bluuebunny/crossref_metadata_2025 huggingface dataset:
Choroidal Vascularity Index in Adult-Onset Foveomacular Vitelliform Dystrophy: A Pilot Study
Authors: Abdolrahimzadeh Solmaz , Fragiotta Serena , Ciacimino Chiara , Di Pippo Mariachiara , Scuderi Gianluca
Published: November 2021

This pilot study aims to investigate choroidal vascular status in eyes with adult-onset foveomacular vitelliform dystrophy (AOFVD), early age-related macular degeneration (AMD), and age-matched controls. In this retrospective study, choroidal thickness (CT) was measured manually using spectral domain optical coherence tomography images of the fovea, and 500 and 1500 µm from the nasal and temporal regions in the fovea. The horizontal B-scan was imported into Fiji software. Choroidal vascularity index (CVI) and luminal and stromal areas were calculated. A total of 36 eyes from 36 patients, including 18 eyes with AOFVD and 18 eyes with CD, and 16 eyes of healthy subjects were included. CVI was significantly different among subgroups (ANOVA, p = 0.004). Eyes with AOFVD presented a higher CVI (+0.03 ± 0.01, p = 0.001) than eyes with CD and controls (p = 0.03). No differences in CVI were detected between controls and eyes with CD (p = 0.25). AOFVD eyes accounted for the greatest luminal area, particularly significant in comparison with healthy controls (+0.27 ± 0.11, p = 0.02). AOFVD eyes present a greater CVI than eyes with CD and controls. The major choroidal involvement is on the luminal component, further corroborating a possible role of the choroidal vasculature in the pathological manifestations of AOFVD disease.
Reconstructed Interpolating Differential Operator Method with Arbitrary Order of Accuracy for the Hyperbolic Equation
Authors: Lin Shijian , Luo Qi , Leng Hongze , Song Junqiang
Published: November 2021

We propose a family of multi-moment methods with arbitrary orders of accuracy for the hyperbolic equation via the reconstructed interpolating differential operator (RDO) approach. Reconstruction up to arbitrary order can be achieved on a single cell from properly allocated model variables including spatial derivatives of varying orders. Then we calculate the temporal derivatives of coefficients of the reconstructed polynomial and transform them into the temporal derivatives of the model variables. Unlike the conventional multi-moment methods which evolve different types of moments by deriving different equations, RDO can update all derivatives uniformly via a simple linear transform more efficiently. Based on difference in introducing interaction from adjacent cells, the central RDO and the upwind RDO are proposed. Both schemes enjoy high-order accuracy which is verified by Fourier analysis and numerical experiments.
Biosynthesis of Poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) from CO2 by a Recombinant Cupriavidusnecator
Authors: Tanaka Kenji , Yoshida Kazumasa , Orita Izumi , Fukui Toshiaki
Published: November 2021

The copolyester of 3-hydroxybutyrate (3HB) and 3-hydoxyhexanoate (3HHx), PHBHHx, is one of the most practical kind of bacterial polyhydroxyalkanoates due to its high flexibility and marine biodegradability. PHBHHx is usually produced from vegetable oils or fatty acids through β-oxidation, whereas biosynthesis from sugars has been achieved by recombinant strains of hydrogen-oxidizing bacterium Cupriavidus necator. This study investigated the biosynthesis of PHBHHx from CO2 as the sole carbon source by engineered C. necator strains. The recombinant strains capable of synthesizing PHBHHx from fructose were cultivated in a flask using complete mineral medium and a substrate gas mixture (H2/O2/CO2 = 8:1:1). The results of GC and 1H NMR analyses indicated that the recombinants of C. necator synthesized PHBHHx from CO2 with high cellular content. When 1.0 g/L (NH4)2SO4 was used as a nitrogen source, the 3HHx composition of PHBHHx in the strain MF01∆B1/pBBP-ccrMeJ4a-emd was 47.7 ± 6.2 mol%. Further investigation demonstrated that the PHA composition can be regulated by using (R)-enoyl-CoA hydratase (PhaJ) with different substrate specificity. The composition of 3HHx in PHBHHx was controlled to about 11 mol%, suitable for practical applications, and high cellular content was kept in the strains transformed with pBPP-ccrMeJAc-emd harboring short-chain-length-specific PhaJ.
Cell Therapy for Neurological Disorders: The Perspective of Promising Cells
Authors: Liu Donghui , Bobrovskaya Larisa , Zhou Xin-Fu
Published: November 2021

Neurological disorders are big public health challenges that are afflicting hundreds of millions of people around the world. Although many conventional pharmacological therapies have been tested in patients, their therapeutic efficacies to alleviate their symptoms and slow down the course of the diseases are usually limited. Cell therapy has attracted the interest of many researchers in the last several decades and has brought new hope for treating neurological disorders. Moreover, numerous studies have shown promising results. However, none of the studies has led to a promising therapy for patients with neurological disorders, despite the ongoing and completed clinical trials. There are many factors that may affect the outcome of cell therapy for neurological disorders due to the complexity of the nervous system, especially cell types for transplantation and the specific disease for treatment. This paper provides a review of the various cell types from humans that may be clinically used for neurological disorders, based on their characteristics and current progress in related studies.
A Study of the Coevolution of Digital Organisms with an Evolutionary Cellular Automaton
Authors: Falgueras-Cano Javier , Falgueras-Cano Juan-Antonio , Moya Andrés
Published: November 2021

