bluuebunny/crossref_metadata_2025 huggingface dataset:
Extra-Articular Manifestations and Comorbidities in Psoriatic Disease: A Journey Into the Immunologic Crosstalk
Authors: Novelli Lucia , Lubrano Ennio , Venerito Vincenzo , Perrotta Fabio Massimo , Marando Francesca , Curradi Giacomo , Iannone Florenzo
Published: September 2021

Psoriatic arthritis (PsA) is a chronic inflammatory disease primarily affecting peripheral and axial joints, with the possible presence of extra-articular manifestations (EAMs), such as psoriasis, uveitis, and inflammatory bowel disease. Recently, the concept of psoriatic disease (PsD) has been proposed to define a systemic condition encompassing, in addition to joints and EAMs, some comorbidities (e.g., metabolic syndrome, type II diabetes, hypertension) that can affect the disease outcome and the achievement of remission. EAMs and comorbidities in PsA share common immunopathogenic pathways linked to the systemic inflammation of this disease; these involve a broad variety of immune cells and cytokines. Currently, various therapeutics are available targeting different cytokines and molecules implicated in the inflammatory response of this condition; however, despite an improvement in the management of PsA, comprehensive disease control is often not achievable. There is, therefore, a big gap to fill especially in terms of comorbidities and EAMs management. In this review, we summarize the clinical aspects of the main comorbidities and EAMs in PsA, and we focus on the immunopathologic features they share with the articular manifestations. Moreover, we discuss the effect of a diverse immunomodulation and the current unmet needs in PsD.
Trends Analysis of Non-Hodgkin Lymphoma at the National, Regional, and Global Level, 1990–2019: Results From the Global Burden of Disease Study 2019
Authors: Cai Wenwen , Zeng Qingle , Zhang Xingxing , Ruan Weiqing
Published: September 2021

Background: Non-Hodgkin lymphoma is a common hematologic malignancy. This article aimed to estimate the trends of non-Hodgkin lymphoma (NHL) globally from 1990 to 2019.

Methods: Data on the NHL burden were explored from the Global Burden of Disease study 2019. The trends of NHL burden were estimated using age-standardized rate (ASR) and estimated annual percentage change (EAPC).

Results: The ASR of NHL incidence showed an increasing trend worldwide from 1990 to 2019, with an EAPC of.56 [95% CI: 0.45–0.66]. Meanwhile, increasing trends were observed in both sexes and in most geographic regions, particularly East Asia (EAPC = 3.57, 95% CI: 3.29–3.86). The most pronounced increasing trends were seen in Georgia (EAPC = 4.7, 95% CI: 4.20–5.21), followed by Belarus and Uzbekistan. However, death and disability-adjusted life years (DALYs) caused by NHL showed decreasing trends globally, in which the respective EAPCs were −0.09 (95% CI: −0.17 to −0.02) and −0.28 (95% CI: −0.35 to −0.22). Decreasing trends were mainly seen in high and high-middle sociodemographic index (SDI) areas. At the national level, the largest increasing trends of death and DALYs were observed in Georgia, in which the respective EAPCs were 4.54 (95% CI: 4.01–5.07) and 4.97 (95% CI: 4.42–5.52).

Conclusions: Decreasing trends of death and DALYs caused by NHL were observed worldwide from 1990 to 2019, but NHL remains a substantial challenge globally. The findings would inform the strategies for reducing the burden of NHL.
Metataxonomic Analysis of Grape Microbiota During Wine Fermentation Reveals the Distinction of Cyprus Regional terroirs
Authors: Kamilari Eleni , Mina Minas , Karallis Christos , Tsaltas Dimitrios
Published: September 2021

Wine production in Cyprus has strong cultural ties with the island’s tradition, influencing local and foreign consumers’ preferences and contributing significantly to Cyprus’ economy. A key contributor to wine quality and sensorial characteristics development is the microbiota that colonizes grapes and performs alcoholic fermentation. Still, the microbial patterns of wines produced in different geographic regions (terroir) in Cyprus remain unknown. The present study investigated the microbial diversity of five terroirs in Cyprus, two from the PGI Lemesos region [Kyperounta (PDO Pitsilia) and Koilani (PDO Krasochoria)], and three from the PGI Pafos region [Kathikas (PDO Laona Akamas), Panayia, and Statos (PDO Panayia)], of two grape varieties, Xynisteri and Maratheftiko, using high-throughput amplicon sequencing. Through a longitudinal analysis, we examined the evolution of the bacterial and fungal diversity during spontaneous alcoholic fermentation. Both varieties were characterized by a progressive reduction in their fungal alpha diversity (Shannon index) throughout the process of fermentation. Additionally, the study revealed a distinct separation among different terroirs in total fungal community composition (beta-diversity) for the variety Xynisteri. Also, Kyperounta terroir had a distinct total fungal beta-diversity from the other terroirs for Maratheftiko. Similarly, a significant distinction was demonstrated in total bacterial diversity between the PGI Lemesos region and the PGI Pafos terroirs for grape juice of the variety Xynisteri. Pre-fermentation, the fungal diversity for Xynisteri and Maratheftiko was dominated by the genera Hanseniaspora, Aureobasidium, Erysiphe, Aspergillus, Stemphylium, Penicillium, Alternaria, Cladosporium, and Mycosphaerella. During and post-fermentation, the species Hanseniaspora nectarophila, Saccharomyces cerevisiae, Hanseniaspora guilliermondii, and Aureobasidium pullulans, became the predominant in most must samples. Regarding the bacterial diversity, Lactobacillus and Streptococcus were the predominant genera for both grape varieties in all stages of fermentation. During fermentation, an increase was observed in the relative abundance of some bacteria, such as Acetobacter, Gluconobacter, and Oenococcus oeni. Finally, the study revealed microbial biomarkers with statistically significant higher relative representation, associated with each geographic region and each grape variety, during the different stages of fermentation. The present study’s findings provide an additional linkage between the grape microbial community and the wine terroir.
A Novel Ferroptosis-Related Gene Signature Predicts Recurrence in Patients With Pancreatic Ductal Adenocarcinoma
Authors: Feng Zengyu , Chen Peng , Li Kexian , Lou Jianyao , Wu Yulian , Li Tao , Peng Chenghong
Published: September 2021

