bluuebunny/crossref_metadata_2025 huggingface dataset:
Moderately and Late Preterm Infants: Short- and Long-Term Outcomes From a Registry-Based Cohort
Authors: Smyrni Nikoletta , Koutsaki Maria , Petra Marianna , Nikaina Eirini , Gontika Maria , Strataki Helen , Davora Fotini , Bouza Helen , Damianos George , Skouteli Helen , Mastroyianni Sotiria , Dalivigka Zoi , Dinopoulos Argyris , Tzaki Margarita , Papavasiliou Antigone
Published: February 2021

Background:While most studies on the association of preterm birth and cerebral palsy (CP) have focused on very preterm infants, lately, attention has been paid to moderately preterm [32 to <34 weeks gestational age (GA)] and late preterm infants (34 to <37 weeks GA).

Methods:In order to report on the outcomes of a cohort of moderately and late preterm infants, derived from a population-based CP Registry, a comparative analysis of data on 95 moderately preterm infants and 96 late preterm infants out of 1,016 with CP, was performed.

Results:Moderately preterm neonates with CP were more likely to have a history of N-ICU admission (p= 0.001) and require respiratory support (p< 0.001) than late preterm neonates. Birth weight was significantly related to early neonatal outcome with children with lower birth weight being more likely to have a history of N-ICU admission [moderately preterm infants (p= 0.006)/late preterm infants (p< 0.001)], to require ventilator support [moderately preterm infants (p= 0.025)/late preterm infants (p= 0.014)] and not to have neonatal seizures [moderately preterm infants (p= 0.044)/late preterm infants (p= 0.263)]. In both subgroups, the majority of children had bilateral spastic CP with moderately preterm infants being more likely to have bilateral spastic CP and less likely to have ataxic CP as compared to late preterm infants (p= 0.006). The prevailing imaging findings were white matter lesions in both subgroups, with statistically significant difference between moderately preterm infants who required ventilator support and mainly presented with this type of lesion vs. those who did not and presented with gray matter lesions, maldevelopments or miscellaneous findings. Gross motor function was also assessed in both subgroups without significant difference. Among late preterm infants, those who needed N-ICU admission and ventilator support as neonates achieved worse fine motor outcomes than those who did not.

Conclusions:Low birth weight is associated with early neonatal problems in both moderately and late preterm infants with CP. The majority of children had bilateral spastic CP and white matter lesions in neuroimaging. GMFCS levels were comparable in both subgroups while BFMF was worse in late preterm infants with a history of N-ICU admission and ventilator support.
Seizure Clusters, Seizure Severity Markers, and SUDEP Risk
Authors: Ochoa-Urrea Manuela , Lacuey Nuria , Vilella Laura , Zhu Liang , Jamal-Omidi Shirin , Rani M. R. Sandhya , Hampson Johnson P. , Dayyani Mojtaba , Hampson Jaison , Hupp Norma J. , Tao Shiqiang , Sainju Rup K. , Friedman Daniel , Nei Maromi , Scott Catherine , Allen Luke , Gehlbach Brian K. , Reick-Mitrisin Victoria , Schuele Stephan , Ogren Jennifer , Harper Ronald M. , Diehl Beate , Bateman Lisa M. , Devinsky Orrin , Richerson George B. , Zhang Guo-Qiang , Lhatoo Samden D.
Published: February 2021

Rationale: Seizure clusters may be related to Sudden Unexpected Death in Epilepsy (SUDEP). Two or more generalized convulsive seizures (GCS) were captured during video electroencephalography in 7/11 (64%) patients with monitored SUDEP in the MORTEMUS study. It follows that seizure clusters may be associated with epilepsy severity and possibly with SUDEP risk. We aimed to determine if electroclinical seizure features worsen from seizure to seizure within a cluster and possible associations between GCS clusters, markers of seizure severity, and SUDEP risk.

Methods: Patients were consecutive, prospectively consented participants with drug-resistant epilepsy from a multi-center study. Seizure clusters were defined as two or more GCS in a 24-h period during the recording of prolonged video-electroencephalography in the Epilepsy monitoring unit (EMU). We measured heart rate variability (HRV), pulse oximetry, plethysmography, postictal generalized electroencephalographic suppression (PGES), and electroencephalography (EEG) recovery duration. A linear mixed effects model was used to study the difference between the first and subsequent seizures, with a level of significance set at p < 0.05.

Results: We identified 112 GCS clusters in 105 patients with 285 seizures. GCS lasted on average 48.7 ± 19 s (mean 49, range 2–137). PGES emerged in 184 (64.6%) seizures and postconvulsive central apnea (PCCA) was present in 38 (13.3%) seizures. Changes in seizure features from seizure to seizure such as seizure and convulsive phase durations appeared random. In grouped analysis, some seizure features underwent significant deterioration, whereas others improved. Clonic phase and postconvulsive central apnea (PCCA) were significantly shorter in the fourth seizure compared to the first. By contrast, duration of decerebrate posturing and ictal central apnea were longer. Four SUDEP cases in the cluster cohort were reported on follow-up.

