bluuebunny/crossref_metadata_2025 huggingface dataset:
Making the Best Use of Available Weapons for the Inevitable Rivalry-Resistance to EGFR-TKIs
Authors: Li Dongyu , Wang Jingnan , Liu Chengming , Luo Yuejun , Xu Haiyan , Wang Yan , Sun Nan , He Jie
Published: April 2023

The emergence of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) revolutionized the treatment of advanced-stage non-small cell lung cancer (NSCLC). Detected in more than 50% of late-stage lung adenocarcinoma in Asian patients, the EGFR mutation was regarded as a golden mutation for Asians. However, resistance to TKIs seems inevitable and severely hinders patients from getting further benefits from treatment. Even though resistance caused by EGFR T790M could be effectively managed by third-generation EGFR-TKIs currently, resistance to third-generation EGFR-TKIs is still a troublesome issue faced by both clinicians and patients. Various efforts have been made to maximize the benefits of patients from EGFR-TKIs therapy. Thus, new requirements and challenges have been posed to clinicians of this era. In this review, we summarized the clinical evidence on the efficacy of third-generation EGFR-TKIs in patients with EGFR-mutated NSCLC. Then, we discussed advancements in sequential treatment aiming to delay the onset of resistance. Moreover, the resistance mechanisms and features were depicted to help us better understand our enemies. Lastly, we put forward future strategies, including recent approaches involving the utilization of antibody drug conjugates against resistance and research directions about shaping the evolution of NSCLC as a core idea in the management of NSCLC.
Intramuscular Hematomas in Patients Receiving Prophylaxis or Anticoagulant Treatment after Spinal Cord Injury (SCI)—A Rare Complication: Description of Seven Cases and a Literature Analysis
Authors: Mackiewicz-Milewska Magdalena , Cisowska-Adamiak Małgorzata , Szymkuć-Bukowska Iwona , Sakwińska Katarzyna , Domarecka Iwona , Lewandowska Anna , Głowacka-Mrotek Iwona
Published: April 2023

Spinal cord injuries (SCIs) are associated with a high risk of thromboembolic complications (VTE), despite the use of antithrombotic prophylaxis in the form of low-molecular-weight heparin (LMWH). The occurrence of VTE requires, as in other diseases, full-dose antithrombotic treatment. Herein, we describe seven cases of soft tissue hemorrhagic complications in the form of spontaneous intramuscular hematomas (SMHs) in patients after SCI undergoing rehabilitation. Four patients received anticoagulant therapy due to previously diagnosed deep vein thrombosis (DVT), and three patients received anticoagulant prophylaxis. None of the patients had a significant injury immediately before the hematoma appeared, and the only symptom was a sudden swelling of the limb without accompanying pain. The hematomas in all patients were treated conservatively. In three patients, significant decreases in hemoglobin were observed; in one patient, a blood transfusion was required for this reason. In all patients treated via anticoagulation, the anticoagulation treatment was modified at the time of diagnosis of the hematoma; in three patients, oral anticoagulants were changed to LMWH in a therapeutic dose, while in one patient, anticoagulant treatment was completely discontinued. Conclusions: Intramuscular hematomas are rare complications after SCI. Each sudden swelling of a limb requires ultrasound-based diagnostics. At the time of diagnosis of a hematoma, the level of hemoglobin and the size of the hematoma should be monitored. The treatment or anticoagulation prophylaxis should be modified if necessary.
Non-Perturbative Identification and Subtyping of Amyloidosis in Human Kidney Tissue with Raman Spectroscopy and Machine Learning
Authors: Kim Jeong Hee , Zhang Chi , Sperati Christopher John , Bagnasco Serena M. , Barman Ishan
Published: April 2023

Amyloids are proteins with characteristic beta-sheet secondary structures that display fibrillary ultrastructural configurations. They can result in pathologic lesions when deposited in human organs. Various types of amyloid protein can be routinely identified in human tissue specimens by special stains, immunolabeling, and electron microscopy, and, for certain forms of amyloidosis, mass spectrometry is required. In this study, we applied Raman spectroscopy to identify immunoglobulin light chain and amyloid A amyloidosis in human renal tissue biopsies and compared the results with a normal kidney biopsy as a control case. Raman spectra of amyloid fibrils within unstained, frozen, human kidney tissue demonstrated changes in conformation of protein secondary structures. By using t-distributed stochastic neighbor embedding (t-SNE) and density-based spatial clustering of applications with noise (DBSCAN), Raman spectroscopic data were accurately classified with respect to each amyloid type and deposition site. To the best of our knowledge, this is the first time Raman spectroscopy has been used for amyloid characterization of ex vivo human kidney tissue samples. Our approach, using Raman spectroscopy with machine learning algorithms, shows the potential for the identification of amyloid in pathologic lesions.
A Colorimetric Aptasensor for Ochratoxin A Detection Based on Tetramethylrhodamine Charge Effect-Assisted Silver Enhancement
Authors: Yang Xiaoyan , Huang Rong , Xiong Lulu , Chen Feng , Sun Wei , Yu Ling
Published: April 2023