Background: Recurrence after surgery is largely responsible for the extremely poor outcomes for patients with pancreatic ductal adenocarcinoma (PDAC). Ferroptosis is implicated in chemotherapy sensitivity and tumor recurrence, we aimed to find out survival-associated ferroptosis-related genes and use them to build a practical risk model with the purpose to predict PDAC recurrence.

Methods: Univariate Cox regression analysis was conducted to obtain prognostic ferroptosis-related genes in The Cancer Genome Atlas (TCGA, N = 140) cohort. Multivariate Cox regression analysis was employed to construct a reliable and credible gene signature. The prognostic performance was verified in a MTAB-6134 (N = 286) validation cohort and a PACA-CA (N = 181) validation cohort. The stability of the signature was tested in TCGA and MTAB-6134 cohorts by ROC analyses. Pathway enrichment analysis was adopted to preliminary illuminate the biological relevance of the gene signature.

Results: Univariate and multivariate Cox regression analyses identified a 5-gene signature that contained CAV1, DDIT4, SLC40A1, SRXN1 and TFAP2C. The signature could efficaciously stratify PDAC patients with different recurrence-free survival (RFS), both in the training and validation cohorts. Results of subgroup receiver operating characteristic curve (ROC) analyses confirmed the stability and the independence of this signature. Our signature outperformed clinical indicators and previous reported models in predicting RFS. Moreover, the signature was found to be closely associated with several cancer-related and drug response pathways.

Conclusion: This study developed a precise and concise prognostic model with the clinical implication in predicting PDAC recurrence. These findings may facilitate individual management of postoperative recurrence in patients with PDAC.
Imaging Acute Stroke: From One-Size-Fit-All to Biomarkers
Authors: Lu Jianfei , Mei Qiyong , Hou Xianhua , Manaenko Anatol , Zhou Lili , Liebeskind David S. , Zhang John H. , Li Yao , Hu Qin
Published: September 2021

In acute stroke management, time window has been rigidly used as a guide for decades and the reperfusion treatment is only available in the first few limited hours. Recently, imaging-based selection of patients has successfully expanded the treatment window out to 16 and even 24 h in the DEFUSE 3 and DAWN trials, respectively. Recent guidelines recommend the use of imaging techniques to guide therapeutic decision-making and expanded eligibility in acute ischemic stroke. A tissue window is proposed to replace the time window and serve as the surrogate marker for potentially salvageable tissue. This article reviews the evolution of time window, addresses the advantage of a tissue window in precision medicine for ischemic stroke, and discusses both the established and emerging techniques of neuroimaging and their roles in defining a tissue window. We also emphasize the metabolic imaging and molecular imaging of brain pathophysiology, and highlight its potential in patient selection and treatment response prediction in ischemic stroke.
Tandem Mass Tag-Based Quantitative Proteomic Analysis Reveals Pathways Involved in Brain Injury Induced by Chest Exposure to Shock Waves
Authors: Tong Changci , Cong Peifang , Liu Ying , Shi Xiuyun , Shi Lin , Mao Shun , Zhao Yan , Hou Mingxiao , Liu Yunen
Published: September 2021

Recurrent chest blast exposure can lead to brain inflammation, oxidative stress, and mental disorders in soldiers. However, the mechanism that underlies brain injury caused indirectly by chest blasts remains unclear. It is urgent to find additional reliable biomarkers to reveal the intimate details of the pathogenesis of this phenomenon. We used the term tandem mass tag (TMT) labeling combined with liquid chromatography–tandem mass spectrometry (LC-MS/MS) to screen for differentially expressed proteins in rat brain at different time points after a chest blast. Data are available via ProteomeXchange with the identifier PXD025204. Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), the Database for Annotation, Visualization and Integrated Discovery (DAVID), and Cytoscape analyses were used to analyze the proteomic profiles of blast-exposed rats. In addition, we performed Western blotting to verify protein levels. We identified 6,931 proteins, of which 255 were differentially expressed and 43, 84, 52, 97, and 49 were identified in brain tissues at 12, 24, 48, and 72 h and 1 week after chest blast exposure, respectively. In this study, the GO, KEGG, Clusters of Orthologous Groups of proteins, and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analyses indicated that brain damage caused by chest blast exposure involved many important biological processes and signaling pathways, such as inflammation, cell adhesion, phagocytosis, neuronal and synaptic damage, oxidative stress, and apoptosis. Furthermore, Western blotting confirmed that these differentially expressed proteins and affected signaling pathways were associated with brain damage caused by chest blast exposure. This study identifies potential protein biomarkers of brain damage caused indirectly by chest blast and new targets for the treatment of this condition.
Combination of Albumin-Globulin Score and Sarcopenia to Predict Prognosis in Patients With Renal Cell Carcinoma Undergoing Laparoscopic Nephrectomy
Authors: Mao Weipu , Zhang Nieke , Wang Keyi , Hu Qiang , Sun Si , Xu Zhipeng , Yu Junjie , Wang Can , Chen Saisai , Xu Bin , Wu Jianping , Zhang Hua , Chen Ming
Published: September 2021