This paper presents an Evolutionary Cellular Automaton (ECA) that simulates the evolutionary dynamics of biological interactions by manipulating strategies of dispersion and associations between digital organisms. The parameterization of the different types of interaction and distribution strategies using configuration files generates easily interpretable results. In that respect, ECA is an effective instrument for measuring the effects of relative adaptive advantages and a good resource for studying natural selection. Although ECA works effectively in obtaining the expected results from most well-known biological interactions, some unexpected effects were observed. For example, organisms uniformly distributed in fragmented habitats do not favor eusociality, and mutualism evolved from parasitism simply by varying phenotypic flexibility. Finally, we have verified that natural selection represents a cost for the emergence of sex by destabilizing the stable evolutionary strategy of the 1:1 sex ratio after generating randomly different distributions in each generation.
Centenary of Soil and Air Borne Wheat Karnal Bunt Disease Research: A Review
Authors: Iquebal Mir Asif , Mishra Pallavi , Maurya Ranjeet , Jaiswal Sarika , Rai Anil , Kumar Dinesh
Published: November 2021

Karnal bunt (KB) of wheat (Triticum aestivum L.), known as partial bunt has its origin in Karnal, India and is caused by Tilletia indica (Ti). Its incidence had grown drastically since late 1960s from northwestern India to northern India in early 1970s. It is a seed, air and soil borne pathogen mainly affecting common wheat, durum wheat, triticale and other related species. The seeds become inedible, inviable and infertile with the precedence of trimethylamine secreted by teliospores in the infected seeds. Initially the causal pathogen was named Tilletia indica but was later renamed Neovossia indica. The black powdered smelly spores remain viable for years in soil, wheat straw and farmyard manure as primary sources of inoculum. The losses reported were as high as 40% in India and also the cumulative reduction of national farm income in USA was USD 5.3 billion due to KB. The present review utilizes information from literature of the past 100 years, since 1909, to provide a comprehensive and updated understanding of KB, its causal pathogen, biology, epidemiology, pathogenesis, etc. Next generation sequencing (NGS) is gaining popularity in revolutionizing KB genomics for understanding and improving agronomic traits like yield, disease tolerance and disease resistance. Genetic resistance is the best way to manage KB, which may be achieved through detection of genes/quantitative trait loci (QTLs). The genome-wide association studies can be applied to reveal the association mapping panel for understanding and obtaining the KB resistance locus on the wheat genome, which can be crossed with elite wheat cultivars globally for a diverse wheat breeding program. The review discusses the current NGS-based genomic studies, assembly, annotations, resistant QTLs, GWAS, technology landscape of diagnostics and management of KB. The compiled exhaustive information can be beneficial to the wheat breeders for better understanding of incidence of disease in endeavor of quality production of the crop.
Toluene Can Disrupt Rat Ovarian Follicullogenesis and Steroidogenesis and Induce Both Autophagy and Apoptosis
Authors: Alrezaki Abdulkarem , Aldawood Nouf , Mansour Lamjed , Ahmed Mukhtar , Sirotkin Alexander V. , Alwasel Saleh , Harrath Abdel Halim
Published: November 2021

Toluene has been shown to be highly toxic to humans and animals and can cause damage to various tissues. However, studies reporting its effects on ovarian function are still limited. In this study, we investigated the in vivo effect of toluene using female Wistar rats. We found that toluene exposure decreased ovarian weight and affected ovarian structure by increasing the number of abnormally growing follicles. Moreover, it significantly increased progesterone and testosterone levels. We also showed that toluene exposure decreased GDF-9 protein and its encoding gene. In addition, it inhibited the expression of most of the genes involved in granulosa cell proliferation and differentiation, such as Insl3, ccnd2 and actb. The TUNEL assay showed that apoptosis occurred at the middle and high doses only (4000 and 8000 ppm, respectively), whereas no effect was observed at the low dose (2000 ppm). Interestingly, we showed that toluene exposure induced autophagy as LC3 protein and its encoding gene significantly increased for all doses of treatment. These results may suggest that the activation of autophagy at a low dose of exposure was to protect ovarian cells against death by inhibiting apoptosis, whereas its activation at high doses of exposure triggered apoptosis leading to cell death.
Characterizing the Genomic Profile in High-Grade Gliomas: From Tumor Core to Peritumoral Brain Zone, Passing through Glioma-Derived Tumorspheres
Authors: Giambra Martina , Messuti Eleonora , Di Cristofori Andrea , Cavandoli Clarissa , Bruno Raffaele , Buonanno Raffaella , Marzorati Matilde , Zambuto Melissa , Rodriguez-Menendez Virginia , Redaelli Serena , Giussani Carlo , Bentivegna Angela
Published: November 2021

Glioblastoma is an extremely heterogeneous disease. Treatment failure and tumor recurrence primarily reflect the presence in the tumor core (TC) of the glioma stem cells (GSCs), and secondly the contribution, still to be defined, of the peritumoral brain zone (PBZ). Using the array-CGH platform, we deepened the genomic knowledge about the different components of GBM and we identified new specific biomarkers useful for new therapies. We firstly investigated the genomic profile of 20 TCs of GBM; then, for 14 cases and 7 cases, respectively, we compared these genomic profiles with those of the related GSC cultures and PBZ biopsies. The analysis on 20 TCs confirmed the intertumoral heterogeneity and a high percentage of copy number alterations (CNAs) in GBM canonical pathways. Comparing the genomic profiles of 14 TC-GSC pairs, we evidenced a robust similarity among the two samples of each patient. The shared imbalanced genes are related to the development and progression of cancer and in metabolic pathways, as shown by bioinformatic analysis using DAVID. Finally, the comparison between 7 TC-PBZ pairs leads to the identification of PBZ-unique alterations that require further investigation.
Possible Role of Leptin in Atopic Dermatitis: A Literature Review
Authors: Jiménez-Cortegana Carlos , Ortiz-García Germán , Serrano Amalia , Moreno-Ramírez David , Sánchez-Margalet Víctor
Published: November 2021