Conclusion: Seizure clusters show variable changes from seizure to seizure. Although clusters may reflect epilepsy severity, they alone may be unrelated to SUDEP risk. We suggest a stochastic nature to SUDEP occurrence, where seizure clusters may be more likely to contribute to SUDEP if an underlying progressive tendency toward SUDEP has matured toward a critical SUDEP threshold.
Personalized Virtual Reality Human-Computer Interaction for Psychiatric and Neurological Illnesses: A Dynamically Adaptive Virtual Reality Environment That Changes According to Real-Time Feedback From Electrophysiological Signal Responses
Authors: Kritikos Jacob , Alevizopoulos Georgios , Koutsouris Dimitris
Published: February 2021

Virtual reality (VR) constitutes an alternative, effective, and increasingly utilized treatment option for people suffering from psychiatric and neurological illnesses. However, the currently available VR simulations provide a predetermined simulative framework that does not take into account the unique personality traits of each individual; this could result in inaccurate, extreme, or unpredictable responses driven by patients who may be overly exposed and in an abrupt manner to the predetermined stimuli, or result in indifferent, almost non-existing, reactions when the stimuli do not affect the patients adequately and thus stronger stimuli are recommended. In this study, we present a VR system that can recognize the individual differences and readjust the VR scenarios during the simulation according to the treatment aims. To investigate and present this dynamically adaptive VR system we employ an Anxiety Disorder condition as a case study, namely arachnophobia. This system consists of distinct anxiety states, aiming to dynamically modify the VR environment in such a way that it can keep the individual within a controlled, and appropriate for the therapy needs, anxiety state, which will be called “desired states” for the study. This happens by adjusting the VR stimulus, in real-time, according to the electrophysiological responses of each individual. These electrophysiological responses are collected by an external electrodermal activity biosensor that serves as a tracker of physiological changes. Thirty-six diagnosed arachnophobic individuals participated in a one-session trial. Participants were divided into two groups, the Experimental Group which was exposed to the proposed real-time adaptive virtual simulation, and the Control Group which was exposed to a pre-recorded static virtual simulation as proposed in the literature. These results demonstrate the proposed system’s ability to continuously construct an updated and adapted virtual environment that keeps the users within the appropriately chosen state (higher or lower intensity) for approximately twice the time compared to the pre-recorded static virtual simulation. Thus, such a system can increase the efficiency of VR stimulations for the treatment of central nervous system dysfunctions, as it provides numerically more controlled sessions without unexpected variations.
The Neural Correlates of Cued Reward Omission
Authors: Mollick Jessica A. , Chang Luke J. , Krishnan Anjali , Hazy Thomas E. , Krueger Kai A. , Frank Guido K. W. , Wager Tor D. , O’Reilly Randall C.
Published: February 2021

Compared to our understanding of positive prediction error signals occurring due to unexpected reward outcomes, less is known about the neural circuitry in humans that drives negative prediction errors during omission of expected rewards. While classical learning theories such as Rescorla–Wagner or temporal difference learning suggest that both types of prediction errors result from a simple subtraction, there has been recent evidence suggesting that different brain regions provide input to dopamine neurons which contributes to specific components of this prediction error computation. Here, we focus on the brain regions responding to negative prediction error signals, which has been well-established in animal studies to involve a distinct pathway through the lateral habenula. We examine the activity of this pathway in humans, using a conditioned inhibition paradigm with high-resolution functional MRI. First, participants learned to associate a sensory stimulus with reward delivery. Then, reward delivery was omitted whenever this stimulus was presented simultaneously with a different sensory stimulus, the conditioned inhibitor (CI). Both reward presentation and the reward-predictive cue activated midbrain dopamine regions, insula and orbitofrontal cortex. While we found significant activity at an uncorrected threshold for the CI in the habenula, consistent with our predictions, it did not survive correction for multiple comparisons and awaits further replication. Additionally, the pallidum and putamen regions of the basal ganglia showed modulations of activity for the inhibitor that did not survive the corrected threshold.
Evaluation of Task fMRI Decoding With Deep Learning on a Small Sample Dataset
Authors: Yotsutsuji Sunao , Lei Miaomei , Akama Hiroyuki
Published: February 2021

Recently, several deep learning methods have been applied to decoding in task-related fMRI, and their advantages have been exploited in a variety of ways. However, this paradigm is sometimes problematic, due to the difficulty of applying deep learning to high-dimensional data and small sample size conditions. The difficulties in gathering a large amount of data to develop predictive machine learning models with multiple layers from fMRI experiments with complicated designs and tasks are well-recognized. Group-level, multi-voxel pattern analysis with small sample sizes results in low statistical power and large accuracy evaluation errors; failure in such instances is ascribed to the individual variability that risks information leakage, a particular issue when dealing with a limited number of subjects. In this study, using a small-size fMRI dataset evaluating bilingual language switch in a property generation task, we evaluated the relative fit of different deep learning models, incorporating moderate split methods to control the amount of information leakage. Our results indicated that using the session shuffle split as the data folding method, along with the multichannel 2D convolutional neural network (M2DCNN) classifier, recorded the best authentic classification accuracy, which outperformed the efficiency of 3D convolutional neural network (3DCNN). In this manuscript, we discuss the tolerability of within-subject or within-session information leakage, of which the impact is generally considered small but complex and essentially unknown; this requires clarification in future studies.
Investigation of Risperidone Treatment Associated With Enhanced Brain Activity in Patients Who Stutter
Authors: Maguire Gerald A. , Yoo Bo Ram , SheikhBahaei Shahriar
Published: February 2021

