bluuebunny/crossref_metadata_2025 huggingface dataset:
Marker-Less Motion Capture of Insect Locomotion With Deep Neural Networks Pre-trained on Synthetic Videos
Authors: Arent Ilja , Schmidt Florian P. , Botsch Mario , Dürr Volker
Published: April 2021

Motion capture of unrestrained moving animals is a major analytic tool in neuroethology and behavioral physiology. At present, several motion capture methodologies have been developed, all of which have particular limitations regarding experimental application. Whereas marker-based motion capture systems are very robust and easily adjusted to suit different setups, tracked species, or body parts, they cannot be applied in experimental situations where markers obstruct the natural behavior (e.g., when tracking delicate, elastic, and/or sensitive body structures). On the other hand, marker-less motion capture systems typically require setup- and animal-specific adjustments, for example by means of tailored image processing, decision heuristics, and/or machine learning of specific sample data. Among the latter, deep-learning approaches have become very popular because of their applicability to virtually any sample of video data. Nevertheless, concise evaluation of their training requirements has rarely been done, particularly with regard to the transfer of trained networks from one application to another. To address this issue, the present study uses insect locomotion as a showcase example for systematic evaluation of variation and augmentation of the training data. For that, we use artificially generated video sequences with known combinations of observed, real animal postures and randomized body position, orientation, and size. Moreover, we evaluate the generalization ability of networks that have been pre-trained on synthetic videos to video recordings of real walking insects, and estimate the benefit in terms of reduced requirement for manual annotation. We show that tracking performance is affected only little by scaling factors ranging from 0.5 to 1.5. As expected from convolutional networks, the translation of the animal has no effect. On the other hand, we show that sufficient variation of rotation in the training data is essential for performance, and make concise suggestions about how much variation is required. Our results on transfer from synthetic to real videos show that pre-training reduces the amount of necessary manual annotation by about 50%.
Dopaminergic Neuromodulation of Spike Timing Dependent Plasticity in Mature Adult Rodent and Human Cortical Neurons
Authors: Louth Emma Louise , Jørgensen Rasmus Langelund , Korshoej Anders Rosendal , Sørensen Jens Christian Hedemann , Capogna Marco
Published: April 2021

Synapses in the cerebral cortex constantly change and this dynamic property regulated by the action of neuromodulators such as dopamine (DA), is essential for reward learning and memory. DA modulates spike-timing-dependent plasticity (STDP), a cellular model of learning and memory, in juvenile rodent cortical neurons. However, it is unknown whether this neuromodulation also occurs at excitatory synapses of cortical neurons in mature adult mice or in humans. Cortical layer V pyramidal neurons were recorded with whole cell patch clamp electrophysiology and an extracellular stimulating electrode was used to induce STDP. DA was either bath-applied or optogenetically released in slices from mice. Classical STDP induction protocols triggered non-hebbian excitatory synaptic depression in the mouse or no plasticity at human cortical synapses. DA reverted long term synaptic depression to baseline in mouse via dopamine 2 type receptors or elicited long term synaptic potentiation in human cortical synapses. Furthermore, when DA was applied during an STDP protocol it depressed presynaptic inhibition in the mouse but not in the human cortex. Thus, DA modulates excitatory synaptic plasticity differently in human vs. mouse cortex. The data strengthens the importance of DA in gating cognition in humans, and may inform on therapeutic interventions to recover brain function from diseases.
Genetic Testing Contributes to Diagnosis in Cerebral Palsy: Aicardi-Goutières Syndrome as an Example
Authors: Beysen Diane , De Cordt Chania , Dielman Charlotte , Ogunjimi Benson , Dandelooy Julie , Reyniers Edwin , Janssens Katrien , Meuwissen Marije M.E.
Published: April 2021

Cerebral palsy (CP) is a non-progressive neurodevelopmental disorder characterized by motor impairments, often accompanied by co-morbidities such as intellectual disability, epilepsy, visual and hearing impairment and speech and language deficits. Despite the established role of hypoxic–ischemic injury in some CP cases, several studies suggest that birth asphyxia is actually an uncommon cause, accounting for <10% of CP cases. For children with CP in the absence of traditional risk factors, a genetic basis to their condition is increasingly suspected. Several recent studies indeed confirm copy number variants and single gene mutations with large genetic heterogeneity as an etiology in children with CP. Here, we report three patients with spastic cerebral palsy and a genetically confirmed diagnosis of Aicardi-Goutières syndrome (AGS), with highly variable phenotypes ranging from clinically suggestive to non-specific symptomatology. Our findings suggest that AGS may be a rather common cause of CP, that frequently remains undiagnosed without additional genetic testing, as in only one case a clinical suspicion of AGS was raised. Our data show that a diagnosis of AGS must be considered in cases with spastic CP, even in the absence of characteristic brain abnormalities. Importantly, a genetic diagnosis of AGS may have significant therapeutic consequences, as targeted therapies are being developed for type 1 interferonopathies, the group of diseases to which AGS belongs. Our findings demonstrate the importance of next generation sequencing in CP patients without an identifiable cause, since targeted diagnostic testing is hampered by the often non-specific presentation.
Intravenous Delayed Gadolinium-Enhanced MR Imaging of the Endolymphatic Space: A Methodological Comparative Study
Authors: Boegle Rainer , Gerb Johannes , Kierig Emilie , Becker-Bense Sandra , Ertl-Wagner Birgit , Dieterich Marianne , Kirsch Valerie
Published: April 2021

