bluuebunny/crossref_metadata_2025 huggingface dataset:
An Insight of RuBisCO Evolution through a Multilevel Approach
Authors: Camel Vladimir , Zolla Gaston
Published: November 2021

RuBisCO is the most abundant enzyme on earth; it regulates the organic carbon cycle in the biosphere. Studying its structural evolution will help to develop new strategies of genetic improvement in order to increase food production and mitigate CO2 emissions. In the present work, we evaluate how the evolution of sequence and structure among isoforms I, II and III of RuBisCO defines their intrinsic flexibility and residue-residue interactions. To do this, we used a multilevel approach based on phylogenetic inferences, multiple sequence alignment, normal mode analysis, and molecular dynamics. Our results show that the three isoforms exhibit greater fluctuation in the loop between αB and βC, and also present a positive correlation with loop 6, an important region for enzymatic activity because it regulates RuBisCO conformational states. Likewise, an increase in the flexibility of the loop structure between αB and βC, as well as Lys330 (form II) and Lys322 (form III) of loop 6, is important to increase photosynthetic efficiency. Thus, the cross-correlation dynamics analysis showed changes in the direction of movement of the secondary structures in the three isoforms. Finally, key amino acid residues related to the flexibility of the RuBisCO structure were indicated, providing important information for its enzymatic engineering.
Ability of a Combined FIB4/miRNA181a Score to Predict Significant Liver Fibrosis in NAFLD Patients
Authors: Lima Rodrigo Vieira Costa , Stefano José Tadeu , Malta Fernanda de Mello , Pinho João Renato Rebello , Carrilho Flair José , Arrese Marco , Oliveira Claudia P.
Published: November 2021

Liver biopsy is the gold standard for assessing fibrosis, but there is a need to seek non-invasive biomarkers for this purpose. The aim of this study was to evaluate the correlation between the serum levels of the microRNAs miR-21, miR-29a, miR-122, miR-155 and miR-181a and the phenotypic expression of NAFLD. A cross-sectional study was carried out on 108 NAFLD patients diagnosed by liver biopsy. FIB-4 and NAFLD fibrosis scores were calculated. The comparison between the distributions of microRNA values according to the presence or absence of histological fibrosis (F2–F4) was performed. A multivariate logistic regression analysis was performed to build a score for predicting fibrosis using FIB-4 and Ln (miR-181a) as independent variables. Only miR-181a showed a statistical difference between patients with significant liver fibrosis (>F2) and those without (F0–F1) (p = 0.017). FIB-4 revealed an AUC on the ROC curve of 0.667 to predict clinically significant fibrosis (F2–F4). When assessed using the score in association with Ln (miR-181a), there was an improvement in the ROC curve, with an AUC of 0.71. miR-181a can be used as a non-invasive method of predicting fibrosis in NAFLD, and an association with FIB-4 has the potential to increase the accuracy of each method alone.
Analysis of the Influence of Jaw Periosteal Cells on Macrophages Phenotype Using an Innovative Horizontal Coculture System
Authors: He Fang , Umrath Felix , von Ohle Christiane , Reinert Siegmar , Alexander Dorothea
Published: November 2021

Jaw periosteum-derived mesenchymal stem cells (JPCs) represent a promising cell source for bone tissue engineering in oral and maxillofacial surgery due to their high osteogenic potential and good accessibility. Our previous work demonstrated that JPCs are able to regulate THP-1-derived macrophage polarization in a direct coculture model. In the present study, we used an innovative horizontal coculture system in order to understand the underlying paracrine effects of JPCs on macrophage phenotype polarization. Therefore, JPCs and THP-1-derived M1/M2 macrophages were cocultured in parallel chambers under the same conditions. After five days of horizontal coculture, flow cytometric, gene and protein expression analyses revealed inhibitory effects on costimulatory and proinflammatory molecules/factors as well as activating effects on anti-inflammatory factors in M1 macrophages, originating from multiple cytokines/chemokines released by untreated and osteogenically induced JPCs. A flow cytometric assessment of DNA synthesis reflected significantly decreased numbers of proliferating M1/M2 cells when cocultured with JPCs. In this study, we demonstrated that untreated and osteogenically induced JPCs are able to switch macrophage polarization from a classical M1 to an alternative M2-specific phenotype by paracrine secretion, and by inhibition of THP-1-derived M1/M2 macrophage proliferation.
Preclinical Assessment of Mesenchymal-Stem-Cell-Based Therapies in Spinocerebellar Ataxia Type 3
Authors: Correia Joana Sofia , Neves-Carvalho Andreia , Mendes-Pinheiro Bárbara , Pires Joel , Teixeira Fábio Gabriel , Lima Rui , Monteiro Susana , Silva Nuno André , Soares-Cunha Carina , Serra Sofia Cravino , Duarte-Silva Sara , Teixeira-Castro Andreia , Salgado António José , Maciel Patrícia
Published: November 2021

