bluuebunny/crossref_metadata_2025 huggingface dataset:
Two Flavors of Hydrogen Atoms: A Possible Explanation of Dark Matter
Authors: Oks Eugene
Published: July 2020

In one of our previous papers, it was shown that for the ground state of hydrogenic atoms/ions, it is possible to match the interior (inside the nucleus) solution of the Dirac equation with the singular exterior solution of the Dirac equation, so that the singular solution should not be rejected for the ground state of hydrogenic atoms/ions. In that paper, there was presented also the first experimental proof of the existence of this Alternative Kind of Hydrogen Atoms (AKHA)—by showing that the presence of the AKHA solves a long-standing mystery of the huge discrepancy between the experimental and previous theoretical results concerning the high-energy tail of the linear momentum distribution in the ground state of hydrogen atoms. In another paper, we showed that for hydrogen atoms, the singular solution of the Dirac equation outside the proton is legitimate not just for the ground state 12S1/2, but also for the states 22S1/2, 32S1/2 and so on: it is legitimate for all the discrete states n2S1/2. Moreover, the singular exterior solution is legitimate also for the l = 0 states of the continuous spectrum. In that paper, we demonstrated that the AKHA can be the basis for explaining the recent puzzling astrophysical observational results concerning the redshifted radio line 21 cm from the early Universe. Thus, there seems to be the astrophysical evidence of the existence of the AKHA—in addition to the already available observational proof of their existence from atomic experiments. In the present paper, we point out that the AKHA provide an alternative view on dark matter—without resorting to new subatomic particles or dramatically changing the existing physical laws. This is because due to the selection rules, the AKHA do not have state that can be coupled by the electric dipole radiation. We also reformulate the above theoretical results in terms that hydrogen atoms can have two flavors: one flavor corresponding to the regular solution outside the proton, another—to the singular solution outside the proton, both solutions corresponding to the same energy. Since this means the additional degeneracy, then according to the fundamental theorem of quantum mechanics, there should be an additional conserved quantity, which we call isohydrogen spin (isohyspin). Further atomic experiments for accurately measuring the high-energy tail of the linear momentum distribution in the ground state of hydrogen atoms, as well as further observational studies of the redshifted 21 cm radio line from the early Universe, could provide a further proof that dark matter or a part of it is the AKHA.
Prospects and Challenges of Translational Corneal Bioprinting
Authors: Fuest Matthias , Yam Gary Hin-Fai , Mehta Jodhbir S. , Duarte Campos Daniela F.
Published: July 2020

Corneal transplantation remains the ultimate treatment option for advanced stromal and endothelial disorders. Corneal tissue engineering has gained increasing interest in recent years, as it can bypass many complications of conventional corneal transplantation. The human cornea is an ideal organ for tissue engineering, as it is avascular and immune-privileged. Mimicking the complex mechanical properties, the surface curvature, and stromal cytoarchitecure of the in vivo corneal tissue remains a great challenge for tissue engineering approaches. For this reason, automated biofabrication strategies, such as bioprinting, may offer additional spatial control during the manufacturing process to generate full-thickness cell-laden 3D corneal constructs. In this review, we discuss recent advances in bioprinting and biomaterials used for in vitro and ex vivo corneal tissue engineering, corneal cell-biomaterial interactions after bioprinting, and future directions of corneal bioprinting aiming at engineering a full-thickness human cornea in the lab.
CMH-Small Molecule Docks into SIRT1, Elicits Human IPF-Lung Fibroblast Cell Death, Inhibits Ku70-deacetylation, FLIP and Experimental Pulmonary Fibrosis
Authors: Konikov-Rozenman Jenya , Breuer Raphael , Kaminski Naftali , Wallach-Dayan Shulamit B.
Published: July 2020

Regenerative capacity in vital organs is limited by fibrosis propensity. Idiopathic pulmonary fibrosis (IPF), a progressive lung disease linked with aging, is a classic example. In this study, we show that in flow cytometry, immunoblots (IB) and in lung sections, FLIP levels can be regulated, in vivo and in vitro, through SIRT1 activity inhibition by CMH (4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide), a small molecule that, as we determined here by structural biology calculations, docked into its nonhistone substrate Ku70-binding site. Ku70 immunoprecipitations and immunoblots confirmed our theory that Ku70-deacetylation, Ku70/FLIP complex, myofibroblast resistance to apoptosis, cell survival, and lung fibrosis in bleomycin-treated mice, are reduced and regulated by CMH. Thus, small molecules associated with SIRT1-mediated regulation of Ku70 deacetylation, affecting FLIP stabilization in fibrotic-lung myofibroblasts, may be a useful strategy, enabling tissue regeneration.
State-of-the-Art CNN Optimizer for Brain Tumor Segmentation in Magnetic Resonance Images
Authors: Yaqub Muhammad , Feng Jinchao , Zia M. , Arshid Kaleem , Jia Kebin , Rehman Zaka , Mehmood Atif
Published: July 2020

