bluuebunny/crossref_metadata_2025 huggingface dataset:
A Contrast Augmentation Approach to Improve Multi-Scanner Generalization in MRI
Authors: Meyer Maria Ines , de la Rosa Ezequiel , Pedrosa de Barros Nuno , Paolella Roberto , Van Leemput Koen , Sima Diana M.
Published: September 2021

Most data-driven methods are very susceptible to data variability. This problem is particularly apparent when applying Deep Learning (DL) to brain Magnetic Resonance Imaging (MRI), where intensities and contrasts vary due to acquisition protocol, scanner- and center-specific factors. Most publicly available brain MRI datasets originate from the same center and are homogeneous in terms of scanner and used protocol. As such, devising robust methods that generalize to multi-scanner and multi-center data is crucial for transferring these techniques into clinical practice. We propose a novel data augmentation approach based on Gaussian Mixture Models (GMM-DA) with the goal of increasing the variability of a given dataset in terms of intensities and contrasts. The approach allows to augment the training dataset such that the variability in the training set compares to what is seen in real world clinical data, while preserving anatomical information. We compare the performance of a state-of-the-art U-Net model trained for segmenting brain structures with and without the addition of GMM-DA. The models are trained and evaluated on single- and multi-scanner datasets. Additionally, we verify the consistency of test-retest results on same-patient images (same and different scanners). Finally, we investigate how the presence of bias field influences the performance of a model trained with GMM-DA. We found that the addition of the GMM-DA improves the generalization capability of the DL model to other scanners not present in the training data, even when the train set is already multi-scanner. Besides, the consistency between same-patient segmentation predictions is improved, both for same-scanner and different-scanner repetitions. We conclude that GMM-DA could increase the transferability of DL models into clinical scenarios.
Lactobacillus paracasei Supplementation Prevents Early Life Stress-Induced Anxiety and Depressive-Like Behavior in Maternal Separation Model-Possible Involvement of Microbiota-Gut-Brain Axis in Differential Regulation of MicroRNA124a/132 and Glutamate Receptors
Authors: Karen Christopher , Shyu Douglas J. H. , Rajan Koilmani Emmanuvel
Published: September 2021

This study was designed to investigate stressful social experience (SSE) in early life by examining how it can induce alterations in the microbiota-gut-brain axis. To test this, different experimental groups of pups experienced the presence of either a stranger (S) with mother (M+P+S) or without their mother (MS+S−M). Animals were assessed for anxiety-like behavior and high-throughput bacterial 16s rRNA sequencing was performed to analyze the structure of the gut microbiota. Our analysis revealed that early life SSE induced anxiety-like behavior and reduced the diversity and richness of gut microbiota. In the second experiment, all groups were supplemented with Lactobacillus paracasei HT6. The findings indicated that Lactobacillus supplementation had a significant beneficial effect on anxiety-like behavior in stressed rats (MS, M+P+S, and MS + S−M) accompanied by normalized levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), glucocorticoid receptor (GR), serotonin (5-HT), dopamine (DA), and noradrenaline (NA). Concomitantly, the expression of microRNA (miR)-124a was down-regulated and miR-132, caspase-3, glutamate receptors (GluR1, GluR 2; NR2A, and NR2B) were up-regulated in stressed groups but remained unchanged by Lactobacillus supplementation in stressed individuals. This indicates that stress-associated GluR1-GR altered interactions can be significantly prevented by Lactobacillus supplementation. Analysis of the fecal metabolite profile was undertaken to analyze the effect of Lactobacillus, revealing that five predicted neuroactive microbial metabolites were reduced by early life SSE. Our results showed a potential link between Lactobacillus supplementation and beneficial effects on anxiety-like behavior, the mechanism of which could be potentially mediated through stress hormones, neurotransmitters, and expression of miRNAs, glutamate receptors, and the microbiota-gut-brain axis.
Can Haptic Stimulation Enhance Music Perception in Hearing-Impaired Listeners?
Authors: Fletcher Mark D.
Published: September 2021

Cochlear implants (CIs) have been remarkably successful at restoring hearing in severely-to-profoundly hearing-impaired individuals. However, users often struggle to deconstruct complex auditory scenes with multiple simultaneous sounds, which can result in reduced music enjoyment and impaired speech understanding in background noise. Hearing aid users often have similar issues, though these are typically less acute. Several recent studies have shown that haptic stimulation can enhance CI listening by giving access to sound features that are poorly transmitted through the electrical CI signal. This “electro-haptic stimulation” improves melody recognition and pitch discrimination, as well as speech-in-noise performance and sound localization. The success of this approach suggests it could also enhance auditory perception in hearing-aid users and other hearing-impaired listeners. This review focuses on the use of haptic stimulation to enhance music perception in hearing-impaired listeners. Music is prevalent throughout everyday life, being critical to media such as film and video games, and often being central to events such as weddings and funerals. It represents the biggest challenge for signal processing, as it is typically an extremely complex acoustic signal, containing multiple simultaneous harmonic and inharmonic sounds. Signal-processing approaches developed for enhancing music perception could therefore have significant utility for other key issues faced by hearing-impaired listeners, such as understanding speech in noisy environments. This review first discusses the limits of music perception in hearing-impaired listeners and the limits of the tactile system. It then discusses the evidence around integration of audio and haptic stimulation in the brain. Next, the features, suitability, and success of current haptic devices for enhancing music perception are reviewed, as well as the signal-processing approaches that could be deployed in future haptic devices. Finally, the cutting-edge technologies that could be exploited for enhancing music perception with haptics are discussed. These include the latest micro motor and driver technology, low-power wireless technology, machine learning, big data, and cloud computing. New approaches for enhancing music perception in hearing-impaired listeners could substantially improve quality of life. Furthermore, effective haptic techniques for providing complex sound information could offer a non-invasive, affordable means for enhancing listening more broadly in hearing-impaired individuals.
The Gut Microbiome and Substance Use Disorder
Authors: Russell Jordan T. , Zhou Yanjiao , Weinstock George M. , Bubier Jason A.
Published: September 2021

