bluuebunny/crossref_metadata_2025 huggingface dataset:
Specific Role for GSK3α in Limiting Long-Term Potentiation in CA1 Pyramidal Neurons of Adult Mouse Hippocampus
Authors: Ebrahim Amini Aeen , Miyata Tsukiko , Lei Gang , Jin Fuzi , Rubie Elizabeth , Bradley Clarrisa A. , Woodgett James R. , Collingridge Graham L. , Georgiou John
Published: June 2022

Glycogen synthase kinase-3 (GSK3) mediates phosphorylation of several hundred proteins, and its aberrant activity is associated with an array of prevalent disorders. The two paralogs, GSK3α and GSK3β, are expressed ubiquitously and fulfill common as well as unique tasks throughout the body. In the CNS, it is established that GSK3 is involved in synaptic plasticity. However, the relative roles of GSK3 paralogs in synaptic plasticity remains controversial. Here, we used hippocampal slices obtained from adult mice to determine the role of each paralog in CA3−CA1 long-term potentiation (LTP) of synaptic transmission, a form of plasticity critically required in learning and memory. Conditional Camk2a Cre-driven neuronal deletion of the Gsk3a gene, but not Gsk3b, resulted in enhanced LTP. There were no changes in basal synaptic function in either of the paralog-specific knockouts, including several measures of presynaptic function. Therefore, GSK3α has a specific role in serving to limit LTP in adult CA1, a postsynaptic function that is not compensated by GSK3β.
Circulating Vitamin D Concentrations and Risk of Atrial Fibrillation: A Mendelian Randomization Study Using Non-deficient Range Summary Statistics
Authors: Zhang Nan , Wang Yueying , Chen Ziliang , Liu Daiqi , Tse Gary , Korantzopoulos Panagiotis , Letsas Konstantinos P. , Goudis Christos A. , Lip Gregory Y. H. , Li Guangping , Zhang Zhiwei , Liu Tong
Published: June 2022

Background and Aims

Vitamin D deficiency is a common disorder and has been linked with atrial fibrillation (AF) in several observational studies, although the causal relationships remain unclear. We conducted a Mendelian randomization (MR) analysis to determine the causal association between serum 25-hydroxyvitamin D [25(OH)D] concentrations and AF.

Methods and Results

The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from large genome-wide association meta-analyses conducted on serum 25(OH)D (N = 79,366) and AF (N = 1,030,836). Six SNPs related to serum 25(OH)D were used as instrumental variables. The association between 25(OH)D and AF was estimated using both the fixed-effect and random-effects inverse variance weighted (IVW) method. The MR analyses found no evidence to support a causal association between circulating 25(OH)D level and risk of AF using random-effects IVW (odds ratio per unit increase in log 25(OH)D = 1.003, 95% CI, 0.841–1.196; P = 0.976) or fixed-effect IVW method (OR = 1.003, 95% CI, 0.876–1.148; P = 0.968). Sensitivity analyses yielded similar results. No heterogeneity and directional pleiotropy were detected.

Conclusion

Using summary statistics, this MR study suggests that genetically predicted circulating vitamin D concentrations, especially for a non-deficient range, were not causally associated with AF in the general population. Future studies using non-linear design and focusing on the vitamin D deficiency population are needed to further evaluate the causal effect of vitamin D concentrations on AF.
Nutrient Deficiencies and Potential Alteration in Plasma Levels of Naturally Acquired Malaria-Specific Antibody Responses in Tanzanian Children
Authors: Mbugi Erasto V. , Hartog Gerco den , Veenemans Jacobien , Chilongola Jaffu O. , Verhoef Hans , Savelkoul Huub F. J.
Published: June 2022

Immunoglobulin G (IgG) subclasses have been suggested to confer naturally acquired immunity to Plasmodium falciparum malaria. Cytophilic IgG1 and IgG3 with their potential for opsonization, phagocytosis, and antibody-dependent cellular inhibition in association with monocytes have been suggested to have a critical role in malaria. The potential for production of antibodies is influenced by micronutrient status. This study aimed at exploring the effect of micronutrients, particularly zinc status, on the profiles of IgG subclasses in 304 Tanzanian children aged ≤ 5 years. An enzyme-linked immunosorbent assay was performed using whole asexual blood stage malaria antigens to determine plasma malaria-specific antibody titers. This baseline cross-sectional study was done from 2005 – 2010 prior to the larger randomized control trial of the Micronutrient and Child Health (MACH) Study. Plasma concentrations of zinc and magnesium were measured by inductively coupled plasma atomic emission spectrometry and results correlated with plasma IgG subclass levels. The findings reveal zinc deficiency to possibly influence the production of IgM, total IgG, and several IgG subclasses in a malaria status-dependent manner. Among IgG subclasses, IgG3 and partly IgG2 displayed a remarkable association with zinc deficiency, particularly IgG3 which was predominant in children with malaria. Nevertheless, zinc, magnesium, and malaria status did not influence the association between IgG3 and IgG4. The study leads to the conclusion that, under conditions of micronutrient deficiency and malaria status, an imbalance in IgG subclass production may occur leading to predominantly higher levels of IgG3 and IgG2 that may not confer sufficient protection from infection. The profile of both cytophilic and non-cytophilic IgG subclasses has been shown to be variably influenced by zinc status; the effects vary with age at least in under-fives. These results provide insight for inclusion of micronutrients, particularly precise amounts of zinc, in future malaria interventional programs in endemic areas.
A Follow-Up Study of Ovarian Cancer (OOPS): A Study Protocol
Authors: Gong Ting-Ting , Liu Fang-Hua , Liu Ya-Shu , Yan Shi , Xu He-Li , He Xin-Hui , Wei Yi-Fan , Qin Xue , Gao Song , Zhao Yu-Hong , Wu Qi-Jun
Published: June 2022