Atopic dermatitis (AD) is the most frequent chronic inflammatory skin disease, and its incidence has been rapidly increasing in developed countries in the last years. AD presents a high degree of heterogeneity due to biases and confounding factors such as age range, sex, or ethnicity. For those reasons, the search for new biomarkers is crucial. At the same time, obesity, which is a global health problem, has also increased over the years. It has been associated with many pathophysiological states, including skin diseases such as AD, mostly in childhood. Obesity promotes a low grade inflammation driven by many different cytokines and adipokines, including leptin, which has a key role in many other diseases due to its pleiotropic effects. Leptin also has a role in both skin and allergic diseases very related to AD. Thus, this adipokine could have an important role in the pathogenesis of AD, especially in its chronicity. Despite the limited literature available, there is some evidence that leads us to consider leptin as an important adipokine in this skin disease. For this reason, here we have reviewed the role of leptin in the pathophysiology of AD.
Data-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors
Authors: Pietruś Wojciech , Kurczab Rafał , Stumpfe Dagmar , Bojarski Andrzej J. , Bajorath Jürgen
Published: November 2021

Currently, G protein-coupled receptors are the targets with the highest number of drugs in many therapeutic areas. Fluorination has become a common strategy in designing highly active biological compounds, as evidenced by the steadily increasing number of newly approved fluorine-containing drugs. Herein, we identified in the ChEMBL database and analysed 1554 target-based FSAR sets (non-fluorinated compounds and their fluorinated analogues) comprising 966 unique non-fluorinated and 2457 unique fluorinated compounds active against 33 different aminergic GPCRs. Although a relatively small number of activity cliffs (defined as a pair of structurally similar compounds showing significant differences of activity −ΔpPot > 1.7) was found in FSAR sets, it is clear that appropriately introduced fluorine can increase ligand potency more than 50-fold. The analysis of matched molecular pairs (MMPs) networks indicated that the fluorination of the aromatic ring showed no clear trend towards a positive or negative effect on affinity; however, a favourable site for a positive potency effect of fluorination was the ortho position. Fluorination of aliphatic fragments more often led to a decrease in biological activity. The results may constitute the rules of thumb for fluorination of aminergic receptor ligands and provide insights into the role of fluorine substitutions in medicinal chemistry.
From Biomarkers to Novel Therapeutic Approaches in Chronic Obstructive Pulmonary Disease
Authors: Wang Hsu-Hui , Cheng Shih-Lung
Published: November 2021

Chronic obstructive pulmonary disease (COPD) is a heterogeneous and complex disorder. In this review, we provided a comprehensive overview of biomarkers involved in COPD, and potential novel biological therapies that may provide additional therapeutic options for COPD. The complex characteristics of COPD have made the recommendation of a generalized therapy challenging, suggesting that a tailored, personalized strategy may lead to better outcomes. Existing and unmet needs for COPD treatment support the continued development of biological therapies, including additional investigations into the potential clinical applications of this approach.
Rodent Brain Pathology, Audiogenic Epilepsy
Authors: Fedotova Irina B. , Surina Natalia M. , Nikolaev Georgy M. , Revishchin Alexandre V. , Poletaeva Inga I.
Published: November 2021

The review presents data which provides evidence for the internal relationship between the stages of rodent audiogenic seizures and post-ictal catalepsy with the general pattern of animal reaction to the dangerous stimuli and/or situation. The wild run stage of audiogenic seizure fit could be regarded as an intense panic reaction, and this view found support in numerous experimental data. The phenomenon of audiogenic epilepsy probably attracted the attention of physiologists as rodents are extremely sensitive to dangerous sound stimuli. The seizure proneness in this group shares common physiological characteristics and depends on animal genotype. This concept could be the new platform for the study of epileptogenesis mechanisms.
Super Insulation Materials—An Application to Historical Buildings
Authors: Vajó Brigitta , Lakatos Ákos
Published: November 2021

The main purpose of this paper is to present the use of super thermal insulation materials for a historical building through a calculation-based case study. The development of the insulation materials is based on the objective of making buildings as energy efficient as possible, and the energy loss should be kept to a minimum, for both new and existing buildings. For this purpose, the thermal insulation materials used so far have not always achieved maximum effectiveness. In the case of historical buildings, it is particularly difficult to solve insulation issues, as the building cannot lose its former appearance. However, aerogel and vacuum insulation panels can also be used as thin thermal protective layers. In this paper, we will specifically deal with the presentation of the possible application of super thermal insulation materials, such as vacuum insulation panels and aerogels. We will present thermal conductivity measurement results as well as their application through building energetic calculations applied to a historical building as a case study. We will also present certain calculations regarding the costs. The paper highlights that savings of energy costs of approximately 30% can be reached using vacuum insulation sandwich panels. Furthermore, the overall thermal transmittance of the building also decreases by about 35% if vacuum insulation sandwich panels are used for the refurbishment.
Metabolomic Analysis of Actinic Keratosis and SCC Suggests a Grade-Independent Model of Squamous Cancerization
Authors: Righi Valeria , Reggiani Camilla , Tarentini Elisabetta , Mucci Adele , Paganelli Alessia , Cesinaro Anna Maria , Mataca Ema , Kaleci Shaniko , Ferrari Barbara , Meleti Marco , Magnoni Cristina
Published: November 2021

