bluuebunny/crossref_metadata_2025 huggingface dataset:
The Value of Total Lymph Nodes Examined and Number of Positive Lymph Nodes in Determining the Role of Adjuvant Radiation in Pancreatic Cancer Patients
Authors: Zhu Fan , Wang Haoyu , Guirguis Adel , Ashamalla Hani
Published: March 2020

Objectives

The aim of this study was to determine the survival benefits by adjuvant radiation therapy (RT) in pancreatic cancer patients with different total lymph nodes examined (TNE), number of positive lymph nodes (NPN), and lymph nodes ratio (LNR).

Methods

National Cancer Database was queried for nonmetastatic pancreatic cancer patients from 2004 to 2015. Cox models were utilized. Interaction terms were applied to evaluate the effect of RT in different NPN, LNR, and margin strata. Multivariate analysis was performed.

Results

Of 19,759 patients identified, 10,910 patients qualified. Compared with TNE of 1 to 9, TNE of 10 to 14, 15 to 19, 20 to 24, and 25 or greater had progressive overall survival (OS) benefits. Adjuvant RT had similar OS benefits among them. In negative margin patients, adjuvant RT improved OS when NPN was 2 to 3 (hazards ratio [HR], 0.84; P = 0.01) or LNR was 0.15 to 0.25 (HR, 0.79; P = 0.002). In positive margin patients, adjuvant RT nonsignificantly improved OS when NPN was 1 to 3 (HR, 0.89; P = 0.36) or when NPN was 4 or greater (HR, 0.79; P = 0.07).

Conclusions

Higher TNE correlates with better survival. Adjuvant RT may not compensate for inadequate lymph node dissection. Adjuvant RT improves survival in negative-margin patients with 2 to 3 positive lymph nodes or LNR of 0.15 to 0.25.
NTRK-rearranged Cervical Sarcoma: Expanding the Clinicopathologic Spectrum
Authors: Hodgson Anjelica , Pun Cherry , Djordjevic Bojana , Turashvili Gulisa
Published: March 2020

The NTRK genes (NTRK1, NTRK2, and NTRK3) encode for TrkA, TrkB, and TrkC, neurotrophic tyrosine receptor kinases which serve a variety of functions including in the regulation of pathways involved in carcinogenesis. A number of reports have described NTRK gene fusions in a variety of adult and pediatric tumor types from various organ systems including the central nervous system, thyroid gland, breast, and soft tissue. NTRK-rearranged uterine sarcomas are a recently described group of tumors which occur in both the uterine corpus and cervix, tend to morphologically resemble fibrosarcoma, and may behave aggressively, although data is limited given the newly recognized nature and thus relative rarity of these tumors. Herein, we present the case of a cervical sarcoma with SPECC1L-NTRK3 fusion (detected with Illumina RNA Fusion Panel), prospectively diagnosed at the time of cervical biopsy and subsequently treated with hysterectomy. The clinical presentation, radiologic findings, morphologic features, and immunohistochemical profile of this case will be reviewed and compared with the body of existing literature to date. Identification of NTRK-rearranged neoplasms is important as targeted therapy in the form of NTRK inhibitors has recently become widely available.
Emotional appraisal processing of computer-generated facial expressions: an functional near-infrared spectroscopy study
Authors: Zhao Tinghao , Chen Jiangtao , Wang Lan , Yan Nan
Published: March 2020

Objective:

The current study aims to investigate whether computer generated (CG) expressions of emotion evoke similar emotional appraisal processing in the lateral orbitofrontal cortex (lOFC) compared to real human expressions, as well as how speech cues would influence the processing.

Methods:

Functional near-infrared spectroscopy was used to measure the neural activations in the prefrontal cortex during emotion recognition task. Thirty normal participants were asked to view videos of dynamic facial expressions and selected the emotions that were best matches with the expressions.

Results:

CG expressions evoked less activation in the lOFC comparing to real human expressions. Furthermore, speech cues increased the activation in the lOFC for CG expressions but not real expressions.

Conclusion:

Comparing to real expressions, CG expressions evoked less appraisal processing related to motivational values although this disadvantage can be compensated to some extent by presenting the expressions with speech cues.
New psychoactive substances in Taiwan: challenges and strategies
Authors: Feng Ling-Yi , Li Jih-Heng
Published: March 2020

Purpose of review

Abuse of new psychoactive substances (NPS) has been a new global concern. So far, there has been no international consensus on legislative control of NPS. Scrutiny of Taiwan's illegal drug use history reveals that legislation and policy play an important role in tackling the drug issues.

Recent findings

Since the early 2000s, use of club drugs (mostly NPS) has become popular in local rave parties and dance clubs in Taiwan. Some NPS, such as ketamine, synthetic cathinones, and para-methoxymethamphetamine, have posed a risk to public health and a challenge to drug policy.

