bluuebunny/crossref_metadata_2025 huggingface dataset:
Phylogenomic Analysis Substantiates the gyrB Gene as a Powerful Molecular Marker to Efficiently Differentiate the Most Closely Related Genera Myxococcus, Corallococcus, and Pyxidicoccus
Authors: Liu Yang , Pei Tao , Yi Shuoxing , Du Juan , Zhang Xianjiao , Deng Xiaoqin , Yao Qing , Deng Ming-Rong , Zhu Honghui
Published: October 2021

Rapid and accurate strain identification of the most closely related genera Myxococcus, Corallococcus, and Pyxidicoccus can enhance the efficiency of the mining of novel secondary metabolites through dereplication. However, the commonly used 16S rRNA gene sequencing cannot accurately differentiate members of the three genera above, and the whole-genome sequencing is unable to rapidly and inexpensively provide species assignation toward a large number of isolates. To overcome the limitations, the gyrB gene was investigated as a candidate genetic marker for exploring the phylogenetic relationships of bacteria within the three genera and for developing the gyrB-based typing method. Here, the bacterial phylogeny and species affiliations of the three genera were determined based on the phylogenomic reconstruction and the analysis of digital DNA–DNA hybridization values among 90 genomes, further confirming nine novel taxa and assigning over one-third of genomes to defined species. The phylogenetic relationships of these strains based on the gyrB gene sequences were congruent with those based on their genome sequences, allowing the use of the gyrB gene as a molecular marker. The gyrB gene-specific primers for the PCR-amplification and sequencing of bacteria within the three genera were designed and validated for 31 isolates from our group collection. The gyrB-based taxonomic tool proved to be able to differentiate closely related isolates at the species level. Based on the newly proposed 98.6% identity threshold for the 966-bp gyrB gene and the phylogenetic inference, these isolates were assigned into two known species and eight additional putative new species. In summary, this report demonstrated that the gyrB gene is a powerful phylogenetic marker for taxonomy and phylogeny of bacteria within the closely related genera Myxococcus, Corallococcus, and Pyxidicoccus, particularly in the case of hundreds or thousands of isolates in environmental studies.
Prognostic Value of N6-Methyladenosine-Related lncRNAs in Early-Stage Colorectal Cancer: Association With Immune Cell Infiltration and Chemotherapeutic Drug Sensitivity
Authors: Xiong Zhizhong , Li Xianzhe , Yin Shi , Xie Minghao , Mao Chaobin , Zhang Fengxiang , Chen Huaxian , Jin Longyang , Lian Lei
Published: October 2021

Purpose: Accumulating evidence indicates that N6-methyladenosine-related long non-coding RNAs (m6A-related lncRNAs) play a crucial role in the occurrence and development of several cancers. We aimed to explore the potential role of m6A-related lncRNA signatures in predicting prognosis for early-stage (stages I and II) colorectal cancer (CRC).

Methods: m6A-related lncRNA data were obtained from The Cancer Genome Atlas. Univariate Cox regression analysis was used to screen for prognostic m6A-related lncRNAs. Immune characteristics were analyzed in different subgroups created via unsupervised clustering analysis. Next, patients were randomly divided into training and test cohorts. In the training cohort, least absolute shrinkage and selection operator (LASSO) regression was performed to establish a prognostic model. The predictive value of the signature was evaluated in the training and test cohorts. Drug sensitivity was also examined.

Results: A total of 1,478 m6A-related lncRNAs were identified. Two subgroups were created based on the expression of seven prognostic m6A-related lncRNAs. Prognosis was worse for cluster 1 than for cluster 2, and cluster 1 was characterized by increased numbers of M2 macrophages, decreased numbers of memory B cells, and higher expression of checkpoint genes when compared with cluster 2. Five m6A-related lncRNAs were selected to establish a risk prediction signature via LASSO regression. The 3 years overall survival (OS) was higher in the low-risk group than in the high-risk group. The area under the curve at 1, 2, and 3 years was 0.929, 0.954, and 0.841 in the training cohort and 0.664, 0.760, and 0.754 in the test cohort, respectively. Multivariate Cox regression analysis suggests that the risk score was an independent predictor of OS in both the training and test cohorts. A prognostic nomogram based on the five m6A-related lncRNAs and their clinical features was built and verified. The high-risk group was more sensitive to chemotherapeutic drugs (camptothecin and cisplatin) than the low-risk group.

Conclusion: We identified two molecular subgroups of early-stage CRC with unique immune features based on seven prognostic m6A-related lncRNAs. Subsequent analyses demonstrated the usefulness of a five m6A-related lncRNA signature as a potential indicator of prognosis in patients with early-stage CRC.
Osh6 Revisited: Control of PS Transport by the Concerted Actions of PI4P and Sac1 Phosphatase
Authors: Eisenreichova Andrea , Różycki Bartosz , Boura Evzen , Humpolickova Jana
Published: October 2021

