Effects of Ab501 (certolizumab mice equivalent) in arthritis induced bone loss.

Introduction - Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease, which causes local and systemic bone damage. The main goal of this work was to analyze, how treatment intervention with Ab501 (certolizumab mice equivalent) prevents the disturbances on bone structure and mechanics induced by arthritis. Methods - Thirty DBA/1 collagen-induced arthritis (CIA) mice were randomly housed in experimental groups, as follows: arthritic untreated (N=9), preventive intervention (N=10) and treatment intervention (N=11).

The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients.

Telomere fusions (TFs) can trigger the accumulation of oncogenic alterations leading to malignant transformation and drug resistance. Despite their relevance in tumour evolution, our understanding of the patterns and consequences of TFs in human cancers remains limited. Here, we characterize the rates and spectrum of somatic TFs across >30 cancer types using whole-genome sequencing data.

The long non-coding RNA OTX2-AS1 promotes tumor growth and predicts response to BCL-2 inhibition in medulloblastoma.

Purpose: Primary brain tumors are a leading cause of cancer-related death in children, and medulloblastoma is the most common malignant pediatric brain tumor. The current molecular characterization of medulloblastoma is mainly based on protein-coding genes, while little is known about the involvement of long non-coding RNAs (lncRNAs). This study aimed to elucidate the role of the lncRNA OTX2-AS1 in medulloblastoma.

Role of UBE2C in Brain Cancer Invasion and Dissemination.

Glioblastoma (GB) and brain metastases (BM) are the most common brain tumors in adults and are invariably associated with a dismal outcome. These highly malignant tumors share common features including increased invasion and migration of the primary or metastatic brain cancer cells, whose triggering mechanisms are largely unknown. Emerging evidence has suggested that the ubiquitin-conjugating enzyme E2C (UBE2C), essential for controlling cell cycle progression, is overexpressed in diverse malignancies, including brain cancer.

Nanoparticle-Based Treatment in Glioblastoma.

Glioblastoma (GB) is a malignant glioma associated with a mean overall survival of 12 to 18 months, even with optimal treatment, due to its high relapse rate and treatment resistance. The standardized first-line treatment consists of surgery, which allows for diagnosis and cytoreduction, followed by stereotactic fractionated radiotherapy and chemotherapy. Treatment failure can result from the poor passage of drugs through the blood-brain barrier (BBB).

UBE2C promotes leptomeningeal dissemination and is a therapeutic target in brain metastatic disease.

Background: Despite current improvements in systemic cancer treatment, brain metastases (BM) remain incurable, and there is an unmet clinical need for effective targeted therapies.

Methods: Here, we sought common molecular events in brain metastatic disease. RNA sequencing of thirty human BM identified the upregulation of , a gene that ensures the correct transition from metaphase to anaphase, across different primary tumor origins.

Highlighted Advances in Therapies for Difficult-To-Treat Brain Tumours Such as Glioblastoma.

Glioblastoma multiforme (GBM) remains a challenging disease, as it is the most common and deadly brain tumour in adults and has no curative solution and an overall short survival time. This incurability and short survival time means that, despite its rarity (average incidence of 3.2 per 100,000 persons), there has been an increased effort to try to treat this disease.

Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor in infants that is characterized by loss of nuclear expression of SMARCB1 or SMARCA4 proteins. Recent studies show that AT/RTs comprise three molecular subgroups, namely AT/RT-TYR, AT/RT-MYC and AT/RT-SHH. The subgroups show distinct expression patterns of genes involved in ciliogenesis, however, little is known about the functional roles of primary cilia in the biology of AT/RT.

Patient-derived models of brain metastases recapitulate human disseminated disease.

Dissemination of cancer cells from primary tumors to the brain occurs in many cancer patients, increasing morbidity and death. There is an unmet medical need to develop translational platforms to evaluate therapeutic responses. Toward this goal, we established a library of 23 patient-derived xenografts (PDXs) of brain metastases (BMs) from eight distinct primary tumors.

Intratumoral heterogeneity of MYC drives medulloblastoma metastasis and angiogenesis.

Background: Intratumoral heterogeneity is crucially involved in metastasis, resistance to therapy, and cancer relapse. Amplifications of the proto-oncogene MYC display notable heterogeneity at the single-cell level and are associated with a particularly dismal prognosis in high-risk medulloblastomas (MBs). The aim of this study was to establish the relevance of interclonal cross-talk between MYC-driven and non-MYC-driven MB cells.

Celastrol Efficacy by Oral Administration in the Adjuvant-Induced Arthritis Model.