The illegal drug use history in Taiwan was firstly briefly reviewed, and the recent NPS use situation was depicted. Heroin and methamphetamine have been the most predominant drugs, but NPS such as ketamine and synthetic cathinones have become a new issue. The toxicological profiles of commonly abused NPS in Taiwan, although limited, were discussed. By comparison of the legislative mechanism for NPS control between Taiwan, South Korea, and Japan, it was found that timely and flexible legislative mechanism(s) is essential for early identification, surveillance, and comprehensive evaluation. In addition, researches on NPS epidemiology and toxicology are needed to firm up evidence-based strategies for effective prevention, treatment, and harm reduction measures.
Behavioural variability contributes to over-staying in patchy foraging
Authors: Cash-Padgett Tyler , Hayden Benjamin
Published: March 2020

Foragers often systematically deviate from rate-maximizing choices in two ways: accuracy and precision. That is, they use suboptimal threshold values and also show variability in their application of those thresholds. We hypothesized that these biases are related and, more specifically, that foragers' widely known accuracy bias––over-staying––could be explained, at least in part, by their imprecision. To test this hypothesis, we analysed choices made by three rhesus macaques in a computerized patch foraging task. Confirming previously observed findings, we found high levels of variability. We then showed, through simulations, that this variability changed optimal thresholds, meaning that a forager aware of its own variability should increase its leaving threshold (i.e. over-stay) to increase performance. All subjects showed thresholds that were biased in the predicted direction. These results indicate that over-staying in patches may reflect, in part, an adaptation to behavioural variability.
Instrument-free detection of polyphenols with a thread-based analytical device
Authors: Song Jiahong , Ouyang Zhuang , Lu Wei , Cai Longfei
Published: March 2020

We described an instrument-free method for quantitative analysis of the total content of tea polyphenols by measurement of the length of a coloured band. Polyphenols react with ferrous ions to form a colourless ferrous-polyphenols complex on cotton threads, which could be adsorbed on the threads. The complex was then oxidized to form a blue-black ferric-polyphenols complex, generating a blue-black band on the cotton thread. The length of this blue-black band was then measured to detect the total content of polyphenols. The advantages of this method include low cost, rapid analysis, low consumption, easy fabrication and operation. Furthermore, the digital instrument (scanner or camera) as well as the image processing software are not required. This proposed method was used to detect polyphenols in tea leaf extracts with an analytical result agreeing well with that obtained by a standard method, which demonstrates its potential in monitoring of tea leaf quality, especially in resource-limited regions and settings.
Baboon thanatology: responses of filial and non-filial group members to infants' corpses
Authors: Carter Alecia J. , Baniel Alice , Cowlishaw Guy , Huchard Elise
Published: March 2020

What do animals know of death? What can animals' responses to death tell us about the evolution of species’ minds, and the origins of humans' awareness of death and dying? A recent surge in interest in comparative thanatology may provide beginnings of answers to these questions. Here, we add to the comparative thanatology literature by reporting 12 cases of group members' responses to infants’ deaths, including 1 miscarriage and 2 stillbirths, recorded over 13 years in wild Namibian chacma baboons. Wild baboons' responses to dead infants were similar to other primates: in general, the mother of the infant carried the infants’ corpse for varying lengths of time (less than 1 h to 10 days) and tended to groom the corpses frequently, though, as in other studies, considerable individual differences were observed. However, we have not yet observed any corpse carriage of very long duration (i.e. greater than 20 days), which, though rare, occurs in other Old World monkeys and chimpanzees. We hypothesize this is due to the costs of carrying the corpse over the greater daily distances travelled by the Tsaobis baboons. Additionally, in contrast to other case reports, we observed male friends' ‘protection’ of the infant corpse on three occasions. We discuss the implications of these reports for current questions in the field.
A grain boundary model considering the grain misorientation within a geometrically nonlinear gradient-extended crystal viscoplasticity theory
Authors: Alipour Atefeh , Reese Stefanie , Svendsen Bob , Wulfinghoff Stephan
Published: March 2020

The main goal of the current work is to present a grain boundary model based on the mismatch between adjacent grains in a geometrically nonlinear crystal viscoplasticity framework including the effect of the dislocation density tensor. To this end, the geometrically nonlinear crystal viscoplasticity theory by Alipour
et al.
(Alipour A
et al
. 2019
Int. J. Plast.
118
, 17–35. (
doi:10.1016/j.ijplas.2019.01.009
)) is extended by a more complex free energy and a geometrical transmissibility parameter is used to evaluate the dislocation transmission at the grain boundaries which includes the orientations of slip directions and slip plane normals. Then, the grain boundary strength is evaluated based on the misorientation between neighbouring grains using the transmissibility parameter. In some examples, the effect of mismatch in adjacent grains on the grain boundary strength, the dislocation transmission at the grain boundaries and the Hall–Petch slope is discussed by a comparison of two-dimensional random-oriented polycrystals and textured polycrystals under shear deformation.
Joining a group diverts regret and responsibility away from the individual
Authors: El Zein Marwa , Bahrami Bahador
Published: March 2020