The ovarian cancer (OC) follow-up study (OOPS) is an on-going hospital-based large prospective longitudinal cohort study aimed to explore the relationship between pre/post-diagnostic biological, clinical, environmental, and lifestyle factors with focus on the diet and OC prognosis (including drug resistance, relapse, and mortality). Patients recruited during the baseline survey were between 18 and 79 years old, with histologically confirmed OC diagnosis. Their follow-up and medical treatment were conducted at the gynecological oncology ward at Shengjing Hospital of China Medical University, Shenyang, China after 2015. A total of 703 OC patients made up the final OOPS study population. The follow-up stage was conducted in both passive and active modes. In the passive mode, the follow-up was performed by linkage to the Liaoning Providence Center for Disease Control and Prevention every 6 months to obtain health outcome results. The status of lifestyle factors was re-estimated using the same measurements as those in the baseline survey. OC participants in the OOPS study completed a questionnaire and anthropometric examinations. In addition, biological specimens were collected during the baseline survey, which included blood, urine, and stool samples that were stored for further use. This article is intended to serve as an introduction to this project and to provide details for investigators who may be carry out related analysis.
A Gene Variation at the ZPR1 Locus (rs964184) Interacts With the Type of Diet to Modulate Postprandial Triglycerides in Patients With Coronary Artery Disease: From the Coronary Diet Intervention With Olive Oil and Cardiovascular Prevention Study
Authors: Alcala-Diaz Juan F. , Arenas-de Larriva Antonio P. , Torres-Peña Jose D. , Rodriguez-Cantalejo Fernando , Rangel-Zuñiga Oriol A. , Yubero-Serrano Elena M. , Gutierrez-Mariscal Francisco M. , Cardelo Magdalena P. , Luque Raul M. , Ordovas Jose M. , Perez-Martinez Pablo , Delgado-Lista Javier , Lopez-Miranda Jose
Published: June 2022

Background and Aims

rs964184 variant in the ZPR1 gene has been associated with blood lipids levels both in fasting and postprandial state and with the risk of myocardial infarction in high-risk cardiovascular patients. However, whether this association is modulated by diet has not been studied.

Objective

To investigate whether the type of diet (low-fat or Mediterranean diets) interacts with genetic variability at this loci to modulate fasting and postprandial lipids in coronary patients.

Materials and Methods

The genotype of the rs964184 polymorphism was determined in the Cordioprev Study population (NCT00924937). Fasting and Postprandial triglycerides were assessed before and after 3 years of dietary intervention with either a Mediterranean or a low-fat diet. Postprandial lipid assessment was done by a 4-h oral fat tolerance test (OFTT). Differences in triglycerides levels were identified using repeated-measures ANCOVA.

Results

From 523 patients (85% males, mean age 59 years) that completed the OFTT at baseline and after 3 years of intervention and had complete genotype information, 125 of them were carriers of the risk allele G. At the start of the study, these patients showed a higher fasting and postprandial triglycerides (TG) plasma levels. After 3 years of dietary intervention, G-carriers following a Mediterranean Diet maintained higher fasting and postprandial triglycerides, while those on the low-fat diet reduced their postprandial triglycerides to similar values to the population without the G-allele.

Conclusion

After 3 years of dietary intervention, the altered postprandial triglyceride response induced by genetic variability in the rs964184 polymorphism of the ZPR1 gene can be modulated by a low-fat diet, better than by a Mediterranean diet, in patients with coronary artery disease.
Association of Dietary Carrot/Carotene Intakes With Colorectal Cancer Incidence and Mortality in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Authors: Jiang Zongze , Chen Huilin , Li Ming , Wang Wei , Fan Chuanwen , Long Feiwu
Published: June 2022

Background:

The evidence of dietary carrot/carotene intake's effect on the association with colorectal cancer (CRC) risk is conflicted. We sought to examine the association of carrot/carotene intake with CRC incidence and mortality in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening cohort.

Methods

In all, 101,680 participants were enrolled between November 1993 and July 2001 from the PLCO cohort. We employed the multivariable Cox regression analyses to estimate the hazard ratios and 95% confidence interval. Subgroup analyses and interaction tests were performed to examine the potential effect modifiers. We further applied the generalized additive model to explore the non-linear trend of the exposure to cancer-related outcomes.

Results

A total of 1,100 CRC cases and 443 cancer-related deaths were documented. We noted that the 4th quintile of dietary carrot intakes was associated with a 21% lower risk of CRC incidence, compared with the lowest quintile group (full-adjusted HRquintile4vs.quintile1 = 0.79, 95%CI = 0.65–0.97, p for trend = 0.05), while the adjusted-HR was 0.95 (95%CI = 0.89–1.02) with per SD increment of carrot intakes, and no statistically significant associations were detected between dietary α-, and β-carotene intake and CRC incidence. There were no statistically significant associations observed between carrot/carotene intakes and CRC mortality. Furthermore, there were no non-linear dose-response relationships between dietary carrot, α-, and β-carotene intake and CRC incidence and mortality (all pnonlinearity > 0.05). Of note, smoking status as a modifier on the association of dietary carrot intakes with CRC incidence but not mortality was observed.