Brain tumors have become a leading cause of death around the globe. The main reason for this epidemic is the difficulty conducting a timely diagnosis of the tumor. Fortunately, magnetic resonance images (MRI) are utilized to diagnose tumors in most cases. The performance of a Convolutional Neural Network (CNN) depends on many factors (i.e., weight initialization, optimization, batches and epochs, learning rate, activation function, loss function, and network topology), data quality, and specific combinations of these model attributes. When we deal with a segmentation or classification problem, utilizing a single optimizer is considered weak testing or validity unless the decision of the selection of an optimizer is backed up by a strong argument. Therefore, optimizer selection processes are considered important to validate the usage of a single optimizer in order to attain these decision problems. In this paper, we provides a comprehensive comparative analysis of popular optimizers of CNN to benchmark the segmentation for improvement. In detail, we perform a comparative analysis of 10 different state-of-the-art gradient descent-based optimizers, namely Adaptive Gradient (Adagrad), Adaptive Delta (AdaDelta), Stochastic Gradient Descent (SGD), Adaptive Momentum (Adam), Cyclic Learning Rate (CLR), Adaptive Max Pooling (Adamax), Root Mean Square Propagation (RMS Prop), Nesterov Adaptive Momentum (Nadam), and Nesterov accelerated gradient (NAG) for CNN. The experiments were performed on the BraTS2015 data set. The Adam optimizer had the best accuracy of 99.2% in enhancing the CNN ability in classification and segmentation.
Targeting Complex Orthography in the Treatment of a Bilingual Aphasia with Acquired Dysgraphia: The Case of a Malay/English Speaker with Conduction Aphasia
Authors: Aziz Mohd Azmarul A , Razak Rogayah A , Garraffa Maria
Published: July 2020

Background: Disruption of spoken language in people with aphasia tends to interfere with the ability to write, which is referred to as dysgraphia. This study examined the effectiveness of the anagram and copy treatment (ACT), administered in English on a bilingual Malay/English patient with conduction aphasia (GM). ACT is the arrangement of component letters presented in scrambled order (i.e., an anagram) so that the patient could use the letters to form target words, followed by repeated copying of the word. Methods: A single-subject multiple-baseline design was used with sets of English words (both nouns and verbs) sequentially targeted for treatment. Prior to the treatment, a series of single word writing and reading baselines were conducted in two languages: English and Malay. The ACT treatment was done in English, the language reported as more dominant for reading by the patient. Probes assessing generalizations to untrained pictures were presented at 8th, 13th, and 18th sessions. Results: GM showed steady and incremental improvement in the writing of trained nouns and verbs, with generalizations to untrained English nouns and verbs. Conclusions: Single word writing treatment in a non-transparent language may improve dysgraphia among adults with bilingual aphasia through the administration of a structured and systematic treatment.
The Fairytale Semantic Differential Technique: A Cross-Cultural Application
Authors: Petrenko Victor , Mitina Olga
Published: July 2020

The “Fairytale Semantic Differential” method, in which the respondent assesses several fairytale characters according to a set of personal characteristics, is designed for individual psychological work with children 4–10 years old. Personality characteristics, according to which the characters are evaluated, are formulated in terms understandable to child respondents, i.e., these are words that parents and teachers use when dealing with children of this age. An analysis of the child’s attitude to a certain fairytale character makes it possible to determine the individual properties of his/her moral value sphere. Quantitative indicators that can be calculated on the basis of the data collected by the questionnaire are discussed. These indicators characterize the child’s personality, his/her understanding of interpersonal relationships, the dimensionality of the categorial space of interpersonal perception, the content of these categories and its hierarchy, the level of cognitive development in this domain, and the degree of socialization. The results of an empirical study that was conducted in Moscow, Baku, and Tashkent are presented. Age and sex differences were found in the cognitive complexity of interpersonal perception and socialization. Also, an example of individual semantic space is presented.
FIGO 2018 Staging for Cervical Cancer: Influence on Stage Distribution and Outcomes in the 3D-Image-Guided Brachytherapy Era
Authors: Tomizawa Kento , Kaminuma Takuya , Murata Kazutoshi , Noda Shin-ei , Irie Daisuke , Kumazawa Takuya , Oike Takahiro , Ohno Tatsuya
Published: July 2020

Recent widespread use of three-dimensional image-guided brachytherapy (3D-IGBT) has improved radiotherapy outcomes of cervical cancer dramatically. In 2018, the International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer was revised. However, the influence of the revisions on the stage distribution and outcomes of cervical cancers treated with 3D-IGBT remains unclear. Here, we retrospectively analyzed 221 patients with cervical squamous cell carcinoma treated with definitive radiotherapy using 3D-IGBT (median follow-up, 60 months). The stage distribution and outcomes were compared between the 2009 and 2018 schemas. Stage migration occurred in 52.9% of the patients. Patients classified with the 2018 criteria as stage IIICr had the highest proportion (43.8%) of migration, and were mainly from the 2009 stages IIB and IIIB. The 2009 and 2018 schemas showed comparable performance at stratifying 5-year overall survival (OS) and 5-year progression-free survival (PFS) for patients in stages IB–IVA. The 2018 criteria effectively stratified 5-year OS and PFS in the stage III substages. The 5-year OS and PFS for stage IIIC1r patients varied according to tumor T stage. These data provide evidence for the utility of the revised 2018 FIGO staging system in the clinical management of cervical cancers in the 3D-IGBT era.
Prognostic Significance of PET/CT in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Frontline Chemoimmunotherapy
Authors: Porrazzo Marika , Nicolai Emanuele , Riminucci Mara , Vitale Candida , Coscia Marta , De Paoli Lorenzo , Rago Angela , Buscicchio Giulia , Maestrini Giacomo , Ligia Silvio , Di Prima Alessio , Corsi Alessandro , Caronna Roberto , Gaidano Gianluca , Mauro Francesca Romana
Published: July 2020