A novel colorimetric aptasensor based on charge effect-assisted silver enhancement was developed to detect ochratoxin A (OTA). To achieve this objective, gold nanoparticles (AuNPs), which can catalyze silver reduction and deposition, were used as the carrier of the aptamers tagged with a positively charged tetramethylrhodamine (TAMRA). Due to the mutual attraction of positive and negative charges, the TAMRA attracted and retained the silver lactate around the AuNPs. Thus, the chance of AuNP-catalyzed silver reduction was increased. The charge effect-assisted silver enhancement was verified by tagging different base pair length aptamers with TAMRA. Under optimized conditions, the as-prepared OTA aptasensor had a working range of 1 × 102–1 × 106 pg mL−1. The detection limit was as low as 28.18 pg mL−1. Moreover, the proposed aptasensor has been successfully applied to determine OTA in actual samples with satisfactory results.
Microglia and Astrocytes Dysfunction and Key Neuroinflammation-Based Biomarkers in Parkinson’s Disease
Authors: Chen Kun , Wang Haoyang , Ilyas Iqra , Mahmood Arif , Hou Lijun
Published: April 2023

Parkinson’s disease (PD) is the second most common neurodegenerative disease, with symptoms such as tremor, bradykinesia with rigidity, and depression appearing in the late stage of life. The key hallmark of PD is the loss or death of dopaminergic neurons in the region substantia nigra pars compacta. Neuroinflammation plays a key role in the etiology of PD, and the contribution of immunity-related events spurred the researchers to identify anti-inflammatory agents for the treatment of PD. Neuroinflammation-based biomarkers have been identified for diagnosing PD, and many cellular and animal models have been used to explain the underlying mechanism; however, the specific cause of neuroinflammation remains uncertain, and more research is underway. So far, microglia and astrocyte dysregulation has been reported in PD. Patients with PD develop neural toxicity, inflammation, and inclusion bodies due to activated microglia and a-synuclein–induced astrocyte conversion into A1 astrocytes. Major phenotypes of PD appear in the late stage of life, so there is a need to identify key early-stage biomarkers for proper management and diagnosis. Studies are under way to identify key neuroinflammation-based biomarkers for early detection of PD. This review uses a constructive analysis approach by studying and analyzing different research studies focused on the role of neuroinflammation in PD. The review summarizes microglia, astrocyte dysfunction, neuroinflammation, and key biomarkers in PD. An approach that incorporates multiple biomarkers could provide more reliable diagnosis of PD.
The Effect of Cognitive Style on Individual Differences in Prismatic Adaptation: A Pilot Study
Authors: Bonavita Alessia , Bellagamba Martina , Verde Paola , Boccia Maddalena , Guariglia Cecilia
Published: April 2023

Prism adaptation (PA) is a well-known and widely used technique for rehabilitating unilateral spatial neglect and studying sensory–motor plasticity. However, there is conflicting evidence in the literature regarding its effectiveness which may arise from differences in the type of prisms used, clinical characteristics of the patients, and the procedure used in training. Individual differences may play a role in PA effectiveness in rehabilitating neglect, affecting both its development and its effects. Field-dependent/independent cognitive style is a pervasive characteristic of individual functioning, affecting how environmental information is processed. Here, we tested the hypothesis that cognitive style plays a role in PA efficacy by submitting to a protocol of prism adaptation to 38 health participants, who were classified as field-dependent (FD, N = 19) or field-independent (FI, N = 19), by using the Embedded Figure Test. Results show that during the exposure phase, FI individuals needed a lesser number of pointing movements to reduce the deviation error than FD individuals. However, there are no differences in the extinction of sensory–motor and cognitive after-effects. These results suggest that prismatic adaptation is affected by individuals’ cognitive style since FI individuals will need fewer trials to reach adaptation and this could explain why using this rehabilitation technique with a unique, standard protocol is not always effective.
The Risk-Taking and Self-Harm Inventory for Adolescents: Validation of the Italian Version (RTSHIA-I)
Authors: Valle Annalisa , Cavalli Giulia , Miraglia Laura , Bracaglia Edoardo Alfredo , Fonagy Peter , Di Dio Cinzia , Marchetti Antonella
Published: April 2023

The aim of the present paper is to establish the factorial validity and reliability of the Risk-Taking and Self-Harm Inventory for Adolescents (RTSHIA), proposed by Vrouva and colleagues in 2010, in an Italian sample. The RTSHIA measures both Risk-Taking and Self-Harm behavior in adolescents. We administered the scale to a total of 1292 Italian adolescents from 9th to 12th grade; to verify the validity of the scale, we also assessed emotion regulation and psychopathological traits. The exploratory factor analysis (EFA) (N = 638) and the confirmatory factor analysis (CFA) (N = 660) confirmed the original two-factor structure of the RTSHIA (Risk-Taking and Self-Harm). The only differences in the Italian version of the RTSHIA (RTSHIA-I) were that one item was moved from the original Risk-Taking factor to the Italian Self-Harm factor, and another item that was not included in the original RTSHIA is now part of the Risk-Taking factor in the Italian version. The reliability of the RTSHIA-I is also confirmed, and both factors correlate with emotion regulation and externalizing/internalizing traits. Our results suggest that the RTSHIA-I is a useful tool for assessing Risk-Taking and Self-Harm behaviors in Italian adolescents, and the correlational patterns indicate that these behaviors may be related to difficulties in mentalization skills.
The Effect of the Secret Agent Society Group Program on Parent-Teacher Agreement Regarding Children’s Social Emotional Functioning
Authors: Gasparro Shannon , Bennett Shannon , Wyka Katarzyna , Temkin-Yu Andrea , Damianides Andreas , Beaumont Renae
Published: April 2023