In-vivonon-invasive verification of endolymphatic hydrops (ELH) by means of intravenous delayed gadolinium (Gd) enhanced magnetic resonance imaging of the inner ear (iMRI) is rapidly developing into a standard clinical tool to investigate peripheral vestibulo-cochlear syndromes. In this context, methodological comparative studies providing standardization and comparability between labs seem even more important, but so far very few are available. One hundred eight participants [75 patients with Meniere's disease (MD; 55.2 ± 14.9 years) and 33 vestibular healthy controls (HC; 46.4 ± 15.6 years)] were examined. The aim was to understand (i) how variations in acquisition protocols influence endolymphatic space (ELS) MR-signals; (ii) how ELS quantification methods correlate to each other or clinical data; and finally, (iii) how ELS extent influences MR-signals. Diagnostics included neuro-otological assessment, video-oculography during caloric stimulation, head-impulse test, audiometry, and iMRI. Data analysis provided semi-quantitative (SQ) visual grading and automatic algorithmic quantitative segmentation of ELS area [2D, mm2] and volume [3D, mm3] using deep learning-based segmentation and volumetric local thresholding. Within the range of 0.1–0.2 mmol/kg Gd dosage and a 4 h ± 30 min time delay, SQ grading and 2D- or 3D-quantifications were independent of signal intensity (SI) and signal-to-noise ratio (SNR; FWE corrected,p< 0.05). The ELS quantification methods used were highly reproducible across raters or thresholds and correlated strongly (0.3–0.8). However, 3D-quantifications showed the least variability. Asymmetry indices and normalized ELH proved the most useful for predicting quantitative clinical data. ELH size influenced SI (cochlear basal turnp< 0.001), but not SNR. SI could not predict the presence of ELH. In conclusion, (1) Gd dosage of 0.1–0.2 mmol/kg after 4 h ± 30 min time delay suffices for ELS quantification. (2) A consensus is needed on a clinical SQ grading classification including a standardized level of evaluation reconstructed to anatomical fixpoints. (3) 3D-quantification methods of the ELS are best suited for correlations with clinical variables and should include both ears and ELS values reported relative or normalized to size. (4) The presence of ELH increases signal intensity in the basal cochlear turn weakly, but cannot predict the presence of ELH.
The Incidence of Stroke in Indigenous Populations of Countries With a Very High Human Development Index: A Systematic Review Protocol
Authors: Balabanski Anna H. , Dos Santos Angela , Woods John A. , Thrift Amanda G. , Kleinig Timothy J. , Suchy-Dicey Astrid , Siri Susanna Ragnhild , Boden-Albala Bernadette , Krishnamurthi Rita , Feigin Valery L. , Buchwald Dedra , Ranta Annemarei , Mienna Christina S. , Zavaleta Carol , Churilov Leonid , Burchill Luke , Zion Deborah , Longstreth W. T. , Tirschwell David L. , Anand Sonia , Parsons Mark W. , Brown Alex , Warne Donald K. , Harwood Matire , Katzenellenbogen Judith M.
Published: April 2021

Background and Aims: Despite known Indigenous health and socioeconomic disadvantage in countries with a Very High Human Development Index, data on the incidence of stroke in these populations are sparse. With oversight from an Indigenous Advisory Board, we will undertake a systematic review of the incidence of stroke in Indigenous populations of developed countries or regions, with comparisons between Indigenous and non-Indigenous populations of the same region, though not between different Indigenous populations.

Methods: Using PubMed, OVID-EMBASE, and Global Health databases, we will examine population-based incidence studies of stroke in Indigenous adult populations of developed countries published 1990-current, without language restriction. Non-peer-reviewed sources, studies including <10 Indigenous People, or with insufficient data to determine incidence, will be excluded. Two reviewers will independently validate the search strategies, screen titles and abstracts, and record reasons for rejection. Relevant articles will undergo full-text screening, with standard data extracted for all studies included. Quality assessment will include Sudlow and Warlow's criteria for population-based stroke incidence studies, the Newcastle-Ottawa Scale for risk of bias, and the CONSIDER checklist for Indigenous research.

Results: Primary outcomes include crude, age-specific and/or age-standardized incidence of stroke. Secondary outcomes include overall stroke rates, incidence rate ratio and case-fatality. Results will be synthesized in figures and tables, describing data sources, populations, methodology, and findings. Within-population meta-analysis will be performed if, and where, methodologically sound and comparable studies allow this.

Conclusion: We will undertake the first systematic review assessing disparities in stroke incidence in Indigenous populations of developed countries. Data outputs will be disseminated to relevant Indigenous stakeholders to inform public health and policy research.
The Brain Alteration of Seafarer Revealed by Activated Functional Connectivity Mode in fMRI Data Analysis
Authors: Shi Yuhu , Zeng Weiming , Wang Nizhuan
Published: April 2021

