Tau- and α-synuclein-targeted gold nanoparticles: applications, opportunities, and future outlooks in the diagnosis and therapy of neurodegenerative diseases.

The use of nanomaterials in medicine offers multiple opportunities to address neurodegenerative disorders such as Alzheimer's and Parkinson's disease. These diseases are a significant burden for society and the health system, affecting millions of people worldwide without sensitive and selective diagnostic methodologies or effective treatments to stop their progression. In this sense, the use of gold nanoparticles is a promising tool due to their unique properties at the nanometric level. They can be functionalized with specific molecules to selectively target pathological proteins such as Tau and α-synuclein for Alzheimer's and Parkinson's disease, respectively. Additionally, these proteins are used as diagnostic biomarkers, wherein gold nanoparticles play a key role in enhancing their signal, even at the low concentrations present in biological samples such as blood or cerebrospinal fluid, thus enabling an early and accurate diagnosis. On the other hand, gold nanoparticles act as drug delivery platforms, bringing therapeutic agents directly into the brain, improving treatment efficiency and precision, and reducing side effects in healthy tissues. However, despite the exciting potential of gold nanoparticles, it is crucial to address the challenges and issues associated with their use in the medical field before they can be widely applied in clinical settings. It is critical to ensure the safety and biocompatibility of these nanomaterials in the context of the central nervous system. Therefore, rigorous preclinical and clinical studies are needed to assess the efficacy and feasibility of these strategies in patients. Since there is scarce and sometimes contradictory literature about their use in this context, the main aim of this review is to discuss and analyze the current state-of-the-art of gold nanoparticles in relation to delivery, diagnosis, and therapy for Alzheimer's and Parkinson's disease, as well as recent research about their use in preclinical, clinical, and emerging research areas.

Manipulating Charge-Transfer States in BODIPYs: A Model Strategy to Rapidly Develop Photodynamic Theragnostic Agents.

On the basis of a family of BINOL (1,1'-bi-2-naphthol)-based O-BODIPY (dioxyboron dipyrromethene) dyes, it is demonstrated that chemical manipulation of the chromophoric push-pull character, by playing with the electron-donating capability of the BINOL moiety (BINOL versus 3,3'-dibromoBINOL) and with the electron-acceptor ability of the BODIPY core (alkyl substitution degree), is a workable strategy to finely balance fluorescence (singlet-state emitting action) versus the capability to photogenerate cytotoxic reactive oxygen species (triplet-state photosensitizing action). It is also shown that the promotion of a suitable charge-transfer character in the involved chromophore upon excitation enhances the probability of an intersystem crossing phenomenon, which is required to populate the triple state enabling singlet oxygen production. The reported strategy opens up new perspectives for rapid development of smarter agents for photodynamic theragnosis, including heavy-atom-free agents, from a selected organic fluorophore precursor.

Gastrokine 1 protein is a potential theragnostic target for gastric cancer.

BACKGROUND: Gastrokine 1 (GKN1) plays important roles in maintaining mucosal homeostasis, and in regulating cell proliferation and differentiation. Here, we determined whether GKN1 is a potential theragnostic marker for gastric cancer. METHODS: We identified GKN1 binding proteins using the protein microarray assay and investigated whether GKN1 is one of the exosomal cargo proteins by western blot, immunoprecipitation, and immunofluorescent assays. Cell proliferation and apoptosis were analyzed by MTT, BrdU incorporation, flow cytometry, and western blot assays. We further validated the functional relevance of exosomal GKN1 in MKN1-injected xenograft mice. The possibility of serum GKN1 as a diagnostic marker for gastric cancer was determined by ELISA assay. RESULTS: In protein microarray assay, GKN1 binding to 27 exosomal proteins was clearly observed. GKN1 was expressed in exosomes derived from HFE-145 gastric epithelial cells by western blot and immunofluorescent assays, but not in exosomes from AGS and MKN1 gastric cancer cells. Exosomes carrying GKN1 inhibited cell proliferation and induced apoptosis in both AGS and MKN1 cells, and exosomes carrying GKN1-treated nude mice-bearing MKN1 xenograft tumors exhibited significantly reduced tumor volume and tumor weight. Silencing of clathrin markedly down-regulated the internalization of exosomal GKN1. Interestingly, serum GKN1 concentrations in patients with gastric cancer were significantly lower than those in healthy individuals and patients with colorectal and hepatocellular carcinomas. CONCLUSIONS: The GKN1 is secreted and internalized in the gastric epithelium by exosome-driven transfer, which inhibits gastric tumorigenesis and supports the clinical application of GKN1 protein in gastric cancer diagnosis and treatment.

