Zh Nevrol Psikhiatr Im S S Korsakova. 2023;123(9):101-105. doi: 10.17116/jnevro2023123091101.

ABSTRACT

Monomelic amyotrophy, also known as Hirayama disease, is a rare neurological disorder characterized by focal and latent onset of upper limb weakness and atrophy in the absence of sensory deficits, bulbar or pyramidal signs. It usually occurs in young patients. The disease usually begins unnoticeably and progresses slowly, and can manifest itself as unilateral or asymmetrical weakness, as well as atrophy of the distal upper limb. Sensory disturbances, reflex changes and signs of lesions of lower motor neurons are rare. This article describes a case of a patient with complaints of weakness not only in the upper but also in the lower extremities.

PMID:37796075 | DOI:10.17116/jnevro2023123091101

Orphanet J Rare Dis. 2023 Oct 4;18(1):310. doi: 10.1186/s13023-023-02916-x.

ABSTRACT

Following the reverse genetics strategy developed in the 1980s to pioneer the identification of disease genes, genome(s) sequencing has opened the era of genomics medicine. The human genome project has led to an innumerable series of applications of omics sciences on global health, from which rare diseases (RDs) have greatly benefited. This has propelled the scientific community towards major breakthroughs in disease genes discovery, in technical innovations in bioinformatics, and in the development of patients' data registries and omics repositories where sequencing data are stored. Rare diseases were the first diseases where nucleic acid-based therapies have been applied. Gene therapy, molecular therapy using RNA constructs, and medicines modulating transcription or translation mechanisms have been developed for RD patients and started a new era of medical science breakthroughs. These achievements together with optimization of highly scalable next generation sequencing strategies now allow movement towards genetic newborn screening. Its applications in human health will be challenging, while expected to positively impact the RD diagnostic journey. Genetic newborn screening brings many complexities to be solved, technical, strategic, ethical, and legal, which the RD community is committed to address. Genetic newborn screening initiatives are therefore blossoming worldwide, and the EU-IMI framework has funded the project Screen4Care. This large Consortium will apply a dual genetic and digital strategy to design a comprehensive genetic newborn screening framework to be possibly translated into the future health care.

PMID:37794437 | PMC:PMC10548672 | DOI:10.1186/s13023-023-02916-x

Eur J Hum Genet. 2023 Oct 4. doi: 10.1038/s41431-023-01464-z. Online ahead of print.

ABSTRACT

During the neonatal period, many genetic disorders present and contribute to neonatal morbidity and mortality. Genomic medicine-the use of genomic information in clinical care- has the potential to significantly reduce morbidity and mortality in the neonatal period and improve outcomes for this population. Diagnostic genomic testing for symptomatic newborns, especially rapid testing, has been shown to be feasible and have diagnostic and clinical utility, particularly in the short-term. Ongoing studies are assessing the feasibility and utility, including personal utility, of implementation in diverse populations. Genomic screening for asymptomatic newborns has also been studied, and the acceptability and feasibility of such an approach remains an active area of investigation. Emerging precision therapies, with examples even at the "n-of-1" level, highlight the promise of precision diagnostics to lead to early intervention and improve outcomes. To sustainably implement genomic medicine in neonatal care in an ethical, effective, and equitable manner, we need to ensure access to genetics and genomics knowledge, access to genomic tests, which is currently limited by payors, feasible processes for ordering these tests, and access to follow up in the clinical and research realms. Future studies will provide further insight into enablers and barriers to optimize implementation strategies.

PMID:37789085 | DOI:10.1038/s41431-023-01464-z

Eur J Hum Genet. 2023 Oct;31(10):1091-1092. doi: 10.1038/s41431-023-01453-2.

NO ABSTRACT

PMID:37783763 | PMC:PMC10545818 | DOI:10.1038/s41431-023-01453-2

Front Public Health. 2023 Sep 15;11:1214766. doi: 10.3389/fpubh.2023.1214766. eCollection 2023.