Conclusions

In summary, this large U.S. prospective cohort study indicated that a moderate consumption of carrots was associated with a lower CRC incidence, which suggested that a certain dose-range of carrots consumed might contribute to a potential cancer-prevention effect, not the more the better.
The Human Milk Oligosaccharide 2′-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice
Authors: Gart Eveline , Salic Kanita , Morrison Martine C. , Giera Martin , Attema Joline , de Ruiter Christa , Caspers Martien , Schuren Frank , Bobeldijk-Pastorova Ivana , Heer Marianne , Qin Yan , Kleemann Robert
Published: June 2022

Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2′-fucosyllactose are thought to primarily improve gut health and it is uncertain whether they would affect more distant organs. This study investigates whether 2′-fucosyllactose can alleviate NAFLD development in manifest obesity. Obese hyperinsulinemic Ldlr-/-.Leiden mice, after an 8 week run-in on a high-fat diet (HFD), were treated with 2′-fucosyllactose by oral gavage until week 28 and compared to HFD-vehicle controls. 2′-fucosyllactose did not affect food intake, body weight, total fat mass or plasma lipids. 2′-fucosyllactose altered the fecal microbiota composition which was paralleled by a suppression of HFD-induced gut permeability at t = 12 weeks. 2′-fucosyllactose significantly attenuated the development of NAFLD by reducing microvesicular steatosis. These hepatoprotective effects were supported by upstream regulator analyses showing that 2′-fucosyllactose activated ACOX1 (involved in lipid catabolism), while deactivating SREBF1 (involved in lipogenesis). Furthermore, 2′-fucosyllactose suppressed ATF4, ATF6, ERN1, and NUPR1 all of which participate in endoplasmic reticulum stress. 2′-fucosyllactose reduced fasting insulin concentrations and HOMA-IR, which was corroborated by decreased intrahepatic diacylglycerols. In conclusion, long-term supplementation with 2′-fucosyllactose can counteract the detrimental effects of HFD on gut dysbiosis and gut permeability and attenuates the development of liver steatosis. The observed reduction in intrahepatic diacylglycerols provides a mechanistic rationale for the improvement of hyperinsulinemia and supports the use of 2′-fucosyllactose to correct dysmetabolism and insulin resistance.
Effects of Dietary Nutrients on Fatty Liver Disease Associated With Metabolic Dysfunction (MAFLD): Based on the Intestinal-Hepatic Axis
Authors: Yao Nan , Yang Yixue , Li Xiaotong , Wang Yuxiang , Guo Ruirui , Wang Xuhan , Li Jing , Xie Zechun , Li Bo , Cui Weiwei
Published: June 2022

Non-alcoholic fatty liver disease (NAFLD) has recently become the most common liver disease with a global prevalence of over 25% and is expected to increase. Recently, experts have reached a consensus that “fatty liver disease associated with metabolic dysfunction or MAFLD” may be a more appropriate and inclusive definition than NAFLD. Like the former name NAFLD, MAFLD, as a manifestation of multiple system metabolic disorders involving the liver, has certain heterogeneity in its pathogenesis, clinical manifestations, pathological changes and natural outcomes. We found that there is a delicate dynamic balance among intestinal microflora, metabolites and host immune system to maintain a healthy intestinal environment and host health. On the contrary, this imbalance is related to diseases such as MAFLD. However, there are no clear studies on how dietary nutrients affect the intestinal environment and participate in the pathogenesis of MAFLD. This review summarizes the interactions among dietary nutrients, intestinal microbiota and MAFLD in an attempt to provide evidence for the use of dietary supplements to regulate liver function in patients with MAFLD. These dietary nutrients influence the development and progression of MAFLD mainly through the hepatic-intestinal axis by altering dietary energy absorption, regulating bile acid metabolism, changing intestinal permeability and producing ethanol. Meanwhile, the nutrients have the ability to combat MAFLD in terms of enriching abundance of intestinal microbiota, reducing Firmicutes/Bacteroidetes ratio and promoting abundance of beneficial gut microbes. Therefore, family therapy with MAFLD using a reasonable diet could be considered.
Linkages of Various Calcium Sources on Immune Performance, Diarrhea Rate, Intestinal Barrier, and Post-gut Microbial Structure and Function in Piglets
Authors: Wang Kaijun , Yang Anqi , Peng Xiaomin , Lv Feifei , Wang Ying , Cui Yao , Wang Yuhan , Zhou Jianqun , Si Hongbin
Published: June 2022

The purpose of this experiment was to investigate the effects of different sources of calcium on immune performance, diarrhea rate, intestinal barrier, and post-intestinal flora structure and function in weaned piglets. A total of 1,000 weaned piglets were randomly assigned to five groups 10 replicate pens per treatment, 20 piglets per pen and fed calcium carbonate, calcium citrate, multiple calcium, and organic trace minerals of different concentrations of acidifier diets. The results of the study showed that the replacement of calcium carbonate with calcium citrate and multiple calcium had almost no significant effect on immune indexes (IL-1β, IL-6, IL-10, TNF-α) of piglets compared with the control group (p > 0.05). The five groups did not show a change in the diarrhea rate and diarrhea index (p > 0.05). The diet containing multiple calcium dramatically decreased the TP compared to the C and L diet (p < 0.05). No significant difference in HDL was noted in the five groups (p > 0.05). However, the concentration of LDL in blood in the multiple calcium group was significantly higher than that in groups L and D (p < 0.05). Moreover, the concentration of Glu in blood in the multiple calcium group was significantly higher than that in group C (p < 0.05). Compared with the control group, calcium citrate plus organic trace minerals diet markedly increased UCG-005 abundance in the colon (p < 0.05). In addition, the relative abundance of Prevotellaceae_NK3B31_group had an upward trend in the colon of the M group compared to the D group (p = 0.070). Meanwhile, calcium citrate plus organic trace minerals diet markedly increased Clostridium_sensu_stricto_1 abundance in the colon (p < 0.05). Metagenomic predictions by PICRUSt suggested that the colonic and fecal microbiota was mainly involved in carbohydrate metabolism, amino acid metabolism, energy metabolism, and metabolism of cofactors and vitamins.
Exercise-Induced Browning of White Adipose Tissue and Improving Skeletal Muscle Insulin Sensitivity in Obese/Non-obese Growing Mice: Do Not Neglect Exosomal miR-27a
Authors: Wang Dongxue , Zhang Xihuan , Li Yibai , Jia Lihong , Zhai Lingling , Wei Wei , Zhang Li , Jiang Hongkun , Bai Yinglong
Published: June 2022