Radionanomedicine: widened perspectives of molecular theragnosis.

Despite of promising preclinical results in the fields of in vivo theragnostics of nanomedicine, a majority of attempt for clinical translation has been blocked by unsolved concerns about possible hazards to human body. Theragnosis of nanomedicine relies on the property of huge surface area to volume ratio of nanomaterials, which can offer potential for multi-functionality. Radionanomedicine has a hybrid characteristic of tracer technology and multi-functionality. Thus, key advantage of radionanomedicine is a possibility of using low amount of nanomaterials for theragnosis. This review article focuses on the concept and advantages of radionanomedicine in theragnosis, formulation of radionanomaterials (particularly encapsulation method), in vivo biodistribution and excretion of radionanomaterials, and immune responses to radionanomaterials. FROM THE CLINICAL EDITOR: The expansion of nanomedicine has recently seen the development of a new branch - radionanomedicine. The core concept of radionanomedicine relies on the labeling of radionuclides onto nanomaterials for use both in diagnosis and therapy. In this article, the authors gave a comprehensive review on the current status of radionanomedicine. This should provide interesting reading for practicing clinicians.

Monocyte-based microrobot with chemotactic motility for tumor theragnosis.

Biocompatibility, sensing, and self-actuation are very important features for a therapeutic biomedical microrobot. As a new concept for tumor theragnosis, this paper proposes a monocyte-based microrobots, which are combining the phagocytosis and engulfment activities containing human acute monocytic leukemia cell line (THP-1) with various sized polystyrene microbeads are engulfed instead of a therapeutic drug. For the validation of the blood vessel barrier-penetrating activity of the monocyte-based microrobot, we fabricate a new cell migration assay with monolayer-cultured endothelial cell (HUVEC), similar with the blood vessels. We perform the penetrating chemotactic motility of the monocyte-based microrobot using various types of the chemo-attractants, such as monocyte chemotactic protein (MCP)-1, human breast cancer cell lines (MCF7)-cell lysates, and -contained alginate spheroids. The monocyte-based microrobot show chemotactic transmigrating motilities similar with what an actual monocyte does. This new paradigm of a monocyte-based microrobot having various useful properties such as biocompatibility, sensing, and self-actuation can become the basis of a biomedical microrobot using monocytes for diagnosis and therapy of various diseases.

Radioimmunotheragnosis in Cancer Research.

The combination of immunoPET-where an antibody (Ab) is labeled with an isotope for PET imaging-and radioimmunotherapy (RIT), using the same antibody with a therapeutic isotope, offers significant advantages in cancer management. ImmunoPET allows non-invasive imaging of antigen expression, which aids in patient selection for subsequent radioimmunotherapy. It also facilitates the assessment of tumor response to therapy, allowing for treatment adjustments if necessary. In addition, immunoPET provides critical pharmacokinetic data, including antibody biodistribution and clearance rates, which are essential for dosimetry calculations and treatment protocol optimization. There are still challenges to overcome. Identifying appropriate target antigens that are selectively expressed on cancer cells while minimally expressed on normal tissues remains a major hurdle to reduce off-target toxicity. In addition, it is critical to optimize the pharmacokinetics of radiolabeled antibodies to maximize tumor uptake and minimize normal tissue uptake, particularly in vital organs such as the liver and kidney. This approach offers the potential for targeted and personalized cancer therapy with reduced systemic toxicity by exploiting the specificity of monoclonal antibodies and the cytotoxic effects of radiation. However, further research is needed to address remaining challenges and to optimize these technologies for clinical use.

Nanomaterials for detection of biomolecules and delivering therapeutic agents in theragnosis: A review.

