bluuebunny/crossref_metadata_2025 huggingface dataset:
Major Adverse Cardiovascular Events and Mortality Prediction by Circulating GDF-15 in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis
Authors: Xie Suyi , Li Qi , Luk Andrea O. Y. , Lan Hui-Yao , Chan Paul K. S. , Bayés-Genís Antoni , Chan Francis K. L. , Fung Erik
Published: July 2022

Background: Growth differentiation factor 15 (GDF-15) is a homeostatic cytokine that regulates neural and cardio-metabolic functions, and its release is increased in response to stress, injury, and inflammation. In patients with coronary artery disease and heart failure (HF), three separate meta-analyses have found that elevated circulating GDF-15 was predictive of major adverse cardiovascular events (MACE), but none has evaluated its effects on incident MACE including HF and mortality hazard in type 2 diabetes. Methods: MEDLINE, EMBASE, and Scopus databases were queried. Articles that met the predefined eligibility criteria, including prospective studies that reported adjusted hazard ratios (aHRs), were selected according to the Cochrane Handbook and PRISMA guidelines. Study endpoints were (1) MACE including HF, and (2) all-cause mortality. Different GDF-15 concentration measurements were harmonized using a validated mathematical approach to express log2-transformed values in per standard deviation (SD). Study heterogeneity (I2), quality, and bias were assessed. Results: 19354 patients in 8 prospective studies were included. In 7 studies that reported 4247 MACE among 19200 participants, the incident rate was 22.1% during a median follow-up of 5.6 years. It was found that four of eight studies included HF decompensation or hospitalization as a component of MACE. In 5 studies that reported all-cause mortality, 1893 of 13223 patients died, at an incidence rate of 15.1% over 5.0 years. Of note, each 1 SD increase of log2[GDF-15] was associated with aHRs of 1.12 (1.09–1.15, I2 = 5%, p < 0.000001) and 1.27 (1.11–1.46, I2 = 86%, p = 0.00062) and for MACE and all-cause mortality, respectively. Conclusion: Elevated circulating level of GDF-15 was robustly predictive of MACE in patients with T2D but its prognostic significance in the prediction of mortality requires further studies.
Research Progress of DNA Methylation in Endometrial Cancer
Authors: Xu Ting , Ding Hongmei , Chen Jie , Lei Jiahui , Zhao Meng , Ji Bingyu , Chen Youguo , Qin Songbing , Gao Qinqin
Published: July 2022

Endometrial cancer (EC)) is one of the most common malignant tumors of the female genital system, with an increasing incidence and mortality, worldwide. Although the therapeutic strategy of EC is still complicated and challenging, further understanding of carcinogenesis from a gene perspective would allow an effort to improve therapeutic precision in this complex malignancy. DNA methylation is the most widely studied epigenetic alteration in human tumors. Aberrant DNA methylation events, resulting in altered gene expression, are features of many tumor types. In this review, we provide an update on evidence about the roles of aberrant DNA methylation within some classical tumor suppressor genes and oncogenes in endometrial carcinogenesis, and report on recent advances in the understanding of the contribution of aberrant DNA methylation to EC, as well as opportunities and challenges of DNA methylation in EC management and prevention.
Re-Programing Glucose Catabolism in the Microalga Chlorella sorokiniana under Light Condition
Authors: Li Tingting , Pang Na , He Lian , Xu Yuan , Fu Xinyu , Tang Yinjie , Shachar-Hill Yair , Chen Shulin
Published: July 2022

The microalga Chlorella sorokiniana has attracted much attention for lipid production and wastewater treatment. It can perform photosynthesis and organic carbon utilization concurrently. To understand its phototrophic metabolism, a biomass compositional analysis, a 13C metabolic flux analysis, and metabolite pool size analyses were performed. Under dark condition, the oxidative pentose phosphate pathway (OPP) was the major route for glucose catabolism (88% carbon flux) and a cyclic OPP–glycolytic route for glucose catabolism was formed. Under light condition, fluxes in the glucose catabolism, tricarboxylic acid (TCA) cycle, and anaplerotic reaction (CO2 fixation via phosphoenolpyruvate carboxylase) were all suppressed. Meanwhile, the RuBisCO reaction became active and the ratio of its carbon fixation to glucose carbon utilization was determined as 7:100. Moreover, light condition significantly reduced the pool sizes of sugar phosphate metabolites (such as E4P, F6P, and S7P) and promoted biomass synthesis (which reached 0.155 h−1). In addition, light condition increased glucose consumption rates, leading to higher ATP and NADPH production and a higher protein content (43% vs. 30%) in the biomass during the exponential growth phase.
Recent Advances in Lignin Depolymerization Techniques: A Comparative Overview of Traditional and Greener Approaches
Authors: Roy Ranen , Rahman Md Sajjadur , Amit Tanvir A. , Jadhav Balawanthrao
Published: July 2022