Substance use disorders (SUDs) remain a significant public health challenge, affecting tens of millions of individuals worldwide each year. Often comorbid with other psychiatric disorders, SUD can be poly-drug and involve several different substances including cocaine, opiates, nicotine, and alcohol. SUD has a strong genetic component. Much of SUD research has focused on the neurologic and genetic facets of consumption behavior. There is now interest in the role of the gut microbiome in the pathogenesis of SUD. In this review, we summarize current animal and clinical evidence that the gut microbiome is involved in SUD, then address the underlying mechanisms by which the gut microbiome interacts with SUD through metabolomic, immune, neurological, and epigenetic mechanisms. Lastly, we discuss methods using various inbred and outbred mice models to gain an integrative understanding of the microbiome and host genetic controls in SUD.
The Emerging Role of Neural Cell-Derived Exosomes in Intercellular Communication in Health and Neurodegenerative Diseases
Authors: Huo Luyao , Du Xinzhe , Li Xinrong , Liu Sha , Xu Yong
Published: September 2021

Intercellular communication in the central nervous system (CNS) is essential for brain growth, development, and homeostasis maintenance and, when dysfunctional, is involved in the occurrence and development of neurodegenerative diseases. Increasing evidence indicates that extracellular vesicles, especially exosomes, are critical mediators of intercellular signal transduction. Under physiological and pathological conditions, neural cells secret exosomes with the influence of many factors. These exosomes can carry specific proteins, lipids, nucleic acids, and other bioactive substances to the recipient cells to regulate their function. Depending on the CNS environment, as well as the origin and physiological or pathological status of parental cells, exosomes can mediate a variety of different effects, including synaptic plasticity, nutritional metabolic support, nerve regeneration, inflammatory response, anti-stress effect, cellular waste disposal, and the propagation of toxic components, playing an important role in health and neurodegenerative diseases. This review will discuss the possible roles of exosomes in CNS intercellular communication in both physiologic and neurodegenerative conditions.
Attentional Disengagement and the Locus Coeruleus – Norepinephrine System in Children With Autism Spectrum Disorder
Authors: Keehn Brandon , Kadlaskar Girija , Bergmann Sophia , McNally Keehn Rebecca , Francis Alexander
Published: September 2021

Background

Differences in non-social attentional functions have been identified as among the earliest features that distinguish infants later diagnosed with autism spectrum disorder (ASD), and may contribute to the emergence of core ASD symptoms. Specifically, slowed attentional disengagement and difficulty reorienting attention have been found across the lifespan in those at risk for, or diagnosed with, ASD. Additionally, the locus coeruleus-norepinephrine (LC-NE) system, which plays a critical role in arousal regulation and selective attention, has been shown to function atypically in ASD. While activity of the LC-NE system is associated with attentional disengagement and reorienting in typically developing (TD) individuals, it has not been determined whether atypical LC-NE activity relates to attentional disengagement impairments observed in ASD.

Objective

To examine the relationship between resting pupil diameter (an indirect measure of tonic LC-NE activation) and attentional disengagement in children with ASD.

Methods

Participants were 21 school-aged children with ASD and 20 age- and IQ-matched TD children. The study consisted of three separate experiments: a resting eye-tracking task and visual and auditory gap-overlap paradigms. For the resting eye-tracking task, pupil diameter was monitored while participants fixated a central crosshair. In the gap-overlap paradigms, participants were instructed to fixate on a central stimulus and then move their eyes to peripherally presented visual or auditory targets. Saccadic reaction times (SRT), percentage of no-shift trials, and disengagement efficiency were measured.

Results

Children with ASD had significantly larger resting pupil size compared to their TD peers. The groups did not differ for overall SRT, nor were there differences in SRT for overlap and gap conditions between groups. However, the ASD group did evidence impairments in disengagement (larger step/gap effects, higher percentage of no-shift trials, and reduced disengagement efficiency) compared to their TD peers. Correlational analyses showed that slower, less efficient disengagement was associated with increased pupil diameter.

Conclusion

Consistent with prior reports, children with ASD show significantly larger resting pupil diameter, indicative of atypically elevated tonic LC-NE activity. Associations between pupil size and measures of attentional disengagement suggest that atypically increased tonic activation of the LC-NE system may be associated with poorer attentional disengagement in children with ASD.
Plasma Lipolysis and Changes in Plasma and Cerebrospinal Fluid Signaling Lipids Reveal Abnormal Lipid Metabolism in Chronic Migraine
Authors: Castor Katherine , Dawlaty Jessica , Arakaki Xianghong , Gross Noah , Woldeamanuel Yohannes W. , Harrington Michael G. , Cowan Robert P. , Fonteh Alfred N.
Published: September 2021

Background

Lipids are a primary storage form of energy and the source of inflammatory and pain signaling molecules, yet knowledge of their importance in chronic migraine (CM) pathology is incomplete. We aim to determine if plasma and cerebrospinal fluid (CSF) lipid metabolism are associated with CM pathology.