It has recently been proposed that a key motivation for joining groups is the protection from the negative consequences of undesirable outcomes. To test this claim, we investigated how experienced outcomes triggering loss and regret impacted people's tendency to decide alone or join a group, and how decisions differed when voluntarily made alone versus in group. Replicated across two experiments, participants (
n
= 125 and
n
= 496) selected whether to play alone or contribute their vote to a group decision. Next, they chose between two lotteries with different probabilities of winning and losing. The higher the negative outcome, the more participants switched from deciding alone to with others. When joining a group to choose the lottery, choices were less driven by outcome and regret anticipation. Moreover, negative outcomes experienced alone, not part of a group vote, led to worse subsequent choices than positive outcomes. These results suggest that the protective shield of the collective reduces the influence of negative emotions that may help individuals re-evaluate past choices.
Autocatalytic chemical networks at the origin of metabolism
Authors: Xavier Joana C. , Hordijk Wim , Kauffman Stuart , Steel Mike , Martin William F.
Published: March 2020

Modern cells embody metabolic networks containing thousands of elements and form autocatalytic sets of molecules that produce copies of themselves. How the first self-sustaining metabolic networks arose at life's origin is a major open question. Autocatalytic sets smaller than metabolic networks were proposed as transitory intermediates at the origin of life, but evidence for their role in prebiotic evolution is lacking. Here, we identify reflexively autocatalytic food-generated networks (RAFs)—self-sustaining networks that collectively catalyse all their reactions—embedded within microbial metabolism. RAFs in the metabolism of ancient anaerobic autotrophs that live from H
2
and CO
2
provided with small-molecule catalysts generate acetyl-CoA as well as amino acids and bases, the monomeric components of protein and RNA, but amino acids and bases without organic catalysts do not generate metabolic RAFs. This suggests that RAFs identify attributes of biochemical origins conserved in metabolic networks. RAFs are consistent with an autotrophic origin of metabolism and furthermore indicate that autocatalytic chemical networks preceded proteins and RNA in evolution. RAFs uncover intermediate stages in the emergence of metabolic networks, narrowing the gaps between early Earth chemistry and life.
Predicting defaunation: accurately mapping bushmeat hunting pressure over large areas
Authors: Deith Mairin C. M. , Brodie Jedediah F.
Published: March 2020

Unsustainable hunting is emptying forests of large animals around the world, but current understanding of how human foraging spreads across landscapes has been stymied by data deficiencies and cryptic hunter behaviour. Unlike other global threats to biodiversity like deforestation, climate change and overfishing, maps of wild meat hunters' movements—often based on forest accessibility—typically cover small scales and are rarely validated with real-world observations. Using camera trapping data from rainforests across Malaysian Borneo, we show that while hunter movements are strongly correlated with the accessibility of different parts of the landscape, accessibility measures are most informative when they integrate fine-scale habitat features like topography and land cover. Measures of accessibility naive to fine-scale habitat complexity, like distance to the nearest road or settlement, generate poor approximations of hunters’ movements. In comparison, accessibility as measured by high-resolution movement models based on circuit theory provides vastly better reflections of real-world foraging movements. Our results highlight that simple models incorporating fine-scale landscape heterogeneity can be powerful tools for understanding and predicting widespread threats to biodiversity.
Origin, maintenance and spread of antibiotic resistance genes within plasmids and chromosomes of bloodstream isolates of Escherichia coli
Authors: Goswami Cosmika , Fox Stephen , Holden Matthew T.G. , Connor Martin , Leanord Alistair , Evans Thomas J.
Published: March 2020

Blood stream invasion by

Escherichia coli

is the commonest cause of bacteremia in the UK and elsewhere with an attributable mortality of about 15–20 %; antibiotic resistance to multiple agents is common in this microbe and is associated with worse outcomes. Genes conferring antimicrobial resistance, and their frequent location on horizontally transferred genetic elements is well-recognised, but the origin of these determinants, and their ability to be maintained and spread within clinically-relevant bacterial populations is unclear. Here, we set out to examine the distribution of antimicrobial resistance genes in chromosomes and plasmids of 16 bloodstream isolates of

E. coli

from patients within Scotland, and how these genes are maintained and spread. Using a combination of short and long-read whole genome sequencing methods, we were able to assemble complete sequences of 44 plasmids, with 16 Inc group F and 20 col plasmids; antibiotic resistance genes located almost exclusively within the F group. bla
CTX-M15 genes had re-arranged in some strains into the chromosome alone (five strains), while others contained plasmid copies alone (two strains). Integrons containing multiple antibiotic genes were widespread in plasmids, notably many with a dfrA7 gene encoding resistance to trimethoprim, thus linking trimethoprim resistance to the other antibiotic resistance genes within the plasmids. This will allow even narrow spectrum antibiotics such as trimethoprim to act as a selective agent for plasmids containing antibiotic resistance genes mediating much broader resistance, including blaCTX-M15. To our knowledge, this is the first analysis to provide complete sequence data of chromosomes and plasmids in a collection of pathogenic human bloodstream isolates of

E. coli

. Our findings reveal the interplay between plasmids and integrative and conjugative elements in the maintenance and spread of antibiotic resistance genes within pathogenic

E. coli

.
Quantifying and contextualizing the impact of bioRxiv preprints through automated social media audience segmentation
Authors: Carlson Jedidiah , Harris Kelley
Published: March 2020

