bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Progress and Challenges of Flexible Zn-Based Batteries with Polymer Electrolyte
Authors: Mo Funian , Guo Binbin , Ling Wei , Wei Jun , Chen Lina , Yu Suzhu , Liang Guojin
Published: June 2022

Zn-based batteries have been identified as promising candidates for flexible and wearable batteries because of their merits of intrinsic safety, eco-efficiency, high capacity and cost-effectiveness. Polymer electrolytes, which feature high solubility of zinc salts and softness, are especially advantageous for flexible Zn-based batteries. However, many technical issues still need to be addressed in Zn-based batteries with polymer electrolytes for their future application in wearable electronics. Recent progress in advanced flexible Zn-based batteries based on polymer electrolytes, including functional hydrogel electrolytes and solid polymer electrolytes, as well as the interfacial interactions between polymer electrolytes and electrodes in battery devices, is comprehensively reviewed and discussed with a focus on their fabrication, performance validation, and intriguing affiliated functions. Moreover, relevant challenges and some potential strategies are also summarized and analyzed to help inform the future direction of polymer-electrolyte-based flexible Zn-based batteries with high practicability.
Tumor Microenvironment—A Short Review of Cellular and Interaction Diversity
Authors: Bożyk Aleksandra , Wojas-Krawczyk Kamila , Krawczyk Paweł , Milanowski Janusz
Published: June 2022

The tumor microenvironment is a complex network of various interactions between immune cells and non-cellular components such as the extracellular matrix, exosomes and interleukins. Moreover, tumor heterogeneity and its constant modification may alter the immunophenotype and become responsible for its resistance regarding the therapies applied However, it should be remembered that in a strongly immunosuppressive neoplastic microenvironment, the immune system cells undergo reprogramming and most often cease to fulfill their original function. Therefore, understanding what happens within the tumor microenvironment, and which mechanisms are responsible for tumor development and progression should let us know how cancer could protect itself against the immune system. The presented review summarizes the latest information on the interactions between the tumor microenvironment and the cellular and non-cellular components, as well as their impact on cancer development, progression and immune system exhaustion.
Ferroptosis-Related Proteins Are Potential Diagnostic Molecular Markers for Patients with Preeclampsia
Authors: Shi Meiting , Yang Xiaofeng , Ding Yuzhen , Sun Lu , Zhang Ping , Liu Mengyuan , Han Xiaoxue , Huang Zhengrui , Li Ruiman
Published: June 2022

Preeclampsia (PE) is the leading cause of maternal and fetal mortality and morbidity. Early and accurate diagnosis is critical to reduce mortality. Placental oxidative stress has been identified as a major pathway to the development of PE. Ferroptosis, a new form of regulated cell death, is associated with iron metabolism and oxidative stress, and has been suspected to play a role in the pathophysiology of PE, although the mechanism is yet to be elucidated. The identification of potential ferroptosis-related biomarkers is of great significance for the early diagnosis and treatment of PE. A gene expression dataset of peripheral blood samples was downloaded from the Gene Expression Omnibus (GEO) dataset. Differentially expressed genes (DEGs) were filtrated with the R package “limma”. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the DEGs were then conducted. Ferroptosis-related DEGs were screened by overlapping the ferroptosis-related genes with DEGs. The protein–protein interaction (PPI) network was used to identify the key ferroptosis-related DEGs. Enzyme-linked immunosorbent assay (ELISA) was used to validate changes in the selected key ferroptosis-related DEGs. The correlations between the key genes and clinical and pathological characteristics were analyzed. Finally, the diagnostic value of these key genes for PE was confirmed by a receiver operating characteristic (ROC) curve. A total of 5913 DEGs were identified and 45 ferroptosis-related DEGs were obtained. Besides, ferroptosis-related pathways were enriched by KEGG using DEGs. The PPI network showed that p53 and c-Jun were the critical hub genes. ELISA showed that p53 in the serum of PE patients was higher than that of the control group, while c-Jun was lower than that of the control group. Analysis of the clinicopathological features showed that p53 and c-Jun were correlated with the PE characteristics. Finally, based on the area under curve (AUC) values, c-Jun had the superior diagnostic power (AUC = 0.87, p < 0.001), followed by p53 (AUC = 0.75, p < 0.001). Our study identified that two key genes, p53 and c-Jun, might be potential diagnostic biomarkers of PE.
Kir4.2 Potassium Channels in Retinal Pigment Epithelial Cells In Vitro: Contribution to Cell Viability and Proliferation, and Down-Regulation by Vascular Endothelial Growth Factor
Authors: Beer Marie-Christin , Kuhrt Heidrun , Kohen Leon , Wiedemann Peter , Bringmann Andreas , Hollborn Margrit
Published: June 2022