Background—Actinic keratoses (AKs) are the most common sun-induced precancerous lesions that can progress to squamocellular carcinoma (SCC). Recently, the grade-independent association between AKs and SCC has been suggested; however, the molecular bases of this potential association have not been investigated. This study has assessed the metabolomic fingerprint of AK I, AK II, AK III and SCC using high resolution magic angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy in order to evaluate the hypothesis of grade-independent association between AK and SCC. Association between AKs and SCCs has also been evaluated by histopathology. Methods—Metabolomic data were obtained through HR-MAS NMR spectroscopy. The whole spectral profiles were analyzed through multivariate statistical analysis using MetaboAnalyst 5.0. Histologic examination was performed on sections stained with hematoxylin and eosin; statistical analysis was performed using STATA software version 14. Results—A group of 35 patients affected by AKs and/or SCCs and 10 healthy controls were enrolled for metabolomics analysis. Histopathological analysis was conducted on 170 specimens of SCCs and AKs (including the ones that underwent metabolomic analysis). SCCs and AK I were found to be significantly associated in terms of the content of some metabolites. Moreover, in the logistic regression model, the presence of parakeratosis in AKs appeared to be less frequently associated with SCCs, while AKs with hypertrophy had a two-fold higher risk of being associated with SCC. Conclusions—Our findings, derived from metabolomics and histopathological data, support the notion that AK I are different from healthy skin and share some different features with SCCs. This may further support the expanding notion that all AKs should be treated independently from their clinical appearance or histological grade because they may be associated with SCC.
ADAM17—A Potential Blood-Based Biomarker for Detection of Early-Stage Ovarian Cancer
Authors: Rogmans Christoph , Kuhlmann Jan Dominik , Hugendieck Gerrit , Link Theresa , Arnold Norbert , Weimer Jörg Paul , Flörkemeier Inken , Rambow Anna-Christina , Lieb Wolfgang , Maass Nicolai , Bauerschlag Dirk O. , Hedemann Nina
Published: November 2021

Ovarian cancer has the highest mortality rate among gynecological tumors. This is based on late diagnosis and the lack of early symptoms. To improve early detection, it is essential to find reliable biomarkers. The metalloprotease ADAM17 could be a potential marker, as it is highly expressed in many solid tumors, including ovarian and breast cancer. The aim of this work is to evaluate the relevance of ADAM17 as a potential diagnostic blood-based biomarker in ovarian cancer. Ovarian cancer cell lines IGROV-1 and A2780, as well as primary patient-derived tumor cells obtained from tumor tissue and ascitic fluid, were cultured to analyze ADAM17 abundance in the culture supernatant. In a translational approach, a cohort of 117 well-characterized ovarian cancer patients was assembled and ADAM17 levels in serum and corresponding ascitic fluid were determined at primary diagnosis. ADAM17 was quantified by enzyme-linked immunosorbent assay (ELISA). In the present study, ADAM17 was detected in the culture supernatant of ovarian cancer cell lines and primary cells. In addition, ADAM17 was found in serum and ascites of ovarian cancer patients. ADAM17 level was significantly increased in ovarian cancer patients compared to an age-matched control group (p < 0.0001). Importantly early FIGO I/II stages, which would not have been detected by CA-125, were associated with higher ADAM17 concentrations (p = 0.007). This is the first study proposing ADAM17 as a serum tumor marker in the setting of a gynecological tumor disease. Usage of ADAM17 in combination with CA-125 and other markers could help detect early stages of ovarian cancer.
A Prospective Study Assessing the Post-Prostatectomy Detection Rate of a Presumed Local Failure at mpMR with Either 64CuCl2 or 64CuPSMA PET/CT
Authors: Faiella Adriana , Sciuto Rosa , Giannarelli Diana , Bottero Marta , Farneti Alessia , Bertini Luca , Rea Sandra , Landoni Valeria , Vici Patrizia , Ferriero Maria Consiglia , Sanguineti Giuseppe
Published: November 2021