Differences in social-emotional processing and functioning characterize children with Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), and Anxiety Disorders. These can contribute to difficulties forming friendships and secondary challenges such as academic underachievement, depression, and substance use in adolescence. To be optimally successful, interventions typically require parents and teachers to have a shared understanding of a child’s social-emotional needs and use consistent support strategies across home and school environments. However, research is yet to examine the effect that clinic-based programs have on parent-teacher agreement regarding children’s social-emotional functioning. To the authors’ knowledge, this is the first published study to explore this. A sample of eighty-nine youth (aged 8 to 12 years) with ASD, ADHD, and/or an Anxiety Disorder participated in the Secret Agent Society Program. The Social Skills Questionnaire and Emotion Regulation and Social Skills Questionnaire were administered to parents and teachers at pre-program, post-program, and six-month follow-up. Parent-teacher agreement was assessed at each time point. Pearson Product Moment correlations and intraclass correlations indicated that parent-teacher agreement on the measures of children’s social-emotional functioning improved over time. These findings suggest that clinic-based programs can contribute to key stakeholders developing a shared understanding of children’s social-emotional needs. The implications of these findings and directions for future research are discussed.
Italian Validation of the Online Student Engagement Scale (OSE) in Higher Education
Authors: Sulla Francesco , Harrad Rachel , Tontodimamma Alice , Limone Pierpaolo , Aquino Antonio
Published: April 2023

During the COVID-19 pandemic, entire university courses were moved online. This represented a challenge for universities, who were required to move toward an entirely online learning environment without adequate time to manage the change from traditional courses to online courses. However, beyond the emergency of the pandemic, higher education does increasingly incorporate an online learning element, and such a provision does appear to reflect both the desires of modern-day students and university offerings. For this reason, assessing students’ online engagement is fundamental, not least because it has been seen to be related both to students’ satisfaction and their academic achievement. A validated measure of student online engagement does not exist in Italy. Therefore, this study aims to assess both the factor structure and the validity of the Online Student Engagement (OSE) Scale in the Italian context. A convenience sample of 299 undergraduate university students completed a series of online questionnaires. The Italian OSE scale presents good psychometric properties and represents a valuable instrument for both practitioners and researchers examining students’ engagement in online learning.
Ethnic Differences in Response to COVID-19: A Study of American-Asian and Non-Asian College Students
Authors: Zhao Yijun , Ding Yi , Chekired Hayet , Wu Ying , Wang Qian
Published: April 2023

Asian American students have experienced additional physical and emotional hardships associated with the COVID-19 pandemic due to increased xenophobic and anti-Asian discrimination. This study investigates different coping patterns and risk factors affecting Asian and non-Asian college students in response to COVID-19 challenges by studying the differences in their responses within four domains after the onset of the pandemic: academic adjustment, emotional adjustment, social support, and discriminatory impacts related to COVID-19. We first employed a machine learning approach to identify well-adjusted and poorly adjusted students in each of the four domains for the Asian and non-Asian groups, respectively. Next, we applied the SHAP method to study the principal risk factors associated with each classification task and analyzed the differences between the two groups. We based our study on a proprietary survey dataset collected from U.S. college students during the initial peak of the pandemic. Our findings provide insights into the risk factors and their directional impact affecting Asian and non-Asian students’ well-being during the pandemic. The results could help universities establish customized strategies to support these two groups of students in this era of uncertainty. Applications for international communities are discussed.
Composite Materials Based on Waste Cooking Oil for Construction Applications
Authors: Staroń Anita
Published: April 2023

Used cooking oil after the thermal processing of food constitutes a difficult-to-degrade waste product, the quantities of which are increasing yearly due to the increasing pace of life and the establishment of new food service outlets. Frying allows for the preparation of a large amount of food for consumption in a short time but alters the physical and chemical properties of the oil used, which then becomes harmful to human health. Despite several possibilities for using waste cooking oil, environmentally safe ways to manage it are still being sought. In an effort to reduce the amount of waste, using cooking oil as a binder for the benefit of the construction industry seems plausible. This paper presents a literature review on the use of waste cooking oil to produce composite materials for construction purposes, addressing the process parameters of tipping solid materials comprising vegetable oil as a binder and examining their strength and absorbability. Methods of obtaining oil binders, either comprising vegetable oil alone or various mixtures, are described. In addition, the advantages of producing and using “green” materials are presented.
Surface Functionalization of (Pyrolytic) Carbon—An Overview
Authors: Pustahija Lucija , Kern Wolfgang
Published: April 2023