ABSTRACT

BACKGROUND: Given the increased availability of data sources such as hospital information systems, electronic health records, and health-related registries, a novel approach is required to develop artificial intelligence-based decision support that can assist clinicians in their diagnostic decision-making and shorten rare disease patients' diagnostic odyssey. The aim is to identify key challenges in the process of mapping European rare disease databases, relevant to ML-based screening technologies in terms of organizational, FAIR and legal principles.

METHODS: A scoping review was conducted based on the PRISMA-ScR checklist. The primary article search was conducted in three electronic databases (MEDLINE/Pubmed, Scopus, and Web of Science) and a secondary search was performed in Google scholar and on the organizations' websites. Each step of this review was carried out independently by two researchers. A charting form for relevant study analysis was developed and used to categorize data and identify data items in three domains - organizational, FAIR and legal.

RESULTS: At the end of the screening process, 73 studies were eligible for review based on inclusion and exclusion criteria with more than 60% (n = 46) of the research published in the last 5 years and originated only from EU/EEA countries. Over the ten-year period (2013-2022), there is a clear cycling trend in the publications, with a peak of challenges reporting every four years. Within this trend, the following dynamic was identified: except for 2016, organizational challenges dominated the articles published up to 2018; legal challenges were the most frequently discussed topic from 2018 to 2022. The following distribution of the data items by domains was observed - (1) organizational (n = 36): data accessibility and sharing (20.2%); long-term sustainability (18.2%); governance, planning and design (17.2%); lack of harmonization and standardization (17.2%); quality of data collection (16.2%); and privacy risks and small sample size (11.1%); (2) FAIR (n = 15): findable (17.9%); accessible sustainability (25.0%); interoperable (39.3%); and reusable (17.9%); and (3) legal (n = 33): data protection by all means (34.4%); data management and ownership (22.9%); research under GDPR and member state law (20.8%); trust and transparency (13.5%); and digitalization of health (8.3%). We observed a specific pattern repeated in all domains during the process of data charting and data item identification - in addition to the outlined challenges, good practices, guidelines, and recommendations were also discussed. The proportion of publications addressing only good practices, guidelines, and recommendations for overcoming challenges when mapping RD databases in at least one domain was calculated to be 47.9% (n = 35).

CONCLUSION: Despite the opportunities provided by innovation - automation, electronic health records, hospital-based information systems, biobanks, rare disease registries and European Reference Networks - the results of the current scoping review demonstrate a diversity of the challenges that must still be addressed, with immediate actions on ensuring better governance of rare disease registries, implementing FAIR principles, and enhancing the EU legal framework.

PMID:37780450 | PMC:PMC10540868 | DOI:10.3389/fpubh.2023.1214766

Orv Hetil. 2023 Oct 1;164(39):1544-1549. doi: 10.1556/650.2023.32866. Print 2023 Oct 1.

ABSTRACT

INTRODUCTION: Popliteal vein aneurysm is a rare, but potentially life-threatening condition that can lead to deep vein thrombosis and/or pulmonary embolism. It is often asymptomatic, but symptoms may include pain, post-thrombotic syndrome or chronic venous insufficiency. An experienced physician may be able to detect a palpable mass in the popliteal fossa. Duplex ultrasound is the first line of diagnosis. CT or MR venography play a role in the diagnosis.

OBJECTIVE: To review the international literature, explain the possible treatment options, and present our case.

CASE REPORT: A 62-year-old female patient had a recurrent pulmonary embolism while on direct-acting oral anticoagulant therapy. Duplex ultrasound and MR angiography were performed and confirmed a partially thrombosed aneurysm of the right popliteal vein. Aneurysm resection and venorrhaphy were performed as treatment. At follow-up, ultrasound showed adequate flow in the deep venous system. 6 months later, the control MR angiography showed good flow without stenosis. There were no postoperative complications. Discussion and literature review: The pathomechanism of the disease remains unclear. Treatment options are conservative therapy and/or surgical intervention, but there is no consensus regarding the therapy of symptomatic or asymptomatic cases. There is no clear statement regarding the method and duration of postoperative anticoagulant therapy.

