Prion Protein Endoproteolysis: Cleavage Sites, Mechanisms and Connections to Prion Disease.

Highly abundant in neurons, the cellular prion protein (PrP) is an obligatory precursor to the disease-associated misfolded isoform denoted PrP that accumulates in the rare neurodegenerative disorders referred to either as transmissible spongiform encephalopathies (TSEs) or as prion diseases. The ability of PrP to serve as a substrate for this template-mediated conversion process depends on several criteria but importantly includes the presence or absence of certain endoproteolytic events performed at the cell surface or in acidic endolysosomal compartments. The major endoproteolytic events affecting PrP are referred to as α- and β-cleavages, and in this review we outline the sites within PrP at which the cleavages occur, the mechanisms potentially responsible and their relevance to pathology.

Lineage tracing studies suggest that the placenta is not a de novo source of hematopoietic stem cells.

Definitive hematopoietic stem and progenitor cells (HSPCs) arise from a small number of hemogenic endothelial cells (HECs) within the developing embryo. Understanding the origin and ontogeny of HSPCs is of considerable interest and potential therapeutic value. It has been proposed that the murine placenta contains HECs that differentiate into HSPCs.

Characterizing temporal and global host innate immune responses against SARS-CoV-1 and -2 infection in pathologically relevant human lung epithelial cells.

Severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and -2 (SARS-CoV-2) are beta-coronaviruses (β-CoVs) that have caused significant morbidity and mortality worldwide. Therefore, a better understanding of host responses to β-CoVs would provide insights into the pathogenesis of these viruses to identify potential targets for medical countermeasures. In this study, our objective is to use a systems biology approach to explore the magnitude and scope of innate immune responses triggered by SARS-CoV-1 and -2 infection over time in pathologically relevant human lung epithelial cells (Calu-3/2B4 cells).

Toll-like receptor 1/2 activation reduces immunoglobulin free light chain production by multiple myeloma cells in the context of bone marrow stromal cells and fibronectin.

Toll-like receptor (TLRs) activation in multiple myeloma (MM) cells induces heterogeneous functional responses including cell growth and proliferation, survival or apoptosis. These effects have been suggested to be partly due to increase in secretion of cytokines such as IL-6 or IFNα among others from MM cells following TLR activation. However, whether triggering of these receptors also modulates production of immunoglobulin free light chains (FLCs), which largely contribute to MM pathology, has not been investigated in MM cells before.

A clinical study exploring the prediction of microvascular invasion in hepatocellular carcinoma through the use of combined enhanced CT and MRI radiomics.

Objective: To develop a predictive model for microvascular invasion (MVI) in hepatocellular carcinoma (HCC) through radiomics analysis, integrating data from both enhanced computed tomography (CT) and magnetic resonance imaging (MRI).

Methods: A retrospective analysis was conducted on 93 HCC patients who underwent partial hepatectomy. The gold standard for MVI was based on the histopathological diagnosis of the tissue.

Fertility before and after treatment of the patient with Leydig cell tumor - case report.

Even though Leydig cell tumor (LCT) represents the most common neoplasia among testicular sex cord-stromal tumors (SCSTs), it is a rare condition, comprising 1-2% of all testicular tumors, with a 10% risk of malignancy most commonly located in retroperitoneal lymph nodes. LCTs may demonstrate various clinical manifestations - from asymptomatic intratesticular swelling through nonspecific symptoms such as loss of libido, impotence or infertility, up to feminizing or virilizing syndromes due to hormonal activity of the tumor. This article presents a case of Leydig cell tumor that was associated with azoospermia what have rarely been reported worldwide.

Immunohistochemical evaluation of SOX-10 in patients with urinary bladder cancer.

Objective: Aim: To evaluate the expression levels of SOX-10 in tissues of bladder tumor and to prove the correlation between SOX-10 expression and clinicopathological characteristics of bladder tumors, including patient age, sex, tumor grade, and muscle invasion.

Patients And Methods: Materials and Methods: Forty formalin fixed paraffin embedded FFPE tissue blocks gathered by transurethral resection of bladder tumor are collected from teaching hospitals at Al-Najaf governorate. Those blocks were stained by hematoxylin and eosin.

Phytochemical analysis of ethanolic leaf extract of Cordia myxa and its anti-Inflammatory and cytotoxic activities.

Objective: Aim: Testing Cordia myxa extract on colon cancer cell line and caspase-3 gene and COX-2 protein expression.

