bluuebunny/crossref_metadata_2025 huggingface dataset:
Peering into the Kaleidoscope of Cyclodextrins
Authors: Braga Susana Santos
Published: January 2021

Cyclodextrins (CDs) are known to us for 130 years, yet they remain ever as new and as fascinating as in their early years, when Villiers marveled at the unexpected growth of “beautiful radiated crystals” in the alcoholic media of his experiments on bacterial fermentation of starches, or when Freudenberg struggled to solve the puzzle of their unusual shape and structure [...]
Modeling the Influenza A NP-vRNA-Polymerase Complex in Atomic Detail
Authors: Miner Jacob C. , Lappala Anna , Fenimore Paul W. , Fischer William M. , McMahon Benjamin H. , Hengartner Nicolas W. , Sanbonmatsu Karissa Y. , Tung Chang-Shung
Published: January 2021

Seasonal flu is an acute respiratory disease that exacts a massive toll on human populations, healthcare systems and economies. The disease is caused by an enveloped Influenza virus containing eight ribonucleoprotein (RNP) complexes. Each RNP incorporates multiple copies of nucleoprotein (NP), a fragment of the viral genome (vRNA), and a viral RNA-dependent RNA polymerase (POL), and is responsible for packaging the viral genome and performing critical functions including replication and transcription. A complete model of an Influenza RNP in atomic detail can elucidate the structural basis for viral genome functions, and identify potential targets for viral therapeutics. In this work we construct a model of a complete Influenza A RNP complex in atomic detail using multiple sources of structural and sequence information and a series of homology-modeling techniques, including a motif-matching fragment assembly method. Our final model provides a rationale for experimentally-observed changes to viral polymerase activity in numerous mutational assays. Further, our model reveals specific interactions between the three primary structural components of the RNP, including potential targets for blocking POL-binding to the NP-vRNA complex. The methods developed in this work open the possibility of elucidating other functionally-relevant atomic-scale interactions in additional RNP structures and other biomolecular complexes.
Glycyl-L-Prolyl-L-Glutamate Pseudotripeptides for Treatment of Alzheimer’s Disease
Authors: Turkez Hasan , Cacciatore Ivana , Marinelli Lisa , Fornasari Erika , Aslan Mehmet Enes , Cadirci Kenan , Kahraman Cigdem Yuce , Caglar Ozge , Tatar Abdulgani , Di Biase Giuseppe , Hacimuftuoglu Ahmet , Di Stefano Antonio , Mardinoglu Adil
Published: January 2021

So far, there is no effective disease-modifying therapies for Alzheimer’s Disease (AD) in clinical practice. In this context, glycine-L-proline-L-glutamate (GPE) and its analogs may open the way for developing a novel molecule for treating neurodegenerative disorders, including AD. In turn, this study was aimed to investigate the neuroprotective potentials exerted by three novel GPE peptidomimetics (GPE1, GPE2, and GPE3) using an in vitro AD model. Anti-Alzheimer potentials were determined using a wide array of techniques, such as measurements of mitochondrial viability (MTT) and lactate dehydrogenase (LDH) release assays, determination of acetylcholinesterase (AChE), α-secretase and β-secretase activities, comparisons of total antioxidant capacity (TAC) and total oxidative status (TOS) levels, flow cytometric and microscopic detection of apoptotic and necrotic neuronal death, and investigating gene expression responses via PCR arrays involving 64 critical genes related to 10 different pathways. Our analysis showed that GPE peptidomimetics modulate oxidative stress, ACh depletion, α-secretase inactivation, apoptotic, and necrotic cell death. In vitro results suggested that treatments with novel GPE analogs might be promising therapeutic agents for treatment and/or or prevention of AD.
Circulating Long and Circular Noncoding RNA as Non-Invasive Diagnostic Tools of Hepatocellular Carcinoma
Authors: Sukowati Caecilia H. C. , Cabral Loraine Kay D. , Tiribelli Claudio , Pascut Devis
Published: January 2021

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide, partially due to late diagnosis of the disease. Growing evidence in the field of biomarker discovery has shown the promising use of nucleic acid in the early detection of many cancers, including HCC. Here, we review data on how various long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) could be used as a diagnostic tool for HCC being differentially expressed in HCC compared to non-HCC patients. These non-coding RNAs (ncRNAs) showed high stability in the blood being present as free-circulating molecules or encapsulated into exosomes. This review reports some recent evidence on the use of lncRNAs and circRNAs as possible diagnostic biomarkers for HCC. Further, their pathophysiological mechanism in liver carcinogenesis was also described, elucidating the complex regulatory networks making these ncRNAs of particular relevance for the study of liver malignancy cancer.
Pharmacoinformatics and Preclinical Studies of NSC765690 and NSC765599, Potential STAT3/CDK2/4/6 Inhibitors with Antitumor Activities against NCI60 Human Tumor Cell Lines
Authors: Lawal Bashir , Liu Yen-Lin , Mokgautsi Ntlotlang , Khedkar Harshita , Sumitra Maryam , Wu Alexander , Huang Hsu-Shan
Published: January 2021

