Full Arch Implant-Prosthetic Rehabilitation in Patients with Cardiovascular Diseases: A 7-Year Follow-Up Prospective Single Cohort Study.

: The rising average age increases edentulous cases, demanding more implant-prosthetic rehabilitation, with cardiovascular diseases being significant factors. This study compared healthy patients (CG = Control Group) and those with cardiovascular disease (TG = Test Group) for implant survival, Marginal Bone Loss (MBL), peri-implant tissue level parameters as Periodontal Screening and Recording (PSR), Plaque Index (PI), Bleeding on Probing (BoP) Peri-implant Probing Depth (PPD), and surgical complications. Smoking impact on both groups and medication influence in the TG were secondary outcomes.

Effect of Spinal Correction Surgery on Lower Limb Strength in Idiopathic Adolescent Scoliosis.

 To analyze the lower limb strength in both untreated and surgically treated adolescent idiopathic scoliosis (AIS) patients and examine its correlation with the distance covered in a six-minute walking test (6MWT).  A total of 88 participants (n = 30 pre-surgery AIS patients, n = 30 post-surgical AIS patients, and n = 28 control) underwent a 6MWT and a muscle strength assessment. The lower limb strength was measured at the knee joint using the knee extension (KE) and knee flexion (KF) peak torque (PT) measurements.

Predatory fireflies and their toxic firefly prey have evolved distinct toxin resistance strategies.

Toxic cardiotonic steroids (CTSs) act as a defense mechanism in many firefly species (Lampyridae) by inhibiting a crucial enzyme called Na,K-ATPase (NKA). Although most fireflies produce these toxins internally, species of the genus Photuris acquire them from a surprising source: predation on other fireflies. The contrasting physiology of toxin exposure and sequestration between Photuris and other firefly genera suggests that distinct strategies may be required to prevent self-intoxication.

Host fecal DNA specific methylation signatures mark gut dysbiosis and inflammation in children affected by autism spectrum disorder.

The gut-brain axis involves several bidirectional pathway communications including microbiome, bacterial metabolites, neurotransmitters as well as immune system and is perturbed both in brain and in gastrointestinal disorders. Consistently, microbiota-gut-brain axis has been found altered in autism spectrum disorder (ASD). We reasoned that such alterations occurring in ASD may impact both on methylation signatures of human host fecal DNA (HFD) and possibly on the types of human cells shed in the stools from intestinal tract giving origin to HFD.

Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth.

Despite intense research efforts, glioblastoma remains an incurable brain tumor with a dismal median survival time of 15 months. Thus, identifying new therapeutic targets is an urgent need. Here, we show that the lysine methyltransferase SETD8 is overexpressed in 50% of high-grade gliomas.

Subclones with variants of uncertain clinical significance might contribute to ineffective hemopoiesis and leukemia predisposition.

Background: Splicing modifications, genomic instability, and hypomethylation are central mechanisms promoting myelodysplasia and acute myeloid leukemia (AML). In this real-life retrospective study, to elucidate pathophysiology of clonal hemopoiesis in hematological malignancies, we investigated clinical significance of mutations in leukemia-related genes of known pathogenetic significance and of variants of uncertain clinical significance (VUS) in a cohort of patients with MDS and AML.

Methods: A total of 59 consecutive subjects diagnosed with MDS, 48 with AML, and 17 with clonal cytopenia with unknown significance were screened for somatic mutations in AML-related genes by next-generation sequencing.

Predatory fireflies and their toxic firefly prey have evolved distinct toxin resistance strategies.

Toxic cardiotonic steroids (CTS) act as a defense mechanism in many firefly species (Lampyridae) by inhibiting a crucial enzyme called Na,K-ATPase (NKA). While most fireflies produce these toxins internally, species of the genus acquire them from a surprising source: predation on other fireflies. The contrasting physiology of toxin exposure and sequestration between and other firefly genera suggests that distinct strategies may be required to prevent self-intoxication.

A Rare Adult Primary Intracranial Sarcoma, -Mutant Identified by Epigenomic Profiling: A Case Report.

Diagnoses of primary malignant mesenchymal brain tumors are a challenge for pathologists. Here, we report the case of a 52-year-old man with a primary brain tumor, histologically diagnosed as a high-grade glioma, not otherwise specified (NOS). The patient underwent two neurosurgeries in several months, followed by radiotherapy and chemotherapy.

