bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Value of Blood Pressure Variability for Patients With Acute or Subacute Intracerebral Hemorrhage: A Meta-Analysis of Prospective Studies
Authors: Liu Weidong , Zhuang Xianbo , Zhang Liyong
Published: March 2021

The results on the role of systolic blood pressure (SBP) variability in the functional outcome for patients with intracerebral hemorrhage (ICH) have been inconsistent. Hence, this meta-analysis of prospective studies was conducted to assess the association between SBP variability and poor outcomes in patients with acute or subacute ICH. PubMed, Embase, and the Cochrane Library were electronically searched for eligible studies from their inception to July 2020. The role of SBP variability assessed using standard deviation (SD), coefficient of variation (CV), successive variation (SV), average real variability (ARV), and residual standard deviation (RSD) in the risk of poor functional outcomes were assessed using odds ratio (OR) with 95% confidence interval (CI) through the random-effects model. Seven prospective studies involving 5,201 patients with ICH were selected for the final meta-analysis. Increased SBP variability was associated with an increased risk of poor functional outcomes, regardless of its assessment using SD (OR: 1.38; 95% CI: 1.14–1.68; P = 0.001), CV (OR: 1.98; 95% CI: 1.13–3.47; P = 0.017), SV (OR: 1.30; 95% CI: 1.08–1.58; P = 0.006), ARV (OR: 1.13; 95% CI: 1.03–1.24; P = 0.010), or RSD (OR: 1.22; 95% CI: 1.00–1.50; P = 0.049). Moreover, the role of SBP variability in the risk of poor functional outcomes for patients with ICH was affected by country, study design, mean age, stroke type, outcome definition, and study quality. This study indicated that SBP variability was a predictor of poor outcomes for patients with ICH.
Decomposing Acute Symptom Severity in Large Vessel Occlusion Stroke: Association With Multiparametric CT Imaging and Clinical Parameters
Authors: Stueckelschweiger Lena , Tiedt Steffen , Puhr-Westerheide Daniel , Fabritius Matthias P. , Mueller Franziska , Kellert Lars , Maurus Stefan , Grosu Sergio , Rueckel Johannes , Herzberg Moriz , Liebig Thomas , Ricke Jens , Dimitriadis Konstantinos , Kunz Wolfgang G. , Reidler Paul
Published: March 2021

Background and Purpose: Acute ischemic stroke of the anterior circulation due to large vessel occlusion (LVO) is a multifactorial process, which causes neurologic symptoms of different degree. Our aim was to examine the impact of neuromorphologic and vascular correlates as well as clinical factors on acute symptom severity in LVO stroke.

Methods: We selected LVO stroke patients with known onset time from a consecutive cohort which underwent multiparametric CT including non-contrast CT, CT angiography and CT perfusion (CTP) before thrombectomy. Software-based quantification was used to calculate CTP total ischemic and ischemic core volume. Symptom severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) upon admission. Multivariable regression analysis was performed to determine independent associations of admission NIHSS with imaging and clinical parameters. Receiver operating characteristics (ROC) analyses were used to examine performance of imaging parameters to classify symptom severity.

Results: We included 142 patients. Linear and ordinal regression analyses for NIHSS and NIHSS severity groups identified significant associations for total ischemic volume [β = 0.31, p = 0.01; Odds ratio (OR) = 1.11, 95%-confidence-interval (CI): 1.02–1.19], clot burden score (β = −0.28, p = 0.01; OR = 0.76, 95%-CI: 0.64–0.90) and age (β = 0.17, p = 0.04). No association was found for ischemic core volume, stroke side, collaterals and time from onset. Stroke topography according to the Alberta Stroke Program CT Score template did not display significant influence after correction for multiple comparisons. AUC for classification of the NIHSS threshold ≥6 by total ischemic volume was 0.81 (p < 0.001).

Conclusions: We determined total ischemic volume, clot burden and age as relevant drivers for baseline NIHSS in acute LVO stroke. This suggests that not only mere volume but also degree of occlusion influences symptom severity. Use of imaging parameters as surrogate for baseline NIHSS reached limited performance underlining the need for combined clinical and imaging assessment in acute stroke management.
Evoked Potentials Differentiate Developmental Coordination Disorder From Attention-Deficit/Hyperactivity Disorder in a Stop-Signal Task: A Pilot Study
Authors: Meachon Emily J. , Meyer Marcel , Wilmut Kate , Zemp Martina , Alpers Georg W.
Published: March 2021