Exercise is considered as a favorable measure to prevent and treat childhood obesity. However, the underlying mechanisms of exercise-induced beneficial effects and the difference between obese and non-obese individuals are largely unclear. Recently, miR-27a is recognized as a central upstream regulator of proliferator-activated receptor γ (PPAR-γ) in contributing to various physiological and pathological processes. This study aims to explore the possible cause of exercise affecting white adipose tissue (WAT) browning and reversing skeletal muscle insulin resistance in obese/non-obese immature bodies. For simulating the process of childhood obesity, juvenile mice were fed with a basal diet or high-fat diet (HFD) and took 1 or 2 h swimming exercise simultaneously for 10 weeks. The obese animal model was induced by the HFD. We found that exercise hindered HFD-induced body fat development in growing mice. Exercise modified glucolipid metabolism parameters differently in the obese/non-obese groups, and the changes of the 2 h exercise mice were not consistent with the 1 h exercise mice. The level of serum exosomal miR-27a in the non-exercise obese group was increased obviously, which was reduced in the exercise obese groups. Results from bioinformatics analysis and dual-luciferase reporter assay showed that miR-27a targeted PPAR-γ. Exercise stimulated WAT browning; however, the response of obese WAT lagged behind normal WAT. In the HFD-fed mice, 2 h exercise activated the IRS-1/Akt/GLUT-4 signaling pathway in the skeletal muscles. In summary, our findings confirmed that exercise-induced beneficial effects are associated with exercise duration, and the response of obese and non-obese bodies is different. Exosomal miR-27a might be a crucial node for the process of exercise-induced browning of WAT and improving skeletal muscle insulin sensitivity.
Adherence to the Mediterranean Diet as a Modifiable Risk Factor for Thyroid Nodular Disease and Thyroid Cancer: Results From a Pilot Study
Authors: Barrea Luigi , Muscogiuri Giovanna , Alteriis Giulia de , Porcelli Tommaso , Vetrani Claudia , Verde Ludovica , Aprano Sara , Fonderico Francesco , Troncone Giancarlo , Colao Annamaria , Savastano Silvia
Published: June 2022

Iodine deficiency is the most important established nutritional risk factor for the development of thyroid nodular disease. Nevertheless, to the best of our knowledge, to date no study focused on the association between the adherence to the Mediterranean diet (MD) and thyroid nodular disease. Adherence to the MD was evaluated using the PREvención con DIetaMEDiterránea (PREDIMED) questionnaire. Physical activity, smoking habits, and anthropometric parameters were studied. PREDIMED was used to evaluate the degree of adherence to the MD. Evaluation of fine needle aspiration cytology of thyroid lesions based on 2013 Italian thyroid cytology classification system. Cytology of thyroid nodules was carried out through sonography-guided fine-needle aspiration and patients were divided into 5 categories: TIR2, TIR3a, TIR3b, TIR4, and TIR5. The study population consisted of 794 subjects (554 females, 69.8%), aged 18–65 years, with BMIs ranging from 19.4 to 55.3 kg/m2. Thyroid nodular disease was present in 391 participants (49.2%), and the most frequent cytological categories was TIR2 (18.3 %), followed by a TIR4 (8.9 %). The presence of thyroid nodules was also significantly associated with the lowest adherence to the MD (OR 6.16, p < 0.001). Patients with TIR5 had the lower adherence to the MD (2.15 ± 1.12 score) compared to other TIRs (p < 0.001). The cytological category with high-risk of malignancy (TIR4/TIR5) was significantly associated with the lowest adherence to the MD (OR 137.55, p < 0.001) and PREDIMED score (OR = 0.33, p < 0.001, 95% IC = 0.26–0.41, R2 = 0.462). At multiple regression analysis, PREDIMED score was the main predictor of both the presence of nodules (p < 0.001) and the cytological category with high-risk of malignancy (p < 0.001). At ROC analysis PREDIMED score ≤ 5 and ≤ 4 (p = 0.001) were the values that predicted the presence of thyroid nodular disease and cytological category with high-risk of malignancy, respectively. In conclusion, our study demonstrated that the low adherence to the MD is associated with the presence of thyroid nodular disease and in particular with those at high-risk of malignancy.
Distinct Gene Expression Profiles in Viable Hepatocellular Carcinoma Treated With Liver-Directed Therapy
Authors: Núñez Kelley G. , Sandow Tyler , Lakey Meredith A. , Fort Daniel , Cohen Ari J. , Thevenot Paul T.
Published: June 2022

Background

Hepatocellular carcinoma is a heterogeneous tumor that accumulates a mutational burden and dysregulated signaling pathways that differ from early to advanced stages. Liver transplant candidates with early-stage hepatocellular carcinoma (HCC) undergo liver-directed therapy (LDT) to delay disease progression and serve as a bridge to liver transplantation (LT). Unfortunately, >80% of LDT-treated patients have viable HCC in the explant liver, dramatically increasing recurrence risk. Understanding the effect of LDT on early-stage HCC could help identify therapeutic targets to promote complete pathologic necrosis and improve recurrence-free survival. In this study, transcriptomic data from viable HCC in LDT-treated bridged to transplant patients were investigated to understand how treatment may affect tumor signaling pathways.