As a special occupational group, the working and living environments faced by seafarers are greatly different from those of land. It is easy to affect the psychological and physiological activities of seafarers, which inevitably lead to changes in the brain functional activities of seafarers. Therefore, it is of great significance to study the neural activity rules of seafarers’ brain. In view of this, this paper studied the seafarers’ brain alteration at the activated voxel level based on functional magnetic resonance imaging technology by comparing the differences in functional connectivities (FCs) between seafarers and non-seafarers. Firstly, the activated voxels of each group were obtained by independence component analysis, and then the distribution of these voxels in the brain and the common activated voxels between the two groups were statistically analyzed. Next, the FCs between the common activated voxels of the two groups were calculated and obtained the FCs that had significant differences between them through two-sample T-test. Finally, all FCs and FCs with significant differences (DFCs) between the common activated voxels were used as the features for the support vector machine to classify seafarers and non-seafarers. The results showed that DFCs between the activated voxels had better recognition ability for seafarers, especially for Precuneus_L and Precuneus_R, which may play an important role in the classification prediction of seafarers and non-seafarers, so that provided a new perspective for studying the specificity of neurological activities of seafarers.
Modulating Frontal Networks’ Timing-Dependent-Like Plasticity With Paired Associative Stimulation Protocols: Recent Advances and Future Perspectives
Authors: Guidali Giacomo , Roncoroni Camilla , Bolognini Nadia
Published: April 2021

Starting from the early 2000s, paired associative stimulation (PAS) protocols have been used in humans to study brain connectivity in motor and sensory networks by exploiting the intrinsic properties of timing-dependent cortical plasticity. In the last 10 years, PAS have also been developed to investigate the plastic properties of complex cerebral systems, such as the frontal ones, with promising results. In the present work, we review the most recent advances of this technique, focusing on protocols targeting frontal cortices to investigate connectivity and its plastic properties, subtending high-order cognitive functions like memory, decision-making, attentional, or emotional processing. Overall, current evidence reveals that PAS can be effectively used to assess, enhance or depress physiological connectivity within frontal networks in a timing-dependent way, in turn modulating cognitive processing in healthy and pathological conditions.
Single-Cell Transcriptomics: Current Methods and Challenges in Data Acquisition and Analysis
Authors: Adil Asif , Kumar Vijay , Jan Arif Tasleem , Asger Mohammed
Published: April 2021

Rapid cost drops and advancements in next-generation sequencing have made profiling of cells at individual level a conventional practice in scientific laboratories worldwide. Single-cell transcriptomics [single-cell RNA sequencing (SC-RNA-seq)] has an immense potential of uncovering the novel basis of human life. The well-known heterogeneity of cells at the individual level can be better studied by single-cell transcriptomics. Proper downstream analysis of this data will provide new insights into the scientific communities. However, due to low starting materials, the SC-RNA-seq data face various computational challenges: normalization, differential gene expression analysis, dimensionality reduction, etc. Additionally, new methods like 10× Chromium can profile millions of cells in parallel, which creates a considerable amount of data. Thus, single-cell data handling is another big challenge. This paper reviews the single-cell sequencing methods, library preparation, and data generation. We highlight some of the main computational challenges that require to be addressed by introducing new bioinformatics algorithms and tools for analysis. We also show single-cell transcriptomics data as a big data problem.
The Effects of Dynamic and Static Emotional Facial Expressions of Humans and Their Avatars on the EEG: An ERP and ERD/ERS Study
Authors: Sollfrank Teresa , Kohnen Oona , Hilfiker Peter , Kegel Lorena C. , Jokeit Hennric , Brugger Peter , Loertscher Miriam L. , Rey Anton , Mersch Dieter , Sternagel Joerg , Weber Michel , Grunwald Thomas
Published: April 2021

This study aimed to examine whether the cortical processing of emotional faces is modulated by the computerization of face stimuli (”avatars”) in a group of 25 healthy participants. Subjects were passively viewing 128 static and dynamic facial expressions of female and male actors and their respective avatars in neutral or fearful conditions. Event-related potentials (ERPs), as well as alpha and theta event-related synchronization and desynchronization (ERD/ERS), were derived from the EEG that was recorded during the task. All ERP features, except for the very early N100, differed in their response to avatar and actor faces. Whereas the N170 showed differences only for the neutral avatar condition, later potentials (N300 and LPP) differed in both emotional conditions (neutral and fear) and the presented agents (actor and avatar). In addition, we found that the avatar faces elicited significantly stronger reactions than the actor face for theta and alpha oscillations. Especially theta EEG frequencies responded specifically to visual emotional stimulation and were revealed to be sensitive to the emotional content of the face, whereas alpha frequency was modulated by all the stimulus types. We can conclude that the computerized avatar faces affect both, ERP components and ERD/ERS and evoke neural effects that are different from the ones elicited by real faces. This was true, although the avatars were replicas of the human faces and contained similar characteristics in their expression.
Impact of Intensive Gait Training With and Without Electromechanical Assistance in the Chronic Phase After Stroke–A Multi-Arm Randomized Controlled Trial With a 6 and 12 Months Follow Up
Authors: Palmcrantz Susanne , Wall Anneli , Vreede Katarina Skough , Lindberg Påvel , Danielsson Anna , Sunnerhagen Katharina S. , Häger Charlotte K. , Borg Jörgen
Published: April 2021

Introduction:Movement related impairments and limitations in walking are common long-term after stroke. This multi-arm randomized controlled trial explored the impact of training with an electromechanically assisted gait training (EAGT) system, i.e., the Hybrid Assistive Limb®(HAL), when integrated with conventional rehabilitation focused on gait and mobility.

Material and Methods:Participants, aged 18–70 years with lower extremity paresis but able to walk with manual support or supervision 1–10 years after stroke, were randomized to (A) HAL-training on a treadmill, combined with conventional rehabilitation interventions (HAL-group), or (B) conventional rehabilitation interventions only (Conventional group), 3 days/week for 6 weeks, or (C) no intervention (Control group). Participants in the Control group were interviewed weekly regarding their scheduled training. Primary outcome was endurance in walking quantified by the 6 Minute Walk Test (6MWT). A rater blinded to treatment allocation performed assessments pre- and post-intervention and at follow-ups at 6 and 12 months. Baseline assessment included the National Institute of Health Stroke Scale (NIHSS) and the Modified Ranking Scale (MRS). Secondary outcomes included the Fugl Meyer Assessment- Lower Extremity, 10 Meter Walk Test, Berg Balance Scale (BBS), Barthel Index (BI) and perceived mobility with the Stroke Impact Scale.