Developmental Coordination Disorder and Attention-Deficit/Hyperactivity Disorder are unique neurodevelopmental disorders with overlaps in executive functions and motor control. The conditions co-occur in up to 50% of cases, raising questions of the pathological mechanisms of DCD versus ADHD. Few studies have examined these overlaps in adults with DCD and/or ADHD. Therefore, to provide insights about executive functions and motor control between adults with DCD, ADHD, both conditions (DCD + ADHD), or typically developed controls, this study used a stop-signal task and parallel EEG measurement. We assessed executive performance via go accuracy and go reaction time, as well as motor response inhibition via stop-signal reaction time. This was complemented with analysis of event-related potentials (ERPs). Based on existing investigations of adults with DCD or ADHD, we expected (1) groups would not differ in behavioral performance on stop and go trials, but (2) differences in ERPs, particularly in components N200 (index of cognitive control) and P300 (index of attention and inhibition) would be evident. The sample included N = 50 adults with DCD (n = 12), ADHD (n = 9), DCD + ADHD (n = 7), and control participants (n = 22). We replicated that there were no between-group differences for behavioral-level executive performance and motor response inhibition. However, on a physiological level, ERP components N200 and P300 differed between groups, particularly during successful response inhibition. These ERPs reflect potential endophenotypic differences not evident in overt behavior of participants with ADHD and/or DCD. This suggests a disorder specific employment of inhibition or general executive functions in groups of adults with DCD, DCD + ADHD, ADHD, or control participants.
Analysis of the Neuroproteome Associated With Cell Therapy After Intranigral Grafting in a Mouse Model of Parkinson Disease
Authors: Dakik Hassan , Mantash Sarah , Nehme Ali , Kobeissy Firas , Zabet-Moghaddam Masoud , Mirzaei Parvin , Mechref Yehia , Gaillard Afsaneh , Prestoz Laetitia , Zibara Kazem
Published: March 2021

Advances in large-scale proteomics analysis have been very useful in understanding pathogenesis of diseases and elaborating therapeutic strategies. Proteomics has been employed to study Parkinson disease (PD); however, sparse studies reported proteome investigation after cell therapy approaches. In this study, we used liquid chromatography–tandem mass spectrometry and systems biology to identify differentially expressed proteins in a translational mouse model of PD after cell therapy. Proteins were extracted from five nigrostriatal-related brain regions of mice previously lesioned with 6-hydroxydopamine in the substantia nigra. Protein expression was compared in non-grafted brain to 1 and 7 days after intranigral grafting of E12.5 embryonic ventral mesencephalon (VM). We found a total of 277 deregulated proteins after transplantation, which are enriched for lipid metabolism, oxidative phosphorylation and PD, thus confirming that our animal model is similar to human PD and that the presence of grafted cells modulates the expression of these proteins. Notably, seven proteins (Acta1, Atp6v1e1, Eci3, Lypla2, Pip4k2a, Sccpdh, and Sh3gl2) were commonly down-regulated after engraftment in all studied brain regions. These proteins are known to be involved in the formation of lipids and recycling of dopamine (DA) vesicle at the synapse. Moreover, intranigral transplantation of VM cells decreased the expression of proteins related to oxidative stress, especially in the nigrostriatal pathway containing the DA grafted neurons. In the same regions, an up-regulation of several proteins including α-synuclein and tyrosine hydroxylase was observed, whereas expression of tetraspanin 7 was shut down. Overall, these results suggest that intranigral transplantation of VM tissue in an animal model of PD may induce a decrease of oxidative stress in the nigrostriatal pathway and a restoration of the machinery of neurotransmitters, particularly DA release to promote DA transmission through a decrease of D2 DA receptors endocytosis. Identification of new mechanistic elements involved in the nigrostriatal reconstruction process, using translational animal models and systems biology, is a promising approach to enhance the repair of this pathway in PD patients undergoing cell therapy.
Neuropeptides as Primary Mediators of Brain Circuit Connectivity
Authors: Guillaumin Mathilde C. C. , Burdakov Denis
Published: March 2021

Across sleep and wakefulness, brain function requires inter-neuronal interactions lasting beyond seconds. Yet, most studies of neural circuit connectivity focus on millisecond-scale interactions mediated by the classic fast transmitters, GABA and glutamate. In contrast, neural circuit roles of the largest transmitter family in the brain–the slow-acting peptide transmitters–remain relatively overlooked, or described as “modulatory.” Neuropeptides may efficiently implement sustained neural circuit connectivity, since they are not rapidly removed from the extracellular space, and their prolonged action does not require continuous presynaptic firing. From this perspective, we review actions of evolutionarily-conserved neuropeptides made by brain-wide-projecting hypothalamic neurons, focusing on lateral hypothalamus (LH) neuropeptides essential for stable consciousness: the orexins/hypocretins. Action potential-dependent orexin release inside and outside the hypothalamus evokes slow postsynaptic excitation. This excitation does not arise from modulation of classic neurotransmission, but involves direct action of orexins on their specific G-protein coupled receptors (GPCRs) coupled to ion channels. While millisecond-scale, GABA/glutamate connectivity within the LH may not be strong, re-assessing LH microcircuits from the peptidergic viewpoint is consistent with slow local microcircuits. The sustained actions of neuropeptides on neuronal membrane potential may enable core brain functions, such as temporal integration and the creation of lasting permissive signals that act as “eligibility traces” for context-dependent information routing and plasticity. The slowness of neuropeptides has unique advantages for efficient neuronal processing and feedback control of consciousness.
Current Approaches for Glioma Gene Therapy and Virotherapy
Authors: Banerjee Kaushik , Núñez Felipe J. , Haase Santiago , McClellan Brandon L. , Faisal Syed M. , Carney Stephen V. , Yu Jin , Alghamri Mahmoud S. , Asad Antonela S. , Candia Alejandro J. Nicola , Varela Maria Luisa , Candolfi Marianela , Lowenstein Pedro R. , Castro Maria G.
Published: March 2021

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.
The Subcortical-Allocortical- Neocortical continuum for the Emergence and Morphological Heterogeneity of Pyramidal Neurons in the Human Brain
Authors: Rasia-Filho Alberto A. , Guerra Kétlyn T. Knak , Vásquez Carlos Escobar , Dall’Oglio Aline , Reberger Roman , Jung Cláudio R. , Calcagnotto Maria Elisa
Published: March 2021