Methods

We obtained plasma and CSF from healthy controls (CT,n= 10) or CM subjects (n= 15) diagnosed using the International Headache Society criteria. We measured unesterified fatty acid (UFA) and esterified fatty acids (EFAs) using gas chromatography-mass spectrometry. Glycerophospholipids (GP) and sphingolipid (SP) levels were determined using LC-MS/MS, and phospholipase A2(PLA2) activity was determined using fluorescent substrates.

Results

Unesterified fatty acid levels were significantly higher in CM plasma but not in CSF. Unesterified levels of five saturated fatty acids (SAFAs), eight monounsaturated fatty acids (MUFAs), five ω-3 polyunsaturated fatty acids (PUFAs), and five ω-6 PUFAs are higher in CM plasma. Esterified levels of three SAFAs, eight MUFAs, five ω-3 PUFAs, and three ω-6 PUFAs, are higher in CM plasma. The ratios C20:4n-6/homo-γ-C20:3n-6 representative of delta-5-desaturases (D5D) and the elongase ratio are lower in esterified and unesterified CM plasma, respectively. In the CSF, the esterified D5D index is lower in CM. While PLA2activity was similar, the plasma UFA to EFA ratio is higher in CM. Of all plasma GP/SPs detected, only ceramide levels are lower (p= 0.0003) in CM (0.26 ± 0.07%) compared to CT (0.48 ± 0.06%). The GP/SP proportion of platelet-activating factor (PAF) is significantly lower in CM CSF.

Conclusions

Plasma and CSF lipid changes are consistent with abnormal lipid metabolism in CM. Since plasma UFAs correspond to diet or adipose tissue levels, higher plasma fatty acids and UFA/EFA ratios suggest enhanced adipose lipolysis in CM. Differences in plasma and CSF desaturases and elongases suggest altered lipid metabolism in CM. A lower plasma ceramide level suggests reducedde novosynthesis or reduced sphingomyelin hydrolysis. Changes in CSF PAF suggest differences in brain lipid signaling pathways in CM. Together, this pilot study shows lipid metabolic abnormality in CM corresponding to altered energy homeostasis. We propose that controlling plasma lipolysis, desaturases, elongases, and lipid signaling pathways may relieve CM symptoms.
Neuronal Avalanches Across the Rat Somatosensory Barrel Cortex and the Effect of Single Whisker Stimulation
Authors: Mariani Benedetta , Nicoletti Giorgio , Bisio Marta , Maschietto Marta , Oboe Roberto , Leparulo Alessandro , Suweis Samir , Vassanelli Stefano
Published: September 2021

Since its first experimental signatures, the so called “critical brain hypothesis” has been extensively studied. Yet, its actual foundations remain elusive. According to a widely accepted teleological reasoning, the brain would be poised to a critical state to optimize the mapping of the noisy and ever changing real-world inputs, thus suggesting that primary sensory cortical areas should be critical. We investigated whether a single barrel column of the somatosensory cortex of the anesthetized rat displays a critical behavior. Neuronal avalanches were recorded across all cortical layers in terms of both multi-unit activities and population local field potentials, and their behavior during spontaneous activity compared to the one evoked by a controlled single whisker deflection. By applying a maximum likelihood statistical method based on timeseries undersampling to fit the avalanches distributions, we show that neuronal avalanches are power law distributed for both multi-unit activities and local field potentials during spontaneous activity, with exponents that are spread along a scaling line. Instead, after the tactile stimulus, activity switches to a transient across-layers synchronization mode that appears to dominate the cortical representation of the single sensory input.
Relationship Between Sleep–Wake Disturbance and Risk of Malnutrition in Hospitalized Patients With Cirrhosis
Authors: Hui Yangyang , Wang Xiaoyu , Yu Zihan , Feng Hongjuan , Li Chaoqun , Mao Lihong , Fan Xiaofei , Lin Lin , Cui Binxin , Chen Xin , Sun Longhao , Wang Bangmao , Sun Chao
Published: September 2021

Both sleep–wake disturbance and malnutrition are common in cirrhosis and might be associated with similar adverse outcomes, such as impaired health-related quality of life, hepatic encephalopathy, and sarcopenia, but there is no study investigating the relationship between these two. We aimed to explore the relationship between sleep–wake disturbance [estimated by the Pittsburgh Sleep Quality Index (PSQI)] and malnutrition risk [estimated by the Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT)]. About 150 patients with cirrhosis were prospectively recruited. The nutritional risk is classified as low (0 points), moderate (1 point), and high (2–7 points) according to the RFH-NPT score. A global PSQI >5 indicated poor sleepers. Furthermore, multivariate linear regression analyses were performed to determine the relationship betweensleep–wakedisturbance and malnutrition. The median PSQI was seven, and RFH-NPT was two in the entire cohort, with 60.67 and 56.67% rated as poor sleep quality and high malnutrition risk, respectively. Patients with cirrhosis with poor sleep quality had significantly higher RFH-NPT score (3 vs. 1,P= 0.007). Our multivariate analyses indicated that male patients (β = 0.279,P< 0.001), ascites (β = 0.210,P= 0.016), and PSQI (β = 0.262,P= 0.001) were independent predictors of malnutrition. In addition, the differences regarding PSQI score were more significant in male patients, as well as those >65 years or with Child-Turcotte-Pugh class A/B (CTP-A/B) or the median model for end-stage liver disease (MELD) <15. Taken together, the sleep–wake disturbance is strongly correlated with high malnutrition risk in patients with cirrhosis. Given sleep–wake disturbance is remediable, it is tempting to incorporate therapies to reverse poor sleep quality for improving nutritional status in patients with cirrhosis.
A Review on Extraction, Characterization, and Applications of Bioactive Peptides From Pressed Black Cumin Seed Cake
Authors: Zaky Ahmed A. , Shim Jae-Han , Abd El-Aty A. M.
Published: September 2021