Methods

Multiplex transcriptomic gene analysis was performed with mRNA extracted from viable tumors of HCC patients bridged to transplant using LDT. The NanoString nCounter® Tumor Signaling 360 panel was used that contained 780 genes from 48 pathways involved in tumor biology within the microenvironment as well as antitumoral immune responses.

Results

Hierarchical clustering separated tumors into three subtypes (HCC-1, HCC-2, and HCC-3) each with distinct differences in anti-tumoral signaling and immune infiltration within the tumor microenvironment. Immune infiltration (neutrophils, T cells, and macrophages) were all lowest in subtype HCC-3. The tumor inflammatory signature consisting of 18 genes associated with PD-1/PD-L1 inhibition, antigen presentation, chemokine secretion, and adaptive immune responses was highest in subtype HCC-1 and lowest in HCC-3. History of decompensation and etiology were associated with HCC subtype favoring downregulations in inflammation and immune infiltration with upregulation of lipid metabolism. Gene expression among intrahepatic lesions was remarkably similar with >85% of genes expressed in both lesions. Genes differentially expressed (<8 genes per patient) in multifocal disease were all upregulated in LDT-treated tumors from pathways involving epithelial mesenchymal transition, extracellular matrix remodeling, and/or inflammation potentially implicating intrahepatic metastases.

Conclusion

Incomplete response to LDT may drive expression patterns that inhibit an effective anti-tumoral response through immune exclusion and induce intrahepatic spread.
Long Noncoding RNA RP11-732M18.3 Promotes Glioma Angiogenesis by Upregulating VEGFA
Authors: Kang Chun-Min , Zhao Jing-Jing , Yuan Ying-Shi , Liao Jia-Min , Yu Ke-Wei , Li Wei-Kang , Jin Xin , Cao Shun-Wang , Chen Wei-Ye , Jin Xing , Chen Lu , Ke Pei-Feng , Li Xue-Heng , Huang Rui-Ying , Hu Yan-Wei , Huang Xian-Zhang
Published: June 2022

Gliomas are the most aggressive and common type of malignant brain tumor, with limited treatment options and a dismal prognosis. Angiogenesis, a hallmarks of cancer, is one of two critical events in the progression of gliomas. Accumulating evidence has demonstrated that in glioma dysregulated molecules like long noncoding RNAs (lncRNAs), are closely linked to tumorigenesis and prognosis. However, the effects of and mechanisms of action of lncRNAs during tumor angiogenesis are poorly understood. The effect of lncRNA RP11-732M18.3 on angiogenesis was elucidated through an intracranial orthotopic glioma model, immunohistochemistry, and an in vitro angiogenesis assay. Co-culture experiments and cell migration assays were performed to investigate the function of lncRNA RP11-732M18.3 in vitro. lncRNA RP11-732M18.3 increased CD31+ microvessel density, and overexpression of lncRNA RP11-732M18.3 resulted in poor mouse survival. lncRNA RP11-732M18.3 promoted endothelial cell migration and tube formation. Nomogram and Kaplan-Meier survival analyses indicated that higher VEGFA is correlated with a poor prognosis. Mechanistically, lncRNA RP11-732M18.3 promotes angiogenesis by increasing the nuclear level of EP300 and facilitating the transcription and secretion of VEGFA. Our study contributes to the latest understanding of glioma angiogenesis and prognosis. lncRNA RP11-732M18.3 may be a potential treatment target in glioma.
Early Prediction of Lung Cancers Using Deep Saliency Capsule and Pre-Trained Deep Learning Frameworks
Authors: Ramana Kadiyala , Kumar Madapuri Rudra , Sreenivasulu K. , Gadekallu Thippa Reddy , Bhatia Surbhi , Agarwal Parul , Idrees Sheikh Mohammad
Published: June 2022

Lung cancer is the cellular fission of abnormal cells inside the lungs that leads to 72% of total deaths worldwide. Lung cancer are also recognized to be one of the leading causes of mortality, with a chance of survival of only 19%. Tumors can be diagnosed using a variety of procedures, including X-rays, CT scans, biopsies, and PET-CT scans. From the above techniques, Computer Tomography (CT) scan technique is considered to be one of the most powerful tools for an early diagnosis of lung cancers. Recently, machine and deep learning algorithms have picked up peak energy, and this aids in building a strong diagnosis and prediction system using CT scan images. But achieving the best performances in diagnosis still remains on the darker side of the research. To solve this problem, this paper proposes novel saliency-based capsule networks for better segmentation and employs the optimized pre-trained transfer learning for the better prediction of lung cancers from the input CT images. The integration of capsule-based saliency segmentation leads to the reduction and eventually reduces the risk of computational complexity and overfitting problem. Additionally, hyperparameters of pretrained networks are tuned by the whale optimization algorithm to improve the prediction accuracy by sacrificing the complexity. The extensive experimentation carried out using the LUNA-16 and LIDC Lung Image datasets and various performance metrics such as accuracy, precision, recall, specificity, and F1-score are evaluated and analyzed. Experimental results demonstrate that the proposed framework has achieved the peak performance of 98.5% accuracy, 99.0% precision, 98.8% recall, and 99.1% F1-score and outperformed the DenseNet, AlexNet, Resnets-50, Resnets-100, VGG-16, and Inception models.
Sclerostin Suppression Facilitates Uveal Melanoma Progression Through Activating Wnt/β-Catenin Signaling Via Binding to Membrane Receptors LRP5/LRP6
Authors: Wang Hanqing , Zhao Sidi , Liu Yang , Sun Fengyuan , Huang Xiaoming , Wu Tong
Published: June 2022

Objective

Uveal melanoma (UM) is the most frequent primary eye cancer in adults with a 50% mortality rate. Characterizing the fundamental signaling pathways that drive UM is of importance for the development of targeted therapy. This study aims to probe the impact of sclerostin (SOST) on malignant progression of UM and regulation of Wnt/β-catenin signaling.