Stuttering is a childhood onset fluency disorder that leads to impairment in speech. A randomized, double-blinded placebo-controlled study was conducted with 10 adult subjects to observe the effects of risperidone (a dopamine receptor 2/serotonin receptor 2 antagonist) on brain metabolism, using [18F] deoxyglucose as the marker. At baseline and after 6 weeks of taking risperidone (0.5–2.0 mg/day) or a placebo pill, participants were assigned to a solo reading aloud task for 30 min and subsequently underwent a 90-min positron emission tomography scan. Pairedt-tests were performed to compare the pre-treatment vs. post-treatment in groups. After imaging and analysis, the blind was broken, which revealed an equal number of subjects of those on risperidone and those on placebo. There were no significant differences in the baseline scans taken before medication randomization. However, scans taken after active treatment demonstrated higher glucose uptake in the specific regions of the brain for those in the risperidone treatment group (p< 0.05). Risperidone treatment was associated with increased metabolism in the left striatum, which consists of the caudate and putamen, and the Broca’s area. The current study strengthens previous research that suggests the role of elevated dopamine activity and striatal hypometabolism in stuttering. We propose that the mechanism of risperidone’s action in stuttering, in part, involves increased metabolism of striatal astrocytes. We conclude that using neuroimaging techniques to visualize changes in the brain of those who stutter can provide valuable insights into the pathophysiology of the disorder and guide the development of future interventions.
The Neural Mechanisms of Tinnitus: A Perspective From Functional Magnetic Resonance Imaging
Authors: Hu Jinghua , Cui Jinluan , Xu Jin-Jing , Yin Xindao , Wu Yuanqing , Qi Jianwei
Published: February 2021

Tinnitus refers to sound perception in the absence of external sound stimulus. It has become a worldwide problem affecting all age groups especially the elderly. Tinnitus often accompanies hearing loss and some mood disorders like depression and anxiety. The comprehensive adverse effects of tinnitus on people determine the severity of tinnitus. Understanding the mechanisms of tinnitus and related discomfort may be beneficial to the prevention and treatment, and then getting patients out of tinnitus distress. Functional magnetic resonance imaging (fMRI) is a powerful technique for characterizing the intrinsic brain activity and making us better understand the tinnitus neural mechanism. In this article, we review fMRI studies published in recent years on the neuroimaging mechanisms of tinnitus. The results have revealed various neural network alterations in tinnitus patients, including the auditory system, limbic system, default mode network, attention system, and some other areas involved in memory, emotion, attention, and control. Moreover, changes in functional connectivity and neural activity in these networks are related to the perception, persistence, and severity of tinnitus. In summary, the neural mechanism of tinnitus is a complex regulatory mechanism involving multiple networks. Future research is needed to study these neural networks more accurately to refine the tinnitus models.
Protein Aggregation Inhibitors as Disease-Modifying Therapies for Polyglutamine Diseases
Authors: Minakawa Eiko N. , Nagai Yoshitaka
Published: February 2021

The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases caused by the abnormal expansion of a CAG trinucleotide repeat that are translated into an expanded polyQ stretch in the disease-causative proteins. The expanded polyQ stretch itself plays a critical disease-causative role in the pathomechanisms underlying polyQ diseases. Notably, the expanded polyQ stretch undergoes a conformational transition from the native monomer into the β-sheet-rich monomer, followed by the formation of soluble oligomers and then insoluble aggregates with amyloid fibrillar structures. The intermediate soluble species including the β-sheet-rich monomer and oligomers exhibit substantial neurotoxicity. Therefore, protein conformation stabilization and aggregation inhibition that target the upstream of the insoluble aggregate formation would be a promising approach toward the development of disease-modifying therapies for polyQ diseases. PolyQ aggregation inhibitors of different chemical categories, such as intrabodies, peptides, and small chemical compounds, have been identified through intensive screening methods. Among them, recent advances in the brain delivery methods of several peptides and the screening of small chemical compounds have brought them closer to clinical utility. Notably, the recent discovery of arginine as a potent conformation stabilizer and aggregation inhibitor of polyQ proteins both in vitro and in vivo have paved way to the clinical trial for the patients with polyQ diseases. Meanwhile, expression reduction of expanded polyQ proteins per se would be another promising approach toward disease modification of polyQ diseases. Gene silencing, especially by antisense oligonucleotides (ASOs), have succeeded in reducing the expression of polyQ proteins in the animal models of various polyQ diseases by targeting the aberrant mRNA with expanded CAG repeats. Of note, some of these ASOs have recently been translated into clinical trials. Here we overview and discuss these recent advances toward the development of disease modifying therapies for polyQ diseases. We envision that combination therapies using aggregation inhibitors and gene silencing would meet the needs of the patients with polyQ diseases and their caregivers in the near future to delay or prevent the onset and progression of these currently intractable diseases.
Preoptic Area Modulation of Arousal in Natural and Drug Induced Unconscious States
Authors: Reitz Sarah L. , Kelz Max B.
Published: February 2021

The role of the hypothalamic preoptic area (POA) in arousal state regulation has been studied since Constantin von Economo first recognized its importance in the early twentieth century. Over the intervening decades, the POA has been shown to modulate arousal in both natural (sleep and wake) as well as drug-induced (anesthetic-induced unconsciousness) states. While the POA is well known for its role in sleep promotion, populations of wake-promoting neurons within the region have also been identified. However, the complexity and molecular heterogeneity of the POA has made distinguishing these two populations difficult. Though multiple lines of evidence demonstrate that general anesthetics modulate the activity of the POA, the region’s heterogeneity has also made it challenging to determine whether the same neurons involved in sleep/wake regulation also modulate arousal in response to general anesthetics. While a number of studies show that sleep-promoting POA neurons are activated by various anesthetics, recent work suggests this is not universal to all arousal-regulating POA neurons. Technical innovations are making it increasingly possible to classify and distinguish the molecular identities of neurons involved in sleep/wake regulation as well as anesthetic-induced unconsciousness. Here, we review the current understanding of the POA’s role in arousal state regulation of both natural and drug-induced forms of unconsciousness, including its molecular organization and connectivity to other known sleep and wake promoting regions. Further insights into the molecular identities and connectivity of arousal-regulating POA neurons will be critical in fully understanding how this complex region regulates arousal states.
Sex-Dependent Dyslipidemia and Neuro-Humoral Alterations Leading to Further Cardiovascular Risk in Juvenile Obesity
Authors: Simoes Estefania , Correia-Lima Joanna , Calfat Elie Leal de Barros , Otani Thais Zélia dos Santos , Vasques Daniel Augusto Correa , Otani Victor Henrique Oyamada , Bertolazzi Pamela , Kochi Cristiane , Seelaender Marilia , Uchida Ricardo Riyoiti
Published: February 2021