The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies for neurodegenerative diseases, including spinocerebellar ataxias. Spinocerebellar ataxia type 3 (SCA3)—or Machado–Joseph disease (MJD)—is the most common dominant ataxia, being mainly characterized by motor deficits; however, SCA3/MJD has a complex and heterogeneous pathophysiology, involving many CNS brain regions, contributing to the lack of effective therapies. Mesenchymal stem cells (MSCs) have been proposed as a potential therapeutic tool for CNS disorders. Beyond their differentiation potential, MSCs secrete a broad range of neuroregulatory factors that can promote relevant neuroprotective and immunomodulatory actions in different pathophysiological contexts. The objective of this work was to study the effects of (1) human MSC transplantation and (2) human MSC secretome (CM) administration on disease progression in vivo, using the CMVMJD135 mouse model of SCA3/MJD. Our results showed that a single CM administration was more beneficial than MSC transplantation—particularly in the cerebellum and basal ganglia—while no motor improvement was observed when these cell-based therapeutic approaches were applied in the spinal cord. However, the effects observed were mild and transient, suggesting that continuous or repeated administration would be needed, which should be further tested.
Endothelial Dysfunction in Pregnancy Complications
Authors: Kornacki Jakub , Gutaj Paweł , Kalantarova Anastasia , Sibiak Rafał , Jankowski Maurycy , Wender-Ozegowska Ewa
Published: November 2021

The endothelium, which constitutes the inner layer of blood vessels and lymphatic structures, plays an important role in various physiological functions. Alterations in structure, integrity and function of the endothelial layer during pregnancy have been associated with numerous gestational complications, including clinically significant disorders, such as preeclampsia, fetal growth restriction, and diabetes. While numerous experimental studies have focused on establishing the role of endothelial dysfunction in pathophysiology of these gestational complications, their mechanisms remain unknown. Numerous biomarkers of endothelial dysfunction have been proposed, together with the mechanisms by which they relate to individual gestational complications. However, more studies are required to determine clinically relevant markers specific to a gestational complication of interest, as currently most of them present a significant overlap. Although the independent diagnostic value of such markers remains to be insufficient for implementation in standard clinical practice at the moment, inclusion of certain markers in predictive multifactorial models can improve their prognostic value. The future of the research in this field lies in the fine tuning of the clinical markers to be used, as well as identifying possible therapeutic techniques to prevent or reverse endothelial damage.
Results of TETimaX Trial of Langerhans Cell Histiocytosis Treatment and Perspectives on the Role of Imatinib Mesylate in the Era of MAPK Signaling
Authors: Montella Liliana , Ottaviano Margaret , Riccio Vittorio , Picozzi Fernanda , Facchini Gaetano , Insabato Luigi , Giuliano Mario , Palmieri Giovannella
Published: November 2021

Langerhans cell histiocytosis (LCH) is a rare disease that has a variable clinical presentation and unpredictable behavior. Until recently, therapeutic options were limited. Insights into the role of mitogen-activated protein kinase (MAPK) signaling have allowed the increased use of targeted treatments. Before the advent of drugs that interfere with this pathway, investigations concerning the tyrosine kinase inhibitor imatinib opened the way to a rationale-based therapeutic approach to the disease. Imatinib block the binding site of ATP in the BCR/ABL protein and is also a platelet-derived growth factor receptor (PDGFR) and a KIT (CD117) kinase inhibitor. A case of refractory LCH with brain involvement was reported to be successfully treated with imatinib. Thereafter, we further explored the role of this tyrosine kinase inhibitor. The present study is composed of an immunohistochemical evaluation of PDGFRβ expression and a clinical evaluation of imatinib in a series of LCH patients. In the first part, a series of 10 samples obtained from LCH patients was examined and a strong immunohistochemistry expression of PDGFRβ was found in 40% of the cases. In the clinical part of the study, five patients were enrolled. Long-lasting disease control was obtained. These results may suggest a potential role for this drug in the current age.
Kidney Cancer and Chronic Kidney Disease: Too Close for Comfort
Authors: Pinto Pedro Caetano , Rönnau Cindy , Burchardt Martin , Wolff Ingmar
Published: November 2021

Kidney cancer and chronic kidney disease are two renal pathologies with very different clinical management strategies and therapeutical options. Nonetheless, the cellular and molecular mechanisms underlying both conditions are closely related. Renal physiology is adapted to operate with a limited oxygen supply, making the kidney remarkably equipped to respond to hypoxia. This tightly regulated response mechanism is at the heart of kidney cancer, leading to the onset of malignant cellular phenotypes. Although elusive, the role of hypoxia in chronic kidney diseases is emerging as related to fibrosis, a pivotal factor in decaying renal function. The present review offers a perspective on the common biological traits shared between kidney cancer and chronic kidney disease and the available and prospective therapies for both conditions.
Two-Photon Polymerization of Albumin Hydrogel Nanowires Strengthened with Graphene Oxide
Authors: Nekrasov Nikita , Yakunina Natalya , Nevolin Vladimir , Bobrinetskiy Ivan , Vasilevsky Pavel , Gerasimenko Alexander Yu.
Published: November 2021

Multifunctional biomaterials can pave a way to novel types of micro- and nanoelectromechanical systems providing benefits in mimicking of biological functions in implantable, wearable structures. The production of biocomposites that hold both superior electrical and mechanical properties is still a challenging task. In this study, we aim to fabricate 3D printed hydrogel from a biocomposite of bovine serum albumin with graphene oxide (BSA@GO) using femtosecond laser processing. We have developed the method for functional BSA@GO composite nanostructuring based on both two-photon polymerization of nanofilaments and direct laser writing. The atomic-force microscopy was used to probe local electrical and mechanical properties of hydrogel BSA@GO nanowires. The improved local mechanical properties demonstrate synergistic effect in interaction of femtosecond laser pulses and novel composite structure.
Semantic Variant Primary Progressive Aphasia: Practical Recommendations for Treatment from 20 Years of Behavioural Research
Authors: Suárez-González Aida , Savage Sharon A. , Bier Nathalie , Henry Maya L. , Jokel Regina , Nickels Lyndsey , Taylor-Rubin Cathleen
Published: November 2021