Due to the increased and excessive consumption of fossil fuels, sustainable alternative energy sources are badly needed to replace fossil fuels. The conversion of biomass into energy and value-added chemicals is one of the most promising potential pathways to solve this problem. Millions of tons of lignin, one of the major components of biomass, are produced annually as a byproduct of various industries, where it is treated as a low-value material. However, since it has an aromatic polymer nature, lignin is a proven source for different value-added products. Studies suggest that the selective cleavage of a specific bond of the complex lignin structure is one of the major challenges of converting lignin to a targeted product. In this study, eight different lignin depolymerization methods, both traditional and green, are reviewed. Acid and base catalytic depolymerization methods are straightforward, but due to their low selectivity and comparatively severe reaction conditions, they are expensive and not eco-friendly. Pyrolysis-based depolymerization comes with similar problems but has a higher conversion. In contrast, greener approaches, such as oxidative, microwave-assisted, super/sub-critical fluids (SCF), ionic liquid (IL), and deep eutectic solvent (DES)-based depolymerization techniques, have shown higher efficiency in terms of converting the lignin into phenolic compounds even under milder reaction conditions. SCF, IL, and DES-based approaches will likely become more popular in the future for their greener nature. Overall, depolymerization of lignin with greener technologies could make this process more economically viable and sustainable.
An Analysis of Microwave Ablation Parameters for Treatment of Liver Tumors from the 3D-IRCADb-01 Database
Authors: Radmilović-Radjenović Marija , Bošković Nikola , Sabo Martin , Radjenović Branislav
Published: July 2022

Simulation techniques are powerful tools for determining the optimal conditions necessary for microwave ablation to be efficient and safe for treating liver tumors. Owing to the complexity and computational resource consumption, most of the existing numerical models are two-dimensional axisymmetric models that emulate actual three-dimensional cancers and the surrounding tissue, which is often far from reality. Different tumor shapes and sizes require different input powers and ablation times to ensure the preservation of healthy tissues that can be determined only by the full three-dimensional simulations. This study aimed to tailor microwave ablation therapeutic conditions for complete tumor ablation with an adequate safety margin, while avoiding injury to the surrounding healthy tissue. Three-dimensional simulations were performed for a multi-slot microwave antenna immersed in two tumors obtained from the 3D-IRCADb-01 liver tumors database. The temperature dependence of the dielectric and thermal properties of healthy and tumoral liver tissues, blood perfusion, and water content are crucial for calculating the correct ablation time and, thereby, the correct ablation process. The developed three-dimensional simulation model may help practitioners in planning patient-individual procedures by determining the optimal input power and duration of the ablation process for the actual shape of the tumor. With proper input power, necrotic tissue is placed mainly in the tumor, and only a small amount of surrounding tissue is damaged.
The Peptide/Antibody-Based Surface Decoration of Calcium Phosphate Nanoparticles Carrying siRNA Influences the p65 NF-κB Protein Expression in Inflamed Cells In Vitro
Authors: Müller Elena K. , Białas Nataniel , Epple Matthias , Hilger Ingrid
Published: July 2022

Earlier studies with nanoparticles carrying siRNA were restricted to investigating the inhibition of target-specific protein expression, while almost ignoring effects related to the nanoparticle composition. Here, we demonstrate how the design and surface decoration of nanoparticles impact the p65 nuclear factor-kappa B (NF-κB) protein expression in inflamed leucocytes and endothelial cells in vitro. We prepared silica-coated calcium phosphate nanoparticles carrying encapsulated siRNA against p65 NF-κB and surface-decorated with peptides or antibodies. We show that RGD-decorated nanoparticles are efficient in down-regulating p65 NF-κB protein expression in endothelial cells as a result of an enhanced specific cellular binding and subsequent uptake of nanoparticles. In contrast, nanoparticles decorated with IgG (whether specific or not for CD69) are efficient in down-regulating p65 NF-κB protein expression in T-cells, but not in B-cells. Thus, an optimized nanoparticle decoration with xenogenic IgG may stimulate a specific cellular uptake. In summary, the composition of siRNA-loaded calcium phosphate nanoparticles can either weaken or stimulate p65 NF-κB protein expression in targeted inflamed leucocytes and endothelial cells. In general, unveiling such interactions may be very useful for the future design of anti-p65 siRNA-based nanomedicines for treatment of inflammation-associated diseases.
Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites
Authors: Rhea Elizabeth M. , Banks William A. , Raber Jacob
Published: July 2022

The concept of insulin resistance has been around since a few decades after the discovery of insulin itself. To allude to the classic Charles Dicken’s novel published 62 years before the discovery of insulin, in some ways, this is the best of times, as the concept of insulin resistance has expanded to include the brain, with the realization that insulin has a life beyond the regulation of glucose. In other ways, it is the worst of times as insulin resistance is implicated in devastating diseases, including diabetes mellitus, obesity, and Alzheimer’s disease (AD) that affect the brain. Peripheral insulin resistance affects nearly a quarter of the United States population in adults over age 20. More recently, it has been implicated in AD, with the degree of brain insulin resistance correlating with cognitive decline. This has led to the investigation of brain or central nervous system (CNS) insulin resistance and the question of the relation between CNS and peripheral insulin resistance. While both may involve dysregulated insulin signaling, the two conditions are not identical and not always interlinked. In this review, we compare and contrast the similarities and differences between peripheral and CNS insulin resistance. We also discuss how an apolipoprotein involved in insulin signaling and related to AD, apolipoprotein E (apoE), has distinct pools in the periphery and CNS and can indirectly affect each system. As these systems are both separated but also linked via the blood–brain barrier (BBB), we discuss the role of the BBB in mediating some of the connections between insulin resistance in the brain and in the peripheral tissues.
Analysis of Purine Metabolism to Elucidate the Pathogenesis of Acute Kidney Injury in Renal Hypouricemia
Authors: Miyamoto Daisuke , Sato Nana , Nagata Koji , Sakai Yukinao , Sugihara Hitoshi , Ohashi Yuki , Stiburkova Blanka , Sebesta Ivan , Ichida Kimiyoshi , Okamoto Ken
Published: July 2022