Signal transducer and activator of transcription 3 (STAT3) is a transcriptional regulator of a number of biological processes including cell differentiation, proliferation, survival, and angiogenesis, while cyclin-dependent kinases (CDKs) are a critical regulator of cell cycle progression. These proteins appear to play central roles in angiogenesis and cell survival and are widely implicated in tumor progression. In this study, we used the well-characterized US National Cancer Institute 60 (NCI60) human tumor cell lines to screen the in vitro anti-cancer activities of our novel small molecule derivatives (NSC765690 and NSC765599) of salicylanilide. Furthermore, we used the DTP-COMPARE algorithm and in silico drug target prediction to identify the potential molecular targets, and finally, we used molecular docking to assess the interaction between the compounds and prominent potential targets. We found that NSC765690 and NSC765599 exhibited an anti-proliferative effect against the 60 panels of NCI human cancer cell lines, and dose-dependent cytotoxic preference for NSCLC, melanoma, renal, and breast cancer cell lines. Protein–ligand interactions studies revealed that NSC765690 and NSC765599 were favored ligands for STAT3/CDK2/4/6. Moreover, cyclization of the salicylanilide core scaffold of NSC765690 mediated its higher anti-cancer activities and had greater potential to interact with STAT3/CDK2/4/6 than did NSC765599 with an open-ring structure. NSC765690 and NSC765599 met the required safety and criteria of a good drug candidate, and are thus worthy of further in-vitro and in-vivo investigations in tumor-bearing mice to assess their full therapeutic efficacy.
Clinical Significance of Preoperative Inflammatory Markers in Prediction of Prognosis in Node-Negative Colon Cancer: Correlation between Neutrophil-to-Lymphocyte Ratio and Poorly Differentiated Clusters
Authors: Turri Giulia , Barresi Valeria , Valdegamberi Alessandro , Gecchele Gabriele , Conti Cristian , Ammendola Serena , Guglielmi Alfredo , Scarpa Aldo , Pedrazzani Corrado
Published: January 2021

Although stage I and II colon cancers (CC) generally show a very good prognosis, a small proportion of these patients dies from recurrent disease. The identification of high-risk patients, who may benefit from adjuvant chemotherapy, becomes therefore essential. We retrospectively evaluated 107 cases of stage I (n = 28, 26.2%) and II (n = 79, 73.8%) CC for correlations among preoperative inflammatory markers, histopathological factors and long-term prognosis. A neutrophil-to-lymphocyte ratio greater than 3 (H-NLR) and a platelet-to-lymphocyte ratio greater than 150 (H-PLR) were significantly associated with the presence of poorly differentiated clusters (PDC) (p = 0.007 and p = 0.039, respectively). In addition, H-NLR and PDC proved to be significant and independent survival prognosticators for overall survival (OS; p = 0.007 and p < 0.001, respectively), while PDC was the only significant prognostic factor for cancer-specific survival (CSS; p < 0.001,). Finally, the combination of H-NLR and PDC allowed an optimal stratification of OS and CSS in our cohort, suggesting a potential role in clinical practice for the identification of high-risk patients with stage I and II CC.
Potential Effects of Poloxamer 188 on Rat Isolated Brain Mitochondria after Oxidative Stress In Vivo and In Vitro
Authors: Pille Johannes A. , Riess Matthias L.
Published: January 2021

Outcome after cerebral ischemia is often dismal. Reperfusion adds significantly to the ischemic injury itself. Therefore, new strategies targeting ischemia/reperfusion (I/R) injury are critically needed. Poloxamer (P)188, an amphiphilic triblock copolymer, is a highly promising pharmacological therapeutic as its capability to insert into injured cell membranes has been reported to protect against I/R injury in various models. Although mitochondrial function particularly profits from P188 treatment after I/R, it remains unclear if this beneficial effect occurs directly or indirectly. Here, rat isolated brain mitochondria underwent oxidative stress in vivo by asphyxial cardiac arrest or in vitro by the addition of hydrogen peroxide (H2O2) after isolation. Mitochondrial function was assessed by adenosine triphosphate synthesis, oxygen consumption, and calcium retention capacity. Both asphyxia and H2O2 exposure significantly impaired mitochondrial function. P188 did not preserve mitochondrial function after either injury mechanism. Further research is indicated.
Physiological and Medico-Social Research Trends of the Wave P300 and More Late Components of Visual Event-Related Potentials
Authors: Lytaev Sergey , Vatamaniuk Irina
Published: January 2021

To extend the application of the late waves of the event-related potentials (ERPs) to multiple modalities, devices and software the underlying physiological mechanisms and responses of the brain for a particular sensory system and mental function must be carefully examined. The objective of this study was aimed to study the sensory processes of the “human-computer interaction” model when classifying visual images with an incomplete set of signs based on the analysis of early, middle, late and slow ERPs components. 26 healthy subjects (men) aged 20–26 years were investigated. ERPs in 19 monopolar sites according to the 10/20 system were recorded. Discriminant and factor analyzes (BMDP Statistical Software) were applied. The component N450 is the most specialized indicator of the perception of unrecognizable (oddball) visual images. The amplitude of the ultra-late components N750 and N900 is also higher under conditions of presentation of the oddball image, regardless of the location of the registration points. In brain pathology along with the pronounced asymmetry of the wave distribution, reduction of the N150 wave and lengthening of its peak latency, a line of regularities were noted. These include–a pronounced reduction in peak latency P250 and N350, an increased amplitude of N350 in the frontal and central points of registration, a decrease in the amplitude of N450 in the left frontal cortex and its increase in the occipital registration points, activation of the occipital cortex at a time interval of 400–500 ms, as well as fusion later waves. We called such phenomena of the development of cognitive ERP in brain pathology “the incongruence of ERP components”. The results of the research are discussed in the light of the paradigm of the P300 wave application in brain-computer interface systems, as well as with the peculiarities in brain pathology.
Genetic and Pharmacological Manipulations of Glyoxalase 1 Mediate Ethanol Withdrawal Seizure Susceptibility in Mice
Authors: Barkley-Levenson Amanda M. , Lee Amy , Palmer Abraham A.
Published: January 2021