People with semantic variant primary progressive aphasia (svPPA) present with a characteristic progressive breakdown of semantic knowledge. There are currently no pharmacological interventions to cure or slow svPPA, but promising behavioural approaches are increasingly reported. This article offers an overview of the last two decades of research into interventions to support language in people with svPPA including recommendations for clinical practice and future research based on the best available evidence. We offer a lay summary in English, Spanish and French for education and dissemination purposes. This paper discusses the implications of right- versus left-predominant atrophy in svPPA, which naming therapies offer the best outcomes and how to capitalise on preserved long-term memory systems. Current knowledge regarding the maintenance and generalisation of language therapy gains is described in detail along with the development of compensatory approaches and educational and support group programmes. It is concluded that there is evidence to support an integrative framework of treatment and care as best practice for svPPA. Such an approach should combine rehabilitation interventions addressing the language impairment, compensatory approaches to support activities of daily living and provision of education and support within the context of dementia.
Neural Correlates of Music Listening: Does the Music Matter?
Authors: Reybrouck Mark , Vuust Peter , Brattico Elvira
Published: November 2021

The last decades have seen a proliferation of music and brain studies, with a major focus on plastic changes as the outcome of continuous and prolonged engagement with music. Thanks to the advent of neuroaesthetics, research on music cognition has broadened its scope by considering the multifarious phenomenon of listening in all its forms, including incidental listening up to the skillful attentive listening of experts, and all its possible effects. These latter range from objective and sensorial effects directly linked to the acoustic features of the music to the subjectively affective and even transformational effects for the listener. Of special importance is the finding that neural activity in the reward circuit of the brain is a key component of a conscious listening experience. We propose that the connection between music and the reward system makes music listening a gate towards not only hedonia but also eudaimonia, namely a life well lived, full of meaning that aims at realizing one’s own “daimon” or true nature. It is argued, further, that music listening, even when conceptualized in this aesthetic and eudaimonic framework, remains a learnable skill that changes the way brain structures respond to sounds and how they interact with each other.
Online Prediction of Lead Seizures from iEEG Data
Authors: Chen Hsiang-Han , Shiao Han-Tai , Cherkassky Vladimir
Published: November 2021

We describe a novel system for online prediction of lead seizures from long-term intracranial electroencephalogram (iEEG) recordings for canines with naturally occurring epilepsy. This study adopts new specification of lead seizures, reflecting strong clustering of seizures in observed data. This clustering results in fewer lead seizures (~7 lead seizures per dog), and hence new challenges for online seizure prediction, that are addressed in the proposed system. In particular, the machine learning part of the system is implemented using the group learning method suitable for modeling sparse and noisy seizure data. In addition, several modifications for the proposed system are introduced to cope with the non-stationarity of a noisy iEEG signal. They include: (1) periodic retraining of the SVM classifier using most recent training data; (2) removing samples with noisy labels from training data; and (3) introducing a new adaptive post-processing technique for combining many predictions made for 20 s windows into a single prediction for a 4 h segment. Application of the proposed system requires only two lead seizures for training the initial model, and results in high prediction performance for all four dogs (with mean 0.84 sensitivity, 0.27 time-in-warning, and 0.78 false-positive rate per day). The proposed system achieves accurate prediction of lead seizures during long-term test periods, 3–16 lead seizures during a 169–364 day test period, whereas earlier studies did not differentiate between lead vs. non-lead seizures and used much shorter test periods (~few days long).
EYE-C: Eye-Contact Robust Detection and Analysis during Unconstrained Child-Therapist Interactions in the Clinical Setting of Autism Spectrum Disorders
Authors: Alvari Gianpaolo , Coviello Luca , Furlanello Cesare
Published: November 2021

The high level of heterogeneity in Autism Spectrum Disorder (ASD) and the lack of systematic measurements complicate predicting outcomes of early intervention and the identification of better-tailored treatment programs. Computational phenotyping may assist therapists in monitoring child behavior through quantitative measures and personalizing the intervention based on individual characteristics; still, real-world behavioral analysis is an ongoing challenge. For this purpose, we designed EYE-C, a system based on OpenPose and Gaze360 for fine-grained analysis of eye-contact episodes in unconstrained therapist-child interactions via a single video camera. The model was validated on video data varying in resolution and setting, achieving promising performance. We further tested EYE-C on a clinical sample of 62 preschoolers with ASD for spectrum stratification based on eye-contact features and age. By unsupervised clustering, three distinct sub-groups were identified, differentiated by eye-contact dynamics and a specific clinical phenotype. Overall, this study highlights the potential of Artificial Intelligence in categorizing atypical behavior and providing translational solutions that might assist clinical practice.
FARCI: Fast and Robust Connectome Inference
Authors: Meamardoost Saber , Bhattacharya Mahasweta , Hwang Eun Jung , Komiyama Takaki , Mewes Claudia , Wang Linbing , Zhang Ying , Gunawan Rudiyanto
Published: November 2021