Objective: Childhood obesity is a growing concern as the World Health Organization (WHO) states that ~10% of adolescents worldwide are overweight or obese. This condition is the reflex of energy imbalance between the calories consumed and those expended. Sex-related responses associated with dyslipidemia, hormonal alterations, and neuro-humoral disruptions in childhood obesity are the focus of the present investigation.

Methods: Ninety-two Brazilian adolescents were enrolled and divided between obese and eutrophic groups. Obesity was assessed using body mass index Z-score according to age and weight. Anthropometrical analyses, blood pressure, blood lipids, metabolism-regulating hormones, and neuropeptides were carried out.

Results: Systolic blood pressure was higher in female and male patients with obesity. Obese females presented alterations in lipid profile and an augment of cardiovascular disease prediction ratios TC/HDL, TG/HDL, LDL/HDL, and VLDL/HDL. The levels of leptin, GIP, and neuropeptide showed sex-dimorphism in obesity. The obese adolescents presented increased levels of circulating insulin, c-peptide, amylin, glucagon, and GLP-1. Correlation analysis showed significant linearity between body mass index, blood pressure, lipids, lipoproteins, hormones, and neuropeptides content.

Conclusions: Our data support an existing link associating hypertension, dyslipidemia, and neuro-hormonal imbalance in childhood obesity. We also described a sex-dependent pattern in childhood obesity-associated dyslipidemia and blood pressure in female patients with obesity solely.
Influence of Facial Morphology on Masticatory Function and Quality of Life in Elders Using Mandibular Overdentures: 3-Year Results
Authors: Possebon Anna Paula da Rosa , Schuster Alessandra Julie , Marcello-Machado Raissa Micaella , Martins Ana Paula Pinto , Pinto Luciana de Rezende , Chagas-Júnior Otacílio Luiz , Del Bel Cury Altair Antoninha , Faot Fernanda
Published: February 2021

Background: Facial types may interfere in the oral health-related quality of life (OHRQoL) and masticatory performance of implant-retained mandibular overdenture (IMO) wearers.

Purpose: Investigate the medium-term changes in the masticatory function (MF) and OHRQoL parameters of IMO users, as a function of facial pattern, anteroposterior skeletal discrepancy, and sex.

Methods: Forty IMO users, most of them Caucasian (90%) with average age of 69.17 years were classified according to their facial pattern and antero-posterior discrepancy prior to rehabilitation. MF was evaluated by the multiple sieves method to determine the average particle size (X50), heterogeneity (B) and masticatory efficiency (ME, calculated as the percentage of material retained in the 5.6 and 2.8 mm sieves), using Masticatory performance (MP) and swallowing threshold (ST) tests. OHRQoL was measured by applying the dental impact on daily life (DIDL) questionnaire. The data were analyzed by Wilcoxon-paired tests to analyze changes in MF parameters over time, and mixed-effect multilevel regression models were employed to verify differences between groups.

Results: Significant changes were still observed in the 3rd year for the ST test with improvements in B for Mesofacial and in time for Dolichofacial individuals, while ME_2.8 deteriorated for Brachyfacial participants. B values of Class I and male individuals improved and brachyfacial individuals still presented worse homogenization (B) than Mesofacial participants in both masticatory tests. Class II and III participants still showed improvements in ME_5.6 and time compared to Class I despite increases in X50. Class II individuals needed less cycles than Class I in the 3rd year. Brachyfacial participants scored lower in the Appearance domain than Mesofacial ones in the 3rd year. Dolichofacial participants and Class III patients scored lower in the Oral Comfort domain than Mesofacial and Class I, respectively. In addition, age influenced the Pain, Oral Comfort and General Performance domains in the 3rd year.

Conclusions: Differences in facial morphology continue to influence the MF and OHRQoL outcomes in the 3rd year, and age influenced some OHRQoL domains. Brachyfacial individuals continue to benefit least from rehabilitation with IMO according to masticatory parameters.
Application of Radiomics Analysis Based on CT Combined With Machine Learning in Diagnostic of Pancreatic Neuroendocrine Tumors Patient’s Pathological Grades
Authors: Zhang Tao , Zhang YueHua , Liu Xinglong , Xu Hanyue , Chen Chaoyue , Zhou Xuan , Liu Yichun , Ma Xuelei
Published: February 2021

Purpose

To evaluate the value of multiple machine learning methods in classifying pathological grades (G1,G2, and G3), and to provide the best machine learning method for the identification of pathological grades of pancreatic neuroendocrine tumors (PNETs) based on radiomics.

Materials and Methods

A retrospective study was conducted on 82 patients with Pancreatic Neuroendocrine tumors. All patients had definite pathological diagnosis and grading results. Using Lifex software to extract the radiomics features from CT images manually. The sensitivity, specificity, area under the curve (AUC) and accuracy were used to evaluate the performance of the classification model.

