bluuebunny/crossref_metadata_2025 huggingface dataset:
Ovarian Cancer in the Era of Immune Checkpoint Inhibitors: State of the Art and Future Perspectives
Authors: Maiorano Brigida Anna , Maiorano Mauro Francesco Pio , Lorusso Domenica , Maiello Evaristo
Published: September 2021

Background: Ovarian cancer (OC) represents the eighth most common cancer and the fifth leading cause of cancer-related deaths among the female population. In an advanced setting, chemotherapy represents the first-choice treatment, despite a high recurrence rate. In the last ten years, immunotherapy based on immune checkpoint inhibitors (ICIs) has profoundly modified the therapeutic scenario of many solid tumors. We sought to summarize the main findings regarding the clinical use of ICIs in OC. Methods: We searched PubMed, Embase, and Cochrane Databases, and conference abstracts from international congresses (such as ASCO, ESMO, SGO) for clinical trials, focusing on ICIs both as monotherapy and as combinations in the advanced OC. Results: 20 studies were identified, of which 16 were phase I or II and 4 phase III trials. These trials used ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, aterolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab). There was no reported improvement in survival, and some trials were terminated early due to toxicity or lack of response. Combining ICIs with chemotherapy, anti-VEGF therapy, or PARP inhibitors improved response rates and survival in spite of a worse safety profile. Conclusions: The identification of biomarkers with a predictive role for ICIs’ efficacy is mandatory. Moreover, genomic and immune profiling of OC might lead to better treatment options and facilitate the design of tailored trials.
Leukoplakia in the Oral Cavity and Oral Microbiota: A Comprehensive Review
Authors: Pietrobon Giacomo , Tagliabue Marta , Stringa Luigi Marco , De Berardinis Rita , Chu Francesco , Zocchi Jacopo , Carlotto Elena , Chiocca Susanna , Ansarin Mohssen
Published: September 2021

We reviewed the current published literature on the impact of oral microbiota on oral cavity leukoplakia (OLK), aiming at clarifying its role in disease transformation. The analysis unveiled that bacterial richness and diversity in the oral cavity tend to be decreased in OLK compared to healthy controls, with a reduction in the prevalent commensals, such as Streptococci, and elevation of anaerobes. Moreover, Fusobacterium nucleatum, Porphyromonas gingivalis and Prevotella intermedia are recurrent findings, and they already have been linked to periodontal disease. These microbial community changes may also represent a marker for the transition from OLK to oral squamous cell carcinoma. Unfortunately, the reviewed studies present several limitations, making an objective comparison difficult. To overcome these biases, longitudinal studies are necessary.
Landscape of Biomarkers and Actionable Gene Alterations in Adenocarcinoma of GEJ and Stomach—A Real World Data Analysis
Authors: Hempel Louisa , de Oliveira Julia Veloso , Gaumann Andreas , Milani Valeria , Schweneker Katrin , Schenck Kristina , Fleischmann Bastian , Philipp Patrick , Mederle Stefanie , Garg Arun , Piehler Armin , Gandorfer Beate , Schick Cordula , Kleespies Axel , Sellmann Ludger , Bartels Marius , Goetze Thorsten Oliver , Stein Alexander , Goekkurt Eray , Pfitzner Lucia , Robert Sebastian , Hempel Dirk
Published: September 2021

After several years of negative phase III trials in gastric and esophageal cancer, a significant breakthrough in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC) is now becoming evident with the emerging of precision oncology and implementation of molecular targets in tumor treatment. In addition, new generation studies such as umbrella and basket trials are focused on these molecular targets, which makes an early molecular diagnosis based on IHC/ISH and NGS necessary. The required companion diagnostics of Her2neu overamplification or PD-L1 expression is based on immunohistochemistry (IHC) or additionally in situ hybridization (ISH) in case of an IHC Her2neu score of 2+. However, there are investigator-dependent differences in the assessment of Her2neu amplification and different PD-L1 scoring systems obtained by IHC/ISH. The use of high-throughput technologies such as next-generation sequencing (NGS) holds the potential to standardize the analysis and thus make them more comparable. In the presented study, real-world multigene sequencing data of 72 Caucasian patients diagnosed with metastatic adenocarcinomas of GEJ and stomach were analyzed. In the clinical companion diagnostics, we found ESCAT level I molecular targets in one-third of our patients, which directly determined the therapy. In addition, we found potential targets in 14/72 patients (19.4%) who potentially qualify for precision therapies in corresponding molecular studies. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment.
Clinical Impact of Unexpected Para-Aortic Lymph Node Metastasis in Surgery for Resectable Pancreatic Cancer
Authors: Lee Ho-Kyoung , Yoon Yoo-Seok , Han Ho-Seong , Lee Jun Suh , Na Hee Young , Ahn Soomin , Park Jaewoo , Jung Kwangrok , Jung Jae Hyup , Kim Jaihwan , Hwang Jin-Hyeok , Lee Jong-Chan
Published: September 2021

