Radiolabeled Gold Nanoseeds Decorated with Substance P Peptides: Synthesis, Characterization and In Vitro Evaluation in Glioblastoma Cellular Models

Despite some progress, the overall survival of patients with glioblastoma (GBM) remains extremely poor. In this context, there is a pressing need to develop innovative therapy strategies for GBM, namely those based on nanomedicine approaches. Towards this goal, we have focused on nanoparticles (AuNP-SP and AuNP-SPTyr8) with a small gold core (ca. 4 nm), carrying DOTA chelators and substance P (SP) peptides. These new SP-containing AuNPs were characterized by a variety of analytical techniques, including TEM and DLS measurements and UV-vis and CD spectroscopy, which proved their high in vitro stability and poor tendency to interact with plasma proteins. Their labeling with diagnostic and therapeutic radionuclides was efficiently performed by DOTA complexation with the trivalent radiometals 67Ga and 177Lu or by electrophilic radioiodination with 125I of the tyrosyl residue in AuNP-SPTyr8. Cellular studies of the resulting radiolabeled AuNPs in NKR1-positive GBM cells (U87, T98G and U373) have shown that the presence of the SP peptides has a crucial and positive impact on their internalization by the tumor cells. Consistently, 177Lu-AuNP-SPTyr8 showed more pronounced radiobiological effects in U373 cells when compared with the non-targeted congener 177Lu-AuNP-TDOTA, as assessed by cell viability and clonogenic assays and corroborated by Monte Carlo microdosimetry simulations.

Biosimilars monoclonal antibodies in the therapy of inflammatory bowel diseases An important milestone in the development of Crohn’s disease and ulcerative colitis therapy, or just a sophisticated generic?

Summary: In 2013, EMA approved the fi rst biosimilar infl iximab CT-P13 for clinical practice in all indications of the original infl iximab. Since 2015, biosimilar infl iximab has been extensively used in patients with Crohn‘s disease and ulcerative colitis also in the Czech Republic. Biosimilar infl iximab is very similar to the original infl iximab in terms of its macromolecular structure, and its clinical eff ects, adverse events and immunogenicity are identical to those of the original infl iximab. Biosimilar biologics which have been introduced in clinical practice signifi cantly reduced therapeutic costs and improved access to an innovative therapy and facilitated a new therapeutic strategy, with pro-active drug monitoring and fl exibility in dosing. Biosimilars are associated with a signifi cant improvement in the therapeutic armamentarium, which makes them one of the important therapeutic milestones in the treatment of infl ammatory bowel disease. Key words: bio similars – bio logic therapy – Crohn’s disease – ulcerative colitis

The Efficacy of Photobiomodulation Therapy in Improving Tissue Resilience and Healing of Radiation Skin Damage

The increased precision, efficacy, and safety of radiation brachytherapy has tremendously improved its popularity in cancer care. However, an unfortunate side effect of this therapy involves localized skin damage and breakdown that are managed palliatively currently. This study was motivated by prior reports on the efficacy of photobiomodulation (PBM) therapy in improving tissue resilience and wound healing. We evaluated the efficacy of PBM therapy on 36 athymic mice with 125I seed (0.42 mCi) implantation over 60 days. PBM treatments were performed with either red (660 nm) or near-infrared (880 nm, NIR) LEDs irradiance of 40 mW/cm2, continuous wave, fluence of 20 J/cm2 once per week. Animals were evaluated every 7 days with digital imaging, laser Doppler flowmetry, thermal imaging, µPET-CT imaging using 18F-FDG, and histology. We observed that both PBM treatments—red and NIR—demonstrated significantly less incidence and severity and improved healing with skin radionecrosis. Radiation exposed tissues had improved functional parameters such as vascular perfusion, reduced inflammation, and metabolic derangement following PBM therapy. Histological analysis confirmed these observations with minimal damage and resolution in tissues exposed to radiation. To our knowledge, this is the first report on the successful use of PBM therapy for brachytherapy. The results from this study support future mechanistic lab studies and controlled human clinical studies to utilize this innovative therapy in managing side effects from radiation cancer treatments.