CONCLUSION: In the case of recurrent pulmonary embolism, the possibility of a popliteal vein aneurysm should be considered. Ultrasound is a non-invasive, widely available initial diagnostic tool. In addition to conservative treatment, the possibility of surgical intervention can be considered. The surgical procedure described in our case was successful. Orv Hetil. 2023; 164(39): 1544-1549.

PMID:37778011 | DOI:10.1556/650.2023.32866

Medicina (Kaunas). 2023 Sep 8;59(9):1632. doi: 10.3390/medicina59091632.

ABSTRACT

Background and Objectives: Gestational trophoblastic disease (GTD) is a group of pregnancy-related malignant and premalignant diseases. The aim of this study was to assess the prognostic value of clinical characteristics to predict treatment outcomes in women with GTD. Materials and Methods: In this retrospective study, 34 patients treated for GTD at the Division of Gynaecology and Perinatology, University Medical Centre Maribor, between 2008 and 2022 were identified. Clinical and pathological characteristics were obtained by analysing patient data records. Results: Within the cohort of 34 patients with GTD, 29 patients (85.3%) had a partial hydatidiform mole (HM) and five patients545 (14.7%) had a complete HM. Two patients with a complete HM developed a postmolar gestational trophoblastic neoplasia (GTN), which represents 5.8% of all cases. Conclusions: GTD is a rare disease that is frequently asymptomatic. The subsequent consequences of GTD, which can lead to malignant transformation, as well life-threatening disease complications, warrant training for early recognition of HMs and timely treatment and surveillance.

PMID:37763750 | PMC:PMC10534929 | DOI:10.3390/medicina59091632

Int J Mol Sci. 2023 Sep 6;24(18):13743. doi: 10.3390/ijms241813743.

ABSTRACT

Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disease that is characterized by progressive muscle atrophy (degeneration), including skeletal muscles in charge of the ability to move. SMA is caused by defects in the SMN1 gene (Survival of Motor Neuron 1) which encodes a protein crucial for the survival and functionality of neuron cells called motor neurons. Decreased level of functioning SMN protein leads to progressive degeneration of alpha-motor neurons performing muscular motility. Over the past decade, many strategies directed for SMN-level-restoration emerged, such as gene replacement therapy (GRT), CRISPR/Cas9-based gene editing, usage of antisense oligonucleotides and small-molecule modulators, and all have been showing their perspectives in SMA therapy. In this review, modern SMA therapy strategies are described, making it a valuable resource for researchers, clinicians and everyone interested in the progress of therapy of this serious disorder.

PMID:37762045 | DOI:10.3390/ijms241813743

Genes (Basel). 2023 Sep 20;14(9):1823. doi: 10.3390/genes14091823.

ABSTRACT

Renal hypouricemia (RHUC) is a rare hereditary disorder caused by loss-of-function mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, encoding urate transporters URAT1 and GLUT9, respectively, that reabsorb urate in the renal proximal tubule. The characteristics of this disorder are low serum urate levels, high renal fractional excretion of urate, and occasional severe complications such as nephrolithiasis and exercise-induced acute renal failure. In this study, we report two Spanish (Caucasian) siblings and a Pakistani boy with clinical characteristics compatible with RHUC. Whole-exome sequencing (WES) analysis identified two homozygous variants: a novel pathogenic SLC22A12 variant, c.1523G>A; p.(S508N), in the two Caucasian siblings and a previously reported SLC2A9 variant, c.646G>A; p.(G216R), in the Pakistani boy. Our findings suggest that these two mutations cause RHUC through loss of urate reabsorption and extend the SLC22A12 mutation spectrum. In addition, this work further emphasizes the importance of WES analysis in clinical settings.

PMID:37761963 | DOI:10.3390/genes14091823

Cells. 2023 Sep 18;12(18):2299. doi: 10.3390/cells12182299.