Radiologically identified para-aortic lymph node (PALN) metastasis is contraindicated for pancreatic cancer (PC) surgery. There is no clinical consensus for unexpected intraoperative PALN enlargement. To analyze the prognostic role of unexpected PALN enlargement in resectable PC, we retrospectively reviewed data of 1953 PC patients in a single tertiary center. Patients with unexpected intraoperative PALN enlargement (group A1, negative pathology, n = 59; group A2, positive pathology, n = 13) showed median overall survival (OS) of 24.6 (95% CI: 15.2–33.2) and 13.0 (95% CI: 4.9–19.7) months, respectively. Patients with radiological PALN metastasis without other metastases (group B, n = 91) showed median OS of 8.6 months (95% CI: 7.4–11.6). Compared with group A1, groups A2 and B had hazard ratios (HRs) of 2.79 (95% CI, 1.4–5.7) and 2.67 (95% CI: 1.8–4.0), respectively. Compared with group A2, group B had HR of 0.96 (95% CI: 0.5–1.9). Multivariable analysis also showed positive PALN as a negative prognostic factor (HR 2.57, 95% CI: 1.2–5.3), whereas positive regional lymph node did not (HR 1.32 95% CI: 0.8–2.3). Thus, unexpected malignant PALN has a negative prognostic impact comparable to radiological PALN metastasis. This results suggests prompt pathologic evaluation for unexpected PALN enlargements is needed and on-site modification of surgical strategy would be considered.
Best Practices for Spatial Profiling for Breast Cancer Research with the GeoMx® Digital Spatial Profiler
Authors: Bergholtz Helga , Carter Jodi , Cesano Alessandra , Cheang Maggie , Church Sarah , Divakar Prajan , Fuhrman Christopher , Goel Shom , Gong Jingjing , Guerriero Jennifer , Hoang Margaret , Hwang E. , Kuasne Hellen , Lee Jinho , Liang Yan , Mittendorf Elizabeth , Perez Jessica , Prat Aleix , Pusztai Lajos , Reeves Jason , Riazalhosseini Yasser , Richer Jennifer , Sahin Özgür , Sato Hiromi , Schlam Ilana , Sørlie Therese , Stover Daniel , Swain Sandra , Swarbrick Alexander , Thompson E. , Tolaney Sara , Warren Sarah ,   on behalf of the GeoMx Breast Cancer Consortium
Published: September 2021

Breast cancer is a heterogenous disease with variability in tumor cells and in the surrounding tumor microenvironment (TME). Understanding the molecular diversity in breast cancer is critical for improving prediction of therapeutic response and prognostication. High-plex spatial profiling of tumors enables characterization of heterogeneity in the breast TME, which can holistically illuminate the biology of tumor growth, dissemination and, ultimately, response to therapy. The GeoMx Digital Spatial Profiler (DSP) enables researchers to spatially resolve and quantify proteins and RNA transcripts from tissue sections. The platform is compatible with both formalin-fixed paraffin-embedded and frozen tissues. RNA profiling was developed at the whole transcriptome level for human and mouse samples and protein profiling of 100-plex for human samples. Tissue can be optically segmented for analysis of regions of interest or cell populations to study biology-directed tissue characterization. The GeoMx Breast Cancer Consortium (GBCC) is composed of breast cancer researchers who are developing innovative approaches for spatial profiling to accelerate biomarker discovery. Here, the GBCC presents best practices for GeoMx profiling to promote the collection of high-quality data, optimization of data analysis and integration of datasets to advance collaboration and meta-analyses. Although the capabilities of the platform are presented in the context of breast cancer research, they can be generalized to a variety of other tumor types that are characterized by high heterogeneity.
Kv1.3 Controls Mitochondrial Dynamics during Cell Cycle Progression
Authors: Capera Jesusa , Pérez-Verdaguer Mireia , Navarro-Pérez María , Felipe Antonio
Published: September 2021

The voltage-gated potassium channel Kv1.3 is a potential therapeutic target for obesity and diabetes. The genetic ablation and pharmacological inhibition of Kv1.3 lead to a lean phenotype in rodents. The mechanism of regulation of body weight and energy homeostasis involves Kv1.3 expression in different organs, including white and brown adipose tissues. Here, we show that Kv1.3 promotes the proliferation of preadipocytes through the control of mitochondrial dynamics. Kv1.3 is expressed in mitochondria exhibiting high affinity for the perinuclear population. The mitochondrial network is highly dynamic during the cell cycle, showing continuous fusion-fission events. The formation of a hyperfused mitochondrial network at the G1/S phase of the cell cycle is dependent on Kv1.3 expression. Our results demonstrate that Kv1.3 promotes preadipocyte proliferation and differentiation by controlling mitochondrial membrane potential and mitochondrial dynamics at the G1 phase of the cell cycle.
Human DLG1 and SCRIB Are Distinctly Regulated Independently of HPV-16 during the Progression of Oropharyngeal Squamous Cell Carcinomas: A Preliminary Analysis
Authors: Lulić Lucija , Jakovčević Antonia , Manojlović Luka , Dediol Emil , Banks Lawrence , Tomaić Vjekoslav
Published: September 2021

The major causative agents of head and neck squamous cell carcinomas (HNSCCs) are either environmental factors, such as tobacco and alcohol consumption, or infection with oncogenic human papillomaviruses (HPVs). An important aspect of HPV-induced oncogenesis is the targeting by the E6 oncoprotein of PDZ domain-containing substrates for proteasomal destruction. Tumor suppressors DLG1 and SCRIB are two of the principal PDZ domain-containing E6 targets. Both have been shown to play critical roles in the regulation of cell growth and polarity and in maintaining the structural integrity of the epithelia. We investigated how modifications in the cellular localization and protein expression of DLG1 and SCRIB in HPV16-positive and HPV-negative histologic oropharyngeal squamous cell carcinomas (OPSCC) might reflect disease progression. HPV presence was determined by p16 staining and HPV genotyping. Whilst DLG1 expression levels did not differ markedly between HPV-negative and HPV16-positive OPSCCs, it appeared to be relocated from cell–cell contacts to the cytoplasm in most samples, regardless of HPV16 positivity. This indicates that alterations in DLG1 distribution could contribute to malignant progression in OPSCCs. Interestingly, SCRIB was also relocated from cell–cell contacts to the cytoplasm in the tumor samples in comparison with normal tissue, regardless of HPV16 status, but in addition there was an obvious reduction in SCRIB expression in higher grade tumors. Strikingly, loss of SCRIB was even more pronounced in HPV16-positive OPSCCs. These alterations in SCRIB levels may contribute to transformation and loss of tissue architecture in the process of carcinogenesis and could potentially serve as markers in the development of OPSCCs.
Prior Exposure to Coxsackievirus A21 Does Not Mitigate Oncolytic Therapeutic Efficacy
Authors: Burnett William J. , Burnett David M. , Parkman Gennie , Ramstead Andrew , Contreras Nico , Gravley William , Holmen Sheri L. , Williams Matthew A. , VanBrocklin Matthew W.
Published: September 2021