Central nervous system (CNS) hyperexcitability is a clinically significant feature of acute ethanol withdrawal. There is evidence for a genetic contribution to withdrawal severity, but specific genetic risk factors have not been identified. The gene glyoxalase 1 (Glo1) has been previously implicated in ethanol consumption in mice, and GLO1 inhibition can attenuate drinking in mice and rats. Here, we investigated whether genetic and pharmacological manipulations of GLO1 activity can also mediate ethanol withdrawal seizure severity in mice. Mice from two transgenic lines overexpressing Glo1 on different genetic backgrounds (C57BL/6J (B6) and FVB/NJ (FVB)) were tested for handling-induced convulsions (HICs) as a measure of acute ethanol withdrawal. Following an injection of 4 g/kg alcohol, both B6 and FVB mice overexpressing Glo1 showed increases in HICs compared to wild-type littermates, though only the FVB line showed a statistically significant difference. We also administered daily ethanol injections (2 g/kg + 9 mg/kg 4-methylpyrazole) to wild-type B6 mice for 10 days and tested them for HICs on the 10th day following treatment with either a vehicle or a GLO1 inhibitor (S-bromobenzylglutathione cyclopentyl diester (pBBG)). Treatment with pBBG reduced HICs, although this effect was only statistically significant following two 10-day cycles of ethanol exposure and withdrawal. These results provide converging genetic and pharmacological evidence that GLO1 can mediate ethanol withdrawal seizure susceptibility.
Indoor Daylighting and Thermal Response of a Passive Solar Building to Selective Components of Solar Radiation
Authors: Overen Ochuko , Meyer Edson , Makaka Golden
Published: January 2021

Solar radiation provides the most significant natural energy in buildings for space heating and daylighting. Due to atmospheric interference, solar radiation received at the Earth’s surface consists of direct beam and diffuse radiation, where diffuse can be further broken down into longwave and visible radiation. Although each of these components co-occurs, their influence on the indoor visual and thermal conditions of a building differ. This study aims to analyze the influence of the various components of solar radiation on the indoor thermal and daylighting of a passive solar building. Thus, a pyrheliometer, pyranometer, shaded-pyranometer, and pyrgeometer mounted on a SOLYS 2 (Kipp & Zonen, Delft, Netherlands) dual Axis sun tracker, were used to monitor direct, global horizontal, diffuse and downward longwave radiation, respectively. The seasonal indoor air temperature and relative humidity were measured using an HMP 60 temperature relative humidity probe. A Li-210R photometric sensor was used to monitor the indoor illuminance. The summer and winter indoor air temperature, as well as relative humidity, were found to be influenced by diffuse horizontal and global horizontal irradiance, respectively. In summer, the indoor air temperature response to diffuse horizontal irradiance was 0.7 °C/ħW/m2 and 1.1 °C/ħW/m2 to global horizontal irradiance in winter, where ħ is 99.9 W/m2. The indoor daylighting which was found to be above the minimum office visual task recommendation in most countries, but within the useful daylight illuminance range was dominated by direct normal irradiance. A response of 260 lux/ħW/m2 was observed. The findings of the study support the strategic locating of the windows in passive solar design. However, the results show that north-facing clerestory windows without shading device could lead to visual discomfort.
CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives
Authors: Roberto Michela , Astone Antonio , Botticelli Andrea , Carbognin Luisa , Cassano Alessandra , D’Auria Giuliana , Fabbri Agnese , Fabi Alessandra , Gamucci Teresa , Krasniqi Eriseld , Minelli Mauro , Orlandi Armando , Pantano Francesco , Paris Ida , Pizzuti Laura , Portarena Ilaria , Salesi Nello , Scagnoli Simone , Scavina Paola , Tonini Giuseppe , Vici Patrizia , Marchetti Paolo
Published: January 2021

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET within their lifetime, ultimately leading to disease recurrence and limited clinical benefit. The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to ET have remarkably improved the outcome of patients with HR+ advanced breast cancer (ABC) compared with anti-estrogens alone, by targeting the cell-cycle machinery and overcoming some aspects of endocrine resistance. However, which patients are the better candidates for these drugs, which are the main characteristics for a better selection of patients or if there are predictive biomarkers of response, is still unknown. In this review we reported the mechanism of action of CDK4/6 inhibitors as well as their potential mechanism of resistance, their implications in clinical practice and the forthcoming strategies to enhance their efficacy in improving survival and quality of life of patients affected with HR+, HER2−, ABC.
Recent Research on Gastrointestinal Carcinoma
Authors: Rovesti Giulia , Marisi Giorgia , Casadei-Gardini Andrea
Published: January 2021

This series of 10 articles (eight original articles and two reviews) is presented by international leaders in gastrointestinal cancer research [...]
Targeting E-selectin to Tackle Cancer Using Uproleselan
Authors: Muz Barbara , Abdelghafer Anas , Markovic Matea , Yavner Jessica , Melam Anupama , Salama Noha Nabil , Azab Abdel Kareem
Published: January 2021