ABSTRACT

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of the LMNA gene. HGPS affects systemic levels, with the exception of cognition or brain development, in children, showing that cellular aging can occur in the short term. Studying progeria could be useful in unraveling the causes of human aging (as well as fatal age-related disorders). Elucidating the clear cause of HGPS or the development of a therapeutic medicine could improve the quality of life and extend the survival of patients. This review aimed to (i) briefly describe how progerin was discovered as the causative agent of HGPS, (ii) elucidate the puzzling observation of the absence of primary neurological disease in HGPS, (iii) present several studies showing the deleterious effects of progerin and the beneficial effects of its inhibition, and (iv) summarize research to develop a therapy for HGPS and introduce clinical trials for its treatment.

PMID:37759521 | DOI:10.3390/cells12182299

Biomedicines. 2023 Sep 10;11(9):2500. doi: 10.3390/biomedicines11092500.

ABSTRACT

Stiff person spectrum disorders (SPSD) are paradigm autoimmune movement disorders characterized by stiffness, spasms and hyperekplexia. Though rare, SPSD represent a not-to-miss diagnosis because of the associated disease burden and treatment implications. After decades as an enigmatic orphan disease, major advances in our understanding of the evolving spectrum of diseases have been made along with the identification of multiple associated autoantibodies. However, the most important recent developments relate to the recognition of a wider affection, beyond the classic core motor symptoms, and to further insights into immunomodulatory and symptomatic therapies. In this review, we summarize the recent literature on the clinical and paraclinical spectrum, current pathophysiological understanding, as well as current and possibly future therapeutic strategies.

PMID:37760941 | DOI:10.3390/biomedicines11092500

Eur J Med Genet. 2023 Nov;66(11):104855. doi: 10.1016/j.ejmg.2023.104855. Epub 2023 Sep 25.

ABSTRACT

ADNP syndrome, also known as the Helsmoortel-Van der Aa syndrome (HVDAS), is a neurodevelopmental disorder characterized by hypotonia, developmental delay, and intellectual disability. Diagnosis is typically made postnatally, and little is known about prenatal presentation of the disorder. We report a child who presented with intrauterine growth restriction, proportionate microcephaly, and an abnormal skull shape on fetal ultrasound. Whole exome sequencing performed on amniotic fluid cells showed a de novo pathogenic variant in the ADNP gene, corresponding to a diagnosis of ADNP syndrome.

PMID:37758165 | DOI:10.1016/j.ejmg.2023.104855

PLoS One. 2023 Sep 27;18(9):e0286380. doi: 10.1371/journal.pone.0286380. eCollection 2023.

ABSTRACT

Barth Syndrome is a rare, X-linked disorder caused by mutation of the gene TAFAZZIN (TAZ). The corresponding Tafazzin protein is involved in the remodeling of cardiolipin, a phospholipid with critical roles in mitochondrial function. While recent clinical trials have been promising, there is still no cure for Barth Syndrome. Because TAZ is highly conserved, multiple animal and cell culture models exist for pre-clinical testing of therapeutics. However, since the same mutation in different patients can lead to different symptoms and responses to treatment, isogenized experimental models can't fully account for human disease conditions. On the other hand, isogenized animal models allow for sufficient numbers to thoroughly establish efficacy for a given genetic background. Therefore, a combined method for testing treatments in a panel of isogenized cohorts that are genetically distinct from each other would be transformative for testing emerging pre-clinical therapies. To aid in this effort, we've created a novel panel of 10 Drosophila lines, each with the same TAZ mutation in highly diverse genetic backgrounds, to serve as a helpful resource to represent natural variation in background genetics in pre-clinical studies. As a proof of principle, we test our panel here using nicotinamide riboside (NR), a treatment with established therapeutic value, to evaluate how robust this therapy is across the 10 genetic backgrounds in this novel reference panel. We find substantial variation in the response to NR across backgrounds. We expect this resource will be valuable in pre-clinical testing of emerging therapies for Barth Syndrome.