Renal hypouricemia is a disease caused by the dysfunction of renal urate transporters. This disease is known to cause exercise-induced acute kidney injury, but its mechanism has not yet been established. To analyze the mechanism by which hypouricemia causes renal failure, we conducted a semi-ischemic forearm exercise stress test to mimic exercise conditions in five healthy subjects, six patients with renal hypouricemia, and one patient with xanthinuria and analyzed the changes in purine metabolites. The results showed that the subjects with renal hypouricemia had significantly lower blood hypoxanthine levels and increased urinary hypoxanthine excretion after exercise than healthy subjects. Oxidative stress markers did not differ between healthy subjects and hypouricemic subjects before and after exercise, and no effect of uric acid as a radical scavenger was observed. As hypoxanthine is a precursor for adenosine triphosphate (ATP) production via the salvage pathway, loss of hypoxanthine after exercise in patients with renal hypouricemia may cause ATP loss in the renal tubules and consequent tissue damage.
Increased Remnant Lipoproteins in Apo E Deficient Mice Induce Coronary Atherosclerosis following Transverse Aortic Constriction and Aggravate the Development of Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure
Authors: Muthuramu Ilayaraja , Mishra Mudit , De Geest Bart
Published: July 2022

Murine coronary arteries are very resistant to the development of atherosclerosis, which may be related to their intramyocardial course. Blood pressure promotes atherosclerotic plaque formation by acting as a physical force that potentiates the migration of pro-atherogenic lipoproteins across the endothelium. C57BL/6N apolipoprotein (apo) E deficient mice have increased remnant lipoproteins that are a risk factor for coronary atherosclerosis. In this study, our aim was to quantify coronary atherosclerosis and artery remodeling following transverse aortic constriction (TAC) in C57BL/6N apo E−/− mice and to evaluate the impact of increased remnant lipoproteins on the development of pressure overload-induced cardiac hypertrophy and heart failure. Advanced atherosclerotic lesions were observed in the left coronary artery of C57BL/6N apo E−/− TAC mice but not in C57BL/6N TAC mice. Pressure overload resulted in markedly increased cardiac hypertrophy and more pronounced heart failure in C57BL/6N apo E−/− TAC mice in comparison to C57BL/6N TAC mice. Pathological hypertrophy, as evidenced by increased myocardial fibrosis and capillary rarefaction, was more prominent in C57BL/6N TAC apo E−/− than in C57BL/6N TAC mice and led to more marked cardiac dysfunction. In conclusion, TAC in apo E deficient mice induces coronary atherosclerosis and aggravates the development of pathological cardiac hypertrophy and heart failure.
The Long-Term Efficacy, Prognostic Factors, Safety, and Hospitalization Costs Following Denervation and Myotomy of the Affected Muscles and Deep Brain Stimulation in 94 Patients with Spasmodic Torticollis
Authors: Cui Zhiqiang , Chen Tong , Wang Jian , Jiang Chao , Gao Qingyao , Mao Zhiqi , Pan Longsheng , Ling Zhipei , Zhang Jianning , Li Xuemei
Published: July 2022

The surgical methods for treating spasmodic torticollis include the denervation and myotomy (DAM) of the affected muscles and deep brain stimulation (DBS). This study reports on the long-term efficacy, prognostic factors, safety, and hospitalization costs following these two procedures. We collected data from 94 patients with spasmodic torticollis, of whom 41 and 53 were treated with DAM and DBS, respectively, from June 2008 to December 2020 at the Chinese People’s Liberation Army General Hospital. We used the Tsui scale and the global outcome score of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) to evaluate the preoperative and postoperative clinical conditions in all patients. We also determined the costs of hospitalization, prognostic factors, and serious adverse events following the two surgical procedures. The mean follow-up time was 68.83 months (range = 13–116). Both resection surgery and DBS showed good results in terms of Tsui (Z = −5.103, p = 0.000; Z = −6.210, p = 0.000) and TWSTRS scores (t = 8.762, p = 0.000; Z = −6.308, p = 0.000). Compared with the DAM group, the preoperative (47.71, range 24–67.25) and postoperative (18.57, range 0–53) TWSTRS scores in the DBS group were significantly higher (Z = −3.161, p = 0.002). We found no correlation between prognostic factors and patient age, gender, or disease duration for either surgical procedure. However, prognostic factors were related to the length of the postoperative follow-up period in the DBS surgery group (Z = −2.068, p = 0.039; Z = −3.287, p = 0.001). The mean hospitalization cost in the DBS group was 6.85 times that found in the resection group (Z = −8.284, p = 0.000). The total complication rate was 4.26%. We found both resection surgery and DBS showed good results in the patients with spasmodic torticollis. Compared with DAM, DBS had a greater improvement in TWSTRS score; however, it was more expensive. Prognostic factors were related to the length of the postoperative follow-up period in patients who underwent DBS surgery.
Assessing the Socio-Economic Impacts of Rural Infrastructure Projects on Community Development
Authors: Hussain Shahid , Maqbool Rashid , Hussain Ammar , Ashfaq Saleha
Published: July 2022

