bluuebunny/crossref_metadata_2025 huggingface dataset:
Elucidating the Neuropathologic Mechanisms of SARS-CoV-2 Infection
Authors: Pacheco-Herrero Mar , Soto-Rojas Luis O. , Harrington Charles R. , Flores-Martinez Yazmin M. , Villegas-Rojas Marcos M. , León-Aguilar Alfredo M. , Martínez-Gómez Paola A. , Campa-Córdoba B. Berenice , Apátiga-Pérez Ricardo , Corniel-Taveras Carolin N. , Dominguez-García Jesabelle de J. , Blanco-Alvarez Víctor Manuel , Luna-Muñoz José
Published: April 2021

The current pandemic caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a public health emergency. To date, March 1, 2021, coronavirus disease 2019 (COVID-19) has caused about 114 million accumulated cases and 2.53 million deaths worldwide. Previous pieces of evidence suggest that SARS-CoV-2 may affect the central nervous system (CNS) and cause neurological symptoms in COVID-19 patients. It is also known that angiotensin-converting enzyme-2 (ACE2), the primary receptor for SARS-CoV-2 infection, is expressed in different brain areas and cell types. Thus, it is hypothesized that infection by this virus could generate or exacerbate neuropathological alterations. However, the molecular mechanisms that link COVID-19 disease and nerve damage are unclear. In this review, we describe the routes of SARS-CoV-2 invasion into the central nervous system. We also analyze the neuropathologic mechanisms underlying this viral infection, and their potential relationship with the neurological manifestations described in patients with COVID-19, and the appearance or exacerbation of some neurodegenerative diseases.
Alteration in Resting-State EEG Microstates Following 24 Hours of Total Sleep Deprivation in Healthy Young Male Subjects
Authors: Ke Ming , Li Jianpan , Wang Lubin
Published: April 2021

Purpose: The cognitive effects of total sleep deprivation (TSD) on the brain remain poorly understood. Electroencephalography (EEG) is a very useful tool for detecting spontaneous brain activity in the resting state. Quasi-stable electrical distributions, known as microstates, carry useful information about the dynamics of large-scale brain networks. In this study, microstate analysis was used to study changes in brain activity after 24 h of total sleep deprivation.

Participants and Methods: Twenty-seven healthy volunteers were recruited and underwent EEG scans before and after 24 h of TSD. Microstate analysis was applied, and six microstate classes (A–F) were identified. Topographies and temporal parameters of the microstates were compared between the rested wakefulness (RW) and TSD conditions.

Results: Microstate class A (a right-anterior to left-posterior orientation of the mapped field) showed lower global explained variance (GEV), frequency of occurrence, and time coverage in TSD than RW, whereas microstate class D (a fronto-central extreme location of the mapped field) displayed higher GEV, frequency of occurrence, and time coverage in TSD compared to RW. Moreover, subjective sleepiness was significantly negatively correlated with the microstate parameters of class A and positively correlated with the microstate parameters of class D. Transition analysis revealed that class B exhibited a higher probability of transition than did classes D and F in TSD compared to RW.

Conclusion: The observation suggests alterations of the dynamic brain-state properties of TSD in healthy young male subjects, which may serve as system-level neural underpinnings for cognitive declines in sleep-deprived subjects.
Regional and Temporal Differences in Brain Activity With Morally Good or Bad Judgments in Men: A Magnetoencephalography Study
Authors: Hiraishi Hirotoshi , Ikeda Takashi , Saito Daisuke N. , Hasegawa Chiaki , Kitagawa Sachiko , Takahashi Tetsuya , Kikuchi Mitsuru , Ouchi Yasuomi
Published: April 2021

Many neuroimaging studies on morality focus on functional brain areas that relate to moral judgment specifically in morally negative situations. To date, there have been few studies on differences in brain activity under conditions of being morally good and bad along a continuum. To explore not only the brain regions involved but also their functional connections during moral judgments, we used magnetoencephalography (MEG), which is superior to other imaging modalities for analyzing time-dependent brain activities; only men were recruited because sex differences might be a confounding factor. While analyses showed that general patterns of brain activation and connectivity were similar between morally good judgments (MGJs) and morally bad judgments (MBJs), activation in brain areas that subserve emotion and “theory of mind” on the right hemisphere was larger in MGJ than MBJ conditions. In the left local temporal region, the connectivity between brain areas related to emotion and reward/punishment was stronger in MBJ than MGJ conditions. The time-frequency analysis showed distinct laterality (left hemisphere dominant) occurring during early moral information processing in MBJ conditions compared to MGJ conditions and phase-dependent differences in the appearance of theta waves between MBJ and MGJ conditions. During MBJs, connections within the hemispheric regions were more robust than those between hemispheric regions. These results suggested that the local temporal region on the left hemisphere is more important in the execution of MBJs during early moral valence processing than in that with MGJs. Shorter neuronal connections within the hemisphere may allow to make MBJs punctual.
A Simple and Effective Way to Study Executive Functions by Using 360° Videos
Authors: Borgnis Francesca , Baglio Francesca , Pedroli Elisa , Rossetto Federica , Riva Giuseppe , Cipresso Pietro
Published: April 2021