Result

Our analysis shows that the CT based radiomics features combined with multi algorithm machine learning method has a strong ability to identify the pathological grades of pancreatic neuroendocrine tumors. DC + AdaBoost, DC + GBDT, and Xgboost+RF were very valuable for the differential diagnosis of three pathological grades of PNET. They showed a strong ability to identify the pathological grade of pancreatic neuroendocrine tumors. The validation set AUC of DC + AdaBoost is 0.82 (G1 vs G2), 0.70 (G2 vs G3), and 0.85 (G1 vs G3), respectively.

Conclusion

In conclusion, based on enhanced CT radiomics features could differentiate between different pathological grades of pancreatic neuroendocrine tumors. Feature selection method Distance Correlation + classifier method Adaptive Boosting show a good application prospect.
Polysaccharides From Lentinus Edodes Inhibits Lymphangiogenesis via the Toll-Like Receptor 4/JNK Pathway of Cancer-Associated Fibroblasts
Authors: Wang Yuanyuan , Zeng Yanqiong , Zhu Linyu , Wan Jiajia , Lei Ningjing , Yao Xiaohan , Duan Xixi , Zhang Yana , Cheng Yanru , Tao Ning , Qin Zhihai
Published: February 2021

Polysaccharides from Lentinus edodes (L. edodes) have been successfully used as adjuvant chemotherapy drug to treat lymphatic metastasis in some malignancies, such as colorectal cancer (CRC), lung cancer and gastric cancer. The CRC could metastasize via lymphatic vessels. Lymphatic metastasis is commonly thought to be the cause of poor prognosis of CRC. The mechanism of polysaccharides from L. edodes inhibiting lymphatic metastasis of CRC is still unclear. In this study, we explored how MPSSS, a novel polysaccharide component of L. edodes, influences lymphangiogenesis and lymph node metastasis. The results show that MPSSS can reduce lymphangiogenesis and lymphatic metastasis of CRC in mouse model. And combined with in vitro study, a likely mechanism is that MPSSS reduce the secretion of VEGF-C by cancer associated fibroblasts (CAFs). This effect can be suppressed by a TLR4 inhibitor, which suggests that MPSSS plays a role in CAFs through the TLR4/JNK signaling pathway. In conclusion, MPSSS may reduce lymphangiogenesis by decreasing the VEGF-C secretion of CAFs, which may provide a new strategy for the comprehensive treatment of CRC.
Combined High-Dose LATTICE Radiation Therapy and Immune Checkpoint Blockade for Advanced Bulky Tumors: The Concept and a Case Report
Authors: Jiang Liuqing , Li Xiaobo , Zhang Jianping , Li Wenyao , Dong Fangfen , Chen Cheng , Lin Qingliang , Zhang Chonglin , Zheng Fen , Yan Weisi , Zheng Yi , Wu Xiaodong , Xu Benhua
Published: February 2021

Although the combination of immune checkpoint blockades with high dose of radiation has indicated the potential of co-stimulatory effects, consistent clinical outcome has been yet to be demonstrated. Bulky tumors present challenges for radiation treatment to achieve high rate of tumor control due to large tumor sizes and normal tissue toxicities. As an alternative, spatially fractionated radiotherapy (SFRT) technique has been applied, in the forms of GRID or LATTICE radiation therapy (LRT), to safely treat bulky tumors. When used alone in a single or a few fractions, GRID or LRT can be best classified as palliative or tumor de-bulking treatments. Since only a small fraction of the tumor volume receive high dose in a SFRT treatment, even with the anticipated bystander effects, total tumor eradications are rare. Backed by the evidence of immune activation of high dose radiation, it is logical to postulate that the combination of High-Dose LATTICE radiation therapy (HDLRT) with immune checkpoint blockade would be effective and could subsequently lead to improved local tumor control without added toxicities, through augmenting the effects of radiation in-situ vaccine and T-cell priming. We herein present a case of non-small cell lung cancer (NSCLC) with multiple metastases. The patient received various types of palliative radiation treatments with combined chemotherapies and immunotherapies to multiple lesions. One of the metastatic lesions measuring 63.2 cc was treated with HDLRT combined with anti-PD1 immunotherapy. The metastatic mass regressed 77.84% over one month after the treatment, and had a complete local response (CR) five months after the treatment. No treatment-related side effects were observed during the follow-up exams. None of the other lesions receiving palliative treatments achieved CR. The dramatic differential outcome of this case lends support to the aforementioned postulate and prompts for further systemic clinical studies.
Prognostic Nomogram for Sorafenib Benefit in Hepatitis B Virus-Related Hepatocellular Carcinoma After Partial Hepatectomy
Authors: Dong Wei , Yan Kai , Yu Hua , Huo Lei , Xian Zhihong , Zhao Yanqing , Li Jutang , Zhang Yuchan , Cao Zhenying , Fu Yong , Cong Wenming , Dong Hui
Published: February 2021

Background

Predicting the long-term prognosis of individuals who experienced sorafenib treatment following partial hepatectomy due to hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) is difficult. This work aims to create an effective prognostic nomogram for HBV related HCC patients who are receiving sorafenib treatment as adjuvant therapy after surgery.