Public construction infrastructure projects have been recognized as one of the fundamental tools in enhancing community socio-economic conditions for community development. The purpose of this study is to empirically investigate the impacts of socio-economic factors on community development of rural regions. Through a questionnaire survey administrated in Pakistan, public construction practitioners’ views were sought and evaluated. Empirical support for the argument originated from the data collected from 213 respondents in Pakistan’s public construction industry. The questionnaire’s data were evaluated employing the partial least square structural equation modeling (PLS-SEM). The study’s findings showed that economic and social factors influence the community development of rural regions. The result obtained from PLS-SEM proposed a more viable method to realize community development and objectives. The study’s results have offered precious lessons for local authorities, policymakers, and project stakeholders to strengthen the drive for achieving community development goals. Strategies supporting community development in rural regions are indispensable for local community development. This study provides empirical confirmation for the understanding and combining the community development concept; it illuminates absent knowledge about community development, especially in rural regions. This is one of the few studies investigating the influencing dimensions of community development in rural regions. To the authors’ best knowledge, this is the first research article providing empirical evidence of the influencing dimensions of community development in rural regions in a developing country.
COL5A1 Promotes the Progression of Gastric Cancer by Acting as a ceRNA of miR-137-3p to Upregulate FSTL1 Expression
Authors: Yang Ming , Lu Zhixing , Yu Bowen , Zhao Jiajia , Li Liang , Zhu Kaiyu , Ma Min , Long Fei , Wu Runliu , Hu Gui , Huang Lihua , Chou Jing , Gong Ni , Yang Kaiyan , Li Xiaorong , Zhang Yi , Lin Changwei
Published: July 2022

MicroRNAs (miRNAs) and their target genes have been shown to play an important role in gastric cancer but have not been fully clarified. Therefore, our goal was to identify the key miRNA–mRNA regulatory network in gastric cancer by utilizing a variety of bioinformatics analyses and experiments. A total of 242 miRNAs and 1080 genes were screened from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. Then, survival-related differentially expressed miRNAs and their differentially expressed target genes were screened. Twenty hub genes were identified from their protein–protein interaction network. After weighted gene co-expression network analysis was conducted, we selected miR-137-3p and its target gene, COL5A1, for further research. We found that miR-137-3p was significantly downregulated and that overexpression of miR-137-3p suppressed the proliferation, invasion, and migration of gastric cancer cells. Furthermore, we found that its target gene, COL5A1, could regulate the expression of another hub gene, FSTL1, by sponging miR-137-3p, which was confirmed by dual-luciferase reporter assays. Knockdown of COL5A1 inhibited the proliferation, invasion, and migration of gastric cancer cells, which could be rescued by the miR-137-3p inhibitor or overexpression of FSTL1. Ultimately, bioinformatics analyses showed that the expression of FSTL1 was highly correlated with immune infiltration.
Implementation of Image-Guided Brachytherapy for Pediatric Vaginal Cancers: Feasibility and Early Clinical Results
Authors: Terlizzi Mario , Minard Véronique , Haie-Meder Christine , Espenel Sophie , Martelli Hélène , Guérin Florent , Chargari Cyrus
Published: July 2022

Background: Brachytherapy (BT) has a major role in pediatric cancers of the lower genital tract, as part of a multimodal organ conservative strategy. Scarce data are available on the location of image-guided BT. Methods: Medical records of all consecutive girls treated in our center between 2005 and 2020 for a vaginal tumor with exclusive image-guided PDR-BT were retrospectively examined, with a focus on treatment parameters, patient compliance, and clinical outcome, including analysis of local control, survival and late toxicity rates. Results: Twenty-six patients were identified, with a median age of 25 months. Histological types were rhabdomyosarcoma, malignant germ cell tumor (MGCT) and clear cell adenocarcinoma in 18 (69%), 7 (27%) and 1 (4%) patients, respectively. Ten (33%) patients had prior surgery and 25 (96%) received chemotherapy prior to BT. The median prescribed dose was 60 Gy through pulses of 0.42 Gy. Global compliance was satisfactory, but three (12%) patients required replanning because of applicator displacement. After a median follow-up of 47.5 months, one patient with MGCT referred for salvage treatment of a local recurrence had a local and metastatic relapse. The local control rate probability was 96% at the last follow-up. Late toxicity rates ≥ grade 2 and ≥ grade 3 were reported in 23% and 11%, respectively, with gynecological toxicities being the most frequent side effect. Two patients required dilatation for vaginal stenosis. Conclusions: PDR-BT allowed similar local control compared to the historical low-dose rate technique. An indirect comparison suggests fewer treatment-related toxicities by integrating image guidance and optimization capabilities, but longer follow-up is necessary. Due to the rarity of the disease and the technical aspects of BT in these very young patients, referral to specialized high-volume centers is recommended.
Scales of Cancer Evolution: Selfish Genome or Cooperating Cells?
Authors: Brutovský Branislav
Published: July 2022

The exploitation of the evolutionary modus operandi of cancer to steer its progression towards drug sensitive cancer cells is a challenging research topic. Integrating evolutionary principles into cancer therapy requires properly identified selection level, the relevant timescale, and the respective fitness of the principal selection unit on that timescale. Interpretation of some features of cancer progression, such as increased heterogeneity of isogenic cancer cells, is difficult from the most straightforward evolutionary view with the cancer cell as the principal selection unit. In the paper, the relation between the two levels of intratumour heterogeneity, genetic, due to genetic instability, and non-genetic, due to phenotypic plasticity, is reviewed and the evolutionary role of the latter is outlined. In analogy to the evolutionary optimization in a changing environment, the cell state dynamics in cancer clones are interpreted as the risk diversifying strategy bet hedging, optimizing the balance between the exploitation and exploration of the cell state space.
Defining Optimal Conditions for Tumor Extracellular Vesicle DNA Extraction for Mutation Profiling
Authors: Elzanowska Julia , Berrocal Laura , García-Peláez Beatriz , Vives-Usano Marta , Sebo Beatriz Passos , Maia Joana , Batista Silvia , Teppo Jaakko , Varjosalo Markku , Moraes Maria Carolina Strano , Molina-Vila Miguel Ángel , Costa-Silva Bruno
Published: July 2022