Epigenetic alterations in glioblastomas: Diagnostic, prognostic and therapeutic relevance.

Glioblastoma, the most common and heterogeneous tumor affecting brain parenchyma, is dismally characterized by a very poor prognosis. Thus, the search of new, more effective treatments is a vital need. Here, we will review the druggable epigenetic features of glioblastomas that are, indeed, currently explored in preclinical studies and in clinical trials for the development of more effective, personalized treatments.

Methylome Profiling in Fabry Disease in Clinical Practice: A Proof of Concept.

Anderson−Fabry disease (FD) is an X-linked disease caused by a functional deficit of the α-galactosidase A enzyme. FD diagnosis relies on the clinical manifestations and research of GLA gene mutations. However, because of the lack of a clear genotype/phenotype correlation, FD diagnosis can be challenging.

Looking Beyond the Glioblastoma Mask: Is Genomics the Right Path?

Glioblastomas are the most frequent and malignant brain tumor hallmarked by an invariably poor prognosis. They have been classically differentiated into primary isocitrate dehydrogenase 1 or 2 () wild-type (wt) glioblastoma (GBM) and secondary IDH mutant GBM, with wt GBMs being commonly associated with older age and poor prognosis. Recently, genetic analyses have been integrated with epigenetic investigations, strongly implementing typing and subtyping of brain tumors, including GBMs, and leading to the new WHO 2021 classification.

MGMT and Whole-Genome DNA Methylation Impacts on Diagnosis, Prognosis and Therapy of Glioblastoma Multiforme.

Epigenetic changes in DNA methylation contribute to the development of many diseases, including cancer. In glioblastoma multiforme, the most prevalent primary brain cancer and an incurable tumor with a median survival time of 15 months, a single epigenetic modification, the methylation of the () gene, is a valid biomarker for predicting response to therapy with alkylating agents and also, independently, prognosis. More recently, the progress from single gene to whole-genome analysis of DNA methylation has allowed a better subclassification of glioblastomas.

Epigenetic remodelling of Fxyd1 promoters in developing heart and brain tissues.

FXYD1 is a key protein controlling ion channel transport. FXYD1 exerts its function by regulating Na/K-ATPase activity, mainly in brain and cardiac tissues. Alterations of the expression level of the FXYD1 protein cause diastolic dysfunction and arrhythmias in heart and decreased neuronal dendritic tree and spine formation in brain.

High-Throughput Screening to Identify Small Molecules That Selectively Inhibit APOL1 Protein Level in Podocytes.

High-throughput phenotypic screening is a key driver for the identification of novel chemical matter in drug discovery for challenging targets, especially for those with an unclear mechanism of pathology. For toxic or gain-of-function proteins, small-molecule suppressors are a targeting/therapeutic strategy that has been successfully applied. As with other high-throughput screens, the screening strategy and proper assays are critical for successfully identifying selective suppressors of the target of interest.

A functional three-dimensional microphysiological human model of myeloma bone disease.

Human myeloma bone disease (MBD) occurs when malignant plasma cells migrate to the bone marrow and commence inimical interactions with stromal cells, disrupting the skeletal remodeling process. The myeloma cells simultaneously suppress osteoblastic bone formation while promoting excessive osteoclastic resorption. This bone metabolism imbalance produces osteolytic lesions that cause chronic bone pain and reduce trabecular and cortical bone structural integrity, and often culminate in pathological fractures.

Evaluation of Gene Methylation in Neuroendocrine Neoplasms.

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the gene, as its product, -methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent.

Accessibility to First-Mile health services: A time-cost model for rural Uganda.

This study estimates the geographical disconnection in rural Low-Middle-Income Countries (LMIC) between First-Mile suppliers of healthcare services and end-users. This detachment is due to geographical barriers and to a shortage of technical, financial, and human resources that enable peripheral health facilities to perform effective and prompt diagnosis. End-users typically have easier access to cell-phones than hospitals, so mHealth can help to overcome such barriers, transforming inpatients/outpatients into home-patients, decongesting hospitals, especially during epidemics.

Utilizing Designed Receptors Exclusively Activated by Designer Drug Chemogenetic Tools to Identify Beneficial G Protein-Coupled Receptor Signaling for Fibrosis.