Methods

Epithelial-type (n=20) and spindle-type (n=16) UM tissues were collected for immunohistochemical staining of SOST, Wnt-1, and β-catenin expressions. SOST was silenced in three UM cell lines (primary spindle-type OCM-1 cells, metastatic epithelial Mum-2B cells, and metastatic spindle-type Mum-2C cells) through transfecting specific siRNA. RT-qPCR and Western blot were presented for examining the levels of SOST, and markers in Wnt/β-catenin signaling. Flow cytometry, MTT, EdU, transwell, and tube formation assays were conducted, respectively. By implanting BALB/c nude murine models in situ, the function of SOST on tumor growth was investigated, followed by immunofluorescence double staining of SOST and LRP5/6.

Results

Low SOST expression as well as high Wnt-1 and β-catenin expressions were found in epithelial-type (high malignancy) than spindle-type (low malignancy) UM tissues. Silencing SOST activated the markers in Wnt/β-catenin signaling as well as accelerated cell cycle progression, migration, invasion, angiogenesis, and reduced apoptosis in UM cells. In situ tumor formation in murine eyes showed that SOST knockdown promoted tumor growth. Moreover, SOST interacted with LRP5/LRP6.

Conclusion

SOST silencing may facilitate the malignant progression of UM cells through activating Wnt/β-catenin signaling. Mechanistically, SOST may exert this function by interacting with LRP5/LRP6 membrane receptors.
Evaluation of HIF-1α Expression in a Rat Glioma Model Using Intravoxel Incoherent Motion and R2* Mapping
Authors: Wang Dongdong , Lu Yiping , Li Xuanxuan , Mei Nan , Wu Pu-Yeh , Geng Daoying , Wu Hao , Yin Bo
Published: June 2022

Accurate evaluation of HIF-1α levels can facilitate the detection of hypoxia niches in glioma and treatment decisions. To investigate the feasibility of intravoxel incoherent motion (IVIM) and R2* Mapping for detecting HIF-1α expression levels, sixteen rats with intracranial C6 gliomas were subjected to IVIM and R2* Mapping using a 7 Tesla MRI scanner. For each model, the brain tissue on the HIF-1α-stained slices was subdivided into multiple square regions of interest (ROIs) with areas of 1 mm2, for which HIF-1α expression was assessed by HALO software to form a maps of HIF scores with a 0–300 range. The IVIM and R2* Mapping images were processed to create maps of the D, D*, f and R2* that were then paired with the corresponding HIF score maps. The average D, D*, f, perfusion (f × D*) and R2* values were calculated for the ROIs in the tumor and normal brain regions with different HIF-1α levels and used in further analysis. In this study, the average tumor size of sixteen C6 model rats was 458 ± 46.52 mm3, and the 482 included ROIs consisted of 280 tumoral and 202 normal ROIs. The average HIF score for the tumor regions was significantly higher than normal brain tissue (p < 0.001), and higher HIF scores were obtained for the central part of tumors than peripheral parts (p=0.03). Compared with normal brain tissues, elevated perfusion and f values were observed in tumor regions (p = 0.021, 0.004). In tumoral ROIs, the R2* values were higher in the group with high HIF-1α expression than in the group with low HIF-1α expression (p = 0.003). A correlation analysis revealed a positive correlation between the R2* value and HIF scores (r = 0.43, p < 0.001) and a negative correlation between D* and the HIF scores (r = -0.30, p = 0.001). Discrepancies in HIF-1α expression were found among different intratumoral areas, and IVIM and R2* Mapping were found to be promising means of noninvasive detection of the distribution and expression level of HIF-1α.
Factors Associated With Choriocarcinoma Syndrome Development in Poor-Risk Patients With Germ Cell Tumors
Authors: Rejlekova Katarina , Kalavska Katarina , Makovnik Marek , Hapakova Nikola , Chovanec Michal , De Angelis Valentina , Obertova Jana , Palacka Patrik , Sycova-Mila Zuzana , Mardiak Jozef , Mego Michal
Published: June 2022

Background

Germ cell tumors (GCTs) represent a highly curable cancer. However, a small proportion of poor-risk patients can develop choriocarcinoma syndrome (CS) connected with acute respiratory distress syndrome (ARDS) with a high mortality rate. Our retrospective study aimed to determine the risk factors of poor-risk GCTs susceptible to CS development.

Patients and Methods

Using a computerized database and a systematic chart review, we identified the records of 532 patients with GCTs treated at the National Cancer Institute from 2000 to 2018. Ninety eligible patients with poor-risk GCTs based on IGCCCG classification were identified. All patients were treated with platinum-based induction chemotherapy. Clinicopathological variables were collected and analyzed in correlation with CS development.

Results

Nine (10%) of 90 patients developed CS in a median of 1 day (1–9 days) after chemotherapy administration. All patients died shortly after the chemotherapy start with a median of 4 days (3–35 days) due to ARDS development. In univariate analysis, metastatic lung involvement ≥50% of lung parenchyma, choriocarcinoma elements in histology specimen, dyspnea, cough, hemoptysis, ECOG PS ≥2, weight loss, hemoglobin ≤100 g/l, and NLR ≥3.3 at the time of presentation were associated with CS development. In multivariate analysis, ECOG PS ≥2 and metastatic lung involvement ≥50% were independently associated with CS. All patients with these two characteristics developed CS, compared to 0% with zero or one of these factors (p < 0.000001).