Osh6, a member of the oxysterol-binding protein–related protein (ORP) family, is a lipid transport protein that is involved in the transport of phosphatidylserine (PS) between the endoplasmic reticulum (ER) and the plasma membrane (PM). We used a biophysical approach to characterize its transport mechanism in detail. We examined the transport of all potential ligands of Osh6. PI4P and PS are the best described lipid cargo molecules; in addition, we showed that PIP2 can be transported by Osh6 as well. So far, it was the exchange between the two cargo molecules, PS and PI4P, in the lipid-binding pocket of Osh6 that was considered an essential driving force for the PS transport. However, we showed that Osh6 can efficiently transport PS along the gradient without the help of PI4P and that PI4P inhibits the PS transport along its gradient. This observation highlights that the exchange between PS and PI4P is indeed crucial, but PI4P bound to the protein rather than intensifying the PS transport suppresses it. We considered this to be important for the transport directionality as it prevents PS from returning back from the PM where its concentration is high to the ER where it is synthesized. Our results also highlighted the importance of the ER resident Sac1 phosphatase that enables the PS transport and ensures its directionality by PI4P consumption. Furthermore, we showed that the Sac1 activity is regulated by the negative charge of the membrane that can be provided by PS or PI anions in the case of the ER membrane.
Microglia Regulate Neuronal Circuits in Homeostatic and High-Fat Diet-Induced Inflammatory Conditions
Authors: Wang Xiao-Lan , Li Lianjian
Published: October 2021

Microglia are brain resident macrophages, which actively survey the surrounding microenvironment and promote tissue homeostasis under physiological conditions. During this process, microglia participate in synaptic remodeling, neurogenesis, elimination of unwanted neurons and cellular debris. The complex interplay between microglia and neurons drives the formation of functional neuronal connections and maintains an optimal neural network. However, activation of microglia induced by chronic inflammation increases synaptic phagocytosis and leads to neuronal impairment or death. Microglial dysfunction is implicated in almost all brain diseases and leads to long-lasting functional deficiency, such as hippocampus-related cognitive decline and hypothalamus-associated energy imbalance (i.e., obesity). High-fat diet (HFD) consumption triggers mediobasal hypothalamic microglial activation and inflammation. Moreover, HFD-induced inflammation results in cognitive deficits by triggering hippocampal microglial activation. Here, we have summarized the current knowledge of microglial characteristics and biological functions and also reviewed the molecular mechanism of microglia in shaping neural circuitries mainly related to cognition and energy balance in homeostatic and diet-induced inflammatory conditions.
Jidong Restless Legs Syndrome Cohort Study: Objectives, Design, and Baseline Screening
Authors: Wang Shu-Hong , Chen Xue-Yu , Wang Xiao-Ping
Published: October 2021

Background: Restless legs syndrome (RLS) is a common neurological disorder with unpleasant leg sensations and serious negative effects on mental and physical health. Many observational studies showed that people with RLS had a high risk of vascular diseases, including cerebrovascular and cardiovascular diseases (CVD), but the findings were conflicting. The Jidong RLS Cohort Study is a prospective cohort study designed to mainly examine whether or not RLS is associated with an increased risk of CVD.

Methods and Design: The study recruited 8,867 healthy participants older than 18 years from October 2014 to December 2015. Participants received a physical examination in the Staff Hospital, Jidong Oilfield Branch, China National Petroleum Corporation. Baseline data and blood samples were collected. Restless legs syndrome was assessed using the international RLS diagnostic criteria. All of subjects would be followed up until December 2025. Major cardiovascular/cerebrovascular events including cardiac death, myocardial infarction, ischemic heart disease, heart failure, atrial fibrillation, ischemic, and hemorrhagic stroke will be the primary outcomes. Secondary outcomes include all-cause mortality, the decline in quality of life, cognitive impairment, and depression.

Discussion: This study will contribute to the scientific evidence on the association between RLS and cardiovascular risks and also provide an unprecedented opportunity for early detection and prevention of CVD.
Charcot–Marie–Tooth Disease With Episodic Rhabdomyolysis Due to Two Novel Mutations in the β Subunit of Mitochondrial Trifunctional Protein and Effective Response to Modified Diet Therapy
Authors: Guan Yuqing , Zhang Yanxia , Shen Xin-Ming , Zhou Liang , Shang Xuan , Peng Yu , Hu Yafang , Li Wei
Published: October 2021

A 29-year-old female experienced chronic progressive peripheral neuropathy since childhood and was diagnosed with Charcot–Marie–Tooth disease (CMT) at age 15. She developed recurrent, fever-induced rhabdomyolysis (RM) at age 24. EMG studies showed decreased amplitude of compound muscle action potential, declined motor conductive velocity, and absence of sensor nerve action potential. Acylcarnitine analysis revealed elevated C16-OH, C18-OH, and C18:1-OH. Muscle biopsy showed scattered foci of necrotic myofibers invaded by macrophages, occasional regenerating fibers, and remarkable muscle fiber type grouping. Whole-exome sequencing identified two novel heterozygous mutations: c.490G>A (p.G164S) and c.686G>A (p.R229Q) in HADHB gene encoding the β-subunit of mitochondrial trifunctional protein (MTP). Reduction of long-chain fatty acid via dietary restrictions alleviated symptoms effectively. Our study indicates that the defect of the MTP β-subunit accounts for both CMT and RM in the same patient and expands the clinical spectrum of disorders caused by the HADHB mutations. Our systematic review of all MTPD patients with dietary treatment indicates that the effect of dietary treatment is related to the age of onset and the severity of symptoms.
Predictors of Functional Outcome and Mortality in Endovascular Treatment for Acute Basilar Artery Occlusion: A Single-Centre Experience
Authors: Cao Jie , Mo Yi , Chen Ronghua , Shao Huaming , Xuan Jinggang , Peng Ya , Zhu Xucheng
Published: October 2021

Background and Purpose: The objective of this study was to identify prognostic factors of endovascular treatment in patients with acute basilar artery occlusion and add evidence about the efficacy and safety of endovascular treatment for acute basilar artery occlusion.