Dedifferentiation and proliferation of retinal pigment epithelial (RPE) cells are characteristics of retinal diseases. Dedifferentiation is likely associated with changes of inwardly rectifying potassium (Kir) channels. The roles of Kir4.2 channels in viability, and proliferation of cultured RPE cells were investigated. Gene expression levels were determined using qRT-PCR. RPE cells expressed Kir2.1, 2.2, 2.4, 3.2, 4.1, 4.2, 6.1, and 7.1 mRNA. Kir4.2 protein was verified by immunocytochemistry and Western blotting. Kir4.2 mRNA in cultured cells was upregulated by hypoxia (hypoxia mimetic CoCl2 or 0.2% O2) and extracellular hyperosmolarity (addition of high NaCl or sucrose). Kir4.2 mRNA was suppressed by vascular endothelial growth factor (VEGF), blood serum, and thrombin whereas platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and transforming growth factor-β1 (TGF-β1) increased it. Hyperosmotic Kir4.2 gene expression was mediated by TGF-β1 receptor signaling while hypoxic gene transcription was dependent on PDGF receptor signaling. VEGF receptor-2 blockade increased Kir4.2 mRNA level under control, hyperosmotic, and hypoxic conditions. SiRNA-mediated knockdown of Kir4.2 decreased the cell viability and proliferation under control and hyperosmotic conditions. Kir4.2 channels play functional roles in maintaining the viability and proliferation of RPE cells. Downregulation of Kir4.2 by VEGF, via activation of VEGF receptor-2 and induction of blood-retinal barrier breakdown, may contribute to decreased viability of RPE cells under pathological conditions.
Virus-Based Immuno-Oncology Models
Authors: Sitta Juliana , Claudio Pier Paolo , Howard Candace M.
Published: June 2022

Immunotherapy has been extensively explored in recent years with encouraging results in selected types of cancer. Such success aroused interest in the expansion of such indications, requiring a deep understanding of the complex role of the immune system in carcinogenesis. The definition of hot vs. cold tumors and the role of the tumor microenvironment enlightened the once obscure understanding of low response rates of solid tumors to immune check point inhibitors. Although the major scope found in the literature focuses on the T cell modulation, the innate immune system is also a promising oncolytic tool. The unveiling of the tumor immunosuppressive pathways, lead to the development of combined targeted therapies in an attempt to increase immune infiltration capability. Oncolytic viruses have been explored in different scenarios, in combination with various chemotherapeutic drugs and, more recently, with immune check point inhibitors. Moreover, oncolytic viruses may be engineered to express tumor specific pro-inflammatory cytokines, antibodies, and antigens to enhance immunologic response or block immunosuppressive mechanisms. Development of preclinical models capable to replicate the human immunologic response is one of the major challenges faced by these studies. A thorough understanding of immunotherapy and oncolytic viruses’ mechanics is paramount to develop reliable preclinical models with higher chances of successful clinical therapy application. Thus, in this article, we review current concepts in cancer immunotherapy including the inherent and synthetic mechanisms of immunologic enhancement utilizing oncolytic viruses, immune targeting, and available preclinical animal models, their advantages, and limitations.
Spontaneous Myocarditis in Mice Predisposed to Autoimmune Disease: Including Vaccination-Induced Onset
Authors: Hayashi Takuma , Ichikawa Motoki , Konishi Ikuo
Published: June 2022

Nonobese diabetic (NOD)/ShiLtJ mice, such as biobreeding rats, are used as an animal model for type 1 diabetes. Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets. The onset of diabetes is associated with moderate glycosuria and nonfasting hyperglycemia. Previously, in NOD/ShiLtJ mice spontaneously developing type 1 diabetes, the possible involvement of decreased expression of nuclear factor-kappa B1 (NF-κB1) (also known as p50) in the development of type 1 diabetes was investigated. In response to these arguments, NOD mice with inconsistent NF-κB1 expression were established. Surprisingly, the majority of NOD Nfκb1 homozygote mice were found to die by the eighth week of life because of severe myocarditis. The incidence of spontaneous myocarditis in mice was slightly higher in males than in females. Furthermore, insulitis was observed in all NOD Nfκb1 heterozygote mice as early as 4 months of age. Additionally, in NOD Nfκb1 heterozygote mice, myocarditis with an increase in cTnT levels due to influenza or hepatitis B virus vaccination was observed with no significant gender difference. However, myocarditis was not observed with the two types of human papillomavirus vaccination. The results of immunological assays and histopathological examinations indicated that vaccination could induce myocarditis in genetically modified mice. In this study, we report that NOD Nfκb1 heterozygote mice can be used for investigating the risk of myocarditis development after vaccination.
The Emerging Role of Branched-Chain Amino Acids in Liver Diseases
Authors: Lo Emily Kwun Kwan , Felicianna  , Xu Jing-Hang , Zhan Qiao , Zeng Zheng , El-Nezami Hani
Published: June 2022

Chronic liver diseases pose a substantial health burden worldwide, with approximately two million deaths each year. Branched-chain amino acids (BCAAs)—valine, leucine, and isoleucine—are a group of essential amino acids that are essential for human health. Despite the necessity of a dietary intake of BCAA, emerging data indicate the undeniable correlation between elevated circulating BCAA levels and chronic liver diseases, including non-alcoholic fatty liver diseases (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC). Moreover, circulatory BCAAs were positively associated with a higher cholesterol level, liver fat content, and insulin resistance (IR). However, BCAA supplementation was found to provide positive outcomes in cirrhosis and HCC patients. This review will attempt to address the contradictory claims found in the literature, with a special focus on BCAAs’ distribution, key signaling pathways, and the modulation of gut microbiota. This should provide a better understanding of BCAAs’ possible contribution to liver health.
Connexins, Pannexins and Gap Junctions in Perinatal Brain Injury
Authors: McDouall Alice , Zhou Kelly Q. , Bennet Laura , Green Colin R. , Gunn Alistair J. , Davidson Joanne O.
Published: June 2022