We previously demonstrated that celastrol has significant anti-inflammatory and bone protective effects when administered via the intraperitoneal route. For further preclinical evaluation, an effective oral administration of celastrol is crucial. Here we aimed to study the therapeutic dose range for its oral administration.

Early arthritis induces disturbances at bone nanostructural level reflected in decreased tissue hardness in an animal model of arthritis.

Introduction: Arthritis induces joint erosions and skeletal bone fragility.

Objectives: The main goal of this work was to analyze the early arthritis induced events at bone architecture and mechanical properties at tissue level.

Methods: Eighty-eight Wistar rats were randomly housed in experimental groups, as follows: adjuvant induced arthritis (AIA) (N = 47) and a control healthy group (N = 41).

Effects of tofacitinib in early arthritis-induced bone loss in an adjuvant-induced arthritis rat model.

Objectives: The main goal of this work was to analyse how treatment intervention with tofacitinib prevents the early disturbances of bone structure and mechanics in the rat model of adjuvant-induced arthritis. This is the first study to access the impact of tofacitinib on the skeletal bone effects of inflammation.

Methods: Fifty Wistar rats with adjuvant-induced arthritis were randomly housed in experimental groups, as follows: non-arthritic healthy group (n = 20); arthritic non-treated group (n = 20); and 10 animals undergoing tofacitinib treatment.

Effect of celastrol on bone structure and mechanics in arthritic rats.

Objective: Rheumatoid arthritis (RA) is characterised by chronic inflammation leading to articular bone and cartilage damage. Despite recent progress in RA management, adverse effects, lack of efficacy and economic barriers to treatment access still limit therapeutic success. Therefore, safer and less expensive treatments that control inflammation and bone resorption are needed.

Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases.

The identification of new bioactive compounds derived from medicinal plants with significant therapeutic properties has attracted considerable interest in recent years. Such is the case of the (TW), an herb used in Chinese medicine. Clinical trials performed so far using its root extracts have shown impressive therapeutic properties but also revealed substantial gastrointestinal side effects.

Decrease of CD68 Synovial Macrophages in Celastrol Treated Arthritic Rats.

Background: Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease characterized by cellular infiltration into the joints, hyperproliferation of synovial cells and bone damage. Available treatments for RA only induce remission in around 30% of the patients, have important adverse effects and its use is limited by their high cost. Therefore, compounds that can control arthritis, with an acceptable safety profile and low production costs are still an unmet need.

Arthritis induces early bone high turnover, structural degradation and mechanical weakness.

Background: We have previously found in the chronic SKG mouse model of arthritis that long standing (5 and 8 months) inflammation directly leads to high collagen bone turnover, disorganization of the collagen network, disturbed bone microstructure and degradation of bone biomechanical properties. The main goal of the present work was to study the effects of the first days of the inflammatory process on the microarchitecture and mechanical properties of bone.

Methods: Twenty eight Wistar adjuvant-induced arthritis (AIA) rats were monitored during 22 days after disease induction for the inflammatory score, ankle perimeter and body weight.

Bone histomorphometry revisited.

Bone histomorphometry is defined as a quantitative evaluation of bone micro architecture, remodelling and metabolism. Bone metabolic assessment is based on a dynamic process, which provides data on bone matrix formation rate by incorporating a tetracycline compound. In the static evaluation, samples are stained and a semi-automatic technique is applied in order to obtain bone microarchitectural parameters such as trabecular area, perimeter and width.

Markers of progression to rheumatoid arthritis: discriminative value of the new ACR/EULAR rheumatoid arthritis criteria in a Portuguese population with early polyarthritis.

Objectives: Our goal was to test the performance of the new American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria for the classification of rheumatoid arthritis (RA) in a cohort of patients with very recent onset polyarthritis.

Patients: Untreated polyarthritis patients with less than 6 weeks of duration were enrolled. All patients were followed-up in order to establish a definitive diagnosis.

Effective treatment of rat adjuvant-induced arthritis by celastrol.

We have previously reported an increase in interleukin (IL)-1β and IL-17 levels, and a continuous activation of caspase-1 in early rheumatoid arthritis (RA) patients. These results suggest that drugs targeting IL-1β regulatory pathways, in addition to tumor necrosis factor (TNF), may constitute promising therapeutic agents in early RA. We have recently used a THP-1 macrophage-like cell line to screen 2320 compounds for those that down-regulate both IL-1β and TNF secretion.

Assessing Noncoding Sequence Variants of GJB2 for Hearing Loss Association.

Involvement of GJB2 noncoding regions in hearing loss (HL) has not been extensively investigated. However, three noncoding mutations, c.-259C>T, c.