Oncolytic viruses (OVs) are being developed as a type of immunotherapy and have demonstrated durable tumor responses and clinical efficacy. One such OV, Coxsackievirus A21 (CVA21), exhibited therapeutic efficacy in early phase clinical trials, demonstrating the ability to infect and kill cancer cells and stimulate anti-tumor immune responses. However, one of the major concerns in using this common cold virus as a therapeutic is the potential for innate and adaptive immune responses to mitigate the benefits of viral infection, particularly in individuals that have been exposed to coxsackievirus prior to treatment. In this study, we assess melanoma responses to CVA21 in the absence or presence of prior exposure to the virus. Melanomas were transplanted into naïve or CVA21-immunized C57BL6 mice and the mice were treated with intratumoral (IT) CVA21. We find that prior exposure to CVA21 does not dramatically affect tumor responses, nor does it alter overall survival. Our results suggest that prior exposure to coxsackievirus is not a critical determinant of patient selection for IT CVA21 interventions.
One-Step Nucleic Acid Amplification (OSNA) of Sentinel Lymph Node in Early-Stage Endometrial Cancer: Spanish Multicenter Study (ENDO-OSNA)
Authors: Diestro María , Berjón Alberto , Zapardiel Ignacio , Yébenes Laura , Ruiz Irune , Lekuona Arantza , Rezola Marta , Jaunarena Ibon , Siegrist Jaime , Sánchez-Pastor Margarita , Cuadra María , Sagasta Amaia , Guerra Isabel , Lete Luis , Roldán Fernando , Marta Carlo , Boillos María , Cardiel María , López-de la Manzanara Carlos , Relea Fernanda , Coronado Pluvio , Pascual Alejandro , Román María , Peiró Gloria , Matute Luis , Montero Beatriz , Muruzábal Juan , Guarch Rosa , Zorrero Cristina , Calatrava Ana , Ribot Laia , Costa Irmgard , Hernández Alicia , Hardisson David
Published: September 2021

The objective of this study was to evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis compared to standard pathological ultrastaging in patients with early-stage endometrial cancer (EC). A total of 526 SLNs from 191 patients with EC were included in the study, and 379 SLNs (147 patients) were evaluated by both methods, OSNA and standard pathological ultrastaging. The central 1 mm portion of each lymph node was subjected to semi-serial sectioning at 200 μm intervals and examined by hematoxylin–eosin and immunohistochemistry with CK19; the remaining tissue was analyzed by OSNA for CK19 mRNA. The OSNA assay detected metastases in 19.7% of patients (14.9% micrometastasis and 4.8% macrometastasis), whereas pathological ultrastaging detected metastasis in 8.8% of patients (3.4% micrometastasis and 5.4% macrometastasis). Using the established cut-off value for detecting SLN metastasis by OSNA in EC (250 copies/μL), the sensitivity of the OSNA assay was 92%, specificity was 82%, diagnostic accuracy was 83%, and the negative predictive value was 99%. Discordant results between both methods were recorded in 20 patients (13.6%). OSNA resulted in an upstaging in 12 patients (8.2%). OSNA could aid in the identification of patients requiring adjuvant treatment at the time of diagnosis.
Tumor Nonimmune-Microenvironment-Related Gene Expression Signature Predicts Brain Metastasis in Lung Adenocarcinoma Patients after Surgery: A Machine Learning Approach Using Gene Expression Profiling
Authors: Haam Seokjin , Han Jae-Ho , Lee Hyun Woo , Koh Young Wha
Published: September 2021

Using a machine learning approach with a gene expression profile, we discovered a tumor nonimmune-microenvironment-related gene expression signature, including extracellular matrix (ECM) remodeling, epithelial–mesenchymal transition (EMT), and angiogenesis, that could predict brain metastasis (BM) after the surgical resection of 64 lung adenocarcinomas (LUAD). Gene expression profiling identified a tumor nonimmune-microenvironment-related 17-gene expression signature that significantly correlated with BM. Of the 17 genes, 11 were ECM-remodeling-related genes. The 17-gene expression signature showed high BM predictive power in four machine learning classifiers (areas under the receiver operating characteristic curve = 0.845 for naïve Bayes, 0.849 for support vector machine, 0.858 for random forest, and 0.839 for neural network). Subgroup analysis revealed that the BM predictive power of the 17-gene signature was higher in the early-stage LUAD than in the late-stage LUAD. Pathway enrichment analysis showed that the upregulated differentially expressed genes were mainly enriched in the ECM–receptor interaction pathway. The immunohistochemical expression of the top three genes of the 17-gene expression signature yielded similar results to NanoString tests. The tumor nonimmune-microenvironment-related gene expression signatures found in this study are important biological markers that can predict BM and provide patient-specific treatment options.
Variable Molecular Weight Polymer Nanoparticles for Detection and Hyperthermia-Induced Chemotherapy of Colorectal Cancer
Authors: Sarkar Santu , Levi Nicole
Published: September 2021