We conducted a multicenter clinical study to construct a novel index based on a combination of albumin-globulin score and sarcopenia (CAS) that can comprehensively reflect patients' nutritional and inflammatory status and assess the prognostic value of CAS in renal cell carcinoma (RCC) patients. Between 2014 and 2019, 443 patients from 3 centers who underwent nephrectomy were collected (343 in the training set and 100 in the test set). Kaplan-Meier curves were employed to analyze the impact of albumin-globulin ratio (AGR), albumin-globulin score (AGS), sarcopenia, and CAS on overall survival (OS) and cancer-specific survival (CSS) in RCC patients. Receiver operating characteristic (ROC) curves were used to assess the predictive ability of AGR, AGS, sarcopenia, and CAS on prognosis. High AGR, low AGS, and nonsarcopenia were associated with higher OS and CSS. According to CAS, the training set included 60 (17.5%) patients in grade 1, 176 (51.3%) patients in grade 2, and 107 (31.2%) patients in grade 3. Lower CAS was linked to longer OS and CSS. Multivariate Cox regression analysis revealed that CAS was an independent risk factor for OS (grade 1 vs. grade 3: aHR = 0.08; 95% CI: 0.01–0.58, p = 0.012; grade 2 vs. grade 3: aHR = 0.47; 95% CI: 0.25–0.88, p = 0.018) and CSS (grade 1 vs. grade 3: aHR = 0.12; 95% CI: 0.02–0.94, p = 0.043; grade 2 vs. grade 3: aHR = 0.31; 95% CI: 0.13–0.71, p = 0.006) in RCC patients undergoing nephrectomy. Additionally, CAS had higher accuracy in predicting OS (AUC = 0.687) and CSS (AUC = 0.710) than AGR, AGS, and sarcopenia. In addition, similar results were obtained in the test set. The novel index CAS developed in this study, which reflects patients' nutritional and inflammatory status, can better predict the prognosis of RCC patients.
Association of Serum 25-Hydroxyvitamin D Concentrations With All-Cause and Cause-Specific Mortality Among Adult Patients With Existing Cardiovascular Disease
Authors: Dai Lei , Liu Man , Chen Liangkai
Published: September 2021

Background: Vitamin D insufficiency and deficiency are common in patients with cardiovascular disease (CVD). We aimed to prospectively examine the associations of serum 25-hydroxyvitamin D [25(OH)D] concentrations with all-cause and cause-specific mortality among adult patients with existing CVD.

Methods: We included 37,079 patients with CVD from the UK Biobank study, a prospective cohort of half a million participants aged 40–69 years. We defined patients with CVD as those who suffered coronary heart disease, atrial fibrillation, heart failure, or stroke. The associations of serum 25(OH)D concentration with all-cause and cause-specific mortality were examined by using multivariable Cox regression models and competing risk analyses.

Results: Among 37,079 patients with CVD at baseline, 57.5% were subjected to vitamin D deficiency (i.e., 25[OH]D <50 nmol/L). During a median follow-up of 11.7 years, 6,319 total deaths occurred, including 2,161 deaths from CVD, 2,230 deaths from cancer, 623 deaths from respiratory disease, and 1,305 other-cause deaths. We observed non-linear inverse associations for all-cause, cancer, respiratory disease, and other-cause mortality (P-non-linearity <0.01) and approximately linear inverse associations for CVD mortality (P-non-linearity = 0.074). Among CVD patients with vitamin D deficiency, per 10 nmol/L increment in serum 25(OH)D concentrations was associated with an 12% reduced risk for all-cause mortality and 9% reduced risk for CVD mortality.

Conclusion: Among patients with existing CVD, increasing levels in serum 25(OH)D were independently associated with a decreased risk of all-cause and cause-specific mortality. These findings suggest that elevated serum 25(OH)D concentration benefits CVD patients with vitamin D deficiency.
Research Progresses in Immunological Checkpoint Inhibitors for Breast Cancer Immunotherapy
Authors: Zhang Wenxiang , Kong Xiangyi , Ai Bolun , Wang Zhongzhao , Wang Xiangyu , Wang Nianchang , Zheng Shan , Fang Yi , Wang Jing
Published: September 2021

Tumor immune escape refers to the phenomenon in which tumor cells escape the recognition and attack of the body’s immune system through various mechanisms so that they can survive and proliferate in vivo. The imbalance of immune checkpoint protein expression is the primary mechanism for breast cancer to achieve immune escape. Cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1)/programmed cell death protein-ligand 1 (PD-L1) are critical immune checkpoints for breast cancer. Immune checkpoint inhibitors block the checkpoint and relieve its inhibition effect on immune cells, reactivate T-cells and destroy cancer cells and restore the body’s ability to resist tumors. At present, immunological checkpoint inhibitors have made significant progress in breast cancer immunotherapy, and it is expected to become a new treatment for breast cancer.
Clinicopathological Characteristics and Response to Chemotherapy in Treatment-Naive Epstein–Barr Virus Associated Gastric Cancer: A Retrospective Study
Authors: Xie Tong , Peng Zhi , Liu Yiqiang , Zhang Zhening , Zhang Xiaotian , Li Jian , Lu Ming , Gong Jifang , Qi Changsong , Ji Jiafu , Shen Lin
Published: September 2021

Background

Epstein–Barr virus associated gastric cancer (EBVaGC) is a special subtype of gastric cancer. However, the perioperative treatment plan and the response to chemotherapy are still uncertain.

Methods

We retrospectively enrolled patients diagnosed with EBVaGC from March 2013 to July 2020 in Beijing Cancer Hospital. Clinicopathological characteristics were recorded. Disease-free survival (DFS) were then calculated, and variants affecting DFS were tested in a Cox proportional regression model.