E-selectin is a vascular adhesion molecule expressed mainly on endothelium, and its primary role is to facilitate leukocyte cell trafficking by recognizing ligand surface proteins. E-selectin gained a new role since it was demonstrated to be involved in cancer cell trafficking, stem-like properties and therapy resistance. Therefore, being expressed in the tumor microenvironment, E-selectin can potentially be used to eradicate cancer. Uproleselan (also known as GMI-1271), a specific E-selectin antagonist, has been tested on leukemia, myeloma, pancreatic, colon and breast cancer cells, most of which involve the bone marrow as a primary or as a metastatic tumor site. This novel therapy disrupts the tumor microenvironment by affecting the two main steps of metastasis—extravasation and adhesion—thus blocking E-selectin reduces tumor dissemination. Additionally, uproleselan mobilized cancer cells from the protective vascular niche into the circulation, making them more susceptible to chemotherapy. Several preclinical and clinical studies summarized herein demonstrate that uproleselan has favorable safety and pharmacokinetics and is a tumor microenvironment-disrupting agent that improves the efficacy of chemotherapy, reduces side effects such as neutropenia, intestinal mucositis and infections, and extends overall survival. This review highlights the critical contribution of E-selectin and its specific antagonist, uproleselan, in the regulation of cancer growth, dissemination, and drug resistance in the context of the bone marrow microenvironment.
The Transcriptomic Landscape of Prostate Cancer Development and Progression: An Integrative Analysis
Authors: Marzec Jacek , Ross-Adams Helen , Pirrò Stefano , Wang Jun , Zhu Yanan , Mao Xueying , Gadaleta Emanuela , Ahmad Amar S. , North Bernard V. , Kammerer-Jacquet Solène-Florence , Stankiewicz Elzbieta , Kudahetti Sakunthala C. , Beltran Luis , Ren Guoping , Berney Daniel M. , Lu Yong-Jie , Chelala Claude
Published: January 2021

Next-generation sequencing of primary tumors is now standard for transcriptomic studies, but microarray-based data still constitute the majority of available information on other clinically valuable samples, including archive material. Using prostate cancer (PC) as a model, we developed a robust analytical framework to integrate data across different technical platforms and disease subtypes to connect distinct disease stages and reveal potentially relevant genes not identifiable from single studies alone. We reconstructed the molecular profile of PC to yield the first comprehensive insight into its development, by tracking changes in mRNA levels from normal prostate to high-grade prostatic intraepithelial neoplasia, and metastatic disease. A total of nine previously unreported stage-specific candidate genes with prognostic significance were also found. Here, we integrate gene expression data from disparate sample types, disease stages and technical platforms into one coherent whole, to give a global view of the expression changes associated with the development and progression of PC from normal tissue through to metastatic disease. Summary and individual data are available online at the Prostate Integrative Expression Database (PIXdb), a user-friendly interface designed for clinicians and laboratory researchers to facilitate translational research.
ctDNA and Adjuvant Therapy for Colorectal Cancer: Time to Re-Invent Our Treatment Paradigm
Authors: Naidoo Mahendra , Gibbs Peter , Tie Jeanne
Published: January 2021

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. While there have been significant developments in the treatments for patients with metastatic CRC in recent years, improving outcomes in the adjuvant setting has been more challenging. Recent technological advances in circulating tumour DNA (ctDNA) assay with the ability to detect minimal residual disease (MRD) after curative intent surgery will fundamentally change how we assess recurrence risk and conduct adjuvant trials. Studies in non-metastatic CRC have now demonstrated the prognostic impact of ctDNA analysis after curative intent surgery over and above current standard of care clinicopathological criteria. This ability of ctDNA analysis to stratify patients into low- and very-high-risk groups provides a window of opportunity to personalise adjuvant treatment where escalation/de-escalation of adjuvant systemic therapy could potentially increase cure rates and also reduce treatment-related physical and financial toxicity. Emerging data suggest that conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy may reflect treatment efficacy. This real-time assessment of treatment benefit could be used as a surrogate endpoint for adjuvant novel drug development. Several ctDNA-based randomized adjuvant trials are ongoing internationally to confirm the clinical utility of ctDNA in colorectal cancer.
An Analysis of Vertebral Body Growth after Proton Beam Therapy for Pediatric Cancer
Authors: Baba Keiichiro , Mizumoto Masashi , Oshiro Yoshiko , Shimizu Shosei , Nakamura Masatoshi , Hiroshima Yuichi , Iizumi Takashi , Saito Takashi , Numajiri Haruko , Nakai Kei , Ishikawa Hitoshi , Okumura Toshiyuki , Maruo Kazushi , Sakurai Hideyuki
Published: January 2021

Impairment of bone growth after radiotherapy for pediatric bone cancer is a well-known adverse event. However, there is limited understanding of the relationship between bone growth and irradiation dose. In this study, we retrospectively analyzed bone growth impairment after proton beam therapy for pediatric cancer. A total of 353 vertebral bodies in 23 patients under 12 years old who received proton beam therapy were evaluated. Compared to the non-irradiated vertebral body growth rate, the irradiated vertebral body rate (%/year) was significantly lower: 77.2%, 57.6%, 40.8%, 26.4%, and 14.1% at 10, 20, 30, 40, and 50 Gy (RBE) irradiation, respectively. In multivariate analysis, radiation dose was the only factor correlated with vertebral body growth. Age, gender, and vertebral body site were not significant factors. These results suggest that the growth rate of the vertebral body is dose-dependent and decreases even at a low irradiated dose. This is the first report to show that proton beam therapy has the same growth inhibitory effect as photon radiotherapy within the irradiated field.
EGR1/GADD45α Activation by ROS of Non-Thermal Plasma Mediates Cell Death in Thyroid Carcinoma
Authors: Jung Seung-Nam , Oh Chan , Chang Jae Won , Liu Lihua , Lim Mi Ae , Jin Yan Li , Piao Yudan , Kim Hae Jong , Won Ho-Ryun , Lee Seong Eun , Lee Min Joung , Heo Jun Young , Jun Sangmi , Lee Doheon , Kang Woo Seok , Kim Dae-Woong , Rha Ki-Sang , Kim Young Il , Kang Yea Eun , Koo Bon Seok
Published: January 2021