This review focuses on techniques for modifying the surface of carbon that is produced from sustainable resources, such as pyrolytic carbon. Many of these materials display high specific surface area and fine particle distribution. Functionalization of a surface is a commonly used approach in designing desired surface properties of the treated material while retaining its bulk properties. Usually, oxidation is a primary step in carbon functionalization. It can be performed as wet oxidation, which is a type of chemical surface modification. Wet oxidation is usually performed using nitric acid and hydrogen peroxide, as well as using hydrothermal and solvothermal oxidation. On the other side, dry oxidation is representative of physical surface modification. This method is based on corona discharge and plasma oxidation which are promising methods that are in line with green chemistry approaches. Whilst the oxidation of the carbon surface is a well-known method, other chemical modification techniques, including cycloadditions and various radical reactions on graphene layers, are presented as an alternative approach. Regarding secondary functionalization, coupling organosilanes to activated carbon is a common technique. Organosilanes bearing reactive groups present a bridge between inorganic species and polymer systems, e.g., epoxy and polyurethane resins, and facilitate the use of carbonaceous materials as reinforcing components for polymers and thermosetting resins. Along with the presented functionalization methods, this review also provides an overview of new applications of modified (i.e., functionalized) carbon materials, e.g., for the building industry, wastewater treatment, semiconducting materials and many more.
Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer
Authors: Alizadeh Javad , Kavoosi Mahboubeh , Singh Navjit , Lorzadeh Shahrokh , Ravandi Amir , Kidane Biniam , Ahmed Naseer , Mraiche Fatima , Mowat Michael R. , Ghavami Saeid
Published: April 2023

Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated with metabolism in mammalian cells, acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. In addition, we discuss the impact of these metabolic pathways on autophagy in lung cancer.
Euchromatic Histone Lysine Methyltransferase 2 Inhibition Enhances Carfilzomib Sensitivity and Overcomes Drug Resistance in Multiple Myeloma Cell Lines
Authors: Mereu Elisabetta , Abbo Damiano , Paradzik Tina , Cumerlato Michela , Bandini Cecilia , Labrador Maria , Maccagno Monica , Ronchetti Domenica , Manicardi Veronica , Neri Antonino , Piva Roberto
Published: April 2023

Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. In addition, adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. Here, to identify compounds that can increase the efficacy of PIs, we performed a functional screening using a library of small-molecule inhibitors covering key signaling pathways. Among the best synthetic lethal interactions, the euchromatic histone-lysine N-methyltransferase 2 (EHMT2) inhibitor UNC0642 displayed a cooperative effect with carfilzomib (CFZ) in numerous multiple myeloma (MM) cell lines, including drug-resistant models. In MM patients, EHMT2 expression correlated to worse overall and progression-free survival. Moreover, EHMT2 levels were significantly increased in bortezomib-resistant patients. We demonstrated that CFZ/UNC0642 combination exhibited a favorable cytotoxicity profile toward peripheral blood mononuclear cells and bone-marrow-derived stromal cells. To exclude off-target effects, we proved that UNC0642 treatment reduces EHMT2-related molecular markers and that an alternative EHMT2 inhibitor recapitulated the synergistic activity with CFZ. Finally, we showed that the combinatorial treatment significantly perturbs autophagy and the DNA damage repair pathways, suggesting a multi-layered mechanism of action. Overall, the present study demonstrates that EHMT2 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients.
Breast Cancer: Impact of New Treatments?
Authors: Storme Guy A.
Published: April 2023

Background: Breast cancer treatment has seen tremendous progress since the early 1980s, with the first findings of new chemotherapy and hormone therapies. Screening started in the same period. Methods: A review of population data (SEER and the literature) shows an increase in recurrence-free survival until 2000 and it stagnates afterwards. Results: Over the period 1980-2000, the 15% survival gain was presented by pharma as a contribution of new molecules. The contribution of screening during that same period was not implemented by them, although screening has been accepted as a routine procedure in the States since the 1980s and everywhere else since 2000. Conclusions: Interpretation of breast cancer outcome has largely focused on drugs, whereas other factors, such as screening, prevention, biologics, and genetics, were largely neglected. More attention should now be paid to examining the strategy based on realistic global data.
Survival Outcomes and Failure Patterns in Patients with Inoperable Non-Metastatic Pancreatic Cancer Treated with Definitive Radiotherapy
Authors: Cao Biyang , Zhang Letian , Wu Chenchen , Liu Xiaoliang , Wang Qianqian , Tong Fang , Yang Wei , Wang Jing
Published: April 2023

This study investigated the long-term results, failure patterns, and prognostic factors of patients with initially inoperable non-metastatic pancreatic cancer (PC) receiving definitive radiotherapy (RT). Between January 2016 and December 2020, a total of 168 non-metastatic PC patients, who were surgically unresectable or medically inoperable, were enrolled to receive definitive RT, with or without chemotherapy. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan–Meier method with a log-rank test. The cumulative incidence of locoregional and distant progression was estimated using the competing risks model. The Cox proportional-hazards model was used to determine the influence of prognostic variables on OS. With a median follow-up of 20.2 months, the median OS (mOS) and median PFS (mPFS) from diagnosis were 18.0 months [95% confidence interval (CI), 16.5–21.7 months] and 12.3 months (95% CI, 10.2–14.3 months), respectively. The mOS and mPFS from RT were 14.3 months (95% CI, 12.7–18.3 months) and 7.7 months (95% CI, 5.5–12.0 months), respectively. The corresponding 1-year, 2-year, and 3-year OS from diagnosis and RT were 72.1%, 36.6%, and 21.5% as well as 59.0%, 28.8%, and 19.0%, respectively. In a multivariate analysis, stage I–II (p = 0.032), pre-RT CA19–9 ≤ 130 U/mL (p = 0.011), receiving chemotherapy (p = 0.003), and a biologically effective dose (BED10) > 80 Gy (p = 0.014) showed a significant favorable influence on OS. Among the 59 available patients with definite progression sites, the recurrences of local, regional, and distant progression were 33.9% (20/59), 18.6% (11/59), and 59.3% (35/59), respectively. The 1-year and 2-year cumulative incidences of locoregional progression after RT were 19.5% (95% CI, 11.5–27.5%) and 32.8% (95% CI, 20.8–44.8%), respectively. Definitive RT was associated with long-term primary tumor control, resulting in superior survival in patients with inoperable non-metastatic PC. Further prospective randomized trials are warranted to validate our results in these patients.
Connection of Cancer Exosomal LncRNAs, Sponging miRNAs, and Exosomal Processing and Their Potential Modulation by Natural Products
Authors: Chuang Ya-Ting , Shiau Jun-Ping , Tang Jen-Yang , Farooqi Ammad Ahmad , Chang Fang-Rong , Tsai Yi-Hong , Yen Ching-Yu , Chang Hsueh-Wei
Published: April 2023