The inference of neuronal connectome from large-scale neuronal activity recordings, such as two-photon Calcium imaging, represents an active area of research in computational neuroscience. In this work, we developed FARCI (Fast and Robust Connectome Inference), a MATLAB package for neuronal connectome inference from high-dimensional two-photon Calcium fluorescence data. We employed partial correlations as a measure of the functional association strength between pairs of neurons to reconstruct a neuronal connectome. We demonstrated using in silico datasets from the Neural Connectomics Challenge (NCC) and those generated using the state-of-the-art simulator of Neural Anatomy and Optimal Microscopy (NAOMi) that FARCI provides an accurate connectome and its performance is robust to network sizes, missing neurons, and noise levels. Moreover, FARCI is computationally efficient and highly scalable to large networks. In comparison with the best performing connectome inference algorithm in the NCC, Generalized Transfer Entropy (GTE), and Fluorescence Single Neuron and Network Analysis Package (FluoroSNNAP), FARCI produces more accurate networks over different network sizes, while providing significantly better computational speed and scaling.
Prevalence of Advanced Parkinson’s Disease in Patients Treated in the Hospitals of the Spanish National Healthcare System: The PARADISE Study
Authors: Martínez-Castrillo Juan Carlos , Martínez-Martín Pablo , Burgos Ángel , Arroyo Gloria , García Natalia , Luquín María Rosario , Arbelo José Matías
Published: November 2021

Background: Advanced Parkinson’s disease (APD) has been recently defined as a stage in which certain symptoms and complications are present, with a detrimental influence on the overall patient’s health conditions and with a poor response to conventional treatments. However, historically, the term APD has been controversial, thus consequently, APD prevalence has not been previously studied. Objectives: The main objective was to determine the prevalence of APD in patients diagnosed with idiopathic PD in hospitals of the Spanish National Healthcare System. Secondary objectives were the prevalence and incidence of PD and the clinical and sociodemographic characteristics and quality of life of patients with APD or non-APD. Methods: This was a non-interventional, cross-sectional, multicenter, national study in the hospital setting. Results: The study population included 929 patients with PD (mean age 71.8 ± 10.1 years; 53.8% male) and a mean time since diagnosis of 6.6 ± 5.4 years. At the time of diagnosis, 613 patients (66.06%) reported having had premotor symptoms. The Hoehn and Yahr stage was 1 in 15.7% of the patients, 2 in 42.8%, 3 in 30.1%, 4 in 9.9%, and 5 in 1.4%; 46.9% of the patients had comorbidities (mean age-adjusted Charlson comorbidity index 3.5 ± 1.7; median 10-year survival 77%) and the mean 8-item Parkinson’s Disease Quality of Life Questionnaire was 27.8 ± 20.5. We found an APD prevalence of 38.21% (95%CI: 35.08–41.42%), a PD prevalence of 118.4 (95%CI: 117.3–119.6), and a PD incidence of 9.4 (95%CI: 5.42–13.4) all per 100,000 population. Among the APD population, a 15.2% were receiving some form of therapy for advanced stages of the disease (deep brain stimulation, levodopa/carbidopa intestinal gel, or apomorphine subcutaneous infusion). Conclusions: The percentage of patients with APD in the hospitals of the Spanish National Healthcare System was 38.2%.
Use of Underground Constructions Enhanced with Evaporative Cooling to Improve Indoor Built Environment in Hot Climate
Authors: Alwetaishi Mamdooh
Published: November 2021

Underground constructions (UGCs) have been used globally to accommodate a wide range of building usage, such as offices and shopping malls. Most of these constructions suffer from a lack of natural ventilation as well as daylight, as they are completely built under the surface of the earth. This has caused many issues related to discomfort, impacting the activity and the productivity of users. This study aimed to analyse the effect of the use of UGCs in hot regions, enhanced by partly elevated external walls which reach aboveground to ensure natural ventilation and daylight, with relatively small amounts of glazing to minimise the influence of solar heat gain. The study used a real built underground room with field measurements for indoor temperature and relative humidity. Moreover, the study used the computer tool EDSL TAS to simulate the performance of the model throughout the year after a field validation. It was concluded that the use of UGCs in hot climates should be encouraged as natural ventilation and daylight can decrease temperatures by 3 °C in summer, and the utilisation of evaporative cooling can cool the indoor environment by nearly 12 °C. Furthermore, heat transfer was highly affected by the external environment. It was found that the amount of heat transfer doubled in comparison between under and aboveground constructions. The use of small windows for ventilation caused high humidity, even in hot regions, during summer.
Effect of Seasonal Ambient Temperature on Sleep and Thermal Comfort in Older People Living in Public Elderly Facilities
Authors: Tsuzuki Kazuyo , Sakoi Tomonori , Sakata Yoko
Published: November 2021