Oxaliplatin plays a significant role as a chemotherapeutic agent for the treatment of colorectal cancer (CRC); however, oxaliplatin-resistant phenotypes make further treatment challenging. Here, we have demonstrated that rapid (60 s) hyperthermia (42 °C), generated by the near-infrared stimulation of variable molecular weight nanoparticles (VMWNPs), increases the effectiveness of oxaliplatin in the oxaliplatin-resistant CRC cells. VMWNP-induced hyperthermia resulted in a higher cell death in comparison to cells exposed to chemotherapy at 42 °C for 2 h. Fluorescence from VMWNPs was observed inside cells, which allows for the detection of CRC. The work further demonstrates that the intracellular thermal dose can be determined using cell luminescence and correlated with the cell viability and response to VMWNP-induced chemotherapy. Mild heating makes oxaliplatin-resistant cancer cells responsive to chemotherapy, and the VMWNPs-induced hyperthermia can induce cell death in a few minutes, compared to classical bulk heating. The results presented here lay the foundation for photothermal polymer nanoparticles to be used for cell ablation and augmenting chemotherapy in drug-resistant colorectal cancer cells.
Targeting S1PR1 May Result in Enhanced Migration of Cancer Cells in Bladder Carcinoma
Authors: Chen Chin-Li , Meng En , Wu Sheng-Tang , Lai Hsing-Fan , Lu Yi-Shan , Yang Ming-Hsin , Tsao Chih-Wei , Kao Chien-Chang , Chiu Yi-Lin
Published: September 2021

Clinical bladder tumor histological analysis shows that high expression of S1PR1 is associated with poor patient prognosis. However, there are no studies that describe the underlying mechanism. To investigate the relative distribution and actual function of S1PR1 in bladder tumors, we analyzed multiple clinical databases in combination with tumor purity and immune cell infiltration simulations, as well as databases of well-defined histological phenotypes of bladder cancer, and single-cell sequencing of adjacent normal tissues and bladder tumors, and further compared them with bladder cancer cell lines. The results showed that S1PR1 expression was generally higher in normal tissues than in bladder cancer tissues, and its distribution was mainly in endothelial cells or immune cells. The association between high S1PR1 expression and poor prognosis may be due to tumor invasion of adjacent normal tissues, where highly expressed S1PR1 may affect prognostic interpretation. The effect of S1PR1 itself on cancer cells was associated with cell adhesion, and in bladder cancer cells, S1PR1 expression was negatively correlated with cell motility. Moreover, the use of FTY-720 will cause an increased metastatic ability of bladder cancer cells. In conclusion, we suggest that the use of S1PR1-specific inhibition as a synergistic treatment requires more observation and consideration.
Poor Neutralizing Antibody Responses in 132 Patients with CLL, NHL and HL after Vaccination against SARS-CoV-2: A Prospective Study
Authors: Terpos Evangelos , Gavriatopoulou Maria , Fotiou Despina , Giatra Chara , Asimakopoulos Ioannis , Dimou Maria , Sklirou Aimilia D. , Ntanasis-Stathopoulos Ioannis , Darmani Ismini , Briasoulis Alexandros , Kastritis Efstathios , Angelopoulou Maria , Baltadakis Ioannis , Panayiotidis Panayiotis , Trougakos Ioannis P. , Vassilakopoulos Theodoros P. , Pagoni Maria , Dimopoulos Meletios A.
Published: September 2021

Emerging data suggest suboptimal antibody responses to COVID-19 vaccination in patients with hematological malignancies. We evaluated the humoral response following the BNT162b2 vaccine in patients with chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma (NHL), and Hodgkin’s lymphoma (HL). An FDA-approved, ELISA-based methodology was implemented to evaluate the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 on day 1 of the first vaccine, and afterwards on day 22 and 50. One hundred and thirty-two patients with CLL/lymphomas and 214 healthy matched controls vaccinated during the same period, at the same center were enrolled in the study (NCT04743388). Vaccination with two doses of the BNT162b2 vaccine led to lower production of NAbs against SARS-CoV-2 in patients with CLL/lymphomas compared with controls both on day 22 and on day 50 (p < 0.001 for all comparisons). Disease-related immune dysregulation and therapy-related immunosuppression are involved in the low humoral response. Importantly, active treatment with Rituximab, Bruton’s tyrosine kinase inhibitors, or chemotherapy was an independent prognostic factor for suboptimal antibody response. Patients with HL showed superior humoral responses to the NHL/CLL subgroups. In conclusion, patients with CLL/lymphomas have low humoral response following COVID-19 vaccination, underlining the need for timely vaccination ideally during a treatment-free period and for continuous vigilance on infection control measures.
Papillary Thyroid Carcinoma with Desmoid-Type Fibromatosis: Review of Published Cases
Authors: Roukain Abdallah , La Rosa Stefano , Bongiovanni Massimo , Nicod Lalonde Marie , Cristina Valérie , Montemurro Michael , Cochet Stephane , Luquain Alexandra , Kopp Peter A. , Sykiotis Gerasimos P.
Published: September 2021

Desmoid-type fibromatosis (DTF) is a very rare variant of papillary thyroid carcinoma (PTC). It is essentially a dual tumor with a component of classical PTC with malignant epithelial proliferation (BRAF-mutated) and another component of mesenchymal proliferation (CTNNB1-mutated). We conducted a literature review on PTC-DTF. In total, 31 articles were identified, that together reported on 54 patients. The mean age was 47 years, with a 2.2:1 female predominance. No ultrasound features were found to be helpful in differentiating PTC-DTF from other PTC variants. Of the 43 cases that reported histological details, 60% had locally infiltrative disease (T3b or T4). Around 48% had cervical lymph node metastases, but none had distant metastases. While PTC-DTF may be locally more aggressive than classic PTC, its overall behavior is similar and can include extrathyroidal extension and lymph node metastases, which may contain a stromal component and show extranodal invasion. The mainstay of treatment for PTC-DTF is surgery, and the DTF component is not expected to be sensitive to radioactive iodine. External radiotherapy, non-steroidal anti-inflammatory drugs, tyrosine kinase inhibitors and chemotherapy have also been used in selected cases. Due to the rarity of these tumors and the lack of specific treatment guidelines, management should be discussed in a multidisciplinary team.
In Vitro and In Vivo Enhancement of Temozolomide Effect in Human Glioblastoma by Non-Invasive Application of Cold Atmospheric Plasma
Authors: Soni Vikas , Adhikari Manish , Simonyan Hayk , Lin Li , Sherman Jonathan H. , Young Colin N. , Keidar Michael
Published: September 2021