Cancerous exosomes contain diverse biomolecules that regulate cancer progression. Modulating exosome biogenesis with clinical drugs has become an effective strategy for cancer therapy. Suppressing exosomal processing (assembly and secretion) may block exosomal function to reduce the proliferation of cancer cells. However, the information on natural products that modulate cancer exosomes lacks systemic organization, particularly for exosomal long noncoding RNAs (lncRNAs). There is a gap in the connection between exosomal lncRNAs and exosomal processing. This review introduces the database (LncTarD) to explore the potential of exosomal lncRNAs and their sponging miRNAs. The names of sponging miRNAs were transferred to the database (miRDB) for the target prediction of exosomal processing genes. Moreover, the impacts of lncRNAs, sponging miRNAs, and exosomal processing on the tumor microenvironment (TME) and natural-product-modulating anticancer effects were then retrieved and organized. This review sheds light on the functions of exosomal lncRNAs, sponging miRNAs, and exosomal processing in anticancer processes. It also provides future directions for the application of natural products when regulating cancerous exosomal lncRNAs.
Rare Non-Neuroendocrine Pancreatic Tumours
Authors: Mormul Agata , Włoszek Emilia , Nowoszewska Julia , Fudalej Marta , Budzik Michał , Badowska-Kozakiewicz Anna , Deptała Andrzej
Published: April 2023

The most common tumour of the pancreas is ductal adenocarcinoma (PDAC). It remains one of the most lethal non-neuroendocrine solid tumours despite the use of a multi-approach strategy. Other, less-common neoplasms, which are responsible for 15% of pancreatic lesions, differ in treatment and prognosis. Due to the low incidence rate, there is a lack of information about the rarest pancreatic tumours. In this review, we described six rare pancreatic tumours: intraductal papillary mucinous neoplasm (IPMN), mucinous cystadenoma (MCN), serous cystic neoplasm (SCN), acinar cell carcinoma (ACC), solid pseudopapillary neoplasm (SPN) and pancreatoblastoma (PB). We distinguished their epidemiology, clinical and gross features, covered the newest reports about courses of treatment and systematised differential diagnoses. Although the most common pancreatic tumour, PDAC, has the highest malignant potential, it is still essential to properly classify and differentiate less-common lesions. It is vital to continue the search for new biomarkers, genetic mutations and the development of more specific biochemical tests for determining malignancy in rare pancreatic neoplasms.
Leukocytic Infiltration of Intraductal Carcinoma of the Prostate: An Exploratory Study
Authors: Diop Mame-Kany , Molina Oscar Eduardo , Birlea Mirela , LaRue Hélène , Hovington Hélène , Têtu Bernard , Lacombe Louis , Bergeron Alain , Fradet Yves , Trudel Dominique
Published: April 2023

Intraductal carcinoma of the prostate (IDC-P) is an aggressive histological subtype of prostate cancer (PCa) detected in approximately 20% of radical prostatectomy (RP) specimens. As IDC-P has been associated with PCa-related death and poor responses to standard treatment, the purpose of this study was to explore the immune infiltrate of IDC-P. Hematoxylin- and eosin-stained slides from 96 patients with locally advanced PCa who underwent RP were reviewed to identify IDC-P. Immunohistochemical staining of CD3, CD8, CD45RO, FoxP3, CD68, CD163, CD209 and CD83 was performed. For each slide, the number of positive cells per mm2 in the benign tissues, tumor margins, cancer and IDC-P was calculated. Consequently, IDC-P was found in a total of 33 patients (34%). Overall, the immune infiltrate was similar in the IDC-P-positive and the IDC-P-negative patients. However, FoxP3+ regulatory T cells (p < 0.001), CD68+ and CD163+ macrophages (p < 0.001 for both) and CD209+ and CD83+ dendritic cells (p = 0.002 and p = 0.013, respectively) were less abundant in the IDC-P tissues compared to the adjacent PCa. Moreover, the patients were classified as having immunologically “cold” or “hot” IDC-P, according to the immune-cell densities averaged in the total IDC-P or in the immune hotspots. The CD68/CD163/CD209-immune hotspots predicted metastatic dissemination (p = 0.014) and PCa-related death (p = 0.009) in a Kaplan–Meier survival analysis. Further studies on larger cohorts are necessary to evaluate the clinical utility of assessing the immune infiltrate of IDC-P with regards to patient prognosis and the use of immunotherapy for lethal PCa.
Tumor-Infiltrating CD45RO+ Memory Cells Are Associated with Favorable Prognosis in Oral Squamous Cell Carcinoma Patients
Authors: Ito Nanako , Yamasaki Sachiko , Shintani Tomoaki , Matsui Kensaku , Obayashi Fumitaka , Koizumi Koichi , Tani Ryouji , Yanamoto Souichi , Okamoto Tetsuji
Published: April 2023