Apoptosis, Autophagy, NETosis, Necroptosis, and Pyroptosis Mediated Programmed Cell Death as Targets for Innovative Therapy in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can lead to clinical manifestations of systemic diseases. Its leading features include chronic synovial inflammation and degeneration of the bones and joints. In the past decades, multiple susceptibilities for rheumatoid arthritis have been identified along with the development of a remarkable variety of drugs for its treatment; which include analgesics, glucocorticoids, nonsteroidal anti-inflammatory medications (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and biologic response modifiers (bDMARDs). Despite the existence of many clinical treatment options, the prognosis of some patients remains poor due to complex mechanism of the disease. Programmed cell death (PCD) has been extensively studied and ascertained to be one of the essential pathological mechanisms of RA. Its dysregulation in various associated cell types contributes to the development of RA. In this review, we summarize the role of apoptosis, cell death-associated neutrophil extracellular trap formation, necroptosis, pyroptosis, and autophagy in the pathophysiology of RA to provide a theoretical reference and insightful direction to the discovery and development of novel therapeutic targets for RA.

Lessons Learned From Translational Research in Neuromuscular Diseases: Impact on Study Design, Outcome Measures and Managing Expectation

Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD), two of the most common, child onset, rare neuromuscular disorders, present a case study for the translation of preclinical research into clinical work. Over the past decade, well-designed clinical trials and innovative methods have led to the approval of several novel therapies for SMA and DMD, with many more in the pipeline. This review discusses several features that must be considered during trial design for neuromuscular diseases, as well as other rare diseases, to maximise the possibility of trial success using historic examples. These features include well-defined inclusion criteria, matching criteria, alternatives to placebo-controlled trials and the selection of trial endpoints. These features will be particularly important in the coming years as the investigation into innovative therapy approaches for neuromuscular diseases continues.

Physical therapy using robotics: A project-based learning experience for undergraduate students

The dynamic society we live in requires constant adaptation and innovation on every aspect of our daily lives, allowing us to improve the necessities of different people by doing it. For this study, we used a new approach with project-based learning to go beyond the typical environment in higher education and bring solutions to real-life scenarios. The project was developed with undergraduate engineering students in collaboration with a rehabilitation institute in Mexico City to design a physical therapy routine using the NAO robot. It allowed interaction between young patients in real time and fostered empathy while developing a final usable product. The study measured the usability of the robotic platform during the rehabilitation sessions and the reproducibility of the project through Cronbach's alpha evaluation. The usability results show a higher interest in the project from both the patients and the medical staff involved while constructing the material needed to develop a product that matches the standards given by the rehabilitation institute. Implications for practice or policy: Therapists could change traditional approaches to caregiving while adopting new technological methodologies using robots. Higher education students could supplement their school curricula with real-case scenarios such as creating innovative therapy sessions for people with physical disabilities. Schools might need to collaborate with a wide range of institutions to provide technological solutions to real problems.

Fondazione Telethon and Unione Italiana Lotta alla Distrofia Muscolare, a successful partnership for neuromuscular healthcare research of value for patients

In 2001, Fondazione Telethon and the Italian muscular dystrophy patient organisation Unione Italiana Lotta alla Distrofia Muscolare joined their efforts to design and launch a call for grant applications specifically dedicated to clinical projects in the field of neuromuscular disorders. This strategic initiative, run regularly over the years and still ongoing, aims at supporting research with impact on the daily life of people with a neuromuscular condition and is centred on macro-priorities identified by the patient organisation. It is investigator-driven, and all proposals are peer-reviewed for quality and feasibility. Over the years, this funding program contributed to strengthening the activities of the Italian neuromuscular clinical network, reaching many achievements in healthcare research. Moreover, it has been an enabling factor for innovative therapy experimentation at international level and prepared the clinical ground to make therapies available to Italian patients. The ultimate scope of healthcare research is to ameliorate the delivery of care. In this paper, the achievements of the funded studies are analysed also from this viewpoint, to ascertain to which extent they have fulfilled the original goals established by the patient organisation. The evidence presented indicates that this has been a highly fruitful program. Factors that contributed to its success, lessons learned, challenges, and issues that remain to be addressed are discussed to provide practical examples of an experience that could inspire also other organizations active in the field of rare disease research.