Plenty of black cumin cake was generated as a natural waste material after pressing the oil. Nigella sativa (black cumin) seeds and cakes are of precious nutritional value as they contain proteins, phenolics, essential amino acids, and bioactive compounds. Owing to their antioxidant properties, scientists and food manufacturers have extensively developed them. Notably, global awareness among consumers about the benefits of innovative food ingredients has been increased. Meanwhile, it has to be noted that vast amounts of cake by-products are not effectively utilized, which might cause economic loss and environmental consequences. This review aimed to highlight the antioxidant abilities, extraction, characterization, functional characteristics, and utilization of active peptides acquired from black seed oil cake. This overview would critically evaluate black seed cake proteins, plentiful in bioactive peptides that might be utilized as valuable additives in feed, food, pharmaceutical, and cosmetic industries. The addition of bioactive peptides to restrain the oxidation of fat-based products and preserve food safety is also addressed.
Comprehensive Analysis of E2F Family Members in Human Gastric Cancer
Authors: Li Shengbo , Yang Xiaofan , Li Wenqing , Chen Zhenbing
Published: September 2021

Gastric cancer (GC) is the second most common cancer and the third most frequent cause of cancer-related deaths in China. E2Fs are a family of transcription factors reported to be involved in the tumor progression of various cancer types; however, the roles of individual E2Fs are still not known exactly in tumor progression of GC. In this study, we examined the expression of E2Fs to investigate their roles in tumor progression in GC patients using multiple databases, including ONCOMINE, GEPIA2, Kaplan-Meier plotter, cBioPortal, Metascape, LinkedOmics, GeneMANIA, STRING and UCSC Xena. We also performed real-time polymerase chain reaction (RT-PCR) to validate the expression levels of individual E2Fs in several GC cell lines. Our results demonstrated that the mRNA levels of E2F1/2/3/5/8 were significantly higher both in GC tissues and cell lines. The expression levels of E2F1 and E2F4 were correlated with poor overall survival (OS), decreased post-progression survival (PPS), and decreased progression-free survival (FP) in patients with GC. However, overexpression of E2F2, E2F5, E2F7 and E2F8 is significantly associated with disease-free survival and overall survival in patients with GC. In addition, higher E2F3 and E2F6 mRNA expression was found to increase GC patients’ OS and PPS. 224 of 415 patients with STAD (54%) had gene mutations that were associated with longer disease-free survival (DFS) but not OS. Cell cycle pathway was closely associated with mRNA level of more than half of E2Fs (E2F1/2/3/7/8). There were close and complicated interactions among E2F family members. Finally, our results indicated the gene expressions of E2Fs had a positive relationship with its copy numbers. Taken together, E2F1/2/3/5/8 can serve as biomarkers for GC patients with high prognostic value for OS of GC patients or therapeutic targets for GC.
Online Magnetic Resonance-Guided Radiotherapy (oMRgRT) for Gynecological Cancers
Authors: Portelance Lorraine , Corradini Stefanie , Erickson Beth , Lalondrelle Susan , Padgett Kyle , van der Leij Femke , van Lier Astrid , Jürgenliemk-Schulz Ina
Published: September 2021

Radiation therapy (RT) is increasingly being used in gynecological cancer management. RT delivered with curative or palliative intent can be administered alone or combined with chemotherapy or surgery. Advanced treatment planning and delivery techniques such as intensity-modulated radiation therapy, including volumetric modulated arc therapy, and image-guided adaptive brachytherapy allow for highly conformal radiation dose delivery leading to improved tumor control rates and less treatment toxicity. Quality on-board imaging that provides accurate visualization of target and surrounding organs at risk is a critical feature of these advanced techniques. As soft tissue contrast resolution is superior with magnetic resonance imaging (MRI) compared to other imaging modalities, MRI has been used increasingly to delineate tumor from adjacent soft tissues and organs at risk from initial diagnosis to tumor response evaluation. Gynecological cancers often have poor contrast resolution compared to the surrounding tissues on computed tomography scan, and consequently the benefit of MRI is high. One example is in management of locally advanced cervix cancer where adaptive MRI guidance has been broadly implemented for adaptive brachytherapy. The role of MRI for external beam RT is also steadily increasing. MRI information is being used for treatment planning, predicting, and monitoring position shifts and accounting for tissue deformation and target regression during treatment. The recent clinical introduction of online MRI-guided radiation therapy (oMRgRT) could be the next step in high-precision RT. This technology provides a tool to take full advantage of MRI not only at the time of initial treatment planning but as well as for daily position verification and online plan adaptation. Cervical, endometrial, vaginal, and oligometastatic ovarian cancers are being treated on MRI linear accelerator systems throughout the world. This review summarizes the current state, early experience, ongoing trials, and future directions of oMRgRT in the management of gynecological cancers.
Synchronous Malignant Gastrointestinal Neuroectodermal Tumor and SMARCA4-Deficient Undifferentiated Carcinoma With Independent Origins in the Small Intestine: A Case Report
Authors: Chen Cuimin , Yin Weihua , Wang Xingen , Li Ping , Chen Yaoli , Jin Xianglan , Yang Ping , Wu Huanwen
Published: September 2021