Results

One hundred sixty consecutive patients were finally included in our study. Of the patients, 96.9% had adenocarcinoma, while five had squamous cell carcinoma component. Most (70.9%) of them were poorly differentiated. Prevalent programmed death-ligand 1 (PD-L1) (69%) and minor HER-2 (3.8%) expression were noticed; all of the patients were MMR proficient (pMMR) or microsatellite stable (MSS). Among 33 patients who experienced neoadjuvant therapy, the number of tumor regression grade (TRG) 1, TRG 2, and TRG 3 was 5, 16, and 12, respectively. Patients with advanced tumor stage and T stage showed poorer response. Thirty-one patients experienced first-line chemotherapy; ORR was 33.3%, and DCR was 61.9%. One hundred forty-seven patients underwent surgery, and 27 of them showed disease recurrence; the 3-year DFS rate was 71.0%. Tumor stage, neoadjuvant chemotherapy, vascular invasion, and negative PD-L1 expression were associated with poorer DFS. Vascular invasion was the independent risk factor of DFS. Only seven patients reached OS with median follow-up time of 14 months.

Conclusion

EBVaGC exhibits unique clinicopathological characteristics. Neoadjuvant chemotherapy may not be suitable for EBVaGC, and EBVaGC exhibited relatively poor response to chemotherapy.
Effects of Serum From Radiofrequency Ablation Patients Receiving General Anesthesia or Local Anesthesia on Hepatocellular Carcinoma Cancer Cell Malignancy: A Prospective Randomized Controlled Trial
Authors: Shi Yumiao , Wu Tong , Wang Tao , Liu Yan , Wang Xiaoqiang , Luo Jiamei , Su Diansan , Zhai Bo , Tian Jie
Published: September 2021

Background

Whether anesthesia methods affect malignant biological behavior of cancer remains unresolved. In this study, we aim to compare the effects of general anesthesia (GA) and local anesthesia (LA) on serum collected from primary hepatocellular carcinoma (HCC) patients presenting for radiofrequency ablation (RFA).

Methods

From August 2020 to December 2020, a prospective, randomized, and controlled study was conducted at Renji Hospital, which is affiliated with Shanghai Jiaotong University School of Medicine. 25 qualified patients from 18 to 65 years of age undergoing RFA were enrolled in the study and randomly assigned into two groups: the GA group (n = 14) and the LA group (n = 11). Venous blood was drawn from all patients preoperatively and 1 hour postoperatively. The serum collected was then used for the culturing of HepG2 cells. The malignant biological behaviors of HepG2 cells, including invasion, migration and proliferation, were observed after 24 hours of exposure to patients’ serum. ELISA was used to compare expression levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and lymphokines (IFN-γ, IL-2) in patients’ serum from both groups.

Results

HepG2 cells cultured with postoperative serum obtained from patients who received GA, but not LA, were associated with significantly increased cell invasion, migration and proliferation, compared to preoperative serum from the same patient group. Expression levels of pro-inflammatory cytokines were significantly higher, and lymphokines significantly lower in postoperative serum from GA patients compared to the corresponding preoperative serum.

Conclusion

GA affects the serum milieu of patients with HCC, promoting the malignant biological behavior of a human HCC cell line.
The Prediction Potential of the Pretreatment Lung Immune Prognostic Index for the Therapeutic Outcomes of Immune Checkpoint Inhibitors in Patients With Solid Cancer: A Systematic Review and Meta-Analysis
Authors: Liu Hui , Yang Xiao-Li , Yang Xiao-Yun , Dong Zhao-Ru , Chen Zhi-Qiang , Hong Jian-Guo , Li Tao
Published: September 2021

Background

The lung immune prognostic index (LIPI) is recently developed to predict immune checkpoint inhibitors (ICIs) treatment outcomes for non-small cell lung cancer. However, its predictive value for other types of cancer remained unclear. This meta-analysis aimed to evaluate the association between pretreatment LIPI score and therapeutic outcomes in cancer patients treated with ICIs.

Methods

We searched PubMed, Cochrane Library literature databases and EMBASE for abstracts and full-text articles published from the inception of the database until 16th, Nov 2020. Meta-analyses were performed separately for progression-free survival (PFS) and overall survival (OS) by using the random-effects model.

Results

A total of 12 studies involving 4883 patients receiving ICIs treatment were identified for the primary analysis. The pooled results implied that compared with good LIPI score groups, patients with poor or intermediate LIPI score were significantly associated with worse OS (HR=3.33, 95%CI 2.64-4.21, P < 0.001, I2 = 64.2%; HR=1.71, 95%CI 1.43-2.04, P < 0.001, I2 = 43.6%, respectively) and PFS (HR=2.73,95%CI 2.00-3.73, P < 0.001, I2 = 78.2%; HR=1.43, 95%CI 1.28-1.61, P < 0.001, I2 = 16.3%, respectively). Also, for 1873 patients receiving chemotherapy, a poor LIPI score was significantly associated with worse OS (HR=2.30, 95%CI 1.73-3.07, P < 0.001; I2 = 56.2%) and PFS (HR=1.92,95%CI 1.69-2.17; P < 0.001; I2 = 0.0%) compared with good LIPI score groups.