Human cortical and subcortical areas integrate emotion, memory, and cognition when interpreting various environmental stimuli for the elaboration of complex, evolved social behaviors. Pyramidal neurons occur in developed phylogenetic areas advancing along with the allocortex to represent 70–85% of the neocortical gray matter. Here, we illustrate and discuss morphological features of heterogeneous spiny pyramidal neurons emerging from specific amygdaloid nuclei, in CA3 and CA1 hippocampal regions, and in neocortical layers II/III and V of the anterolateral temporal lobe in humans. Three-dimensional images of Golgi-impregnated neurons were obtained using an algorithm for the visualization of the cell body, dendritic length, branching pattern, and pleomorphic dendritic spines, which are specialized plastic postsynaptic units for most excitatory inputs. We demonstrate the emergence and development of human pyramidal neurons in the cortical and basomedial (but not the medial, MeA) nuclei of the amygdala with cells showing a triangular cell body shape, basal branched dendrites, and a short apical shaft with proximal ramifications as “pyramidal-like” neurons. Basomedial neurons also have a long and distally ramified apical dendrite not oriented to the pial surface. These neurons are at the beginning of the allocortex and the limbic lobe. “Pyramidal-like” to “classic” pyramidal neurons with laminar organization advance from the CA3 to the CA1 hippocampal regions. These cells have basal and apical dendrites with specific receptive synaptic domains and several spines. Neocortical pyramidal neurons in layers II/III and V display heterogeneous dendritic branching patterns adapted to the space available and the afferent inputs of each brain area. Dendritic spines vary in their distribution, density, shapes, and sizes (classified as stubby/wide, thin, mushroom-like, ramified, transitional forms, “atypical” or complex forms, such as thorny excrescences in the MeA and CA3 hippocampal region). Spines were found isolated or intermingled, with evident particularities (e.g., an extraordinary density in long, deep CA1 pyramidal neurons), and some showing a spinule. We describe spiny pyramidal neurons considerably improving the connectional and processing complexity of the brain circuits. On the other hand, these cells have some vulnerabilities, as found in neurodegenerative Alzheimer’s disease and in temporal lobe epilepsy.
Characteristics of T-Cell Receptor Repertoire and Correlation With EGFR Mutations in All Stages of Lung Cancer
Authors: Yang Huaxia , Wang Yadong , Jia Ziqi , Wang Yanyu , Yang Xiaoying , Wu Pancheng , Song Yang , Xu Huihui , Gu Dejian , Chen Rongrong , Xia Xuefeng , Bing Zhongxing , Gao Chao , Cao Lei , Li Shanqing , Cao Zhili , Liang Naixin
Published: March 2021

Lung cancer is the leading cause of cancer-related deaths worldwide, and its occurrence is related to the accumulation of gene mutations and immune escape of the tumor. Sequencing of the T-cell receptor (TCR) repertoire can reveal the immunosurveillance status of the tumor microenvironment, which is related to tumor escape and immunotherapy. This study aimed to determine the characteristics and clinical significance of the TCR repertoire in lung cancer. To comprehensively profile the TCR repertoire, results from high-throughput sequencing of samples from 93 Chinese patients with lung cancer were analyzed. We found that the TCR clonality of tissues was related to smoking, with higher clonality in patients who had quit smoking for less than 1 year. As expected, TCR clonality was correlated with stages: patients with stage IV disease showed higher clonality than others. The correlation between TCR repertoire and epidermal growth factor receptor (EGFR) status was also investigated. Patients with EGFR non-L858R mutations showed higher clonality and a lower Shannon index than other groups, including patients with EGFR L858R mutation and wild-type EGFR. Furthermore, we analyzed the TCR similarity metrics—that is, the TCR shared between postoperative peripheral blood and tissue of patients with non-distant metastasis of lung cancer. A similar trend was found, in which patients with EGFR L858R mutations had lower overlap index (OLI) and Morisita index (MOI) scores. Moreover, the OLI showed a positive correlation with several clinical characteristics, including the tumor mutational burden of tissues and the maximum somatic allele frequency of blood; OLI showed a negative correlation with the ratio of CD4+CD28+ in CD4+ cells and the ratio of CD8+CD28+ in CD8+ cells. In conclusion, TCR clonality and TCR similarity metrics correlated with clinical characteristics of patients with lung cancer. Differences in TCR clonality, Shannon index, and OLI across EGFR subtypes provide information to improve understanding about varied responses to immunotherapy in patients with different EGFR mutations.
A Clinical Decision Support System for Predicting Invasive Breast Cancer Recurrence: Preliminary Results
Authors: Massafra Raffaella , Latorre Agnese , Fanizzi Annarita , Bellotti Roberto , Didonna Vittorio , Giotta Francesco , La Forgia Daniele , Nardone Annalisa , Pastena Maria , Ressa Cosmo Maurizio , Rinaldi Lucia , Russo Anna Orsola Maria , Tamborra Pasquale , Tangaro Sabina , Zito Alfredo , Lorusso Vito
Published: March 2021