Nanomaterials are emerging facts used to deliver therapeutic agents in living systems. Nanotechnology is used as a compliment by implementing different kinds of nanotechnological applications such as nano-porous structures, functionalized nanomaterials, quantum dots, carbon nanomaterials, and polymeric nanostructures. The applications are in the initial stage, which led to achieving several diagnoses and therapy in clinical practice. This review conveys the importance of nanomaterials in post-genomic employment, which includes the design of immunosensors, immune assays, and drug delivery. In this view, genomics is a molecular tool containing large databases that are useful in choosing an apt molecular inhibitor such as drug, ligand and antibody target in the drug delivery process. This study identifies the expression of genes and proteins in analysis and classification of diseases. Experimentally, the study analyses the design of a disease model. In particular, drug delivery is a boon area to treat cancer. The identified drugs enter different phase trails (Trails I, II, and III). The genomic information conveys more essential entities to the phase I trials and helps to move further for other trails such as trails-II and III. In such cases, the biomarkers play a crucial role by monitoring the unique pathological process. Genetic engineering with recombinant DNA techniques can be employed to develop genetically engineered disease models. Delivering drugs in a specific area is one of the challenging issues achieved using nanoparticles. Therefore, genomics is considered as a vast molecular tool to identify drugs in personalized medicine for cancer therapy.

Same-day comparative protocol PET/CT-PET/MRI [68 Ga]Ga-DOTA-TOC in paragangliomas and pheochromocytomas: an approach to personalized medicine.

BACKGROUND: PET/MRI is an emerging imaging modality which enables the evaluation and quantification of biochemical processes in tissues, complemented with accurate anatomical information and low radiation exposure. In the framework of theragnosis, PET/MRI is of special interest due to its ability to delineate small lesions, adequately quantify them, and therefore to plan targeted therapies. The aim of this study was to validate the diagnostic performance of [68 Ga]Ga-DOTA-TOC PET/MRI compared to PET/CT in advanced disease paragangliomas and pheochromocytomas (PGGLs) to assess in which clinical settings, PET/MRI may have a greater diagnostic yield. METHODS: We performed a same-day protocol with consecutive acquisition of a PET/CT and a PET/MRI after a single [68 Ga]Ga-DOTA-TOC injection in 25 patients. Intermodality agreement, Krenning Score (KS), SUVmax (Standard Uptake Value), target-to-liver-ratio (TLR), clinical setting, location, and size were assessed. RESULTS: The diagnostic accuracy with PET/MRI increased by 14.6% compared to PET/CT especially in bone and liver locations (mean size of new lesions was 3.73 mm). PET/MRI revealed a higher overall lesion uptake than PET/CT (TLR 4.12 vs 2.44) and implied an upward elevation of the KS in up to 60% of patients. The KS changed in 30.4% of the evaluated lesions (mean size 11.89 mm), in 18.4% of the lesions it increased from KS 2 on PET/CT to a KS ≥ 3 on PET/MRI and 24.96% of the lesions per patient with multifocal disease displayed a KS ≥ 3 on PET/MR, that were not detected or showed lower KS on PET/CT. In 12% of patients, PET/MRI modified clinical management. CONCLUSIONS: PET/MRI showed minor advantages over conventional PET/CT in the detection of new lesions but increased the intensity of SSRs expression in a significant number of them, opening the door to select which patients and clinical settings can benefit from performing PET/MRI.

Multi-functionalization of reduced graphene oxide nanosheets for tumor theragnosis: Synthesis, characterization, enzyme assay, in-silico study, radiolabeling and in vivo targeting evaluation.

BACKGROUND: In this study, a combination of nanotechnology, organic synthesis and radiochemistry were utilized in order to design an efficient nano-system conjugated with a suitable radionuclide and an antitumor agent for possible application as tumor theragnostic agent. METHOD: Four novel compounds (3 and 4a-c) bearing tetrahydroquinazoline-7-sulfonohydrazide or 1,2,3,4-tetrahydroquinazoline-7-sulfonamide scaffold were designed. Then, docking study predicted that the compounds can be considered as potential inhibitors for PARP-1. Following that; the four compounds were synthesized and properly characterized using 1HNMR, 13CNMR, IR and Mass spectroscopy. The cytotoxic effect of the four compounds was evaluated against breast cancer cell line (MDA-MB-436), where compound 3 showed the most promising cytotoxic effect. The inhibitory effect of the four compounds was evaluated in vitro against PARP-1. RESULT: Carboxylated graphene oxide nanosheets (NGO-COOH) were synthesized by a modified Hummer's method and has size of range 40 nm. The NGO-COOH nanosheets were proven to be safe and biocompatible when tested in vitro against normal human lung fibroblast cells (MRC-5). The prepared NGO-COOH nanosheets were conjugated with compound 3 then radiolabeled with 99mTc to yield 99mTc-NGO-COOH-3 with a radiochemical yield of 98.5.0 ± 0.5%. 99mTc-NGO-COOH-3 was injected intravenously in solid tumor bearing mice to study the degree of localization of the nano-system at tumor tissue. The results of the study revealed, excellent localization and retention of the designed nano-system at tumor tissues with targeting ratio of 9.0. CONCLUSION: Stirred a new candidate tumor theragnostic agent that is safe, selective and stable.