The role of positron emission tomography/computed tomography (PET/CT) in identifying Richter Syndrome (RS) is well established, while its impact on the survival of patients with chronic lymphocytic leukemia (CLL) has been less explored. The clinical characteristics and PET/CT data of 40 patients with a biopsy-proven CLL who required frontline chemoimmunotherapy, FCR (fludarabine, cyclophosphamide, rituximab) in 20 patients, BR (bendamustine, rituximab) in 20, were retrospectively analyzed. Standardized uptake volume (SUVmax) values ≥ 5 were observed more frequently in patients with deletion 11q (p = 0.006) and biopsies characterized by a rate of Ki67 positive cells ≥ 30% (p = 0.02). In the multivariate analysis, the presence of large and confluent PCs emerged as the only factor with a negative impact on progression-free survival (PFS), and overall survival (OS). Deletion 11q also revealed a significant and independent effect on PFS. SUVmax values ≥ 5 showed no statistical impact on PFS while in multivariate analysis, they revealed a significant adverse impact on OS (median survival probability not reached vs. 56 months; p = 0.002). Moreover, patients with higher SUVmax values more frequently developed Richter Syndrome (p = 0.015). Our results show that higher SUVmax values identify CLL patients with a pronounced rate of proliferating cells in the lymph-node compartment, inferior survival, and an increased risk of developing RS.
Mechanosensitive Piezo Channels in Cancer: Focus on altered Calcium Signaling in Cancer Cells and in Tumor Progression
Authors: De Felice Dario , Alaimo Alessandro
Published: July 2020

Mechanotransduction, the translation of mechanical stimuli into biological signals, is a crucial mechanism involved in the function of fundamentally all cell types. In many solid tumors, the malignant transformation is often associated with drastic changes in cell mechanical features. Extracellular matrix stiffness, invasive growth, and cell mobility are just a few hallmarks present in cancer cells that, by inducing mechanical stimuli, create positive feedbacks promoting cancer development. Among the molecular players involved in these pathophysiological processes, the mechanosensitive Ca2+-permeable Piezo channels have emerged as major transducers of mechanical stress into Ca2+ dependent signals. Piezo channels are overexpressed in several cancers, such as in breast, gastric, and bladder, whereas their downregulation has been described in other cancers. Still, the roles of mechanosensitive Piezos in cancer are somewhat puzzling. In this review, we summarize the current knowledge on the pathophysiological roles of these Ca2+-permeable channels, with special emphasis on their functional involvement in different cancer types progression.
Epigenetic Silencing of miR-9 Promotes Migration and Invasion by EZH2 in Glioblastoma Cells
Authors: Chien Yi-Chung , Chen Jia-Ni , Chen Ya-Huey , Chou Ruey-Hwang , Lee Han-Chung , Yu Yung-Luen
Published: July 2020

Glioblastoma (GBM) is the most common primary brain tumor in adults. Tumor invasion is the major reason for treatment failure and poor prognosis in GBM. Inhibiting migration and invasion has become an important therapeutic strategy for GBM treatment. Enhancer of zeste homolog 2 (EZH2) and C-X-C motif chemokine receptor 4 (CXCR4) have been determined to have important roles in the occurrence and development of tumors, but the specific relationship between EZH2 and CXCR4 expression in GBM is less well characterized. In this study, we report that EZH2 and CXCR4 were overexpressed in glioma patients. Furthermore, elevated EZH2 and CXCR4 were correlated with shorter disease-free survival. In three human GBM cell lines, EZH2 modulated the expression of miR-9, which directly targeted the oncogenic signaling of CXCR4 in GBM. The ectopic expression of miR-9 dramatically inhibited the migratory capacity of GBM cells in vitro. Taken together, our results indicate that miR-9, functioning as a tumor-suppressive miRNA in GBM, is suppressed through epigenetic silencing by EZH2. Thus, miR-9 may be an attractive target for therapeutic intervention in GBM.
Machine Learning-Based Ensemble Recursive Feature Selection of Circulating miRNAs for Cancer Tumor Classification
Authors: Lopez-Rincon Alejandro , Mendoza-Maldonado Lucero , Martinez-Archundia Marlet , Schönhuth Alexander , Kraneveld Aletta D. , Garssen Johan , Tonda Alberto
Published: July 2020