The mortality associated to breast cancer is in many cases related to metastasization and recurrence. Personalized treatment strategies are critical for the outcomes improvement of BC patients and the Clinical Decision Support Systems can have an important role in medical practice. In this paper, we present the preliminary results of a prediction model of the Breast Cancer Recurrence (BCR) within five and ten years after diagnosis. The main breast cancer-related and treatment-related features of 256 patients referred to Istituto Tumori “Giovanni Paolo II” of Bari (Italy) were used to train machine learning algorithms at the-state-of-the-art. Firstly, we implemented several feature importance techniques and then we evaluated the prediction performances of BCR within 5 and 10 years after the first diagnosis by means different classifiers. By using a small number of features, the models reached highly performing results both with reference to the BCR within 5 years and within 10 years with an accuracy of 77.50% and 80.39% and a sensitivity of 92.31% and 95.83% respectively, in the hold-out sample test. Despite validation studies are needed on larger samples, our results are promising for the development of a reliable prognostic supporting tool for clinicians in the definition of personalized treatment plans.
Peripheral Blood Genetic Biomarkers for the Early Diagnosis of Hepatocellular Carcinoma
Authors: Song Ting , Li Li , Wu Shaobo , Liu Yan , Guo Caiping , Wang Wen , Dai Lili , Zhang Tong , Wu Hao , Su Bin
Published: March 2021

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has high mortality. Biomarkers related to HCC, such as alpha-fetoprotein, and imaging technology, such as ultrasound and computed tomography, have been used to screen and monitor HCC, but HCC is still difficult to diagnose effectively in the early stage due to the low sensitivity of the above mentioned traditional methods. There is an urgent need for noninvasive biomarkers to facilitate the screening and early diagnosis of HCC. With the advancement of next-generation sequencing, genetic biomarkers are becoming the core of cancer diagnosis. Genetic biomarkers such as peripheral blood circulating tumor DNA, microRNAs, long noncoding RNAs, circular RNAs, and exosomes have become the focus of early HCC diagnostics. HCC genetic biomarkers have been implemented in clinical practice. In this review, we describe the available literature on peripheral blood genetic biomarkers in the diagnosis of early HCC.
The Prognostic Value of Plasma Cell-Free DNA Concentration in the Prostate Cancer: A Systematic Review and Meta-Analysis
Authors: Liu Hongtao , Gao Yuzhen , Vafaei Somayeh , Gu Xiao , Zhong Xiaoli
Published: March 2021

Objective

By virtue of largely disparate clinical outcomes of prostate cancer (PCA), there is a pressing need to search for useful biomarkers for PCA prognosis. Cell-free DNA (cfDNA) is a promising biomarker for detecting, monitoring, and predicting survival of prostate cancer (PCA). However, the utility of total cfDNA quantitation in PCA in clinical setting remains elusive. Here, we performed a thorough meta-analysis to assess the prognostic value of cfDNA concentration for patients with PCA. In addition, we tested the possibility of the combination of PSA and cfDNA test results to improve the prediction power in PCA prognosis.

Method and Materials

More than six databases, including PubMed, Web of Science, Medline, PMC, EMBASE and the Cochrane Library were searched. Results yielded all eligible articles from the date of inception to June 30, 2020. Continuous, diagnostic, and prognostic variables in cfDNA in PCA were included in the meta-analysis by STATA.

Results

A total of 23 articles were enrolled in our meta-analysis: 69.6% (16/23) were related to diagnosis, and 56.5% (13/23) were related to prognosis. The pooled concentration of cfDNA in PCA patients was significantly higher than in the control group (SMD = 0.89, 95%CI = 0.53, 1.26), mirroring results for the prostate-specific antigen (PSA). For the detection test variables, the SROC with 95%CI was 0.87 (0.84–0.90) for cfDNA concentration. In terms of prognostic variables, the concentrations of cfDNA were significantly related with progression-free survival (PFS, logHR = 0.84 (95%CI0.39, 1.28) and overall survival [OS, log HR = 0.60 (95%CI0.29, 0.90)]. Lastly, the test showed no significant publication bias in the present meta-analysis, excluding the diagnostic meta-analysis.

Conclusions

The concentration of cell-free DNA is high in the prostate cancer patients. The present study substantiates the prognostic value of the cfDNA concentration. High concentration cfDNA correlates with poor disease outcome of CRPC. The study cohort with large sample size is needed to evaluate the prognosis value of cfDNA in the future. We also emphasized that combination of PSA and cf DNA quantitation is important in future large individual meta study.
The Local Anesthetic Bupivacaine Inhibits the Progression of Non-Small Cell Lung Cancer by Inducing Autophagy Through Akt/mTOR Signaling
Authors: Gu Jian-Hua , Liu Cui-Cui , Xie Jin-Lan , Ma Bin , Cui Shao-Min , Yang Guang-Zhu , He Shun-Cheng
Published: March 2021