Methods

A total of 233 HBV-related HCC patients treated with or without sorafenib following partial hepatectomy at the Eastern Hepatobiliary Surgery Hospital from 2008 to 2013 were matched with propensity score matching analysis. The optimal cut-off point of the overall survival (OS) factor level was determined by x-tile. The selection of indicators was based on clinical findings. The Cox regression model with an interaction term was employed for evaluating the predictive value. Using a multivariate Cox proportional hazards model, a nomogram was subsequently formulated to analyze 111 patients treated with sorafenib. The nomogram’s discriminative ability and predictive accuracy were determined using the concordance index (C-index), calibration, and ROC curve.

Results

The matched sorafenib cohort of 111 patients and control cohort of 118 patients were analyzed. Subgroup analysis revealed that low GPC3, pERK, pAKT, serum AFP levels, without MVI, under 50 years old, male, TNM stage I/II and BCLC stage 0/A were significantly associated with a better OS in patients subjected to sorafenib treatment compared to those without sorafenib treatment after surgery. Multivariate analysis of the sorafenib cohort revealed GPC3, pERK, pAKT, serum AST, and BCLC stage as independent factors for OS, and all were included in the nomogram. The survival probability based on the calibration curve showed that the prediction of the nomogram was in good agreement with the actual observation. The C-index of the nomogram for predicting survival was 0.73(95% CI, 0.67–0.78). The area under the ROC curve (AUC) for the nomogram to predict the survival for 1, 3, and 5-year was 0.726, 0.816, and 0.823, respectively.

Conclusion

This proposed nomogram shows the potential to make a precise prediction regarding the prognosis of HBV-related HCC patients and may help to stratify patients for personalized therapy following partial hepatectomy.
Doxycycline Inhibits Cancer Stem Cell-Like Properties via PAR1/FAK/PI3K/AKT Pathway in Pancreatic Cancer
Authors: Liu Huijuan , Tao Honglian , Wang Hongqi , Yang Yuyan , Yang Ru , Dai Xintong , Ding Xiujuan , Wu Haidong , Chen Shuang , Sun Tao
Published: February 2021

Pancreatic cancer stem cells (CSCs) play an important role in the promotion of invasion and metastasis of pancreatic cancer. Protease activation receptor 1 (PAR1) is closely related to malignant progression of tumors, however, its effects on pancreatic cancer stem cell-like (CSC-like) properties formation have not been reported. In this work, the effects of PAR1 on pancreatic cancer stem cell-like (CSC-like) properties formation were studied. PAR1 overexpression can induce CSC-like properties in Aspc-1 cells, whereas interference of PAR1 in Panc-1 cells showed the contrary results. Data on patients with pancreatic cancer obtained from TCGA showed that high PAR1 expression and focal adhesion kinase (FAK) protein considerably affect the prognosis of patients. Further experiments showed that PAR1 could regulate FAK, PI3K, and AKT phosphorylation and the epithelial–mesenchymal transformation (EMT) in Aspc-1 and Panc-1 cells. Doxycycline, as a PAR1 inhibitor, could effectively inhibit the CSC-like properties of pancreatic cancer cells and the FAK/PI3K/AKT pathway activation. Doxycycline inhibits the growth of pancreatic cancer and enhances the treatment effect of 5-fluorouracil (5-FU) in Panc-1 xenograft mouse model. In conclusion, PAR1 promotes the CSC-like properties and EMT of pancreatic cancer cells via the FAK/PI3K/AKT pathway. Doxycycline inhibits the pancreatic cancer through the PAR1/FAK/PI3K/AKT pathway and enhances the therapeutic effect of 5-FU.
A Prospective Controlled Study on Long-Term Outcomes of Facial Lacerations in Children
Authors: Fontana Sonja , Schiestl Clemens M. , Landolt Markus A. , Staubli Georg , von Salis Sara , Neuhaus Kathrin , Mohr Christoph , Elrod Julia
Published: February 2021

Background: Although skin adhesives have been used for decades to treat skin lacerations, uncertainty remains about long-term results, and complications.

Methods: In this prospective, controlled, single-blinded, observational cohort study, outcomes were assessed by five plastic surgeons with standardized photographs at 6–12 months using a modified Patient and Observer Scar Assessment Scale (POSAS) and Vancouver Scar Scale (VSS); additionally, the POSAS was performed by the patients/caregivers and the physician; pain, requirement of anesthesia, treatment time, costs, complications, and quality of live (QoL) were assessed.

Results: A total of 367 patients were enrolled; 230 were included in the main analysis; 96 wounds were closed using tissue adhesives (group 1); 134 were sutured (group 2). Assessment by the independent observers revealed an improved mean modified overall POSAS score in group 1 in comparison with group 2 [2.1, 95% CI [1.97–2.25] vs. 2.5, 95% CI [2.39–2.63]; p < 0.001, d = 0.58] and mean VSS score [1.2, 95% CI [0.981–1.34] vs. 1.6, 95% CI [1.49–1.79], p < 0.001, d = 0.53]. At the early follow-up, dehiscence rate was 12.5% in group 1 and 3.7% in group 2 (p < 0.001); later on, one dehiscence remained per group. Mild impairment of QoL was found at the early follow-up in both groups, with no impairment remaining later on. Duration of treatment and treatment costs were lower in group 1.

Conclusion: Both modalities of wound closure yield favorable esthetic results, and complications are rare. Adhesives are more cost-effective, and its application is less time-consuming; therefore, tissue adhesives offer considerable advantages when used appropriately.