Executive dysfunctions constitute a significant public health problem due to their high impact on everyday life and personal independence. Therefore, the identification of early strategies to assess and rehabilitate these impairments appears to be a priority. The ecological limitations of traditional neuropsychological tests and the numerous difficulties in administering tests in real-life scenarios have led to the increasing use of virtual reality (VR) and 360° environment-based tools for assessing executive functions (EFs) in real life. This perspective aims at proposing the development and implementation of Executive-functions Innovative Tool 360° (EXIT 360°), an innovative, enjoyable, and ecologically valid tool for a multidimensional and multicomponent evaluation of executive dysfunctions. EXIT 360° allows a complete and integrated executive functioning assessment through an original task for EFs delivered via a mobile-powered VR headset combined with eye tracker (ET) and electroencephalograms (EEG). Our tool is born as a 360°-based instrument, easily accessible and clinically usable, that will radically transform clinicians’ and patient’s assessment experience. In EXIT 360°, patients are engaged in a “game for health,” where they must perform everyday subtasks in 360° daily life environments. In this way, the clinicians can obtain quickly more ecologically valid information about several aspects of EFs (e.g., planning, problem-solving). Moreover, the multimodal approach allows completing the assessment of EFs by integrating verbal responses, reaction times, and physiological data (eye movements and brain activation). Overall, EXIT 360° will allow obtaining simultaneously and in real time more information about executive dysfunction and its impact in real life, allowing clinicians to tailor the rehabilitation to the subject’s needs.
Mitochondrial Dynamics: A Key Role in Neurodegeneration and a Potential Target for Neurodegenerative Disease
Authors: Yang Danying , Ying Jun , Wang Xifeng , Zhao Tiancheng , Yoon Sungtae , Fang Yang , Zheng Qingcui , Liu Xing , Yu Wen , Hua Fuzhou
Published: April 2021

In neurodegenerative diseases, neurodegeneration has been related to several mitochondrial dynamics imbalances such as excessive fragmentation of mitochondria, impaired mitophagy, and blocked mitochondria mitochondrial transport in axons. Mitochondria are dynamic organelles, and essential for energy conversion, neuron survival, and cell death. As mitochondrial dynamics have a significant influence on homeostasis, in this review, we mainly discuss the role of mitochondrial dynamics in several neurodegenerative diseases. There is evidence that several mitochondrial dynamics-associated proteins, as well as related pathways, have roles in the pathological process of neurodegenerative diseases with an impact on mitochondrial functions and metabolism. However, specific pathological mechanisms need to be better understood in order to propose new therapeutic strategies targeting mitochondrial dynamics that have shown promise in recent studies.
Systemic Chemotherapy Including Ramucirumab in Combination With Pressurized Intra-Peritoneal Aerosol Chemotherapy Is a Safe Treatment Option for Peritoneal Metastasis of Gastric Cancer
Authors: Feldbrügge Linda , Gronau Felix , Brandl Andreas , Auer Timo Alexander , Oeff Alan , Thuss-Patience Peter , Pratschke Johann , Rau Beate
Published: April 2021

Background

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a laparoscopic technique for local chemotherapy. It has been used for treatment of peritoneal metastasis of gastric cancer (PM GC) in combination with systemic therapy. VEGFR2 antagonist ramucirumab is a second-line therapy for GC, and has been suspected to cause wound healing disorders.

Methods

This is a retrospective single center cohort study of patients with PM GC, who received PIPAC treatment in combination with systemic chemotherapy with and without ramucirumab. Data on patients’ characteristics and their perioperative courses were collected and complication rates were compared with regard to preoperative use of ramucirumab and time between last dose of systemic therapy and PIPAC treatment.

Results

Fifty patients underwent 90 PIPAC treatments for PM GC in 3 years. Overall postoperative morbidity was 11% with 6% severe complications. The mean interval between systemic therapy and PIPAC was 20 days. Neither the length of interval nor the use of ramucirumab had an effect on complication rates.

Conclusion

Our study suggests that addition of ramucirumab to pre-PIPAC systemic therapy, irrespective of the length of the treatment-free interval before PIPAC, does not increase the risk of postoperative complications and is therefore a safe option for treatment of PM GC.
Prognostic Modeling of Patients Undergoing Surgery Alone for Esophageal Squamous Cell Carcinoma: A Histopathological and Computed Tomography Based Quantitative Analysis
Authors: Wu Lei-Lei , Wang Jin-Long , Huang Wei , Liu Xuan , Huang Yang-Yu , Zeng Jing , Cui Chun-Yan , Lu Jia-Bin , Lin Peng , Long Hao , Zhang Lan-Jun , Wei Jun , Lu Yao , Ma Guo-Wei
Published: April 2021

Objective

To evaluate the effectiveness of a novel computerized quantitative analysis based on histopathological and computed tomography (CT) images for predicting the postoperative prognosis of esophageal squamous cell carcinoma (ESCC) patients.

Methods

We retrospectively reviewed the medical records of 153 ESCC patients who underwent esophagectomy alone and quantitatively analyzed digital histological specimens and diagnostic CT images. We cut pathological images (6000 × 6000) into 50 × 50 patches; each patient had 14,400 patches. Cluster analysis was used to process these patches. We used the pathological clusters to all patches ratio (PCPR) of each case for pathological features and we obtained 20 PCPR quantitative features. Totally, 125 computerized quantitative (20 PCPR and 105 CT) features were extracted. We used a recursive feature elimination approach to select features. A Cox hazard model with L1 penalization was used for prognostic indexing. We compared the following prognostic models: Model A: clinical features; Model B: quantitative CT and clinical features; Model C: quantitative histopathological and clinical features; and Model D: combined information of clinical, CT, and histopathology. Indices of concordance (C-index) and leave-one-out cross-validation (LOOCV) were used to assess prognostic model accuracy.

Results

Five PCPR and eight CT features were treated as significant indicators in ESCC prognosis. C-indices adjusted for LOOCV were comparable among four models, 0.596 (Model A) vs. 0.658 (Model B) vs. 0.651 (Model C), and improved to 0.711with Model D combining information of clinical, CT, and histopathology (all p<0.05). Using Model D, we stratified patients into low- and high-risk groups. The 3-year overall survival rates of low- and high-risk patients were 38.0% and 25.0%, respectively (p<0.001).