Non-small cell lung cancer (NSCLC) is a prevalent malignancy with high mortality and poor prognosis. Bupivacaine serves as a widely used local anesthetic and presents potential anti-tumor activity. Nevertheless, the function of bupivacaine in the NSCLC development remains elusive. Here, we tried to investigate the impact of bupivacaine on the NSCLC progression. Significantly, we revealed that bupivacaine was able to reduce the proliferation and induce the apoptosis of NSCLC cells. Bupivacaine could attenuate the invasion and migration in the cells. Mechanically, the treatment of bupivacaine increased the expression ratio of light chain 3B-II (LC3B-II)/LC3B-I and the expression of Beclin-1 in the NSCLC cells. Meanwhile, the expression of the autophagic adaptor protein p62 was decreased by bupivacaine treatment in the cells. The treatment of bupivacaine attenuated the phosphorylation of AKT and mTOR in the NSCLC cells. The AKT activator SC79 and autophagy inhibitor 3-methyladenine (3-MA) reversed the bupivacaine-inhibited phosphorylation of AKT and mTOR and bupivacaine-induced autophagy, as well as the bupivacaine-attenuated NSCLC progression in the cells. Bupivacaine could inhibit the tumor growth in vivo. In conclusion, we discovered that the local anesthetic bupivacaine inhibited the progression of NSCLC by inducing autophagy through Akt/mTOR signaling. Our finding provides new insights into the mechanism by which bupivacaine attenuates the development of NSCLC. Bupivacaine may serve as a potential anti-tumor candidate for the therapeutic strategy of NSCLC.
High Pretreatment LDH Predicts Poor Prognosis in Hypopharyngeal Cancer
Authors: Wu Jialing , You Kaiyun , Chen Changlong , Zhong Huimin , Jiang Yanhui , Mo Huaqian , Song Juanjuan , Qiu Xingsheng , Liu Yimin
Published: March 2021

Background

Elevated pretreatment lactate dehydrogenase (LDH) has been associated with poor prognosis in various malignancies; however, its prognostic role in hypopharyngeal cancer remains elusive. In this study, we aimed to assess the association between pretreatment LDH and clinical outcome of hypopharyngeal cancer.

Methods

We retrospectively collected 198 hypopharyngeal cancer patients treated with surgery in our institution between 2004 and 2018. The prognostic role of pretreatment LDH was explored by using univariate and multivariate analyses. Besides, subgroup analysis was performed based on T stage.

Results

Three-year and Five-year of disease-free survival (DFS, 67.0 vs. 57.4%, 65.8 vs. 39.8%, p = 0.007) and overall survival (OS, 74.8 vs. 68.9%, 66.8 vs. 50.8%, p = 0.006) exhibited significant differences between low LDH level and high LDH level groups. Univariate analysis showed that pretreatment elevated serum LDH served as an unfavorable determinant with regard to DFS and OS. Further multivariate analysis also confirmed that LDH was an independent predictor for DFS and OS. Additionally, N status and age were also found to be significantly associated with both DFS and OS.

Conclusion

Pretreatment elevated serum LDH is an inferior prognostic factor for patients with hypopharyngeal cancer. These results should be validated by more multicenter and prospective studies.
Outcomes of Adults With Relapsed/Refractory Acute Myeloid Leukemia Treated With Venetoclax Plus Hypomethylating Agents at a Comprehensive Cancer Center
Authors: Tenold Matthew E. , Moskoff Benjamin N. , Benjamin David J. , Hoeg Rasmus T. , Rosenberg Aaron S. , Abedi Mehrdad , Tuscano Joseph M. , Jonas Brian A.
Published: March 2021

Relapsed/refractory acute myeloid leukemia (AML) is a devastating disease with a poor prognosis and represents a major unmet medical need. We report on a real-world academic center experience of treating 25 patients with relapsed/refractory AML using venetoclax in combination with decitabine or azacitidine, which is not otherwise widely evaluated in the current literature. Our patients come from a large, socioeconomically and geographically diverse area including the majority of Northern California. Most had ELN Adverse Risk (52%) or Intermediate Risk (44%) AML, and most had an ECOG Performance Status of 1 (64%). Over half (52%) had prior hypomethylating agent exposure, and 40% had Secondary AML. We observed an overall response rate of 52%, with eight patients (32%) achieving composite complete remission. Median overall survival was 5.5 months, and for patients achieving composite complete remission this was 21.6 months. One-year estimated overall survival was 38%. Three patients were able to proceed directly to stem cell transplant for consolidation, and all three were alive at last follow-up, ranging 13.8–24.0 months. We found venetoclax in combination with hypomethylating agents to be well tolerated and potentially efficacious in securing long-term remissions for patients with relapsed/refractory AML.
SLC1A4: A Powerful Prognostic Marker and Promising Therapeutic Target for HCC
Authors: Peng Xiaozhen , Chen Ruochan , Cai Shenglan , Lu Shanshan , Zhang Yiya
Published: March 2021

SLC1A4, a Na-dependent neutral amino acid transporter, was considered to participate in the various pathobiological process, including tumorigenesis. However, the correlation between SLC1A4 and Hepatocellular Carcinoma (HCC) remains unclear. In our study, integrative bioinformatics and functional profiling were performed to reveal the prognosis and potential function of SLC1A4 in HCC. The results showed that the mRNA and protein levels of SLC1A4 were elevated in HCC, and it was a powerful independent prognostic marker for overall survival (OS). The co-expressed genes analysis and GSEA analysis showed that SLC1A4 was related to cell cycle, metabolism, cancer-related pathway. Furthermore, the functional analysis revealed that silenced SLC1A4 inhibited cell proliferation, migration, cell cycle, and promoted cell apoptosis in HCC. Next, immune analysis showed that SLC1A4 expression was positively associated with immune infiltration and immune-related chemokine expression in HCC. Silenced SLC1A4 evidently reduced these chemokines expression in HCC cells. Finally, drug sensitivity analysis revealed potential five sensitivity drugs for HCC patients with high-expressed SLC1A4. In conclusion, our results suggested that SLCIA4 could be a novel predictor prognosis and immunotherapeutic targets of HCC, and the sensitivity drugs may be effective therapeutic strategy for HCC patients with high-expressed SLC1A4.
Biomarkers in Immunotherapy-Based Precision Treatments of Digestive System Tumors
Authors: Zeng Zhu , Yang Biao , Liao Zhengyin
Published: March 2021