Background

Malignant gastrointestinal neuroectodermal tumor (GNET) is a rare malignant mesenchymal neoplasm that commonly arises in the small bowel, stomach or colon. Meanwhile, SMARCA4-deficient undifferentiated carcinoma is a rarely reported entity with highly aggressive behavior that may involve the ovary, lung, gastrointestinal (GI) tract, endometrium and other organs. To our knowledge, we describe for the first time, an extremely rare case of synchronous GNET and SMARCA4-deficient undifferentiated carcinoma with independent origins in the small intestine.

Case Presentation

A 46-year-old woman presented with multiple small intestine masses and underwent surgical resection. Two distinct entities, GNET and SMARCA4-deficient undifferentiated carcinoma, were identified. GNET was composed of epithelioid and spindle cells with clear or eosinophilic cytoplasm arranged in sheets, nest, papillary, fascicular, palisade, rosette like or pseudoalveolar pattern. The neoplastic cells were positive for S-100 and SOX-10. Ewing sarcoma breakpoint region 1 gene (EWSR1) rearrangement was confirmed by fluorescence in situ hybridization (FISH), and EWSR1-CREB1 fusion was revealed by next-generation sequencing (NGS). SMARCA4-deficient undifferentiated carcinoma was composed mainly of poorly adhesive rhabdoid cells with eosinophilic cytoplasm arranged in a diffuse pattern. Multifocal necrosis, brisk mitotic figures as well as multinucleated tumor cells were observed. The neoplastic cells diffusely expressed pancytokeratin and vimentin, and was negative for SMARCA4(BRG1). Frame shift mutation of SMARCA4 was detected by NGS.

Conclusions

This is the first report that GNET and SMARCA4-deficient undifferentiated carcinoma occurred simultaneously in the small intestine, with the latter showing multiple involvement of the jejunum and ileum. The potential mechanism underlying co-existence of these two rare malignancies is unknown and need further investigations and concern.
Spatiotemporal Patterns of Loco-Regional Recurrence After Breast-Conserving Surgery
Authors: Qu Fei-Lin , Mao Rui , Liu Zhe-Bin , Lin Cai-Jin , Cao A-Yong , Wu Jiong , Liu Guang-Yu , Yu Ke-Da , Di Gen-Hong , Li Jun-Jie , Shao Zhi-Ming
Published: September 2021

Background

Loco-regional recurrences (LRR) following breast-conserving surgery (BCS) remain a heterogeneous class of disease that has significant variation in its biological behavior and prognosis.

Methods

To delineate the spatiotemporal patterns of LRR after BCS, we analyzed the data of 4325 patients treated with BCS from 2006 to 2016. Clinico-pathological and treatment specific factors were analyzed using the Cox proportional hazards model to identify factors predictive for LRR events. Recurrence patterns were scrutinized based on recurrence type and recurrence-free interval (RFI). Annual recurrence rates (ARR) were compared according to recurrence type and molecular subtype.

Results

With a median follow-up of 66 months, 120 (2.8%) LRRs were recorded as the first site of failure. Age, pathologic stage, and molecular subtype were identified as predictors of LRR. The major recurrence type was ipsilateral breast tumor recurrence, which mainly (83.6%) occurred ≤5y post surgery. In the overall population, ARR curves showed that relapse peaked in the first 2.5 years. Patients with regional nodal recurrence, shorter RFI, and synchronous distant metastasis were associated with a poorer prognosis. HER2-positive disease had a higher rate of LRR events, more likely to have in-breast recurrence, and had an earlier relapse peak in the first 2 years after surgery.

Conclusions

LRR risk following BCS is generally low in Chinese ethnicity. Different recurrence patterns after BCS were related to distinct clinical outcomes. Management of LRR should be largely individualized and tailored to the extent of disease, the molecular profile of the recurrence, and to baseline clinical variables.
A New Clinical Nomogram From the TCGA Database to Predict the Prognosis of Hepatocellular Carcinoma
Authors: Ye Dingde , Qu Jiamu , Wang Jian , Li Guoqiang , Sun Beicheng , Xu Qingxiang
Published: September 2021

Background and Aim

Hepatocellular carcinoma is a common malignant tumor of the digestive system with a poor prognosis. The high recurrence rate and metastasis after surgery reduce the survival time of patients. Therefore, assessing the overall survival of patients with hepatocellular carcinoma after hepatectomy is critical to clinicians’ clinical decision-making. Conventional hepatocellular carcinoma assessment systems (such as tumor lymph node metastasis and Barcelona clinical hepatocellular carcinoma) are obviously insufficient in assessing the overall survival rate of patients. This research is devoted to the development of nomogram assessment tools to assess the overall survival probability of patients undergoing liver resection.