Conclusions

In our study, we identified factors associated with CS development. These factors might improve the risk stratification of the patients susceptible to CS and improve their outcome.
Systematic Pelvic and Para-Aortic Lymphadenectomy During Fertility-Sparing Surgery in Patients With Early-Stage Epithelial Ovarian Cancer: A Retrospective Study
Authors: Li Tingting , Liu Ya , Xie Sixia , Wang Hongjing
Published: June 2022

Objective

The implication of pelvic and para-aortic lymphadenectomy in surgical staging of early-stage epithelial ovarian cancer (eEOC) is still debated. Limited data are available about systematic lymphadenectomy during fertility-sparing surgery (FSS) in patients with eEOC.

Methods

The medical records of 38 patients with FIGO stage I EOC and below 40 years who underwent FSS at our hospital between January 2003 and December 2018 were retrospectively reviewed.

Results

Among them, 18 patients (47.4%) underwent comprehensive lymphadenectomy, 11 patients (28.9%) underwent lymph node sampling, and 9 patients (23.7%) did not undergo lymphadenectomy. There was no statically significant difference in age, histology, grade, surgical approach, chemotherapy, and gestation among the three groups. With a median follow-up of 52.5 months (range: 24–153), three patients (7.9%) with FIGO stage IC EOC developed tumor recurrence. In these patients, progress-free survival (PFS) was 92.1%, and overall survival (OS) was 94.7%. No significant difference in the OS. Three patients had among all the patients, 15 patients (39.5%) had gestation after treatment, and 23 patients (60.5%) did not have gestation after treatment.

Conclusion

The number of lymph nodes removed did not significantly affect survival eEOC with FSS. Systematic pelvic and para-aortic lymphadenectomy could not be performed for mucious eEOC patients with FSS if intraoperative freezing in confirmed and no suspicious lymph nodes are found. A better understanding of sentinel lymph node biopsy may help to identify whether the patient requires FSS.
Novel Insights Into Mesothelioma Therapy: Emerging Avenues and Future Prospects
Authors: Kuryk Lukasz , Rodella Giulia , Staniszewska Monika , Pancer Katarzyna Wanda , Wieczorek Magdalena , Salmaso Stefano , Caliceti Paolo , Garofalo Mariangela
Published: June 2022

Malignant mesothelioma is a rare and aggressive cancer that develops in the thin layer surrounding the mesothelium and is mainly caused by asbestos exposure. Despite improvements in patient prognosis with conventional cancer treatments, such as surgery, chemotherapy, and radiotherapy, there are still no curative treatment modalities for advanced disease. In recent years, new therapeutic avenues have been explored. Improved understanding of the mechanisms underlying the dynamic tumor interaction with the immune system has led to the development of immunotherapeutic approaches. Numerous recent clinical trials have shown a desire to develop more effective treatments that can be used to fight against the disease. Immune checkpoint inhibitors, oncolytic adenoviruses, and their combination represent a promising strategy that can be used to synergistically overcome immunosuppression in the mesothelioma tumor microenvironment. This review provides a synthesized overview of the current state of knowledge on new therapeutic options for mesothelioma with a focus on the results of clinical trials conducted in the field.
Exercise-induced Laryngeal Obstruction: Protocol for a Randomized Controlled Treatment Trial
Authors: Clemm Hege , Røksund Ola D. , Andersen Tiina , Heimdal John-Helge , Karlsen Tom , Hilland Magnus , Fretheim-Kelly Zoe , Hufthammer Karl Ove , Sandnes Astrid , Hjelle Sigrun , Vollsæter Maria , Halvorsen Thomas ,   Bergen ILO-group
Published: June 2022

Background

Exercise-induced laryngeal obstruction (EILO) is a common cause of exertional breathing problems in young individuals, caused by paradoxical inspiratory adduction of laryngeal structures, and diagnosed by continuous visualization of the larynx during high-intensity exercise. Empirical data suggest that EILO consists of different subtypes, possibly requiring different therapeutic approaches. Currently applied treatments do not rest on randomized controlled trials, and international guidelines based on good evidence can therefore not be established. This study aims to provide evidence-based information on treatment schemes commonly applied in patients with EILO.

Methods and Analysis

Consenting patients consecutively diagnosed with EILO at Haukeland University Hospital will be randomized into four non-invasive treatment arms, based on promising reports from non-randomized studies: (A) standardized information and breathing advice only (IBA), (B) IBA plus inspiratory muscle training, (C) IBA plus speech therapy, and (D) IBA plus inspiratory muscle training and speech therapy. Differential effects in predefined EILO subtypes will be addressed. Patients failing the non-invasive approach and otherwise qualifying for surgical treatment by current department policy will be considered for randomization into (E) standard or (F) minimally invasive laser supraglottoplasty or (G) no surgery. Power calculations are based on the main outcomes, laryngeal adduction during peak exercise, rated by a validated scoring system before and after the interventions.