Immunotherapy, represented by immune checkpoint inhibitors (mainly referring to programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockades), derives durable remission and survival benefits for multiple tumor types including digestive system tumors [gastric cancer (GC), colorectal cancer (CRC), and hepatocellular carcinoma (HCC)], particularly those with metastatic or recurrent lesions. Even so, not all patients would respond well to anti-programmed death-1/programmed death-ligand 1 agents (anti-PD-1/PD-L1) in gastrointestinal malignancies, suggesting the need for biomarkers to identify the responders and non-responders, as well as to predict the clinical outcomes. PD-L1expression has increasingly emerged as a potential biomarker when predicting the immunotherapy-based efficacy; but regrettably, PD-L1 alone is not sufficient to differentiate patients. Other molecules, such as tumor mutational burden (TMB), microsatellite instability (MSI), and circulating tumor DNA (ctDNA) as well, are involved in further explorations. Overall, there are not still no perfect or well-established biomarkers in immunotherapy for digestive system tumors at present as a result of the inherent limitations, especially for HCC. Standardizing and harmonizing the assessments of existing biomarkers, and meanwhile, switching to other novel biomarkers are presumably wise and feasible.
Studying the Effects of Granulocyte-Macrophage Colony-Stimulating Factor on Fetal Lung Macrophages During the Perinatal Period Using the Mouse Model
Authors: Cheah Fook-Choe , Presicce Pietro , Tan Tian-Lee , Carey Brenna C. , Kallapur Suhas G.
Published: March 2021

Background:Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory cytokine that is increased in the amniotic fluid in chorioamnionitis and elevated in the fetal lung with endotoxin exposure. Although GM-CSF has a pivotal role in fetal lung development, it stimulates pulmonary macrophages and is associated with the development of bronchopulmonary dysplasia (BPD). How antenatal GM-CSF results in recruitment of lung macrophage leading to BPD needs further elucidation. Hence, we used a transgenic and knock-out mouse model to study the effects of GM-CSF focusing on the fetal lung macrophage.

Methods:Using bitransgenic (BTg) mice that conditionally over-expressed pulmonary GM-CSF after doxycycline treatment, and GM-CSF knock-out (KO) mice with no GM-CSF expression, we compared the ontogeny and immunophenotype of lung macrophages in BTg, KO and control mice at various prenatal and postnatal time points using flow cytometry and immunohistology.

Results:During fetal life, compared to controls, BTg mice over-expressing pulmonary GM-CSF had increased numbers of lung macrophages that were CD68+and these were primarily located in the interstitium rather than alveolar spaces. The lung macrophages that accumulated were predominantly CD11b+F4/80+indicating immature macrophages. Conversely, lung macrophages although markedly reduced, were still present in GM-CSF KO mice.

Conclusion:Increased exposure to GM-CSF antenatally, resulted in accumulation of immature macrophages in the fetal lung interstitium. Absence of GM-CSF did not abrogate but delayed the transitioning of interstitial macrophages. Together, these results suggest that other perinatal factors may be involved in modulating the maturation of alveolar macrophages in the developing fetal lung.
Referential Values of Testicular Volume Measured by Ultrasonography in Normal Children and Adolescents: Z-Score Establishment
Authors: Liu Chen , Liu Xiao , Zhang Xiangxiang , Yang Boyang , Huang Lan , Wang Hongying , Yu Hongkui
Published: March 2021

Objective: To establish Z-score regression equation derived from age for testicular volume measured by ultrasonography in normal boys aged 0 to 18 years old.

Method: The length (L), width (W), and height (H) of 3,328 testicles from 1,664 Chinese boys were measured by ultrasonography. Lambert's formula: L × W × H × 0.71 was used to calculate testicular volume. Z-score regression equation derived from age was established by regression analysis of predicted values of testicular volume and standard deviations.

Result: There was no significant difference between left and right testicular volumes. Testicular volume was positively correlated with age, and logarithmic transformation of testicular volume can show a fine curve fit with age. To establish Z-score regression equation derived from age, the predicted values of testicular volume used cubic regression equations, and the standard deviation used square regression equations. The Z-score regression equation derived from age was calculated by the formula: z = [lg (L × W × H × 0.71) – (−0.3524-0.01759 × x+0.009417 × x2-0.0001840 × x3)]/(0.1059+0.01434 × x-0.0005324 × x2).

Conclusion: The current study provided a reference value for testicular volume of boys aged 0 to 18 years old. Z-score regression equation derived from age for testicular volume can be established. Z-score will be of great value for the testicular development assessment and disease diagnosis and follow-up.
Doubling the Dose of Bevacizumab Beyond Progression in Metastatic Colorectal Cancer–the Experience of a Tertiary Cancer Center
Authors: Căinap Călin , Bochiş Ovidiu-Vasile , Vlad Cătălin , Popita Raluca , Achimaş-Cadariu Patriciu , Havasi Andrei , Vidrean Andreea , Dranca Alexandra , Piciu Andra , Constantin Anne-Marie , Tat Tiberiu , Dana Maniu , Crişan Ovidiu , Cioban Cosmin Vasile , Bălăcescu Ovidiu , Coza Ovidiu , Bălăcescu Loredana , Marta Monica Mihaela , Bota Madalina , Căinap Simona
Published: March 2021

Background: Colorectal cancer (CRC) is the third most common cancer in Europe, with an annual increase in incidence ranging between 0.4 and 3.6% in various countries. Although the development of CRC was extensively studied, limited number of new therapies were developed in the last few years. Bevacizumab is frequently used as first- and second-line therapy for management of metastatic CRC (mCRC). The aim of this study is to present our experience with using bevacizumab beyond disease progression at different dosage levels in mCRC patients, in terms of overall survival, progression-free survival, time to treatment failure, and toxicities.