PMID:37756350 | PMC:PMC10529581 | DOI:10.1371/journal.pone.0286380

Epilepsy Res. 2023 Nov;197:107231. doi: 10.1016/j.eplepsyres.2023.107231. Epub 2023 Sep 20.

ABSTRACT

BACKGROUND: CDKL5 Deficiency Disorder (CDD) is a severe X-linked developmental and epileptic encephalopathy. Existing developmental outcome measures have floor effects and cannot capture incremental changes in symptoms. We modified the caregiver portion of a CDD clinical severity assessment (CCSA) and assessed content and response-process validity.

METHODS: We conducted cognitive interviews with 15 parent caregivers of 1-39-year-old children with CDD. Caregivers discussed their understanding and concerns regarding appropriateness of both questions and answer options. Item wording and questionnaire structure were adjusted iteratively to ensure questions were understood as intended.

RESULTS: The CCSA was refined during three rounds of cognitive interviews into two measures: (1) the CDD Developmental Questionnaire - Caregiver (CDQ-Caregiver) focused on developmental skills, and (2) the CDD Clinical Severity Assessment - Caregiver (CCSA-Caregiver) focused on symptom severity. Branching logic was used to ensure questions were age and skill appropriate. Initial pilot data (n = 11) suggested no floor effects.

CONCLUSIONS: This study modified the caregiver portion of the initial CCSA and provided evidence for its content and response process validity.

PMID:37751639 | DOI:10.1016/j.eplepsyres.2023.107231

Orphanet J Rare Dis. 2023 Sep 26;18(1):303. doi: 10.1186/s13023-023-02915-y.

ABSTRACT

OBJECTIVES: The aims of this paper is to search and explore publications in the field of pharmacovigilance for rare diseases and to visualize general information, research hotspots, frontiers and future trends in the field using the bibliometric tool CiteSpace to provide evidence-based evidence for scholars.

METHODS: We searched the Web of Science Core Collection (WoSCC) for studies related to pharmacovigilance for rare diseases, spanning January 1, 1997-October 25, 2022. CiteSpace software was utilized to discuss countries/regions, institutions, authors, journals, and keywords.

RESULTS: After screening, a total of 599 valid publications were included in this study, with a significant upward trend in the number of publications. These studies were from 68 countries/regions with the United States and the United Kingdom making the largest contributions to the field. 4,806 research scholars from 493 institutions conducted studies on pharmacovigilance for rare diseases. Harvard University and University of California were the top two productive institutions in the research field. He Dian of the Affiliated Hospital of Guizhou Medical University and Peter G.M. Mol of the University of Groningen, The Netherlands, were the two most prolific researchers. The Cochrane Database of Systematic Reviews and the New England Journal of Medicine were the journals with the highest number of articles and co-citation frequency respectively. Clinical trial, therapy and adverse event were the top three most cited keywords.

CONCLUSIONS: Based on keywords co-occurrence analysis, four research topics were identified: orphan drug clinical trials, postmarketing ADR surveillance for orphan drugs, rare diseases and orphan drug management, and diagnosis and treatment of rare diseases. Immune-related adverse reactions and benefit-risk assessment of enzyme replacement therapy were at the forefront of research in this field. Treatment outcomes, early diagnosis and natural history studies of rare diseases may become hotspots for future research.

PMID:37752556 | PMC:PMC10523788 | DOI:10.1186/s13023-023-02915-y

J Patient Rep Outcomes. 2023 Sep 26;7(1):95. doi: 10.1186/s41687-023-00635-2.

ABSTRACT

BACKGROUND: Classic Galactosemia (CG) is a rare, autosomal recessive condition. Newborn screening and a timely galactose-restricted diet can resolve acute symptoms and decrease fatalities, but significant chronic, progressive morbidities remain and significantly impact daily life. The objective of this study was to better understand the burden of disease in children and adults with CGs and describe how morbidities evolve over time.

