Review of the Ubiquitin Role in DNA Repair and Tumorigenesis, with Emphasis in Breast Cancer Treatment; Current Data and Future Options

Breast carcinoma remains the commonest carcinoma among women worldwide. Despite the fact that impressive progression has been achieved so far regarding pathophysiology, histopathology and treatment of this cancer, there are still undiscovered fields on molecular and therapeutic levels. The need of resolving problems such as chemoresistance, recurrence and metastasis has led in revealing key molecules in the development and progression of malignancies, including breast tumors. In this review, we will briefly describe the functions of ubiquitin and post-translational modifications (PTMs) focusing specially in DNA repair and then discuss about the implication of ubiquitin and related molecules in tumorigenesis and specifically in breast carcinoma. So far there are only few drugs approved by FDA that target the ubiquitin system. There will be an analysis regarding the current and potential anti-cancer therapeutic strategies based on targeting specific ubiquitin-related molecules

PRELIMINARY OUTCOMES AND CHALLENGES TO IMPLEMENTING SCHOOL-WIDE POSITIVE BEHAVIOR INTERVENTIONS AND SUPPORTS IN 30 GREEK PRIMARY SCHOOLS

School-Wide Positive Behavior Interventions and Supports (SWPBIS) is an evidence-based three-tier school-wide framework for preventing and treating challenging behavior in schools, improving overall school climate, and promoting teachers' teaming and collaboration. SWPBIS outcomes, such as the decrease of students' behavioral problems and improvement of teachers' cooperation, have been well established across various educational systems in many countries. The purpose of this qualitative study is to investigate stakeholders' perceptions about the preliminary outcomes and challenges of the SWPBIS Tier 1 implementation in 30 Greek primary schools. A semi-structured focus group was conducted with stakeholders from Greek primary schools about their experiences from the implementation of SWPBIS Tier 1 during the 2019-2020 school year. Three key categories were identified: (a) perceptions about the initial SWPBIS outcomes, (b) implementation challenges, and (c) suggestions on additional supports. Practical implications and results are discussed in terms of how they can be used in sustaining SWPBIS in the Greek context.  Article visualizations

Comparison of Chromogenic In Situ Hybridisation with Fluorescence In Situ Hybridisation and Immunohistochemistry for the Assessment of Her-2/neu Oncogene in Archival Material of Breast Carcinoma

The successful treatment of breast cancer is dependent upon a number of complex factors. Her-2/neu gene amplification is known to be one of the most common genetic alterations associated with breast cancer and its accurate determination has become necessary for the selection of patients for trastuzumab therapy

Nitrosative and Oxidative Stresses Contribute to Post-Ischemic Liver Injury Following Severe Hemorrhagic Shock: The Role of Hypoxemic Resuscitation

Purpose: Hemorrhagic shock and resuscitation is frequently associated with liver ischemia-reperfusion injury. The aim of the study was to investigate whether hypoxemic resuscitation attenuates liver injury. Methods: Anesthetized, mechanically ventilated New Zealand white rabbits were exsanguinated to a mean arterial pressure of 30 mmHg for 60 minutes. Resuscitation under normoxemia (Normox-Res group, n = 16, PaO2 = 95–105 mmHg) or hypoxemia (Hypox-Res group, n = 15, PaO 2 = 35–40 mmHg) followed, modifying the FiO 2. Animals not subjected to shock constituted the sham group (n = 11, PaO 2 = 95–105 mmHg). Indices of the inflammatory, oxidative and nitrosative response were measured and histopathological and immunohistochemical studies of the liver were performed. Results: Normox-Res group animals exhibited increased serum alanine aminotransferase, tumor necrosis factor- alpha, interleukin (IL)-1b and IL-6 levels compared with Hypox-Res and sham groups. Reactive oxygen species generation, malondialdehyde formation and myeloperoxidase activity were all elevated in Normox-Res rabbits compared with Hypox-Res and sham groups. Similarly, endothelial NO synthase and inducible NO synthase mRNA expression was up-regulated and nitrotyrosine immunostaining increased in animals resuscitated normoxemically, indicating a more intense nitrosative stress. Hypox-Res animals demonstrated a less prominent histopathologic injury which was similar to sham animals. Conclusions: Hypoxemic resuscitation prevents liver reperfusion injury through attenuation of the inflammatory respons

Divulging the Critical Role of HuR in Pancreatic Cancer as a Therapeutic Target and a Means to Overcome Chemoresistance