This study aimed to investigate the thermal environment and thermal comfort of elderly occupants living in elder care facilities and to compare the quality of sleep, in all four seasons, of these elderly occupants. A total of 16 healthy participants with a mean age of 80 ± 5 years (range, 70–87 years) were recruited in two elderly facilities, of which, 13 participated in all four measurements. The sleep parameter was measured by a wrist actigraph which the participants were requested to wear and analyzed with commercial software using the Cole–Kripke algorithm, to assign scores for sleeping and waking patterns. Both ambient temperature (Ta) and relative humidity (Rh) levels were found to be lower in the winter and higher in the summer. The Ta in the summer and Rh in the winter were not within the scope of the Japanese Standard for Maintenance of Sanitation in Buildings, as the central HVAC and air conditioners were turned off due to the absence of facility managers. More than 50% of the elderly occupants used fans and increased airflow by opening windows during the summer nights as an adaptive thermal approach. The slope of the relationship between prevailing mean outdoor temperature and indoor Ta determined in this study was similar to the adaptive model and the regression line lies over the upper limits of the adaptive model. No significant difference was found in the sleep parameter among the four seasons; however, a sex difference was found in the sleep latency and length of waking period during the sleep. The sleep parameters such as sleep efficiency indexes were significantly better for elderly women than men. The adaptive approach is not enough to improve the sleep efficiency of sleeping elderly people even within the acceptable temperature range based on the thermal comfort, especially for elderly men.
Dynamic Quality Monitoring System to Assess the Quality of Asphalt Concrete Pavement
Authors: Ma Ziyuan , Zhang Jingxiao , Philbin Simon P. , Li Hui , Yang Jie , Feng Yunlong , Ballesteros-Pérez Pablo , Skitmore Martin
Published: November 2021

With the rapid development of new technologies, such as big data, the Internet of Things (IoT) and intelligent sensing, the traditional asphalt pavement construction quality evaluation method has been unable to meet the needs of road digital construction. At the same time, the development of such technologies enables a new management system for asphalt pavement construction. In this study, firstly, the dynamic quality monitoring system of asphalt concrete pavement is established by adopting the BeiDou Navigation Satellite System, intelligent sensing, the IoT and 5G technology. This allows key technical indicators to be collected and transmitted for the whole process of asphalt mixture, which includes the mixing plant, transport vehicle, paving and compaction. Secondly, combined with AHP and the entropy weight (EW) method, the index combination weight is calculated. The comprehensive index for the pavement digital construction quality index (PCQ) is proposed to reflect the impact of monitoring indicators on pavement quality. An expert decision-making model is formed by using the improved particle swarm optimization (PSO) algorithm coupled with radial basis function neural network (RBF). Finally, the digital monitoring index and pavement performance index are connected to establish a full-time and multi-dimensional digital construction quality evaluation model. This study is verified by a database created from the digital monitoring data of pavement construction collected from a highway construction project. The system proposed in this study can accurately reflect the quality of pavement digital construction and solve the lag problem existing in the feedback of construction site.
Active Thermal Method Applied to the In Situ Characterization of Insulating Materials in a Wall
Authors: Biteau Elorn , Defer Didier , Brachelet Franck , Zalewski Laurent
Published: November 2021

An in situ estimation of the thermal properties of bio-sourced building wall insulation components is of critical importance in improving both the energy efficiency of buildings and the development of construction materials with a smaller environmental footprint. Depending on weather conditions, passive methods are not always feasible; they require time to conduct lengthy testing and may lead to significant uncertainties. This article presents an active method based on power dissipation via flat electrical resistance. The method can be implemented regardless of outdoor weather conditions and is suitable for walls with high overall thermal resistance for which the small average component of the through flow is difficult to estimate. Measurements are conducted of both wall input flows and temperatures. An inverse method, derived from a finite difference model of 1D transfers along with a multi-objective approach, enables the characteristics of a two-material assembly to be identified. A multi-objective method was chosen to solve the problems of high correlation between the thermal parameters of the model. However, the method requires the use of two temperature sensors integrated inside the wall. Following a laboratory validation phase on a PVC/plasterboard assembly, the method is implemented on an actual wall. A coating/hemp concrete assembly is also characterized as part of this work program. The thermal conductivity of the hemp concrete block was estimated at 0.12 W m−1 K−1 and is consistent with values found in the literature.
Bayesian Networks to Support Decision-Making for Immune-Checkpoint Blockade in Recurrent/Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC)
Authors: Huehn Marius , Gaebel Jan , Oeser Alexander , Dietz Andreas , Neumuth Thomas , Wichmann Gunnar , Stoehr Matthaeus
Published: November 2021

New diagnostic methods and novel therapeutic agents spawn additional and heterogeneous information, leading to an increasingly complex decision-making process for optimal treatment of cancer. A great amount of information is collected in organ-specific multidisciplinary tumor boards (MDTBs). By considering the patient’s tumor properties, molecular pathological test results, and comorbidities, the MDTB has to consent an evidence-based treatment decision. Immunotherapies are increasingly important in today’s cancer treatment, resulting in detailed information that influences the decision-making process. Clinical decision support systems can facilitate a better understanding via processing of multiple datasets of oncological cases and molecular genetic information, potentially fostering transparency and comprehensibility of available information, eventually leading to an optimum treatment decision for the individual patient. We constructed a digital patient model based on Bayesian networks to combine the relevant patient-specific and molecular data with depended probabilities derived from pertinent studies and clinical guidelines to calculate treatment decisions in head and neck squamous cell carcinoma (HNSCC). In a validation analysis, the model can provide guidance within the growing subject of immunotherapy in HNSCC and, based on its ability to calculate reliable probabilities, facilitates estimation of suitable therapy options. We compared actual treatment decisions of 25 patients with the calculated recommendations of our model and found significant concordance (Cohen’s κ = 0.505, p = 0.009) and 84% accuracy.
Novel Liver Stiffness-Based Nomogram for Predicting Hepatocellular Carcinoma Risk in Patients with Chronic Hepatitis B Virus Infection Initiating Antiviral Therapy
Authors: Lee Jae Seung , Lee Hyun Woong , Lim Tae Seop , Shin Hye Jung , Lee Hye Won , Kim Seung Up , Park Jun Yong , Kim Do Young , Ahn Sang Hoon , Kim Beom Kyung
Published: November 2021