Conclusions

A good LIPI score was significantly correlated with improved OS and PFS in cancer patients receiving ICIs or chemotherapy, regardless of the types of cancer.
Inexpensive Systemic Inflammatory Biomarkers in Ovarian Cancer: An Umbrella Systematic Review of 17 Prognostic Meta-Analyses
Authors: El Bairi Khalid , Al Jarroudi Ouissam , Afqir Said
Published: September 2021

The association of several inflammation-based biomarkers [lymphocyte-to-monocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte ratios (LMR, NLR, and PLR, respectively)] with the survival of epithelial ovarian cancer (EOC) patients has been extensively investigated in several systematic reviews and meta-analyses (MAs) of observational studies. The aim of this umbrella systematic review is to appraise all available results in published MAs that explored the association between these biomarkers and EOC outcomes. An umbrella systematic review of the current evidence for systemic inflammatory biomarkers in the peripheral blood of EOC patients was performed by searching several databases including PubMed/Medline and Web of Science. The quality of the MAs was appraised using the AMSTAR-2 tool as well as other qualitative criteria. The evidence was graded from convincing (Class I) to weak (Class IV). Our umbrella review appraised 17 MAs of retrospective studies (range: 7–16) with a number of enrolled patients ranging from 1,636 to 4,910 patients in each MA. All these MAs demonstrated that pretreatment high NLR and PLR, as well as low LMR, were independent predictors of poor overall survival and progression-free survival in EOC. Nearly all published MAs were conducted by Chinese researchers (16/17) and were redundant in their character. Another issue in these MAs is the absence of prior PROSPERO database registration as well as the earlier exclusion of the gray literature. On the other hand, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analyses Of Observational Studies in Epidemiology (MOOSE)-based reporting guidelines were used in nine out of the 17 MAs. A good number of MAs have transparently provided funding acknowledgment. The AMSTAR-2-based assessment showed low quality in 11 out of the 17 reviewed MAs. This negative rating was largely due to the absence of critical domains. Finally, all evaluated MAs were rated as Class III or IV (suggestive and weak, respectively). Despite the power of MAs in increasing sampling and precision, the quality of the current non-randomized evidence on this topic is still weak.

Systematic Review Registration

PROSPERO, identifier CRD42020201493.
HNRNPA2B1, as a m6A Reader, Promotes Tumorigenesis and Metastasis of Oral Squamous Cell Carcinoma
Authors: Zhu Feiya , Yang Tianru , Yao Mianfeng , Shen Ting , Fang Changyun
Published: September 2021

N6-methyladenosine (m6A) modification is the most prevalent modification on eukaryotic RNA, and the m6A modification regulators were involved in the progression of various cancers. However, the functions of m6A regulators in oral squamous cell carcinoma (OSCC) remain poorly understood. In this study, we demonstrated that 13 of 19 m6A-related genes in OSCC tissues are dysregulated, and HNRNPA2B1 was the most prognostically important locus of the 19 m6A regulatory genes in OSCC. Moreover, HNRNPA2B1 expression is elevated in OSCC, and a high level of HNRNPA2B1 is significantly associated with poor overall survival in OSCC patients. Functional studies, combined with further analysis of the correlation between the expression of HNRNPA2B1 and the EMT-related markers from the TCGA database, reveal that silencing HNRNPA2B1 suppresses the proliferation, migration, and invasion of OSCC via EMT. Collectively, our work shows that HNRNPA2B1 may have the potential to promote carcinogenesis of OSCC by targeting EMT via the LINE-1/TGF-β1/Smad2/Slug signaling pathway and provide insight into the critical roles of HNRNPA2B1 in OSCC.
Exosome Released FZD10 Increases Ki-67 Expression via Phospho-ERK1/2 in Colorectal and Gastric Cancer
Authors: Scavo Maria Principia , Rizzi Federica , Depalo Nicoletta , Armentano Raffaele , Coletta Sergio , Serino Grazia , Fanizza Elisabetta , Pesole Pasqua Letizia , Cervellera Alessandra , Carella Nicola , Curri Maria Lucia , Giannelli Gianluigi
Published: September 2021

Frizzled (FZD) proteins are primary receptors for Wnt signaling that activates the mitogen-activated protein kinase (MAPK) pathways. Dysfunction of Wnt signals with consequently abnormal activation of MAPK3 pathways was found in colorectal cancer (CRC) and gastric cancer (GC). Upregulation of FZD10 protein, localized in the exosomes isolated from plasma of CRC and GC patients, was associated with a poor prognosis. Herein, the expression levels of circulating FZD10 were found to be strongly correlated to their expression levels in the corresponding tissues in CRC and GC patients. Bioinformatic prediction revealed a link between FZD10 and Ki-67 through MAPK3. In both CRC and GC tissues, pERK1/2 levels were significantly increased at more advanced disease stages, and pERK1/2 and Ki-67 were correlated. Silencing of FZD10 in CRC and GC cells resulted in a significant reduction of pERK1/2 and Ki-67 expression, while subsequent treatment with exogenous exosomes partially restored their expression levels. The strong correlation between the expression of Ki-67 in tissues and of FZD10 in exosomes suggests that the exosome-delivered FZD10 may be a promising novel prognostic and diagnostic biomarker for CRC and GC.
Purified Vitexin Compound 1 Serves as a Promising Antineoplastic Agent in Ovarian Cancer
Authors: Ma Kewen , Wang Kuansong , Zhou Yingjun , Liu Nian , Guo Wei , Qi Jialin , Hu Zhenmin , Su Shitong , Tang Ping , Zhou Xunjian
Published: September 2021