Perinatal brain injury secondary to hypoxia-ischemia and/or infection/inflammation remains a major cause of disability. Therapeutic hypothermia significantly improves outcomes, but in randomized controlled trials nearly half of infants still died or survived with disability, showing that additional interventions are needed. There is growing evidence that brain injury spreads over time from injured to previously uninjured regions of the brain. At least in part, this spread is related to opening of connexin hemichannels and pannexin channels, both of which are large conductance membrane channels found in many brain cells. Opening of these membrane channels releases adenosine triphosphate (ATP), and other neuroactive molecules, into the extracellular space. ATP has an important role in normal signaling, but pathologically can trigger the assembly of the multi-protein inflammasome complex. The inflammasome complex promotes activation of inflammatory caspases, and release of inflammatory cytokines. Overall, the connexin hemichannel appears to play a primary role in propagation of injury and chronic disease, and connexin hemichannel blockade has been shown to be neuroprotective in multiple animal models. Thus, there is potential for some blockers of connexin or pannexin channels to be developed into targeted interventions that could be used in conjunction with or separate to therapeutic hypothermia.
A Simple Optical Aerosol Sensing Method of Sauter Mean Diameter for Particulate Matter Monitoring
Authors: Li Liangbo , Chen Ang , Deng Tian , Zeng Jin , Xu Feifan , Yan Shu , Wang Shu , Cheng Wenqing , Zhu Ming , Xu Wenbo
Published: June 2022

Mass concentration is a commonly used but insufficient metric to evaluate the particulate matter (PM) exposure hazard. Recent studies have declared that small particles have more serious impacts on human health than big particles given the same mass concentration. However, state-of-the-art PM sensors cannot provide explicit information of the particle size for further analysis. In this work, we adopt Sauter mean diameter (SMD) as a key metric to reflect the particle size besides the mass concentration. To measure SMD, an effective optical sensing method and a proof-of-concept prototype sensor are proposed by using dual wavelengths technology. In the proposed method, a non-linear conversion model is developed to improve the SMD measurement accuracy for aerosol samples of different particle size distributions and reflective indices based on multiple scattering channels. In the experiment of Di-Ethyl-Hexyl-Sebacate (DEHS) aerosols, the outputs of our prototype sensor demonstrated a good agreement with existing laboratory reference instruments with maximum SMD measurement error down to 7.04%. Furthermore, the simplicity, feasibility and low-cost features of this new method present great potential for distributed PM monitoring, to support sophisticated human exposure hazard assessment.
Brain Asymmetry and Its Effects on Gait Strategies in Hemiplegic Patients: New Rehabilitative Conceptions
Authors: Vismara Luca , Cimolin Veronica , Buffone Francesca , Bigoni Matteo , Clerici Daniela , Cerfoglio Serena , Galli Manuela , Mauro Alessandro
Published: June 2022

Brain asymmetry is connected with motor performance, suggesting that hemiparetic patients have different gait patterns depending on the side of the lesion. This retrospective cohort study aims to further investigate the difference between right and left hemiplegia in order to assess whether the injured side can influence the patient’s clinical characteristics concerning gait, thus providing insights for new personalized rehabilitation strategies. The data from 33 stroke patients (17 with left and 16 with right hemiplegia) were retrospectively compared with each other and with a control group composed of 20 unaffected age-matched individuals. The 3D gait analysis was used to assess kinematic data and spatio-temporal parameters. Compared to left hemiplegic patients, right hemiplegic patients showed worse spatio-temporal parameters (p < 0.05) and better kinematic parameters (p < 0.05). Both pathological groups were characterized by abnormal gait parameters in comparison with the control group (p < 0.05). These findings show an association between the side of the lesion—right or left—and the different stroke patients’ gait patterns: left hemiplegic patients show better spatio-temporal parameters, whereas right hemiplegic patients show better segmentary motor performances. Therefore, further studies may develop and assess new personalized rehabilitation strategies considering the injured hemisphere and brain asymmetry.
Linking BIM to Power BI and HoloLens 2 to Support Facility Management: A Case Study Approach
Authors: Harode Ashit , Ensafi Mahnaz , Thabet Walid
Published: June 2022

Facility lifecycle data captured in BIM during design and construction are very valuable for effective facility operations and maintenance. Traditionally, model authoring and analysis tools have been used to search and query model information. These tools are not well designed to search and display needed data and they require a steep learning curve. In this paper, the authors propose the use of Power BI dashboards to facilitate easy access and display of lifecycle data embedded in the model. The implementation and use of dashboards for facility management are discussed using a case study. The effectiveness and usability of the dashboards are validated using a focus group of six industry experts that were first interviewed then asked to complete a questionnaire. Feedback from interviews indicated that customized dashboards are effective tools to view, analyze and draw insights on data from various sources and can improve facility operations and management. Numerical results from the PSSUQ using fourteen questions indicated positive responses overall with an average score of four or five from the majority of respondents. Finally, the authors tested integration of the Power BI dashboards with the HoloLens 2 to deliver relevant up-to-date facility lifecycle data in near real-time to field staff.
Self-Reported Health Problems and Quality of Life in a Sample of Colombian Childhood Cancer Survivors: A Descriptive Cross-Sectional Study
Authors: Godoy-Casasbuenas Natalia , de Vries Esther
Published: June 2022

