attenuates Hepatocellular Carcinoma Progression through Epigenetic Regulation of Metabolism
Authors: Cai Ling-Yan , Chen Shi-Jie , Xiao Sen-Hao , Sun Qin-Juan , Ding Chen-Hong , Zheng Bai-Nan , Zhu Xin-Yan , Liu Shu-Qing , Yang Feng , Yang Ya-Xi , Zhou Bing , Luo Cheng , Zhang Xin , Xie Wei-Fen
Published: December 2020

Targeting epigenetics in cancer has emerged as a promising anticancer strategy. p300/CBP is a central regulator of epigenetics and plays an important role in hepatocellular carcinoma (HCC) progression. Tumor-associated metabolic alterations contribute to the establishment and maintenance of the tumorigenic state. In this study, we used a novel p300 inhibitor, B029-2, to investigate the effect of targeting p300/CBP in HCC and tumor metabolism. p300/CBP–mediated acetylation of H3K18 and H3K27 increased in HCC tissues compared with surrounding noncancerous tissues. Conversely, treatment with B029-2 specifically decreased H3K18Ac and H3K27Ac and displayed significant antitumor effects in HCC cells in vitro and in vivo. Importantly, ATAC-seq and RNA-seq integrated analysis revealed that B029-2 disturbed metabolic reprogramming in HCC cells. Moreover, B029-2 decreased glycolytic function and nucleotide synthesis in Huh7 cells by reducing H3K18Ac and H3K27Ac levels at the promoter regions of amino acid metabolism and nucleotide synthesis enzyme genes, including PSPH, PSAT1, ALDH18A1, TALDO1, ATIC, and DTYMK. Overexpression of PSPH and DTYMK partially reversed the inhibitory effect of B029-2 on HCC cells. These findings suggested that p300/CBP epigenetically regulates the expression of glycolysis-related metabolic enzymes through modulation of histone acetylation in HCC and highlights the value of targeting the histone acetyltransferase activity of p300/CBP for HCC therapy.

Significance:

This study demonstrates p300/CBP as a critical epigenetic regulator of glycolysis-related metabolic enzymes in HCC and identifies the p300/CBP inhibitor B029-2 as a potential therapeutic strategy in this disease.
Improved Antitumor Activity of the Fluoropyrimidine Polymer CF10 in Preclinical Colorectal Cancer Models through Distinct Mechanistic and Pharmacologic Properties
Authors: Gmeiner William H. , Dominijanni Anthony , Haber Alex O. , Ghiraldeli Lais P. , Caudell David L. , D’Agostino Ralph , Pasche Boris C. , Smith Thomas L. , Deng Zhiyong , Kiren Sezgin , Mani Chinnadurai , Palle Komaraiah , Brody Jonathan R.
Published: December 2020

Chemotherapy regimens that include 5-fluorouracil (5-FU) are central to colorectal cancer treatment; however, risk/benefit concerns limit 5-FU’s use, necessitating development of improved fluoropyrimidine (FP) drugs. In our study, we evaluated a second-generation nanoscale FP polymer, CF10, for improved antitumor activity. CF10 was more potent than the prototype FP polymer F10 and much more potent than 5-FU in multiple colorectal cancer cell lines including HCT-116, LS174T, SW480, and T84D. CF10 displayed improved stability to exonuclease degradation relative to F10 and reduced susceptibility to thymidine antagonism due to extension of the polymer with arabinosyl cytidine. In colorectal cancer cells, CF10 strongly inhibited thymidylate synthase (TS), induced Top1 cleavage complex formation and caused replication stress, while similar concentrations of 5-FU were ineffective. CF10 was well tolerated in vivo and invoked a reduced inflammatory response relative to 5-FU. Blood chemistry parameters in CF10-treated mice were within normal limits. In vivo, CF10 displayed antitumor activity in several colorectal cancer flank tumor models including HCT-116, HT-29, and CT-26. CF10’s antitumor activity was associated with increased plasma levels of FP deoxynucleotide metabolites relative to 5-FU. CF10 significantly reduced tumor growth and improved survival (84.5 days vs. 32 days; P < 0.0001) relative to 5-FU in an orthotopic HCT-116-luc colorectal cancer model that spontaneously metastasized to liver. Improved survival in the orthotopic model correlated with localization of a fluorescent CF10 conjugate to tumor. Together, our preclinical data support an early-phase clinical trial of CF10 for treatment of colorectal cancer.
Genomic Alterations during the In Situ to Invasive Ductal Breast Carcinoma Transition Shaped by the Immune System
Authors: Trinh Anne , Gil Del Alcazar Carlos R. , Shukla Sachet A. , Chin Koei , Chang Young Hwan , Thibault Guillaume , Eng Jennifer , Jovanović Bojana , Aldaz C. Marcelo , Park So Yeon , Jeong Joon , Wu Catherine , Gray Joe , Polyak Kornelia
Published: December 2020