Diagnosis, Management and Theragnostic Approach of Gastro-Entero-Pancreatic Neuroendocrine Neoplasms.

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) constitute an ideal target for radiolabeled somatostatin analogs. The theragnostic approach is able to combine diagnosis and therapy by the identification of a molecular target that can be diagnosed and treated with the same radiolabeled compound. During the last years, advances in functional imaging with the introduction of somatostatin analogs and peptide receptor radionuclide therapy, have improved the diagnosis and treatment of GEP-NENs. Moreover, PET/CT imaging with 18F-FDG represents a complementary tool for prognostic evaluation of patients with GEP-NENs. In the field of personalized medicine, the theragnostic approach has emerged as a promising tool in diagnosis and management of patients with GEP-NENs. The aim of this review is to summarize the current evidence on diagnosis and management of patients with GEP-NENs, focusing on the theragnostic approach.

Virus-like nanoparticles as a theranostic platform for cancer.

Virus-like nanoparticles (VLPs) are natural polymer-based nanomaterials that mimic viral structures through the hierarchical assembly of viral coat proteins, while lacking viral genomes. VLPs have received enormous attention in a wide range of nanotechnology-based medical diagnostics and therapies, including cancer therapy, imaging, and theranostics. VLPs are biocompatible and biodegradable and have a uniform structure and controllable assembly. They can encapsulate a wide range of therapeutic and diagnostic agents, and can be genetically or chemically modified. These properties have led to sophisticated multifunctional theranostic platforms. This article reviews the current progress in developing and applying engineered VLPs for molecular imaging, drug delivery, and multifunctional theranostics in cancer research.

Clinical Feasibility Study of Gold Nanoparticles as Theragnostic Agents for Precision Radiotherapy.

BACKGROUND: Gold nanoparticles (AuNP) may be useful in precision radiotherapy and disease monitoring as theragnostic agents. In diagnostics, they can be detected by computerized tomography (CT) because of their higher atomic number. AuNP may also improve the treatment results in radiotherapy due to a higher cross-section, locally improving the physically absorbed dose. METHODS: Key parameters values involved in the use of AuNP were imposed to be optimal in the clinical scenario. Mass concentration of AuNP as an efficient contrast agent in clinical CT was found and implemented in a Monte Carlo simulation method for dose calculation under different proposed therapeutic beams. The radiosensitization effect was determined in irradiated cells with AuNP. RESULTS: an AuNP concentration was found for a proper contrast level and enhanced therapeutic effect under a beam typically used for image-guided therapy and monitoring. This lower energetic proposed beam showed potential use for treatment monitoring in addition to absorbed dose enhancement and higher radiosensitization at the cellular level. CONCLUSION: the results obtained show the use of AuNP concentration around 20 mg Au·mL-1 as an efficient tool for diagnosis, treatment planning, and monitoring treatment. Simultaneously, the delivered prescription dose provides a higher radiobiological effect on the cancer cell for achieving precision radiotherapy.

Autophagopathies: from autophagy gene polymorphisms to precision medicine for human diseases.

At a time when complex diseases affect globally 280 million people and claim 14 million lives every year, there is an urgent need to rapidly increase our knowledge into their underlying etiologies. Though critical in identifying the people at risk, the causal environmental factors (microbiome and/or pollutants) and the affected pathophysiological mechanisms are not well understood. Herein, we consider the variations of autophagy-related (ATG) genes at the heart of mechanisms of increased susceptibility to environmental stress. A comprehensive autophagy genomic resource is presented with 263 single nucleotide polymorphisms (SNPs) for 69 autophagy-related genes associated with 117 autoimmune, inflammatory, infectious, cardiovascular, neurological, respiratory, and endocrine diseases. We thus propose the term 'autophagopathies' to group together a class of complex human diseases the etiology of which lies in a genetic defect of the autophagy machinery, whether directly related or not to an abnormal flux in autophagy, LC3-associated phagocytosis, or any associated trafficking. The future of precision medicine for common diseases will lie in our ability to exploit these ATG SNP x environment relationships to develop new polygenetic risk scores, new management guidelines, and optimal therapies for afflicted patients.Abbreviations: ATG, autophagy-related; ALS-FTD, amyotrophic lateral sclerosis-frontotemporal dementia; ccRCC, clear cell renal cell carcinoma; CD, Crohn disease; COPD, chronic obstructive pulmonary disease; eQTL, expression quantitative trait loci; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; GTEx, genotype-tissue expression; GWAS, genome-wide association studies; LAP, LC3-associated phagocytosis; LC3-II, phosphatidylethanolamine conjugated form of LC3; LD, linkage disequilibrium; LUAD, lung adenocarcinoma; MAF, minor allele frequency; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NSCLC, non-small cell lung cancer; OS, overall survival; PtdIns3K CIII, class III phosphatidylinositol 3 kinase; PtdIns3P, phosphatidylinositol-3-phosphate; SLE, systemic lupus erythematosus; SNPs, single-nucleotide polymorphisms; mQTL, methylation quantitative trait loci; ULK, unc-51 like autophagy activating kinase; UTRs, untranslated regions; WHO, World Health Organization.