Circulating microRNAs (miRNA) are small noncoding RNA molecules that can be detected in bodily fluids without the need for major invasive procedures on patients. miRNAs have shown great promise as biomarkers for tumors to both assess their presence and to predict their type and subtype. Recently, thanks to the availability of miRNAs datasets, machine learning techniques have been successfully applied to tumor classification. The results, however, are difficult to assess and interpret by medical experts because the algorithms exploit information from thousands of miRNAs. In this work, we propose a novel technique that aims at reducing the necessary information to the smallest possible set of circulating miRNAs. The dimensionality reduction achieved reflects a very important first step in a potential, clinically actionable, circulating miRNA-based precision medicine pipeline. While it is currently under discussion whether this first step can be taken, we demonstrate here that it is possible to perform classification tasks by exploiting a recursive feature elimination procedure that integrates a heterogeneous ensemble of high-quality, state-of-the-art classifiers on circulating miRNAs. Heterogeneous ensembles can compensate inherent biases of classifiers by using different classification algorithms. Selecting features then further eliminates biases emerging from using data from different studies or batches, yielding more robust and reliable outcomes. The proposed approach is first tested on a tumor classification problem in order to separate 10 different types of cancer, with samples collected over 10 different clinical trials, and later is assessed on a cancer subtype classification task, with the aim to distinguish triple negative breast cancer from other subtypes of breast cancer. Overall, the presented methodology proves to be effective and compares favorably to other state-of-the-art feature selection methods.
Population Pharmacokinetics of Vincristine Related to Infusion Duration and Peripheral Neuropathy in Pediatric Oncology Patients
Authors: van de Velde Mirjam Esther , Panetta John Carl. , Wilhelm Abraham J. , van den Berg Marleen H. , van der Sluis Inge M. , van den Bos Cor , Abbink Floor C.H. , van den Heuvel-Eibrink Marry M. , Segers Heidi , Chantrain Christophe , van der Werff Ten Bosch Jutte , Willems Leen , Evans William E. , Kaspers Gertjan L.
Published: July 2020

Vincristine (VCR) is frequently used in pediatric oncology and can be administered intravenously through push injections or 1 h infusions. The effects of administration duration on population pharmacokinetics (PK) are unknown. We described PK differences related to administration duration and the relation between PK and VCR-induced peripheral neuropathy (VIPN). PK was assessed in 1–5 occasions (1–8 samples in 24 h per occasion). Samples were analyzed using high-performance liquid chromatography/tandem mass spectrometry. Population PK of VCR and its relationship with administration duration was determined using a non-linear mixed effect. We estimated individual post-hoc parameters: area under the concentration time curve (AUC) and maximum concentration (Cmax) in the plasma and peripheral compartment. VIPN was assessed using Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score (ped-mTNS). Overall, 70 PK assessments in 35 children were evaluated. The population estimated that the intercompartmental clearance (IC-Cl), volume of the peripheral compartment (V2), and Cmax were significantly higher in the push group. Furthermore, higher IC-Cl was significantly correlated with VIPN development. Administration of VCR by push led to increased IC-Cl, V2, and Cmax, but were similar to AUC, compared to 1 h infusions. Administration of VCR by 1 h infusions led to similar or higher exposure of VCR without increasing VIPN.
Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells
Authors: Cash Timothy P. , Alcalá Sonia , Rico-Ferreira María del Rosario , Hernández-Encinas Elena , García Jennifer , Albarrán María Isabel , Valle Sandra , Muñoz Javier , Martínez-González Sonia , Blanco-Aparicio Carmen , Pastor Joaquín , Serrano Manuel , Sainz Bruno
Published: July 2020

Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures. The anti-CSC mechanism of action of this specific chemical series was found to rely on induction of lysosomal membrane permeabilization (LMP), which is likely associated with the increased lysosomal mass observed in PaCSCs. Using the well characterized LMP-inducer siramesine as a tool molecule, we show elimination of the PaCSC population in mice implanted with tumors from two PDX models. Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC.
Prognostic Significance of the Pluripotency Factors NANOG, SOX2, and OCT4 in Head and Neck Squamous Cell Carcinomas
Authors: Pedregal-Mallo Daniel , Hermida-Prado Francisco , Granda-Díaz Rocío , Montoro-Jiménez Irene , Allonca Eva , Pozo-Agundo Esperanza , Álvarez-Fernández Mónica , Álvarez-Marcos César , García-Pedrero Juana M. , Rodrigo Juan Pablo
Published: July 2020

Cancer stem cells (CSCs) play major roles in tumor initiation, progression, and resistance to cancer therapy. Several CSC markers have been studied in head and neck squamous cell carcinomas (HNSCC), including the pluripotency factors NANOG, SOX2, and OCT4; however, their clinical significance is still unclear. NANOG, SOX2, and OCT4 expression was evaluated by immunochemistry in 348 surgically-treated HNSCC, and correlated with clinicopathological parameters and patient outcomes. mRNA expression was further analyzed in 530 The Cancer Genome Atlas (TCGA) HNSCC. NANOG protein expression was detected in 250 (72%) cases, more frequently in patients with lymph node metastasis (p = 0.003), and was an independent predictor of better survival in multivariate analysis. While OCT4 expression was undetectable, SOX2 expression was observed in 105 (30%) cases, and strongly correlated with NANOG expression. Combined expression of both proteins showed the highest survival rates, and double-negative cases the worst survival. Strikingly, the impact of NANOG and SOX2 on outcome varied depending on tumor site and lymph node infiltration, specifically showing prognostic significance in pharyngeal tumors. Correlation between NANOG and SOX2 at mRNA and protein was specifically observed in node positive (N+) patients, and consistently correlated with better survival rates. According to our findings, NANOG protein expression is frequent in HNSCC, thereby emerging as an independent predictor of better prognosis in pharyngeal tumors. Moreover, this study uncovers a differential impact of NANOG and SOX2 expression on HNSCC prognosis, depending on tumor site and lymph node infiltration, which could facilitate high-risk patient stratification.
Digital Pathology and PD-L1 Testing in Non Small Cell Lung Cancer: A Workshop Record
Authors: Pagni Fabio , Malapelle Umberto , Doglioni Claudio , Fontanini Gabriella , Fraggetta Filippo , Graziano Paolo , Marchetti Antonio , Guerini Rocco Elena , Pisapia Pasquale , Vigliar Elena V. , Buttitta Fiamma , Jaconi Marta , Fusco Nicola , Barberis Massimo , Troncone Giancarlo
Published: July 2020