The drivers of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) transition are poorly understood. Here, we conducted an integrated genomic, transcriptomic, and whole-slide image analysis to evaluate changes in copy-number profiles, mutational profiles, expression, neoantigen load, and topology in 6 cases of matched pure DCIS and recurrent IDC. We demonstrate through combined copy-number and mutational analysis that recurrent IDC can be genetically related to its pure DCIS despite long latency periods and therapeutic interventions. Immune “hot” and “cold” tumors can arise as early as DCIS and are subtype-specific. Topologic analysis showed a similar degree of pan-leukocyte-tumor mixing in both DCIS and IDC but differ when assessing specific immune subpopulations such as CD4 T cells and CD68 macrophages. Tumor-specific copy-number aberrations in MHC-I presentation machinery and losses in 3p, 4q, and 5p are associated with differences in immune signaling in estrogen receptor (ER)-negative IDC. Common oncogenic hotspot mutations in genes including TP53 and PIK3CA are predicted to be neoantigens yet are paradoxically conserved during the DCIS-to-IDC transition, and are associated with differences in immune signaling. We highlight both tumor and immune-specific changes in the transition of pure DCIS to IDC, including genetic changes in tumor cells that may have a role in modulating immune function and assist in immune escape, driving the transition to IDC.

Implications:

We demonstrate that the in situ to IDC evolutionary bottleneck is shaped by both tumor and immune cells.
Alpha-Fetoprotein-Producing Lung Hepatoid Adenocarcinoma with Brain Metastasis Treated with S-1
Authors: Muroyama Yuki , Tamiya Hiroyuki , Tanaka Goh , Tanaka Wakae , Huang Alexander C. , Oldridge Derek A. , Matsusaka Keisuke , Takazawa Yutaka , Jo Taisuke , Ushiku Tetsuo , Nagase Takahide
Published: December 2020

Lung hepatoid adenocarcinoma (HAC) is a rare primary lung carcinoma pathologically characterized by hepatocellular carcinoma-like tumor cells, the majority of which produce alpha-fetoprotein (AFP). The clinical prognosis of lung HAC is generally poor, and effective therapeutic regimens for inoperable or recurrent cases have not been established. Here, we report a case of AFP-producing lung HAC with brain metastasis with long-term disease control, treated with the 5-fluorouracil-derived regimen S-1. The patient was a 66-year-old male admitted to the hospital with alexia. Chest X-ray revealed a massive tumor in the left upper lobe, and a head CT scan revealed a metastasis in the left parietal lobe. The laboratory data showed a remarkably elevated AFP level (97,561 ng/mL). Pathological assessment of the resected brain tumor revealed HAC, which was compatible with the lung biopsies. Together with the absence of other metastatic lesions, a final diagnosis of primary lung HAC, stage IV T4N3M1b, was given. The patient first underwent non-small cell lung cancer chemotherapy regimens (carboplatin and paclitaxel as the first line, and pemetrexed as the second line), but had clinical progression. After third-line oral S-1 (tegafur/gimeracil/oteracil) administration, the serum AFP level significantly dropped and the patient achieved long-term disease control without relapse, surviving more than 19 months after disease presentation. The autopsy result was consistent with the diagnosis of primary lung HAC, and immunohistochemical staining was AFP+, glypican 3+, and spalt-like transcription factor 4+. Here, we report the case of a rare primary lung HAC with apparent disease control on S-1 therapy, together with a literature review.
Vertigo and Balance Disorders – The Role of Osteopathic Manipulative Treatment: A Systematic Review
Authors: Tramontano Marco , Consorti Giacomo , Morone Giovanni , Lunghi Christian
Published: December 2020