The role of PSMA radioligands in the diagnosis and treatment of prostate carcinoma.

Prostate cancer (PC) is the most common tumor in men in the West and the fifth leading cause of cancer-related death. The use of PSMA radioligands has represented an important advance both in its diagnosis, through PET molecular imaging, and in its treatment in advanced stages of the disease. This article reviews the contribution of PET studies with PSMA radioligands in initial staging, in tumor detection in biochemical recurrence (elevation of PSA) after treatment with curative intent, and in the more advanced stages of the disease (castration resistant PC or CRPC). The contribution of PSMA radioligand therapy (PSMA-RLT) in CRPC patients who progress to standard therapy is also analyzed.

RNA interference (RNAi)-based plasmonic nanomaterials for cancer diagnosis and therapy.

RNA interference (RNAi) is being extensively investigated as a potential therapeutic strategy for cancer treatment. However, RNAi-based therapeutics have not yet been used to treat cancer because of their instability and the difficulty of microRNA (miRNA) delivery. Plasmonic nanoparticle-based RNAi nanotherapeutics have been developed for accurate and sensitive diagnosis and a strong therapeutic effect on cancers by leveraging their ease-of-use and specific properties such as photothermal conversion. In this review, recent strategies and advances in plasmonic nanoparticle-based miRNA delivery are briefly presented to facilitate the detection and treatment of several cancers. The challenges and potential opportunities afforded by the RNAi-based theragnosis field are discussed. We expect that the RNAi-integrated plasmonic nanotherapeutics discussed in this review can provide insights for the early diagnosis and effective treatment of cancer.

Benefits of Using Fluorescence Induced Theragnosis in Fixed Orthodontic Therapy: Status, Technology and Future Trends.

Dental biofilm is often found to be the source of bacteria that releases toxins, peptides, lipopolysaccharides as well as organic acids, which lead to gingival inflammation and tooth caries. Further, the persistent plaque may result in the continued destruction of the surrounding soft and hard tissues. During fixed orthodontic therapy, arch-wires, brackets, and elastic modules have been shown to be sites of significant plaque accumulation, making it difficult for a patient to maintain proper oral hygiene. The problem most dentists face is that they cannot visualize this biofilm completely to be able to carry out efficient plaque removal. Visual assessment is, to date, the most common method for plaque visualization, and various indexes have been demonstrated to be sufficient for quantification of the amount of plaque present. However, the problem is that visual assessments are inconsistent, operator dependent and often subjective, which can lead to inconsistency in results. Fluorescence is one such method that can be explored for its use in effective plaque identification and removal. Literature has it that dentists and patients find it particularly useful for monitoring oral hygiene status during treatment. Fluorescence has the capability of offering clinical orthodontists and researchers a new method of detection of demineralization during orthodontic treatment, furthermore, for efficient removal of orthodontic adhesive cements, fluorescent light may be used in conjunction with high-speed burs to deliver fast, less time consuming, and safer results. The benefit of direct visual treatment using fluorescence enhanced theragnosis is that the patient receives controlled and guided therapy. It has multiple benefits, such as early diagnosis of caries, biofilm identification, and even helps to achieve improved treatment outcomes by better resin selection for esthetic procedures.

Recent Progress on Molecular Photoacoustic Imaging with Carbon-Based Nanocomposites.