Glioblastoma (GBM) is one of the most aggressive forms of adult brain cancers and is highly resistant to treatment, with a median survival of 12–18 months after diagnosis. The poor survival is due to its infiltrative pattern of invasion into the normal brain parenchyma, the diffuse nature of its growth, and its ability to quickly grow, spread, and relapse. Temozolomide is a well-known FDA-approved alkylating chemotherapy agent used for the treatment of high-grade malignant gliomas, and it has been shown to improve overall survival. However, in most cases, the tumor relapses. In recent years, CAP has been used as an emerging technology for cancer therapy. The purpose of this study was to implement a combination therapy of CAP and TMZ to enhance the effect of TMZ and apparently sensitize GBMs. In vitro evaluations in TMZ-sensitive and resistant GBM cell lines established a CAP chemotherapy enhancement and potential sensitization effect across various ranges of CAP jet application. This was further supported with in vivo findings demonstrating that a single CAP jet applied non-invasively through the skull potentially sensitizes GBM to subsequent treatment with TMZ. Gene functional enrichment analysis further demonstrated that co-treatment with CAP and TMZ resulted in a downregulation of cell cycle pathway genes. These observations indicate that CAP can be potentially useful in sensitizing GBM to chemotherapy and for the treatment of glioblastoma as a non-invasive translational therapy.
Subpopulations of Circulating Cells with Morphological Features of Malignancy Are Preoperatively Detected and Have Differential Prognostic Significance in Non-Small Cell Lung Cancer
Authors: Fina Emanuela , Federico Davide , Novellis Pierluigi , Dieci Elisa , Monterisi Simona , Cioffi Federica , Mangiameli Giuseppe , Finocchiaro Giovanna , Alloisio Marco , Veronesi Giulia
Published: September 2021

Background: Non-small cell lung cancer (NSCLC) frequently presents when surgical intervention is no longer feasible. Despite local treatment with curative intent, patients might experience disease recurrence. In this context, accurate non-invasive biomarkers are urgently needed. We report the results of a pilot study on the diagnostic and prognostic role of circulating tumor cells (CTCs) in operable NSCLC. Methods: Blood samples collected from healthy volunteers (n = 10), nodule-negative high-risk individuals enrolled in a screening program (n = 7), and NSCLC patients (n = 74) before surgery were analyzed (4 mL) for the presence of cells with morphological features of malignancy enriched through the ISET® technology. Results: CTC detection was 60% in patients, while no target cells were found in lung cancer-free donors. We identified single CTCs (sCTC, 46%) and clusters of CTCs and leukocytes (heterotypic clusters, hetCLU, 31%). The prevalence of sCTC (sCTC/4 mL ≥ 2) or the presence of hetCLU predicted the risk of disease recurrence within the cohort of early-stage (I–II, n = 52) or advanced stage cases (III–IVA, n = 22), respectively, while other tumor-related factors did not inform prognosis. Conclusions: Cancer cell hematogenous dissemination occurs frequently in patients with NSCLC without clinical evidence of distant metastases, laying the foundation for the application of cell-based tests in screening programs. CTC subpopulations are fine prognostic classifiers whose clinical validity should be further investigated in larger studies.
Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer
Authors: Oo Htoo Zarni , Lohinai Zoltan , Khazamipour Nastaran , Lo Joey , Kumar Gunjan , Pihl Jessica , Adomat Hans , Nabavi Noushin , Behmanesh Hakhamanesh , Zhai Beibei , Dagil Robert , Choudhary Swati , Gustavsson Tobias , Clausen Thomas M. , Esko Jeffrey D. , Allen Jeffrey W. , Thompson Michael A. , Tran Nhan L. , Moldvay Judit , Dome Balazs , Salanti Ali , Al-Nakouzi Nader , Weiss Glen J. , Daugaard Mads
Published: September 2021

Broad-spectrum therapeutics in non-small cell lung cancer (NSCLC) are in demand. Most human solid tumors express proteoglycans modified with distinct oncofetal chondroitin sulfate (CS) chains that can be detected and targeted with recombinant VAR2CSA (rVAR2) proteins and rVAR2-derived therapeutics. Here, we investigated expression and targetability of oncofetal CS expression in human NSCLC. High oncofetal CS expression is associated with shorter disease-free survival and poor overall survival of clinically annotated stage I and II NSCLC patients (n = 493). Oncofetal CS qualifies as an independent prognosticator of NSCLC in males and smokers, and high oncofetal CS levels are more prevalent in EGFR/KRAS wild-type cases, as compared to mutation cases. NSCLC cell lines express oncofetal CS-modified proteoglycans that can be specifically detected and targeted by rVAR2 proteins in a CSA-dependent manner. Importantly, a novel VAR2-drug conjugate (VDC-MMAE) efficiently eliminates NSCLC cells in vitro and in vivo. In summary, oncofetal CS is a prognostic biomarker and an actionable glycosaminoglycan target in NSCLC.
Targeting Bone Metastasis in Cancers
Authors: Bonnelye Edith , Juárez Patricia
Published: September 2021

This Special Issue of Cancers covers different aspects of bone physiopathology in oncology that combine the microenvironment and the factors involved in bone metastasis dormancy and progression [...]
The Expression Profiles and Deregulation of UDP-Glycosyltransferase (UGT) Genes in Human Cancers and Their Association with Clinical Outcomes
Authors: Hu Dong Gui , Marri Shashikanth , Mackenzie Peter I. , Hulin Julie-Ann , McKinnon Ross A. , Meech Robyn
Published: September 2021