Materials and Methods: We reviewed the data of 101 patients with acute basilar artery occlusion receiving endovascular treatment from January 2013 to September 2019. Baseline characteristics and outcomes were evaluated. A favourable functional outcome was defined as a mRS of 0 to 2 assessed at the 3 month follow-up. The association of clinical and procedural characteristics with the functional outcome and mortality was assessed.

Results: The study population consisted of 101 patients: 83 males and 18 females. Successful recanalization was achieved in 99 patients (97.1%). A favourable clinical outcome was observed in 50 patients (49.5%), and the overall mortality rate was 26.7%. A favourable outcome was significantly associated with NIHSS score at admission and lung infection. Mortality was associated with NIHSS score at admission, the number of thrombectomy device passes, the postoperative pons-midbrain index, and diabetes mellitus.

Conclusions: This study suggested that NIHSS score at admission, the number of thrombectomy device passes, the postoperative pons-midbrain index, diabetes mellitus, and lung infection can predict the functional outcome and mortality. These initial results add evidence about the efficacy and safety of endovascular treatment for acute basilar artery occlusion and need to be confirmed by further prospective studies.
Abnormal Stability of Dynamic Functional Architecture in Amyotrophic Lateral Sclerosis: A Preliminary Resting-State fMRI Study
Authors: Wei Jin , Lin Jia-Hui , Cai Li-Min , Shi Jia-Yan , Zhang Xiao-Hong , Zou Zhang-Yu , Chen Hua-Jun
Published: October 2021

Purpose: Static and dynamic analyses for identifying functional connectivity (FC) have demonstrated brain dysfunctions in amyotrophic lateral sclerosis (ALS). However, few studies on the stability of dynamic FC have been conducted among ALS patients. This study explored the change of functional stability in ALS and how it correlates with disease severity.

Methods: We gathered resting-state functional magnetic resonance data from 20 patients with ALS and 22 healthy controls (HCs). The disease severity was assessed with the Revised ALS Functional Rating Scale (ALSFRS-R). We used a sliding window correlation approach to identify dynamic FC and measured the concordance of dynamic FC over time to obtain the functional stability of each voxel. We assessed the between-group difference in functional stability by voxel-wise two-sample t-test. The correlation between the functional stability index and ALSFRS-R in ALS patients was evaluated using Spearman's correlation analysis.

Results: Compared with the HC group, the ALS group had significantly increased functional stability in the left pre-central and post-central gyrus and right temporal pole while decreased functional stability in the right middle and inferior frontal gyrus. The results revealed a significant correlation between ALSFRS-R and the mean functional stability in the right temporal pole (r = −0.452 and P = 0.046) in the ALS patients.

Conclusions: ALS patients have abnormal stability of brain functional architecture, which is associated with the severity of the disease.
Identifying Depressed Essential Tremor Using Resting-State Voxel-Wise Global Brain Connectivity: A Multivariate Pattern Analysis
Authors: Li Yufen , Tao Li , Chen Huiyue , Wang Hansheng , Zhang Xiaoyu , Zhang Xueyan , Duan Xiyue , Fang Zhou , Li Qin , He Wanlin , Lv Fajin , Luo Jin , Xiao Zheng , Cao Jun , Fang Weidong
Published: October 2021

Background and Objective: Although depression is one of the most common non-motor symptoms in essential tremor (ET), its pathogenesis and diagnosis biomarker are still unknown. Recently, machine learning multivariate pattern analysis (MVPA) combined with connectivity mapping of resting-state fMRI has provided a promising way to identify patients with depressed ET at the individual level and help to reveal the brain network pathogenesis of depression in patients with ET.

Methods: Based on global brain connectivity (GBC) mapping from 41 depressed ET, 49 non-depressed ET, 45 primary depression, and 43 healthy controls (HCs), multiclass Gaussian process classification (GPC) and binary support vector machine (SVM) algorithms were used to identify patients with depressed ET from non-depressed ET, primary depression, and HCs, and the accuracy and permutation tests were used to assess the classification performance.

Results: While the total accuracy (40.45%) of four-class GPC was poor, the four-class GPC could discriminate depressed ET from non-depressed ET, primary depression, and HCs with a sensitivity of 70.73% (P < 0.001). At the same time, the sensitivity of using binary SVM to discriminate depressed ET from non-depressed ET, primary depression, and HCs was 73.17, 80.49, and 75.61%, respectively (P < 0.001). The significant discriminative features were mainly located in cerebellar-motor-prefrontal cortex circuits (P < 0.001), and a further correlation analysis showed that the GBC values of significant discriminative features in the right middle prefrontal gyrus, bilateral cerebellum VI, and Crus 1 were correlated with clinical depression severity in patients with depressed ET.