Background: Tumor-infiltrating lymphocytes (TILs) have been used to predict the prognosis of solid tumors. In this study, we investigated which molecules in TILs play a role in the prognosis of patients with oral squamous cell carcinoma (OSCC). Methods: In a retrospective case-control study, we immunohistochemically evaluated the expression of CD3, CD8, CD45RO, Granzyme B, and the major histocompatibility complex class I chain-related molecule A (MICA) of the histocompatibility complex as predictors of prognosis in 33 patients with OSCC. The patients were classified as TILsHigh or TILsLow according to the number of TILs for each molecule in the central tumor (CT) and invasive margin (IM). Furthermore, MICA expression scores were determined based on the intensity of the staining. Results: CD45RO+/TIL in the nonrecurrent group were significantly higher than those in the recurrent group in the CT and IM areas (p < 0.05). The disease-free survival/overall survival rate of the CD45RO+/TILsLow group in the CT and IM areas and the Granzyme B+/TILsLow group in the IM area was significantly lower than that of the CD45RO+/TILsHigh group and the Granzyme B+/TILsHigh group, respectively (p < 0.05). Furthermore, the MICA expression score of tumors around the CD45RO+/TILsHigh group was significantly higher than that of the CD45RO+/TILsLow group (p < 0.05). Conclusions: A high ratio of CD45RO-expressing TILs was associated with a disease-free/overall survival improvement in OSCC patients. Furthermore, the number of TILs that express CD45RO was associated with the expression of MICA in tumors. These results suggest that CD45RO-expressing TILs are useful biomarkers for OSCC.
Immune Checkpoint Neuropilins as Novel Biomarkers and Therapeutic Targets for Pancreatic Cancer
Authors: He Li-Hong , Zhang Xiao-Zhen , Lao Meng-Yi , Zhang Han-Jia , Yang Han-Shen , Bai Xue-Li
Published: April 2023

The traditional immune checkpoint blockade therapy benefits some patients with cancer, but elicits no response in certain cancers, such as pancreatic adenocarcinoma (PAAD); thus, novel checkpoints and effective targets are required. Here, we found that there was a higher Neuropilin (NRP) expression in tumor tissues as novel immune checkpoints, which was associated with poor prognosis and pessimistic responses to immune checkpoint blockade therapy. In the tumor microenvironment of PAAD samples, NRPs were widely expressed in tumor, immune and stromal cells. The relationship of NRPs with tumor immunological features in PAAD and pan-cancer was evaluated using bioinformatics methods; it was positively correlated with the infiltration of myeloid immune cells and the expression of most immune checkpoint genes. Bioinformatics analysis, in vitro and in vivo experiments suggested that NRPs exhibit potential immune-related and immune-independent pro-tumor effects. NRPs, especially NRP1, are attractive biomarkers and therapeutic targets for cancers, particularly PAAD.
Integrated Microbiota and Metabolite Changes following Rice Bran Intake during Murine Inflammatory Colitis-Associated Colon Cancer and in Colorectal Cancer Survivors
Authors: Weber Annika M. , Ibrahim Hend , Baxter Bridget A. , Kumar Robin , Maurya Akhilendra K. , Kumar Dileep , Agarwal Rajesh , Raina Komal , Ryan Elizabeth P.
Published: April 2023

Dietary rice bran-mediated inhibition of colon carcinogenesis was demonstrated previously for carcinogen-induced rodent models via multiple anti-cancer mechanisms. This study investigated the role of dietary rice bran-mediated changes to fecal microbiota and metabolites over the time course of colon carcinogenesis and compared murine fecal metabolites to human stool metabolic profiles following rice bran consumption by colorectal cancer survivors (NCT01929122). Forty adult male BALB/c mice were subjected to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated colon carcinogenesis and randomized to control AIN93M (n = 20) or diets containing 10% w/w heat-stabilized rice bran (n = 20). Feces were serially collected for 16S rRNA amplicon sequencing and non-targeted metabolomics. Fecal microbiota richness and diversity was increased in mice and humans with dietary rice bran treatment. Key drivers of differential bacterial abundances from rice bran intake in mice included Akkermansia, Lactococcus, Lachnospiraceae, and Eubacterium xylanophilum. Murine fecal metabolomics revealed 592 biochemical identities with notable changes to fatty acids, phenolics, and vitamins. Monoacylglycerols, dihydroferulate, 2-hydroxyhippurate (salicylurate), ferulic acid 4-sulfate, and vitamin B6 and E isomers significantly differed between rice bran- and control-fed mice. The kinetics of murine metabolic changes by the host and gut microbiome following rice bran consumption complemented changes observed in humans for apigenin, N-acetylhistamine, and ethylmalonate in feces. Increased enterolactone abundance is a novel diet-driven microbial metabolite fecal biomarker following rice bran consumption in mice and humans from this study. Dietary rice bran bioactivity via gut microbiome metabolism in mice and humans contributes to protection against colorectal cancer. The findings from this study provide compelling support for rice bran in clinical and public health guidelines for colorectal cancer prevention and control.
Degradation of Sulfamethoxazole in Aqueous Solution by Low-Energy X-ray Irradiation
Authors: Yao Jun , Rao Weidong , Kong Hua , Sun Wentao , Guo Dengzhu , Li Zhiwei , Wei Xianlong
Published: April 2023