METHODS: A total of 49 individuals with CG from the United States (US) were included in the qualitative surveys (13 adults [9 self-reported] and 36 pediatric patients). Fifteen follow-up interviews were conducted with 5 adults and 10 caregivers, discussing 17 individuals with CG overall (2 caregivers each discussed 2 children).

RESULTS: Qualitative survey and interview data demonstrated the substantial burden of CG. Difficulties in a wide range of functions were experienced, which included: speech articulation; language and communication; cognition, memory and learning; emotions; and social interactions. Most difficulties appeared in childhood and persisted or worsened with age. Most adults did not live independently. Others lived semi-independently and experienced many daily challenges and required support. Caregivers also described the burden of caring for someone with CG and spoke about the impact this has on their day-to-day life, work, and relationships.

CONCLUSIONS: These findings demonstrate the pronounced and persistent burden of disease encountered by individuals with CG, and that the condition has a significant impact on the quality of life of caregivers.

PMID:37751006 | DOI:10.1186/s41687-023-00635-2

J Transl Med. 2023 Sep 27;21(1):667. doi: 10.1186/s12967-023-04531-7.

ABSTRACT

BACKGROUND: Spinal cord glioma (SCG) is considered an orphan disease that lacks effective treatment options with margins that are surgically inaccessible and an overall paucity of literature on the topic. The tumor microenvironment is a critical factor to consider in treatment and modeling design, especially with respect to the unresectable tumor edge. Recently, our group developed a high-grade spinal cord glioma (SCG) model in Göttingen minipigs.

METHODS: Immunofluorescence and ELISA were performed to explore the microenvironmental features and inflammation cytokines in this minipig SCG model. Protein carbonyl assay and GSH/GSSG assay were analyzed in the core and edge lesions in the minipig SCG model. The primary core and edge cells proliferation rate were shown in vitro, and the xenograft model in vivo.

RESULTS: We identified an elevated Ki-67 proliferative index, vascular and pericyte markers, CD31 and desmin in the tumor edge as compared to the tumor core. In addition, we found that the tumor edge demonstrated increased pro-inflammatory and gliomagenic cytokines including TNF-α, IL-1β, and IL-6. Furthermore, the mediation of oxidative stress is upregulated in the tumor edge. Hypoxic markers had statistically significant increased staining in the tumor core, but were notably still present in the tumor edge. The edge cells cultures derived from SCG biopsy also demonstrated an increased proliferative rate compared to core cell cultures in a xenotransplantation model.

CONCLUSIONS: Our study demonstrates heterogeneity in microenvironmental features in our minipig model of high-grade SCG, with a phenotype at the edge showing increased oxidative stress, proliferation, inflammatory cytokines, neovascularization, and decreased but present staining for hypoxic markers. These findings support the utility of this model as a means for investigating therapeutic approaches targeting the more aggressive and surgically unresectable tumor border.

PMID:37752585 | DOI:10.1186/s12967-023-04531-7

BJS Open. 2023 Sep 5;7(5):zrad094. doi: 10.1093/bjsopen/zrad094.

ABSTRACT

BACKGROUND: Groove pancreatitis is a focal form of chronic pancreatitis affecting the area of the paraduodenal groove. The aim of this systematic review was to assess the clinical presentation, diagnosis and treatment of patients with groove pancreatitis.

METHODS: Medical literature databases (Embase, Medline via PubMed and Cochrane Central Register of Controlled Trials) were systematically searched for data recorded between 1 January 1990 and 31 August 2022 regarding patient characteristics, diagnosis, surgical treatment and outcomes. The following inclusion criteria were applied: RCTs, observational studies (cohort and case-control studies) and case studies with >3 cases including patients with groove pancreatitis undergoing medical, endoscopic or surgical treatment with available clinical and diagnostic data. Fisher's exact test for binary data and Mann-Whitney U test or Student t-test for continuous data were adopted for statistical analysis.