Methods: We performed a consecutive retrospective analysis of patients with confirmed mCRC who were treated with bevacizumab at "Prof Dr. Ion Chiricuta" Institute of Oncology, Cluj-Napoca, Romania. We included patients who had received bevacizumab as first- or second-line therapy and further stratified them according to the dose administered as a second-line (either standard dose of 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks, or double dose of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks–depending on the classical chemotherapy partner). All patients had received bevacizumab beyond progression (BYP) which is defined as continuing bevacizumab administration through second-line treatment despite disease progression. In each group, we evaluated the prognostic factors that influenced survival and treatment outcome.

Results: One hundred and fifty-one (151) patients were included in the study. Themedian age of patients receiving double dose bevacizumab (DDB) and standard dose bevacizumab (SDB) was 58 years (range 41–71) and 57 years (range 19–75), respectively. The median overall survival in the DDB group was 41 months (range 27–49) compared to 25 months (range 23–29) in the SDB group (p = 0.01 log-rank test). First-line oxaliplatin-based treatment was used more frequently regardless of group, while irinotecan-based more frequently used as a second-line treatment (p = 0.014). Both oxaliplatin- and irinotecan-based regimens were found to be suitable partners for BYP. Statistical analysis revealed that dose intensity, primary tumor location, and cumulative exposure to BYP had significant influence on survival.

Conclusion: Doubling the dose of bevacizumab after first progression may improve survival in mCRC patients. Increasing bevacizumab dose intensity could override the prognostic impact of primary tumor location in patients receiving double the dose of bevacizumab after first disease progression.
Update on Calcium Signaling in Cystic Fibrosis Lung Disease
Authors: Rimessi Alessandro , Vitto Veronica A. M. , Patergnani Simone , Pinton Paolo
Published: March 2021

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by mutations in the cystic fibrosis transmembrane conductance regulator gene, which causes multifunctional defects that preferentially affect the airways. Abnormal viscosity of mucus secretions, persistent pathogen infections, hyperinflammation, and lung tissue damage compose the classical pathological manifestation referred to as CF lung disease. Among the multifunctional defects associated with defective CFTR, increasing evidence supports the relevant role of perturbed calcium (Ca2+) signaling in the pathophysiology of CF lung disease. The Ca2+ ion is a critical player in cell functioning and survival. Its intracellular homeostasis is maintained by a fine balance between channels, transporters, and exchangers, mediating the influx and efflux of the ion across the plasma membrane and the intracellular organelles. An abnormal Ca2+ profile has been observed in CF cells, including airway epithelial and immune cells, with heavy repercussions on cell function, viability, and susceptibility to pathogens, contributing to proinflammatory overstimulation, organelle dysfunction, oxidative stress, and excessive cytokines release in CF lung. This review discusses the role of Ca2+ signaling in CF and how its dysregulation in airway epithelial and immune cells contributes to hyperinflammation in the CF lung. Finally, we provide an outlook on the therapeutic options that target the Ca2+ signaling to treat the CF lung disease.
Sini Decoction Ameliorates Colorectal Cancer and Modulates the Composition of Gut Microbiota in Mice
Authors: Wang Yishan , Zhang Xiaodi , Li Jiawei , Zhang Ying , Guo Yingjie , Chang Qing , Chen Li , Wang Yiwei , Wang Siyao , Song Yu , Zhao Yongkun , Wang Zhihong
Published: March 2021

Sini Decoction (SND), as a classic prescription of Traditional Chinese Medicine (TCM), has been proved to be clinically useful in cardiomyopathy and inflammatory bowel diseases. However, the role and mechanism of SND in colitis-associated cancer remains unclear. This study aims to evaluate the effect of SND on colorectal cancer(CRC) symptoms and further explore the changes of gut microbes mediated by SND extract in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC mice through 16 S rRNA sequencing. Our results indicated that treatment with SND extract could ameliorate the tumors' malignant degree by decreasing tumor number and size. Also, the expression levels of Cyclooxygenase 2 and Mucin-2, which are typical CRC biomarkers, were reduced compared to the CRC group. In the meantime, SND extract can upregulate CD8+ T lymphocytes' expression and Occludin in the colonic mucosal layer. Besides, SND inhibited the expression of CD4+ T cells and inflammatory cytokines in CRC tissue. According to bioinformatics analysis, SND extract was also suggested could modulate the gut microbial community. After the SND treatment, compared with the CRC mice model, the number of pathogenic bacteria showed a significant reduction, including Bacteroides fragilis and Sulphate-reducing bacteria; and SND increased the relative contents of the beneficial bacteria, including Lactobacillus, Bacillus coagulans, Akkermansia muciniphila, and Bifidobacterium. In summary, SND can effectively intervene in colorectal cancer development by regulating intestinal immunity, protecting the colonic mucosal barrier, and SND can change the intestinal microbiota composition in mice.
Efficacy of a Combined Antiplatelet Therapy Is Not Affected by a Simultaneous Binding of Cangrelor and PSB 0777 to Albumin
Authors: Wzorek Joanna , Bednarek Radosław , Watala Cezary , Boncler Magdalena
Published: March 2021