Background: We aimed assess the detection rate (DR) of positron emission tomography/computed tomography with two novel tracers in patients referred for salvage radiotherapy (sRT) with a presumed local recurrence at multiparametric magnetic resonance (mpMR) after radical prostatectomy (RP). Methods: The present prospective study was conducted at a single institution between August 2017 and June 2020. Eligibility criteria were undetectable PSA after RP; subsequent biochemical recurrence (two consecutive PSA rises to 0.2 ng/mL or greater); a presumed local failure at mpMR; no distant metastases at 18F-fluorocholine PET/CT (CH/PET); no previous history of androgen deprivation therapy. Patients were offered both 64CuCl2 PET/CT (CU/PET) and 64Cu-PSMA PET/CT (PSMA/PET) before sRT. After image co-registration, PET findings were compared to mpMR ones in terms of DR and independent predictors of DR investigated at logistic regression. Results: A total of 62 patients with 72 nodules at mpMR were accrued. Compared to mpMR (DR = 100%, 95%CI: 94.9–100%), DRs were 47.2% (95%CI: 36.1–58.6%) and 54.4% (95%CI: 42.7–65.7%) for CU/PET and PSMA/PET, respectively (p < 0.001 for both). Both experimental PET/CT performed particularly poorly at PSA levels consistent with early sRT. Conclusions: The two novel radiotracers are inferior to mpMR in restaging the prostatic fossa for sRT planning purposes, particularly in the context of early salvage radiotherapy.
A Pilot Study to Evaluate Early Predictive Value of Thorax Perfusion-CT in Advanced NSCLC
Authors: Aya Francisco , Benegas Mariana , Viñolas Nuria , Reyes Roxana , Vollmer Ivan , Arcocha Ainara , Sánchez Marcelo , Reguart Noemi
Published: November 2021

Background: The role of perfusion computed tomography (pCT) in detecting changes in tumor vascularization as part of a response to antiangiogenic therapy in non-small cell lung cancer (NSCLC) remains unclear. Methods: In this prospective pilot study (IMPACT trial, NCT02316327), we aimed to determine the ability of pCT to detect early changes in blood flow (BF), blood volume (BV), and permeability (PMB), and to explore whether these changes could predict the response at day +42 in patients with advanced, treatment-naive, non-squamous NSCLC treated with cisplatin and gemcitabine plus bevacizumab. Results: All of the perfusion parameters showed a consistent decrease during the course of treatment. The BV difference between baseline and early assessment was significant (p = 0.013), whereas all perfusion parameters showed significant differences between baseline and day +42 (p = 0.003, p = 0.049, and p = 0.002, respectively). Among the 16 patients evaluable for efficacy, a significant decline in BV at day +7 from baseline was observed in tumors with no response (p = 0.0418). Conclusions: Our results confirm that pCT can capture early changes in tumor vasculature. A substantial early decline of BV from baseline might identify tumors less likely responsive to antiangiogenic-drugs.
Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models
Authors: Brai Annalaura , Riva Valentina , Clementi Letizia , Falsitta Lucia , Zamperini Claudio , Sinigiani Virginia , Festuccia Claudio , Sabetta Samantha , Aiello Davide , Roselli Camilla , Garbelli Anna , Trivisani Claudia Immacolata , Maccari Laura , Bugli Francesca , Sanguinetti Maurizio , Calandro Pierpaolo , Chiariello Mario , Quaranta Paola , Botta Lorenzo , Angelucci Adriano , Maga Giovanni , Botta Maurizio
Published: November 2021

DDX3X is an ATP-dependent RNA helicase that has recently attracted interest for its involvement in viral replication and oncogenic progression. Starting from hit compounds previously identified by our group, we have designed and synthesized a new series of DDX3X inhibitors that effectively blocked its helicase activity. These new compounds were able to inhibit the proliferation of cell lines from different cancer types, also in DDX3X low-expressing cancer cell lines. According to the absorption, distribution, metabolism, elimination properties, and antitumoral activity, compound BA103 was chosen to be further investigated in glioblastoma models. BA103 determined a significant reduction in the proliferation and migration of U87 and U251 cells, downregulating the oncogenic protein β-catenin. An in vivo evaluation demonstrated that BA103 was able to reach the brain and reduce the tumor growth in xenograft and orthotopic models without evident side effects. This study represents the first demonstration that DDX3X-targeted small molecules are feasible and promising drugs also in glioblastoma.
Radioimmunotherapy in Oncology: Overview of the Last Decade Clinical Trials
Authors: Rondon Aurélie , Rouanet Jacques , Degoul Françoise
Published: November 2021

The specific irradiation of tumors with selective radiolabeled antibodies constitutes an attractive therapeutic approach. Consequent preclinical research has been conducted by both biologists to identify pertinent targets and to select corresponding antibodies (mAb) and by radiochemists to radiolabel mAbs. These numerous preclinical investigations have ascertained the therapeutic interest of radioimmunotherapy (RIT) protocols in mice models. Here, we summarize the clinical studies that have been performed the last decade, including clinical trials (phases I, II, and III), prospective and retrospective studies, and cases series. We thereby reported 92 clinical studies. Among them, 62 concern the treatment of hematological malignancies, and 30 concern solid tumors. For hematologic diseases, the analysis was complex due to the high discrepancy of therapeutic strategies (first-line therapy, consolidation, stem cell transplantation conditioning) as well as the high variety of malignancies that were treated. The clinical studies from the last decade failed to expand anti-CD20 RIT indications but confirmed that RIT using radiolabeled anti-CD20 remains a pertinent choice for patients with relapse follicular lymphomas. For solid tumors, the positive benefit of RIT is more mitigated, apart for few malignancies that can be treated locally. Clinical trials also demonstrated the potential of some antibody formats, such as F(ab′)2, which has already been approved by the China State FDA under the trend name Licartin®. Despite disparate results, mAb fragments are an interesting prospect for the improvement of RIT efficiency as well as for pretargeted strategies that delay the injection of radioactive treatments from the mAb ones.
Type I Interferon Promotes Antitumor T Cell Response in CRPC by Regulating MDSC
Authors: Fan Lilv , Xu Guiliang , Cao Jingjing , Li Min , Zhang Huihui , Li Fanlin , Qi Xinyue , Zhang Xiaoqing , Li Zeyu , Han Ping , Yang Xuanming
Published: November 2021