RESULTS: Of 649 studies, 44 were included, involving reports on 1404 patients with a mean age of 49 years. In 41 of the 44 studies in which patient gender was described, 86 per cent (N = 1023) of patients were male. Information on the risk factors of alcohol and nicotine was available in 37 and 23 studies, respectively. Seventy-nine per cent (N = 886) of patients had a history of excessive alcohol consumption and 83 per cent (N = 595) were smokers. Information on clinical symptoms was available in 37 of the 44 included studies and 78.5 per cent (N = 870) presented with abdominal pain. Some 27 studies comprising 920 groove pancreatitis patients were treatment oriented. Seventy-four per cent (N = 682) of patients were treated conservatively, 26.4 per cent (N = 134) underwent endoscopic treatment and 54.7 per cent (N = 503) required surgery. There was complete relief of symptoms in 35.6 per cent (N = 243) after conservative treatment, 55.2 per cent (N = 74) after endoscopic treatment and 69.6 per cent (N = 350) after surgical treatment. The median follow-up time was 42 months (range, 1-161 months).

CONCLUSION: Groove pancreatitis shows on imaging a typical triad: cystic lesions in the pancreatic duct or duodenal wall, calcifications, and thickenings of the duodenal wall. Surgery appears to be the most effective treatment modality.

PMID:37749756 | PMC:PMC10519812 | DOI:10.1093/bjsopen/zrad094

Orphanet J Rare Dis. 2023 Sep 25;18(1):301. doi: 10.1186/s13023-023-02876-2.

ABSTRACT

BACKGROUND: Glioblastoma (GBM) is the most aggressive and common malignant primary brain tumor; however, treatment remains a significant challenge. This study aims to identify drug repurposing or repositioning candidates for GBM by developing an integrative rare disease profile network containing heterogeneous types of biomedical data.

METHODS: We developed a Glioblastoma-based Biomedical Profile Network (GBPN) by extracting and integrating biomedical information pertinent to GBM-related diseases from the NCATS GARD Knowledge Graph (NGKG). We further clustered the GBPN based on modularity classes which resulted in multiple focused subgraphs, named mc_GBPN. We then identified high-influence nodes by performing network analysis over the mc_GBPN and validated those nodes that could be potential drug repurposing or repositioning candidates for GBM.

RESULTS: We developed the GBPN with 1,466 nodes and 107,423 edges and consequently the mc_GBPN with forty-one modularity classes. A list of the ten most influential nodes were identified from the mc_GBPN. These notably include Riluzole, stem cell therapy, cannabidiol, and VK-0214, with proven evidence for treating GBM.

CONCLUSION: Our GBM-targeted network analysis allowed us to effectively identify potential candidates for drug repurposing or repositioning. Further validation will be conducted by using other different types of biomedical and clinical data and biological experiments. The findings could lead to less invasive treatments for glioblastoma while significantly reducing research costs by shortening the drug development timeline. Furthermore, this workflow can be extended to other disease areas.

PMID:37749605 | PMC:PMC10519087 | DOI:10.1186/s13023-023-02876-2

Orphanet J Rare Dis. 2023 Sep 22;18(1):299. doi: 10.1186/s13023-023-02909-w.

ABSTRACT

For the development of a test treatment or drug product, it is necessary to conduct composite hypothesis testing to test for effectiveness and safety simultaneously, since some approved drug products have been recalled due to safety concerns. One of the major issues in conducting a composite hypothesis testing for effectiveness and safety is the requirement of a huge sample size to achieve the desired power for detecting clinically meaningful differences in both safety and effectiveness. Situation can be much difficult in orphan drug development. In this article, a generalized two-stage innovative approach to test for effectiveness and safety simultaneously is proposed. Additionally, to alleviate the requirement of a large randomized clinical trial (RCT) and revealing effectiveness, real-world data is suggested to use in conjunction with RCT data for orphan drug development. The proposed approach can help investigators test for effectiveness and safety at the same time without worrying about the sample size. It also helps reduce the probability of approving a drug product with safety concerns.

PMID:37740206 | PMC:PMC10517458 | DOI:10.1186/s13023-023-02909-w