Conclusion: Our findings demonstrated that GBC mapping combined with machine learning MVPA could be used to identify patients with depressed ET, and the GBC changes in cerebellar-prefrontal cortex circuits not only posed as the significant discriminative features but also helped to understand the network pathogenesis underlying depression in patients with ET.
Emulation of Astrocyte Induced Neural Phase Synchrony in Spin-Orbit Torque Oscillator Neurons
Authors: Garg Umang , Yang Kezhou , Sengupta Abhronil
Published: October 2021

Astrocytes play a central role in inducing concerted phase synchronized neural-wave patterns inside the brain. In this article, we demonstrate that injected radio-frequency signal in underlying heavy metal layer of spin-orbit torque oscillator neurons mimic the neuron phase synchronization effect realized by glial cells. Potential application of such phase coupling effects is illustrated in the context of a temporal “binding problem.” We also present the design of a coupled neuron-synapse-astrocyte network enabled by compact neuromimetic devices by combining the concepts of local spike-timing dependent plasticity and astrocyte induced neural phase synchrony.
Upper-Limb Electromyogram Classification of Reaching-to-Grasping Tasks Based on Convolutional Neural Networks for Control of a Prosthetic Hand
Authors: Kim Keun-Tae , Park Sangsoo , Lim Tae-Hyun , Lee Song Joo
Published: October 2021

In recent years, myoelectric interfaces using surface electromyogram (EMG) signals have been developed for assisting people with physical disabilities. Especially, in the myoelectric interfaces for robotic hands or arms, decoding the user’s upper-limb movement intentions is cardinal to properly control the prosthesis. However, because previous experiments were implemented with only healthy subjects, the possibility of classifying reaching-to-grasping based on the EMG signals from the residual limb without the below-elbow muscles was not investigated yet. Therefore, we aimed to investigate the possibility of classifying reaching-to-grasping tasks using the EMG from the upper arm and upper body without considering wrist muscles for prosthetic users. In our study, seven healthy subjects, one trans-radial amputee, and one wrist amputee were participated and performed 10 repeatable 12 reaching-to-grasping tasks based on the Southampton Hand Assessment Procedure (SHAP) with 12 different weighted (light and heavy) objects. The acquired EMG was processed using the principal component analysis (PCA) and convolutional neural network (CNN) to decode the tasks. The PCA–CNN method showed that the average accuracies of the healthy subjects were 69.4 ± 11.4%, using only the EMG signals by the upper arm and upper body. The result with the PCA–CNN method showed 8% significantly higher accuracies than the result with the widely used time domain and auto-regressive-support vector machine (TDAR–SVM) method as 61.6 ± 13.7%. However, in the cases of the amputees, the PCA–CNN showed slightly lower performance. In addition, in the aspects of assistant daily living, because grip force is also important when grasping an object after reaching, the possibility of classifying the two light and heavy objects in each reaching-to-grasping task was also investigated. Consequently, the PCA–CNN method showed higher accuracy at 70.1 ± 9.8%. Based on our results, the PCA–CNN method can help to improve the performance of classifying reaching-to-grasping tasks without wrist EMG signals. Our findings and decoding method can be implemented to further develop a practical human–machine interface using EMG signals.
Potential Common Genetic Risks of Sporadic Parkinson’s Disease and Amyotrophic Lateral Sclerosis in the Han Population of Mainland China
Authors: Lu Yi , Chen Wenzhi , Wei Caihui , Zhu Yu , Xu Renshi
Published: October 2021

Sporadic Parkinson’s disease (sPD) and sporadic amyotrophic lateral sclerosis (sALS) are neurodegenerative diseases characterized by progressive and selective neuron death, with some genetic similarities. In order to investigate the genetic risk factors common to both sPD and sALS, we carried out a screen of risk alleles for sALS and related loci in 530 sPD patients and 530 controls from the Han population of Mainland China (HPMC). We selected 27 single-nucleotide polymorphisms in 10 candidate genes associated with sALS, and we performed allelotyping and genotyping to determine their frequencies in the study population as well as bioinformatics analysis to assess their functional significance in these diseases. The minor alleles of rs17115303 in DAB adaptor protein 1 (DAB1) gene and rs6030462 in protein tyrosine phosphatase receptor type T (PTPRT) gene were correlated with increased risk of both sPD and sALS. Polymorphisms of rs17115303 and rs6030462 were associated with alterations in transcription factor binding sites, secondary structures, long non-coding RNA interactions, and nervous system regulatory networks; these changes involved biological processes associated with neural cell development, differentiation, neurogenesis, migration, axonogenesis, cell adhesion, and metabolism of phosphate-containing compounds. Thus, variants ofDAB1gene (rs17115303) andPTPRTgene (rs6030462) are risk factors common to sPD and sALS in the HPMC. These findings provide insight into the molecular pathogenesis of both diseases and can serve as a basis for the development of targeted therapies.
Genetic Modification of Mucor circinelloides for Canthaxanthin Production by Heterologous Expression of β-carotene Ketolase Gene
Authors: Naz Tahira , Yang Junhuan , Nosheen Shaista , Sun Caili , Nazir Yusuf , Mohamed Hassan , Fazili Abu Bakr Ahmad , Ullah Samee , Li Shaoqi , Yang Wu , Garre Victoriano , Song Yuanda
Published: October 2021

Canthaxanthin is a reddish-orange xanthophyll with strong antioxidant activity and higher bioavailability than carotenes, primarily used in food, cosmetics, aquaculture, and pharmaceutical industries. The spiking market for natural canthaxanthin promoted researchers toward genetic engineering of heterologous hosts for canthaxanthin production.Mucor circinelloidesis a dimorphic fungus that produces β-carotene as the major carotenoid and is considered as a model organism for carotenogenic studies. In this study, canthaxanthin-producingM. circinelloidesstrain was developed by integrating the codon-optimized β-carotene ketolase gene (bkt) of theHaematococcus pluvialisinto the genome of the fungus under the control of strong promoterzrt1. First, a basic plasmid was constructed to disruptcrgAgene, a negative regulator of carotene biosynthesis resulted in substantial β-carotene production, which served as the building block for canthaxanthin by further enzymatic reaction of the ketolase enzyme. The genetically engineered strain produced a significant amount (576 ± 28 μg/g) of canthaxanthin, which is the highest amount reported inMucorto date. Moreover, the cell dry weight of the recombinant strain was also determined, producing up to more than 9.0 g/L, after 96 h. The mRNA expression level ofbktin the overexpressing strain was analyzed by RT-qPCR, which increased by 5.3-, 4.1-, and 3-folds at 24, 48, and 72 h, respectively, compared with the control strain. The canthaxanthin-producingM. circinelloidesstrain obtained in this study provided a basis for further improving the biotechnological production of canthaxanthin and suggested a useful approach for the construction of more valuable carotenoids, such as astaxanthin.
Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins
Authors: Deng Mingjuan , Li Xingqi , Li Weiwei , Gong Jiahui , Zhang Xiaoying , Ge Shaoyang , Zhao Liang
Published: October 2021