(1) Background: Nonthermal plasma (NTP) induces cell death in various types of cancer cells, providing a promising alternative treatment strategy. Although recent studies have identified new mechanisms of NTP in several cancers, the molecular mechanisms underlying its therapeutic effect on thyroid cancer (THCA) have not been elucidated. (2) Methods: To investigate the mechanism of NTP-induced cell death, THCA cell lines were treated with NTP-activated medium -(NTPAM), and gene expression profiles were evaluated using RNA sequencing. (3) Results: NTPAM upregulated the gene expression of early growth response 1 (EGR1). NTPAM-induced THCA cell death was enhanced by EGR1 overexpression, whereas EGR1 small interfering RNA had the opposite effect. NTPAM-derived reactive oxygen species (ROS) affected EGR1 expression and apoptotic cell death in THCA. NTPAM also induced the gene expression of growth arrest and regulation of DNA damage-inducible 45α (GADD45A) gene, and EGR1 regulated GADD45A through direct binding to its promoter. In xenograft in vivo tumor models, NTPAM inhibited tumor progression of THCA by increasing EGR1 levels. (4) Conclusions: Our findings suggest that NTPAM induces apoptotic cell death in THCA through a novel mechanism by which NTPAM-induced ROS activates EGR1/GADD45α signaling. Furthermore, our data provide evidence that the regulation of the EGR1/GADD45α axis can be a novel strategy for the treatment of THCA.
Physical Interaction between HPV16E7 and the Actin-Binding Protein Gelsolin Regulates Epithelial-Mesenchymal Transition via HIPPO-YAP Axis
Authors: Matarrese Paola , Vona Rosa , Ascione Barbara , Paggi Marco G. , Mileo Anna Maria
Published: January 2021

Human papillomavirus 16 (HPV16) exhibits a strong oncogenic potential mainly in cervical, anogenital and oropharyngeal cancers. The E6 and E7 viral oncoproteins, acting via specific interactions with host cellular targets, are required for cell transformation and maintenance of the transformed phenotype as well. We previously demonstrated that HPV16E7 interacts with the actin-binding protein gelsolin, involved in cytoskeletal F-actin dynamics. Herein, we provide evidence that the E7/gelsolin interaction promotes the cytoskeleton rearrangement leading to epithelial-mesenchymal transition-linked morphological and transcriptional changes. E7-mediated cytoskeletal actin remodeling induces the HIPPO pathway by promoting the cytoplasmic retention of inactive P-YAP. These results suggest that YAP could play a role in the “de-differentiation” process underlying the acquisition of a more aggressive phenotype in HPV16-transformed cells. A deeper comprehension of the multifaceted mechanisms elicited by the HPV infection is vital for providing novel strategies to block the biological and clinical features of virus-related cancers.
Ex Vivo Mitochondrial Respiration Parallels Biochemical Response to Ibrutinib in CLL Cells
Authors: Chowdhury Subir Roy , Peltier Cheryl , Hou Sen , Singh Amandeep , Johnston James B. , Gibson Spencer B. , Marshall Aaron J. , Banerji Versha
Published: January 2021

Mitochondrial respiration is becoming more commonly used as a preclinical tool and potential biomarker for chronic lymphocytic leukemia (CLL) and activated B-cell receptor (BCR) signaling. However, respiration parameters have not been evaluated with respect to dose of ibrutinib given in clinical practice or the effect of progression on ibrutinib treatment on respiration of CLL cells. We evaluated the impact of low and standard dose ibrutinib on CLL cells from patients treated in vivo on mitochondrial respiration using Oroboros oxygraph. Cytokines CCL3 and CCL4 were evaluated using the Mesoscale. Western blot analysis was used to evaluate the BCR and apoptotic pathways. We observed no difference in the mitochondrial respiration rates or levels of plasma chemokine (C-C motif) ligands 3 and 4 (CCL3/CCL4), β-2 microglobulin (β-2 M) and lactate dehydrogenase (LDH) between low and standard doses of ibrutinib. This may confirm why clinical observations of the safety and efficacy of low dose ibrutinib are observed in practice. Of interest, we also observed that the mitochondrial respiration of CLL cells paralleled the increase in β-2 M and LDH at progression. Our study further supports mitochondrial respiration as a biomarker for response and progression on ibrutinib in CLL cells and a valuable pre-clinical tool.
A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro
Authors: Gelardi Edoardo L. M. , Colombo Giorgia , Picarazzi Francesca , Ferraris Davide M. , Mangione Andrea , Petrarolo Giovanni , Aronica Eleonora , Rizzi Menico , Mori Mattia , La Motta Concettina , Garavaglia Silvia
Published: January 2021

Aldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+-dependent reaction. Previous clinical studies highlighted the high expression of ALDH1A3 in cancer stem cells (CSCs) correlated to a higher risk of cancer relapses, chemoresistance and a poor clinical outcome. We report on the structural, biochemical, and cellular characterization of NR6, a new selective ALDH1A3 inhibitor derived from an already published ALDH non-selective inhibitor with cytotoxic activity on glioblastoma and colorectal cancer cells. Crystal structure, through X-Ray analysis, showed that NR6 binds a non-conserved tyrosine residue of ALDH1A3 which drives the selectivity towards this isoform, as supported by computational binding simulations. Moreover, NR6 shows anti-metastatic activity in wound healing and invasion assays and induces the downregulation of cancer stem cell markers. Overall, our work confirms the role of ALDH1A3 as an important target in glioblastoma and colorectal cells and propose NR6 as a promising molecule for future preclinical studies.
Estimation of the Potentially Avoidable Excess Deaths Associated with Socioeconomic Inequalities in Cancer Survival in Germany
Authors: Jansen Lina , Kanbach Josephine , Finke Isabelle , Arndt Volker , Emrich Katharina , Holleczek Bernd , Kajüter Hiltraud , Kieschke Joachim , Maier Werner , Pritzkuleit Ron , Sirri Eunice , Schwettmann Lars , Erb Cynthia , Brenner Hermann , Group for the German Cancer Survival Working
Published: January 2021

Many countries have reported survival inequalities due to regional socioeconomic deprivation. To quantify the potential gain from eliminating cancer survival disadvantages associated with area-based deprivation in Germany, we calculated the number of avoidable excess deaths. We used population-based cancer registry data from 11 of 16 German federal states. Patients aged ≥15 years diagnosed with an invasive malignant tumor between 2008 and 2017 were included. Area-based socioeconomic deprivation was assessed using the quintiles of the German Index of Multiple Deprivation (GIMD) 2010 on a municipality level nationwide. Five-year age-standardized relative survival for 25 most common cancer sites and for total cancer were calculated using period analysis. Incidence and number of avoidable excess deaths in Germany in 2013–2016 were estimated. Summed over the 25 cancer sites, 4100 annual excess deaths (3.0% of all excess deaths) could have been avoided each year in Germany during the period 2013–2016 if relative survival were in all regions comparable with the least deprived regions. Colorectal, oral and pharynx, prostate, and bladder cancer contributed the largest numbers of avoidable excess deaths. Our results provide a good basis to estimate the potential of intervention programs for reducing socioeconomic inequalities in cancer burden in Germany.
Global Trends of Latent Prostate Cancer in Autopsy Studies
Authors: Kimura Takahiro , Sato Shun , Takahashi Hiroyuki , Egawa Shin
Published: January 2021

The incidence of prostate cancer (PC) has been increasing in Asian countries, where it was previously low. Although the adoption of a Westernized lifestyle is a possible explanation, the incidence is statistically biased due to the increase in prostate-specific antigen (PSA) screening and the accuracy of national cancer registration systems. Studies on latent PC provide less biased information. This review included studies evaluating latent PC in several countries after excluding studies using random or single-section evaluations and those that did not mention section thickness. The findings showed that latent PC prevalence has been stable since 1950 in Western countries, but has increased over time in Asian countries. Latent PC in Asian men has increased in both prevalence and number of high-grade cases. Racial differences between Caucasian and Asian men may explain the tumor location of latent PC. In conclusion, the recent increase in latent PC in Asian men is consistent with an increase in clinical PC. Evidence suggests that this increase is caused not only by the increase in PSA screening, but also by the adoption of a more Westernized lifestyle. Autopsy findings suggest the need to reconsider the definition of clinically insignificant PC.
Dehydrogenation of Formic Acid to CO2 and H2 by Manganese(I)–Complex: Theoretical Insights for Green and Sustainable Route
Authors: Marino Tiziana , Prejanò Mario
Published: January 2021

In this work, a detailed computational study on a recently synthetized Mn(I)-dependent complex [(tBuPNNOP)Mn(CO)2]+ is reported. This species promotes the dehydrogenation of formic acid to carbon dioxide and hydrogen. The here proposed catalytic cycle proceeds through the formation of stabilized adduct between [(tBuPNNOPtBu)Mn(CO)2]+ and formate and the progressive release of CO2 and H2, mediated by the presence of trimethylamine. In order to evaluate the influence of the environment on the catalytic activity, different solvents have been taken into account. The computed barriers and the geometrical parameters account well for the available experimental data, confirming the robustness of the complex and reproducing its good catalytic performance. Outcomes from the present investigation can stimulate further experimental works in the design of new more efficient catalysts devoted to H2 production.
The Importance of Stromal Endometriosis in Thoracic Endometriosis
Authors: Mecha Ezekiel , Makunja Roselydiah , Maoga Jane B. , Mwaura Agnes N. , Riaz Muhammad A. , Omwandho Charles O. A. , Meinhold-Heerlein Ivo , Konrad Lutz
Published: January 2021