Background: Balance disorders are among the most frequent reasons for consultation and referral to specialist care. Osteopathic Manipulative Treatment (OMT) can influence the proprioceptive system by inducing alterations in the proprioceptive stimuli, hence affecting postural control. Objective: The present systematic review aimed to explore the effects of OMT in managing patients with vertigo and balance disorders. Methods: MEDLINE (PubMed), ScienceDirect, and Google Scholar were searched. Clinical trials and prospective observational studies were considered. Only studies that considered OMT as the main intervention, provided alone or combined with other interventions, were included. The methodological quality of the evidence was assessed with a modified version of the Newcastle-Ottawa Scale. Results: Five studies that enrolled a total of 114 subjects met our inclusion criteria. Overall, it has been observed that there is a positive effect on balance disorders through different outcomes in all of the included studies. Only two studies (9 subjects) mentioned low to moderate adverse events after OMT. Conclusions: OMT showed weak positive effects on balance function, encouraging the connection of conventional medicine and evidence-based complementary medicine for integrative clinical practice and interprofessional work. However, full-sized adequately powered randomized trials are required to determine the effectiveness of OMT for vertigo and balance disorders.
How to Testify to the Emergence of an Idea in Conversation: Methodological Avenues for Exploring Children’s Interviews
Authors: Sorsana Christine
Published: December 2020

In line with socioconstructivist works analysing the impact of social interactions on cognitive development, the present study discusses how to capture, describe, and analyse the emergent co-production of new ideas or creative cognitive solutions. After introducing the methodologies that are currently used in this field, we recall the relevance of pragmatic analyses of conversations. We then identify several possible methodologies for probing and finely analysing the emergence of children’s new thinking, by cross-referencing third-person (i.e., from the researcher’s point of view) and first-person (i.e., from the children’s point of view, following an explicitation interview) analyses.
Os signos da morte e a exclusão decorrente da velhice em “Feliz aniversário”, de Clarice Lispector
Authors: Leonardi Carla Casarin
Published: December 2020

Este artigo, fruto de uma pesquisa de Iniciação Científica que abordou a velhice da mulher em quatro contos de Clarice Lispector, debruça-se especificamente sobre “Feliz aniversário”, publicado no livro Laços de Família, em 1960. Protagonizada por Dona Anita, a aniversariante que completa 89 anos, a narrativa toma o microcosmo familiar para lançar luz sobre questões que situam a senilidade feminina na sociedade, dando destaque a aspectos como a reificação da mulher idosa, a exclusão no discurso, a solidão em meio à presença do outro e os signos da morte como um prenúncio do que está por vir. Para a análise do conto, foi importante recorrer a outros pesquisadores que se dedicaram ao seu estudo, bem como a outros textos do repertório clariceano, buscando acrescentar novas visadas à fortuna crítica da autora.
Transvaloração em Crônica da casa assassinada: Timóteo e o punhal de Lúcio Cardoso
Authors: Lima Diogo Andrade de
Published: December 2020

Crônica da casa assassinada é, segundo Lúcio Cardoso, parte de seu movimento de luta contra Minas Gerais. Este artigo propõe uma análise da relação entre o autor e a sua terra natal, buscando compreender as razões pelas quais Lúcio se colocava contra Minas e a herança cultural dela advinda. Sob essa perspectiva, a noção nietzschiana de transvaloração de todos os valores se mostra como chave interpretativa válida, uma vez que o escritor brasileiro condenava a moral judaica. De tal modo, sendo o movimento de luta um movimento transvalorativo, tentar-se-á mostrar que Timóteo é aquele responsável pelo golpe final contra os Meneses, tornando-se o “assassino” da casa.
Clinical and Anatomic Complexity of Patients Undergoing Coronary Intervention With and Without On-Site Surgical Capabilities
Authors: Waldo Stephen W. , Hebbe Annika , Grunwald Gary K. , Doll Jacob A. , Schofield Richard
Published: December 2020

Background:

Professional society consensus statements articulate the clinical and anatomic complexity of patients that may undergo percutaneous coronary intervention (PCI) without on-site cardiothoracic surgery, although compliance with these recommendations has not been assessed. We sought to evaluate the clinical and anatomic complexity of patients undergoing PCI with and without cardiothoracic surgery on-site.