Objectives: To describe the self-reported health problems and quality of life among adult-aged Colombian childhood and adolescent cancer survivors. Methods: This is a descriptive cross-sectional study with Colombian childhood cancer survivors (CCS) who were diagnosed before the age of 18, at the moment of study were ≥18 years, and at least 5 years had passed since diagnosis. Each participant completed a self-reported study-specific online questionnaire along with the SF-36 Health Survey to assess the prevalence of health problems and current quality of life (QoL). Data were analyzed using descriptive statistics and independent sample t-tests. Results: Out of the 122 CCS who participated, 100% reported at least one health problem, mostly gastritis, headaches, and lack of concentration, followed by obesity and fertility issues. In general, they had a good perception of their QoL, which was, on average, only diminished in the areas of vitality, emotional role functioning, and social functioning. Conclusion: Perceived health problems among the participating Colombian CCS were prevalent; most reported a good self-perceived QoL. This is the first study on understanding health problems and QoL of CCS treated in Colombia and South America. It reopens the debate on the need to carry out long-term follow-up in this population among Colombian society.
PET-CT in Clinical Adult Oncology—IV. Gynecologic and Genitourinary Malignancies
Authors: Salem Ahmed Ebada , Fine Gabriel C. , Covington Matthew F. , Koppula Bhasker R. , Wiggins Richard H. , Hoffman John M. , Morton Kathryn A.
Published: June 2022

Concurrently acquired positron emission tomography and computed tomography (PET-CT) is an advanced imaging modality with diverse oncologic applications, including staging, therapeutic assessment, restaging and longitudinal surveillance. This series of six review articles focuses on providing practical information to providers and imaging professionals regarding the best use and interpretative strategies of PET-CT for oncologic indications in adult patients. In this fourth article of the series, the more common gynecological and adult genitourinary malignancies encountered in clinical practice are addressed, with an emphasis on Food and Drug Administration (FDA)-approved and clinically available radiopharmaceuticals. The advent of new FDA-approved radiopharmaceuticals for prostate cancer imaging has revolutionized PET-CT imaging in this important disease, and these are addressed in this report. However, [18F]F-fluoro-2-deoxy-d-glucose (FDG) remains the mainstay for PET-CT imaging of gynecologic and many other genitourinary malignancies. This information will serve as a guide for the appropriate role of PET-CT in the clinical management of gynecologic and genitourinary cancer patients for health care professionals caring for adult cancer patients. It also addresses the nuances and provides guidance in the accurate interpretation of FDG PET-CT in gynecological and genitourinary malignancies for imaging providers, including radiologists, nuclear medicine physicians and their trainees.
Post-Neoadjuvant Treatment in HER2-Positive Breast Cancer: Escalation and De-Escalation Strategies
Authors: Krawczyk Natalia , Fehm Tanja , Ruckhaeberle Eugen , Brus Laura , Kopperschmidt Valeria , Rody Achim , Hanker Lars , Banys-Paluchowski Maggie
Published: June 2022

Patients with high-risk non-metastatic breast cancer are recommended for chemotherapy, preferably in the neoadjuvant setting. Beyond advantages such as a better operability and an improved assessment of individual prognosis, the preoperative administration of systemic treatment offers the unique possibility of selecting postoperative therapies according to tumor response. In patients with HER2-positive disease, both the escalation of therapy in the case of high-risk features and the de-escalation in patients with a low tumor load are currently discussed. Patients with small node-negative tumors receive primary surgery and, upon confirmation of pathological T1 N0 status, de-escalated adjuvant therapy with paclitaxel and trastuzumab. For those with a large tumor and/or nodal involvement, neoadjuvant polychemotherapy with a dual antibody blockade is recommended. Patients with invasive residual disease benefit from switching postoperative therapy to the antibody-drug-conjugate trastuzumab emtansine (T-DM1). In this review, we discuss current evidence and controversies regarding post-neoadjuvant treatment strategies in HER2-positive breast cancer.
Anthracycline-Free Neoadjuvant Treatment in Patients with HER2-Positive Breast Cancer: Real-Life Use of Pertuzumab, Trastuzumab and Taxanes Association with an Exploratory Analysis of PIK3CA Mutational Status
Authors: Irelli Azzurra , Parisi Alessandro , D’Orazio Carla , Sidoni Tina , Rotondaro Silvia , Patruno Leonardo , Pavese Francesco , Bafile Alberto , Resta Valter , Pizzorno Laura , Ciuffetelli Virginia , Dal Mas Antonella , Calvisi Giuseppe , Di Sibio Alessandra , Marzullo Anna , Zelli Veronica , Compagnoni Chiara , Tessitore Alessandra , Alesse Edoardo , Ficorella Corrado , Cortellini Alessio , Cannita Katia
Published: June 2022

HER2 is considered one of the most traditional prognostic and predictive biomarkers in breast cancer. Literature data confirmed that the addition of pertuzumab to a standard neoadjuvant chemotherapy backbone (either with or without anthracyclines), in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), leads to a higher pathological complete response (pCR) rate, which is known to correlate with a better prognosis. In this retrospective analysis, 47 consecutive patients with HER2-positive EBC received sequential anthracyclines and taxanes plus trastuzumab (ATH) or pertuzumab, trastuzumab and docetaxel (THP). Despite the limited sample size, this monocentric experience highlights the efficacy (in terms of pCR) and safety of THP in the neoadjuvant setting of HER2-positive EBC as an anthracycline-free approach. Given the role of PIK3CA as a prognostic and therapeutic target in breast cancer, tumors were also analyzed to assess the PIK3CA mutational status. Thirty-eight out of forty-seven patients were evaluated, and PIK3CA variants were identified in 21% of tumor samples: overall, one mutation was detected in exon 4 (2.6%), two in exon 9 (5.3%) and four in exon 20 (10.5%). Of note, one sample showed concurrent mutations in exons 9 (codon 545) and 20 (codon 1047). Among patients reaching pCR (n = 13), 38.5% were PIK3CA mutants; on the other hand, among those lacking pCR (n = 25), just 12% showed PIK3CA variants. Regarding THP-treated mutant patients (n = 5), 80% reached pCR (three hormone-receptor-negative, one hormone-receptor-positive). Interestingly, the only patient not achieving pCR had a tumor with two co-occurring PIK3CA mutations. In conclusion, this study provides new evidence about the efficacy and good safety profile of THP, compared to the ATH regimen, as an anthracycline-free neoadjuvant treatment of HER2-positive EBC. Further studies on larger/multicentric cohorts are planned for more in-depth analysis to confirm our molecular and clinical results.
Ability of Delta Radiomics to Predict a Complete Pathological Response in Patients with Loco-Regional Rectal Cancer Addressed to Neoadjuvant Chemo-Radiation and Surgery
Authors: Nardone Valerio , Reginelli Alfonso , Grassi Roberta , Vacca Giovanna , Giacobbe Giuliana , Angrisani Antonio , Clemente Alfredo , Danti Ginevra , Correale Pierpaolo , Carbone Salvatore Francesco , Pirtoli Luigi , Bianchi Lorenzo , Vanzulli Angelo , Guida Cesare , Grassi Roberto , Cappabianca Salvatore
Published: June 2022