Results:A total of 48 participants completed the intervention period. The HAL-group walked twice as far as the Conventional group during the intervention. Post-intervention, both groups exhibited improved 6 MWT results, while the Control group had declined. A significant improvement was only found in the Conventional group and when compared to the Control group (Tukey HSDp= 0.022), and not between the HAL group and Conventional group (Tukey HSDp= 0.258) or the HAL- group and the Control group (Tukey HSDp= 0.447). There was also a significant decline in the Conventional group from post-intervention to 6 months follow up (p= 0.043). The best fitting model to predict outcome included initial balance (BBS), followed by stroke severity (NIHSS), and dependence in activity and participation (BI and MRS).

Conclusion:Intensive conventional gait training induced significant improvements long-term after stroke while integrating treadmill based EAGT had no additional value in this study sample. The results may support cost effective evidence-based interventions for gait training long-term after stroke and further development of EAGT.

Trial registration:Published onclinicaltrials.gov(NCT02545088) August 24, 2015.
Protect Others to Protect Myself: A Weakness of Western Countries in the Face of Current and Future Pandemics? Psychological and Neuroscientific Perspectives
Authors: Mermillod Martial , Morisseau Tiffany
Published: April 2021

The COVID-19 pandemic has generated a large number of publications in the medical and biological fields concerning the virus and its treatments, as well as in psychology, social sciences, and data sciences with regard to the spread of the virus. Surprisingly, far fewer neuroscientific articles have been published in this field of research and one might well ask whether the cognitive neurosciences have anything to say at all about this vital topic. In this article, we highlight a research perspective relating to differences in the individual perception of the pandemic in Western compared to Eastern countries. Although this problem is complex, multifaceted and subsumes many other social variables, we suggest that the cognitive neurosciences do have important and fundamental insights to contribute concerning the collective response observed within these populations. More precisely, we propose the hypothesis that differences in the propensity to adopt a holistic perception of contamination processes at the group level, involving brain structures that are also associated with perspective-taking and empathy such as, in particular, the medial prefrontal cortex (MPFC) and the anterior cingulate cortex (ACC), could help explain the differences in the perception of the pandemic observed between Western and Eastern countries.
Computed-Tomography-Based Radiomics Model for Predicting the Malignant Potential of Gastrointestinal Stromal Tumors Preoperatively: A Multi-Classifier and Multicenter Study
Authors: Wang Minhong , Feng Zhan , Zhou Lixiang , Zhang Liang , Hao Xiaojun , Zhai Jian
Published: April 2021

Background: Our goal was to establish and verify a radiomics risk grading model for gastrointestinal stromal tumors (GISTs) and to identify the optimal algorithm for risk stratification.

Methods: We conducted a retrospective analysis of 324 patients with GISTs, the presence of which was confirmed by surgical pathology. Patients were treated at three different hospitals. A training cohort of 180 patients was collected from the largest center, while an external validation cohort of 144 patients was collected from the other two centers. To extract radiomics features, regions of interest (ROIs) were outlined layer by layer along the edge of the tumor contour on CT images of the arterial and portal venous phases. The dimensionality of radiomic features was reduced, and the top 10 features with importance value above 5 were selected before modeling. The training cohort used three classifiers [logistic regression, support vector machine (SVM), and random forest] to establish three GIST risk stratification prediction models. The receiver operating characteristic curve (ROC) was used to compare model performance, which was validated by external data.

Results: In the training cohort, the average area under the curve (AUC) was 0.84 ± 0.07 of the logistic regression, 0.88 ± 0.06 of the random forest, and 0.81 ± 0.08 of the SVM. In the external validation cohort, the AUC was 0.85 of the logistic regression, 0.90 of the random forest, and 0.80 of the SVM. The random forest model performed the best in both the training and the external validation cohorts and could be generalized.

Conclusion: Based on CT radiomics, there are multiple machine-learning models that can predict the risk of GISTs. Among them, the random forest algorithm had the highest prediction efficiency and could be readily generalizable. Through external validation data, we assume that the random forest model may be used as an effective tool to guide preoperative clinical decision-making.
Cryptotanshinone Inhibits ERα-Dependent and -Independent BCRP Oligomer Formation to Reverse Multidrug Resistance in Breast Cancer
Authors: Ni Wenting , Fan Hui , Zheng Xiuqin , Xu Fangming , Wu Yuanyuan , Li Xiaoman , Wang Aiyun , Huang Shile , Chen Wenxing , Wang Shijun , Lu Yin
Published: April 2021