Conclusion

Quantitative prognostic modeling using a combination of clinical data, histopathological, and CT images can stratify ESCC patients with surgery alone into high-risk and low-risk groups.
High TIL, HLA, and Immune Checkpoint Expression in Conventional High-Grade and Dedifferentiated Chondrosarcoma and Poor Clinical Course of the Disease
Authors: Nota Sjoerd P. F. T. , Al-Sukaini Ahmad , Patel Shalin S. , Sabbatino Francesco , Nielsen G. Petur , Deshpande Vikram , Yearley Jennifer H. , Ferrone Soldano , Wang Xinhui , Schwab Joseph H.
Published: April 2021

Purpose

The aim of this study was to characterize chondrosarcoma tumor infiltration by immune cells and the expression of immunologically relevant molecules. This information may contribute to our understanding of the role of immunological events in the pathogenesis of chondrosarcoma and to the rational design of immunotherapeutic strategies.

Patients and Methods

A tissue microarray (TMA) containing 52 conventional and 24 dedifferentiated chondrosarcoma specimens was analyzed by immunohistochemical staining for the expression of parameters associated with tumor antigen-specific immune responses, namely, CD4+and CD8+tumor infiltrating lymphocytes (TILs) and the expression of HLA class I heavy chain, beta-2 microglobulin (β2m), HLA class II and immune checkpoint molecules, B7-H3 and PD-1/PD-L1. The results were correlated with histopathological characteristics and the clinical course of the disease.

Results

CD8+TILs were present in 21% of the conventional and 90% of the dedifferentiated chondrosarcoma tumors tested. B7-H3 was expressed in 69% of the conventional and 96% of the dedifferentiated chondrosarcoma tumors tested. PD-1 and PD-L1 were expressed 53% and 33% respectively of the dedifferentiated tumors tested. PD-L1 expression was associated with shorter time to metastasis.

Conclusion

The tumor infiltration by lymphocytes suggests that chondrosarcoma is immunogenic. Defects in HLA class I antigen and expression of the checkpoint molecules B7-H3 and PD-1/PD-L1 suggest that tumor cells utilize escape mechanisms to avoid immune recognition and destruction. This data implies that chondrosarcoma will benefit from strategies that enhance the immunogenicity of tumor antigens and/or counteract the escape mechanisms.
Identification of Hub Genes Associated With Sensitivity of 5-Fluorouracil Based Chemotherapy for Colorectal Cancer by Integrated Bioinformatics Analysis
Authors: Wang Ya , Wei Qunhui , Chen Yuqiao , Long Shichao , Yao Yuanbing , Fu Kai
Published: April 2021

Colorectal cancer (CRC) is one of the most common malignant tumors. 5-fluorouracil (5-FU) has been used for the standard first-line treatment for CRC patients for several decades. Although 5-FU based chemotherapy has increased overall survival (OS) of CRC patients, the resistance of CRC to 5-FU based chemotherapy is the principal cause for treatment failure. Thus, identifying novel biomarkers to predict response to 5-FU based chemotherapy is urgently needed. In the present study, the gene expression profile of GSE3964 from the Gene Expression Omnibus database was used to explore the potential genes related to intrinsic resistance to 5-FU. A gene module containing 81 genes was found to have the highest correlation with chemotherapy response using Weighted Gene Co-expression Network Analysis (WGCNA). Then a protein-protein interaction (PPI) network was constructed and ten hub genes (TGFBI, NID, LEPREL2, COL11A1, CYR61, PCOLCE, IGFBP7, COL4A2, CSPG2, and VTN) were identified using the CytoHubba plugin of Cytoscape. Seven of these hub genes showed significant differences in expression between chemotherapy-sensitive and chemotherapy-resistant samples. The prognostic value of these seven genes was evaluated using TCGA COAD (Colorectal Adenocarcinoma) data. The results showed that TGFBI was highly expressed in chemotherapy-sensitive patients, and patients with high TGFBI expression have better survival.
Rapamycin Antagonizes BCRP-Mediated Drug Resistance Through the PI3K/Akt/mTOR Signaling Pathway in mPRα-Positive Breast Cancer
Authors: Zhang Jing , Hu Jing , Li Weiwei , Zhang Chunyan , Su Peng , Wang Yan , Sun Wei , Wang Xiao , Li Li , Wu Xiaojuan
Published: April 2021

Purpose

Overexpression of breast cancer (BCa) resistance protein (BCRP) is detected in approximately 30% of BCa cases. BCRP indicates a poor response to chemotherapy, and it has become a classic target to overcome drug-resistant tumor cells. In this study, we aimed to explore the mechanism of BCRP overexpression and a strategy to reverse this overexpression in invasive BCa.

Methods

BCRP expression in BCa tissues was determined by immunohistochemistry. GSE25066 was downloaded from the NCBI GEO database. Western blot was used to determine the expression of key molecules in vitro. Cell counting kit-8 assays were used to assess the drug response of BCa cells.

Results

Our results suggested that BCRP is an independent risk factor for BCa. We further established that upon 17α-PG binding, membrane progesterone receptor α (mPRα) promoted BCRP expression via the PI3K/Akt/mTOR signaling pathway. mPRα physically interacted with p-Akt1 S473. Moreover, rapamycin, an inhibitor of mTOR complex 1 (mTORC1), downregulated BCRP expression and enhanced the effects of particular drugs, including doxorubicin and paclitaxel.