Background: Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among prostate cancer patients. Here, our aim was to ascertain the immune regulatory mechanisms involved in CRPC development and identify potential immunotherapies against CRPC. Methods: A CRPC model was established using Myc-CaP cells in immune-competent FVB mice following castration. The immune cell profile of the tumor microenvironment (TME) was analyzed during CRPC development. Different immunotherapies were screened in the CRPC tumor model, and their efficacies and underlying mechanisms were investigated in vitro and in vivo. Results: During CRPC development, the proportion of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the TME increased. Among the immunotherapies tested, IFNα was more effective than anti-PD-L1, anti-CTLA-4, anti-4-1BB, IL-2, and IL-9 in reducing Myc-CaP CRPC tumor growth. IFNα reduced the number of G-MDSCs both in vitro during differentiation and in vivo in CRPC mice. Furthermore, IFNα reduced the suppressive function of G-MDSCs on T cell proliferation and activation. Conclusion: G-MDSCs are crucial to effective immunotherapy against CRPC. Treatment with IFNα presents a promising therapeutic strategy against CRPC. Besides the direct inhibition of tumor growth and the promotion of T cell priming, IFNα reduces the number and the suppressive function of G-MDSCs and restores T cell activation.
Autophagy in Cancer Therapy—Molecular Mechanisms and Current Clinical Advances
Authors: Ganzleben Ingo , Neurath Markus F. , Becker Christoph
Published: November 2021

Autophagy is a crucial general survival tactic of mammalian cells. It describes the capability of cells to disassemble and partially recycle cellular components (e.g., mitochondria) in case they are damaged and pose a risk to cell survival or simply if their resources are urgently needed elsewhere at the time. Autophagy-associated pathomechanisms have been increasingly recognized as important disease mechanisms in non-malignant (neurodegeneration, diffuse parenchymal lung disease) and malignant conditions alike. However, the overall consequences of autophagy for the organism depend particularly on the greater context in which autophagy occurs, such as the cell type or whether the cell is proliferating. In cancer, autophagy sustains cancer cell survival under challenging, i.e., resource-depleted, conditions. However, this leads to situations in which cancer cells are completely dependent on autophagy. Accordingly, autophagy represents a promising yet complex target in cancer treatment with therapeutically induced increase and decrease of autophagic flux as important therapeutic principles.
In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling
Authors: Romualdo Guilherme Ribeiro , Leroy Kaat , Costa Cícero Júlio Silva , Prata Gabriel Bacil , Vanderborght Bart , da Silva Tereza Cristina , Barbisan Luís Fernando , Andraus Wellington , Devisscher Lindsey , Câmara Niels Olsen Saraiva , Vinken Mathieu , Cogliati Bruno
Published: November 2021

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death globally. HCC is a complex multistep disease and usually emerges in the setting of chronic liver diseases. The molecular pathogenesis of HCC varies according to the etiology, mainly caused by chronic hepatitis B and C virus infections, chronic alcohol consumption, aflatoxin-contaminated food, and non-alcoholic fatty liver disease associated with metabolic syndrome or diabetes mellitus. The establishment of HCC models has become essential for both basic and translational research to improve our understanding of the pathophysiology and unravel new molecular drivers of this disease. The ideal model should recapitulate key events observed during hepatocarcinogenesis and HCC progression in view of establishing effective diagnostic and therapeutic strategies to be translated into clinical practice. Despite considerable efforts currently devoted to liver cancer research, only a few anti-HCC drugs are available, and patient prognosis and survival are still poor. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC with a specific focus on their key molecular hallmarks.
The Growing Relevance of Immunoregulation in Pediatric Brain Tumors
Authors: Melcher Viktoria , Kerl Kornelius
Published: November 2021

Pediatric brain tumors are genetically heterogeneous solid neoplasms. With a prevailing poor prognosis and widespread resistance to conventional multimodal therapy, these aggressive tumors are the leading cause of childhood cancer-related deaths worldwide. Advancement in molecular research revealed their unique genetic and epigenetic characteristics and paved the way for more defined prognostication and targeted therapeutic approaches. Furthermore, uncovering the intratumoral metrics on a single-cell level placed non-malignant cell populations such as innate immune cells into the context of tumor manifestation and progression. Targeting immune cells in pediatric brain tumors entails unique challenges but promising opportunities to improve outcome. Herein, we outline the current understanding of the role of the immune regulation in pediatric brain tumors.
Synthesis and Characterization of Sn/Ni Single Doped and Co–Doped Anatase/Rutile Mixed–Crystal Nanomaterials and Their Photocatalytic Performance under UV–Visible Light
Authors: Qin Qin , Wang Juan , Xia Yangwen , Yang Daixiong , Zhou Qin , Zhu Xiaodong , Feng Wei
Published: November 2021