We performed a pilot study to evaluate the use of MRI delta texture analysis (D-TA) as a methodological item able to predict the frequency of complete pathological responses and, consequently, the outcome of patients with locally advanced rectal cancer addressed to neoadjuvant chemoradiotherapy (C-RT) and subsequently, to radical surgery. In particular, we carried out a retrospective analysis including 100 patients with locally advanced rectal adenocarcinoma who received C-RT and then radical surgery in three different oncological institutions between January 2013 and December 2019. Our experimental design was focused on the evaluation of the gross tumor volume (GTV) at baseline and after C-RT by means of MRI, which was contoured on T2, DWI, and ADC sequences. Multiple texture parameters were extracted by using a LifeX Software, while D-TA was calculated as percentage of variations in the two time points. Both univariate and multivariate analysis (logistic regression) were, therefore, carried out in order to correlate the above-mentioned TA parameters with the frequency of pathological responses in the examined patients’ population focusing on the detection of complete pathological response (pCR, with no viable cancer cells: TRG 1) as main statistical endpoint. ROC curves were performed on three different datasets considering that on the 21 patients, only 21% achieved an actual pCR. In our training dataset series, pCR frequency significantly correlated with ADC GLCM-Entropy only, when univariate and binary logistic analysis were performed (AUC for pCR was 0.87). A confirmative binary logistic regression analysis was then repeated in the two remaining validation datasets (AUC for pCR was 0.92 and 0.88, respectively). Overall, these results support the hypothesis that D-TA may have a significant predictive value in detecting the occurrence of pCR in our patient series. If confirmed in prospective and multicenter trials, these results may have a critical role in the selection of patients with locally advanced rectal cancer who may benefit form radical surgery after neoadjuvant chemoradiotherapy.
Human γδ T Cell Subsets and Their Clinical Applications for Cancer Immunotherapy
Authors: Lee Derek , Rosenthal Carl J. , Penn Natalie E. , Dunn Zachary Spencer , Zhou Yang , Yang Lili
Published: June 2022

Gamma delta (γδ) T cells are a minor population of T cells that share adaptive and innate immune properties. In contrast to MHC-restricted alpha beta (αβ) T cells, γδ T cells are activated in an MHC-independent manner, making them ideal candidates for developing allogeneic, off-the-shelf cell-based immunotherapies. As the field of cancer immunotherapy progresses rapidly, different subsets of γδ T cells have been explored. In addition, γδ T cells can be engineered using different gene editing technologies that augment their tumor recognition abilities and antitumor functions. In this review, we outline the unique features of different subsets of human γδ T cells and their antitumor properties. We also summarize the past and the ongoing pre-clinical studies and clinical trials utilizing γδ T cell-based cancer immunotherapy.
Patient Derived Ex-Vivo Cancer Models in Drug Development, Personalized Medicine, and Radiotherapy
Authors: Zitter Ryan , Chugh Rishi Man , Saha Subhrajit
Published: June 2022

The field of cancer research is famous for its incremental steps in improving therapy. The consistent but slow rate of improvement is greatly due to its meticulous use of consistent cancer biology models. However, as we enter an era of increasingly personalized cancer care, including chemo and radiotherapy, our cancer models must be equally able to be applied to all individuals. Patient-derived organoid (PDO) and organ-in-chip (OIC) models based on the micro-physiological bioengineered platform have already been considered key components for preclinical and translational studies. Accounting for patient variability is one of the greatest challenges in the crossover from preclinical development to clinical trials and patient derived organoids may offer a steppingstone between the two. In this review, we highlight how incorporating PDO’s and OIC’s into the development of cancer therapy promises to increase the efficiency of our therapeutics.
Liquid Biopsy Landscape in Patients with Primary Upper Tract Urothelial Carcinoma
Authors: Shishido Stephanie N. , Ghoreifi Alireza , Sayeed Salmaan , Courcoubetis George , Huang Amy , Ye Brandon , Mrutyunjaya Sankalp , Gill Inderbir S. , Kuhn Peter , Mason Jeremy , Djaladat Hooman
Published: June 2022