Chronic kidney disease (CKD) is characterized with the influx of uremic toxins, which impairs the gut microbiome by decreasing beneficial bacteria that produce short-chain fatty acids (SCFAs) and increasing harmful bacteria that produce gut-derived protein-bound uremic toxins (PBUTs). This study aimed to assess the proapoptotic effects of three major gut-derived PBUTs in hepatocytes, and the effects of SCFAs on apoptosis phenotype in vitro. HepG2 (human liver carcinoma cells) and THLE-2 (immortalized human normal liver cells) cell line were incubated with 0, 2, 20, 200, 2000 μM p-cresol sulfate (PCS), indoxyl sulfate (IS), and hippuric acid (HA), respectively, for 24 h. Flow cytometry analysis indicated that three uremic toxins induced varying degrees of apoptosis in hepatocytes and HA represented the highest efficacy. These phenotypes were further confirmed by western blot of apoptosis protein expression [Caspase-3, Caspase-9, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax)]. Human normal hepatocytes (THLE-2) are more sensitive to PBUTs-induced apoptosis compared with human hepatoma cells (HepG2). Mechanistically, extracellular HA could enter hepatocytes, increase reactive oxygen species (ROS) generation, and decrease mitochondrial membrane potential dose-dependently in THLE-2 cells. Notably, coculture with SCFAs (acetate, propionate, butyrate) for 24 h significantly improved HA-induced apoptosis in THLE-2 cells, and propionate (500 μM) represented the highest efficacy. Propionate reduction of apoptosis was associated with improving mitochondria dysfunction and oxidative stress in a manner involving reducing Caspase-3 expression, ROS production, and increasing the Bcl-2/Bax level. As such, our studies validated PBUTs accumulation might be an important cause of liver dysfunction in patients with CKD, and supplementation of SCFAs might be a viable way to protect the liver for patients with CKD.
Correlation of DCE-MRI Perfusion Parameters and Molecular Biology of Breast Infiltrating Ductal Carcinoma
Authors: Liu Li , Mei Nan , Yin Bo , Peng Weijun
Published: October 2021

Objective

We aimed to investigate the correlation of the perfusion parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with the molecular biological expression of breast infiltrating ductal carcinoma (IDC) in order to guide appropriate therapeutic advice and clinical outcome prediction.

Materials and Methods

In a prospective analysis of 67 patients with breast IDC, preoperative DCE-MRI and routine MRI images were obtained. The double-chamber model (extended Tofts model) was employed to calculate the perfusion parameters. Postoperative pathological immunohistochemistry was examined, including human epidermal growth factor receptor 2 (HER-2), estrogen receptor (ER), progesterone receptor (PR), cell nuclear-associated antigen (Ki-67), cytokeratin 5/6 (CK5/6), and epidermal growth factor receptor (EGFR). Statistical analysis was applied to explore the relationship between the perfusion parameters and the molecular biomarkers of breast cancer.

Results

A total of 67 lesions were included in our study. The mean maximum diameter of lesions was 4.48 ± 1.73 cm. Perfusion parameters had no correlation with tumor diameters (p > 0.05). The volume transfer constant (Ktrans) and the rate constant (kep) had positive correlations with Ki-67 (p < 0.05). The plasma volume ratio (vp) had a statistical difference between CK5/6 positivity and CK5/6 negativity. The maximum rising slope (MAX Slope) was higher in HER-2-enriched tumors than that in luminal A or B tumors (p < 0.05). kep was higher in HER-2-enriched tumors than that in luminal A tumors (p < 0.05). The extravascular extracellular space volume fraction (ve) was higher in triple-negative tumors than that in HER-2-enriched and in luminal A and B tumors (p < 0.05). The time to peak enhancement (TTP) was lower in HER-2-enriched tumors than that in luminal A and B tumors (p < 0.05). Maximum concentration (MAX Conc) was higher in triple-negative tumors than that in luminal B tumors (p < 0.05).