(1) Background: Extracellular vesicles (EVs) have emerged as crucial players in the communication between cells in both physiological and pathological scenarios. The functions of EVs are strongly determined by their molecular content, which includes all bioactive molecules, such as proteins, lipids, RNA, and, as more recently described, double-stranded DNA. It has been shown that in oncological settings DNA associated with EVs (EV-DNA) is representative of the genome of parental cells and that it reflects the mutational status of the tumor, gaining much attention as a promising source of biomarker mutant DNA. However, one of the challenges in studies of EV-DNA is the lack of standardization of protocols for the DNA extraction from EVs, as well as ways to assess quality control, which hinders its future implementation in clinics. (2) Methods: We performed a comprehensive comparison of commonly used approaches for EV-DNA extraction by assessing DNA quantity, quality, and suitability for downstream analyses. (3) Results: We here established strategic points to consider for EV-DNA preparation for mutational analyses, including qPCR and NGS. (4) Conclusions: We put in place a workflow that can be applied for the detection of clinically relevant mutations in the EV-DNA of cancer patients.
Correction: Kudura et al. Prediction of Early Response to Immune Checkpoint Inhibition Using FDG-PET/CT in Melanoma Patients. Cancers 2021, 13, 3830
Authors: Kudura Ken , Dimitriou Florentia , Basler Lucas , Förster Robert , Mihic-Probst Daniela , Kutzker Tim , Dummer Reinhard , Mangana Joanna , Burger Irene A. , Kreissl Michael C.
Published: July 2022

The authors wish to make the following corrections to this paper [...]
Neurobehavioral Impairment in Pediatric Brain Tumor Survivors: A Meta-Analysis
Authors: Wang Yuliang , Liu Anthony Pak Yin , Lee Tatia Mei-Chun , Wong Wilfred Hing Sang , Fong Daniel Yee Tak , Leung Lok Kan , Shing Matthew Ming Kong , Ku Dennis Tak-Loi , Chan Godfrey Chi-Fung , Tso Winnie Wan-Yee
Published: July 2022

Purpose: The neurocognitive outcomes of pediatric brain tumor survivors have been extensively studied but the risk and predictors for neurobehavioral impairment are less clearly defined. We systematically analyzed the rates of emotional, psychosocial, and attention problems in pediatric brain tumor survivors. Methods: PubMed, Web of Science, Embase, Scopus, and Cochrane were searched for articles published between January 2012 to April 2022. Eligible studies reported neurobehavioral outcomes for PBTS aged 2 to <23 years with a brain tumor diagnosis before 18 years of age. A random-effect meta-analysis was performed in R. Results: The search yielded 1187 unique publications, of which 50 were included in the quantitative analysis. The estimated risk of having emotional, psychosocial, and attention problems were 15% (95%CI 10–20%), 12% (95%CI 9–16%), and 12% (95%CI 9–16%), respectively. PBTS were more likely to have emotional difficulties (Hedge’s g = 0.43 [95%CI 0.34–0.52]), psychosocial problems (Hedge’s g = 0.46 [95%CI 0.33–0.58]), and attention problems (Hedge’s g = 0.48 [95%CI 0.34–0.63]) compared to normal/healthy control subjects. There was no significant difference in the rates of neurobehavioral impairment between children with and without history of cranial radiotherapy. Conclusions: PBTS are at elevated risk of neurobehavioral impairment. Neurobehavioral monitoring should be considered as the standard of care for PBTS.
Diverse Functions of KDM5 in Cancer: Transcriptional Repressor or Activator?
Authors: Ohguchi Yasuyo , Ohguchi Hiroto
Published: July 2022

Epigenetic modifications are crucial for chromatin remodeling and transcriptional regulation. Post-translational modifications of histones are epigenetic processes that are fine-tuned by writer and eraser enzymes, and the disorganization of these enzymes alters the cellular state, resulting in human diseases. The KDM5 family is an enzymatic family that removes di- and tri-methyl groups (me2 and me3) from lysine 4 of histone H3 (H3K4), and its dysregulation has been implicated in cancer. Although H3K4me3 is an active chromatin marker, KDM5 proteins serve as not only transcriptional repressors but also transcriptional activators in a demethylase-dependent or -independent manner in different contexts. Notably, KDM5 proteins regulate the H3K4 methylation cycle required for active transcription. Here, we review the recent findings regarding the mechanisms of transcriptional regulation mediated by KDM5 in various contexts, with a focus on cancer, and further shed light on the potential of targeting KDM5 for cancer therapy.
Circulating Tumor DNA-Based Genomic Profiling Assays in Adult Solid Tumors for Precision Oncology: Recent Advancements and Future Challenges
Authors: Chan Hiu Ting , Chin Yoon Ming , Low Siew-Kee
Published: July 2022