Ovarian cancer is a common gynecologic aggressive neoplasm. The mortality of ovarian cancer is top among gynecologic malignancies due to the insidious onset, atypical early symptoms, and chemoresistance. Therefore, it is urgent to seek another promising treatment for ovarian cancer. Purified vitexin compound 1 (VB1) is a kind of neolignan from the seed of traditional Chinese herb vitex negundo that possessed diverse pharmacological effects. VB1 can exhibit anti-neoplastic activities against various cancers. However, the role of VB1 in ovarian cancer treatment has not been elaborated, and the mechanism is unknown. The aim of this study was to investigate the therapeutic effects of VB1 in ovarian cancer cells both in vitro and in vivo, along with the molecular mechanism of action. In vitro, VB-1 can effectively suppress the proliferation, induce apoptosis, and block cell cycle at G2/M phase with a concentration dependent manner in ovarian cancer cells. Western blot assay showed that VB1 induce apoptosis via upregulating expression of cleaved-caspase3 and block cell cycle at G2/M phase through upregulating expression of P21. Meanwhile, VB1 can effectively inhibit tumor growth in xenograft mouse model. Our research indicated that VB1 can significantly exert its anti-neoplastic effects and may represent a new class of agents in ovarian cancer therapy.
Merkel Cell Carcinoma: An Immunotherapy Fairy-Tale?
Authors: Tanda Enrica Teresa , d’Amato Agostina Lagodin , Rossi Giovanni , Croce Elena , Boutros Andrea , Cecchi Federica , Spagnolo Francesco , Queirolo Paola
Published: September 2021

Merkel cell carcinoma (MCC) is a rare, highly aggressive, neuroendocrine cutaneous tumor. The incidence of MCC is growing worldwide, and the disease-related mortality is about three-fold higher than melanoma. Since a few years ago, very little has been known about this disease, and chemotherapy has been the standard of care. Nowadays, new discoveries about the pathophysiology of this neoplasm and the introduction of immunotherapy allowed to completely rewrite the history of these patients. In this review, we provide a summary of the most important changes in the management of Merkel cell carcinoma, with a focus on immunotherapy and a landscape of future treatment strategies.
Factors Associated With Dysfunction of Glymphatic System in Patients With Glioma
Authors: Toh Cheng Hong , Siow Tiing Yee
Published: September 2021

Objectives

Rodent experiments have provided some insights into the changes of glymphatic function associated with glioma growth. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) method offers an opportunity for the noninvasive investigation of the glymphatic system in patients with glioma. We aimed to investigate the factors associated with glymphatic function changes in patients with glioma.

Materials and Methods

A total of 201 glioma patients (mean age = 47.4 years, 116 men; 86 grade II, 52 grade III, and 63 grade IV) who had preoperative diffusion tensor imaging for calculation of the ALPS index were retrospectively included. Information collected from each patient included sex, age, tumor grade, isocitrate dehydrogenase 1 (IDH1) mutation status, peritumoral brain edema volume, tumor volume, and ALPS index. Group differences in the ALPS index according to sex, tumor grade, and IDH1 mutation status were assessed using analysis of covariance with age adjustment. Linear regression analyses were performed to identify the factors associated with the ALPS index.

Results

Group comparisons revealed that the ALPS index of grade II/III gliomas was significantly higher than that of grade IV gliomas (p < 0.001). The ALPS index of IDH1 mutant gliomas was significantly higher than that of IDH1 wild-type gliomas (p < 0.001). On multivariable linear regression analysis, IDH1 mutation (β = 0.308, p < 0.001) and peritumoral brain edema volume (β = −0.353, p < 0.001) were the two independent factors associated with the ALPS index.

Conclusion

IDH1 wild-type gliomas and gliomas with larger peritumoral brain edema volumes were associated with a lower ALPS index, which may reflect impaired glymphatic function.
Histone Deacetylase Inhibitor Trichostatin A Reduces Endothelial Cell Proliferation by Suppressing STAT5A-Related Gene Transcription
Authors: Li Yize , Zhao Yongmei , Peng Hongyan , Zhang Jing , Bo Lun , Wen Lei , Liu Wenchao , Bai Wendong , Zhang Hongmei
Published: September 2021

Inhibitors of histone deacetylases (HDACi) have shown promising effects in preclinical applications for the treatment of many diseases. Confusedly though, the effects of the HDACi trichostatin A (TSA) on angiogenesis are variable among different diseases. This study investigated the direct effects of TSA on endothelial cells, which plays essential roles in angiogenesis and the underlying molecular events. TSA reduced the viability of human umbilical vein endothelial cells (HUVECs), in which proliferation-related genes including BIRC5, CKS1B, and NDC80 were found to be involved. Furthermore, signal transducer and activator of transcription 5 A (STAT5A) was demonstrated to be reduced by TSA and to mediate TSA-induced downregulation of BIRC5, CKS1B, and NDC80 and HUVEC proliferation. Mechanistically, data showed that STAT5A directly bound to the promoters of BIRC5, CKS1B, and NDC80 and activated their transcription through special DNA sequence sites. Finally, the TSA–STAT5A–BIRC5, CKS1B, and NDC80 axis also worked in a cancerous endothelial cell angiogenesis model. The results of this study revealed novel mechanisms underlying the effects of TSA on endothelial cells and provided insights for angiogenesis-associated diseases.
Harnessing the Power of Hybrid Light Propagation Model for Three-Dimensional Optical Imaging in Cancer Detection
Authors: Wang Lin , Zhu Wentao , Zhang Ying , Chen Shangdong , Yang Defu
Published: September 2021