Conclusion

BCRP is a potential biomarker of poor prognosis in BCa. BCRP expression is regulated by 17α-PG in mPRα-positive BCa cells through the PI3K/Akt/mTOR signaling pathway. Rapamycin might enhance the therapeutic effect of chemotherapy agents in mPRα-positive MDA-MB-453/BCRP cells and might be a therapeutic option for mPRα-positive invasive BCa with BCRP overexpression.
Prognostic Impact of Radiological Consolidation Tumor Ratio in Clinical Stage IA Pulmonary Ground Glass Opacities
Authors: Xi Junjie , Yin Jiacheng , Liang Jiaqi , Zhan Cheng , Jiang Wei , Lin Zongwu , Xu Songtao , Wang Qun
Published: April 2021

Objectives

Our study aimed to validate pathologic findings of ground-glass nodules (GGOs) of different consolidation tumor ratios (CTRs), and to explore whether GGOs could be stratified according to CTR with an increment of 0.25 based on its prognostic role.

Methods

We retrospectively evaluated patients with clinical stage IA GGOs who underwent curative resection between 2011 and 2016. The patients were divided into 4 groups according to CTR step by 0.25. Cumulative survival rates were calculated by the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were conducted to obtain the risk factors on relapse-free survival (RFS). The surv_function of the R package survminer was used to determine the optimal cutoff value. Receiver operating characteristic (ROC) analysis was generated to validate optimal cutoff points of factors.

Results

A total of 862 patients (608 women; median age, 59y) were included, with 442 patients in group A (CTR ≤ 0.25), 210 patients in group B (0.25<CTR ≤ 0.5), 173 patients in group C (0.5<CTR ≤ 0.75), and 37 patients in group D (0.75<CTR<1). The rate of adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA) in group A (70.6%) was much higher than other three groups (p<0.001). Multivariable Cox regression revealed that CTR (HR, 1.865; 95%CI, 1.312-2.650; p = 0.001) and lymph node metastasis (HR, 10.407; 95%CI, 1.957-55.343; p = 0.006) were independent prognostic factors for recurrence free survival. In addition, CTR was the only risk factor for the presence of micropapillary or solid pattern (OR=133.9, 95%CI:32.2-556.2, P<0.001) and lymph node metastasis (OR=292498.8, 95%CI:1.2-7.4×1010, P=0.047). Paired comparison showed that rate of presence of micropapillary or solid pattern was highest in group D, followed by group C and group A/B (p<0.001). Lymph node metastasis occurred in group D only (p=0.002).

Conclusions

CTR is an independent prognostic factor for clinical stage IA lung adenocarcinoma manifesting as GGO in CT scan. Radiologic cutoffs of CTR 0.50 and 0.75 were able to subdivide patients with different prognosis.
Association of Immune Related Adverse Events With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Cancers: A Systemic Review and Meta-analysis
Authors: Fan Yong , Xie Wenhui , Huang Hong , Wang Yunxia , Li Guangtao , Geng Yan , Hao Yanjie , Zhang Zhuoli
Published: April 2021

Objectives

Immune checkpoint inhibitors (ICIs) have brought impressive benefits to cancer patients, however often accompanied with immune-related adverse events (irAEs). We aimed to investigate the association of irAEs with efficacy and overall survival in cancer patients treated by ICIs, and further quantify the association by stratifying subgroups.

Methods

PubMed, EMBASE and Cochrane library from database inception to 29 August 2019 were systematically searched. Articles reporting association of objective response rate (ORR), progression-free survival (PFS), overall survival (OS) with irAEs in cancer patients treated with approved ICIs were included. Adjusted odds ratios (OR) with 95% confidential intervals (CIs) were calculated for ORR, and hazard ratios (HR) were used for PFS and OS.

Results

A total of 52 articles comprising 9,156 patients were included. Pooled data demonstrated a statistically significant greater probability of achieving objective tumor response for patients with irAEs compared to those without (OR 3.91, 95% CI 3.05–5.02). In overall meta-analysis, patients who developed irAEs presented a prolonged PFS (HR 0.54; 95% CI 0.46–0.62) and OS (HR 0.51; 95% CI 0.41–0.59). More specifically, irAEs in certain cancer types (NSCLC and melanoma) and organs (skin and endocrine) were robustly associated with better clinical outcomes, while this association needs further verification regarding other tumors. High grade toxicities (G3–5) were not associated with a significantly favorable PFS or OS. Additionally, the association between irAEs and clinical benefit seemed to be more definite in patients receiving PD-(L)1 blockade than CTLA-4 blockade. Pooled data from landmark analyses displayed consistent results.

Conclusions

The occurrence of irAEs predicted improved tumor response and better survival in overall cancer patients treated with ICIs. Notably, the association stayed robust in certain cancer types (NSCLC and melanoma) and organ-specific irAEs (skin and endocrine).
Identification of the Roles of a Stemness Index Based on mRNA Expression in the Prognosis and Metabolic Reprograming of Pancreatic Ductal Adenocarcinoma
Authors: Tang Rong , Liu Xiaomeng , Wang Wei , Hua Jie , Xu Jin , Liang Chen , Meng Qingcai , Liu Jiang , Zhang Bo , Yu Xianjun , Shi Si
Published: April 2021

Background

Cancer stem cells (CSCs) are widely thought to contribute to the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC). CSCs share biological features with adult stem cells, such as longevity, self-renewal capacity, differentiation, drug resistance, and the requirement for a niche; these features play a decisive role in cancer progression. A prominent characteristic of PDAC is metabolic reprogramming, which provides sufficient nutrients to support rapid tumor cell growth. However, whether PDAC stemness is correlated with metabolic reprogramming remains unknown.

Method

RNA sequencing data of PDAC, including read counts and fragments per kilobase of transcript per million mapped reads (FPKM), were collected from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA-PAAD) database. Single-sample gene set enrichment analysis (GSEA) was used to calculate the relative activities of metabolic pathways in each PDAC sample. Quantitative real-time PCR was performed to validate the expression levels of genes of interest.