Engagement with scientific manuscripts is frequently facilitated by Twitter and other social media platforms. As such, the demographics of a paper’s social media audience provide a wealth of information about how scholarly research is transmitted, consumed, and interpreted by online communities. By paying attention to public perceptions of their publications, scientists can learn whether their research is stimulating positive scholarly and public thought. They can also become aware of potentially negative patterns of interest from groups that misinterpret their work in harmful ways, either willfully or unintentionally, and devise strategies for altering their messaging to mitigate these impacts. In this study, we collected 331,696 Twitter posts referencing 1,800 highly tweeted bioRxiv preprints and leveraged topic modeling to infer the characteristics of various communities engaging with each preprint on Twitter. We agnostically learned the characteristics of these audience sectors from keywords each user’s followers provide in their Twitter biographies. We estimate that 96% of the preprints analyzed are dominated by academic audiences on Twitter, suggesting that social media attention does not always correspond to greater public exposure. We further demonstrate how our audience segmentation method can quantify the level of interest from non-specialist audience sectors such as mental health advocates, dog lovers, video game developers, vegans, bitcoin investors, conspiracy theorists, journalists, religious groups, and political constituencies. Surprisingly, we also found that 10% of the highly tweeted preprints analyzed have sizable (>5%) audience sectors that are associated with right-wing white nationalist communities. Although none of these preprints intentionally espouse any right-wing extremist messages, cases exist where extremist appropriation comprises more than 50% of the tweets referencing a given preprint. These results present unique opportunities for improving and contextualizing research evaluation as well as shedding light on the unavoidable challenges of scientific discourse afforded by social media.
Analytical sensibility and specificity of two RT-qPCR protocols for SARS-CoV-2 detection performed in an automated workflow
Authors: Barra Gustavo Barcelos , Santa Rita Ticiane Henriques , Góes Mesquita Pedro , Jácomo Rafael Henriques , Abdalla Nery Lídia Freire
Published: March 2020

The World Health Organization declared that COVID-19 outbreak constituted a Public Health Emergency of International Concern and the development of reliable laboratory diagnosis of SARS-CoV-2 became mandatory to identify, isolate and provide optimized care for patients early. RT-qPCR testing of respiratory secretions is routinely used to detect causative viruses in acute respiratory infection. RT-qPCR in-house protocols to detect the SARS-CoV-2 have been described. Validations of these protocols are considered a key knowledge gap for COVID-19, especially if executed in a high throughput format. Here, we investigate the analytical sensitivity and specificity of two interim RT-qPCR protocols for the qualitative detection of SARS-CoV-2 executed in a fully automated platform. Under our conditions, the N1 and RdRP (modified) showed the highest analytical sensitivity for their RNA targets. E assay, in its original concentration, was considered a tertiary confirmatory assay. Taken together, N1, RdRP (optimized) and E presented appropriated analytical sensibility and specificity in our automated RT-qPCR workflow for COVID-19 virus, E being at least 4-fold less sensitive than the others. This study highlights the importance of local validation of in-house assays before its availability to the population. The use of the synthetic RT-qPCR target to investigate novel assays diagnostic parameters in automated workflows is a quick, simple effective way to be prepared for upcoming threats. The proposed assay detected the fisrt SARS-CoV-2 infection in Brazilian Central-West.
Baseline analysis of patients presenting for surgical review of ACL rupture reveals heterogeneity in patient-reported outcome measures
Authors: Ting Chee Han , Scholes Corey , Zbrojkiewicz David , Bell Christopher
Published: March 2020

Despite establishment of successful surgical techniques and rehabilitation protocols for ACL reconstruction, published return to sport rates are less than satisfactory. This has led orthopaedic surgeons and researchers to develop more robust patient selection methods and investigate prognostic patient characteristics. No previous studies have integrated baseline characteristics and responses to PROMs of patients with ACL rupture presenting for surgical review.

Patients electing to undergo ACL reconstruction under the care of a single orthopaedic surgeon at a metropolitan public hospital were enrolled in a clinical quality registry. Patients completed VR-12 PCS and MCS scores, Tegner activity scale and IKDC questionnaires at presentation. Total scores were extracted from the electronic registry, and a machine learning approach (k-means) was used to identify subgroups based on similarity of questionnaire responses. The average scores in each cluster were compared using ANOVA (Kruskal-Wallis) and nominal logistic regression was performed to determine relationships between cluster membership and patient age, gender, BMI and injury-to-examination delay.

A sample of 107 patients with primary ACL rupture were extracted, with 97 (91%) available for analysis with complete datasets. Four clusters were identified with distinct patterns of PROMs responses. These ranged from lowest (Cluster 1) to highest scores for VR-12 and IKDC (Cluster 4). In particular, Cluster 4 returned median scores within 6 points of the PASS for the IKDC score for ACL reconstruction (70.1, IQR 59 - 78). Significant (p<0.05) differences in PROMs between clusters was observed using ANOVA, with variance explained ranging from 40-69%. However, cluster membership was not significantly associated with patient age, gender, BMI or injury-to-examination delay.