Urothelial carcinomas (UCs) are a broad and heterogeneous group of malignancies, with the prevalence of upper tract urothelial carcinoma (UTUC) being rare, accounting for only 5–10% of total malignancies. There is a need for additional toolsets to assist the current clinical paradigm of care for patients with UTUC. As a non-invasive tool for the discovery of cancer-related biomarkers, the liquid biopsy has the potential to represent the complex process of tumorigenesis and metastasis. Herein, we show the efficacy of the liquid biopsy as a source of biomarkers for detecting UTUC. Using the third-generation high-definition single-cell assay (HDSCA3.0) workflow, we investigate liquid biopsy samples collected from patients with UTUC and normal donors (NDs) to provide critical information regarding the molecular and morphological characteristics of circulating rare events. We document several important findings from the liquid biopsy analysis of patients diagnosed with UTUC prior to surgery: (1) Large extracellular vesicles (LEVs) and circulating tumor cells (CTCs) are detectable in the peripheral blood. (2) The rare-event profile is highly heterogeneous. (3) Clinical data elements correlate with liquid biopsy analytes. Overall, this study provides evidence for the efficacy of the liquid biopsy in understanding the biology of UTUC with the future intent of informing clinical decision making, ultimately improving patient outcomes.
Methods of Esthetic Assessment after Adjuvant Whole-Breast Radiotherapy in Breast Cancer Patients: Evaluation of the BCCT.core Software and Patients’ and Physicians’ Assessment from the Randomized IMRT-MC2 Trial
Authors: Forster Tobias , Köhler Clara , Dorn Melissa , Häfner Matthias Felix , Arians Nathalie , König Laila , Harrabi Semi Ben , Schlampp Ingmar , Meixner Eva , Heinrich Vanessa , Weidner Nicola , Golatta Michael , Hennigs André , Heil Jörg , Hof Holger , Krug David , Debus Jürgen , Hörner-Rieber Juliane
Published: June 2022

The present analysis compares the esthetics assessment by the BCCT.core software in relation to patients’ and physicians’ ratings, based on the IMRT-MC2 trial. Within this trial, breast cancer patients received breast-conserving surgery (BCS) and adjuvant radiotherapy. At the baseline, 6 weeks, and 2 years after radiotherapy, photos of the breasts were assessed by the software and patients’ and physicians’ assessments were performed. Agreement rates of the assessments and their correlation with breast asymmetry indices were evaluated. The assessments of the software and the physicians were significantly correlated with asymmetry indices. Before and 6 weeks after radiotherapy, the patients’ self-assessment was only correlated with the lower breast contour (LBC) and upward nipple retraction (UNR), while after 2 years, there was also a correlation with other indices. Only a slight agreement between the BCCT.core software and the physicians’ or patients’ assessment was seen, while a moderate and substantial agreement was detected between the physicians’ and the patients’ assessment after 6 weeks and 2 years, respectively. The BCCT.core software is a reliable tool to measure asymmetries, but may not sufficiently evaluate the esthetic outcome as perceived by patients. It may be more appropriate for a long-term follow-up, when symmetry appears to increase in importance.
Nanomaterials for Photocatalytic Degradations of Analgesic, Mucolytic and Anti-Biotic/Viral/Inflammatory Drugs Widely Used in Controlling SARS-CoV-2
Authors: Ebrahimi Mahsa , Akhavan Omid
Published: June 2022

The COVID-19 pandemic has been transformed into one of the main worldwide challenges, in recent years. For controlling symptoms that are caused by this disease (e.g., chills or fever, shortness of breath and/or difficulty in breathing, cough, sore throat, fatigue, headache, muscle aches, the new loss of tastes and/or smells, congestion or runny nose, nausea, vomiting and/or diarrhea), lots of medicines including analgesics, mucolytics, and anti-biotic/viral/inflammatory drugs have been frequently prescribed. As these medicines finally contaminate terrestrial and aquatic habitats by entering surface waterways through pharmaceutical production and excreting trace amounts of waste after human usage, they have negative impacts on wildlife’s health and ecosystem. Residual drugs in water have the potential to harm aquatic creatures and disrupt their food chain as well as the breeding cycle. Therefore, proper degradation of these broadly used medicines is highly crucial. In this work, the use of nanomaterials applicable in photocatalytic degradations of analgesics (e.g., acetaminophen, aspirin, ibuprofen, and naproxen), mucolytics (e.g., ambroxol), antibiotics (e.g., azithromycin and quinolones including hydroxychloroquine and chloroquine phosphate), anti-inflammatory glucocorticoids (e.g., dexamethasone and cortisone acetate), antihistamines (e.g., diphenhydramine), H2 blockers (e.g., famotidine), anthelmintics (e.g., praziquantel), and finally antivirals (e.g., ivermectin, acyclovir, lopinavir/ritonavir, favipiravir, nitazoxanide, and remdesivir) which widely used in controlling/treating the coronavirus have been reviewed and discussed.
Soot Oxidation in a Plasma-Catalytic Reactor: A Case Study of Zeolite-Supported Vanadium Catalysts
Authors: Zhu Xinbo , Wu Hanpeng , Luo Jianbin , Liu Jin , Yan Jiahao , Zhou Zijian , Yang Zhengda , Jiang Ye , Chen Geng , Yang Guohua
Published: June 2022