Antibiotic resistance has been a serious health threat of widespread concern, as antibiotics are difficult to degrade effectively in the environment. In this study, sulfamethoxazole (SMZ), a common antibiotic in an aqueous solution, was irradiated by low-energy X-ray to investigate the effect of the absorption dose, initial concentration, initial pH, irradiation energy and other conditions on the degradation of SMZ, as well as the kinetic mechanism of SMZ degradation. The results showed that low-energy X-ray irradiation could effectively degrade SMZ in an aqueous solution at different initial concentrations and acid-base degrees, and the degradation effect of irradiation in the range of 60–80 keV is independent of the energy of X-rays. The degradation rate of the SMZ solution, with an initial concentration of 10.70 mg/L, was 94.6% at an absorbed dose of 890 Gray, with a pH of 3.5. Similar to other works on the degradation of antibiotics by ionizing irradiation, the degradation of SMZ solutions conformed to a pseudo-first-order kinetic mechanism.
Preparation of Co-CNK-OH and Its Performance in Fenton-like Photocatalytic Degradation of Tetracycline
Authors: Hou Dongrui , Luo Jing , Sun Qinggong , Zhang Mengyang , Wang Jianfeng
Published: April 2023

In this study, Co-modified alkalinized g-C3N4 (named Co-CNK-OH) was prepared for the Fenton-like photocatalytic degradation of tetracycline (TC) via a simple yet effective calcination–impregnation method. In all samples of CNK-OH with different Co2+ loadings, Co-CNK-OH catalyst with the optimal content (9%) exhibited the highest catalytic activity, with 87.1% tetracycline removal and 50% removal efficiency of the total organic carbon (TOC). Mechanism studies revealed that the 9%Co-CNK-OH catalyst had the lower electrical resistance after alkalization treatment and Co2+ modification, leading to a significantly accelerated interfacial charge transfer to the electron acceptor as well as effectively separating electrons and holes. The intermediates generated during the TC degradation in the photo-Fenton process were detected by HPLC-MS, which proved that the holes, superoxide radicals, and singlet oxygen are the key reactive species in the Fenton-like photocatalysis. This study provides a new option for the treatment of TC in wastewater.
Insights on Host–Parasite Immunomodulation Mediated by Extracellular Vesicles of Cutaneous Leishmania shawi and Leishmania guyanensis
Authors: Weber Juliana Inês , Rodrigues Armanda Viana , Valério-Bolas Ana , Nunes Telmo , Carvalheiro Manuela , Antunes Wilson , Alexandre-Pires Graça , da Fonseca Isabel Pereira , Santos-Gomes Gabriela
Published: April 2023

Leishmaniasis is a parasitic disease caused by different species of Leishmania and transmitted through the bite of sand flies vector. Macrophages (MΦ), the target cells of Leishmania parasites, are phagocytes that play a crucial role in the innate immune microbial defense and are antigen-presenting cells driving the activation of the acquired immune response. Exploring parasite–host communication may be key in restraining parasite dissemination in the host. Extracellular vesicles (EVs) constitute a group of heterogenous cell-derived membranous structures, naturally produced by all cells and with immunomodulatory potential over target cells. This study examined the immunogenic potential of EVs shed by L. shawi and L. guyanensis in MΦ activation by analyzing the dynamics of major histocompatibility complex (MHC), innate immune receptors, and cytokine generation. L. shawi and L. guyanensis EVs were incorporated by MΦ and modulated innate immune receptors, indicating that EVs cargo can be recognized by MΦ sensors. Moreover, EVs induced MΦ to generate a mix of pro- and anti-inflammatory cytokines and favored the expression of MHCI molecules, suggesting that EVs antigens can be present to T cells, activating the acquired immune response of the host. Since nano-sized vesicles can be used as vehicles of immune mediators or immunomodulatory drugs, parasitic EVs can be exploited by bioengineering approaches for the development of efficient prophylactic or therapeutic tools for leishmaniasis.
The RUNX Family of Proteins, DNA Repair, and Cancer
Authors: Krishnan Vaidehi
Published: April 2023

The RUNX family of transcription factors, including RUNX1, RUNX2, and RUNX3, are key regulators of development and can function as either tumor suppressors or oncogenes in cancer. Emerging evidence suggests that the dysregulation of RUNX genes can promote genomic instability in both leukemia and solid cancers by impairing DNA repair mechanisms. RUNX proteins control the cellular response to DNA damage by regulating the p53, Fanconi anemia, and oxidative stress repair pathways through transcriptional or non-transcriptional mechanisms. This review highlights the importance of RUNX-dependent DNA repair regulation in human cancers.
Hypercontractile Cardiac Phenotype in Mice with Migraine-Associated Mutation in the Na+,K+-ATPase α2-Isoform
Authors: Rajanathan Rajkumar , Riera Clàudia Vilaseca i , Pedersen Tina Myhre , Staehr Christian , Bouzinova Elena V. , Nyengaard Jens Randel , Thomsen Morten B. , Bøtker Hans Erik , Matchkov Vladimir V.
Published: April 2023