The human UDP-glycosyltransferase (UGTs) superfamily has 22 functional enzymes that play a critical role in the metabolism of small lipophilic compounds, including carcinogens, drugs, steroids, lipids, fatty acids, and bile acids. The expression profiles of UGT genes in human cancers and their impact on cancer patient survival remains to be systematically investigated. In the present study, a comprehensive analysis of the RNAseq and clinical datasets of 9514 patients from 33 different TCGA (the Genome Cancer Atlas) cancers demonstrated cancer-specific UGT expression profiles with high interindividual variability among and within individual cancers. Notably, cancers derived from drug metabolizing tissues (liver, kidney, gut, pancreas) expressed the largest number of UGT genes (COAD, KIRC, KIRP, LIHC, PAAD); six UGT genes (1A6, 1A9, 1A10, 2A3, 2B7, UGT8) showed high expression in five or more different cancers. Kaplan–Meier plots and logrank tests revealed that six UGT genes were significantly associated with increased overall survival (OS) rates [UGT1A1 (LUSC), UGT1A6 (ACC), UGT1A7 (ACC), UGT2A3 (KIRC), UGT2B15 (BLCA, SKCM)] or decreased OS rates [UGT2B15 (LGG), UGT8 (UVM)] in specific cancers. Finally, differential expression analysis of 611 patients from 12 TCGA cancers identified 16 UGT genes (1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2A1, 2A3, 2B4, 2B7, 2B11, 2B15, 3A1, 3A2, UGT8) that were up/downregulated in at least one cancer relative to normal tissues. In conclusion, our data show widespread expression of UGT genes in cancers, highlighting the capacity for intratumoural drug metabolism through the UGT conjugation pathway. The data also suggests the potentials for specific UGT genes to serve as prognostic biomarkers or therapeutic targets in cancers.
Intracranial Treatment in Melanoma Patients with Brain Metastasis Is Associated with Improved Survival in the Era of Immunotherapy and Anti-BRAF Therapy
Authors: Dalmasso Céline , Pagès Cécile , Chaltiel Léonor , Sibaud Vincent , Moyal Elisabeth , Chira Ciprian , Sol Jean Christophe , Latorzeff Igor , Meyer Nicolas , Modesto Anouchka
Published: September 2021

Metastatic melanoma patients are at high risk of brain metastases (BM). Although intracranial control is a prognostic factor for survival, impact of local (intracranial) treatment (LT), surgery and/or radiotherapy (stereotactic or whole brain) in the era of novel therapies remains unknown. We evaluated BM incidence in melanoma patients receiving immune checkpoint inhibitors (ICI) or anti-BRAF therapy and identified prognostic factors for overall survival (OS). Clinical data and treatment patterns were retrospectively collected from all patients treated for newly diagnosed locally advanced or metastatic melanoma between May 2014 and December 2017 with available BRAF mutation status and receiving systemic therapy. Prognostic factors for OS were analyzed with univariable and multivariable survival analyses. BMs occurred in 106 of 250 eligible patients (42.4%), 64 of whom received LT. Median OS in patients with BM was 7.8 months (95% CI [5.4–10.4]). In multivariable analyses, LT was significantly correlated with improved OS (HR 0.21, p < 0.01). Median OS was 17.3 months (95% CI [8.3–22.3]) versus 3.6 months (95% CI [1.4–4.8]) in patients with or without LT. LT correlates with improved OS in melanoma patients with BM in the era of ICI and anti-BRAF therapy. The use of LT should be addressed at diagnosis of BM while introducing systemic treatment.
MgCr-LDH Nanoplatelets as Effective Oxidation Catalysts for Visible Light-Triggered Rhodamine B Degradation
Authors: Nayak Susanginee , Parida Kulamani
Published: September 2021

In this work, we successfully exfoliated MgCr-(NO3−) LDH with large purity by a simple formamide method followed by post-hydrothermal treatment and characterized by different physico-chemical techniques. The UV-DRS study persuades the red-shifted absorption band and suitable band gap of MgCr-(NO3−) LDH for optimum light harvestation ability related to the optical properties. Alternatively, the production of elevated photocurrent density of MgCr-(NO3−) LDH (3:1, 80 °C) in the anodic direction was verified by the LSV study, which further revealed their effective charge separation efficacy. These MgCr-LDH nanosheets (3:1, 80 °C) displayed the superior Rhodamine B (RhB) degradation efficiency of 95.0% at 0.80 kW/m2 solar light intensity in 2 h. The tremendous catalytic performances of MgCr-LDH (3:1, 80 °C) were typically linked with the formation of surface-active sites for the charge trapping process due to the presence of uncoordinated metallocenters during the exfoliation process. Furthermore, the maximum amount of the active free atoms at the edges of the hexagonal platelet of MgCr-LDH causes severance of the nanosheets, which generates house of platelets of particle size ~20–50 nm for light harvestation, promoting easy charge separation and catalytic efficiency. In addition, radical quenching tests revealed that h+ and •OH play as major active species responsible for the RhB degradation.
Creating and Preserving Nanoparticles during Co-Sintering of Solid Oxide Electrodes and Its Impact on Electrocatalytic Activity
Authors: Muhoza Sixbert P. , Gross Michael D.
Published: September 2021