Methods

We collected the clinical and pathological information of 438 hepatocellular carcinoma patients undergoing surgery from The Cancer Genome Atlas (TCGA) database, then excluded 87 patients who did not meet inclusion criteria. Univariate and multivariate analyses were performed on patient characteristics and related pathological factors. Finally, we developed a nomogram model to predict patient’s prognosis.

Results

A retrospective analysis of 438 consecutive samples from the TCGA database of patients with hepatocellular carcinoma who underwent potentially curative liver resections. Six risk factors were included in the final model. In the training set, the discriminative ability of the nomogram was very good (concordance index = 0.944), and the external verification method (concordance index = 0.962) was used for verification. At the same time, the internal and external calibration of the model was verified, showing that the model was well calibrated. The calibration between the evaluation of the nomogram and the actual observations was good. According to the patient’s risk factors, we determined the patient’s Kaplan-Meyer survival analysis curve. Finally, the clinical decision curve was used to compare the benefits of two different models in evaluating patients’ clinical outcomes.

Conclusions

The nomogram can be used to evaluate the post-hepatectomy 1-, 3-, and 5-year survival rates of patients with hepatocellular carcinoma. The Kaplan-Meyer curve can intuitively display the survival differences among patients with various risk factors. The clinical decision curve is a good reference guide for clinical application.
The Development and Validation of a CT-Based Radiomics Nomogram to Preoperatively Predict Lymph Node Metastasis in High-Grade Serous Ovarian Cancer
Authors: Chen Hui-zhu , Wang Xin-rong , Zhao Fu-min , Chen Xi-jian , Li Xue-sheng , Ning Gang , Guo Ying-kun
Published: September 2021

Purpose

To develop and validate a radiomics model for predicting preoperative lymph node (LN) metastasis in high-grade serous ovarian cancer (HGSOC).

Materials and Methods

From May 2008 to January 2018, a total of 256 eligible HGSOC patients who underwent tumor resection and LN dissection were divided into a training cohort (n=179) and a test cohort (n=77) in a 7:3 ratio. A Radiomics Model was developed based on a training cohort of 179 patients. A radiomics signature (defined as the Radscore) was selected by using the random forest method. Logistics regression was used as the classifier for modeling. An Integrated Model that incorporated the Radscore and CT_reported LN status (CT_LN_report) was developed and presented as a radiomics nomogram. Its performance was determined by the area under the curve (AUC), calibration, and decision curve. The radiomics nomogram was internally tested in an independent test cohort (n=77) and a CT-LN-report negative subgroup (n=179) using the formula derived from the training cohort.

Results

The AUC value of the CT_LN_report was 0.688 (95% CI: 0.626, 0.759) in the training cohort and 0.717 (95% CI: 0.630, 0.804) in the test cohort. The Radiomics Model yielded an AUC of 0.767 (95% CI: 0.696, 0.837) in the training cohort and 0.753 (95% CI: 0.640, 0.866) in the test. The radiomics nomogram demonstrated favorable calibration and discrimination in the training cohort (AUC=0.821), test cohort (AUC=0.843), and CT-LN-report negative subgroup (AUC=0.82), outperforming the Radiomics Model and CT_LN_report alone.

Conclusions

The radiomics nomogram derived from portal phase CT images performed well in predicting LN metastasis in HGSOC and could be recommended as a new, convenient, and non-invasive method to aid in clinical decision-making.
Targeting Versican as a Potential Immunotherapeutic Strategy in the Treatment of Cancer
Authors: Hirani Priyanka , Gauthier Valentine , Allen Carys E. , Wight Thomas N. , Pearce Oliver M. T.
Published: September 2021

A growing body of literature links events associated with the progression and severity of immunity and inflammatory disease with the composition of the tissue extracellular matrix as defined by the matrisome. One protein in the matrisome that is common to many inflammatory diseases is the large proteoglycan versican, whose varied function is achieved through multiple isoforms and post-translational modifications of glycosaminoglycan structures. In cancer, increased levels of versican are associated with immune cell phenotype, disease prognosis and failure to respond to treatment. Whether these associations between versican expression and tumour immunity are the result of a direct role in the pathogenesis of tumours is not clear. In this review, we have focused on the role of versican in the immune response as it relates to tumour progression, with the aim of determining whether our current understanding of the immunobiology of versican warrants further study as a cancer immunotherapy target.
Validating HMMR Expression and Its Prognostic Significance in Lung Adenocarcinoma Based on Data Mining and Bioinformatics Methods
Authors: Li Xia , Zuo Haiwei , Zhang Li , Sun Qiuwen , Xin Yong , Zhang Longzhen
Published: September 2021