Trial Registration: Public trial registration was performed at www.ClinicalTrials.gov (Identifier: NCT03080467).
Sex-Specific Survival, Growth, Immunity and Organ Development in Preterm Pigs as Models for Immature Newborns
Authors: Bæk Ole , Cilieborg Malene Skovsted , Nguyen Duc Ninh , Bering Stine Brandt , Thymann Thomas , Sangild Per Torp
Published: February 2021

Background: After very preterm birth, male infants show higher mortality than females, with higher incidence of lung immaturity, neurological deficits, infections, and growth failure. In modern pig production, piglets dying in the perinatal period (up to 20%) often show signs of immature organs, but sex-specific effects are not clear. Using preterm pigs as model for immature infants and piglets, we hypothesized that neonatal survival and initial growth and immune development depend on sex.

Methods: Using data from a series of previous intervention trials with similar delivery and rearing procedures, we established three cohorts of preterm pigs (90% gestation), reared for 5, 9, or 19 days before sample collection (total n = 1,938 piglets from 109 litters). Partly overlapping endpoints among experiments allowed for multiple comparisons between males and females for data on mortality, body and organ growth, gut, immunity, and brain function.

Results: Within the first 2 days, males showed higher mortality than females (18 vs. 8%, P < 0.001), but less severe immune response to gram-positive infection. No effect of sex was observed for thermoregulation or plasma cortisol. Later, infection resistance did not differ between sexes, but growth rate was reduced for body (up to −40%) and kidneys (−6%) in males, with higher leucocyte counts (+15%) and lower CD4 T cell fraction (−5%) on day 9 and lower monocyte counts (−18%, day 19, all P < 0.05). Gut structure, function and necrotizing enterocolitis (NEC) incidence were similar between groups, but intestinal weight (−3%) and brush-border enzyme activities were reduced at day 5 (lactase, DPP IV, −8%) in males. Remaining values for blood biochemistry, hematology, bone density, regional brain weights, and visual memory (tested in a T maze) were similar.

Conclusion: Following preterm birth, male pigs show higher mortality and slower growth than females, despite limited differences in organ growth, gut, immune, and brain functions. Neonatal intensive care procedures may be particularly important for compromised newborns of the male sex. Preterm pigs can serve as good models to study the interactions of sex- and maturation-specific survival and physiological adaptation in mammals.
Return of Spontaneous Circulation Depends on Cardiac Rhythm During Neonatal Cardiac Arrest in Asphyxiated Newborn Animals
Authors: Wagner Michael , Cheung Po-Yin , Yaskina Maryna , Lee Tze-Fun , Vieth Vanessa A. , O'Reilly Megan , Schmölzer Georg M.
Published: February 2021

Objective: Pulseless electrical activity (PEA) occurs in asphyxiated newborn piglets and infants. We aimed to examine whether different cardiac rhythms (asystole, bradycardia, PEA) affects the resuscitation outcomes during continuous chest compressions (CC) during sustained inflations (CC+SI).

Design: This study is a secondary analysis of four previous randomized controlled animal trials that compared CC+SI with different CC rate (90 or 120/min), SI duration (20 or 60 s), peak inflation pressure (10, 20, or 30 cmH2O), and oxygen concentration (18, 21, or 100%).

Setting and Subjects: Sixty-six newborn mixed breed piglets (1–3 days of age, weight 1.7–2.4 kg) were obtained on the day of experimentation from the University Swine Research Technology Center.

Interventions: In all four studies, piglets were randomized into intervention or sham. Piglets randomized to “intervention” underwent both hypoxia and asphyxia, whereas, piglets randomized to “sham” received the same surgical protocol, stabilization, and equivalent experimental periods without hypoxia and asphyxia.

Measurements: To compare differences in asphyxiation time, time to return of spontaneous circulation (ROSC), hemodynamics, and survival rate in newborn piglets with asystole, bradycardia or PEA.

Main Results: Piglets with PEA (n = 29) and asystole (n = 13) had a significantly longer asphyxiation time and time to ROSC vs. bradycardia (n = 24). Survival rates were similar between all groups. Compared to their baseline, mean arterial pressure and carotid blood flow were significantly lower 4 h after resuscitation in all groups, while being significantly higher in the bradycardia group.

Conclusion: This study indicates that cardiac rhythm before resuscitation influences the time to ROSC and hemodynamic recovery after ROSC.
Protective Effect of Adenosine A2B Receptor Agonist, BAY60-6583, Against Transient Focal Brain Ischemia in Rat
Authors: Dettori Ilaria , Gaviano Lisa , Ugolini Filippo , Lana Daniele , Bulli Irene , Magni Giada , Rossi Francesca , Giovannini Maria Grazia , Pedata Felicita
Published: February 2021

Cerebral ischemia is a multifactorial pathology characterized first by an acute injury, due to excitotoxicity, followed by a secondary brain injury that develops hours to days after ischemia. During ischemia, adenosine acts as an endogenous neuroprotectant. Few studies have investigated the role of A2B receptor in brain ischemia because of the low potency of adenosine for it and the few selective ligands developed so far. A2B receptors are scarcely but widely distributed in the brain on neurons, glial and endothelial cells and on hematopoietic cells, lymphocytes and neutrophils, where they exert mainly anti-inflammatory effects, inhibiting vascular adhesion and inflammatory cells migration. Aim of this work was to verify whether chronic administration of the A2B agonist, BAY60-6583 (0.1 mg/kg i.p., twice/day), starting 4 h after focal ischemia induced by transient (1 h) Middle Cerebral Artery occlusion (tMCAo) in the rat, was protective after the ischemic insult. BAY60-6583 improved the neurological deficit up to 7 days after tMCAo. Seven days after ischemia BAY60-6583 reduced significantly the ischemic brain damage in cortex and striatum, counteracted ischemia-induced neuronal death, reduced microglia activation and astrocytes alteration. Moreover, it decreased the expression of TNF-α and increased that of IL-10 in peripheral plasma. Two days after ischemia BAY60-6583 reduced blood cell infiltration in the ischemic cortex. The present study indicates that A2B receptors stimulation can attenuate the neuroinflammation that develops after ischemia, suggesting that A2B receptors may represent a new interesting pharmacological target to protect from degeneration after brain ischemia.
Neuroprotective Role of GLP-1 Analog for Retinal Ganglion Cells via PINK1/Parkin-Mediated Mitophagy in Diabetic Retinopathy
Authors: Zhou Huan-ran , Ma Xue-fei , Lin Wen-jian , Hao Ming , Yu Xin-yang , Li Hong-xue , Xu Cheng-ye , Kuang Hong-yu
Published: February 2021