Optical imaging is an emerging technology capable of qualitatively and quantitatively observing life processes at the cellular or molecular level and plays a significant role in cancer detection. In particular, to overcome the disadvantages of traditional optical imaging that only two-dimensionally and qualitatively detect biomedical information, the corresponding three-dimensional (3D) imaging technology is intensively explored to provide 3D quantitative information, such as localization and distribution and tumor cell volume. To retrieve these information, light propagation models that reflect the interaction between light and biological tissues are an important prerequisite and basis for 3D optical imaging. This review concentrates on the recent advances in hybrid light propagation models, with particular emphasis on their powerful use for 3D optical imaging in cancer detection. Finally, we prospect the wider application of the hybrid light propagation model and future potential of 3D optical imaging in cancer detection.
Case Report: A Domestic Sponge Brush Used to Clean a Milk Feeding Bottle: The Source of Neonatal Meningitis Caused by Pseudomonas aeruginosa
Authors: Mizuno Shinsuke , Matsuzaki Sayaka , Yokoyama Koji , Hamahata Keigo , Yoshida Akira
Published: September 2021

Pseudomonas aeruginosa is a relatively rare cause of neonatal meningitis, and most patients have serious underlying diseases, prematurity, immunodeficiency, or anatomical abnormalities. We report the case of a 7-day-old girl with meningitis caused by P. aeruginosa. She was born full-term and had no immunodeficiency or anatomical abnormalities as far as our investigation ascertained. Through the use of anti-Pseudomonas antibiotics, she recovered without any complications other than a slight hearing disability revealed by audiology testing. P. aeruginosa was also isolated from a domestic sponge brush used to clean her milk bottle. Physicians should consider P. aeruginosa as a possible pathogen of neonatal meningitis even in full-term infants with no immunodeficiency or anatomical abnormalities. Physicians should give advice concerning appropriate hygiene practices to be applied to the neonate's environment.
Inhibitory Effects of Rhaponticin on Osteoclast Formation and Resorption by Targeting RANKL-Induced NFATc1 and ROS Activity
Authors: He Jianbo , Chen Kai , Deng Tiancheng , Xie Jiewei , Zhong Kunjing , Yuan Jinbo , Wang Ziyi , Xiao Zhifeng , Gu Ronghe , Chen Delong , Li Xiaojuan , Lin Dingkun , Xu Jiake
Published: September 2021

The extravagant osteoclast formation and resorption is the main cause of osteoporosis. Inhibiting the hyperactive osteoclastic resorption is considered as an efficient treatment for osteoporosis. Rhaponticin (RH) is a small molecule that has been reported to possess anti-inflammatory, anti-allergic, anti-fibrotic, and anti-diabetic activities. However, the influence of RH on osteoclasts differentiation and function is still unclear. To this end, an array of assays including receptor activator of nuclear factor kappa-Β (NF-κB) ligand (RANKL) induced osteoclastogenesis, tartrate-resistant acidic phosphatase (TRAcP) staining, immunofluorescence, and hydroxyapatite resorption were performed in this study. It was found that RH had significant anti-catabolic effects by inhibiting osteoclastogenesis and bone resorption without cytotoxicity. Mechanistically, the expression of NADPH oxidase 1 (Nox1) was found to be suppressed and antioxidant enzymes including catalase, superoxide dismutase 2 (SOD-2), and heme oxygenase-1(HO-1) were enhanced following RH treatment, suggesting RH exhibited antioxidant activity by reducing the generation of reactive oxygen species (ROS) as well as enhancing the depletion of ROS. In addition, MAPKs, NF-κB, and intracellular Ca2+ oscillation pathways were significantly inhibited by RH. These changes led to the deactivation of osteoclast master transcriptional factor-nuclear factor of activated T cells 1 (NFATc1), as examined by qPCR and Western blot assay, which led to the decreased expression of downstream integrin β3, c-Fos, cathepsin K, and Atp6v0d2. These results suggested that RH could effectively suppress RANKL-regulated osteoclast formation and bone resorption. Therefore, we propose that RH can represent a novel natural small molecule for the treatment of osteoporosis by inhibiting excessive osteoclast activity.
Active Fraction Combination From Liuwei Dihuang Decoction Improves Adult Hippocampal Neurogenesis and Neurogenic Microenvironment in Cranially Irradiated Mice
Authors: Wei Mingxiao , Feng Shufang , Zhang Lin , Wang Chen , Chu Shasha , Shi Tianyao , Zhou Wenxia , Zhang Yongxiang
Published: September 2021

Background: Cranial radiotherapy is clinically used in the treatment of brain tumours; however, the consequent cognitive and emotional dysfunctions seriously impair the life quality of patients. LW-AFC, an active fraction combination extracted from classical traditional Chinese medicine prescription Liuwei Dihuang decoction, can improve cognitive and emotional dysfunctions in many animal models; however, the protective effect of LW-AFC on cranial irradiation–induced cognitive and emotional dysfunctions has not been reported. Recent studies indicate that impairment of adult hippocampal neurogenesis (AHN) and alterations of the neurogenic microenvironment in the hippocampus constitute critical factors in cognitive and emotional dysfunctions following cranial irradiation. Here, our research further investigated the potential protective effects and mechanisms of LW-AFC on cranial irradiation–induced cognitive and emotional dysfunctions in mice.

Methods: LW-AFC (1.6 g/kg) was intragastrically administered to mice for 14 days before cranial irradiation (7 Gy γ-ray). AHN was examined by quantifying the number of proliferative neural stem cells and immature neurons in the dorsal and ventral hippocampus. The contextual fear conditioning test, open field test, and tail suspension test were used to assess cognitive and emotional functions in mice. To detect the change of the neurogenic microenvironment, colorimetry and multiplex bead analysis were performed to measure the level of oxidative stress, neurotrophic and growth factors, and inflammation in the hippocampus.