Results

The overall survival (OS) of patients with high mRNA expression-based stemness index (mRNAsi) values was significantly worse than that of their counterparts with low mRNAsi values (P = 0.003). This survival disadvantage was independent of baseline clinical characteristics. Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and GSEA showed that the differentially expressed genes between patients with high and low mRNAsi values were mainly enriched in oncogenic and metabolic pathways. Weighted gene coexpression network analysis (WGCNA) revealed 8 independent gene modules that were significantly associated with mRNAsi and 12 metabolic pathways. Unsupervised clustering based on the key genes in each module identified two PDAC subgroups characterized by different mRNAsi values and metabolic activities. Univariate Cox regression analysis identified 14 genes beneficial to OS from 95 key genes selected from the eight independent gene modules from WGCNA. Among them, MAGEH1, MAP3K3, and PODN were downregulated in both pancreatic tissues and cell lines.

Conclusion

The present study showed that PDAC samples with high mRNAsi values exhibited aberrant activation of multiple metabolic pathways, and the patients from whom these samples were obtained had a poor prognosis. Future studies are expected to investigate the underlying mechanism based on the crosstalk between PDAC stemness and metabolic rewiring.
Factors Modifying Outcome After MIBG Therapy in Children With Neuroblastoma—A National Retrospective Study
Authors: Ussowicz Marek , Wieczorek Aleksandra , Dłużniewska Agnieszka , Pieczonka Anna , Dębski Robert , Drabko Katarzyna , Goździk Jolanta , Balwierz Walentyna , Handkiewicz-Junak Daria , Wachowiak Jacek
Published: April 2021

Background

Neuroblastoma is the most common pediatric extracranial tumor with varied prognoses, but the survival of treated refractory or relapsing patients remains poor.

Objective

This analysis presents the outcomes of children with neuroblastoma undergoing MIBG therapy in Poland in 2006-2019.

Study Design

A retrospective cohort of 55 patients with refractory or relapsed neuroblastoma treated with I-131 MIBG in Poland in 2006-2019 was analyzed. The endpoints were overall survival (OS), event-free survival (EFS), cumulative incidence (CI) of second cancers and CI of hypothyroidism. Survival curves were estimated using the Kaplan-Meier method and compared between the cohorts by the log-rank test. Cox modeling was adopted to estimate hazard ratios for OS and EFS, considering factors with P < 0.2.

Results

Fifty-five patients with a median age of 78.4 months (range 18-193) with neuroblastoma underwent one or more (4 patients) courses of MIBG I-131 therapy. Fifteen patients were not administered chemotherapy, 3 children received standard-dose chemotherapy, and 37 patients were administered high-dose chemotherapy (HDCT) (busulfan-melphalan in 24 and treosulfan-based in 12 patients). Forty-six patients underwent stem cell transplantation, with autologous (35 patients), haploidentical (6), allogeneic (4), and syngeneic grafts (1). The median time from first MIBG therapy to SCT was 22 days. Children with relapsing tumors had inferior OS compared to those with primary resistant disease (21.2% vs 58.7%, p=0.0045). Survival was better in patients without MYCN gene amplification. MIBG therapy was never curative, except in patients further treated with HDCT with stem cell rescue irrespective of the donor type. 31 patients were referred for immune therapy after MIBG therapy, and the 5-year OS in this group was superior to the untreated children (55.2% vs 32.7%, p=0.003), but the difference in the 5-year EFS was not significant (25.6% vs 32.9%, p=ns). In 3 patients, a second malignancy was diagnosed. In 19.6% of treated children, hypothyroidism was diagnosed within 5 years after MIBG therapy.

Conclusion

MIBG therapy can be incorporated into the therapeutic strategy of relapsed or resistant neuroblastoma patients as preconditioning with HDCT rather than stand-alone therapy. Follow-up is required due to the incidence of thyroid failure and risk of second cancers.
The Central THαβ Immunity Associated Cytokine: IL-10 Has a Strong Anti-Tumor Ability Toward Established Cancer Models In Vivo and Toward Cancer Cells In Vitro
Authors: Hu Wan-Chung
Published: April 2021

Immunotherapy is a promising new approach for cancer treatment. In this study, I propose to use the THαβ-mediated immune response for cancer treatment. The THαβ-mediated immune response is activated by IL-10 and IL-15. Thus, I used IL-10 and-15 as therapeutic agents in the 4T1 cell line, which is a mouse cell line of breast cancer, and the NXS2 cell line, which is a mouse cell line of neuroblastoma. Cells from 4T1 and NXS2 were subcutaneously inoculated in wild type BALB/c female mice and AJ mice, respectively, and administered cytokines or an antibody treatment at various dosages. My results showed that IL-10 and IL-15 administration led to reduction in tumor volume and increase in survival. However, traditional TH1 cytokine IFN-γ administration led to increase in tumor volume and decline in survival. Antibody treatment in conjunction with IL-10 was not significantly better than IL-10, due to the expression of GD2 on immune cells. Moreover, an anti-GD2 antibody inhibited the immune cells themselves. Additionally, I found that IL-10 was directly toxic to tumor cellsin vitro. Thus, I conclude that the THαβ immunological pathway is a good treatment strategy for cancer.
Curcumin Regulates Cancer Progression: Focus on ncRNAs and Molecular Signaling Pathways
Authors: Wang Haijun , Zhang Ke , Liu Jia , Yang Jie , Tian Yidan , Yang Chen , Li Yushan , Shao Minglong , Su Wei , Song Na
Published: April 2021