GLP-1 analogs have been widely used to treat patients with type 2 diabetes in recent years and studies have found that GLP-1 analogs have multiple organ benefits. However, the role of GLP-1 analogs in diabetic retinopathy (DR), a common complication of diabetes mellitus (DM), remains controversial. Retinal ganglion cells (RGCs) are the only afferent neurons responsible for transmitting visual information to the visual center and are vulnerable in the early stage of DR. Protection of RGC is vital for visual function. The incretin glucagon-like peptide-1 (GLP-1), which is secreted by L-cells after food ingestion, could lower blood glucose level through stimulating the release of insulin. In the present study, we evaluated the effects of GLP-1 analog on RGCs both in vitro and in vivo. We established diabetic rat models in vivo and applied an RGC-5 cell line in vitro. The results showed that in high glucose conditions, GLP-1 analog alleviated the damage of RGCs. In addition, GLP-1 analog prevented mitophagy through the PINK1/Parkin pathway. Here we demonstrated the neuroprotective effect of GLP-1 analog, which may be beneficial for retinal function, and we further elucidated a novel mechanism in GLP-1 analog-regulated protection of the retina. These findings may expand the multi-organ benefits of GLP-1 analogs and provide new insights for the prevention of DR.
Saikosaponin D Rescues Deficits in Sexual Behavior and Ameliorates Neurological Dysfunction in Mice Exposed to Chronic Mild Stress
Authors: Wang Zhuo , Li Jianwei , Wu Wei , Qi Tao , Huang Zhansen , Wang Bo , Li Shixiong , Li Chen , Ding Jiuyang , Zeng Yuanning , Huang Peng , Zhou Zhihua , Huang Yanjun , Huang Jian , Wang Xiaohan , Huang Qiyuan , Zhang Guanghuan , Qiu Pingming , Chen Jun
Published: February 2021

Often associated with sexual dysfunction (SD), chronic stress is the main contributing risk factor for the pathogenesis of depression. Radix bupleuri had been widely used in traditional Chinese medicine formulation for the regulation of emotion and sexual activity. As the main active component of Radix bupleuri, saikosaponin D (SSD) has a demonstrated antidepressant effect in preclinical studies. Herein, we sought to investigate the effect of SSD to restore sexual functions in chronically stressed mice and elucidate the potential brain mechanisms that might underly these effects. SSD was gavage administered for three weeks during the induction of chronic mild stress (CMS), and its effects on emotional and sexual behaviors in CMS mice were observed. The medial posterodorsal amygdala (MePD) was speculated to be involved in the manifestation of sexual dysfunctions in CMS mice. Our results revealed that SSD not only alleviated CMS-induced depressive-like behaviors but also rescued CMS-induced low sexual motivation and poor sexual performance. CMS destroyed astrocytes and activated microglia in the MePD. SSD treatment reversed the changes in glial pathology and inhibited neuroinflammatory and oxidative stress in the MePD of CMS mice. The neuronal morphological and functional deficits in the MePD were also alleviated by SSD administration. Our results provide insights into the central mechanisms involving the brain associated with sexual dysfunction. These findings deepen our understanding of SSD in light of the psychopharmacology of stress and sexual disorders, providing a theoretical basis for its potential clinical application.
The Role of Periprostatic Adipose Tissue on Prostate Function in Vascular-Related Disorders
Authors: Passos Gabriela Reolon , Ghezzi Ana Carolina , Antunes Edson , de Oliveira Mariana Gonçalves , Mónica Fabiola Zakia
Published: February 2021

The lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) are highly prevalent worldwide. Clinical and experimental data suggest that the incidence of LUTS-BPH is higher in patients with vascular-related disorders such as in pelvic ischemia, obesity and diabetes as well as in the ageing population. Obesity is an important risk factor that predisposes to glucose intolerance, insulin resistance, dyslipidemia, type 2 diabetes mellitus and cardiovascular disorders. Prospective studies showed that obese men are more likely to develop LUTS-BPH than non-obese men. Yet, men with greater waist circumferences were also at a greater risk of increased prostate volume and prostate-specific antigen than men with lower waist circumference. BPH is characterized by an enlarged prostate and increased smooth muscle tone, thus causing urinary symptoms. Data from experimental studies showed a significant increase in prostate and epididymal adipose tissue weight of obese mice when compared with lean mice. Adipose tissues that are in direct contact with specific organs have gained attention due to their potential paracrine role. The prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is believed to play a paracrine role by releasing growth factors, pro-inflammatory, pro-oxidant, contractile and anti-contractile substances that interfere in prostate reactivity and growth. Therefore, this review is divided into two main parts, one focusing on the role of adipokines in the context of obesity that can lead to LUTS/BPH and the second part focusing on the mediators released from PPAT and the possible pathways that may interfere in the prostate microenvironment.