Two α-isoforms of the Na+,K+-ATPase (α1 and α2) are expressed in the cardiovascular system, and it is unclear which isoform is the preferential regulator of contractility. Mice heterozygous for the familial hemiplegic migraine type 2 (FHM2) associated mutation in the α2-isoform (G301R; α2+/G301R mice) have decreased expression of cardiac α2-isoform but elevated expression of the α1-isoform. We aimed to investigate the contribution of the α2-isoform function to the cardiac phenotype of α2+/G301R hearts. We hypothesized that α2+/G301R hearts exhibit greater contractility due to reduced expression of cardiac α2-isoform. Variables for contractility and relaxation of isolated hearts were assessed in the Langendorff system without and in the presence of ouabain (1 µM). Atrial pacing was performed to investigate rate-dependent changes. The α2+/G301R hearts displayed greater contractility than WT hearts during sinus rhythm, which was rate-dependent. The inotropic effect of ouabain was more augmented in α2+/G301R hearts than in WT hearts during sinus rhythm and atrial pacing. In conclusion, cardiac contractility was greater in α2+/G301R hearts than in WT hearts under resting conditions. The inotropic effect of ouabain was rate-independent and enhanced in α2+/G301R hearts, which was associated with increased systolic work.
Untargeted Metabolomics Reveals a Multi-Faceted Resistance Response to Fusarium Head Blight Mediated by the Thinopyrum elongatum Fhb7E Locus Transferred via Chromosome Engineering into Wheat
Authors: Fanelli Giuseppina , Kuzmanović Ljiljana , Giovenali Gloria , Tundo Silvio , Mandalà Giulia , Rinalducci Sara , Ceoloni Carla
Published: April 2023

The Thinopyrum elongatum Fhb7E locus has been proven to confer outstanding resistance to Fusarium Head Blight (FHB) when transferred into wheat, minimizing yield loss and mycotoxin accumulation in grains. Despite their biological relevance and breeding implications, the molecular mechanisms underlying the resistant phenotype associated with Fhb7E have not been fully uncovered. To gain a broader understanding of processes involved in this complex plant–pathogen interaction, we analysed via untargeted metabolomics durum wheat (DW) rachises and grains upon spike inoculation with Fusarium graminearum (Fg) and water. The employment of DW near-isogenic recombinant lines carrying or lacking the Th. elongatum chromosome 7E region including Fhb7E on their 7AL arm, allowed clear-cut distinction between differentially accumulated disease-related metabolites. Besides confirming the rachis as key site of the main metabolic shift in plant response to FHB, and the upregulation of defence pathways (aromatic amino acid, phenylpropanoid, terpenoid) leading to antioxidants and lignin accumulation, novel insights were revealed. Fhb7E conferred constitutive and early-induced defence response, in which specific importance of polyamine biosynthesis, glutathione and vitamin B6 metabolisms, along with presence of multiple routes for deoxynivalenol detoxification, was highlighted. The results suggested Fhb7E to correspond to a compound locus, triggering a multi-faceted plant response to Fg, effectively limiting Fg growth and mycotoxin production.
Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer’s Disease
Authors: Steinke Ian , Govindarajulu Manoj , Pinky Priyanka Das , Bloemer Jenna , Yoo Sieun , Ward Tracey , Schaedig Taylor , Young Taylor , Wibowo Fajar Setyo , Suppiramaniam Vishnu , Amin Rajesh H.
Published: April 2023

Background: The continuously increasing association of Alzheimer’s disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer’s disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application. Methods: We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain. Results: This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals. Conclusions: Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD.
The Impact of Different Types of Physical Effort on the Expression of Selected Chemokine and Interleukin Receptor Genes in Peripheral Blood Cells
Authors: Nowak Robert , Trzeciak-Ryczek Alicja , Ciechanowicz Andrzej , Brodkiewicz Andrzej , Urasińska Elżbieta , Kostrzewa-Nowak Dorota
Published: April 2023

This study aimed to assess the post-effort transcriptional changes of selected genes encoding receptors for chemokines and interleukins in young, physically active men to better understand the immunomodulatory effect of physical activity. The participants, aged 16–21 years, performed physical exercise tasks of either a maximal multistage 20 m shuttle-run test (beep test) or a repeated speed ability test. The expression of selected genes encoding receptors for chemokines and interleukins in nucleated peripheral blood cells was determined using RT-qPCR. Aerobic endurance activity was a positive stimulant that induced increased expression of CCR1 and CCR2 genes following lactate recovery, while the maximum expression of CCR5 was found immediately post-effort. The increase in the expression of inflammation-related genes encoding chemokine receptors triggered by aerobic effort strengthens the theory that physical effort induces sterile inflammation. Different profiles of studied chemokine receptor gene expression induced by short-term anaerobic effort suggest that not all types of physical effort activate the same immunological pathways. A significant increase in IL17RA gene expression after the beep test confirmed the hypothesis that cells expressing this receptor, including Th17 lymphocyte subsets, can be involved in the creation of an immune response after endurance efforts.