A meeting among expert pathologists was held in 2019 in Rome to verify the results of the previous harmonization efforts on the PD-L1 immunohistochemical testing by scoring a representative series of non-small cell lung cancer (NSCLC) digital slides. The current paper shows the results of this digital experimental meeting and the expertise achieved by the community of Italian pathologists. PD-L1 protein expression was determined using tumor proportion score (TPS), i.e., the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. The gold standard was defined as the final PD-L1 score formulated by a panel of seven lung committed pathologists. PD-L1 status was clustered in three categories, namely negative (TPS < 1), low (TPS 1–49%), and high (TPS ≥ 50%). In 23 cases (71.9%) PD-L1 staining was performed using the companion diagnostic 22C3 pharmDx kit on Dako Autostainer, while in nine (28.1%) cases it was performed using the SP263 Ventana kit on BenchMark platform. A complete PD-L1 scoring agreement between the panel of experts and the participants was reached in 57.1% of cases, whereas a minor disagreement in 16.1% of cases was recorded. Italian pathologists performed best in strong positive cases (i.e., tumor proportion score TPS > 50%), whereas only 10.8% of disagreement with the gold standard was observed, and 55.6% regarded a single challenging case. The worst performance was achieved in the negative cases, with 32.0% disagreement. A significant difference resulted from the analysis of the data separated by the different clones used: 22.3% and 38.1% disagreement (p = 0.01) was found in the group of cases analyzed by 22C3 and SP263 antibody clones, respectively. In conclusion, this workshop record proposed the application of a digital pathology platform to share controversial cases in educational meetings as an alternative possibility for improving the interpretation and reporting of specific histological tools. Due to the crucial role of PD-L1 TPS for the selection of patients for immunotherapy, the identification of unconventional approaches as virtual slides to focus experiences and give more detailed practical verifications of the standard quality reached may be a considerable option.
Harnessing NK Cell Checkpoint-Modulating Immunotherapies
Authors: Chauhan Sachin Kumar Singh , Koehl Ulrike , Kloess Stephan
Published: July 2020

During the host immune response, the precise balance of the immune system, regulated by immune checkpoint, is required to avoid infection and cancer. These immune checkpoints are the mainstream regulator of the immune response and are crucial for self-tolerance. During the last decade, various new immune checkpoint molecules have been studied, providing an attractive path to evaluate their potential role as targets for effective therapeutic interventions. Checkpoint inhibitors have mainly been explored in T cells until now, but natural killer (NK) cells are a newly emerging target for the determination of checkpoint molecules. Simultaneously, an increasing number of therapeutic dimensions have been explored, including modulatory and inhibitory checkpoint molecules, either causing dysfunction or promoting effector functions. Furthermore, the combination of the immune checkpoint with other NK cell-based therapeutic strategies could also strengthen its efficacy as an antitumor therapy. In this review, we have undertaken a comprehensive review of the literature to date regarding underlying mechanisms of modulatory and inhibitory checkpoint molecules.
Genomic and Transcriptomic Characterisation of Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer
Authors: Toomey Sinead , Gunther Jillian , Carr Aoife , Weksberg David C. , Thomas Valentina , Salvucci Manuela , Bacon Orna , Sherif El-Masry , Fay Joanna , Kay Elaine W. , Sheehan Katherine M. , McNamara Deborah A. , Sanders Keith L , Mathew Geena , Breathnach Oscar S. , Grogan Liam , Morris Patrick G. , Foo Wai C. , You Yi-Qian N. , Prehn Jochen H. , O’Neill Brian , Krishnan Sunil , Hennessy Bryan T. , Furney Simon J.
Published: July 2020

Standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (NACRT), followed by surgical resection. However, >70% of patients do not achieve a complete pathological response and have higher rates of relapse and death. There are no validated pre- or on-treatment factors that predict response to NACRT besides tumour stage and size. We characterised the response of 33 LARC patients to NACRT, collected tumour samples from patients prior to, during and after NACRT, and performed whole exome, transcriptome and high-depth targeted sequencing. The pre-treatment LARC genome was not predictive of response to NACRT. However, in line with the increasing recognition of microbial influence in cancer, RNA analysis of pre-treatment tumours suggested a greater abundance of Fusobacteria in intermediate and poor responders. In addition, we investigated tumour heterogeneity and evolution in response to NACRT. While matched pre-treatment, on-treatment and post-treatment tumours revealed minimal genome evolution overall, we identified cases in which microsatellite instability developed or was selected for during NACRT. Recent research has suggested a role for adaptive mutability to targeted therapy in colorectal cancer cells. We provide preliminary evidence of selection for mismatch repair deficiency in response to NACRT. Furthermore, pre-NACRT genomic landscapes do not predict treatment response but pre-NACRT microbiome characteristics may be informative.
Proliferative Classification of Intracranially Injected HER2-positive Breast Cancer Cell Lines
Authors: Kuroiwa Yuka , Nakayama Jun , Adachi Chihiro , Inoue Takafumi , Watanabe Shinya , Semba Kentaro
Published: July 2020