Patients And Methods: Materials and Methods: This study used Cordia myxa ethanolic extract at various dosages on SW480 cells. Cell proliferation was measured using MTT, also examined effect of Cordia myxa extract on caspase-3 gene expression using quantitative real-time polymerase chain reaction.

Immunohistochemical evaluation of GATA-3 in patients with urinary bladder cancer.

Objective: Aim: To analyze expression levels of GATA-3 in bladder tumor tissues and to prove a relation between expression of GATA-3 and clinicopathological characteristics of bladder tumors, including patient age, sex, tumor grade, and muscle invasion.

Patients And Methods: Materials and Methods: Forty formalin fixed paraffin embedded (FFPE) tissue blocks obtained from bladder tumor by transurethral resection are collected from teaching hospitals at Al-Najaf governorate. Those blocks are stained by using hematoxylin and eosin stain.

Deciphering the dose-dependent effects of thymoquinone on cellular proliferation and transcriptomic changes in A172 glioblastoma cells.

Glioblastoma multiforme (GBM), the most prevalent primary malignant brain tumor in adults, exhibits a dismal 6.9% five-year survival rate post-diagnosis. Thymoquinone (TQ), the most abundant bioactive compound in Nigella sativa, has been extensively researched for its anticancer properties across various human cancers.

Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain.

Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson's disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and Ub phosphorylation.

Triethylamine-mediated protonation-deprotonation unlocks dual-drug self assembly to suppress breast cancer progression and metastasis.

Carrier-free nanomedicines exhibited significant potential in elevating drug efficacy and safety for tumor management, yet their self assembly typically relied on chemical modifications of drugs or the incorporation of surfactants, thereby compromising the drug's inherent pharmacological activity. To address this challenge, we proposed a triethylamine (TEA)-mediated protonation-deprotonation strategy that enabled the adjustable-proportion self assembly of dual drugs without chemical modification, achieving nearly 100% drug loading capacity. Molecular dynamic simulations, supported by experiment evidence, elucidated the underlying self-assembly mechanism.

Suppressing APOE4-induced neural pathologies by targeting the VHL-HIF axis.

The ε4 variant of human apolipoprotein E () is a key genetic risk factor for neurodegeneration in Alzheimer's disease and elevated all-cause mortality in humans. Understanding the factors and mechanisms that can mitigate the harmful effects of has significant implications. In this study, we find that inactivating the VHL-1 (Von Hippel-Lindau) protein can suppress mortality, neural and behavioral pathologies caused by transgenic human in .

Neomorphic leukemia-derived mutations in the TET2 enzyme induce genome instability via a substrate shift from 5-methylcytosine to thymine.

Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (mC) in DNA, contributing to the regulation of gene transcription. Diverse mutations of TET2 are frequently found in various blood cancers, yet the full scope of their functional consequences has been unexplored. Here, we report that a subset of TET2 mutations identified in leukemia patients alter the substrate specificity of TET2 from acting on mC to thymine.

Transthyretin variants impact blood-nerve barrier and neuroinflammation in amyloidotic neuropathy.

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a neurodegenerative disease caused by mutations in the gene encoding transthyretin (TTR). Despite amyloid deposition being pathognomonic for diagnosis, this pathology in nervous tissues cannot fully account for nerve degeneration, implying additional pathophysiology for neurodegeneration, which, however, has not yet been fully elucidated. In this study, neuroinflammation in ATTRv-PN was investigated by examining nerve morphometry, the blood-nerve barrier, and macrophage infiltration in the sural nerves of ATTRv-PN patients and the sciatic nerves of a complementary mouse system, i.

Performance analysis of a deep-learning algorithm to detect the presence of inflammation in MRI of sacroiliac joints in patients with axial spondyloarthritis.

Objectives: To assess the ability of a previously trained deep-learning algorithm to identify the presence of inflammation on MRI of sacroiliac joints (SIJ) in a large external validation set of patients with axial spondyloarthritis (axSpA).

Methods: Baseline SIJ MRI scans were collected from two prospective randomised controlled trials in patients with non-radiographic (nr-) and radiographic (r-) axSpA (RAPID-axSpA: NCT01087762 and C-OPTIMISE: NCT02505542) and were centrally evaluated by two expert readers (and adjudicator in case of disagreement) for the presence of inflammation by the 2009 Assessment of SpondyloArthritis International Society (ASAS) definition. Scans were processed by the deep-learning algorithm, blinded to clinical information and central expert readings.

Comparison of definitions of early knee osteoarthritis for likelihood of progression at 2-year and 5-year follow-up: the Multicenter Osteoarthritis Study.