Methods:

We identified all patients undergoing PCI in the Veterans Affairs health care system between October 2009 and September 2017. The clinical and anatomic complexity of patients treated at sites with or without cardiothoracic surgery was evaluated with a comparative interrupted time series, and mortality was ascertained in a propensity-matched cohort.

Results:

We identified 75 564 patients who underwent PCI, with the majority (53 708, 71%) treated at sites with cardiothoracic surgery. The overall clinical complexity was statistically greater for those treated at sites with cardiothoracic surgery (National Cardiovascular Data Registries CathPCI: 18.4) compared with those at sites without (17.8,
P
<0.001) throughout the study, with similar annual increases in complexity before (2% versus 3%;
P
=0.107) and after (3% versus 3%;
P
=0.704) January 2014. The anatomic complexity of patients treated was also statistically greater (Veterans Affairs SYNTAX: 11.0 versus 10.2;
P
<0.001) and increased at comparable rates (2% versus 1%,
P
=0.731) before 2014. After publication of the consensus statement, anatomic complexity declined at sites with cardiothoracic surgery (−2%) but increased at sites without on-site surgery (5%,
P
=0.025) such that it was similar at the end of the study (
P
=0.622). Referrals for emergent cardiothoracic surgery were rare regardless of treatment venue (61, 0.08%) and the hazard for mortality was similar (hazard ratio, 0.883 [95% CI, 0.662–1.176]) after propensity matching.

Conclusions:

There are minor differences in complexity of patients undergoing coronary intervention at sites with and without cardiothoracic surgery. Clinical outcomes are similar regardless of treatment venue, suggesting an opportunity to improve access to complex interventional care without sacrificing quality.
SIRT6 Protects Smooth Muscle Cells From Senescence and Reduces Atherosclerosis
Authors: Grootaert Mandy O.J. , Finigan Alison , Figg Nichola L. , Uryga Anna K. , Bennett Martin R.
Published: December 2020

Rationale:

Vascular smooth muscle cell (VSMC) senescence promotes atherosclerosis and features of plaque instability, in part, through lipid-mediated oxidative DNA damage and telomere dysfunction. SIRT6 (Sirtuin 6) is a nuclear deacetylase involved in DNA damage response signaling, inflammation, and metabolism; however, its role in regulating VSMC senescence and atherosclerosis is unclear.

Objective:

We examined SIRT6 expression in human VSMCs, the role, regulation, and downstream pathways activated by SIRT6, and how VSMC SIRT6 regulates atherogenesis.

Methods and Results:

SIRT6 protein, but not mRNA, expression was markedly reduced in VSMCs in human and mouse atherosclerotic plaques, and in human VSMCs derived from plaques or undergoing replicative or palmitate-induced senescence versus healthy aortic VSMCs. The ubiquitin ligase CHIP (C terminus of HSC70-interacting protein) promoted SIRT6 stability, but CHIP expression was reduced in human and mouse plaque VSMCs and by palmitate in a p38- and c-Jun N-terminal kinase-dependent manner. SIRT6 bound to telomeres, while SIRT6 inhibition using shRNA or a deacetylase-inactive mutant (SIRT6
H133Y
) shortened human VSMC lifespan and induced senescence, associated with telomeric H3K9 (histone H3 lysine 9) hyperacetylation and 53BP1 (p53 binding protein 1) binding, indicative of telomere damage. In contrast, SIRT6 overexpression preserved telomere integrity, delayed cellular senescence, and reduced inflammatory cytokine expression and changes in VSMC metabolism associated with senescence. SIRT6, but not SIRT6
H133Y
, promoted proliferation and lifespan of mouse VSMCs, and prevented senescence-associated metabolic changes. ApoE
−/−
(apolipoprotein E) mice were generated that overexpress SIRT6 or SIRT6
H133Y
in VSMCs only. SM22α-hSIRT6/ApoE
−/−
mice had reduced atherosclerosis, markers of senescence and inflammation compared with littermate controls, while plaques of SM22α-hSIRT6
H133Y
/ApoE
−/−
mice showed increased features of plaque instability.

Conclusions:

SIRT6 protein expression is reduced in human and mouse plaque VSMCs and is positively regulated by CHIP. SIRT6 regulates telomere maintenance and VSMC lifespan and inhibits atherogenesis, all dependent on its deacetylase activity. Our data show that endogenous SIRT6 deacetylase is an important and unrecognized inhibitor of VSMC senescence and atherosclerosis.