Conclusion

DCE-MRI perfusion parameters can behave as a noninvasive tool to assess the molecular biological expression and the molecular subtypes of breast IDC. They may aid in predicting breast IDC invasiveness, metastasis, and prognosis.
Targeting BRCA and DNA Damage Repair Genes in GI Cancers: Pathophysiology and Clinical Perspectives
Authors: Zimmer Kai , Kocher Florian , Puccini Alberto , Seeber Andreas
Published: October 2021

Mutated germline alleles in the DNA damage repair (DDR) genes “breast cancer gene 1” (BRCA1) andBRCA2have originally been identified as major susceptibility genes in breast and ovarian cancers. With the establishment and approval of more cost-effective gene sequencing methods, germline and somaticBRCAmutations have been detected in several cancers. Since the approval of poly (ADP)-ribose polymerase inhibitors (PARPi) forBRCA-mutated cancers,BRCAmutations gained rising therapeutic implications. The impact and significance ofBRCAmutations have been evaluated extensively in the last decades. Moreover, other genes involved in the DDR pathway, such asATM,ATR, orCHK1, have emerged as potential new treatment targets, as inhibitors of these proteins are currently under clinical investigation. This review gives a concise overview on the emerging clinical implications of mutations in the DDR genes in gastrointestinal cancers with a focus onBRCAmutations.
AGIG Chemo-Immunotherapy in Patients With Advanced Pancreatic Cancer: A Single-Arm, Single-Center, Phase 2 Study
Authors: Dai Wangshu , Qiu Xin , Lu Changchang , Zou Zhengyun , Sha Huizi , Kong Weiwei , Liu Baorui , Du Juan
Published: October 2021

Background

To date, chemotherapy remains the only effective treatment of unresectable pancreatic adenocarcinoma. In the past few years, the interest in immunological anticancer therapy rises sharply. AGIG is a novel chemo-immunotherapy regimen that combines nab-paclitaxel + gemcitabine chemotherapy with sequential recombinant interleukin-2 (IL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF) therapy. We conducted a single-arm prospective phase II study to determine the efficacy and safety of the first-line treatment of advanced pancreatic cancer with AGIG regimen.

Methods

Nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) were administered intravenously to all patients on days 1 and 8 triweekly, interleukin-2 (1000000U) and GM-CSF (100 µg) were administered subcutaneously on days 3-5 after chemotherapy. The primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS). Patients’ conditions along with the efficacy and safety were assessed every two cycles.

Results

Between 11/2018 and 01/2020, sixty-four patients were enrolled. In the sixty-four evaluable patients, the disease control rate (DCR) and overall response rate (ORR) were 76.6% and 43.75%, respectively. The median follow-up time was 12.1 (range 7.1–22.4) months. The median PFS was 5.7 (range 1.63–15.8) months. The median OS was 14.2 (range 2.9–22.0) months. The most common adverse event was fever (75%). The incidence of III/IV grade neutropenia was 4.69%. In subgroup analyses, we found that eosinophil count in the blood elevated three times higher than baseline level predicted a longer survival.

Conclusions

The AGIG chemo-immunotherapy regimen has presented favorable ORR, OS, and manageable toxicities as first-line therapeutic strategy of advanced pancreatic cancer treatment. This regimen may be a novel reliable therapeutic option for patients with preserved performance status. The improvement of treatment efficiency may be related to the activation of non-specific immune response.

Clinical Trial Registration

https://clinicaltrials.gov/. identifier NCT03768687.
Variations in Head and Neck Treatment Plan Quality Assessment Among Radiation Oncologists and Medical Physicists in a Single Radiotherapy Department
Authors: Cagni Elisabetta , Botti Andrea , Rossi Linda , Iotti Cinzia , Iori Mauro , Cozzi Salvatore , Galaverni Marco , Rosca Ala , Sghedoni Roberto , Timon Giorgia , Spezi Emiliano , Heijmen Ben
Published: October 2021

Background

Agreement between planners and treating radiation oncologists (ROs) on plan quality criteria is essential for consistent planning. Differences between ROs and planning medical physicists (MPs) in perceived quality of head and neck cancer plans were assessed.

Materials and Methods

Five ROs and four MPs scored 65 plans for in total 15 patients. For each patient, the clinical (CLIN) plan and two or four alternative plans, generated with automated multi-criteria optimization (MCO), were included. There was always one MCO plan aiming at maximally adhering to clinical plan requirements, while the other MCO plans had a lower aimed quality. Scores were given as follows: 1–7 and 1–2, not acceptable; 3–5, acceptable if further planning would not resolve perceived weaknesses; and 6–7, straightway acceptable. One MP and one RO repeated plan scoring for intra-observer variation assessment.

Results

For the 36 unique observer pairs, the median percentage of plans for which the two observers agreed on a plan score (100% = 65 plans) was 27.7% [6.2, 40.0]. In the repeat scoring, agreements between first and second scoring were 52.3% and 40.0%, respectively. With a binary division between unacceptable (scores 1 and 2) and acceptable (3–7) plans, the median inter-observer agreement percentage was 78.5% [63.1, 86.2], while intra-observer agreements were 96.9% and 86.2%. There were no differences in observed agreements between RO–RO, MP–MP, and RO–MP pairs. Agreements for the highest-quality, automatically generated MCO plans were higher than for the CLIN plans.

Conclusions

Inter-observer differences in plan quality scores were substantial and could result in inconsistencies in generated treatment plans. Agreements among ROs were not better than between ROs and MPs, despite large differences in training and clinical role. High-quality automatically generated plans showed the best score agreements.
Characterization of Plasma Protein Alterations in Pregnant and Postpartum Individuals Living With HIV to Support Physiologically-Based Pharmacokinetic Model Development
Authors: Zhao Sherry , Gockenbach Mary , Grimstein Manuela , Sachs Hari Cheryl , Mirochnick Mark , Struble Kimberly , Belew Yodit , Wang Jian , Capparelli Edmund V. , Best Brookie M. , Johnson Tamara , Momper Jeremiah D. , Maharaj Anil R.
Published: October 2021

Background: Alterations in plasma protein concentrations in pregnant and postpartum individuals can influence antiretroviral (ARV) pharmacokinetics. Physiologically-based pharmacokinetic (PBPK) models can serve to inform drug dosing decisions in understudied populations. However, development of such models requires quantitative physiological information (e.g., changes in plasma protein concentration) from the population of interest.