Concurrent administration of two drugs may complicate the management of acute coronary syndromes: competitive drug displacement diminishes drug binding and alters drug pharmacodynamics. We investigated the interaction of two antiplatelet compounds (PSB 0777 and cangrelor) with human serum albumin (HSA) to determine whether they compete with one another for the binding to albumin. Both examined compounds have been earlier claimed to bind to HSA (PSB 0777) or plasma proteins (cangrelor). Fluorescence spectroscopy, surface plasmon resonance spectroscopy and molecular modeling indicated that PSB 0777 and cangrelor interacted with HSA with moderate affinity (KD∼10−5 M). The binding of cangrelor to HSA involved primarily hydrophobic interactions, while the interaction of PSB 0777 with HSA was driven by hydrophobic and electrostatic forces. It was found that PSB 0777 and cangrelor do not share the same binding site on the protein. Our findings highlight the importance of albumin in the transport of PSB 0777 and cangrelor and suggest that the antiplatelet activity of the examined compounds used in combination is not affected by competition-induced changes in drug binding to HSA.
Optimal Candidates to Do Fresh Embryo Transfer in Those Using Oral Contraceptive Pretreatment in IVF Cycles
Authors: Lu Yao , Niu Yichao , Wang Yuan , He Yaqiong , Ding Ying , Lu Xinyuan , Xu Bing , Lindheim Steven R. , Sun Yun
Published: March 2021

Objective

Concern regarding the adverse impact of pretreatment of oral contraceptives (OC) prior to ovarian stimulation for in vitro fertilization (IVF) on pregnancy outcome has been debated. We investigated factors that may be associated with live birth rate (LBR) in fresh embryo transfer cycles after OC pretreatment.

Methods

A retrospective study was conducted at the Reproductive Center of Ren Ji Hospital, Shanghai, China. 814 women aged 20–35 years undergoing their first autologous IVF cycle and fresh embryo transfer after OC pretreatment were included. Long gonadotropin releasing hormone (GnRH) agonist (a) or GnRH antagonist (ant) protocol was used for ovarian stimulation. Predictive factors for LBR were identified using multivariate logistic regression analysis.

Results

Multivariate logistic regression analysis demonstrated that using GnRH-ant protocol for ovarian stimulation was associated with significantly lower LBR (OR 0.70, 95% CI 0.52–0.93), while endometrial thickness on day of hCG trigger was associated with increased LBR (OR 1.16, 95% CI 1.06–1.27). Despite comparable patients’ age, duration of infertility, BMI and basal FSH between GnRH-a and GnRH-ant groups, those using GnRH-ant resulted in significantly lower LBR compared to the GnRH-a group (37.4 vs. 48.5%, p = 0.002). Using ROC analysis and a cut-off endometrial thickness of < and ≥ 9.5 mm, those < 9.5 mm using GnRH-ant resulted in significantly lower LBR (28.5 vs. 43.4%, p = 0.004), while no differences were noted with an endometrial thickness ≥9.5 mm (49.6 vs. 51.1%, p = 0.78).

Conclusions

Live birth was significantly impacted in OC pre-treated GnRH-ant cycles with an endometrial thickness of <9.5 mm on day of hCG trigger. Cryopreservation of all embryos in these cycles should be considered.
Prediction of Mortality in Hemodialysis Patients Using Moving Multivariate Distance
Authors: Liu Mingxin , Legault Véronique , Fülöp Tamàs , Côté Anne-Marie , Gravel Dominique , Blanchet F. Guillaume , Leung Diana L. , Lee Sylvia Juhong , Nakazato Yuichi , Cohen Alan A.
Published: March 2021

There is an increasingly widespread use of biomarkers in network physiology to evaluate an organism’s physiological state. A recent study showed that albumin variability increases before death in chronic hemodialysis patients. We hypothesized that a multivariate statistical approach would better allow us to capture signals of impending physiological collapse/death. We proposed a Moving Multivariate Distance (MMD), based on the Mahalanobis distance, to quantify the variability of the multivariate biomarker profile as a whole from one visit to the next. Biomarker profiles from a visit were used as the reference to calculate MMD at the subsequent visit. We selected 16 biomarkers (of which 11 are measured every 2 weeks) from blood samples of 763 chronic kidney disease patients hemodialyzed at the CHUS hospital in Quebec, who visited the hospital regularly (∼every 2 weeks) to perform routine blood tests. MMD tended to increase markedly preceding death, indicating an increasing intraindividual multivariate variability presaging a critical transition. In survival analysis, the hazard ratio between the 97.5th percentile and the 2.5th percentile of MMD reached as high as 21.1 [95% CI: 14.3, 31.2], showing that higher variability indicates substantially higher mortality risk. Multivariate approaches to early warning signs of critical transitions hold substantial clinical promise to identify early signs of critical transitions, such as risk of death in hemodialysis patients; future work should also explore whether the MMD approach works in other complex systems (i.e., ecosystems, economies), and should compare it to other multivariate approaches to quantify system variability.