Curcumin [(1E,6E) ‑1,7‑bis(4‑hydroxy‑3‑methoxyphenyl) hepta‑1,6‑diene‑3,5‑ dione] is a natural polyphenol derived from the rhizome of the turmeric plant Curcuma longa. Accumulated evidences have presented curcumin’s function in terms of anti-inflammatory, antioxidant properties, and especially anti-tumor activities. Studies demonstrated that curcumin could exert anti-tumor activity via multiple biological signaling pathways, such as PI3K/Akt, JAK/STAT, MAPK, Wnt/β-catenin, p53, NF-ĸB and apoptosis related signaling pathways. Moreover, Curcumin can inhibit tumor proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), invasion and metastasis by regulating tumor related non-coding RNA (ncRNA) expression. In this review, we summarized the roles of curcumin in regulating signaling pathways and ncRNAs in different kinds of cancers. We also discussed the regulatory effect of curcumin through inhibiting carcinogenic miRNA and up regulating tumor suppressive miRNA. Furthermore, we aim to illustrate the cross regulatory relationship between ncRNA and signaling pathways, further to get a better understanding of the anti-tumor mechanism of curcumin, thus lay a theoretical foundation for the clinical application of curcumin in the future.
Molecular and Clinical Insights in Malignant Brenner Tumor of the Testis With Liver Metastases:A Case Report
Authors: Parcesepe Pietro , Coppola Luigi , Remo Andrea , D’Andrea Mario Rosario , Coppola Giulia , Simbolo Michele , Manfrin Erminia , Scarpa Aldo , De Santis Elena , Giordano Guido
Published: April 2021

Malignant Brenner Tumor (mBT) is extremely rare. Although BT are almost exclusive ovarian neoplasms, they may constitute a highly unusual tumor of the testis; in fact, only seven fully documented cases have been reported to date. Because of their rarity, the pathogenesis of these tumors has not been clarified and there is no standard therapeutic approach. We report the first case of epididymal mBT with synchronous, multiple, liver metastases and a very dramatic clinical course. Both primary tumor and metastasis were subjected to mutational analysis of 20 cancer associated genes. Primary tumor showed FGFR3 Tyr375Cys and PIK3CA His1047Arg missense mutations. Both mutations are reported as pathogenic in ClinVar database. The same FGFR3 mutation was present in liver metastasis. Based on these results we believe that the FGFR pathway could be an ideal candidate for personalized treatment, offering hope to a subset of patients with mBT. Personalized approach, including mutational analysis and molecular testing should be required in patients with rare tumors in order to clarify diagnosis and improve therapeutic strategies.
Consolidation With Pembrolizumab and Nab-Paclitaxel After Induction Platinum-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer
Authors: Patel Shetal A. , Gerber David E. , Deal Allison , Douglas Kathe , Pecot Chad V. , Lee Carrie , Schiller Joan , Dhruva Nirav , Weiss Jared
Published: April 2021

Background

Induction with four cycles of platinum-based chemotherapy was the standard of care for metastatic non-small cell lung cancer (NSCLC) until the approval of immune checkpoint blockade (ICB) in the first-line setting. Switch maintenance therapy has shown promise in improving survival by exposing patients to novel, non-cross–resistant agents earlier in their treatment course.

Methods

We performed this open-label, three-arm, randomized phase II study (NCT02684461) to evaluate three sequences of consolidation with pembrolizumab and nab-paclitaxel in patients without progressive disease post induction chemotherapy. Consolidation was either sequential with pembrolizumab for four cycles followed by nab-paclitaxel for four cycles (P→A), nab-paclitaxel followed by pembrolizumab (A→P), or concurrent nab-paclitaxel and pembrolizumab for four cycles (AP).

Results

Twenty patients were randomized before the study was closed early due to the approval of first-line checkpoint inhibitors. We found that consolidation is feasible and well tolerated, with 30% of patients experiencing grade 3 toxicity. The median progression-free survival and OS in months (95% CI) in P→A were 10.1 (1.5–NR), 27.6 (1.7–NR); 8.4 (1.2–9.0), 12.7 (4.4–NR) in A→P; and 10.2 (5.1–NR), NR. Quality of life as measured by FACT-L improved in the majority of patients during the course of the study.

Conclusion

Sequential and concurrent consolidation regimens are well tolerated and have encouraging overall survival in patients with metastatic NSCLC.
Does Delayed Cord Clamping Improve Long-Term (≥4 Months) Neurodevelopment in Term Babies? A Systematic Review and a Meta-Analysis of Randomized Clinical Trials
Authors: Xodo Serena , Xodo Luigi , Baccarini Giovanni , Driul Lorenza , Londero Ambrogio P.
Published: April 2021

Background: Recently, the literature suggested that placental transfusion facilitated by delayed cord clamping (DCC), besides having benefits on hematological parameters, might improve the infants' brain development.

Objective: The present review primarily evaluates the Ages and Stages Questionnaire (ASQ) total score mean difference (MD) at long-term follow-up (≥4 months) comparing DCC (>90 or >180 s) to early cord clamping (ECC). Secondary aims consisted of evaluating the ASQ domains' MD and the results obtained from other methods adopted to evaluate the infants' neurodevelopment.

Methods: MEDLINE, Scopus, Cochrane, and ClinicalTrials.gov databases were searched (up to 2nd November 2020) for systematic review and meta-analysis. All randomized controlled trials (RCTs) of term singleton gestations received DCC or ECC. Multiple pregnancies, pre-term delivery, non-randomized studies, and articles in languages other than English were excluded. The included studies were assessed for bias and quality. ASQ data were pooled stratified by time to follow up.