For biomedical imaging, the interest in noninvasive imaging methods is ever increasing. Among many modalities, photoacoustic imaging (PAI), which is a combination of optical and ultrasound imaging techniques, has received attention because of its unique advantages such as high spatial resolution, deep penetration, and safety. Incorporation of exogenous imaging agents further amplifies the effective value of PAI, since they can deliver other specified functions in addition to imaging. For these agents, carbon-based materials can show a large specific surface area and interesting optoelectronic properties, which increase their effectiveness and have proved their potential in providing a theragnostic platform (diagnosis + therapy) that is essential for clinical use. In this review, we introduce the current state of the PAI modality, address recent progress on PAI imaging that takes advantage of carbon-based agents, and offer a future perspective on advanced PAI systems using carbon-based agents.

Diagnosis of Biofilm-Associated Peri-Implant Disease Using a Fluorescence-Based Approach.

Dental implants have become a routine component of daily dental practice and the demand for dental implants is expected to increase significantly in the future. Despite the high success rates of dental implants, failures do occur, resulting in discomfort, rampant destruction of the oral health, or painful and costly surgical replacement of a failed implant. Peri-implant diseases are inflammatory conditions affecting the soft/hard tissues surrounding a functional dental implant. Plenty of experimental evidence indicates that the accumulation of dental plaque at the soft tissue-implant interface and the subsequent local inflammatory response seems to be key in the pathogenesis of the peri-implant mucositis. Such peri-implant-soft tissue interface is less effective than natural teeth in resisting bacterial invasion, enhancing vulnerability to subsequent peri-implant disease. Furthermore, in certain individuals, it will progress to peri-implantitis, resulting in alveolar bone loss and implant failure. Although early diagnosis and accurate identification of risk factors are extremely important to effectively prevent peri-implant diseases, current systematic reviews revealed that a uniform classification and diagnostic methodology for peri-implantitis are lacking. Recent progress on fluorescence-based technology enabled rapid diagnosis of the disease and effective removal of plaques. Here, we briefly review biofilm-associated peri-implant diseases and propose a fluorescence-based approach for more accurate and objective diagnoses. A fluorescence-based diagnosis tool through headlights combined with special-filtered dental loupes may serve as a hands-free solution for both precise diagnosis and effective removal of plaque-biofilms.

Incidence and Demographic Profile of Ewings Sarcoma: Experience From a Tertiary Care Hospital.

Introduction Ewing sarcoma (ES) family of tumors (EFT) represents the second most common primary bone malignancy affecting children and adolescents after osteosarcoma. The tumor is characteristically associated with a chromosomal translocation resulting in a fusion transcript (EWSR1-FLI1). However, new molecular techniques have significantly transformed our understanding of this rare disease. The present study aims to analyze the incidence and demographic profile of Ewings sarcoma with an insight into the recent updates of the Ewing sarcoma (ES) family of tumors (EFT). Materials and methods All cases of Ewings sarcoma/peripheral neuroectodermal tumor (PNET) presented at a tertiary care center in South India from January 2010-December 2020 were included in this study. The demographic profile and patient details were obtained from the medical records section. Pathology reports of the included cases were retrieved, and associated factors were analyzed, including immunohistochemical studies and molecular workup. Results Out of the 58 cases included in the study, 30 cases (52%) were children and adolescents (< 20 years) and the rest 28 cases (48%) were adults. The mean age was 22.56. Female preponderance was noted, with 32 cases (56%) being females and 26 cases (44%) were males. The location of the tumor was variable. Twenty-five (25) cases (44%) were found in bones such as the clavicle, tibia, and mandible. Seven cases were seen on the anterior chest wall. Other sites included the oropharynx, lungs, endobronchial, infrascapular region, retroperitoneum, and thighs. One case presented as metastatic Ewings sarcoma with divergent differentiation in lungs with the primary site of the tumor being the right humerus. Immunohistochemical (IHC) studies were done on 55 of the 58 tumors. Forty-six (46) cases (80.9%) were CD99 positive and 41 cases(71.4%) were FLI-1 positive. Eleven (11) cases were both CD 99 and FLI-1 positive. NKX2.2, a recent IHC marker, was positive in six cases. Conclusion Ewings sarcoma has a peak incidence in the second decade of life with a propensity toward the axial skeletal location. Understanding the pathobiology and molecular updates of ES is significant to differentiate them from aggressive round cell sarcomas. They not only aid in predicting the prognosis of these aggressive tumors but also guide in therapy.

Theragnosis for Duchenne Muscular Dystrophy.

Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA's metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.