Patients electing to undergo ACL reconstruction do not conform to a homogenous group but represent a spectrum of knee function, general physical and mental health, and preinjury activity levels, which may not lend itself to uniform treatment and rehabilitation protocols. The factors driving these distinct responses to PROMs remain unknown, but are unrelated to common demographic variables.
A deterministic epidemic model for the emergence of COVID-19 in China
Authors: Wang Meng , Qi Jingtao
Published: March 2020

Coronavirus disease (COVID-19) broke out in Wuhan, Hubei province, China, in December 2019 and soon after Chinese health authorities took unprecedented prevention and control measures to curb the spreading of the novel coronavirus-related pneumonia. We develop a mathematical model based on daily updates of reported cases to study the evolution of the epidemic. With the model, on 95% confidence level, we estimate the basic reproduction number, R0 = 2.82 ± 0.11, time between March 19 and March 21 when the effective reproduction number becoming less than one, the epidemic ending after April 2 and the total number of confirmed cases approaching 14408 ± 429 on the Chinese mainland excluding Hubei province.
Handedness measures for the Human Connectome Project: Implications for data analysis
Authors: Ruck Lana , Schoenemann P. Thomas
Published: March 2020

Open data initiatives such as the UK Biobank and Human Connectome Project provide researchers with access to neuroimaging, genetic, and other data for large samples of left-and right-handed participants, allowing for more robust investigations of handedness than ever before. Handedness inventories are universal tools for assessing participant handedness in these large-scale neuroimaging contexts. These self-report measures are typically used to screen and recruit subjects, but they are also widely used as variables in statistical analyses of fMRI and other data. Recent investigations into the validity of handedness inventories, however, suggest that self-report data from these inventories might not reflect hand preference/performance as faithfully as previously thought. Using data from the Human Connectome Project, we assessed correspondence between three handedness measures – the Edinburgh Handedness Inventory (EHI), the Rolyan 9-hole pegboard, and grip strength – in 1179 healthy subjects. We show poor association between the different handedness measures, with roughly 10% of the sample having at least one behavioral measure which indicates hand-performance biasoppositeto the EHI score, and over 65% of left-handers having one or more mismatched handedness scores. We discuss implications for future work, urging researchers to critically consider direction, degree,andconsistency of handedness in their data.
The role of the metabolic profile in mediating the relationship between body mass index and left ventricular mass in adolescents: analysis of a prospective cohort study
Authors: Carter Alice R , Ferreira Diana L. Santos , Taylor Amy E , Lawlor Deborah A , Smith George Davey , Sattar Naveed , Chaturvedi Nishi , Hughes Alun D , Howe Laura D
Published: March 2020

Background

We aimed to quantify the role of the plasma metabolic profile in explaining the effect of adiposity on cardiac structure.

Methods

Body mass index (BMI) was measured at age 11 in the Avon Longitudinal Study of Parents and Children. Left ventricular mass indexed to height2.7 (LVMI), was assessed by echocardiography at age 17. The metabolic profile was quantified via nuclear magnetic resonance spectroscopy at age 15.

Multivariable confounder (maternal age, parity, highest qualification, maternal smoking, pre-pregnancy BMI, pre-pregnancy height, household social class and adolescent birthweight, adolescent smoking, fruit and vegetable consumption, physical activity) -adjusted linear regression estimated the association of BMI with LVMI and mediation by metabolic traits. We considered 156 metabolomic traits individually, jointly as principal components (PCs) explaining 95% of the variance in the NMR platform, and assessed whether the PCs for the metabolic traits added to the proportion of the association explained by established cardiovascular risk factors (systolic and diastolic blood pressure, insulin, triglycerides, low density lipoprotein, and glucose).

Results

A 1kg/m2 higher BMI was associated with a 0.70 g/m2.7 (0.53, 0.88) and 0.66 g/m2.7 (0.53, 0.79) higher LVMI in males (N=437) and females (N=536), respectively. Established risk factors explained 3% (95% CI: 2% to 5%) of this association in males, increasing to 10% (95% CI: 8%, 13%) when including metabolic PCs. In females, the standard risk factors explained 3% (95% CI: 2%, 5%) of the association, and did not increase when including the metabolic PCs.

Conclusion

The addition of the NMR measured metabolic traits appear to mediate more of the effect of BMI on LVMI than the established risk factors alone in adolescent males, but not females.
Spatially fractionated stereotactic body radiotherapy (Lattice SBRT) for large tumors
Authors: Duriseti Sai , Kavanaugh James , Goddu Sreekrishna , Price Alex , Knutson Nels , Reynoso Francisco , Michalski Jeff , Mutic Sasa , Robinson Clifford , Spraker Matthew B
Published: March 2020