Management of Hemorrhoids with Doppler-Guided Hemorrhoidal Artery Ligation

Background An innovative therapy for symptomatic hemorrhoids has been recently proposed it relies on the reduction of hemorrhoidal vascular flow by suturing hemorrhoidal arteries, which are previously located by means of an ultrasound transducer. Objective To evaluate retrospectively the outcome of Doppler-guided hemorrhoidal artery ligation in the management of symptomatic hemorrhoids. Patients and Methods Aretrospective study. The study conducted in Ain Shams University Hosptial (El Demerdash) under supervision of these supervisors. Study period: Six months. Results In our series, the HAL technique has achieved complete control of symptoms in 93.3% of patients after six-monthes follow-up. Conclusion Hemorrhoid ligation with mucopexy is a simple, safe and cost-effective ambulatory treatment for the patients of symptomatic hemorrhoids. It can be performed on an outpatient or day care basis on all grades of hemorrhoids to control bleeding and prolapsing hemorrhoids. Overall the results of hemorrhoid ligation and mucopexy were satisfactory with good control of patients complains.

Uveal Melanoma Metastasis

Uveal melanoma (UM) is characterized by relatively few, highly incident molecular alterations and their association with metastatic risk is deeply understood. Nevertheless, this knowledge has so far not led to innovate therapies for the successful treatment of UM metastases or for adjuvant therapy, leaving survival after diagnosis of metastatic UM almost unaltered in decades. The driver mutations of UM, mainly in the G-protein genes GNAQ and GNA11, activate the MAP-kinase pathway as well as the YAP/TAZ pathway. At present, there are no drugs that target the latter and this likely explains the failure of MEK-inhibitors. Immune checkpoint blockers, despite the game changing effect in cutaneous melanoma (CM) show only marginal effects in UM probably because of the low mutational burden of 0.5 per megabase and the unavailability of antibodies targeting the main immune checkpoint active in UM. The highly pro-tumorigenic microenvironment of UM also contributes to therapy resistance. However, T-cell redirection by a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment, local, liver specific therapy, new immune checkpoint blockers and YAP/TAZ specific drugs give new hope to repeat the success of innovative therapy obtained for CM.

Exploring evidence-based innovative therapy for the treatment of chronic HBV infection: experimental and clinical

With the advent of various vaccines and antimicrobial agents during the 20th century, the control and containment of infectious diseases appeared to be a matter of time. However, studies unveiled the diverse natures of microbes, their lifestyle, and pathogenetic potentials. Since the ground-breaking discovery of the hepatitis B virus (HBV) by Baruch Blumberg and the subsequent development of a vaccine in the early 1980s, the main task of the scientific community has been to develop a proper management strategy for HBV-induced chronic liver diseases. In the early 1980’s, standard interferon (IFN) induced a reduction of HBV DNA levels, followed by the normalization of serum transaminases (alanine aminotransferase, ALT), in some chronic hepatitis B (CHB) patients. However, in the course of time, the limitations of standard IFN became evident, and the search for an alternative began. In the late 1980’s, nucleoside analogs entered the arena of CHB treatment as oral drugs with potent antiviral capacities. At the beginning of the 21st century, insights were developed into the scope and limitations of standard IFN, pegylated-IFN as well as nucleoside analogs for treating CHB. Considering the non-cytopathic nature of the HBV, the presence of covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocytes and HBV-induced immune-mediated liver damages, a new field of CHB management was initiated by modulating the hosts’ immune system through immune therapy. This review will discuss the nature and design of innovative immune therapy for CHB.