Background: Preventing worsening osteoarthritis (OA) in persons with early OA is a major treatment goal. We evaluated if different early OA definitions yielded enough cases of worsening OA within 2-5 years to make trial testing treatments feasible.

Methods: We assessed different definitions of early OA using data from Multicenter Osteoarthritis (MOST) Study participants who were followed up longitudinally.

Deciphering the interplay between SETD2 mediated H3K36me3 and RNA N6-methyladenosine in clear cell renal cell carcinoma (ccRCC).

RNA N6-methyladenosine (m6A) plays diverse roles in RNA metabolism and its deregulation contributes to tumor initiation and progression. Clear cell renal cell carcinoma (ccRCC) is characterized by near ubiquitous loss of followed by mutations in epigenetic regulators , , and . Mutations in , a histone H3 lysine 36 trimethylase (H3K36me3), are associated with reduced survival, greater metastatic propensity, and metabolic reprogramming.

Role of Leucine-Rich Repeat-Containing G-Protein-Coupled Receptors 4-6 (LGR4-6) in the Ovary and Other Female Reproductive Organs: A Literature Review.

Leucine-rich repeat-containing G-protein-coupled receptors regulate stem cell activity and tissue homeostasis within female reproductive organs, primarily through their interaction with the Wnt/β-catenin signaling pathway. LGR4-6 are increasingly recognized for their roles in organ development, regeneration, and cancer. This review aims to provide a comprehensive overview of the roles of LGR4-6 in female reproductive organs, highlighting their significance in normal physiology and disease states, specifically in the context of ovarian cancer.

The Added Effect of Artificial Intelligence in CT Assessment of Abdominal Lymphadenopathy.

Lymphadenopathy is associated with lymph node abnormal size or consistency due to many causes. We employed the deep convolutional neural network ResNet-34 to detect and classify CT images from patients with abdominal lymphadenopathy and healthy controls. We created a single database containing 1400 source CT images for patients with abdominal lymphadenopathy (n = 700) and healthy controls (n = 700).

Validation of a New Measurement Device (Perikit®) For Perimetry and Volumetry of The Lower Limb: Metrological and Intra-Observer Comparative Study.

Accurate quantitative assessments are crucial to understanding development of diseases and their effective treatments. Various validated perimetry and volumetry measurement methods for patients with lymphedema exist and each has its own advantages and limitations and choosing the right instrument is essential. PeriKit® (PK) is a new measurement device that requires validation.

Segment specific loss of NFAT5 function in the kidneys is sufficient to induce a global kidney injury like phenotype.

Nuclear factor of activated T-cells 5 (NFAT5) is a transcription factor known for its role in osmotic stress adaptation in the renal inner medulla, due to the osmotic gradient that is generated between the renal cortex and renal inner medulla. However, its broader implications in kidney injury and chronic kidney disease (CKD) are less understood. Here we used two different Cre deleter mice (Ksp1.

Immunohistochemical Expression of PD-L1 and CTLA-4 in Triple Negative Breast Cancer and Their Prognostic Associations.

Objective: Programmed Death-Ligand 1 (PD-L1) and Cytotoxic T Lymphocyte -Associated Antigen-4 (CTLA-4) are presently considered as prognostic markers and therapeutic targets in numerous human malignancies. The goal of this study was to determine whether PD-L1 and CTLA-4 might be used to predict patients' survival in Triple Negative Breast Cancer (TNBC).

Methods: This retrospective cohort study analyzed 100 primary TNBC cases that had surgical resection at the Oncology Center of Mansoura University (OCMU), Faculty of Medicine, Egypt.

8-OHdG and Nrf2 Protein are Expressed Consistently in Various T Stages of Invasive Breast Carcinoma.

Objective: Oxidative stress prompts breast cancer cells to adapt by raising the lethal threshold and enhancing the antioxidant mechanism, thereby enabling survival and continuous proliferation that facilitates tumor progression. Nrf2 and 8-OHdG are indicative of oxidative stress activity and impact the progression of breast cancer. We aimed to analyze the expression of Nrf2 and 8-OHdG in various T stages of breast cancer in our hospital.

Bioinformatics Analysis of Programmed Death-1-Trastuzumab Resistance Regulatory Networks in Breast Cancer Cells.

Objective: Programmed cell death-1 (PD-1, encoded by PDCD1) regulatory network participates in glioblastoma multiforme development. However, such a network in trastuzumab-resistant human epidermal growth factor receptor 2-positive (HER2+) breast cancer remains to be determined. Accordingly, this study was aimed to explore the PD-1 regulatory network responsible for the resistance of breast cancer cells to trastuzumab through a bioinformatics approach.