Stereotactic body radiotherapy (SBRT) has demonstrated clinical benefit for patients with metastatic and/or unresectable cancer. Technical considerations of treatment delivery and sensitive organs at risk (OARs) limit the use of SBRT in large tumors or those in unfavorable locations. Spatially fractionated radiotherapy (SFRT) delivers high-dose radiation to discrete sub-volume vertices within a tumor target while restricting the remainder of the target to low dose. SFRT has been utilized for treatment of large tumors with reported dramatic tumor response and minimal side effects. Lattice is a modern approach to SFRT that can be delivered with arc-based therapy, which allows for the rapid dose fall-off required for high quality SBRT. In order to overcome the limitations of SBRT for large tumors, we developed Lattice SBRT. Here we report the results of a dosimetry and quality assurance (QA) feasibility study of Lattice SBRT in 11 patients with 12 tumor targets, each ≥ 10 cm in an axial dimension. Prior CT simulation scans were used to generate volumetric-modulated arc therapy (VMAT) Lattice SBRT plans that were then delivered on clinically available Linacs. QA testing included external portal imaging device (EPID) and ion chamber (IC) analysis. All generated plans were able to meet the standard SBRT dose constraints, such as those from AAPM Task Group 101. Additionally, we provide a step-by-step approach for generating and delivering Lattice SBRT plans using commercially available treatment technology. Lattice SBRT is currently being tested in a prospective trial for patients with metastatic cancer needing palliation of large tumors (NCTXXXX).
Closed-loop stimulation of the medial septum terminates epileptic seizures
Authors: Takeuchi Yuichi , Harangozó Márk , Pedraza Lizeth , Földi Tamás , Kozák Gábor , Berényi Antal
Published: March 2020

Temporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, due to its large size and irregular shape. In contrast, the medial septum (MS) is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this ‘proxy intervention’ concept and precisely timed stimulation, we report here that closed-loop MS electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell-type-specific stimulation revealed that precisely timed activation of MS GABAergic neurons underlay the effects. Our concept of phase-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and its current embodiment can be directly translated into clinical application.
Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients
Authors: Syrimi Eleni , Khan Naeem , Murray Paul , Willcox Carrie , Haigh Tracey , Willcox Benjamin , Masand Navta , Zuo Jianmin , Barone Sierra M , Irish Jonathan M , Kearns Pamela , Taylor Graham S
Published: March 2020

Systemic immunity plays an important role in cancer immune surveillance and therapy but there is little detailed knowledge about the immune status of healthy children or children with cancer. We performed a high dimensional single cell analysis of systemic immunity in pediatric cancer patients and age-matched healthy children. In young children with cancer (age < 8years) NK cells were decreased in frequency, maturity, expression of perforin and granzyme-B, and were less cytotoxic in ex vivo assays. NK cell activity was restored after in vitro culture with interleukin-2. In contrast, older children with cancer (>8 years old) had decreased naive CD4 and CD8 T-cells with concomitant increases in effector memory and T effector memory RA-revertant (TEMRA) T-cells. These immunological changes in pediatric cancer patients are relevant to the better understanding of how cancers diagnosed in childhood interact with systemic immunity and could inform the development and application of effective immune-modulating therapies in the pediatric population.

One Sentence Summary

High dimensional analysis of systemic immunity in pediatric cancer patients reveals clinically relevant immune changes in NK and T-cells that vary with patient age.
Alcohol-Induced Increase in the Content of CYP2E1 in Human Liver Microsomes Causes a Multifold Activation of CYP3A4 and Attenuates its Cooperativity
Authors: Dangi Bikash , Davydova Nadezhda Y. , Vavilov Nikita E. , Zgoda Victor G. , Davydov Dmitri R.
Published: March 2020

Here we investigate the effect of alcohol-induced increase in the content of CYP2E1 in human liver microsomes (HLM) on the function of CYP3A4. In these studies we used a model that implements enrichment of HLM samples with CYP2E1 through membrane incorporation of the purified protein. Enrichment of HLM with CYP2E1 considerably increases the rate of metabolism of 7-benzyloxyquinoline (BQ) and attenuates the homotropic cooperativity observed with this CYP3A4-specific substrate. Incorporation of CYP2E1 also eliminates the activating effect of α-Naphthoflavone (ANF) on BQ metabolism seen in some untreated HLM samples. To probe the physiological relevance of these effects we compared three pooled preparations of HLM from normal donors (HLM-N) with a preparation obtained from heavy alcohol consumers (HLM-A). The composition of the P450 pool in all four samples was characterized with mass-spectrometric determination of 11 cytochrome P450 species. The molar content of CYP2E1 in HLM-A was from 2.5 to 3.3 times higher than that found in HLM-N. In contrast, the content of CYP3A4 in HLM-A was the lowest among all four HLM samples. Despite of that, HLM-A exhibited much higher rate of metabolism and lower degree of homotropic cooperativity with BQ, similar to that observed in CYP2E1-enriched HLM-N. In order to substantiate the hypothesis on the involvement of physical interactions between CYP2E1 and CYP3A4 in the observed effects we probed hetero-association of these proteins in Supersomes™ containing recombinant CYP3A4 with a technique based on homo-FRET and employing CYP2E1 labeled with BODIPY-618 maleimide. These experiments demonstrated high affinity interactions between the two enzymes and revealed an inhibitory effect of ANF on their hetero-association. Our results demonstrate that the catalytic activity and allosteric properties of CYP3A4 are fundamentally dependent on the composition of the cytochrome P450 ensemble and imply a profound impact of chronic alcohol exposure on the pharmacokinetics of drugs metabolized by CYP3A4.
Caloric restriction alters lipid metabolism to contribute to tumor growth inhibition
Authors: Lien Evan C. , Westermark Anna M. , Li Zhaoqi , Sapp Kiera M. , Vander Heiden Matthew G.
Published: March 2020