Pure and Sn/Ni co–doped TiO2 nanomaterials with anatase/rutile mixed crystal were prepared and characterized. The results show that pure TiO2 is a mixed crystal structure composed of a large amount of anatase and a small amount of rutile. Sn doping promotes the phase transformation from anatase to rutile, while Ni doping inhibits the transformation. Both single doping and co–doping are beneficial to the inhibition of photoinduced charge recombination. Sn doping shows the best inhibitory effect on photogenerated charge recombination, and increases the utilization of visible light, displaying the highest photocatalytic activity. The decolorization degree of methylene blue (MB) by Sn–TiO2 is 79.5% after 150 min. The reaction rate constant of Sn–TiO2 is 0.01022 min−1, which is 5.6 times higher than pure TiO2 (0.00181 min–1).
Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats
Authors: Liu Szu-Yu , Huang Chia-Chang , Huang Shiang-Fen , Liao Tsai-Ling , Kuo Nai-Rong , Yang Ying-Ying , Li Tzu-Hao , Liu Chih-Wei , Hou Ming-Chih , Lin Han-Chieh
Published: November 2021

Endotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation-related splanchnic and pulmonary dysfunction in cirrhosis. This study explored the mechanism and effects of pioglitazone treatment on the abovementioned renal dysfunction in cirrhotic rats. Cirrhotic ascitic rats were induced with renal dysfunction by bile duct ligation (BDL). Then, 2 weeks of pioglitazone treatment (Pio, PPAR gamma agonist, 12 mg/kg/day, using the azert osmotic pump) was administered from the 6th week after BDL. Additionally, acute lipopolysaccharide (LPS, Escherichia coli 0111:B4; Sigma, 0.1 mg/kg b.w, i.p. dissolved in NaCl 0.9%) was used to induce acute renal dysfunction. Subsequently, various circulating, renal arterial and renal tissue pathogenic markers were measured. Cirrhotic BDL rats are characterized by decreased mean arterial pressure, increased cardiac output and portal venous pressure, reduced renal arterial blood flow (RABF), increased renal vascular resistance (RVR), increased relative renal weight/hydroxyproline, downregulated renal PPARγ expression, upregulated renal inflammatory markers (TNFα, NFκB, IL-6, MCP-1), increased adhesion molecules (VCAM-1 and ICAM-1), increased renal macrophages (M1, CD68), and progressive renal dysfunction (increasing serum and urinary levels of renal injury markers (lipocalin-2 and IL-18)). In particular, acute LPS administration induces acute on chronic renal dysfunction (increasing serum BUN/creatinine, increasing RVR and decreasing RABF) by increased TNFα-NFκB-mediated renal inflammatory markers as well as renal M1 macrophage infiltration. In comparison with the BDL+LPS group, chronic pioglitazone pre-treatment prevented LPS-induced renal pathogenic changes in the BDL-Pio+LPS group. Activation of systemic, renal vessel and renal tissue levels of PPARγ by chronic pioglitazone treatment has beneficial effects on the endotoxemia-related TNFα/NFκB-mediated acute and chronic renal inflammation in cirrhosis. This study revealed that normalization of renal and renal arterial levels of PPARγ effectively prevented LPS-induced acute and chronic renal dysfunction in cirrhotic ascitic rats.
Proteolytic and Structural Changes in Rye and Triticale Roots under Aluminum Stress
Authors: Szewińska Joanna , Różańska Elżbieta , Papierowska Ewa , Labudda Mateusz
Published: November 2021

Proteolysis and structural adjustments are significant for defense against heavy metals. The purpose of this study was to evaluate whether the Al3+ stress alters protease activity and the anatomy of cereale roots. Azocaseinolytic and gelatinolytic measurements, transcript-level analysis of phytocystatins, and observations under microscopes were performed on the roots of Al3+-tolerant rye and tolerant and sensitive triticales exposed to Al3+. In rye and triticales, the azocaseinolytic activity was higher in treated roots. The gelatinolytic activity in the roots of rye was enhanced between 12 and 24 h in treated roots, and decreased at 48 h. The gelatinolytic activity in treated roots of tolerant triticale was the highest at 24 h and the lowest at 12 h, whereas in treated roots of sensitive triticale it was lowest at 12 h but was enhanced at 24 and 48 h. These changes were accompanied by increased transcript levels of phytocystatins in rye and triticale-treated roots. Light microscope analysis of rye roots revealed disintegration of rhizodermis in treated roots at 48 h and indicated the involvement of root border cells in rye defense against Al3+. The ultrastructural analysis showed vacuoles containing electron-dense precipitates. We postulate that proteolytic-antiproteolytic balance and structural acclimation reinforce the fine-tuning to Al3+.
Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2
Authors: Rinaldi Roberta , Miglionico Rocchina , Nigro Ilaria , D’Orsi Rosarita , Chiummiento Lucia , Funicello Maria , Lupattelli Paolo , Laurenzana Ilaria , Sgambato Alessandro , Monné Magnus , Bisaccia Faustino , Armentano Maria Francesca
Published: November 2021