A novel processing method that creates and preserves ceramic nanoparticles in solid oxide electrodes during co-sintering at traditional sintering temperatures is introduced. Specifically, carbon templated samarium-doped ceria nanoparticles (nSDC) were successfully integrated with commercial lanthanum strontium cobalt ferrite (LSCF) and commercial SDC powders, producing LSCF-SDC-nSDC cathodes upon processing. The effect of nSDC concentration on cathode electrocatalytic activity was investigated at low operational temperatures, 600 °C–700 °C, with symmetrical cells. Low nSDC loadings, ≤5 wt% nSDC, significantly decreased cell polarization resistance whereas higher loadings increased it. The best electrochemical performance was achieved with 5 wt% nSDC, lowering the polarization resistance by 41% at 600 °C. Fuel cell tests demonstrate that adding 5 wt% nSDC increased the maximum fuel cell power density by 38%. Electrochemical impedance spectra showed substantial improvements in both fuel cell polarization resistance and ohmic resistance, indicating that nSDC increased the electrocatalytically active area of the cathode. This work demonstrates a simple, novel method for effectively increasing electrocatalytic activity of solid oxide electrodes at low operational temperatures.
Comparison of a New 68Ga-Radiolabelled PET Imaging Agent sCD146 and RGD Peptide for In Vivo Evaluation of Angiogenesis in Mouse Model of Myocardial Infarction
Authors: Moyon Anaïs , Garrigue Philippe , Fernandez Samantha , Hubert Fabien , Balasse Laure , Brige Pauline , Hache Guillaume , Nail Vincent , Blot-Chabaud Marcel , Dignat-George Françoise , Rochais Francesca , Guillet Benjamin
Published: September 2021

Ischemic vascular diseases are associated with elevated tissue expression of angiomotin (AMOT), a promising molecular target for PET imaging. On that basis, we developed an AMOT-targeting radiotracer, 68Ga-sCD146 and performed the first in vivo evaluation on a myocardial infarction mice model and then, compared AMOT expression and αvβ3-integrin expression with 68Ga-sCD146 and 68Ga-RGD2 imaging. After myocardial infarction (MI) induced by permanent ligation of the left anterior descending coronary artery, myocardial perfusion was evaluated by Doppler ultrasound and by 18F-FDG PET imaging. 68Ga-sCD146 and 68Ga-RGD2 PET imaging were performed. In myocardial infarction model, heart-to-muscle ratio of 68Ga-sCD146 imaging showed a significantly higher radiotracer uptake in the infarcted area of MI animals than in sham (* p = 0.04). Interestingly, we also observed significant correlations between 68Ga-sCD146 imaging and delayed residual perfusion assessed by 18F-FDG (* p = 0.04), with lowest tissue fibrosis assessed by histological staining (* p = 0.04) and with functional recovery assessed by ultrasound imaging (** p = 0.01). 68Ga-sCD146 demonstrated an increase in AMOT expression after MI. Altogether, significant correlations of early post-ischemic 68Ga-sCD146 uptake with late heart perfusion, lower tissue fibrosis and better functional recovery, make 68Ga-sCD146 a promising radiotracer for tissue angiogenesis assessment after MI.
N-Glycomic Analysis of the Cell Shows Specific Effects of Glycosyl Transferase Inhibitors
Authors: Zhou Qingwen , Xie Yixuan , Lam Matthew , Lebrilla Carlito B.
Published: September 2021

Glycomic profiling methods were used to determine the effect of metabolic inhibitors on glycan production. These inhibitors are commonly used to alter the cell surface glycosylation. However, structural analysis of the released glycans has been limited. In this research, the cell membranes were enriched and the glycans were released to obtain the N-glycans of the glycocalyx. Glycomic analysis using liquid chromatography–mass spectrometry (LC–MS) with a PGC chip column was used to profile the structures in the cell membrane. Glycans of untreated cells were compared to glycans of cells treated with inhibitors, including kifunensine, which inhibits the formation of complex- and hybrid-type structures, 2,4,7,8,9-Penta-O-acetyl-N-acetyl-3-fluoro-b-d-neuraminic acid methyl ester for sialylated glycans, 2-deoxy-2-fluorofucose, and 6-alkynyl fucose for fucosylated glycans. Kifunensine was the most effective, converting nearly 95% of glycans to high mannose types. The compound 6-alkynyl fucose inhibited some fucosylation but also incorporated into the glycan structure. Proteomic analysis of the enriched membrane for the four inhibitors showed only small changes in the proteome accompanied by large changes in the N-glycome for Caco-2. Future works may use these inhibitors to study the cellular behavior associated with the alteration of glycosylation in various biological systems, e.g., viral and bacterial infection, drug binding, and cell–cell interactions.
Induced Pluripotent Stem Cells (iPSCs)—Roles in Regenerative Therapies, Disease Modelling and Drug Screening
Authors: Aboul-Soud Mourad A. M. , Alzahrani Alhusain J. , Mahmoud Amer
Published: September 2021

The discovery of induced pluripotent stem cells (iPSCs) has made an invaluable contribution to the field of regenerative medicine, paving way for identifying the true potential of human embryonic stem cells (ESCs). Since the controversy around ethicality of ESCs continue to be debated, iPSCs have been used to circumvent the process around destruction of the human embryo. The use of iPSCs have transformed biological research, wherein increasing number of studies are documenting nuclear reprogramming strategies to make them beneficial models for drug screening as well as disease modelling. The flexibility around the use of iPSCs include compatibility to non-invasive harvesting, and ability to source from patients with rare diseases. iPSCs have been widely used in cardiac disease modelling, studying inherited arrhythmias, neural disorders including Alzheimer’s disease, liver disease, and spinal cord injury. Extensive research around identifying factors that are involved in maintaining the identity of ESCs during induction of pluripotency in somatic cells is undertaken. The focus of the current review is to detail all the clinical translation research around iPSCs and the strength of its ever-growing potential in the clinical space.
Effects of Therapy with Fibrin Glue combined with Mesenchymal Stem Cells (MSCs) on Bone Regeneration: A Systematic Review
Authors: Ortiz Adriana de Cássia , Fideles Simone Ortiz Moura , Pomini Karina Torres , Reis Carlos Henrique Bertoni , Bueno Cleuber Rodrigo de Souza , Pereira Eliana de Souza Bastos Mazuqueli , Rossi Jéssica de Oliveira , Novais Paulo Cezar , Pilon João Paulo Galletti , Rosa Junior Geraldo Marco , Buchaim Daniela Vieira , Buchaim Rogerio Leone
Published: September 2021