The plasma-catalytic oxidation of soot was studied over zeolite-supported vanadium catalysts, while four types of zeolites (MCM-41, mordenite, USY and 5A) were used as catalyst supports. The soot oxidation rate followed the order of V/MCM-41 > V/mordenite > V/USY > V/5A, while 100% soot oxidation was achieved at 54th min of reaction over V/MCM-41 and V/mordenite. The CO2 selectivity of the process follows the opposite order of oxidation rate over the V/M catalyst. A wide range of catalyst characterizations including N2 adsorption–desorption, XRD, XPS, H2-TPR and O2-TPD were performed to obtain insights regarding the reaction mechanisms of soot oxidation in plasma-catalytic systems. The redox properties were recognized to be crucial for the soot oxidation process. The effects of discharge power, gas flow rate and reaction temperature on soot oxidation were also investigated. The results showed that higher discharge power, higher gas flow rate and lower reaction temperature were beneficial for soot oxidation rate. However, these factors would impose a negative effect on CO2 selectivity. The proposed “plasma-catalysis” method possessed the unique advantages of quick response, mild operation conditions and system compactness. The method could be potentially applied for the regeneration of diesel particulate filters (DPF) at low temperatures and contribute to the the emission control of diesel engines.
Ocrelizumab in Patients with Active Primary Progressive Multiple Sclerosis: Clinical Outcomes and Immune Markers of Treatment Response
Authors: Boziki Marina , Bakirtzis Christos , Sintila Styliani-Aggeliki , Kesidou Evangelia , Gounari Evdoxia , Ioakimidou Aliki , Tsavdaridou Vasiliki , Skoura Lemonia , Fylaktou Asimina , Nikolaidou Vasiliki , Stangou Maria , Nikolaidis Ioannis , Giantzi Virginia , Karafoulidou Eleni , Theotokis Paschalis , Grigoriadis Nikolaos
Published: June 2022

Ocrelizumab is a B-cell-depleting monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) and active primary progressive MS (aPPMS). This prospective, uncontrolled, open-label, observational study aimed to assess the efficacy of ocrelizumab in patients with aPPMS and to dissect the clinical, radiological and laboratory attributes of treatment response. In total, 22 patients with aPPMS followed for 24 months were included. The primary efficacy outcome was the proportion of patients with optimal response at 24 months, defined as patients free of relapses, free of confirmed disability accumulation (CDA) and free of T1 Gd-enhancing lesions and new/enlarging T2 lesions on the brain and cervical MRI. In total, 14 (63.6%) patients and 13 patients (59.1%) were classified as responders at 12 and 24 months, respectively. Time exhibited a significant effect on mean absolute and normalized gray matter cerebellar volume (F = 4.342, p = 0.23 and F = 4.279, p = 0.024, respectively). Responders at 24 months exhibited reduced peripheral blood ((%) of CD19+ cells) plasmablasts compared to non-responders at the 6-month point estimate (7.69 ± 4.4 vs. 22.66 ± 7.19, respectively, p = 0.043). Response to ocrelizumab was linked to lower total and gray matter cerebellar volume loss over time. Reduced plasmablast depletion was linked for the first time to sub-optimal response to ocrelizumab in aPPMS.
The Prognostic and Predictive Significance of Tumor-Infiltrating Memory T Cells Is Reversed in High-Risk HNSCC
Authors: Hartan Rebekka , Schnellhardt Sören , Büttner-Herold Maike , Daniel Christoph , Hartmann Arndt , Fietkau Rainer , Distel Luitpold
Published: June 2022

Tumor-infiltrating CD45RO+ memory T cells have unanimously been described as a positive prognostic factor in head and neck squamous cell carcinomas (HNSCCs). Here, we investigated the long-term prognostic relevance of CD45RO+ memory T cells in HNSCC with special regard to the influence of clinical characteristics. Pre-treatment biopsy samples from 306 patients with predominantly advanced HNSCC were analyzed. Immunohistochemistry was used to stain tissue microarrays for CD45RO+ memory T cells. CD45RO cell densities were semi-automatically registered and used for survival analysis. High CD45RO+ cell densities were clearly associated with prolonged overall survival (OS) and recurrence-free survival as well as no evidence of disease status after 10 years (p < 0.05). In contrast, the prognostic significance of tumor-infiltrating memory T cells was completely reversed in high-risk groups: in poorly differentiated tumors (G3, G4) and in cases with lymph node involvement (N+), high memory T cell densities correlated with reduced 10-year OS (p < 0.05). In conclusion, an increased density of tumor-infiltrating CD45RO+ cells in HNSCC can be a positive as well as a negative prognostic factor, depending on disease stage and histological grade. Therefore, if CD45RO+ cell density is to be used as a prognostic biomarker, further clinical characteristics must be considered.
Deltamethrin-Evoked ER Stress Promotes Neuroinflammation in the Adult Mouse Hippocampus
Authors: Hossain Muhammad M. , Toltin Abigail C. , Gamba Laura M. , Molina Maria A.
Published: June 2022