Genomic profiling using tumor biopsies remains the standard approach for the selection of approved molecular targeted therapies. However, this is often limited by its invasiveness, feasibility, and poor sample quality. Liquid biopsies provide a less invasive approach while capturing a contemporaneous and comprehensive tumor genomic profile. Recent advancements in the detection of circulating tumor DNA (ctDNA) from plasma samples at satisfactory sensitivity, specificity, and detection concordance to tumor tissues have facilitated the approval of ctDNA-based genomic profiling to be integrated into regular clinical practice. The recent approval of both single-gene and multigene assays to detect genetic biomarkers from plasma cell-free DNA (cfDNA) as companion diagnostic tools for molecular targeted therapies has transformed the therapeutic decision-making procedure for advanced solid tumors. Despite the increasing use of cfDNA-based molecular profiling, there is an ongoing debate about a ‘plasma first’ or ‘tissue first’ approach toward genomic testing for advanced solid malignancies. Both approaches present possible advantages and disadvantages, and these factors should be carefully considered to personalize and select the most appropriate genomic assay. This review focuses on the recent advancements of cfDNA-based genomic profiling assays in advanced solid tumors while highlighting the major challenges that should be tackled to formulate evidence-based guidelines in recommending the ‘right assay for the right patient at the right time’.
Metabolic Diseases and Risk of Head and Neck Cancer: A Cohort Study Analyzing Nationwide Population-Based Data
Authors: Choi Soo-Young , Cheong Hyeon-Kyoung , Lee Min-Kyeong , Kang Jeong-Wook , Lee Young-Chan , Oh In-Hwan , Eun Young-Gyu
Published: July 2022

The aim of the study was to investigate the association between metabolic diseases and the risk of head and neck cancer (HNC) using nationwide population-based big data. This retrospective cohort study was conducted using the Korean National Health Insurance Service health checkup database. A total of 4,575,818 participants aged >40 years who received a health checkup in 2008 were enrolled, and we studied the incidence of HNC until 2019. We analyzed the risk of HNC according to the presence of metabolic diseases, such as obesity, dyslipidemia, hypertension, and diabetes. Although metabolic syndrome itself was not associated with HNC, each component of metabolic syndrome was associated with HNC. Underweight and diabetes were risk factors for HNC (HR: 1.694). High total cholesterol and high low-density lipoprotein cholesterol levels were factors that decreased the risk (HR 0.910 and 0.839). When we analyzed men and women separately, low total cholesterol level, low low-density lipoprotein cholesterol level, and hypertension were risk factors only in men. In addition, pre-obesity, obesity, and central obesity decreased the risk only in men. Each metabolic disease affects HNC in different ways. Underweight and diabetes increased the risk of HNC, whereas high total cholesterol and high low-density lipoprotein cholesterol levels decreased the risk of HNC.
Phytochemicals for the Prevention and Treatment of Renal Cell Carcinoma: Preclinical and Clinical Evidence and Molecular Mechanisms
Authors: Bajalia Essa M. , Azzouz Farah B. , Chism Danielle A. , Giansiracusa Derrek M. , Wong Carina G. , Plaskett Kristina N. , Bishayee Anupam
Published: July 2022

Renal cell carcinoma (RCC) is associated with about 90% of renal malignancies, and its incidence is increasing globally. Plant-derived compounds have gained significant attention in the scientific community for their preventative and therapeutic effects on cancer. To evaluate the anticancer potential of phytocompounds for RCC, we compiled a comprehensive and systematic review of the available literature. Our work was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. The literature search was performed using scholarly databases such as PubMed, Scopus, and ScienceDirect and keywords such as renal cell carcinoma, phytochemicals, cancer, tumor, proliferation, apoptosis, prevention, treatment, in vitro, in vivo, and clinical studies. Based on in vitro results, various phytochemicals, such as phenolics, terpenoids, alkaloids, and sulfur-containing compounds, suppressed cell viability, proliferation and growth, showed cytotoxic activity, inhibited invasion and migration, and enhanced the efficacy of chemotherapeutic drugs in RCC. In various animal tumor models, phytochemicals suppressed renal tumor growth, reduced tumor size, and hindered angiogenesis and metastasis. The relevant antineoplastic mechanisms involved upregulation of caspases, reduction in cyclin activity, induction of cell cycle arrest and apoptosis via modulation of a plethora of cell signaling pathways. Clinical studies demonstrated a reduced risk for the development of kidney cancer and enhancement of the efficacy of chemotherapeutic drugs. Both preclinical and clinical studies displayed significant promise of utilizing phytochemicals for the prevention and treatment of RCC. Further research, confirming the mechanisms and regulatory pathways, along with randomized controlled trials, are needed to establish the use of phytochemicals in clinical practice.
Highly Efficient Decarboxylation of L-Lysine to Cadaverine Catalyzed by RuO2 Encapsulated in FAU Zeolite
Authors: Ma Zhanling , Xin Zongwu , Qin Shaojie , Huang Yuhong
Published: July 2022

The development of an efficient catalyst especially with a high productivity for decarboxylation of L-lysine to cadaverine, is of both industrial and economic significance. Here, we reported the synthesis of RuO2 well-confined in the supercage of FAU zeolite (RuO2@FAU) through in situ hydrothermal strategies. A set of characterizations, such as XRD, Raman, TEM, XPS, NH3-TPD and N2 physical adsorption, confirmed the successful encapsulation of RuO2 clusters (~1.5 nm) inside the FAU zeolite. RuO2@FAU had the higher cadaverine productivity of 120.9 g/L/h/mmol cat., which was almost six times that of traditionally supported ruthenium oxide catalysts (21.2 g/L/h/mmol cat.). RuO2@FAU catalysts with different ammonia exchange degrees, as well as different Si/Al ratios were further evaluated. After optimization, the highest cadaverine productivity of 480.3 g/L/h/mmol cat. was obtained. Deep analysis of the electronic properties of RuO2@FAU indicated that the surface defect structures, such as oxygen vacancies, played a vital role in the adsorption or activation of L-lysine which finally led to a boosted performance. Furthermore, the mechanism of decarboxylation of L-lysine to cadaverine was proposed.
Skeletal Muscle Pathogenesis in Polyglutamine Diseases
Authors: Marchioretti Caterina , Zuccaro Emanuela , Pandey Udai Bhan , Rosati Jessica , Basso Manuela , Pennuto Maria
Published: July 2022