Both long-term anti-estrogen therapy and estrogen receptor-negative breast cancer contribute to drug resistance, causing poor prognosis in breast cancer patients. Breast cancer resistance protein (BCRP) plays an important role in multidrug resistance. Here, we show that cryptotanshinone (CPT), an anti-estrogen compound, inhibited the oligomer formation of BCRP on the cell membrane, thus blocking its efflux function. The inhibitory effect of CPT on BCRP was dependent on the expression level of estrogen receptor α (ERα) in ERα-positive breast cancer cells. Furthermore, ERα-negative breast cancer cells with high expression of BCRP were also sensitive to CPT because CPT was able to bind to BCRP and inhibit its oligomer formation on the cell membrane, suggesting that the high level of BCRP expression is crucial for CPT to reverse drug resistance. The combination of CPT and chemotherapeutic agents displayed enhanced anticancer effects. The results suggest that CPT is a novel BCRP inhibitor via blocking the oligomer formation of BCRP on the cell membrane. CPT is able to inhibit the activity of BCRP in an ERα-dependent and -independent manner, sensitizing breast cancer cells to chemotherapy.
Laparoscopic vs. Open Repeat Hepatectomy for Recurrent Liver Tumors: A Propensity Score–Matched Study and Meta-Analysis
Authors: Chen Jia-Feng , Fu Xiu-Tao , Gao Zheng , Shi Ying-Hong , Tang Zheng , Liu Wei-Ren , Zhang Xin , Gao Qiang , Ding Guang-Yu , Song Kang , Wang Xiao-Ying , Zhou Jian , Fan Jia , Ding Zhen-Bin
Published: April 2021

Background: It remains unclear whether the short-term benefits of laparoscopic repeat hepatectomy (LRH) accrue to patients with recurrent liver tumors. The present study aimed to report our own center's experience and perform a meta-analysis to evaluate the safety and feasibility of LRH in comparison with open repeat hepatectomy (ORH) for treating recurrent liver tumors.

Patients and Methods: A propensity score–matched study was performed including 426 patients receiving LRH or ORH for recurrent hepatocellular carcinoma between January 2017 and December 2018. Surgical outcomes and perioperative inflammation-based markers, including monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and systemic immune–inflammation index were collected from medical records and analyzed. Additionally, a systematic literature review was performed to identify relevant studies in PubMed, EMBASE, Web of Science, and Cochrane library databases up to October 1, 2020. Information including patient demographics, pathologic characteristics, and short-term outcomes was extracted and analyzed using random- or fixed-effects models.

Results: Of 68 LRHs, 57 were matched with an ORH finally. Our study demonstrated that LRH was significantly associated with less intraoperative blood loss (50 vs. 100 mL; P < 0.001), lower rate of hepatic inflow occlusion (10.52 vs. 33.3%; P = 0.003), and shorter postoperative hospital stay (5 vs. 6 days; P = 0.001) after 1:1 propensity score matching. The operation time, rate of blood transfusion, and postoperative complications were similar between the two groups. Moreover, all four inflammation-based markers were significantly lower in LRH group on postoperative day 1. In the meta-analysis, a total of 12 studies comprising 1,315 patients receiving repeat hepatectomy met the selection criteria. Similar to our own study, the meta-analysis showed shorter hospital stay [standard mean difference (SMD) = −0.51, 95% confidence interval (CI) = −0.79 to −0.22, P < 0.001], less intraoperative blood loss (SMD = −0.79, 95% CI = −1.11 to −0.47, P < 0.001), and lower rate of major postoperative complications [odds ratio (OR) = 0.35, 95% CI = 0.19–0.66, P = 0.001] in the LRH group. There was no difference in the field of overall postoperative complication and operation time between LRH and ORH groups.

Conclusion: Compared with ORH, LRH results in relatively better surgical outcomes and faster postoperative recovery. It could be considered a feasible and effective option for the treatment of recurrent liver tumors.
Extracellular Matrix: Emerging Roles and Potential Therapeutic Targets for Breast Cancer
Authors: Zhao Yunchun , Zheng Xiaoling , Zheng Yongquan , Chen Yue , Fei Weidong , Wang Fengmei , Zheng Caihong
Published: April 2021

Increasing evidence shows that the extracellular matrix (ECM) is an important regulator of breast cancer (BC). The ECM comprises of highly variable and dynamic components. Compared with normal breast tissue under homeostasis, the ECM undergoes many changes in composition and organization during BC progression. Induced ECM proteins, including fibrinogen, fibronectin, hyaluronic acid, and matricellular proteins, have been identified as important components of BC metastatic cells in recent years. These proteins play major roles in BC progression, invasion, and metastasis. Importantly, several specific ECM molecules, receptors, and remodeling enzymes are involved in promoting resistance to therapeutic intervention. Additional analysis of these ECM proteins and their downstream signaling pathways may reveal promising therapeutic targets against BC. These potential drug targets may be combined with new nanoparticle technologies. This review summarizes recent advances in functional nanoparticles that target the ECM to treat BC. Accurate nanomaterials may offer a new approach to BC treatment.
A Combined Prediction Model for Lymph Node Metastasis Based on a Molecular Panel and Clinicopathological Factors in Oral Squamous Cell Carcinoma
Authors: Wang Shu , Li Tiancheng , Liu Huan , Wei Wei , Yang Yang , Wang Chong , Li Bo , Han Zhengxue , Feng Zhien
Published: April 2021

Objective

Lymph node metastasis is the most important factor influencing the prognosis of oral squamous cell carcinoma (OSCC) patients. However, there is no proper method for predicting lymph node metastasis. This study aimed to construct and validate a preoperative prediction model for lymph node metastasis and guide personalized neck management based on the gene expression profile and clinicopathological parameters of OSCC.

Methods

Based on a previous study of related genes in OSCC, the mRNA expression of candidate genes was evaluated by real-time PCR in OSCC specimens. In this retrospective study, the gene expression profile and clinicopathological parameters of 112 OSCC patients were combined to construct the best prediction model for lymph node metastasis of OSCC. The model was validated with 95 OSCC samples in this study. Logistic regression analysis was used. The area under the curve (AUC) ultimately determined the diagnostic value of the prediction model.