Endoplasmic reticulum (ER) stress and neuroinflammation are involved in the pathogenesis of many neurodegenerative disorders. Previously, we reported that exposure to pyrethroid insecticide deltamethrin causes hippocampal ER stress apoptosis, a reduction in neurogenesis, and learning deficits in adult male mice. Recently, we found that deltamethrin exposure also increases the markers of neuroinflammation in BV2 cells. Here, we investigated the potential mechanistic link between ER stress and neuroinflammation following exposure to deltamethrin. We found that repeated oral exposure to deltamethrin (3 mg/kg) for 30 days caused microglial activation and increased gene expressions and protein levels of TNF-α, IL-1β, IL-6, gp91phox, 4HNE, and iNOS in the hippocampus. These changes were preceded by the induction of ER stress as the protein levels of CHOP, ATF-4, and GRP78 were significantly increased in the hippocampus. To determine whether induction of ER stress triggers the inflammatory response, we performed an additional experiment with mouse microglial cell (MMC) line. MMCs were treated with 0–5 µM deltamethrin for 24–48 h in the presence or absence of salubrinal, a pharmacological inhibitor of the ER stress factor eIF2α. We found that salubrinal (50 µM) prevented deltamethrin-induced ER stress, as indicated by decreased levels of CHOP and ATF-4, and attenuated the levels of GSH, 4-HNE, gp91phox, iNOS, ROS, TNF-α, IL-1β, and IL-6 in MMCs. Together, these results demonstrate that exposure to deltamethrin leads to ER stress-mediated neuroinflammation, which may subsequently contribute to neurodegeneration and cognitive impairment in mice.
Optimizing Soluble Cues for Salivary Gland Tissue Mimetics Using a Design of Experiments (DoE) Approach
Authors: Piraino Lindsay R. , Benoit Danielle S. W. , DeLouise Lisa A.
Published: June 2022

The development of therapies to prevent or treat salivary gland dysfunction has been limited by a lack of functional in vitro models. Specifically, critical markers of salivary gland secretory phenotype downregulate rapidly ex vivo. Here, we utilize a salivary gland tissue chip model to conduct a design of experiments (DoE) approach to test combinations of seven soluble cues that were previously shown to maintain or improve salivary gland cell function. This approach uses statistical techniques to improve efficiency and accuracy of combinations of factors. The DoE-designed culture conditions improve markers of salivary gland function. Data show that the EGFR inhibitor, EKI-785, maintains relative mRNA expression of Mist1, a key acinar cell transcription factor, while FGF10 and neurturin promote mRNA expression of Aqp5 and Tmem16a, channel proteins involved in secretion. Mist1 mRNA expression correlates with increased secretory function, including calcium signaling and mucin (PAS-AB) staining. Overall, this study demonstrates that media conditions can be efficiently optimized to support secretory function in vitro using a DoE approach.
Rapid Actions of the Nuclear Progesterone Receptor through cSrc in Cancer
Authors: Bello-Alvarez Claudia , Zamora-Sánchez Carmen J. , Camacho-Arroyo Ignacio
Published: June 2022

The nuclear progesterone receptor (PR) is mainly known for its role as a ligand-regulated transcription factor. However, in the last ten years, this receptor’s extranuclear or rapid actions have gained importance in the context of physiological and pathophysiological conditions such as cancer. The PR’s polyproline (PXPP) motif allows protein–protein interaction through SH3 domains of several cytoplasmatic proteins, including the Src family kinases (SFKs). Among members of this family, cSrc is the most well-characterized protein in the scenario of rapid actions of the PR in cancer. Studies in breast cancer have provided the most detailed information on the signaling and effects triggered by the cSrc–PR interaction. Nevertheless, the study of this phenomenon and its consequences has been underestimated in other types of malignancies, especially those not associated with the reproductive system, such as glioblastomas (GBs). This review will provide a detailed analysis of the impact of the PR–cSrc interplay in the progression of some non-reproductive cancers, particularly, in GBs.
Correction: Nguyen et al. The Nephrotoxin Puromycin Aminonucleoside Induces Injury in Kidney Organoids Differentiated from Induced Pluripotent Stem Cells. Cells 2022, 11, 635
Authors: Nguyen Lisa , Wruck Wasco , Erichsen Lars , Graffmann Nina , Adjaye James
Published: June 2022

In the original publication [...]
Alterations of Serum Magnesium Concentration in Animal Models of Seizures and Epilepsy—The Effects of Treatment with a GPR39 Agonist and Knockout of the Gpr39 Gene
Authors: Doboszewska Urszula , Sawicki Jan , Sajnóg Adam , Szopa Aleksandra , Serefko Anna , Socała Katarzyna , Pieróg Mateusz , Nieoczym Dorota , Mlyniec Katarzyna , Nowak Gabriel , Barałkiewicz Danuta , Sowa Ireneusz , Wlaź Piotr
Published: June 2022

Several ligands have been proposed for the GPR39 receptor, including the element zinc. The relationship between GPR39 and magnesium homeostasis has not yet been examined, nor has such a relationship in the context of seizures/epilepsy. We used samples from mice that were treated with an agonist of the GPR39 receptor (TC-G 1008) and underwent acute seizures (maximal electroshock (MES)- or 6-hertz-induced seizures) or a chronic, pentylenetetrazole (PTZ)-induced kindling model of epilepsy. MES seizures and PTZ kindling, unlike 6 Hz seizures, increased serum magnesium concentration. In turn, Gpr39-KO mice that underwent PTZ kindling displayed decreased concentrations of this element in serum, compared to WT mice subjected to this procedure. However, the levels of expression of TRPM7 and SlC41A1 proteins—which are responsible for magnesium transport into and out of cells, respectively—did not differ in the hippocampus between Gpr39-KO and WT mice. Furthermore, laser ablation inductively coupled plasma mass spectrometry applied to hippocampal slices did not reveal differences in magnesium levels between the groups. These data show the relationship between magnesium homeostasis and certain types of acute or chronic seizures (MES seizures or PTZ kindling, respectively), but do not explicitly support the role of GPR39 in mediating magnesium balance in the hippocampus in the latter model. However, decreased expression of TRPM7 and increased expression of SLC41A1—which were observed in the hippocampi of Gpr39-KO mice treated with TC-G 1008, in comparison to WT mice that received the same treatment—implicitly support the link between GPR39 and hippocampal magnesium homeostasis.