Objective: To quantitatively describe the time-course of albumin and α1-acid glycoprotein (AAG) concentrations in pregnant and postpartum women living with HIV.

Methods: Serum and plasma protein concentrations procured from the International Maternal Pediatric Adolescent AIDS Clinical Trial Protocol 1026s (P1026s) were analyzed using a generalized additive modeling approach. Separate non-parametric smoothing splines were fit to albumin and AAG concentrations as functions of gestational age or postpartum duration.

Results: The analysis included 871 and 757 serum albumin concentrations collected from 380 pregnant (~20 to 42 wks gestation) and 354 postpartum (0 to 46 wks postpartum) women, respectively. Thirty-six and 32 plasma AAG concentrations from 31 pregnant (~24 to 38 wks gestation) and 30 postpartum women (~2–13 wks postpartum), respectively, were available for analysis. Estimated mean albumin concentrations remained stable from 20 wks gestation to term (33.4 to 34.3 g/L); whereas, concentrations rapidly increased postpartum until stabilizing at ~42.3 g/L 15 wk after delivery. Estimated AAG concentrations slightly decreased from 24 wks gestation to term (53.6 and 44.9 mg/dL) while postpartum levels were elevated at two wks after delivery (126.1 mg/dL) and subsequently declined thereafter. Computational functions were developed to quantitatively communicate study results in a form that can be readily utilized for PBPK model development.

Conclusion: By characterizing the trajectory of plasma protein concentrations in pregnant and postpartum women living with HIV, our analysis can increase confidence in PBPK model predictions for HIV antiretrovirals and better inform drug dosing decisions in this understudied population.
Critically Ill Children in a Swiss Pediatric Emergency Department With an Interdisciplinary Approach: A Prospective Cohort Study
Authors: Simma Leopold , Stocker Martin , Lehner Markus , Wehrli Lea , Righini-Grunder Franziska
Published: October 2021

Objective:Delivery of prompt and adequate care for critically ill and injured children presenting to the pediatric emergency department (PED) is paramount for optimal outcomes. Knowledge of the local epidemiology, patient profile, and presentation modes are key for organizational planning, staff education strategy, and optimal care in a PED. Our aim was to analyze the profile of critically ill and injured children admitted to a tertiary, non-academic Swiss PED, to investigate potential risk factors associated with admission to the pediatric intensive care unit (PICU), and the outcomes mortality and PICU admission.

Methods:Prospective cohort study of critically ill and injured children presenting to the PED over a two-year period (2018–2019). Inclusion criteria were Australasian triage scale category (ATS) 1, trauma team activation (TTA), medical emergency response (MER) activation, additional critical care consult, and transfer to an outside hospital.

Results:Of 42,579 visits during the two-year period, 347 presentations matched the inclusion criteria (0.81%). Leading presentations were central nervous system (CNS) disorders (26.2%), trauma (25.1%), and respiratory emergencies (24.2%). 288 out of 347 cases (83%) arrived during the day or evening with an even distribution over the days of the week. 128 out of 347 (37%) arrived unexpectedly as walk-ins. 233 (67.15%) were ATS category 1. 51% of the cohort was admitted to PICU. Australasian triage scale category 1 was significantly more common in this group (p= 0.0001). Infants with respiratory disease had an increased risk of PICU transfer compared to other age groups (OR 4.18 [95%CI 2.46, 7.09]p= 0.0001), and this age group presented mainly as walk-in (p= 0.0001). Pediatric intensive care unit admissions had a longer hospital stay (4 [2, 8] days vs. 2 [1, 4] days,p= 0.0001) compared to other patients. 0.045% of all PED patients had to be transferred out. Three deaths (0.86%) occurred in the PED, 10 patients died in the PICU (2.9%).

Conclusions:High acuity presentations in the PED were rare, more likely to be young with CNS disorders, trauma and respiratory diseases. A significant proportion were unexpected walk-in presentations, mainly during day and evening shifts. Low exposure to high-acuity patients highlights the importance of deliberate learning and simulation for all professionals in the PED.
The Role of Video-Assisted Thoracoscopic Surgery in Pediatric Oncology: Single-Center Experience and Review of the Literature
Authors: Riccipetitoni Giovanna , Bertozzi Mirko , Gazzaneo Marta , Raffaele Alessandro , Vatta Fabrizio
Published: October 2021

Aim:Video-assisted thoracoscopic surgery (VATS) has been widely used in the last decades. Nevertheless, the pros and cons of thoracoscopy vs. open surgery in pediatric oncology are still under debate. In literature, VATS has been applied for both diagnostic and ablative surgery to treat neurogenic tumors, thymic neoplasms, lung tumors and metastases, germ cell tumors, lymphoproliferative diseases, and other rare tumors. Recent reviews described excellent outcomes in pediatric oncology as well as in the treatment of adult lung cancer, with a significantly higher rate of mortality and complication in thoracotomy compared to VATS. We reviewed our experience on thoracoscopy in pediatric malignancy and compared it to the literature.

Materials and Methods:This was a retrospective cohort-study of pediatric oncological patients who underwent VATS at our institution from 2007 to 2020, and a review of the recent literature on the topic.