Hyaluronic acid-mediated motility receptor (HMMR), a tumor-related gene, plays a vital role in the occurrence and progression of various cancers. This research is aimed to reveal the effect of HMMR in lung adenocarcinoma (LUAD). We first obtained the gene expression profiles and clinical data of patients with LUAD from The Cancer Genome Atlas (TCGA) database. Then, based on the TCGA cohort, the HMMR expression difference between LUAD tissues and nontumor tissues was detected and verified with public tissue microarrays (TMAs), clinical LUAD specimen cohort, and Gene Expression Omnibus (GEO) cohort. Logistic regression analysis and chi-square test were adopted to study the correlation between HMMR expression and clinicopathological parameters. The effect of HMMR expression on survival was evaluated by Kaplan–Meier survival analysis and using the Cox regression model. Furthermore, Gene Set Enrichment Analysis (GSEA) was utilized to screen out signaling pathways related to LUAD and the co-expression analysis was employed to build the protein–protein interaction (PPI) network. The HMMR expression level in LUAD tissues was dramatically higher than that in nontumor tissues. Logistic regression analysis and chi-square test demonstrated that the high HMMR expression in LUAD has relation with gender, pathological stage, T classification, lymph node metastasis, and distant metastasis. The Kaplan–Meier curve suggested a poor prognosis for LUAD patients with high HMMR expression. Multivariate analysis implied that the high HMMR expression was a vital independent predictor of poor overall survival (OS). GSEA indicated that a total of 15 signaling pathways were enriched in samples with the high HMMR expression phenotype. The PPI network gave 10 genes co-expressed with HMMR. HMMR may be an oncogene in LUAD and is expected to become a potential prognostic indicator and therapeutic target for LUAD.
MiR-199b-5p Promotes Gastric Cancer Progression by Regulating HHIP Expression
Authors: Chen Songda , Wu Huijie , Zhu Lingyu , Jiang Mengjie , Wei Shuli , Luo Jinhua , Liu Aiqun
Published: September 2021

Objectives

Gastric cancer (GC) is one of the most common malignant tumors. More and more evidences support the role of microRNAs (miRNAs) in tumor progression. However, the role of miRNAs in human GC remains largely unknown.

Methods

Based on the published gastric cancer expression profile data, combined with bioinformatics analysis, potential miRNAs in the process of GC were screened. The expression of miR-199b-5p in GC cells and patients’ plasma was detected by RT-PCR. The effects of miR-199b-5p on GC in vitro were detected by EdU proliferation assay, colony formation assay, Transwell assay and wound healing assay. Western blot was used to detect epithelial-mesenchymal transition (EMT) related proteins. The subcutaneous tumorigenesis model and metastatic tumor model of mice were used to study its effect in vivo. Bioinformatics and Dual luciferase reporter assay were used to verify the effect of miR-199b-5p and its target gene.

Results

Through bioinformatics analysis, we screened a novel miRNA miR-199b-5p that was significantly up-regulated in GC tissue and associated with poor prognosis of GC patients. RT-PCR results showed that its expression was also up-regulated in GC cell lines and patients’ plasma. MiR-199b-5p can significantly promote GC cell proliferation and migration in vitro and in vivo. Western blot showed that miR-199b-5p could promote the EMT process of GC. HHIP has been proved to be a target of miR-199b-5p, and the recovery of HHIP can weaken the effect of miR-199b-5p.

Conclusion

MiR-199b-5p may play an oncogene role in GC by targeting HHIP, suggesting that miR-199b-5p may be a potential therapeutic target for GC.
PET/CT-Based Salvage Radiotherapy for Recurrent Prostate Cancer After Radical Prostatectomy: Impact on Treatment Management and Future Directions
Authors: le Guevelou Jennifer , Achard Vérane , Mainta Ismini , Zaidi Habib , Garibotto Valentina , Latorzeff Igor , Sargos Paul , Ménard Cynthia , Zilli Thomas
Published: September 2021

Biochemical recurrence is a clinical situation experienced by 20 to 40% of prostate cancer patients treated with radical prostatectomy (RP). Prostate bed (PB) radiation therapy (RT) remains the mainstay salvage treatment, although it remains non-curative for up to 30% of patients developing further recurrence. Positron emission tomography with computed tomography (PET/CT) using prostate cancer-targeting radiotracers has emerged in the last decade as a new-generation imaging technique characterized by a better restaging accuracy compared to conventional imaging. By adapting targeting of recurrence sites and modulating treatment management, implementation in clinical practice of restaging PET/CT is challenging the established therapeutic standards born from randomized controlled trials. This article reviews the potential impact of restaging PET/CT on changes in the management of recurrent prostate cancer after RP. Based on PET/CT findings, it addresses potential adaptation of RT target volumes and doses, as well as use of androgen-deprivation therapy (ADT). However, the impact of such management changes on the oncological outcomes of PET/CT-based salvage RT strategies is as yet unknown.
An Experimental Model of Bronchopulmonary Dysplasia Features Long-Term Retinal and Pulmonary Defects but Not Sustained Lung Inflammation
Authors: Wickramasinghe Lakshanie C. , van Wijngaarden Peter , Johnson Chad , Tsantikos Evelyn , Hibbs Margaret L.
Published: September 2021