Fibrosis or accumulation of extracellular matrix is an evolutionarily conserved mechanism adopted by an organism as a response to chronic injury. Excessive fibrosis, however, leads to disruption of organ homeostasis and is a common feature of many chronic diseases. G protein-coupled receptors (GPCRs) are important cell signaling mediators and represent molecular targets for many Food and Drug Administration-approved drugs.

Human ileal organoid model recapitulates clinical incidence of diarrhea associated with small molecule drugs.

Drug-induced gastrointestinal toxicity (GIT) is a common treatment-emergent adverse event that can negatively impact dosing, thereby limiting efficacy and treatment options for patients. An in vitro assay of GIT is needed to address patient variability, mimic the microphysiology of the gut, and accurately predict drug-induced GIT. Primary human ileal organoids (termed 'enteroids') have proven useful for stimulating intestinal stem cell proliferation and differentiation to multiple cell types present in the gut epithelium.

Exploiting immune-dependent effects of microtubule-targeting agents to improve efficacy and tolerability of cancer treatment.

Microtubule-targeting agents (MTAs), like taxanes and vinca alkaloids, are tubulin-binding drugs that are very effective in the treatment of various types of cancers. In cell cultures, these drugs appear to affect assembly of the mitotic spindle and to delay progression through mitosis and this correlates with their ability to induce cell death. Their clinical efficacy is, however, limited by resistance and toxicity.

Cell-Based In Vitro Assay Automation: Balancing Technology and Data Reproducibility/Predictability.

G-protein-coupled receptors (GPCRs) are modulated by many marketed drugs, and as such, they continue to be key targets for drug discovery and development. Many GPCR targets at Merck Research Laboratories (MRL) are profiled using homogenous time-resolved fluorescence (HTRF) inositol monophosphate (IP-1) cell-based functional assays using adherent cells in 384-well microplates. Due to discrepancies observed across several in vitro assays supporting lead optimization structure-activity relationship (SAR) efforts, different assay paradigms were evaluated for removing growth medium from the assay plates prior to compound addition and determination of IP-1 accumulation.

Analysis of CCDC6 as a novel biomarker for the clinical use of PARP1 inhibitors in malignant pleural mesothelioma.

Objectives: CCDC6 (coiled-coil domain containing 6) is a player of the HR response to DNA damage and has been predicted to interact with BAP1, another HR-DNA repair gene highly mutated in Malignant Pleural Mesothelioma (MPM), an aggressive cancer with poor prognosis. CCDC6 levels are modulated by the deubiquitinase USP7, and CCDC6 defects have been reported in several tumors determining PARP-inhibitors sensitivity. Our aim was to investigate the functional role of CCDC6 in MPM carcinogenesis and response to PARP-inhibitors.

Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations.

Wee1 kinase is an inhibitor of cyclin-dependent kinase (cdk)s, crucial cell cycle progression drivers. By phosphorylating cdk1 at tyrosine 15, Wee1 inhibits activation of cyclin B-cdk1 (Cdk1), preventing cells from entering mitosis with incompletely replicated or damaged DNA. Thus, inhibiting Wee1, alone or in combination with DNA damaging agents, can kill cancer cells by mitotic catastrophe, a tumor suppressive response that follows mitosis onset in the presence of under-replicated or damaged DNA.

New combinatorial strategies to improve the PARP inhibitors efficacy in the urothelial bladder Cancer treatment.

Background: Novel therapeutic strategies are urgently needed for the treatment of metastatic Urothelial Bladder Cancer. DNA damaging repair (DDR) targeting has been introduced in cinical trials for bladder cancer patients that carry alterations in homologous DNA repair genes, letting to envisage susceptibility to the Poly (adenosine diphosphate [ADP]) ribose polymerase (PARP) inhibitors.

Main Body: PARP inhibition, by amplifying the DNA damage, augments the mutational burden and promotes the immune priming of the tumor by increasing the neoantigen exposure and determining upregulation of programmed death ligand 1 (PD-L1) expression.

CCDC6 and USP7 expression levels suggest novel treatment options in high-grade urothelial bladder cancer.

Background: The muscle invasive form of urothelial bladder cancer (UBC) is a deadly disease. Currently, the therapeutic approach of UBC is mostly based on surgery and standard chemotherapy. Biomarkers to establish appropriate drugs usage are missing.