Hepatocellular carcinoma (HCC) risk prediction is important to developing individualized surveillance approaches. We designed a novel HCC prediction model using liver stiffness on transient elastography for patients receiving antiviral therapy against hepatitis B virus (HBV) infection. We recruited 2037 patients receiving entecavir or tenofovir as first-line antivirals and used the Cox regression analysis to determine key variables for model construction. Within 58.1 months (median), HCC developed in 182 (8.9%) patients. Patients with HCC showed a higher prevalence of cirrhosis (90.7% vs. 45.9%) and higher liver stiffness values (median 13.9 vs. 7.2 kPa) than those without. A novel nomogram (score 0–304) was established using age, platelet count, cirrhosis development, and liver stiffness values, which were independently associated with increased HCC risk, along with hepatitis B e antigen positivity and serum albumin and total bilirubin levels. Cumulative HCC probabilities were 0.7%, 5.0%, and 22.7% in the low- (score ≤87), intermediate- (88–222), and high-risk (≥223) groups, respectively. The c-index value was 0.799 (internal validity: 0.805), higher than that of the PAGE-B (0.726), modified PAGE-B (0.756), and modified REACH-B (0.761) models (all p < 0.05). Our nomogram showed acceptable performance in predicting HCC in Asian HBV-infected patients receiving potent antiviral therapy.
Stem Cell Markers CXCR-4 and CD133 Predict Aggressive Phenotype and Their Double Positivity Indicates Poor Prognosis of Oral Squamous Cell Carcinoma
Authors: Caspa Gokulan Ravindran , Devaraj Halagowder
Published: November 2021

The activation of the SDF-1/CXCR-4 pathway is crucial for the invasion and metastasis of oral cancer cells. The CXCR-4 positive cells possess stem cell characteristics and express the cancer stem cell marker, CD133, in tumors of colon and pancreas. Despite several studies, the co-expression of CXCR-4 and CD133 and its significance is still largely unknown in oral cancer. Therefore, we aimed to investigate the impact of CXCR-4 and CD133 double positivity in the prognosis of oral cancer. The significance of PKC-δ, one of the key signaling molecules that regulates CXCR-4, was also analyzed. Immunohistochemistry and double immunofluorescence was used to investigate the co-localization of CXCR-4, PKC-δ and CD133 in the human tissues and cell lines of oral squamous cell carcinoma. The expression of CXCR-4, PKC-δ and CD133 were found to be higher in poorly differentiated and lymph node metastasis-positive cases. Interestingly, CXCR-4 positive cells showed positive staining for PKC-δ and CD133 in oral cancer tissue and cell lines. Moreover, CXCR-4+/CD133+ and CXCR-4+/PKC-δ+ double positive cases have the worst survival. We discovered, for the first time, that patients with expression of both CXCR-4 and CD133 have a lower survival rate, and CXCR-4+/CD133+, as well as CXCR-4+/PKC-δ+ double positivity, can be utilized to predict poor prognosis. CXCR-4, PKC-δ and CD133 might regulate aggressiveness and invasion of oral cancer cells.
Antiangiogenic Therapy in Clear Cell Renal Carcinoma (CCRC): Pharmacological Basis and Clinical Results
Authors: Comandone Alessandro , Vana Federica , Comandone Tiziana , Tucci Marcello
Published: November 2021

Angiogenesis has a direct stimulatory effect on tumor growth, duplication, invasion and metastatic development. A significant portion of conventional renal cell carcinomas are angiogenesis-dependent tumors and the pathways supporting this process have been thoroughly investigated over the last 20 years. As a consequence, many tyrosine kinase inhibitors (TKIs) (sunitinib, sorafenib, pazopanib, axitinib, and cabozantinib), one monoclonal antibody (bevacizumab), and two mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus) have been investigated and approved for the treatment of advanced or metastatic clear cell renal carcinoma (metastatic CCRC) in first-line, as well as second-line, therapy, with impressive results in progression-free survival and in the objective response rate compared with previously available therapies or placebo. Recently, a new type of drug has been approved for metastatic CCRC: immunomodulatory checkpoint inhibitors (ICIs), alone or in combination with TKIs. However, many questions and areas to be explored still remain with regard to clear cell renal carcinoma (CCRC) treatment: research on predictive biomarkers, the best patient selection, how to overcome the mechanisms of resistance, and the best sequence of therapies in daily clinical practice. This review focuses on the pharmacological properties and anticancer activities of these drugs. The toxicity profile and clinical limitations of these therapies are also discussed.
Chromosome Imbalances in Neuroblastoma—Recent Molecular Insight into Chromosome 1p-deletion, 2p-gain, and 11q-deletion Identifies New Friends and Foes for the Future
Authors: Guan Jikui , Hallberg Bengt , Palmer Ruth H.
Published: November 2021