Bronchopulmonary dysplasia (BPD) is a severe lung disease that affects preterm infants receiving oxygen therapy. No standardized, clinically-relevant BPD model exists, hampering efforts to understand and treat this disease. This study aimed to evaluate and confirm a candidate model of acute and chronic BPD, based on exposure of neonatal mice to a high oxygen environment during key lung developmental stages affected in preterm infants with BPD. Neonatal C57BL/6 mouse pups were exposed to 75% oxygen from postnatal day (PN)-1 for 5, 8, or 14 days, and their lungs were examined at PN14 and PN40. While all mice showed some degree of lung damage, mice exposed to hyperoxia for 8 or 14 days exhibited the greatest septal wall thickening and airspace enlargement. Furthermore, when assessed at PN40, mice exposed for 8 or 14 days to supplemental oxygen exhibited augmented septal wall thickness and emphysema, with the severity increased with the longer exposure, which translated into a decline in respiratory function at PN80 in the 14-day model. In addition to this, mice exposed to hyperoxia for 8 days showed significant expansion of alveolar epithelial type II cells as well as the greatest fibrosis when assessed at PN40 suggesting a healing response, which was not seen in mice exposed to high oxygen for a longer period. While evidence of lung inflammation was apparent at PN14, chronic inflammation was absent from all three models. Finally, exposure to high oxygen for 14 days also induced concurrent outer retinal degeneration. This study shows that early postnatal exposure to high oxygen generates hallmark acute and chronic pathologies in mice that highlights its use as a translational model of BPD.
Comparative Study of Parenteral Penicillin G vs. Amoxicillin-Clavulanate for the Treatment of Dentoalveolar Abscess in Hospitalized Children
Authors: Adler Amos , Gadot de-Vries Irit , Amir Jacob , Ashkenazi-Hoffnung Liat
Published: September 2021

Objectives: To compare the clinical efficacy and the safety profiles of parenteral penicillin G vs. amoxicillin-clavulanate for the treatment of dentoalveolar abscess (DA) in hospitalized pediatric patients.

Methods: A retrospective cohort study that was conducted at the Schneider Children's Medical Center in Israel.

Results: Seventy-one patients that were included, 25 received parenteral penicillin G and 46 amoxicillin-clavulanate. There were no significant differences in the baseline clinical features except for higher rate of females in the amoxicillin-clavulanate group. Patients that were treated with penicillin G had shorter duration of fever, swelling and total length-of-stay (4.16 vs. 5 days in the penicillin G vs. amoxicillin-clavulanate groups, respectively, p = 0.007) and lower need for surgical intervention. Side effect were minor in both groups. In multivariate analysis, antimicrobial regimen was the only significant factor related with the total length-of-stay (p < 0.001).

Conclusions: In pediatric patients hospitalized for DA, parenteral penicillin G was associated with better outcome compared with amoxicillin-clavulanate.
Comparison of Body Mass Index and Fat Indices in Predicting the Severity of Nonalcoholic Fatty Liver Disease Among Children Who Are Overweight and Obese
Authors: Chao Hsun-Chin , Lin Hsin-Yeh
Published: September 2021

Background: Information of the relationships between body mass parameters and the severity of fatty liver is deficient in pediatric nonalcoholic fatty liver disease (NAFLD).

Methods: The relationships between body mass parameters (waist circumference [WC], body mass index [BMI], and abdominal subcutaneous fat thickness [ASFT]) and the severity of fatty liver were prospectively evaluated in pediatric patients who are overweight or obese, suffering from NAFLD. Ultrasonography was performed to assess fatty liver and its severity on a three-grade scale (low-grade fatty liver [LGFL], grade 1 or 2; high-grade fatty liver [HGFL], grade 3).

Results: A total of 110 subjects (55 LGFL and 55 HGFL) aged 6.2–17.9 years were included. The WC, BMI, and ASFT values were significantly higher in the HGFL group compared to those in the LGFL group (p = 0.00004, 0.01, and 0.04, respectively). WC had the greatest power to predict HGFL under receiver-operating characteristic curve analyses and was positively correlated with the severity of fatty liver in subjects aged 6–12-year old and 13–17-year old (p = 0.007, and 0.0039, respectively). ASFT showed a positive correlation with the severity of fatty liver in subjects aged 13–17-year old (p = 0.04).

Conclusions: WC, BMI, and ASFT are predictive of severe NAFLD among children who are overweight and obese; particularly, WC has the most predictive accuracy. Among the parameters, WC and ASFT are predictive in specific age groups.
A Review of CYP3A Drug-Drug Interaction Studies: Practical Guidelines for Patients Using Targeted Oral Anticancer Drugs
Authors: Molenaar-Kuijsten Laura , Van Balen Dorieke E. M. , Beijnen Jos H. , Steeghs Neeltje , Huitema Alwin D. R.
Published: September 2021

Many oral anticancer drugs are metabolized by CYP3A. Clinical drug-drug interaction (DDI) studies often only examine the effect of strong CYP3A inhibitors and inducers. The effect of moderate or weak inhibitors or inducers can be examined using physiologically based pharmacokinetic simulations, but data from these simulations are not always available early after approval of a drug. In this review we provide recommendations for clinical practice on how to deal with DDIs of oral anticancer drugs if only data from strong CYP3A inhibitors or inducers is available. These recommendations were based on reviewed data of oral anticancer drugs primarily metabolized by CYP3A and approved for the treatment of solid tumors from January 1st, 2013 to December 31st, 2015. In addition, three drugs that were registered before the new EMA guideline was issued (i.e., everolimus, imatinib, and sunitinib), were reviewed. DDIs are often complex, but if no data is available from moderate CYP3A inhibitors/inducers, a change in exposure of 50% compared with strong inhibitors/inducers can be assumed. No a priori dose adaptations are indicated for weak inhibitors/inducers, because their interacting effect is small. In case pharmacologically active metabolites are involved, the metabolic pathway, the ratio of the parent to the metabolites, and the potency of the metabolites should be taken into account.