Thoracic endometriosis (TE) is a rare type of endometriosis, where endometrial tissue is found in or around the lungs and is frequent among extra-pelvic endometriosis patients. Catamenial pneumothorax (CP) is the most common form of TE and is characterized by recurrent lung collapses around menstruation. In addition to histology, immunohistochemical evaluation of endometrial implants is used more frequently. In this review, we compared immunohistochemical (CPE) with histological (CPH) characterizations of TE/CP and reevaluated arguments in favor of the implantation theory of Sampson. A summary since the first immunohistochemical description in 1998 until 2019 is provided. The emphasis was on classification of endometrial implants into glands, stroma, and both together. The most remarkable finding is the very high percentage of stromal endometriosis of 52.7% (CPE) compared to 10.2% (CPH). Chest pain, dyspnea, right-sided preference, and diaphragmatic endometrial implants showed the highest percentages in both groups. No significant association was found between the recurrence rate and the various appearances of endometriosis. Sometimes in CPE (6.8%) and CPH (30.6%) no endometrial implants were identified underlining the importance of sensitive detection of endometriosis during and after surgery. We suggest that immunohistochemical evaluation should become mandatory and will improve diagnosis and classification of the disease.
Cytosolic 5′-Nucleotidase II Is a Sensor of Energy Charge and Oxidative Stress: A Possible Function as Metabolic Regulator
Authors: Pesi Rossana , Allegrini Simone , Balestri Francesco , Garcia-Gil Mercedes , Cividini Federico , Colombaioni Laura , Jordheim Lars Petter , Camici Marcella , Tozzi Maria Grazia
Published: January 2021

Cytosolic 5′-nucleotidase II (NT5C2) is a highly regulated enzyme involved in the maintenance of intracellular purine and the pyrimidine compound pool. It dephosphorylates mainly IMP and GMP but is also active on AMP. This enzyme is highly expressed in tumors, and its activity correlates with a high rate of proliferation. In this paper, we show that the recombinant purified NT5C2, in the presence of a physiological concentration of the inhibitor inorganic phosphate, is very sensitive to changes in the adenylate energy charge, especially from 0.4 to 0.9. The enzyme appears to be very sensitive to pro-oxidant conditions; in this regard, the possible involvement of a disulphide bridge (C175-C547) was investigated by using a C547A mutant NT5C2. Two cultured cell models were used to further assess the sensitivity of the enzyme to oxidative stress conditions. NT5C2, differently from other enzyme activities, was inactivated and not rescued by dithiothreitol in a astrocytoma cell line (ADF) incubated with hydrogen peroxide. The incubation of a human lung carcinoma cell line (A549) with 2-deoxyglucose lowered the cell energy charge and impaired the interaction of NT5C2 with the ice protease-activating factor (IPAF), a protein involved in innate immunity and inflammation.
Hippo Signaling Pathway in Gliomas
Authors: Masliantsev Konstantin , Karayan-Tapon Lucie , Guichet Pierre-Olivier
Published: January 2021

The Hippo signaling pathway is a highly conserved pathway involved in tissue development and regeneration that controls organ size through the regulation of cell proliferation and apoptosis. The core Hippo pathway is composed of a block of kinases, MST1/2 (Mammalian STE20-like protein kinase 1/2) and LATS1/2 (Large tumor suppressor 1/2), which inhibits nuclear translocation of YAP/TAZ (Yes-Associated Protein 1/Transcriptional co-activator with PDZ-binding motif) and its downstream association with the TEAD (TEA domain) family of transcription factors. This pathway was recently shown to be involved in tumorigenesis and metastasis in several cancers such as lung, breast, or colorectal cancers but is still poorly investigated in brain tumors. Gliomas are the most common and the most lethal primary brain tumors representing about 80% of malignant central nervous system neoplasms. Despite intensive clinical protocol, the prognosis for patients remains very poor due to systematic relapse and treatment failure. Growing evidence demonstrating the role of Hippo signaling in cancer biology and the lack of efficient treatments for malignant gliomas support the idea that this pathway could represent a potential target paving the way for alternative therapeutics. Based on recent advances in the Hippo pathway deciphering, the main goal of this review is to highlight the role of this pathway in gliomas by a state-of-the-art synthesis.
mRNA-Enhanced Cell Therapy and Cardiovascular Regeneration
Authors: Chanda Palas K. , Sukhovershin Roman , Cooke John P.
Published: January 2021

mRNA has emerged as an important biomolecule in the global call for the development of therapies during the COVID-19 pandemic. Synthetic in vitro-transcribed (IVT) mRNA can be engineered to mimic naturally occurring mRNA and can be used as a tool to target “undruggable” diseases. Recent advancement in the field of RNA therapeutics have addressed the challenges inherent to this drug molecule and this approach is now being applied to several therapeutic modalities, from cancer immunotherapy to vaccine development. In this review, we discussed the use of mRNA for stem cell generation or enhancement for the purpose of cardiovascular regeneration.
White Matter Interstitial Neurons in the Adult Human Brain: 3% of Cortical Neurons in Quest for Recognition
Authors: Sedmak Goran , Judaš Miloš
Published: January 2021