Results: LW-AFC exerted beneficial effects on the contextual fear memory, anxiety behaviour, and depression behaviour in irradiated mice. Moreover, LW-AFC increased the number of proliferative neural stem cells and immature neurons in the dorsal hippocampus, displaying a regional specificity of neurogenic response. For the neurogenic microenvironment, LW-AFC significantly increased the contents of superoxide dismutase, glutathione peroxidase, glutathione, and catalase and decreased the content of malondialdehyde in the hippocampus of irradiated mice, accompanied by the increase in brain-derived neurotrophic factor, insulin-like growth factor-1, and interleukin-4 content. Together, LW-AFC improved cognitive and emotional dysfunctions, promoted AHN preferentially in the dorsal hippocampus, and ameliorated disturbance in the neurogenic microenvironment in irradiated mice.

Conclusion: LW-AFC ameliorates cranial irradiation–induced cognitive and emotional dysfunctions, and the underlying mechanisms are mediated by promoting AHN in the dorsal hippocampus and improving the neurogenic microenvironment. LW-AFC might be a promising therapeutic agent to treat cognitive and emotional dysfunctions in patients receiving cranial radiotherapy.
SPICE Simulation of RRAM-Based Cross-Point Arrays Using the Dynamic Memdiode Model
Authors: Aguirre Fernando L. , Pazos Sebastián M. , Palumbo Félix , Suñé Jordi , Miranda Enrique
Published: September 2021

We thoroughly investigate the performance of the Dynamic Memdiode Model (DMM) when used for simulating the synaptic weights in large RRAM-based cross-point arrays (CPA) intended for neuromorphic computing. The DMM is in line with Prof. Chua’s memristive devices theory, in which the hysteresis phenomenon in electroformed metal-insulator-metal structures is represented by means of two coupled equations: one equation for the current-voltage characteristic of the device based on an extension of the quantum point-contact (QPC) model for dielectric breakdown and a second equation for the memory state, responsible for keeping track of the previous history of the device. By considering ex-situ training of the CPA aimed at classifying the handwritten characters of the MNIST database, we evaluate the performance of a Write-Verify iterative scheme for setting the crosspoint conductances to their target values. The total programming time, the programming error, and the inference accuracy obtained with such writing scheme are investigated in depth. The role played by parasitic components such as the line resistance as well as some CPA’s particular features like the dynamical range of the memdiodes are discussed. The interrelationship between the frequency and amplitude values of the write pulses is explored in detail. In addition, the effect of the resistance shift for the case of a CPA programmed with no errors is studied for a variety of input signals, providing a design guideline for selecting the appropriate pulse’s amplitude and frequency.
Acclimation of Photosynthesis to Changes in the Environment Results in Decreases of Oxidative Stress in Arabidopsis thaliana
Authors: Karim Mohd Fauzihan , Johnson Giles N.
Published: September 2021

The dynamic acclimation of photosynthesis plays an important role in increasing the fitness of a plant under variable light environments. Since acclimation is partially mediated by a glucose-6-phosphate/phosphate translocator 2 (GPT2), this study examined whether plants lacking GPT2, which consequently have defective acclimation to increases in light, are more susceptible to oxidative stress. To understand this mechanism, we used the model plant Arabidopsis thaliana [accession Wassilewskija-4 (Ws-4)] and compared it with mutants lacking GPT2. The plants were then grown at low light (LL) at 100 μmol m−2 s−1 for 7 weeks. For the acclimation experiments, a set of plants from LL was transferred to 400 μmol m−2 s−1 conditions for 7 days. Biochemical and physiological analyses showed that the gpt2 mutant plants had significantly greater activity for ascorbate peroxidase (APX), guiacol peroxidase (GPOX), and superoxide dismutase (SOD). Furthermore, the mutant plants had significantly lower maximum quantum yields of photosynthesis (Fv/Fm). A microarray analysis also showed that gpt2 plants exhibited a greater induction of stress-related genes relative to wild-type (WT) plants. We then concluded that photosynthetic acclimation to a higher intensity of light protects plants against oxidative stress.
A Novel R2R3-MYB Gene LoMYB33 From Lily Is Specifically Expressed in Anthers and Plays a Role in Pollen Development
Authors: Liu Xinyue , Wu Ze , Feng Jingxian , Yuan Guozhen , He Ling , Zhang Dehua , Teng Nianjun
Published: September 2021

Lily (Lilium spp.) is an important commercial flower crop, but its market popularity and applications are adversely affected by severe pollen pollution. Many studies have examined pollen development in model plants, but few studies have been conducted on flower crops such as lily. GAMYBs are a class of R2R3-MYB transcription factors and play important roles in plant development and biotic resistance; their functions vary in different pathways, and many of them are involved in anther development. However, their function and regulatory role in lily remain unclear. Here, the GAMYB homolog LoMYB33 was isolated and identified from lily. The open reading frame of LoMYB33 was 1620 bp and encoded a protein with 539 amino acids localized in the nucleus and cytoplasm. Protein sequence alignment showed that LoMYB33 contained a conserved R2R3 domain and three BOX motifs (BOX1, BOX2, and BOX3), which were unique to the GAMYB family. LoMYB33 had transcriptional activation activity, and its transactivation domain was located within 90 amino acids of the C-terminal. LoMYB33 was highly expressed during the late stages of anther development, especially in pollen. Analysis of the promoter activity of LoMYB33 in transgenic Arabidopsis revealed that the LoMYB33 promoter was highly activated in the pollen of stage 12 to 13 flowers. Overexpression of LoMYB33 in Arabidopsis significantly retarded growth; the excess accumulation of LoMYB33 also negatively affected normal anther development, which generated fewer pollen grains and resulted in partial male sterility in transgenic plants. Silencing of LoMYB33 in lily also greatly decreased the amount of pollen. Overall, our results suggested that LoMYB33 might play an important role in the anther development and pollen formation of lily.