Ethics and Dissemination

The study will assess approaches to EILO treatments that despite widespread use, are insufficiently tested in structured, verifiable, randomized, controlled studies, and is therefore considered ethically sound. The study will provide knowledge listed as a priority in a recent statement issued by the European Respiratory Society, requested by clinicians and researchers engaged in this area, and relevant to 5–7% of young people. Dissemination will occur in peer-reviewed journals, at relevant media platforms and conferences, and by engaging with patient organizations and the healthcare bureaucracy.
An Adolescent Patient With Idiopathic Pulmonary Arterial Hypertension Weaned Off Intravenous Epoprostenol Following Treatment With Selexipag: A Case Report
Authors: Chida-Nagai Ayako , Tsujioka Takao , Sasaki Daisuke , Izumi Gaku , Yamazawa Hirokuni , Takeda Atsuhito
Published: June 2022

Idiopathic pulmonary arterial hypertension (PAH) is a rare, progressive disease affecting the pulmonary arteries. Epoprostenol, a synthetic prostaglandin analog, is the most potent pharmacological treatment modality used in patients with PAH. However, it requires continuous intravenous infusion, which negatively impacts the patient’s quality of life and frequently results in complications, such as catheter-related bloodstream infection. We weaned an adolescent female patient off epoprostenol by gradually introducing oral selexipag over a sustained period, following many years of continuous intravenous epoprostenol use alone. Oral selexipag might have an efficacy comparable to epoprostenol in young patients with PAH.
Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance
Authors: Evans Nick , Grygorash Ruslan , Williams Paul , Kyle Andrew , Kantner Terrence , Pathak Ravindra , Sheng XiaoBo , Simoes Fabio , Makwana Hiteshri , Resende Ricardo , de Juan Elena , Jenkins Alan , Morris David , Michelet Aurelie , Jewitt Frances , Rudge Felicity , Camper Nicolas , Manin Anaïs , McDowell William , Pabst Martin , Godwin Antony , Frigerio Mark , Bird Matthew
Published: June 2022

Antibody-drug conjugates (ADCs) have begun to fulfil their promise as targeted cancer therapeutics with ten clinical approvals to date. As the field matures, much attention has focused upon the key factors required to produce safe and efficacious ADCs. Recently the role that linker-payload reagent design has on the properties of ADCs has been highlighted as an important consideration for developers. We have investigated the effect of incorporating hydrophilic macrocycles into reagent structures on the in vitro and in vivo behavior of ADCs. Bis-sulfone based disulfide rebridging reagents bearing Val-Cit-PABC-MMAE linker-payloads were synthesized with a panel of cyclodextrins and crown ethers integrated into their structures via a glutamic acid branching point. Brentuximab was selected as a model antibody and ten ADCs with a drug-to-antibody ratio (DAR) of 4 were prepared for biological evaluation. In vitro, the ADCs prepared showed broadly similar potency (range: 16–34 pM) and were comparable to Adcetris® (16 pM). In vivo, the cyclodextrin containing ADCs showed greater efficacy than Adcetris® and the most efficacious variant (incorporating a 3′-amino-α-cyclodextrin component) matched a 24-unit poly(ethylene glycol) (PEG) containing comparator. The ADCs bearing crown ethers also displayed enhanced in vivo efficacy compared to Adcetris®, the most active variant (containing a 1-aza-42-crown-14 macrocycle) was superior to an analogous ADC with a larger 24-unit PEG chain. In summary, we have demonstrated that hydrophilic macrocycles can be effectively incorporated into ADC reagent design and offer the potential for enhanced alternatives to established drug-linker architectures.
TLRs-JNK/ NF-κB Pathway Underlies the Protective Effect of the Sulfide Salt Against Liver Toxicity
Authors: Abdel-latif Rania , Heeba Gehan Hussein , Hassanin Soha Osama , Waz Shaimaa , Amin Amr
Published: June 2022

Hydrogen sulfide (H2S) is an endogenously gas transmitter signaling molecule with known antioxidant, anti-inflammatory, and cytoprotective properties. Although accumulating evidence shows the therapeutic potential of H2S in various hepatic diseases, its role in cyclophosphamide (CP)-induced hepatotoxicity remains elusive. The present study was undertaken to investigate the impact of endogenous and exogenous H2S on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in CP-induced hepatotoxicity. Either an H2S donor (NaHS (100 μM/kg) or an H2S blocker [dl-propargylglycine (PAG) (30 mg/kg, i. p.)], was administered for 10 days before a single ip injection of CP (200 mg/kg). NaHS attenuated conferred hepatoprotection against CP-induced toxicity, significantly decreasing serum hepatic function tests and improving hepatic histopathology. Additionally, NaHS-treated rats exhibited antioxidant activity in liver tissues compared with the CP group. The upregulated hepatic levels of TLR2/4 and their downstream signaling molecules including c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) were also suppressed by NaHS protective treatment. NaHS showed anti-inflammatory and antiapoptotic effects; reducing hepatic level tumor necrosis factor-alpha (TNF-α) and caspase-3 expression. Interestingly, the cytotoxic events induced in CP-treated rats were not significantly altered upon the blocking of endogenous H2S. Taken together, the present study suggested that exogenously applied H2S rather than the endogenously generated H2S, displayed a hepatoprotective effect against CP-induced hepatotoxicity that might be mediated by TLRs-JNK/NF-κB pathways.
Food for Thought: Leptin and Hippocampal Synaptic Function
Authors: Harvey Jenni
Published: June 2022

It is well documented that the endocrine hormone, leptin controls energy homeostasis by providing key signals to specific hypothalamic nuclei. However, our knowledge of leptin’s central actions has advanced considerably over the last 20 years, with the hippocampus now established as an important brain target for this hormone. Leptin receptors are highly localised to hippocampal synapses, and increasing evidence reveals that activation of synaptically located leptin receptors markedly impacts cognitive processes, and specifically hippocampal-dependent learning and memory. Here, we review the recent actions of leptin at hippocampal synapses and explore the consequences for brain health and disease.