Results

The two genes CDKN2A + PLAU were closely related to lymph node metastasis of oral squamous cell carcinoma. The model with the combination of CDKN2A, PLAU, T stage and pathological grade was the best in predicting lymph node metastasis (AUC = 0.807, 95% CI: 0.713-0.881, P=0.0001). The prediction model had a specificity of 96% and sensitivity of 72.73% for stage T1 and T2 OSCC (AUC = 0.855, 95% CI: 0.697-0.949, P=0.0001).

Conclusions

High expression of CDKN2A and PLAU was associated with lymph node metastasis in OSCC. The prediction model including CDKN2A, PLAU, T stage and pathological grade can be used as the best diagnostic model for lymph node metastasis in OSCC.
Lung Stereotactic Body Radiotherapy (SBRT) Using Spot-Scanning Proton Arc (SPArc) Therapy: A Feasibility Study
Authors: Liu Gang , Zhao Lewei , Qin An , Grills Inga , Deraniyagala Rohan , Stevens Craig , Zhang Sheng , Yan Di , Li Xiaoqiang , Ding Xuanfeng
Published: April 2021

Purpose

We developed a 4D interplay effect model to quantitatively evaluate breathing-induced interplay effects and assess the feasibility of utilizing spot-scanning proton arc (SPArc) therapy for hypo-fractionated lung stereotactic body radiotherapy (SBRT). The model was then validated by retrospective application to clinical cases.

Materials and Methods

A digital lung 4DCT phantoms was used to mimic targets in diameter of 3cm with breathing motion amplitudes: 5, 10, 15, and 20 mm, respectively. Two planning groups based on robust optimization were generated: (1) Two-field Intensity Modulated Proton Therapy (IMPT) plans and (2) SPArc plans via a partial arc. 5,000 cGy relative biological effectiveness (RBE) was prescribed to the internal target volume (ITV) in five fractions. To quantitatively assess the breathing induced interplay effect, the 4D dynamic dose was calculated by synchronizing the breathing pattern with the simulated proton machine delivery sequence, including IMPT, Volumetric repainting (IMPTvolumetric), iso-layered repainting (IMPTlayer) and SPArc. Ten lung patients’ 4DCT previously treated with VMAT SBRT, were used to validate the digital lung tumor model. Normal tissue complicated probability (NTCP) of chestwall toxicity was calculated.

Result

Target dose were degraded as the tumor motion amplitude increased. The 4D interplay effect phantom model indicated that motion mitigation effectiveness using SPArc was about five times of IMPTvolumetric or IMPTlayer using maximum MU/spot as 0.5 MU at 20 mm motion amplitude. The retrospective study showed that SPArc has an advantage in normal tissue sparing. The probability of chestwall’s toxicity were significantly improved from 40.2 ± 29.0% (VMAT) (p = 0.01) and 16.3 ± 12.0% (IMPT) (p = 0.01) to 10.1 ± 5.4% (SPArc). SPArc could play a significant role in the interplay effect mitigation with breathing-induced motion more than 20 mm, where the target D99 of 4D dynamic dose for patient #10 was improved from 4,514 ± 138 cGy [RBE] (IMPT) vs. 4,755 ± 129 cGy [RBE] (SPArc) (p = 0.01).

Conclusion

SPArc effectively mitigated the interplay effect for proton lung SBRT compared to IMPT with repainting and was associated with normal tissue sparing. This technology may make delivery of proton SBRT more technically feasible and less complex with fewer concerns over underdosing the target compared to other proton therapy techniques.
Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells
Authors: Tucci Jonathan , Chen Ting , Margulis Katherine , Orgel Etan , Paszkiewicz Rebecca L. , Cohen Michael D. , Oberley Matthew J. , Wahhab Rachel , Jones Anthony E. , Divakaruni Ajit S. , Hsu Cheng-Chih , Noll Sarah E. , Sheng Xia , Zare Richard N. , Mittelman Steven D.
Published: April 2021

Background

There is increasing evidence that adipocytes play an active role in the cancer microenvironment. We have previously reported that adipocytes interact with acute lymphoblastic leukemia (ALL) cells, contributing to chemotherapy resistance and treatment failure. In the present study, we investigated whether part of this resistance is due to adipocyte provision of lipids to ALL cells.

Methods

We cultured 3T3-L1 adipocytes, and tested whether ALL cells or ALL-released cytokines induced FFA release. We investigated whether ALL cells took up these FFA, and using fluorescent tagged BODIPY-FFA and lipidomics, evaluated which lipid moieties were being transferred from adipocytes to ALL. We evaluated the effects of adipocyte-derived lipids on ALL cell metabolism using a Seahorse XF analyzer and expression of enzymes important for lipid metabolism, and tested whether these lipids could protect ALL cells from chemotherapy. Finally, we evaluated a panel of lipid synthesis and metabolism inhibitors to determine which were affected by the presence of adipocytes.