Cell therapy strategies using mesenchymal stem cells (MSCs) carried in fibrin glue have shown promising results in regenerative medicine. MSCs are crucial for tissue healing because they have angiogenic, anti-apoptotic and immunomodulatory properties, in addition to the ability to differentiate into several specialized cell lines. Fibrin sealant or fibrin glue is a natural polymer involved in the coagulation process. Fibrin glue provides a temporary structure that favors angiogenesis, extracellular matrix deposition and cell-matrix interactions. Additionally, fibrin glue maintains the local and paracrine functions of MSCs, providing tissue regeneration through less invasive clinical procedures. Thus, the objective of this systematic review was to assess the potential of fibrin glue combined with MSCs in bone or cartilage regeneration. The bibliographic search was performed in the PubMed/MEDLINE, LILACS and Embase databases, using the descriptors (“fibrin sealant” OR “fibrin glue”) AND “stem cells” AND “bone regeneration”, considering articles published until 2021. In this case, 12 preclinical and five clinical studies were selected to compose this review, according to the eligibility criteria. In preclinical studies, fibrin glue loaded with MSCs, alone or associated with bone substitute, significantly favored bone defects regeneration compared to scaffold without cells. Similarly, fibrin glue loaded with MSCs presented considerable potential to regenerate joint cartilage injuries and multiple bone fractures, with significant improvement in clinical parameters and absence of postoperative complications. Therefore, there is clear evidence in the literature that fibrin glue loaded with MSCs, alone or combined with bone substitute, is a promising strategy for treating lesions in bone or cartilaginous tissue.
Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Echinoderms: Structure and Possible Functions
Authors: Dolmatov Igor Yu. , Nizhnichenko Vladimir A. , Dolmatova Lyudmila S.
Published: September 2021

Echinoderms are one of the most ancient groups of invertebrates. The study of their genomes has made it possible to conclude that these animals have a wide variety of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The phylogenetic analysis shows that the MMPs and TIMPs underwent repeated duplication and active divergence after the separation of Ambulacraria (Echinodermata+Hemichordata) from the Chordata. In this regard the homology of the proteinases and their inhibitors between these groups of animals cannot be established. However, the MMPs of echinoderms and vertebrates have a similar domain structure. Echinoderm proteinases can be structurally divided into three groups—archetypal MMPs, matrilysins, and furin-activatable MMPs. Gelatinases homologous to those of vertebrates were not found in genomes of studied species and are probably absent in echinoderms. The MMPs of echinoderms possess lytic activity toward collagen type I and gelatin and play an important role in the mechanisms of development, asexual reproduction and regeneration. Echinoderms have a large number of genes encoding TIMPs and TIMP-like proteins. TIMPs of these animals, with a few exceptions, have a structure typical for this class of proteins. They contain an NTR domain and 10–12 conservatively located cysteine residues. Repeated duplication and divergence of TIMP genes of echinoderms was probably associated with an increase in the functional importance of the proteins encoded by them in the physiology of the animals.
Nickel-Oxide Based Thick-Film Gas Sensors for Volatile Organic Compound Detection
Authors: Ayyala Sai Kiran , Covington James A.
Published: September 2021

In this paper, we report on the development of a highly sensitive and humidity-tolerant metal-oxide-based volatile organic compound (VOC) sensor, capable of rapidly detecting low concentrations of VOCs. For this, we successfully fabricated two different thicknesses of nickel oxide (NiO) sensors using a spin-coating technique and tested them with seven different common VOCs at 40% r.h. The measured film thickness of the spin-coated NiO was ~5 μm (S-5) and ~10 μm (S-10). The fastest response and recovery times for all VOCs were less than 80 s and 120 s, respectively. The highest response (Rg/Ra = 1.5 for 5 ppm ethanol) was observed at 350 °C for both sensors. Sensors were also tested in two different humidity conditions (40% and 90% r.h.). The humidity did not significantly influence the observed sensitivity of the films. Furthermore, S-10 NiO showed only a 3% drift in the baseline resistance between the two humidity conditions, making our sensor humidity-tolerant compared to traditional n-type sensors. Thus, we propose thick-film NiO (10 μm) sensing material as an interesting alternative VOC sensor that is fast and humidity-tolerant.
Measurement of Behavioral Emotion Regulation Strategies in Early Childhood: The Early Emotion Regulation Behavior Questionnaire (EERBQ)
Authors: Perry Nicole B. , Dollar Jessica M.
Published: September 2021

The Early Emotion Regulation Behavior Questionnaire (EERBQ) assesses children’s emotion regulation (ER) behavioral strategies in both positive and negative emotional contexts. Psychometric properties and factor structure were tested in a sample of caregivers across the United States (N = 362) with children ages 2–6 years-old (56% male; 73% White). Findings suggest that the EERBQ is psychometrically sound and correlates with other well-established measures of children’s socioemotional functioning. Previously, researchers have only been able to assess children’s emotional behavioral regulatory strategies in a laboratory setting. Thus, use of the EERBQ addresses a critical gap in the current literature by providing researchers and practitioners with an instrument to measure young children’s early emotional functioning outside of a laboratory context. This is particularly salient because early difficulty regulating emotions is often a precursor to persistent adverse developmental outcomes. Thus, the ability to easily to collect rich and predictive behavioral regulation data is imperative for early identification and treatment of youths’ emotional and behavioral problems.