Polyglutamine diseases are characterized by selective dysfunction and degeneration of specific types of neurons in the central nervous system. In addition, nonneuronal cells can also be affected as a consequence of primary degeneration or due to neuronal dysfunction. Skeletal muscle is a primary site of toxicity of polyglutamine-expanded androgen receptor, but it is also affected in other polyglutamine diseases, more likely due to neuronal dysfunction and death. Nonetheless, pathological processes occurring in skeletal muscle atrophy impact the entire body metabolism, thus actively contributing to the inexorable progression towards the late and final stages of disease. Skeletal muscle atrophy is well recapitulated in animal models of polyglutamine disease. In this review, we discuss the impact and relevance of skeletal muscle in patients affected by polyglutamine diseases and we review evidence obtained in animal models and patient-derived cells modeling skeletal muscle.
Lysine-Specific Demethylase 1 (LSD1/KDM1A) Inhibition as a Target for Disease Modification in Myelofibrosis
Authors: Gill Harinder
Published: July 2022

Myelofibrosis (MF) is the most symptomatic form of myeloproliferative neoplasm and carries the worst outcome. Allogeneic hematopoietic stem cell transplantation is the only therapy with potential for cure at present, but is limited by significant mortality and morbidity. JAK inhibition is the mainstay of treatment for intermediate- and high-risk MF. Ruxolitinib is the most widely used JAK1/2 inhibitor and provides durable effects in controlling symptom burden and spleen volumes. Nevertheless, ruxolitinib may not adequately address the underlying disease biology. Its effects on mutant allele burden, bone marrow fibrosis, and the prevention of leukemic transformation are minimal. Multiple small molecules are being tested in multiple phase 2 and 3 studies as either monotherapy or in combination with JAK2 inhibitors. In this review, the role of LSD1/KDM1A inhibition as a potential disease-modification strategy in patients with myelofibrosis is described and discussed.
CaMKII Inhibition Attenuates Distinct Gain-of-Function Effects Produced by Mutant Nav1.6 Channels and Reduces Neuronal Excitability
Authors: Zybura Agnes S. , Sahoo Firoj K. , Hudmon Andy , Cummins Theodore R.
Published: July 2022

Aberrant Nav1.6 activity can induce hyperexcitability associated with epilepsy. Gain-of-function mutations in the SCN8A gene encoding Nav1.6 are linked to epilepsy development; however, the molecular mechanisms mediating these changes are remarkably heterogeneous and may involve post-translational regulation of Nav1.6. Because calcium/calmodulin-dependent protein kinase II (CaMKII) is a powerful modulator of Nav1.6 channels, we investigated whether CaMKII modulates disease-linked Nav1.6 mutants. Whole-cell voltage clamp recordings in ND7/23 cells show that CaMKII inhibition of the epilepsy-related mutation R850Q largely recapitulates the effects previously observed for WT Nav1.6. We also characterized a rare missense variant, R639C, located within a regulatory hotspot for CaMKII modulation of Nav1.6. Prediction software algorithms and electrophysiological recordings revealed gain-of-function effects for R639C mutant channel activity, including increased sodium currents and hyperpolarized activation compared to WT Nav1.6. Importantly, the R639C mutation ablates CaMKII phosphorylation at a key regulatory site, T642, and, in contrast to WT and R850Q channels, displays a distinct response to CaMKII inhibition. Computational simulations demonstrate that modeled neurons harboring the R639C or R850Q mutations are hyperexcitable, and simulating the effects of CaMKII inhibition on Nav1.6 activity in modeled neurons differentially reduced hyperexcitability. Acute CaMKII inhibition may represent a promising mechanism to attenuate gain-of-function effects produced by Nav1.6 mutations.
The Endocrine Adipose Organ: A System Playing a Central Role in COVID-19
Authors: Cinti Francesca , Cinti Saverio
Published: July 2022

In the last 30 years the adipose cell has been object of several studies, turning its reputation from an inert cell into the main character involved in the pathophysiology of multiple diseases, including the ongoing COVID-19 pandemic, which has changed the clinical scenario of the last two years. Composed by two types of tissue (white and brown), with opposite roles, the adipose organ is now classified as a real endocrine organ whose dysfunction is involved in different diseases, mainly obesity and type 2 diabetes. In this mini-review we aim to retrace the adipose organ history from physiology to physiopathology, to provide therapeutic perspectives for the prevention and treatment of its two main related diseases (obesity and type 2 diabetes) and to summarize the most recent discoveries linking adipose tissue to COVID-19.
Epigenetic Alterations in Cryopreserved Human Spermatozoa: Suspected Potential Functional Defects
Authors: Wang Wanxue , Todorov Plamen , Pei Cheng , Wang Mengying , Isachenko Evgenia , Rahimi Gohar , Mallmann Peter , Isachenko Vladimir
Published: July 2022