Neuroblastoma is the most common extracranial solid pediatric tumor, with around 15% childhood cancer-related mortality. High-risk neuroblastomas exhibit a range of genetic, morphological, and clinical heterogeneities, which add complexity to diagnosis and treatment with existing modalities. Identification of novel therapies is a high priority in high-risk neuroblastoma, and the combination of genetic analysis with increased mechanistic understanding—including identification of key signaling and developmental events—provides optimism for the future. This focused review highlights several recent findings concerning chromosomes 1p, 2p, and 11q, which link genetic aberrations with aberrant molecular signaling output. These novel molecular insights contribute important knowledge towards more effective treatment strategies for neuroblastoma.
Receptor-Tyrosine Kinase Inhibitor Ponatinib Inhibits Meningioma Growth In Vitro and In Vivo
Authors: Yu Tao , Cao Junguo , Alaa Eddine Montadar , Moustafa Mahmoud , Mock Andreas , Erkut Cihan , Abdollahi Amir , Warta Rolf , Unterberg Andreas , Herold-Mende Christel , Jungwirth Gerhard
Published: November 2021

To date, there is no standard-of-care systemic therapy for the treatment of aggressive meningiomas. Receptor tyrosine kinases (RTK) are frequently expressed in aggressive meningiomas and are associated with poor survival. Ponatinib is a FDA- and EMA-approved RTK inhibitor and its efficacy in meningioma has not been studied so far. Therefore, we investigated ponatinib as a potential drug candidate against meningioma. Cell viability and cell proliferation of ponatinib-treated meningioma cells were assessed using crystal violet assay, manual counting and BrdU assay. Treated meningioma cell lines were subjected to flow cytometry to evaluate the effects on cell cycle and apoptosis. Meningioma-bearing mice were treated with ponatinib to examine antitumor effects in vivo. qPCR was performed to assess the mRNA levels of tyrosine kinase receptors after ponatinib treatment. Full-length cDNA sequencing was carried out to assess differential gene expression. IC50 values of ponatinib were between 171.2 and 341.9 nM in three meningioma cell lines. Ponatinib induced G0/G1 cell cycle arrest and subsequently led to an accumulation of cells in the subG1-phase. A significant induction of apoptosis was observed in vitro. In vivo, ponatinib inhibited meningioma growth by 72.6%. Mechanistically, this was associated with downregulation of PDGFRA/B and FLT3 mRNA levels, and mitochondrial dysfunction. Taken together, ponatinib is a promising candidate for targeted therapy in the treatment of aggressive meningioma.
CYCLON and NPM1 Cooperate within an Oncogenic Network Predictive of R-CHOP Response in DLBCL
Authors: Bouroumeau Antonin , Bussot Lucile , Hamaidia Sieme , Garcìa-Sandoval Andrea , Bergan-Dahl Anna , Betton-Fraisse Patricia , Duley Samuel , Fournier Cyril , Aucagne Romain , Adrait Annie , Couté Yohann , McLeer Anne , Col Edwige , David-Boudet Laurence , Raskovalova Tatiana , Jacob Marie-Christine , Vettier Claire , Chevalier Simon , Carras Sylvain , Lefebvre Christine , Algrin Caroline , Gressin Rémy , Callanan Mary B. , Sartelet Hervé , Bonnefoix Thierry , Emadali Anouk
Published: November 2021

R-CHOP immuno-chemotherapy significantly improved clinical management of diffuse large B-cell lymphoma (DLBCL). However, 30–40% of DLBCL patients still present a refractory disease or relapse. Most of the prognostic markers identified to date fail to accurately stratify high-risk DLBCL patients. We have previously shown that the nuclear protein CYCLON is associated with DLBCL disease progression and resistance to anti-CD20 immunotherapy in preclinical models. We also recently reported that it also represents a potent predictor of refractory disease and relapse in a retrospective DLBCL cohort. However, only sparse data are available to predict the potential biological role of CYCLON and how it might exert its adverse effects on lymphoma cells. Here, we characterized the protein interaction network of CYCLON, connecting this protein to the nucleolus, RNA processing, MYC signaling and cell cycle progression. Among this network, NPM1, a nucleolar multi-functional protein frequently deregulated in cancer, emerged as another potential target related to treatment resistance in DLBCL. Immunohistochemistry evaluation of CYCLON and NPM1 revealed that their co-expression is strongly related to inferior prognosis in DLBCL. More specifically, alternative sub-cellular localizations of the proteins (extra-nucleolar CYCLON and pan-cellular NPM1) represent independent predictive factors specifically associated to R-CHOP refractory DLBCL patients, which could allow them to be orientated towards risk-adapted or novel targeted therapies.
Proteomic Analysis Identifies FNDC1, A1BG, and Antigen Processing Proteins Associated with Tumor Heterogeneity and Malignancy in a Canine Model of Breast Cancer
Authors: Cordeiro Yonara G. , Mulder Leandra M. , van Zeijl René J. M. , Paskoski Lindsay B. , van Veelen Peter , de Ru Arnoud , Strefezzi Ricardo F. , Heijs Bram , Fukumasu Heidge
Published: November 2021