White matter interstitial neurons (WMIN) are a subset of cortical neurons located in the subcortical white matter. Although they were fist described over 150 years ago, they are still largely unexplored and often considered a small, functionally insignificant neuronal population. WMIN are adult remnants of neurons located in the transient fetal subplate zone (SP). Following development, some of the SP neurons undergo apoptosis, and the remaining neurons are incorporated in the adult white matter as WMIN. In the adult human brain, WMIN are quite a large population of neurons comprising at least 3% of all cortical neurons (between 600 and 1100 million neurons). They include many of the morphological neuronal types that can be found in the overlying cerebral cortex. Furthermore, the phenotypic and molecular diversity of WMIN is similar to that of the overlying cortical neurons, expressing many glutamatergic and GABAergic biomarkers. WMIN are often considered a functionally unimportant subset of neurons. However, upon closer inspection of the scientific literature, it has been shown that WMIN are integrated in the cortical circuitry and that they exhibit diverse electrophysiological properties, send and receive axons from the cortex, and have active synaptic contacts. Based on these data, we are able to enumerate some of the potential WMIN roles, such as the control of the cerebral blood flow, sleep regulation, and the control of information flow through the cerebral cortex. Also, there is a number of studies indicating the involvement of WMIN in the pathophysiology of many brain disorders such as epilepsy, schizophrenia, Alzheimer’s disease, etc. All of these data indicate that WMIN are a large population with an important function in the adult brain. Further investigation of WMIN could provide us with novel data crucial for an improved elucidation of the pathophysiology of many brain disorders. In this review, we provide an overview of the current WMIN literature, with an emphasis on studies conducted on the human brain.
Towards a Functional Cure for Diabetes Using Stem Cell-Derived Beta Cells: Are We There Yet?
Authors: Bourgeois Stephanie , Sawatani Toshiaki , Van Mulders Annelore , De Leu Nico , Heremans Yves , Heimberg Harry , Cnop Miriam , Staels Willem
Published: January 2021

Diabetes mellitus is a pandemic metabolic disorder that results from either the autoimmune destruction or the dysfunction of insulin-producing pancreatic beta cells. A promising cure is beta cell replacement through the transplantation of islets of Langerhans. However, donor shortage hinders the widespread implementation of this therapy. Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, represent an attractive alternative beta cell source for transplantation. Although major advances over the past two decades have led to the generation of stem cell-derived beta-like cells that share many features with genuine beta cells, producing fully mature beta cells remains challenging. Here, we review the current status of beta cell differentiation protocols and highlight specific challenges that are associated with producing mature beta cells. We address the challenges and opportunities that are offered by monogenic forms of diabetes. Finally, we discuss the remaining hurdles for clinical application of stem cell-derived beta cells and the status of ongoing clinical trials.
New Prognostic Biomarkers in Metastatic Castration-Resistant Prostate Cancer
Authors: Conteduca Vincenza , Mosca Alessandra , Brighi Nicole , de Giorgi Ugo , Rescigno Pasquale
Published: January 2021

Prostate cancer is one of the most frequent cancers in men and is a common cause of cancer-related death. Despite significant progress in the diagnosis and treatment of this tumor, patients who relapse after radical treatments inevitably develop metastatic disease. Patient stratification is therefore key in this type of cancer, and there is an urgent need for prognostic biomarkers that can define patients’ risk of cancer-related death. In the last 10 years, multiple prognostic factors have been identified and studied. Here, we review the literature available and discuss the most common aberrant genomic pathways in metastatic castration-resistant prostate cancer shown to have a prognostic relevance in this setting.
In Vivo Assessment of Synthetic and Biological-Derived Calcium Phosphate-Based Coatings Fabricated by Pulsed Laser Deposition: A Review
Authors: Duta Liviu
Published: January 2021

The aim of this review is to present the state-of-the art achievements reported in the last two decades in the field of pulsed laser deposition (PLD) of biocompatible calcium phosphate (CaP)-based coatings for medical implants, with an emphasis on their in vivo biological performances. There are studies in the dedicated literature on the in vivo testing of CaP-based coatings (especially hydroxyapatite, HA) synthesized by many physical vapor deposition methods, but only a few of them addressed the PLD technique. Therefore, a brief description of the PLD technique, along with some information on the currently used substrates for the synthesis of CaP-based structures, and a short presentation of the advantages of using various animal and human implant models will be provided. For an in-depth in vivo assessment of both synthetic and biological-derived CaP-based PLD coatings, a special attention will be dedicated to the results obtained by standardized and micro-radiographies, (micro) computed tomography and histomorphometry, tomodensitometry, histology, scanning and transmission electron microscopies, and mechanical testing. One main specific result of the in vivo analyzed studies is related to the demonstrated superior osseointegration characteristics of the metallic (generally Ti) implants functionalized with CaP-based coatings when compared to simple (control) Ti ones, which are considered as the “gold standard” for implantological applications. Thus, all such important in vivo outcomes were gathered, compiled and thoroughly discussed both to clearly understand the current status of this research domain, and to be able to advance perspectives of these synthetic and biological-derived CaP coatings for future clinical applications.
Microstructure and Corrosion Properties of La2Zr2O7/NiCoAlY Thermal Barrier Coatings Deposited on Inconel 718 Superalloy by Laser Cladding
Authors: Huang Kaijin , Li Wei , Pan Kai , Lin Xin , Wang Aihua
Published: January 2021

In order to improve the seawater corrosion resistance of Inconel 718 superalloy, a La2Zr2O7/NiCoCrAlY thermal barrier coating corrosion resistant to 3.5 wt.% NaCl aqueous solution was prepared by laser cladding on Inconel 718 superalloy. X-ray diffraction (XRD), Scanning Electron Microscope (SEM), and electrochemical techniques were used to study the microstructure and the corrosion performance of the coating in 3.5 wt.% NaCl solution. The results show that the thermal barrier coating is mainly composed of primary La2Zr2O7 phase and γ + laves/δ phase eutectic structure. The corrosion potential and corrosion current of the coating in 3.5 wt.% NaCl solution are higher and lower than that of the Inconel 718 substrate, respectively, indicating that the corrosion performance of the coating is better than that of the Inconel 718 substrate. The presence of La2Zr2O7 phase in the thermal barrier coating is the main reason for its corrosion resistance to 3.5 wt.% NaCl solution.