Results: This meta-analysis of 4 articles from 3 RCTs includes 765 infants with four-month follow-up and 672 with 12 months follow-up. Primary aim (ASQ total score) pooled analysis was possible only for 12 months follow-up, and no differences were found between DCC and ECC (MD 1.1; CI 95: −5.1; 7.3). DCC approach significantly improves infants' communication domains (MD 0.6; CI 95: 0.1; 1.1) and personal-social assessed (MD 1.0; CI 95: 0.3; 1.6) through ASQ at 12 months follow-up. Surprisingly, the four-month ASQ personal social domain (MD −1.6; CI 95: −2.8; −0.4) seems to be significantly lower in the DCC group than in the ECC group.

Conclusions: DCC, a simple, non-interventional, and cost-effective approach, might improve the long-term infants' neurological outcome. Single-blinding and limited studies number were the main limitations. Further research should be performed to confirm these observations, ideally with RCTs adopting standard methods to assess infants' neurodevelopment.

Trial registration: NCT01245296, NCT01581489, NCT02222805, NCT01620008, IRCT201702066807N19, and NCT02727517
Xiaoyaosan Alleviates Hippocampal Glutamate-Induced Toxicity in the CUMS Rats via NR2B and PI3K/Akt Signaling Pathway
Authors: Zhou Xue-Ming , Liu Chen-Yue , Liu Yue-Yun , Ma Qing-Yu , Zhao Xin , Jiang You-Ming , Li Xiao-Juan , Chen Jia-Xu
Published: April 2021

Purpose: It is revealed that Xiaoyaosan could reduce glutamate level in the hippocampus of depressed rats, whose metabolism leads to the pathophysiology of depression. However, the underlying mechanism remains unclear. This study aims to explore the effect of Xiaoyaosan on glutamate metabolism, and how to regulate the excitatory injury caused by glutamate.

Methods: Rats were induced by chronic unpredictable mild stress, then divided into control, vehicle (distilled water), Xiaoyaosan, fluoxetine, vehicle (DMSO), Xiaoyaosan + Ly294002 and Ly294002 groups. Ly294002 was microinjected into the lateral ventricular catheterization at 5 mM. Xiaoyaosan (2.224 g/kg) and fluoxetine (2.0 mg/kg) were orally administered for three weeks. The open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were used to assess depressive behavior. The glutamate and corticosterone (CORT) levels were detected by ELISA. Western blot, immunochemistry or immunofluorescence were used to detect the expressions of NR2B, MAP2, PI3K and P-AKT/Akt in the hippocampal CA1 region. The mRNA level of MAP2, NR2B and PI3K were detected by RT-qPCR.

Results: Compared to the rats in control group, body weight and food intake of CUMS rats was decreased. CUMS rats also showed depression-like behavior as well as down regulate the NR2B and PI3K/Akt signaling pathway. Xiaoyaosan treatments could increase food intake and body weight as well as improved time spent in the central area, total distance traveled in the OFT. Xiaoyaosan could also decrease the immobility time as well as increase the sucrose preference in SPT. Moreover, xiaoyaosan decreased the level of glutamate in the hippocampal CA1 region and serum CORT in CUMS rats. Furthermore, xiaoyaosan improved the expression of MAP2 as well as increased the expression of NR2B, PI3K and the P-AKT/AKT ratio in the hippocampal CA1 region in the CUMS rats.

Conclusion: Xiaoyaosan treatment can exert the antidepressant effect by rescuing hippocampal neurons loss induced by the glutamate-mediated excitotoxicity in CUMS rats. The underlying pathway maybe through NR2B and PI3K/Akt signaling pathways. These results may suggest the potential of Xiaoyaosan in preventing the development of depression.
5-Bis-(2,6-difluoro-benzylidene) Cyclopentanone Acts as a Selective 11β-Hydroxysteroid Dehydrogenase one Inhibitor to Treat Diet-Induced Nonalcoholic Fatty Liver Disease in Mice
Authors: Guan Hongguo , Wang Yiyan , Li Huitao , Zhu Qiqi , Li Xiaoheng , Liang Guang , Ge Ren-Shan
Published: April 2021

Background: 11β-Hydroxysteroid dehydrogenase one is responsible for activating inert glucocorticoid cortisone into biologically active cortisol in humans and may be a novel target for the treatment of nonalcoholic fatty liver disease.

Methods: A series of benzylidene cyclopentanone derivatives were synthesized, and the selective inhibitory effects on rat, mouse and human 11β-hydroxysteroid dehydrogenase one and two were screened. The most potent compound [5-bis-(2,6-difluoro-benzylidene)-cyclopentanone] (WZS08), was used to treat nonalcoholic fatty liver disease in mice fed a high-fat-diet for 100 days.

Results: WZS08 was the most potent inhibitor of rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, with half maximum inhibitory concentrations of 378.0, 244.1, and 621.1 nM, respectively, and it did not affect 11β-hydroxysteroid dehydrogenase two at 100 μM. When mice were fed WZS08 (1, 2, and 4 mg/kg) for 100 days, WZS08 significantly lowered the serum insulin levels and insulin index at 4 mg/kg. WZS08 significantly reduced the levels of serum triglycerides, cholesterol, low-density lipoprotein, and hepatic fat ratio at low concentration of 1 mg/kg. It down-regulated Plin2 expression and up-regulated Fabp4 expression at low concentration of 1 mg/kg. It significantly improved the morphology of the non-alcoholic fatty liver.

Conclusion: WZS08 selectively inhibits rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, and can treat non-alcoholic fatty liver disease in a mouse model.
Potential Mechanism Prediction of Herbal Medicine for Pulmonary Fibrosis Associated with SARS-CoV-2 Infection Based on Network Analysis and Molecular Docking
Authors: Jin De , An Xuedong , Zhang Yuqing , Zhao Shenghui , Duan Liyun , Duan Yingying , Lian Fengmei , Tong Xiaolin
Published: April 2021

Background: Coronavirus Disease 2019 (COVID-19) is still a relevant global problem. Although some patients have recovered from COVID-19, the sequalae to the SARS-CoV-2 infection may include pulmonary fibrosis, which may contribute to considerable economic burden and health-care challenges. Convalescent Chinese Prescription (CCP) has been widely used during the COVID-19 recovery period for patients who were at high risk of pulmonary fibrosis and is recommended by the Diagnosis and Treatment Protocol for COVID-19 (Trial Version sixth, seventh). However, its underlying mechanism is still unclear.