New insights into the underlying biological processes of breast cancer are needed for the development of improved markers and treatments. The complex nature of mammary cancer in dogs makes it a great model to study cancer biology since they present a high degree of tumor heterogeneity. In search of disease-state biomarkers candidates, we applied proteomic mass spectrometry imaging in order to simultaneously detect histopathological and molecular alterations whilst preserving morphological integrity, comparing peptide expression between intratumor populations in distinct levels of differentiation. Peptides assigned to FNDC1, A1BG, and double-matching keratins 18 and 19 presented a higher intensity in poorly differentiated regions. In contrast, we observed a lower intensity of peptides matching calnexin, PDIA3, and HSPA5 in poorly differentiated cells, which enriched for protein folding in the endoplasmic reticulum and antigen processing, assembly, and loading of class I MHC. Over-representation of collagen metabolism, coagulation cascade, extracellular matrix components, cadherin-binding and cell adhesion pathways also distinguished cell populations. Finally, an independent validation showed FNDC1, A1BG, PDIA3, HSPA5, and calnexin as significant prognostic markers for human breast cancer patients. Thus, through a spatially correlated characterization of spontaneous carcinomas, we described key proteins which can be further validated as potential prognostic biomarkers.
Is There an Interplay between Oral Microbiome, Head and Neck Carcinoma and Radiation-Induced Oral Mucositis?
Authors: Gugnacki Patryk , Sierko Ewa
Published: November 2021

Head and neck carcinoma is one of the most common human malignancy types and it ranks as the sixth most common cancer worldwide. Nowadays, a great potential of microbiome research is observed in oncology—investigating the effect of oral microbiome in oncogenesis, occurrence of treatment side effects and response to anticancer therapies. The microbiome is a unique collection of microorganisms and their genetic material, interactions and products residing within the mucous membranes. The aim of this paper is to summarize current research on the oral microbiome and its impact on the development of head and neck cancer and radiation-induced oral mucositis. Human microbiome might determine an oncogenic effect by, among other things, inducing chronic inflammatory response, instigating cellular antiapoptotic signals, modulation of anticancer immunity or influencing xenobiotic metabolism. Influence of oral microbiome on radiation-induced oral mucositis is expressed by the production of additional inflammatory cytokines and facilitates progression and aggravation of mucositis. Exacerbated acute radiation reaction and bacterial superinfections lead to the deterioration of the patient’s condition and worsening of the quality of life. Simultaneously, positive effects of probiotics on the course of radiation-induced oral mucositis have been observed. Understanding the impact on the emerging acute radiation reaction on the composition of the microflora can be helpful in developing a multifactorial model to forecast the course of radiation-induced oral mucositis. Investigating these processes will allow us to create optimized and personalized preventive measures and treatment aimed at their formation mechanism. Further studies are needed to better establish the structure of the oral microbiome as well as the dynamics of its changes before and after therapy. It will help to expand the understanding of the biological function of commensal and pathogenic oral microbiota in HNC carcinogenesis and the development of radiation-induced oral mucositis.
Combining ReACp53 with Carboplatin to Target High-Grade Serous Ovarian Cancers
Authors: Neal Adam , Lai Tiffany , Singh Tanya , Rahseparian Neela , Grogan Tristan , Elashoff David , Scott Peter , Pellegrini Matteo , Memarzadeh Sanaz
Published: November 2021

Ovarian malignancies are a leading cause of cancer-related death for US women. High-grade serous ovarian carcinomas (HGSOCs), the most common ovarian cancer subtype, are aggressive tumors with poor outcomes. Mutations in TP53 are common in HGSOCs, with a subset resulting in p53 aggregation and misregulation. ReACp53 is a peptide designed to inhibit mutant p53 aggregation and has been shown efficacious in targeting cancer cells in vitro and in vivo. As p53 regulates apoptosis, combining ReACp53 with carboplatin represents a logical therapeutic strategy. The efficacy of this combinatorial approach was tested in eight ovarian cancer cell lines and 10 patient HGSOC samples using an in vitro organoid drug assay, with the SynergyFinder tool utilized for calculating drug interactions. Results demonstrate that the addition of ReACp53 to carboplatin enhanced tumor cell targeting in the majority of samples tested, with synergistic effects measured in 2 samples, additivity measured in 14 samples, and antagonism measured in 1 sample. This combination was found to be synergistic in OVCAR3 ovarian cancer cells in vitro through enhanced apoptosis, and survival of mice bearing OVCAR3 intraperitoneal xenografts was extended when treated with the addition of ReACp53 to carboplatin versus carboplatin alone. Results suggest that carboplatin and ReACp53 may be a potential strategy in targeting a subset of HGSOCs.
Colorectal Cancer Stem Cells: An Overview of Evolving Methods and Concepts
Authors: De Angelis Maria , Francescangeli Federica , Zeuner Ann , Baiocchi Marta
Published: November 2021

Colorectal cancer (CRC) represents one of the most deadly cancers worldwide. Colorectal cancer stem cells (cCSCs) are the driving units of CRC initiation and development. After the concept of cCSC was first formulated in 2007, a huge bulk of research has contributed to expanding its definition, from a cell subpopulation defined by a fixed phenotype in a plastic entity modulated by complex interactions with the tumor microenvironment, in which cell position and niche-driven signals hold a prominent role. The wide development of cellular and molecular technologies recent years has been a main driver of advancements in cCSCs research. Here, we will give an overview of the parallel role of technological progress and of theoretical evolution in shaping the concept of cCSCs.