Results

Adipocytes release free fatty acids (FFA) when in the presence of ALL cells. These FFA are taken up by the ALL cells and incorporated into triglycerides and phospholipids. Some of these lipids are stored in lipid droplets, which can be utilized in states of fuel deprivation. Adipocytes preferentially release monounsaturated FFA, and this can be attenuated by inhibiting the desaturating enzyme steroyl-CoA decarboxylase-1 (SCD1). Adipocyte-derived FFA can relieve ALL cell endogenous lipogenesis and reverse the cytotoxicity of pharmacological acetyl-CoA carboxylase (ACC) inhibition. Further, adipocytes alter ALL cell metabolism, shifting them from glucose to FFA oxidation. Interestingly, the unsaturated fatty acid, oleic acid, protects ALL cells from modest concentrations of chemotherapy, such as those that might be present in the ALL microenvironment. In addition, targeting lipid synthesis and metabolism can potentially reverse adipocyte protection of ALL cells.

Conclusion

These findings uncover a previously unidentified interaction between ALL cells and adipocytes, leading to transfer of FFA for use as a metabolic fuel and macromolecule building block. This interaction may contribute to ALL resistance to chemotherapy, and could potentially be targeted to improve ALL treatment outcome.
Morphine Suppresses Liver Cancer Cell Tumor Properties In Vitro and In Vivo
Authors: Zhang Hao-Wen , Wang Fei , Zhou Ya-Qun , Xu San-Ping , Yu Shi-Ying , Zhang Zhan-Guo
Published: April 2021

Morphine is an analgesic widely adopted to relieve cancer pain. A number of discrepancies, however, are presented by the published literature, with reports suggesting that opioids may either promote or inhibit the spread of cancer. It is of great significance to determine whether morphine may increase the risk of metastasis while utilized in liver cancer surgical treatment. In this study, we explore the effects of morphine on liver cancer cells in vitro and in vivo. Our results showed that morphine does not promote proliferative ability to cultured liver cancer cells. While morphine could increase the apoptosis rate of Hep3B/HepG2 cells. Furthermore, morphine could significantly inhibit the migratory and invasion ability of Hep3B/HepG2 cells. Subsequent investigations disclosed that morphine could inhibit sphere formation ability of Hep3B/HepG2 cells by using sphere formation assay. Based on nude mouse models, we demonstrated that morphine significantly reduced pulmonary tumorigenicity of Hep3B/HepG2 cells. In conclusion, our results found that morphine at clinical concentrations could suppress liver cancer cell tumor properties in vitro and in vivo, indicating the safety of morphine utilization in HCC patients’ pain management.
An Immune-Related lncRNA Expression Profile to Improve Prognosis Prediction for Lung Adenocarcinoma: From Bioinformatics to Clinical Word
Authors: Zhang Boxiang , Wang Rui , Li Kai , Peng Ziyang , Liu Dapeng , Zhang Yunfeng , Zhou Liuzhi
Published: April 2021

Background

Lung cancer is still the top-ranked cancer-related deaths all over the world. Now immunotherapy has emerged as a promising option for treating lung cancer. Recent evidence indicated that lncRNAs were also key regulators in immune system. We aimed to develop a novel prognostic signature based on the comprehensive analysis of immune-related lncRNAs to predict survival outcome of LUAD patients.

Methods

The gene expression profiles of 491 LUAD patients were downloaded from TCGA. 1047 immune-related lncRNAs were obtained through Pearson correlation analysis of immune genes and lncRNAs using statistical software R language. Univariate and multivariate Cox regression analysis were performed to determine the optimal immune-related lncRNAs prognostic signature (ITGCB-DT, ABALON, TMPO-AS1 and VIM-AS1). Finally, we validated the immune-related lncRNAs prognostic signature in The First Affiliated Hospital of Xi’an Jiaotong University cancer center cohort.

Results

A four immune-related lncRNAs prognostic signature was constructed to predict the survival outcome of LUAD patients. Statistical significance were found that the LUAD patients in high-risk group suffered shorter overall survival than those in low-risk group (P <0.001). ROC curve analysis shown that the four immune-related lncRNAs prognostic signature had the best predictive effect compared with age, gender, AJCC-stage, T stage, N stage, M stage (AUC = 0.756). More importantly, clinical cohort studies proved that the signature could predict the overall survival of LUAD patients with an AUC = 0.714.

Conclusions

In summary, we demonstrated that the novel immune-related lncRNAs signature had the ability to predict the prognosis of LUAD patients, which might serve as potential prognostic biomarkers and guide the individualized treatment strategies for LUAD patients.
Molecular Pathology of Pulmonary Large Cell Neuroendocrine Carcinoma: Novel Concepts and Treatments
Authors: Yoshimura Masayo , Seki Kurumi , Bychkov Andrey , Fukuoka Junya
Published: April 2021

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an aggressive neoplasm with poor prognosis. Histologic diagnosis of LCNEC is not always straightforward. In particular, it is challenging to distinguish small cell lung carcinoma (SCLC) or poorly differentiated carcinoma from LCNEC. However, histological classification for LCNEC as well as their therapeutic management has not changed much for decades. Recently, genomic and transcriptomic analyses have revealed different molecular subtypes raising hopes for more personalized treatment. Two main molecular subtypes of LCNEC have been identified by studies using next generation sequencing, namely type I with TP53 and STK11/KEAP1 alterations, alternatively called as non-SCLC type, and type II with TP53 and RB1 alterations, alternatively called as SCLC type. However, there is still no easy way to classify LCNEC subtypes at the actual clinical level. In this review, we have discussed histological diagnosis along with the genomic studies and molecular-based treatment for LCNEC.
Cardiovascular Pharmacological Support Among Preterm Infants in Chinese Referral Center Neonatal Intensive Care Units
Authors: Luo Ningxin , Jiang Siyuan , McNamara Patrick J. , Li Xiaoying , Guo Yan , Wang Yang , Han Junyan , Deng Yingping , Yang Yi , Lee Shoo K. , Cao Yun
Published: April 2021

Objective: To describe cardiovascular pharmacological support in infants born at <34 weeks' gestation within the first postnatal week in Chinese neonatal intensive care units (NICUs).