Results:A total of 43 procedures were performed on 38 oncological patients (18 males, 20 females). Median age was years 7.72 (0.35–18.6). Diagnosis: 10 neurogenic tumors, nine hematological diseases, five metastases, four lypoblastomas, three thymic pathologies, three germ cell tumors, two pleuropneumoblastomas, two myofibroblastic tumors, one myoepithelial carcinoma, one liposarcoma, and three suspected oncological mass. In three cases, a 3D model was elaborated to better plan the surgical approach. Diagnostic biopsies were 22 (51.1%), and ablative surgeries, 21 (48.9%). One neurogenic tumor was resected with the Da Vinci Robot. Median operative time was 120 min (30–420). A drain was left in place in 20 (46.5%) for a median of 4 days. Median length of hospitalization was 5 days (1–18). One case (2.3%) was converted (intraoperative bleeding). There were three post-operative complications (7.0%): one pneumonia, one pleural effusion, and one diaphragmatic paralysis (need for plication). Results were compared to recent literature, and morbidity and conversion rate were comparable to reviewed publications.

Conclusion:VATS represents a valuable tool for diagnostic and therapeutic procedures in pediatric oncology. Nonetheless, it is a challenging technique that should be performed by expert surgeons on oncological and mini-invasive surgery. Three-dimensional reconstruction can optimize the pre-operative planning and guarantee a safer and more targeted treatment. Finally, the advent of robotics-assisted surgery represents a new challenge that may further implement the advantages of VATS.
Comparison of Three Gestational Weight Gain Guidelines Under Use in Latin America
Authors: Mardones Francisco , Rosso Pedro , Erazo Álvaro , Farías Marcelo
Published: October 2021

Presently, three guidelines are used in Latin America to assess adequacy of maternal body mass index (BMI) during pregnancy: (1) the chart proposed by the Institute of Medicine of the United States (IOM), (2) the Rosso-Mardones Chart (RM), and (3) a modified RM chart proposed by Atalah et al. (AEA). The aim of the present review was to explore available information on the sensitivity, specificity, and both positive (PPV) and negative predictive values (NPV) of these charts to detect women at risk of delivering babies with the following signs of abnormal fetal growth: (a) length at birth (BL) <50 cm; (b) birth weight (BW) <3,000 g; and (c) BW ≥ 4,000 or 4,250 g. Data from studies conducted in large samples of Chilean and Uruguayan women indicate that the RM chart has the greatest sensitivity to identify at risk cases. However, predictive values were similar for the three charts. Thus, the use of the RM chart should be preferred. The main limitation for using the IOM weight gain recommendations in Latin American women stems from the fact that their average height is approximately 20 cm lower than US women.
A Novel Long Noncoding RNA lincRNA00892 Activates CD4+ T Cells in Systemic Lupus Erythematosus by Regulating CD40L
Authors: Liu Xiao , Lin Jinran , Wu Hao , Wang Yilun , Xie Lin , Wu Jinfeng , Qin Haihong , Xu Jinhua
Published: October 2021

Objective:The mechanism of CD4+T-cell dysfunction in systemic lupus erythematosus (SLE) has not been fully understood. Increasing evidence show that long noncoding RNAs (lncRNAs) can regulate immune responses and take part in some autoimmune diseases, while little is known about the lncRNA expression and function in CD4+T of SLE. Here, we aimed to detect the expression profile of lncRNAs in lupus CD4+T cells and explore the mechanism that how lincRNA00892 in CD4+T cells is involved in the pathogenesis of SLE.

Methods:The expression profiles of lncRNAs and mRNAs in CD4+T cells from SLE patients and healthy controls were detected by microarray. LincRNA00892 and CD40L were chosen for validation by quantitative real-time PCR (qRT-PCR). Coexpression network was conducted to predict the potential target genes of lincRNA00892. Then lincRNA00892 was overexpressed in normal CD4+T cells via lentivirus transfection. The expression of lincRNA00892 was detected by qRT-PCR. The expression of CD40L was detected by qRT-PCR, western blotting, and flow cytometry, respectively. The expression of CD69 and CD23 was measured by flow cytometry. The secretion of IgG was determined by enzyme-linked immunosorbent assay (ELISA). The proteins targeted by lincRNA00892 were measured by RNA pulldown and subsequent mass spectrometry (MS). The interaction between heterogeneous nuclear ribonucleoprotein K (hnRNP K) and lincRNA00892 or CD40L was detected by RNA immunoprecipitation (RIP) assay.

Results:A total of 1887 lncRNAs and 3375 mRNAs were found to be aberrantly expressed in CD4+T cells of SLE patients compared to healthy controls. LincRNA00892 and CD40L were confirmed to be upregulated in CD4+T cells of SLE patients by qRT-PCR. The lncRNA–mRNA coexpression network analysis indicated that CD40L was a potential target of lincRNA00892. Overexpression of lincRNA00892 enhanced CD40L protein levels while exerting little influence on CD40L mRNA levels in CD4+T cells. In addition, lincRNA00892 could induce the activation of CD4+T cells. Furthermore, lincRNA00892 led to the activation of B cells and subsequent secretion of IgG in a CD4+T-cell–dependent manner. Finally, hnRNP K was found to be among the proteins pulled down by lincRNA00892, and hnRNP K could bind to lincRNA00892 or CD40L directly.

Conclusion:Our results showed that the lncRNA expression profile was altered in CD4+T cells of SLE. LincRNA00892 possibly contributed to the pathogenesis of SLE by targeting hnRNP K and subsequently upregulating CD40L expression to activate CD4+T and B cells. These provided us a potential target for further mechanistic studies of SLE pathogenesis.