Simple Summary With pancreatic cancer incidence constantly rising, constituting one of the most lethal type of cancers worldwide, the need for discovering novel therapeutic targets and approaches becomes of the utmost importance. Meanwhile, modern eating habits, hyperadiposity, mutational burden affecting core signaling pathways and the unique tumor microenvironment of pancreatic cancer tissues intermingle and form a disease that is lethal and hard to treat. The importance of HuR in pancreatic cancer has repeatedly been observed and represents a key molecule in pancreatic carcinogenesis and chemoresistance. Therefore, creating and obtaining new therapeutic skills against HuR protein could prove to be the answer to pancreatic cancer therapy. Pancreatic cancer is set to become the most lethal and common type of cancer worldwide. This is partly attributed to the mutational burden that affects core signaling pathways and the crosstalk of tumor cells with their surrounding microenvironment, but it is also due to modern eating habits. Hyperadiposity along with the constant rise in metabolic syndrome's incidence contribute to a state of metaflammation that impacts immune cells and causes them to shift towards an immunosuppressive phenotype that, ultimately, allows tumor cells to evade immune control. Unfortunately, among the conventional therapeutic modalities and the novel therapeutic agents introduced, pancreatic cancer still holds one of the lowest response rates to therapy. Human antigen R (HuR), an RNA binding protein (RBP), has been repeatedly found to be implicated in pancreatic carcinogenesis and chemotherapy resistance through the posttranscriptional binding and regulation of mRNA target genes. Additionally, its overexpression has been linked to adverse clinical outcomes, in terms of tumor grade, stage, lymph node status and metastasis. These properties suggest the prospective role that HuR's therapeutic targeting can play in facilitating pancreatic neoplasia and could provide the means to overcome chemoresistance

Utilizing Exosomal-EPHs/Ephrins as Biomarkers and as a Potential Platform for Targeted Delivery of Therapeutic Exosomes

Exosomes are cell-secreted nanoparticles containing various molecules including small vesicles, microRNAs (miRNAs), messenger RNAs or bioactive proteins which are thought to be of paramount importance for intercellular communication. The unique effects of exosomes in terms of cell penetration capacity, decreased immunogenicity and inherent stability, along with their key role in mediating information exchange among tumor cells and their surrounding tumor microenvironment (TME), render them a promising platform for drug targeted delivery. Compared to synthetic drugs, exosomes boast a plethora of advantages, including higher biocompatibility, lower toxicity and increased ability of tissue infiltration. Nevertheless, the use of artificial exosomes can be limited in practice, partly due to their poor targeting ability and partly due to their limited efficacy. Therefore, efforts have been made to engineer stem cell-derived exosomes in order to increase selectiveness and effectivity, which can then become loaded with various active substances depending on the therapeutic approach followed. Erythropoietin-producing human hepatocellular receptors (EPHs), along with their ligands, the EPH family receptor interacting proteins (ephrins), have been extensively investigated for their key roles in both physiology and cancer pathogenesis. EPHs/ephrins exhibit both tumorigenic and tumor suppressing properties, with their targeting representing a promising, novel therapeutic approach in cancer patients’ management. In our review, the use of ephrin-loaded exosomes as a potential therapeutic targeted delivery system in cancer will be discussed

SDH-deficient renal cell carcinoma: A case report associated with a novel germline mutation

The highly syndromic nature of succinate dehydrogenase-deficient RCCs constitutes their active surveillance and molecular profiling the alpha and omega

Immunohistochemical Study of Bladder Cancer Molecular Subtypes and Their Association with PD-L1 Expression

The significant heterogeneity in clinical outcomes among patients with bladder cancer has highlighted the existence of different biological subtypes of muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). Meanwhile, immune checkpoint proteins and their interference with tumor-related immune-evasive strategies has led to the development of several immunotherapeutic drugs targeting programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1). However, the lack of any known biomarker that could predict responses to immunotherapy has led to a more agnostic therapeutic approach. Here, we present a study conducted in 77 bladder cancer (BC) patients (n = 77), ranging from stages pTa to pT2. Tumor specimens were resected via transurethral resection of bladder tumor (TURBT) and consistuted of 24 low-grade (LG) and 53 high-grade (HG) tumors. Patients’ tumors were then categorized into molecular subtypes, via immunohistochemistry (CK5/6 and GATA3). Furthermore, all tumor specimens were stained with anti-PD-L1 and demonstrated significant correlations with basal immunophenotype, stage pT2 and HG tumors. As such, we attempted to stratify patients into groups of likely-responders and likely-not-responders to immunotherapy with anti-PD-L1, based on their molecular phenotype. Finally, in acknowledging the fact that there is a universal lack of biomarkers associated with predicting BC response to immunotherapeutic drugs, we tested all tumors for deficiency of mismatch repair proteins (MMR)

Immunohistochemical Study of Bladder Cancer Molecular Subtypes and Their Association with PD-L1 Expression

The significant heterogeneity in clinical outcomes among patients with bladder cancer has highlighted the existence of different biological subtypes of muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). Meanwhile, immune checkpoint proteins and their interference with tumor-related immune-evasive strategies has led to the development of several immunotherapeutic drugs targeting programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1). However, the lack of any known biomarker that could predict responses to immunotherapy has led to a more agnostic therapeutic approach. Here, we present a study conducted in 77 bladder cancer (BC) patients (n = 77), ranging from stages pTa to pT2. Tumor specimens were resected via transurethral resection of bladder tumor (TURBT) and consistuted of 24 low-grade (LG) and 53 high-grade (HG) tumors. Patients’ tumors were then categorized into molecular subtypes, via immunohistochemistry (CK5/6 and GATA3). Furthermore, all tumor specimens were stained with anti-PD-L1 and demonstrated significant correlations with basal immunophenotype, stage pT2 and HG tumors. As such, we attempted to stratify patients into groups of likely-responders and likely-not-responders to immunotherapy with anti-PD-L1, based on their molecular phenotype. Finally, in acknowledging the fact that there is a universal lack of biomarkers associated with predicting BC response to immunotherapeutic drugs, we tested all tumors for deficiency of mismatch repair proteins (MMR)