Dietary interventions can change metabolite levels in the tumor microenvironment, which may then affect cancer cell metabolism to alter tumor growth1–6. Although caloric restriction (CR) and the ketogenic diet (KD) are often thought to inhibit tumor growth through lowering blood glucose and insulin levels7–12, only CR inhibits the growth of pancreatic ductal adenocarcinoma allografts in mice, demonstrating that this diet can limit tumor growth in other ways. A change in nutrient availability observed with CR, but not the KD, that can contribute to tumor growth inhibition is lower lipid levels in the plasma and in tumor interstitial fluid. Limiting exogenous lipid availability to cultured cancer cells results in up-regulation of stearoyl-CoA desaturase (SCD), an enzyme that converts saturated fatty acids to monounsaturated fatty acids. Fatty acid desaturation is required to dispose of toxic saturated fatty acids, and not because monounsaturated fatty acids are specifically needed for proliferation. Surprisingly, CR also inhibits tumor SCD activity, and enforced SCD expression confers resistance to the effects of CR. Therefore, CR both limits lipid availability and impairs tumor SCD activity, thereby limiting cancer cell adaptation to a diet-induced change in the tumor microenvironment that results in tumor growth inhibition.
A new genetic method to predict the prognostic outcome of melanoma
Authors: GuoHu Hong , Qing Guan , XinHua Luo
Published: March 2020

Cutaneous melanoma is quite often encountered in dermato-oncology. This paper describes a new genetic method to predict the prognostic outcome of melanoma. Data were collected from the TCGA databases. According to tumor progression status, the data were divided into two groups to evaluate the significant biological processes and key genes influencing the outcome of melanoma using a bioinformatics method. By adopting a statistical regression analysis method, a novel score based on the contributing genes was developed. Cox regression analysis was used to validate the effectiveness of the genetic risk score in predicting the outcome. Seven biological processes associated with melanocytes were identified. A protein-protein interactions network showed that 27 functional genes were associated with the outcome of melanoma. Among these, three genes (COL17A1, ITGA6, and SPRR2F) were used to calculate the genetic risk score, which was regarded as an independent and effective risk factor for disease progression or overall survival in melanoma.
An emergent population code in primary auditory cortex supports selective attention to spectral and temporal sound features
Authors: Downer Joshua D. , Verhein Jessica R. , Rapone Brittany C. , O’Connor Kevin N. , Sutter Mitchell L.
Published: March 2020

Textbook descriptions of primary sensory cortex (PSC) revolve around single neurons’ representation of low-dimensional sensory features, such as visual object orientation in V1, location of somatic touch in S1, and sound frequency in A1. Typically, studies of PSC measure neurons’ responses along few (1 or 2) stimulus and/or behavioral dimensions. However, real-world stimuli usually vary along many feature dimensions and behavioral demands change constantly. In order to illuminate how A1 supports flexible perception in rich acoustic environments, we recorded from A1 neurons while rhesus macaques performed a feature-selective attention task. We presented sounds that varied along spectral and temporal feature dimensions (carrier bandwidth and temporal envelope, respectively). Within a block, subjects attended to one feature of the sound in a selective change detection task. We find that single neurons tend to be high-dimensional, in that they exhibit substantial mixed selectivity for both sound features, as well as task context. Contrary to common findings in many previous experiments, attention does not enhance the single-neuron representation of attended features in our data. However, a population-level analysis reveals that ensembles of neurons exhibit enhanced encoding of attended sound features, and this population code tracks subjects’ performance. Importantly, surrogate neural populations with intact single-neuron tuning but shuffled higher-order correlations among neurons failed to yield attention-related effects observed in the intact data. These results suggest that an emergent population code not measurable at the single-neuron level might constitute the functional unit of sensory representation in PSC.

SIGNIFICANCE STATEMENT

The ability to adapt to a dynamic sensory environment promotes a range of important natural behaviors. We recorded from single neurons in monkey primary auditory cortex while subjects attended to either the spectral or temporal features of complex sounds. Surprisingly, we find no average increase in responsiveness to, or encoding of, the attended feature across single neurons. However, when we pool the activity of the sampled neurons via targeted dimensionality reduction, we find enhanced population-level representation of the attended feature and suppression of the distractor feature. This dissociation of the effects of attention at the level of single neurons vs. the population highlights the synergistic nature of cortical sound encoding and enriches our understanding of sensory cortical function.
Universal principles of lineage architecture and stem cell identity in renewing tissues
Authors: Greulich Philip , MacArthur Ben D. , Parigini Cristina , Sánchez-García Rubén J.
Published: March 2020