Design: A secondary analysis of data from a multicenter randomized controlled study (REIN-EPIQ). A questionnaire regarding cardiovascular support practices was also completed by all participating NICUs.

Setting: Twenty-five tertiary hospitals from 19 provinces in China.

Patients: All infants born at <34 weeks' gestation and admitted to participating NICUs within the first postnatal week from May 2015 to April 2018 were included. Infants who were discharged against medical advice were excluded.

Measures and Main Results: Among the 26,212 preterm infants <34 weeks, 16.1% received cardiovascular pharmacological support. The use rates increased with decreasing gestational age and birth weight, with 32.5% among infants <28 weeks and 35.9% among infants <1,000 g. Cardiovascular pharmacological support was independently associated with higher risks of death (aOR 2.8; 95% CI 2.4–3.3), severe intraventricular hemorrhage (IVH) (aOR 2.1; 95% CI 1.8–2.5) and bronchopulmonary dysplasia (BPD) (aOR 2.2; 95% CI 2.0–2.5). Overall 63.1% courses of cardiovascular pharmacological support were >3 days. Prolonged cardiovascular pharmacological support (>3 days) was independently associated with lower rates of survival without morbidity in very-low-birth-weight infants, compared with infants with shorter durations. Dopamine was the most commonly used cardiovascular agent. The cardiovascular pharmacological support rates varied from 1.9 to 65.8% among the participating NICUs.

Conclusions: The rate of cardiovascular pharmacological support within the first postnatal week was high with prolonged durations in Chinese NICUs. Marked variation in cardiovascular support existed among participating NICUs. Cardiovascular pharmacological support during the early postnatal period, especially prolonged, may be associated with adverse neonatal outcomes.

Clinical Trial Registration: The original trial was registered as “Reduction of Infection in Neonatal Intensive Care Units using the Evidence-based Practice for Improving Quality” (ID: NCT02600195) on clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02600195?term=NCT02600195&draw=2&rank=1.
Fecal and Duodenal Microbiota in Pediatric Celiac Disease
Authors: Abdukhakimova Diyora , Dossybayeva Kuanysh , Poddighe Dimitri
Published: April 2021

Background and Objective: The gut microbiota plays a role in regulating the host immunity. Therefore, alterations in gut microbiota (or dysbiosis) have been investigated in several gastrointestinal diseases, including Celiac Disease (CD). The aim of this study is to summarize the main characteristics of the gut microbiota in pediatric CD.

Methods: We performed a systematic review to retrieve the available studies investigating the gut microbiota in pediatric CD patients and controls. In detail, after the screening of >2,200 titles from the medical literature, 397 articles were assessed for eligibility based on the abstracts: of those, 114 full-text original articles were considered as eligible according to the aim of this systematic review.

Results: The final search output consisted of 18 articles describing the gut microbiota of CD children and including one or more control groups. Eleven pediatric studies provided information on the duodenal microbiota and as many investigated the fecal microbiota; three articles analyzed the microbiota on both fecal and duodenal samples from the same cohorts of patients.

Conclusion: Due to the heterogeneity of the experimental procedures and study design, it is not possible to evidence any specific celiac signature in the fecal and/or duodenal microbiota of CD children. However, some specific components of the fecal microbiota and, in detail, Bifidobacterium spp. (e.g., Bifidobacterium longum) may deserve additional research efforts, in order to understand their potential value as both probiotic therapy and diagnostic/prognostic biomarker.
Prevalence of and Trends in the Co-Existence of Obesogenic Behaviors in Adolescents From 15 Countries
Authors: Fan Hui , Zhang Xingyu
Published: April 2021

Background:The global epidemic of pediatric obesity is well-known, but data on co-existence of obesogenic behaviors are limited. We aim to report the prevalence of and trends in the co-existence of obesogenic behaviors in adolescents from 15 countries.

Methods:This study was based on the Global School-based Student Health Survey 2003–2017 and included 121,963 adolescents aged 12–15 years from 15 countries where at least 2 cross-sectional surveys were conducted. We used sampling weights and calculated the country-level prevalence of and trends in the co-existence of obesogenic behaviors (low fruit and vegetable intake, anxiety-induced insomnia, no physical activity, and sedentary behavior) during survey years. Pooled prevalence and trend estimates were calculated with random-effects models.

Results:Pooled prevalence of exposure ≥ 1, ≥2, and ≥3 obesogenic behaviors was 88.2, 44.9, and 9.8% in the first survey and 88.4, 46.4, and 10.2% in the last survey, respectively. Plateauing, increasing, and decreasing trends in the co-existence of obesogenic behaviors were observed in different countries. Specifically, we identified a plateauing pooled trend in the exposure ≥ 1, ≥2, and ≥3 obesogenic behaviors [odds ratios (95% confidence intervals): 1.03 (0.93, 1.14), 1.05 (0.97, 1.13), and 1.06 (0.95, 1.18), respectively].

Conclusion:Trends in the prevalence of the co-existence of obesogenic behaviors varied significantly across different countries, but the prevalence remained high in most countries. These findings suggest the need for behavioral interventions to mitigate obesogenic behaviors in adolescents for overweight and obesity prevention.