Methods: In this study, an integrated pharmacology approach was implemented, which involved evaluation of absorption, distribution, metabolism and excretion of CCP, data mining of the disease targets, protein-protein interaction (PPI) network construction, and analysis, enrichment analysis, and molecular docking simulation, to predict the bioactive components, potential targets, and molecular mechanism of CCP for pulmonary fibrosis associated with SARS-CoV-2 infection.

Results: The active compound of CCP and the candidate targets, including pulmonary fibrosis targets, were obtained through database mining. The Drug-Disease network was constructed. Sixty-five key targets were identified by topological analysis. The findings of Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation suggested that the VEGF, Toll-like 4 receptor, MAPK signaling pathway, and TGF-β1 signaling pathways may be involved in pulmonary fibrosis. In the molecular docking analyses, VEGF, TNF-α, IL-6, MMP9 exhibited good binding activity. Findings from our study indicated that CCP could inhibit the expression of VEGF, TNF-α, IL-6, MMP9, TGF-β1 via the VEGF, Toll-like 4 receptor, MAPK, and TGF-β1 signaling pathways.

Conclusion: Potential mechanisms involved in CCP treatment for COVID-19 pulmonary fibrosis associated with SARS-CoV-2 infection involves multiple components and multiple target points as well as multiple pathways. These findings may offer a profile for further investigations of the anti-fibrotic mechanism of CCP.
Development, Characterization and Stability Evaluation of Topical Gel Loaded With Ethosomes Containing Achillea millefolium L. Extract
Authors: Andleeb Mehwish , Shoaib Khan Haij Muhammad , Daniyal Muhammad
Published: April 2021

Background: Delivering plant extract at high loading with intact antioxidants and efficient skin permeation always remains a challenge. To address this, we prepared a stable gel formulation containing nanoethosomes loaded with Achillea millefolium L. (AM) extract for topical drug delivery.

Method: The AM extract was tested at first for phytochemical analysis, antioxidant activity, total phenolic and flavonoid content, and FTIR examination. The nanoethosomes containing AM extract were synthesized and characterized by size, surface charge, and morphology, and entrapment efficiency (EE) was determined. The optimized nanoethosomes were then incorporated to develop a topical gel formulation and subjected to skin for permeation, pH, viscosity, and organoleptic evaluation for up to three months.

Results: The AM ethanolic extract demonstrated 88% free radical scavenging activity and notable phenolic and flavonoid contents of up to 123 mg GAE/g and 42 mg QE/g, respectively. The optimized nanoethosomes encapsulated with AM extract (240 nm) were spherical in shape, with −31.1 mV of surface charge, and showed considerable entrapment efficiency (90%). Furthermore, the selected topical gel remained stable during the study period. The Exvivo permeation study of ethosomal gel showed the highest release percentage of 79.8%.

Conclusion: The study concludes that topical gel loaded with nanoethosomes containing AM extract is an encouraging approach for topical drug delivery.
3′-Sialyllactose Protects SW1353 Chondrocytic Cells From Interleukin-1β-Induced Oxidative Stress and Inflammation
Authors: Baek Ahreum , Jung So Hee , Pyo Soonil , Kim Soo Yeon , Jo Seongmoon , Kim Lila , Lee Eun Young , Kim Sung Hoon , Cho Sung-Rae
Published: April 2021

Osteoarthritis (OA) is a major degenerative joint disease. Oxidative stress and inflammation play key roles in the pathogenesis of OA. 3′-Sialyllactose (3′-SL) is derived from human milk and is known to regulate a variety of biological functions related to immune homeostasis. This study aimed to investigate the therapeutic mechanisms of 3′-SL in interleukin-1β (IL-1β)-treated SW1353 chondrocytic cells. 3′-SL potently suppressed IL-1β-induced oxidative stress by increasing the levels of enzymatic antioxidants. 3′-SL significantly reversed the IL-1β mediated expression levels of reactive oxygen species in IL-1β-stimulated chondrocytic cells. In addition, 3′-SL could reverse the increased levels of inflammatory markers such as nitrite, prostaglandin E2, inducible nitric oxide synthase, cyclooxygenase-2, IL-1β, and IL-6 in IL-1β-stimulated chondrocytic cells. Moreover, 3′-SL significantly inhibited the apoptotic process, as indicated by the downregulation of the pro-apoptotic protein Bax, upregulation of the anti-apoptotic protein Bcl-2 expression, and significant reduction in the number of TUNEL-positive cells in the IL-1β-treated chondrocytic cells. Furthermore, 3′-SL reversed cartilage destruction by decreasing the release of matrix metalloproteinases (MMP), such as MMP1, MMP3, and MMP13. In contrast, 3′-SL significantly increased the expression levels of matrix synthesis proteins, such as collagen II and aggrecan, in IL-1β-treated chondrocytic cells. 3′-SL dramatically suppressed the activation of mitogen-activated protein kinases (MAPK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways, which are related to the pathogenesis of OA. Taken together, our data suggest that 3′-SL alleviates IL-1β-induced OA pathogenesis via inhibition of activated MAPK and PI3K/AKT/NF-κB signaling cascades with the downregulation of oxidative stress and inflammation. Therefore, 3′-SL has the potential to be used as a natural compound for OA therapy owing to its ability to activate the antioxidant defense system and suppress inflammatory responses.