Adult tissues in multicellular organisms typically contain a variety of stem, progenitor and differentiated cell types arranged in a lineage hierarchy that regulates healthy tissue turnover and repair. Lineage hierarchies in disparate tissues often exhibit common features, yet the general principles regulating their architecture are not known. Here, we provide a formal framework for understanding the relationship between cell molecular ‘states’ (patterns of gene, protein expression etc. in the cell) and cell ‘types’ that uses notions from network science to decompose the structure of cell state trajectories into functional units. Using this framework we show that many widely experimentally observed features of cell lineage architectures – including the fact that a single adult stem cell type always resides at the apex of a lineage hierarchy – arise as a natural consequence of homeostasis, and indeed are the only possible way that lineage architectures can be constructed to support homeostasis in renewing tissues. Furthermore, under suitable feedback regulation, for example from the stem cell niche, we show that the property of ‘stemness’ is entirely determined by the cell environment. Thus, we argue that stem cell identities are contextual and not determined by hard-wired, cell-intrinsic, characteristics.
Transcriptome analysis of IPF fibroblastic foci identifies key pathways involved in fibrogenesis
Authors: Guillotin Delphine , Taylor Adam R. , Platé Manuela , Mercer Paul F. , Edwards Lindsay M. , Haggart Ross , Miele Gino , McAnulty Robin J. , Maher Toby M. , Hynds Robert E. , Jamal-Hanjani Mariam , Marshall Richard P. , Fisher Andrew J. , Blanchard Andy D. , Chambers Rachel C.
Published: March 2020

Fibroblastic foci (FF) represent the cardinal pathogenic lesion in idiopathic pulmonary fibrosis (IPF) and comprise activated fibroblasts and myofibroblasts, the key effector cells responsible for dysregulated extracellular matrix deposition in multiple fibrotic conditions. The aim of this study was to define the major transcriptional programmes involved in fibrogenesis in IPF by profiling un-manipulated myo/fibroblasts within FFin situby laser capture microdissection.

The challenges associated with deriving gene calls from low amounts of RNA and the absence of a meaningful comparator cell type were overcome by adopting novel data mining strategies and by using weighted gene co-expression network analysis (WGCNA), as well as aneigengene-based approach to identify transcriptional signatures which correlate with fibrillar collagen gene expression. WGCNA identified prominent clusters of genes associated with cell cycle, inflammation/differentiation, translation and cytoskeleton/cell adhesion. Collageneigengeneanalysis revealed that TGF-β1, RhoA kinase and the TSC2/RHEB axis formed major signalling clusters associated with collagen gene expression. Functional studies using CRISPR-Cas9 gene edited cells demonstrated a key role for the TSC2/RHEB axis in regulating TGF-β1-induced mTORC1 activation and collagen I deposition in mesenchymal cells reflecting IPF and other disease settings, including cancer-associated fibroblasts. These data provide strong support for the human tissue-based and bioinformatics approaches adopted to identify critical transcriptional nodes associated with the key pathogenic cell responsible for fibrogenesisin situand further identifies the TSC2/RHEB axis as a potential novel target for interfering with excessive matrix deposition in IPF and other fibrotic conditions.

What is the key question?

Can we identify a transcriptional signature associated with collagen gene expression in the fibrotic focus, the cardinal fibrotic lesion in IPF?

What is the bottom line?

We herein define the major transcriptional programmes involved in fibrogenesis in IPF by profiling myo/fibroblasts within FFin situby laser capture microdissection.

Why read on?

The data provide strong support for a human tissue-based approach to identify critical transcriptional nodes associated with fibrogenesisin situand further identifies the TSC2/RHEB axis as a potential novel target for interfering with excessive matrix deposition in IPF and other fibrotic conditions.
In vivocharacterization of chick embryo mesoderm by optical coherence tomography assisted microindentation
Authors: Marrese Marica , Antonovaité Nelda , Nelemans Ben K.A. , Ahmadzada Ariana , Iannuzzi Davide , Smit Theodoor H.
Published: March 2020

Embryos are growing organisms with highly heterogeneous properties in space and time. Understanding the mechanical properties is a crucial prerequisite for the investigation of morphogenesis. During the last ten years, new techniques have been developed to evaluate the mechanical properties of biological tissuesin vivo. To address this need, we employed a new instrument that, via the combination of micro-indentation with Optical Coherence Tomography (OCT), allows us to determine both, the spatial distribution of mechanical properties of chick embryos and the structural changes in real-time provided by OCT. We report here the stiffness measurements on live chicken mesoderm during somite formation, from the mesenchymal tailbud to the epithelialized somites. The storage modulus of the mesoderm increases from (176±18) Pa in the tail up to (716±117) Pa in the somitic region. The midline has a storage modulus of (947±111) Pa in the caudal presomitic mesoderm, indicating a stiff rod along the body axis, which thereby mechanically supports the surrounding tissue. The difference in stiffness between midline and presomitic mesoderm decreases as the mesoderm forms somites. The viscoelastic response of the somites develops further until somite IV, which is commensurate with the slow process of epithelization of somites between S0 and SIV.

Overall, this study provides an efficient method for the biomechanical characterization of soft biological tissuesin vivoand shows that the mechanical properties strongly relate to different morphological features of the investigated regions.