Background: Gene set enrichment analysis (GSEA) was conducted on raw data, and alternative splicing (AS) events were found after mRNA sequencing of human spermatozoa. In this study, we aimed to compare unknown micro-epigenetics alternations in fresh and cryopreserved spermatozoa to evaluate the effectivity of cryopreservation protocols. Methods: Spermatozoa were divided into three groups: fresh spermatozoa (group 1), cryoprotectant-free vitrified spermatozoa (group 2), and conventionally frozen spermatozoa (group 3). Nine RNA samples (three replicates in each group) were detected and were used for library preparation with an Illumina compatible kit and sequencing by the Illumina platform. Results: Three Gene Ontology (GO) terms were found to be enriched in vitrified spermatozoa compared with fresh spermatozoa: mitochondrial tRNA aminoacylation, ATP-dependent microtubule motor activity, and male meiotic nuclear division. In alternative splicing analysis, a number of unknown AS events were found, including functional gene exon skipping (SE), alternative 5′ splice sites (A5SS), alternative 3′ splice sites (A3SS), mutually exclusive exon (MXE), and retained intron (RI). Conclusions: Cryopreservation of spermatozoa from some patients can agitate epigenetic instability, including increased alternative splicing events and changes in crucial mitochondrial functional activities. For fertilization of oocytes, for such patients, it is recommended to use fresh spermatozoa whenever possible; cryopreservation of sperm is recommended to be used only in uncontested situations.
Activation of Autophagic Flux Maintains Mitochondrial Homeostasis during Cardiac Ischemia/Reperfusion Injury
Authors: He Lihao , Chu Yuxin , Yang Jing , He Jin , Hua Yutao , Chen Yunxi , Benavides Gloria , Rowe Glenn C. , Zhou Lufang , Ballinger Scott , Darley-Usmar Victor , Young Martin E. , Prabhu Sumanth D. , Sethu Palaniappan , Zhou Yingling , Zhang Cheng , Xie Min
Published: July 2022

Reperfusion injury after extended ischemia accounts for approximately 50% of myocardial infarct size, and there is no standard therapy. HDAC inhibition reduces infarct size and enhances cardiomyocyte autophagy and PGC1α-mediated mitochondrial biogenesis when administered at the time of reperfusion. Furthermore, a specific autophagy-inducing peptide, Tat-Beclin 1 (TB), reduces infarct size when administered at the time of reperfusion. However, since SAHA affects multiple pathways in addition to inducing autophagy, whether autophagic flux induced by TB maintains mitochondrial homeostasis during ischemia/reperfusion (I/R) injury is unknown. We tested whether the augmentation of autophagic flux by TB has cardioprotection by preserving mitochondrial homeostasis both in vitro and in vivo. Wild-type mice were randomized into two groups: Tat-Scrambled (TS) peptide as the control and TB as the experimental group. Mice were subjected to I/R surgery (45 min coronary ligation, 24 h reperfusion). Autophagic flux, mitochondrial DNA (mtDNA), mitochondrial morphology, and mitochondrial dynamic genes were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were treated with a simulated I/R injury to verify cardiomyocyte specificity. The essential autophagy gene, ATG7, conditional cardiomyocyte-specific knockout (ATG7 cKO) mice, and isolated adult mouse ventricular myocytes (AMVMs) were used to evaluate the dependency of autophagy in adult cardiomyocytes. In NRVMs subjected to I/R, TB increased autophagic flux, mtDNA content, mitochondrial function, reduced reactive oxygen species (ROS), and mtDNA damage. Similarly, in the infarct border zone of the mouse heart, TB induced autophagy, increased mitochondrial size and mtDNA content, and promoted the expression of PGC1α and mitochondrial dynamic genes. Conversely, loss of ATG7 in AMVMs and in the myocardium of ATG7 cKO mice abolished the beneficial effects of TB on mitochondrial homeostasis. Thus, autophagic flux is a sufficient and essential process to mitigate myocardial reperfusion injury by maintaining mitochondrial homeostasis and partly by inducing PGC1α-mediated mitochondrial biogenesis.
An Overview on the Recent Advances in Alternative Solvents as Stabilizers of Proteins and Enzymes
Authors: Almeida Jéssica S. , Capela Emanuel V. , Loureiro Ana M. , Tavares Ana P. M. , Freire Mara G.
Published: July 2022

Currently, the use of alternative solvents is increasing, namely ionic liquids (ILs) and deep eutectic solvents (DESs) in diverse fields of knowledge, such as biochemistry, chemistry, chemical engineering, biotechnology and biomedicine. Particularly, when compared to traditional solvents, these alternative solvents have great importance for biomolecules due to the enhanced solubility, structure stability and the biological activity of biomolecules, such as protein and enzymes. Thus, in this review article, the recent developments and efforts on the technological developments carried out with ILs and DESs for the stabilization and activation of proteins and enzymes are provided. The most studied IL- and DES-based formulations for proteins and enzymes are discussed and the molecular mechanisms and interactions related to the increased stability promoted by these alternative solvents are disclosed, while emphasizing their main advantages.
Evaluation of the Adsorptive Process on Adsorbent Surfaces as a Function of Pressure in an Isosteric System Compared with Adsorption Isotherm
Authors: Ntsondwa Sindisiwe , Msomi Velaphi , Basitere Moses
Published: July 2022

The developing significance of adsorption has brought about a steadily expanding quantity of logical and innovative writing on different adsorbents. This paper intends to propose experimental and computational methods for measuring the strength of adsorbate–solid interactions. It primarily focuses on the use of graphs to measure the effectiveness of an adsorbate’s bonds with the solid adsorbent by determining the isosteric heat. The Clausius–Clapeyron model equation is used to determine the isosteric enthalpy of adsorption from two adsorption isotherms at various but close temperatures, with ΔT of 10 °C. A full computational explanation of the Clausius–Clapeyron model equation for determining ΔHads is provided using experimental data. Logarithmic plots of uptakes vs. p in the low-pressure zone for the Freundlich–Langmuir graph are used to assess and confirm the quality of the crucial underlying isotherms. The isosteric heat was found to be between 13.5 kJ/mol and 16 kJ/mol.