HER2 is overexpressed in 25–30% of breast cancers, and approximately 30% of HER2-positive breast cancers metastasize to the brain. Although the incidence of brain metastasis in HER2-positive breast cancer is high, previous studies have been mainly based on cell lines of the triple-negative subtype, and the molecular mechanisms of brain metastasis in HER2-positive breast cancer are unclear. In the present study, we performed intracranial injection using nine HER2-positive breast cancer cell lines to evaluate their proliferative activity in brain tissue. Our results show that UACC-893 and MDA-MB-453 cells rapidly proliferated in the brain parenchyma, while the other seven cell lines moderately or slowly proliferated. Among these nine cell lines, the proliferative activity in brain tissue was not correlated with either the HER2 level or the HER2 phosphorylation status. To extract signature genes associated with brain colonization, we conducted microarray analysis and found that these two cell lines shared 138 gene expression patterns. Moreover, some of these genes were correlated with poor prognosis in HER2-positive breast cancer patients. Our findings might be helpful for further studying brain metastasis in HER2-positive breast cancer.
Bone, a Secondary Growth Site of Breast and Prostate Carcinomas: Role of Osteocytes
Authors: Maroni Paola , Bendinelli Paola
Published: July 2020

Bone is the primarily preferred site for breast and prostate cancer to metastasize. Bone metastases are responsible for most deaths related to breast and prostate cancer. The bone’s particular microenvironment makes it conducive for the growth of cancer cells. Studies on bone metastasis have focused on the interaction between cancer cells and the bone microenvironment. Osteocytes, the most common cell type of bone tissue, have received little attention in bone metastasis, although they are master signal sensors, integrators, and skeleton transducers. They play an important role in regulating bone mass by acting on both osteoblasts and osteoclasts, through the release of proteins such as sclerostin, Dickkopf-1 (DKK-1), and fibroblast growth factor 23 (FGF23). Osteocytes have been extensively re-evaluated, in light of their multiple functions: with different experimental approaches, it has been shown that, indeed, osteocytes are actively involved in the colonization of bone tissue by cancer cells. The present review focuses on recent research on the role that osteocytes play in bone metastasis of breast and prostate cancers. Moreover, the studies here summarized open up perspectives for new therapeutic approaches focused on modulating the activity of osteocytes to improve the condition of the bone metastatic patients. A better understanding of the complex interactions between cancer cells and bone-resident cells is indispensable for identifying potential therapeutic targets to stop tumor progression and prevent bone metastases.
Facile Synthesis of Porous Hexapod Ag@AgCl Dual Catalysts for In Situ SERS Monitoring of 4-Nitrothiophenol Reduction
Authors: Lu Yuxiang , Mao Jikai , Wang Zelin , Qin Yazhou , Zhou Jianguang
Published: July 2020

Controllable morphological metal catalytic materials have always been a focus in research. In the previous work, hexapod AgCl was successfully synthesized. In this paper, hexapod Ag@AgCl microstructures with diverse Ag contents are prepared through NaBH4 reduction. They are characterized by scanning electron microscopy (SEM) and the element distribution is proved by an energy dispersive X-ray spectrometer (EDS). They are porous dendritic microstructures with a large specific surface area and a rough surface, which display high catalytic performance and surface-enhanced Raman spectroscopy (SERS) activity. Furthermore, the hexapod Ag@AgCl microstructure is devoted as a dual catalyst to monitor the reduction of 4-nitrothiophenol (4-NTP) to 4-aminothiophenol (4-ATP) in situ using SERS. Ultraviolet–visible (UV–Vis) spectroscopy was employed to evaluate the catalytic performance of the hexapod Ag@AgCl microstructures. The consequences show that the velocity of reaction became faster with a corresponding increase in silver content and the reaction mechanism was cleared. In addition to preparing a good catalyst, this work also promotes the combination of micro-nano materials and spectroscopy technology.
KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway
Authors: Sousa Luis , Pankonien Ines , Clarke Luka A , Silva Iris , Kunzelmann Karl , Amaral Margarida D
Published: July 2020

Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation—F508del—occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue regeneration, and, when dysfunctional, cancer. However, the mechanisms that regulate such relationships are not fully elucidated. Krüppel-like factors (KLFs) are a family of transcription factors (TFs) playing central roles in development, stem cell differentiation, and proliferation. Herein, we hypothesized that these TFs might have an impact on CFTR expression and function, being its missing link to differentiation. Our results indicate that KLF4 (but not KLF2 nor KLF5) is upregulated in CF vs. non-CF cells and that it negatively regulates wt-CFTR expression and function. Of note, F508del–CFTR expressing cells are insensitive to KLF4 modulation. Next, we investigated which KLF4-related pathways have an effect on CFTR. Our data also show that KLF4 modulates wt-CFTR (but not F508del–CFTR) via both the serine/threonine kinase AKT1 (AKT) and glycogen synthase kinase 3 beta (GSK3β) signaling. While AKT acts positively, GSK3β is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT/ GSK3β signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation.
Identification of miRNA Master Regulators in Breast Cancer
Authors: Martinez-Gutierrez Antonio Daniel , Cantú de León David , Millan-Catalan Oliver , Coronel-Hernandez Jossimar , Campos-Parra Alma D. , Porras-Reyes Fany , Exayana-Alderete Angelica , López-Camarillo César , Jacobo-Herrera Nadia J , Ramos-Payan Rosalio , Pérez-Plasencia Carlos
Published: July 2020

Breast cancer is the neoplasm with the highest number of deaths in women. Although the molecular mechanisms associated with the development of this tumor have been widely described, metastatic disease has a high mortality rate. In recent years, several studies show that microRNAs or miRNAs regulate complex processes in different biological systems including cancer. In the present work, we describe a group of 61 miRNAs consistently over-expressed in breast cancer (BC) samples that regulate the breast cancer transcriptome. By means of data mining from TCGA, miRNA and mRNA sequencing data corresponding to 1091 BC patients and 110 normal adjacent tissues were downloaded and a miRNA–mRNA network was inferred. Calculations of their oncogenic activity demonstrated that they were involved in the regulation of classical cancer pathways such as cell cycle, PI3K–AKT, DNA repair, and k-Ras signaling. Using univariate and multivariate analysis, we found that five of these miRNAs could be used as biomarkers for the prognosis of overall survival. Furthermore, we confirmed the over-expression of two of them in 56 locally advanced BC samples obtained from the histopathological archive of the National Cancer Institute of Mexico, showing concordance with our previous bioinformatic analysis.
Purinergic Signaling in the Hallmarks of Cancer
Authors: Campos-Contreras Anaí del Rocío , Díaz-Muñoz Mauricio , Vázquez-Cuevas Francisco G.
Published: July 2020

Cancer is a complex expression of an altered state of cellular differentiation associated with severe clinical repercussions. The effort to characterize this pathological entity to understand its underlying mechanisms and visualize potential therapeutic strategies has been constant. In this context, some cellular (enhanced duplication, immunological evasion), metabolic (aerobic glycolysis, failure in DNA repair mechanisms) and physiological (circadian disruption) parameters have been considered as cancer hallmarks. The list of these hallmarks has been growing in recent years, since it has been demonstrated that various physiological systems misfunction in well-characterized ways upon the onset and establishment of the carcinogenic process. This is the case with the purinergic system, a signaling pathway formed by nucleotides/nucleosides (mainly adenosine triphosphate (ATP), adenosine (ADO) and uridine triphosphate (UTP)) with their corresponding membrane receptors and defined transduction mechanisms. The dynamic equilibrium between ATP and ADO, which is accomplished by the presence and regulation of a set of ectonucleotidases, defines the pro-carcinogenic or anti-cancerous final outline in tumors and cancer cell lines. So far, the purinergic system has been recognized as a potential therapeutic target in cancerous and tumoral ailments.
Water-Soluble closo-Docecaborate-Containing Pteroyl Derivatives Targeting Folate Receptor-Positive Tumors for Boron Neutron Capture Therapy
Authors: Nakagawa Fumiko , Kawashima Hidehisa , Morita Taiki , Nakamura Hiroyuki
Published: July 2020

Water-soluble pteroyl-closo-dodecaborate conjugates (PBCs 1–4), were developed as folate receptor (FRα) targeting boron carriers for boron neutron capture therapy (BNCT). PBCs 1–4 had adequately low cytotoxicity with IC50 values in the range of 1~3 mM toward selected human cancer cells, low enough to use as BNCT boron agents. PBCs 1–3 showed significant cell uptake by FRα positive cells, especially U87MG glioblastoma cells, although the accumulation of PBC 4 was low compared with PBCs 1–3 and L-4-boronophenylalanine (L-BPA). The cellular uptake of PBC 1 and PBC 3 by HeLa cells was arrested by increasing the concentration of folate in the medium, indicating that the major uptake mechanisms of PBC 1–3 are primarily through FRα receptor-mediated endocytosis.
A Perspective on Molecular Structure and Bond-Breaking in Radiation Damage in Serial Femtosecond Crystallography
Authors: Caleman Carl , Jares Junior Francisco , Grånäs Oscar , Martin Andrew V.
Published: July 2020

X-ray free-electron lasers (XFELs) have a unique capability for time-resolved studies of protein dynamics and conformational changes on femto- and pico-second time scales. The extreme intensity of X-ray pulses can potentially cause significant modifications to the sample structure during exposure. Successful time-resolved XFEL crystallography depends on the unambiguous interpretation of the protein dynamics of interest from the effects of radiation damage. Proteins containing relatively heavy elements, such as sulfur or metals, have a higher risk for radiation damage. In metaloenzymes, for example, the dynamics of interest usually occur at the metal centers, which are also hotspots for damage due to the higher atomic number of the elements they contain. An ongoing challenge with such local damage is to understand the residual bonding in these locally ionized systems and bond-breaking dynamics. Here, we present a perspective on radiation damage in XFEL experiments with a particular focus on the impacts for time-resolved protein crystallography. We discuss recent experimental and modelling results of bond-breaking and ion motion at disulfide bonding sites in protein crystals.
Complications in Idiopathic Pulmonary Fibrosis: Focus on Their Clinical and Radiological Features
Authors: Galioto Federica , Palmucci Stefano , Astuti Giovanna M. , Vancheri Ada , Distefano Giulio , Tiralongo Francesco , Libra Alessandro , Cusumano Giacomo , Basile Antonio , Vancheri Carlo
Published: July 2020

Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with uncertain origins and pathogenesis; it represents the most common interstitial lung disease (ILD), associated with a pathological pattern of usual interstitial pneumonitis (UIP). This disease has a poor prognosis, having the most lethal prognosis among ILDs. In fact, the progressive fibrosis related to IPF could lead to the development of complications, such as acute exacerbation, lung cancer, infections, pneumothorax and pulmonary hypertension. Pneumologists, radiologists and pathologists play a key role in the identification of IPF disease, and in the characterization of its complications—which unfortunately increase disease mortality and reduce overall survival. The early identification of these complications is very important, and requires an integrated approach among specialists, in order to plane the correct treatment. In some cases, the degree of severity of patients having IPF complications may require a personalized approach, based on palliative care services. Therefore, in this paper, we have focused on clinical and radiological features of the complications that occurred in our IPF patients, providing a comprehensive and accurate pictorial essay for clinicians, radiologists and surgeons involved in their management.
Ultrasonic Assessment of the Medial Temporal Lobe Tissue Displacements in Alzheimer’s Disease
Authors: Baranauskas Mindaugas , Jurkonis Rytis , Lukoševičius Arūnas , Makūnaitė Monika , Matijošaitis Vaidas , Gleiznienė Rymantė , Rastenytė Daiva
Published: July 2020

We aim to estimate brain tissue displacements in the medial temporal lobe (MTL) using backscattered ultrasound radiofrequency (US RF) signals, and to assess the diagnostic ability of brain tissue displacement parameters for the differentiation of patients with Alzheimer’s disease (AD) from healthy controls (HC). Standard neuropsychological evaluation and transcranial sonography (TCS) for endogenous brain tissue motion data collection are performed for 20 patients with AD and for 20 age- and sex-matched HC in a prospective manner. Essential modifications of our previous method in US waveform parametrization, raising the confidence of micrometer-range displacement signals in the presence of noise, are done. Four logistic regression models are constructed, and receiver operating characteristic (ROC) curve analyses are applied. All models have cut-offs from 61.0 to 68.5% and separate AD patients from HC with a sensitivity of 89.5% and a specificity of 100%. The area under a ROC curve of predicted probability in all models is excellent (from 95.2 to 95.7%). According to our models, AD patients can be differentiated from HC by a sharper morphology of some individual MTL spatial point displacements (i.e., by spreading the spectrum of displacements to the high-end frequencies with higher variability across spatial points within a region), by lower displacement amplitude differences between adjacent spatial points (i.e., lower strain), and by a higher interaction of these attributes.
Integrated Genomic Analysis of Chromosomal Alterations and Mutations in B-Cell Acute Lymphoblastic Leukemia Reveals Distinct Genetic Profiles at Relapse
Authors: Forero-Castro Maribel , Montaño Adrián , Robledo Cristina , García de Coca Alfonso , Fuster José Luis , de las Heras Natalia , Queizán José Antonio , Hernández-Sánchez María , Corchete-Sánchez Luis A. , Martín-Izquierdo Marta , Ribera Jordi , Ribera José-María , Benito Rocío , Hernández-Rivas Jesús M.
Published: July 2020

The clonal basis of relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is complex and not fully understood. Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH), and multiplex ligation-dependent probe amplification (MLPA) were carried out in matched diagnosis–relapse samples from 13 BCP-ALL patients to identify patterns of genetic evolution that could account for the phenotypic changes associated with disease relapse. The integrative genomic analysis of aCGH, MLPA and NGS revealed that 100% of the BCP-ALL patients showed at least one genetic alteration at diagnosis and relapse. In addition, there was a significant increase in the frequency of chromosomal lesions at the time of relapse (p = 0.019). MLPA and aCGH techniques showed that IKZF1 was the most frequently deleted gene. TP53 was the most frequently mutated gene at relapse. Two TP53 mutations were detected only at relapse, whereas the three others showed an increase in their mutational burden at relapse. Clonal evolution patterns were heterogeneous, involving the acquisition, loss and maintenance of lesions at relapse. Therefore, this study provides additional evidence that BCP-ALL is a genetically dynamic disease with distinct genetic profiles at diagnosis and relapse. Integrative NGS, aCGH and MLPA analysis enables better molecular characterization of the genetic profile in BCP-ALL patients during the evolution from diagnosis to relapse.
Reply to “Missing Skeletal Muscle Metastases of Papillary Thyroid Carcinoma”
Authors: Hitu Liviu , Cainap Calin , Apostu Dragos , Gabora Katalin , Bonci Eduard-Alexandru , Badan Marius , Mester Alexandru , Piciu Andra
Published: July 2020

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