Background: Several pre-clinical and clinical reports suggest that HIV-1 protease inhibitors, in addition to the antiretroviral properties, possess pleiotropic pharmacological effects including anticancer action. Therefore, we investigated the pro-apoptotic activity in tumor cells of two molecules, RDD-19 and RDD-142, which are hydroxyethylamine derivatives’ precursors of darunavir and several HIV-1 protease inhibitors. Methods: Three hepatoma cell lines and one non-pathological cell line were treated with RDD-19 and RDD-142, and cell viability was assessed. The expression levels of several markers for ER stress, autophagy, cellular ubiquitination, and Akt activation were quantified in HepG2 cells treated with RDD-19 and RDD-142 to evaluate apoptotic and non-apoptotic cell death. Results: RDD-19 and RDD-142 showed a greater dose-dependent cytotoxicity towards the hepatic tumor cell line HepG2 compared to the non-pathological hepatic cell line IHH. Both molecules caused two types of cell death, a caspase-dependent apoptosis, which was ascertained by a series of biochemical and morphological assays, and a caspase-independent death that was characterized by the induction of ER stress and autophagy. The strong increase of ubiquitinated proteins inside the cells suggested that the target of these molecules could be the proteasome and in silico molecular docking analysis that was used to support the plausibility of this hypothesis. Furthermore, cells treated with the two compounds displayed decreased levels of p-AKT, which interferes with cell survival and proliferation. Conclusions: These findings demonstrate that two compounds, RDD-19 and RDD-142, have pleiotropic effects and that they may represent promising anticancer candidates.
YAP Promotes Cell Proliferation and Stemness Maintenance of Porcine Muscle Stem Cells under High-Density Condition
Authors: Liu Zheng , Lin Ling , Zhu Haozhe , Wu Zhongyuan , Ding Xi , Hu Rongrong , Jiang Yichen , Tang Changbo , Ding Shijie , Guo Renpeng
Published: November 2021

Muscle stem cells (MuSCs) isolated ex vivo are essential original cells to produce cultured meat. Currently, one of the main obstacles for cultured meat production derives from the limited capacity of large-scale amplification of MuSCs, especially under high-density culture condition. Here, we show that at higher cell densities, proliferation and differentiation capacities of porcine MuSCs are impaired. We investigate the roles of Hippo-YAP signaling, which is important regulators in response to cell contact inhibition. Interestingly, abundant but not functional YAP proteins are accumulated in MuSCs seeded at high density. When treated with lysophosphatidic acid (LPA), the activator of YAP, porcine MuSCs exhibit increased proliferation and elevated differentiation potential compared with control cells. Moreover, constitutively active YAP with deactivated phosphorylation sites, but not intact YAP, promotes cell proliferation and stemness maintenance of MuSCs. Together, we reveal a potential molecular target that enables massive MuSCs expansion for large-scale cultured meat production under high-density condition.
Monocyte Maturation Mediators Upregulate CD83, ICAM-1 and MHC Class 1 Expression on Ewing’s Sarcoma, Enhancing T Cell Cytotoxicity
Authors: Biele Emilie , Schober Sebastian J. , Prexler Carolin , Thiede Melanie , Heyking Kristina von , Gassmann Hendrik , Eck Jennifer , Xue Busheng , Burdach Stefan , Thiel Uwe
Published: November 2021

Ewing’s sarcoma (EwS) is a pediatric solid tumor entity with low somatic mutational burden and a low rate of tumor-infiltrating T cells, indicating a low extent of immunogenicity. In EwS, immunogenicity may furthermore be significantly diminished by a predominantly M2 macrophage driven pro-tumorigenic tumor microenvironment. In the past, we demonstrated that CHM1319-specific TCR-transgenic T cells are able to control EwS growth in a preclinical mouse model as well as in a patient with metastatic disease. However, new adjuvant techniques to induce long lasting and curative CHM1319-specific TCR-transgenic T cell-mediated anti-tumor responses are needed. In this work, we sought to identify a technique to improve the cytotoxic effect of CHM1319-specific TCR-transgenic T cell by altering the immunogenic cell surface marker expression on EwS cell lines using different cytokines. We demonstrate that TNF, IL-6, IL-1β and PGE2 cause pro-immunogenic CD83, MHC class I and II as well as ICAM-1 upregulation in EwS cell lines. This observation was associated with significantly improved recognition and killing of the tumor cells by EwS-specific CHM1319/HLA-A*02:01-restricted TCR-transgenic T cells. Conclusively, we demonstrate that the induction of an inflammatory signature renders EwS more susceptible to adoptive T cell therapy. TNF, which is upregulated during inflammatory processes, is of particular translational interest as its secretion may be induced in the patients e.g., by irradiation and hyperthermia in the clinical setting. In future clinical protocols, this finding may be important to identify appropriate conditioning regimens as well as point of time for adoptive T cell-based immunotherapy in EwS patients.
Association of Diabetes Mellitus and Alcohol Abuse with Cancer: Molecular Mechanisms and Clinical Significance
Authors: Lam Bao Q. , Srivastava Rashmi , Morvant Jason , Shankar Sharmila , Srivastava Rakesh K.
Published: November 2021

Diabetes mellitus (DM), one of the metabolic diseases which is characterized by sustained hyperglycemia, is a life-threatening disease. The global prevalence of DM is on the rise, mainly in low- and middle-income countries. Diabetes is a major cause of blindness, heart attacks, kidney failure, stroke, and lower limb amputation. Type 2 diabetes mellitus (T2DM) is a form of diabetes that is characterized by high blood sugar and insulin resistance. T2DM can be prevented or delayed by a healthy diet, regular physical activity, maintaining normal body weight, and avoiding alcohol and tobacco use. Ethanol and its metabolites can cause differentiation defects in stem cells and promote inflammatory injury and carcinogenesis in several tissues. Recent studies have suggested that diabetes can be treated, and its consequences can be avoided or delayed with proper management. DM has a greater risk for several cancers, such as breast, colorectal, endometrial, pancreatic, gallbladder, renal, and liver cancer. The incidence of cancer is significantly higher in patients with DM than in those without DM. In addition to DM, alcohol abuse is also a risk factor for many cancers. We present a review of the recent studies investigating the association of both DM and alcohol abuse with cancer incidence.